U.S.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER
FOR BIOLOGICS EVALUATION AND RESEARCH
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VACCINES AND RELATED BIOLOGICAL PRODUCTS
ADVISORY COMMITTEE
+ + + + +
97TH MEETING
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WEDNESDAY,
FEBRUARY 18, 2004
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The Advisory Committee met at 8:30 a.m. in
the Embassy Room of the Sheraton Four‑Points
Hotel,
8400 Wisconsin Avenue, Bethesda, Maryland, DR.
GARY
OVERTURF, Chairman, presiding.
This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food & Drug Admin. Makes no representation as to its accuracy.
PRESENT:
GARY D. OVERTURF, M.D.
MICHAEL D. DECKER, M.D.
MONICA M. FARLEY, M.D.
RUTH A. KARRON, M.D.
PHILIP S. LaRUSSA, Ph.D.
DAVID MARKOVITZ, M.D.
PETER PALESE, Ph.D.
CINDY LYN PROVINCE
WILLIAM FREAS, Ph.D.
I‑N‑D‑E‑X
AGENDA ITEM PAGE
Call to Order, Dr. Gary Overturf, Chair 9
Administrative Matters, Dr. Bill Freas 3
Presentation of Plaques to Retiring 9
Members, Dr. Karen Midthun
OPEN Session 11
Strain Selection for Influenza Virus 11
Vaccine for the 2004‑2005 Season
Introduction, Dr. Roland Levandowski, FDA 11
Vaccine Effectiveness, Dr. Carolyn 61
Bridges, CDC
Col. James Neville, DOD
90
Dr. Antoine Flahault, INSERM, Paris
104
U.S.
Surveillance, Ann Moen, CDC
118
Open Public Hearing
World Surveillance and Strain
Characterization, Dr. Nancy Cox, CDC 139
Additional Reports, Linda Canas, DOD
Dr. Maria Zambon, HPA, UK
176
Vaccine Responses,
Dr.
Roland Levandowski, FDA
195
Availability of Strains and Reagents, 216
Dr.
Zhiping Ye, FDA
Comments from Manufacturers 220
Update on H5, Dr. Nancy Cox, CDC 241
Dr.
Phil Minor, NIBSC
262
NIH
Speaker (TBA)
Adjourn 300
P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S
(8:37 a.m.)
ADMINISTRATIVE MATTERS
MEMBER FREAS: Mr. Chairman,
members of
the Committee, invited speakers, and members of
the
public, I would like to welcome all of you to
this,
our 97th meeting of the Vaccines and Related
Biological Products Advisory Committee meeting.
I am Bill Freas. I am the Acting
Executive Secretary for today. At this time, before
the meeting, begins, I would like to go around
and
introduce to the public the members seated at the
head
table.
We will start on the right side of the
table.
That is the audience's right‑hand side. And
I will read the names of the people at the table.
Would the members please raise their hands as I
call
their names?
David Markovitz, Professor, Division of
Infectious Diseases, University of Michigan
Medical
Center.
Next is Dr. Walter Dowdle, Senior Public
Health Consultant, The Task Force for Child
Survival
and Development.
Next is Dr. Judith Goldberg, Director,
Division of Biostatistics, New York University
School
of Medicine.
Next is Dr. Ruth Karron, Associate
Professor, Johns Hopkins School of Hygiene and
Public
Health.
Next is Dr. Walter Royal, Associate
Professor of Medicine, Morehouse School of
Medicine.
Next is Dr. Monica Farley, Professor of
Medicine, Emory University School of Medicine.
Next is Dr. Pamela McInnes, Deputy
Director, Division of Microbiology and Infectious
Diseases, NIH.
Next is Ms. Cindy Lyn Province, Associate
Director, Bioethics Center of St. Louis.
Next is Dr. Bruce Gellin, Director,
National Vaccine Program.
In the empty chair, we will soon be joined
by Dr. Stephen Phillips, Director, Deployment
Medicine
and Surveillance, Office of Assistant Secretary
of
Defense.
Next I would like to introduce you to the
Chair of this Committee, Dr. Gary Overturf,
Professor
of Medicine, University of New Mexico School of
Medicine.
Coming around the table, we have Dr.
Philip LaRussa, Professor of Clinical Pediatrics,
Columbia‑Presbyterian Hospital.
Next we have Dr. Martin Myers,
Co‑Director, Public Health Policy and
Education,
University of Texas Medical Branch.
Next we have Dr. Bonnie Word, Assistant
Professor of Pediatrics, Baylor College of
Medicine.
Next we have Dr. Peter Palese, Chairman
and Professor, Department of Microbiology, Mt.
Sinai
School of Medicine.
Next we have Dr. Arnold Monto, Professor,
The University of Michigan.
Next we have Dr. Ted Eickhoff, Professor
of Medicine, University of Colorado Health
Sciences
Center.
Next we have our nonvoting industry
representative, Dr. Michael Decker, Vice President,
Scientific and Medical Affairs of Aventis
Pasteur.
Next we have a nonvoting participant, Dr.
Nancy Cox, Chief of the Influenza Branch, Centers
for
Disease Control and Prevention.
Next we have Dr. Roland Levandowski from
the FDA.
Dr. Richard Whitley, University of
Alabama, member of this Committee, has recused
himself
from today's participation.
I would like to thank the members for
attending.
There is one other person I would like to
introduce at this time. Many people have asked me,
"When are you going to get a real executive
secretary
for this Advisory Committee?" I would like to
introduce this morning Christine Walsh, who will
be
the next Executive Secretary for this Committee
at the
next meeting, which will be announced later. It will
be either in March or May. We have a teleconference
scheduled for March the 17th at this time.
I would now like to read the conflict of
interest statement into the record. Before I do that,
I would like to ask the members of the public if
they
could put their cell phones on silence mode, it
would
be appreciated.
"The following announcement addresses the
conflict of interest issues associated with the
Vaccines and Related Biological Products Advisory
Committee meeting on February 18th and 19th,
2004.
The Director of the Center of Biologics
Evaluation and
Research has appointed Drs. Walter Dowdle, Ted
Eickhoff, Bruce Gellin, Judith Goldberg, Pamela
McInnes, Arnold Monto, Martin Myers, and Stephen
Phillips as temporary voting members for this
meeting.
"Based on the agenda, it has been
determined that there are no specific products
being
approved at this meeting. The Committee participants
have been screened for their financial
interests. To
determine if any conflicts of interest existed,
the
agency reviewed the agenda and all relevant
financial
interests reported by the meeting participants.
"The Food and Drug Administration prepared
general matters waivers for participants who
required
a waiver under 18 U.S. Code 208. Because general
topics impact on many entities, it is not prudent
to
recite all potential conflicts of interest as
they
apply to each member. FDA acknowledges that there may
be potential conflicts of interest, but because
of the
general nature of the discussions before the
Committee, these potential conflicts of interest
are
mitigated.
"We would like to note for the record that
Dr. Michael Decker is a nonvoting industry
representative for this Committee acting on
behalf of
a regulated industry. Dr. Decker's appointment is not
subject to 18 U.S. Code 208. He is employed by
Aventis and, thus, has a financial interest in
his
employer.
In addition, in the interest of fairness,
FDA is disclosing that his employer, Aventis, is
a
manufacturer of a product that could be affected
by
today's discussions.
"With regards to FDA's invited guest
speakers, the agency has determined that the
services
of these speakers are essential. The following
interests are being made public to allow meeting
participants to objectively evaluate any
presentation
and/or comment made by the speakers.
"Dr. Antoine Flahault is employed by the
World Health Organization Collaborating Center
for
Electronic Disease Surveillance in France. He has
associations with firms that could be affected by
the
Committee discussion.
"Dr. Maria Zambon is employed by the
Respiratory Virus Unit, Health Protection Agency
in
England.
Her agency's laboratory conducts tests on
licensed influenza vaccines. Her employers
collaborates with firms that could be affected by
the
Committee discussions.
"In addition, there are vaccine
manufacturers making industry presentations. These
speakers have financial interests associated with
their employer and with other regulated
firms. They
were not screened for conflict of interest.
"Members and consultants are aware of the
need to exclude themselves from the discussions
involving specific products or firms for which
they
have not been screened for conflict of interest.
Their exclusion will be noted in the public
record.
"With respect to all other meeting
participants, we ask in the interest of fairness
that
you address any current or previous financial
involvement with any firm or product you wish to
comment upon.
Waivers are available by written
request under the Freedom of Information
Act."
So ends the reading of the conflicts of
interest statement. Dr. Overturf, I turn the meeting
over to you.
CALL TO ORDER
CHAIRMAN OVERTURF: Good
morning. I would
like to welcome everybody to this meeting of the
VRBPAC Advisory Committee February 18th and 19th.
Dr. Midthun, would you like to make
presentations to retiring members?
PRESENTATION OF PLAQUES TO RETIRING MEMBERS
DR. MIDTHUN: Good morning. I would like
to ask Dr. Judith Goldberg to please come up to
the
podium. I
would like to thank her for her many years
of service on this Advisory Committee. She has always
been here with great dedication, always has
prepared
extremely well, and provided excellent input to
us.
We are really going to miss her and really
appreciate
all that she has given to us.
I think I am supposed to stand over here
so we can get with the picture of the
plaque. Thank
you. And
we also have a letter here for you from Mr.
Peter Pitts, who is our Associate Commissioner
for
External Relations. So thank you so much.
(Applause.)
DR. GOLDBERG: I just want to thank all of
you because it has really been a privilege to
serve on
this Committee.
I have enjoyed every minute of it,
and I have learned a tremendous amount.
DR. MIDTHUN: Thank you so much.
CHAIRMAN OVERTURF: I think we
will
proceed.
As you know, there has been a great deal of
interest in influenza, for those of you who
forgot
about last winter. So this year I think will be a
striking update of last year. So that I think we will
begin with the data that is going to be presented
by
Dr. Roland Levandowski and his associates. Thank you.
DR. LEVANDOWSKI: Great. Thanks very
much, Dr. Overturf.
OPEN SESSION
STRAIN
SELECTION FOR INFLUENZA VIRUS VACCINE
FOR THE 2004‑2005 SEASON
INTRODUCTION
DR. LEVANDOWSKI: I am going to
try to
give a somewhat extended review of what has been
happening this last season. Generally I do give a
fairly brief review, but today I am going to be
going
into a little bit more detail.
There is an awful lot that is going on.
What we would like to try to cover, just as a
reminder, the real business for today is what is
first
on this list of topics for us to take a look
at. We
are really here today to make the recommendations
for
the strains that should be used in next year's
trivalent vaccine, for the 2004‑2005
trivalent vaccine
for the H1N1, H3N2, and Influenza B viruses.
We do also on this program, as you will
see from the agenda, have some other items that
we
wanted to bring to the attention of the
Committee. In
particular, there are some items that we have
that we
would like to bring to the attention of the
Committee
just mainly for information for things that are
happening.
There has been a lot of interest this year
about the effectiveness of vaccines. This has been a
discussion point at this Committee on many
occasions
in the past.
In fact, I can't remember one when it
hasn't been discussed in recent memory of mine.
So we have several speakers: Dr.
Carolyn
Bridges from CDC, Col. James Neville from the
Department of Defense, and Dr. Antoine Flahault
from
the Institut National de la Sante et de la
Recherche
Medicale, who will be talking about some studies
that
they have ongoing to look at vaccine
effectiveness.
Some of these are still in progress, but we will
at
least get to hear what is happening to try to
look at
this in an ongoing manner.
I also wanted to bring to the attention of
the Committee what is happening with H5 avian
influenza in Asia. At this time last year, you might
remember we were talking about what is happening
with
SARS. So
we know that the Committee will be very
interested to hear this information. We also want to
bring it to the attention of the Committee
because
there may need to be some activities that go on
at a
later date.
We just wanted to have them informed as
much as we can at this point.
Finally, on the agenda, we have something
that we would like to have some discussion with
the
Committee.
This relates to a point that was brought
up last year about use of tissue culture isolates
from
field laboratories for preparation of influenza
vaccines.
You will see on the agenda that tomorrow
toward the conclusion of the meeting we have a
couple
of presentations by one of my colleagues, Zhiping
Ye,
Center for Biologics, and also Dr. Phil Minor
from
NIBSC, to talk about our perspectives on what the
issues might be with issue of tissue culture
isolates.
So this is the main business.
Again, this
is the question that we are asking the Committee
to
give us recommendations today. We are asking for a
vote on this.
This is the abbreviated version of the
question, what strain should be recommended for
the
antigenic composition of the 2004‑2005
influenza virus
vaccine for use in the United States?
Just by way of review, this was the
recommendation that was made by the Committee
last
year at this time. It was for a trivalent vaccine
that would contain an A/New Caledonia/20/99 H1N1‑like
strain.
Actually, it was A/New Caledonia/20/99.
It would also contain a B/Hong
Kong/330/01‑like strain. And in our case, the strains
that were used for vaccine preparation were the
actual
strain, B/Hong Kong/330/2001 or B/Hong
Kong/1434/2002.
The H3N2 component that was recommended based on
all
of the information was for an A/Panama/2007/99‑like
strain.
Why do we change strains for influenza
vaccines?
Well, we do it because the vaccine efficacy
is really related to two things. One is how much
antigen is present in the vaccine and then, very
importantly, what the match of the vaccine,
hemagglutinin and neuraminidase, are with the
wild
type circulating strains. This has been very clear to
us since the earliest days of influenza vaccine
use.
You might remember that influenza viruses
were first isolated in the mid '30s, human
influenza
viruses, mid '30s to early '40s. And it was very
quickly that some vaccines were prepared as whole
virus vaccines.
The first vaccine was licensed in the
United States in 1945. And within two years, by 1947,
it was pretty clear that when there were
antigenic
changes occurring by way of mutation in the
viruses,
that there was reduced vaccine
effectiveness. That
led to setting up the global surveillance system.
What we know from that period of time
onward is that there have been continuous
antigenic
changes in the hemagglutinin and neuraminidase of
both
influenza A and influenza B viruses.
These are the questions that are asked in
order to answer the question for
recommendations. I
will just go over these a little bit with
you. First
of all, we want to know, are there new either
drifted
or shifted antigen influenza viruses
present? Drift
is point mutation occurring in the viruses. And shift
would be exchange of an entire gene segment.
I guess I should remind you that influenza
viruses have a segmented genome. There are eight gene
segments for either influenza A or influenza
B. These
can reassort in nature to put new hemagglutinin
and
neuraminidases into human influenza viruses. That
usually results in a pandemic. But, anyway, the
question is, are there new influenza viruses
present?
This is the purpose that surveillance
serves.
It provides us with that information as to
whether there are new viruses that are occurring.
Mainly we are interested in, are they new in
terms of
their antigenic properties, mainly for the
hemagglutinin but also for the neuraminidase?
It is also from surveillance that we get
the viruses that are used for vaccine
preparation. So
without that underpinning, there really isn't
anything
that we would be able to accomplish.
The question to be answered if there are
new viruses, ‑‑ and they almost
always are new viruses
that are being identified because of the
continuity of
evolution of the viruses ‑‑ are they
spreading in
people?
It is not unusual to see that there are
influenza viruses that are really wildly
different,
but it turns out they are one off. So that occurs
from time to time. And it takes a while, in fact, to
have an understanding as to whether these new
viruses
really have any significance or a potential
impact
that we need to take into consideration for
vaccine
preparation.
If there are new viruses spreading, then
we also want to know whether our current vaccines
are
going to have any likelihood of having
effectiveness
against these new strains. And, for that purpose, we
look at responses from people who have been
immunized
with the current vaccines. Often the case is that
although there are some new viruses that are
spreading, the current vaccines actually make
antibodies that cross‑react fairly well.
And while the differences you will see for
these two different activities are somewhat
complementary, there are thousands of influenza
viruses that are examined with a relatively small
number ‑‑ it is not entirely small,
but it is a
relatively small number of sera that are used to
categorize them.
With the human serologies, we are
looking at the reverse, where we have several
hundred
different sera from people who have been infected
or
immunized and looking at a relatively small,
select
group of these viruses that have been identified
in
surveillance.
And then, last but not least, if it is
true that there are new viruses, they are
spreading,
the current vaccines don't look like they produce
very
good antibody responses to those new strains,
then we
still need to know, "Can we do something
about it?
And are there any strains that are suitable for
use in
vaccines?"
And so, to answer the questions, last
year, just to review what we did, were there new
influenza A, H1N1, viruses? No.
The answer was no.
The HA of all of the strains was very similar to
the
vaccine strain.
For H3N2, the answer, however, was yes.
There were quite a few strains that were
identified.
Although most of these strains were originally
very
much like the current vaccine strain, there were
some
strains that were identified early in 2003 that
were
antigenically distinguishable. And it was a
relatively small proportion to begin with, but
that is
not unusual either that it starts out small and
quickly snowballs.
However, after collecting information and
analyzing, it wasn't really until February of
last
year that it was clear that there was a cluster
that
were antigenically and genetically related that
seemed
to be the ones that were most likely to spread
further.
For influenza B viruses, again, the answer
was really no.
There weren't really any new viruses
that were found.
The majority of the strains were
very similar to what was in the vaccine, but
there
were a small number of strains that are
different.
There actually have been two hemagglutinin
lineages for influenza B viruses co‑circulating
for at
least the past 15 years. One or the other of these
hemagglutinin lineages has tended to be the
predominant strain. We had just left a period of time
where for about ten years, the strains in the
so‑called B/Yamagata/16/88 lineage were the
ones that
were predominant, particularly outside of Asia.
For the last two years, however, the
strains that have been predominating are on the
other
HA lineage.
They are in the B/Victoria/2/87
hemagglutinin lineage. And that is what we have
currently in our vaccine. But there was a small
proportion of viruses last year that were
identified
that were in the B/Yamagata/16/88 lineage. That was
being paid attention to, but it was not
sufficient to
think that there was something really happening
there.
Were these viruses spreading?
For the
H3N2, as I mentioned, the answer was yes. By the time
the Committee was meeting in February or March,
it was
pretty clear that there were some of these
viruses
found on several continents, including Asia,
Europe,
and North America. Were these viruses inhibited by
the current vaccines? And the answer to that was
partially no.
There were a number of strains that were
very much like the Panama/2007/99 vaccine strain.
Those were very well‑inhibited. But for the group
that we are now calling A/Fujian‑like
strains, some of
these were relatively well‑inhibited by
current
vaccines and some were not. It was not a very
homogeneous situation.
Then, to answer the question, were strains
suitable for manufacturing available? The answer was
actually no.
And it related to the fact that all of
this information was coming out just at the time
that
decisions need to be made in order to prepare a
vaccine.
I will give a little bit of explanation
shortly about why that is true, why the timing
was
off.
Sort of in a nutshell here, the
manufacturing does depend on having an egg‑adapted
strain that will grow well. It could be either
wild‑type or a high growth reassortant for
the
influenza A viruses. Generally it needs to be a high
growth reassortment.
The fact that these first Fujian‑like
strains were first identified in February made
this
difficult.
The first egg isolate of an A Fujian‑like
strain wasn't until April. The first high growth
reassortant wasn't prepared until toward the end
of
June.
That timing also is fairly typical for dealing
with new influenza viruses as they are appearing.
So the implications of the strain
selection from last year were that the
preparation of
vaccines this current year was very much on
schedule.
I will provide some information about that. And the
supply of vaccine matched the demand that was
expected
by the previous year's experiences.
There were some other implications.
One,
this year there was an early widespread
appearance of
drift variant of A Fujian‑like viruses in
the United
States.
There were reports of mortality in children.
Now, that significantly increased vaccine demand.
And although there were several million
doses of vaccine, both of inactivated and live
vaccine, that were still available in mid
November.
And it appeared that we were headed toward a
situation
where a lot of vaccine would not be used again,
which
has frequently been the case in the past, not
just the
year before but for many years running. The amount of
vaccine that was available was not sufficient to
avoid
some spot shortages that occurred after the
Thanksgiving holiday in the United States.
And then again, the effectiveness of the
vaccines against this drift variant has been
questioned.
So there are some studies that are
ongoing.
We are going to be hearing about those.
So for the United States, we have three
licensed influenza vaccine manufacturers. Two of them
produce inactivated vaccine: Aventis Pasteur and
Evans Vaccines.
Evans is now part of Chiron. So
I
have to be careful. It is hard for me to keep up with
the changes that occur business‑wise, but
these two
companies have been licensed in the United States
for
quite some time, as you can see here.
And last year, between the two companies,
there was production of about 83 million doses of
vaccine.
Put that into a little bit of perspective.
Inactivated vaccines around 1990, there were
approximately 25 to 30 million doses produced per
year. So
over the decade of the '90s, vaccine
production had increased substantially.
And our license manufacturer for live
attenuated vaccine is MedImmune. They were licensed,
as you might recall, in June of 2003. And they
produced about four million doses of vaccine for
use.
The timelines for vaccine production
are
shown here.
And it is a little bit of a pyramid
scheme.
What most everybody is interested in or what
gets the most visibility is vaccine use, which
occurs
in the fall through the early winter. But supporting
that, underneath that, is all the work that the
manufacturers have to do to prepare the
vaccine. And,
even before that, surveillance and other
activities
are required.
We are right here in February to March.
So we are right down here in this period of
time. It
is early days for vaccine preparation, and it is
months away from vaccine use.
As I mentioned, without surveillance, we
would not have strains for use in vaccine
production
in the first place. And there is a lot of work that
goes on between surveillance and trying to
develop new
strains throughout the year, although there may
be
periods of time when there is more activity than
others.
But there is some activity going on pretty
much all the time.
Recommendations are generally made by the
WHO for the Northern Hemisphere and for the
winter
months here and for the Southern Hemisphere and
for
the winter months there. But these recommendations
are important so that the manufacturers know what
they
should do.
Too, as there are reference strains that
are getting worked, the manufacturers throughout
the
year are working on their seed viruses, which
were
proprietary to them. They worked with the virus to
make sure that it is going to be appropriate for
the
manufacturing conditions. And although there may be
some early seed viruses that are used in
production,
there is some continuous work that goes on to try
to
make that better so that manufacturing can be
smoothed
out. I
will show a little bit of information about
that, too.
Production of the monovalent components of
the vaccine takes many, many months. And, really, it
starts maybe earlier than January. Manufacturers may
be working at risk before recommendations are
made to
produce monovalent components. They don't do this
without some education. They are paying close
attention to the surveillance that is being
reported
throughout the year by WHO and our colleagues at
CDC.
Once all three of the components are
present, trivalent vaccine can be produced, but
you
will see that there is still overlap. There is still
for quite a long time, actually, many years, work
being done with the monovalent vaccines. And so there
is some vaccine that starts to come out, but it
doesn't all come out at one time. And that vaccine
uses the desired goal at the top again.
So to try to also give some understanding
about how long it takes, when there is a new
strain
that is recommended, when there is a new
reference
virus that is identified, for the point of time
that
that new reference is identified to the time that
that
is available for sending out to manufacturers to
develop their seed viruses, for the period of
several
weeks, part of this is trying to understand, is
this
the best strain that is available or are these
the
best strains that are available for producing the
vaccine?
It takes some analysis. It takes
some
collaboration between the WHO centers to come to
that
understanding.
Part of the time for influenza A viruses
and probably for influenza B viruses in the
future is
preparing the high growth reassortants that make
it
more expeditious for producing the vaccine. At the
same time that that is happening, reference
reagents
for standardization of the vaccine need to be
prepared. And this is true not only for inactivated
vaccines, but it may be necessary for the live
vaccines also.
Potency testing for these is dependent
upon having antisera that can be used for the
tests
that are done to try to standardize in terms of
potency.
Once the manufacturer has a seed virus
prepared, then they can start to
manufacture. As I
mentioned, there may be manufacturing at risk
when the
strains are not changed. Those strains can be
prepared in advance of this meeting if the
manufacturers so desire, but they really can't do
anything until they have in their hand something
that
is appropriate for making a seed virus. And they
can't manufacture all the strains without having
those
available.
So this just shows manufacturing three
different strains. And I am showing down here vaccine
release.
There are activities that go on between the
manufacturer and regulatory authorities to try to
make
sure that these seed viruses: first, are appropriate
for use, that they maintain their antigenic
characteristics; and, second, that other kinds of
qualities are maintained.
Now, this bar is about three weeks long
for each of the monovalents. That is an
approximation.
Most of that time I think you will
hear from our colleagues from industry relates to
quality control, not necessarily interaction with
regulatory authorities but just needing to meet
their
own good manufacturing practices and be sure that
the
vaccines are going to meet all of the
specifications
that are set for them.
Once the three strains are produced, then
it is possible to go ahead and formulate vaccine
and
to fill it and to send it out. You see, each of these
points have bars that are about three weeks long
as
well. And
there are some release activities that go
on for the trivalent vaccines.
This duration of time here again is not so
much the actual physical manipulation of the
vaccine.
It has to do with the quality control measures
that
need to be met and some very important ones, like
sterility for inactivated vaccines, for example.
So once that has all happened, then, of
course, the vaccine can be distributed. But, you see,
this time line up here, for a new strain, I am
indicating about 20 weeks. I think that is a
reasonable estimate. If you put that in months, that
is about five months from the time of the first
appearance of the new strain until there is
really the
possibility of having a product in hand that can
be
used.
That is just the first. Once the
first
comes out, then, of course, it just keeps
rolling.
Again, to try to put this into some more
perspective,
it seems to be cut off a little bit on the
boundaries.
That is okay.
I went back and reviewed monovalent
vaccines that were produced for inactivated
vaccine
over the last several years. What I am trying to show
you here is that when strains are changed and
those
are shown across the bottom, the relative
proportion
‑‑ this should add up to 100 percent
for all 3 strains
‑‑ of the strains that are produced
really tends to
favor the new strains that are added. So you can see
between 1998 and 1999, there was a new influenza
B
virus.
And although 38 percent of all of the
monovalent concentrates produced in 1998 were
influenza B, over half of them, about 55 percent,
were
influenza B.
You see that with other changes.
In 2000,
we added a new H1N1 and H3N2. And you can see in both
instances, the amount of effort, the relative
amount
of effort, in terms of the number of monovalent
concentrates that had to be produced was mostly
devoted toward the new strains. You can see that all
the way across here, that when new strains were
added,
that there needs to be an adjustment that it is
the
early work that has to be done by the
manufacturers to
figure out how best to get things growing.
Once they get it organized, you can see
that it is possible that things may even out a
little
bit more between the three strains, but the
strain
that has changed, the strains that are changed
are the
ones that are the most difficult in terms of
overall
production, at least for the first year.
In terms of timing of these things, this
is what we see in terms of submission to the
Center
for Biologics for Release. I am showing the number of
lots here against the month for both the
monovalent
vaccine and the trivalent.
What I really want to point out to you on
this slide, the numbers aren't so important. It is
the overall pattern. You see that there is kind of
this buildup of more and more monovalent
concentrates
coming in up until about August‑September. And then
it starts to wane.
And this relates to the point at which
manufacturers when they are trying to meet the
need
for vaccine in October and November have already
planned out how they are going to be putting
together
how they are going to be manufacturing the
vaccine
components, when they need to have them on tap
and so
on. And
so they come to a decision point about August
or September where they have to decide whether it
is
worthwhile for them to continue manufacturing or
not.
There is a lot of effort and money that
goes into that continuation. And it is possible for
them to do so.
They could keep going if they knew
that there would be demand, for example, within
our
current system.
It is possible to make more vaccine.
It doesn't have to stop right here, but it does
because there is a target that has been developed
from
sales and demand. And it is really kind of a
practical decision.
You see that there still is overlap
between the preparation of the trivalent vaccine
and
preparation of the monovalent right on out to the
end
of the overall campaign for the year.
For this year, because the strains were
the same as the previous year and the demand was
fairly well‑understood at the beginning of
the year,
it was possible to get everything ready.
This curve shows cumulative percent of all
the lots that are submitted to us for release
from
June to December. Two thousand was the year that we
had the shortages or delays that were
concerning. And
this was an atypical year in that the point at
which
50 percent of the vaccine that was available was
shifted out substantially from where it normally
is.
These curves over here are more typical of
what we would be seeing. And generally 100 percent of
the vaccine in the past has been out by about
October.
And that is where we are here. This is the red color
here, the diamonds. The red diamonds are this year,
2003.
So you can see that vaccine was being
produced fairly consistently throughout this
period of
time and very expeditiously met the overall goal
for
this production campaign without any delays.
So why are influenza vaccines important?
Well, they are important because influenza has a
lot
of economic consequences, the lost work, school
time,
and so on.
We know that morbidity is high,
particularly in the very young.
Pneumonia and Influenza, that is the only
category that is in the top ten causes of death
in the
United States, the only infectious diseases
category
that is in the top ten causes of death in the
United
States.
And this is for ages overall. It
is not for
a specific age group but for the ages overall.
We know from other statistics that we can
expect somewhere between 20,000 and 40,000 deaths
in
a typical year related to influenza. That is
generally in the elderly. And we know that pandemics
cause even more.
I just wanted to read a couple of things
that were from some publications that sort of put
this
into perspective. So I am quoting here. It
says,
"Early apprehension was increased by the
fact that
when the first indications of the outbreak were
observed in the country, the influenza had
already
attained epidemic proportions in England.
The sharp rise in influenza deaths,
however, was found not to be due to virulence of
the
causative organism but to a high case
incidence. The
term "lightening influenza" was used in
newspaper
reports.
Also, the epidemic caused by influenza A
viruses was unusually severe for the inner
pandemic
period.
The attack rate in children was much higher
than for adults.
At least 30 percent of children
under 5 years of age were ill. And most were taken to
medical care facilities.
Over 320 children per day crowded into the
pediatric outpatient clinic at Ben Taub
Hospital. So
you might think that was this year, but the first
one
is from 1943 and the second one is from 1975.
I just wanted to try to remind everybody
that what we are dealing with here is something
that
maybe has been a little bit forgotten but that we
should remember that influenza is a very serious
disease.
And to try to highlight that more, I have
got some other slides here that I have taken from
some
of the older literature. This is data from
door‑to‑door surveillance activities
in Baltimore that
were undertaken during and after the pandemic of
1918
to try to get some information about what was
happening.
Unfortunately, my legend is cut off over
here. The
red one is 1918. The purplish one down
here is 1919.
The green one is 1928 to '29.
And the
black one down here is '40 to '41. This is 1943 to
1944.
That quote that I was reading partly
related to this.
There was what was seen as a
relatively large incidence of case attack rate in
children predominantly during that period of
time.
There was a large fear that this was the return
of the
1918 pandemic strain. So you can see, by comparison,
it wasn't quite as high an attack rate, but it
was
much higher than what had been seen in some of
these
intervening years. So there was a lot of concern
about that.
I think what it indicates to us is that
attack rates can be higher or lower. It is sort of
interesting that in the case of both of these
years,
there is sort of a relative disproportionality in
terms of younger children and then sort of young
adults.
It caught my attention because I think that
may relate a little bit to what we are seeing
this
year as well.
I think we are seeing more activity,
and I think we will hear more about that.
So in terms of pneumonia ‑‑ and these were
cases per 10,000 shown on the other slide, and it
is
the same scale here, but the numbers are
drastically
different.
So this is the pneumonia cases in those
same surveys.
You can see from 1918 to 1919, this very
much parallels the mortality curve, where there
was a
kind of instead of a U‑shape, where it is
very high at
both ends in the very young and the very old,
there
was this extra peak occurring in young otherwise
healthy adults.
And there is a small echo of that in
the year following 1918, during 1919 and 1920.
What I am showing here is that this blue
down here again is 1943, where there is a huge
number
of cases occurring, but the amount of pneumonia
that
was being identified in Baltimore was relatively
low,
particularly in young healthy adults. There was a
little bit of an increase more in elderly than in
children, but the young children were affected as
well.
These are some data from 1975‑1976 in
Houston during an A/Victoria/3/75 epidemic of
influenza.
I am showing this. Again, I am
trying to
use that same scale. This is hospitalizations per
10,000.
These are the ages of the individuals.
I guess what I should have said in my
previous two slides is that a lot of this, of
course,
1918, some of this could have been something
other
than flu.
We didn't really have virologic
capabilities until later, but it is based on the
sharpness of the peak of the epidemic. And it is
probably true a little bit here for these data as
well.
These are not all virus isolates.
These
are clinical studies that were done to try to
define
what was happening in the epidemic. But this is
during an epidemic in Houston. Again, you see this
U‑shaped curve, where the hospitalizations
are most
marked for the very young and the very old. In fact,
the number of hospitalizations in this particular
instance appear to be probably more than in the
elderly.
But you see some level of hospitalization
during this relatively severe influenza season in
all
age groups.
Different from that, however, is what has
been seen for mortality in some of these
epidemics.
This is a different age 3 and 2 epidemic in
Houston,
encompassing Harris County, Texas, the
statistics,
health statistics, from there. Again, these are
deaths per 10,000 at different ages.
Here you can see that, really, it is the
elderly who are most markedly affected. They are the
ones who die when they become ill and develop
pneumonia.
But there are deaths that are reported in
all ages.
It is kind of a small number here in the
young adults.
And there are quite a few more seen in
young children but not nearly what we see in the
elderly.
So from this information, the effects
here, we know that influenza attack rates are
often
highest in children who are less than ten years
ago.
There is serious illness in all of the age
brackets,
with the young and the old most affected. And the
mortality is generally highest in the elderly,
although it is also seen in young children. And in
some instances, it seems to parallel the
incidence of
pneumonia during the period of time that the
influenza
epidemic is occurring.
So a brief history of influenza vaccine
efficacy.
In 1941, there was a request to license the
first inactivated vaccine in the United States,
but
the regulatory authorities at the time, who were
part
of NIH under the Public Health Service Act,
thought
that it was best to get efficacy. That wasn't really
required, I believe. It was mainly safety data that
were needed.
But there was a request to show that the
vaccine would actually be efficacious.
They were set to do the study.
They had
all of the materials in place and the desire to
do the
study in 1942, but this often happens to those
people
who are trying to study influenza. There was no
epidemic that year. So it was not possible to do the
studies.
Instead, there were some challenge studies
that were done at the time, which demonstrated
that
these vaccines were effective against influenza A
and
B.
Those studies were published as well as
the information from the studies that were done
later
from large‑scale field studies. Those were done in
1943 through 1945. And they were done with bivalent
vaccine using influenza A and B viruses.
The first vaccine was licensed in the
United States in 1945. And, as I mentioned before, it
was very shortly after that that it was
recognized
that antigenic drift could reduce the
effectiveness of
vaccines and the Global Surveillance System was
inaugurated to try to identify changes that were
occurring and to be able to make alterations in
influenza vaccine as necessary.
So the first studies that were done by
Tommy Francis and Jonas Salk and others with the
armed
forces and a special commission that was set up
to
investigate influenza, the studies that I am
going to
be talking about were done as randomized
placebo‑controlled field efficacy studies
between 1943
and 1945.
The vaccines that were used at that time
were whole virus, formal and inactivated. They were
highly formalin‑inactivated reactogenic.
A large percentage of the people who got
the vaccines felt ill for a couple of days. Some of
them went to infirmary. The antigens that were
contained in the vaccine, it was actually
trivalent
vaccine.
It had two H1N1 components:
A/Puerto
Rico/8/34 and A/Weiss/43. There was an influenza B
component.
It was B/Lee/40.
The studies were done at the Army
specialized training program centers around the
country at the time. These were located in a number
of universities and medical schools. In these
particular studies, there were more than 10,000
participants.
What they were looking at, mainly they
were looking at the clinical endpoint. It was
influenza illness. It was most important.
They did
have the capability. And they were using it during
the studies to identify infection by
culture. They
also could look for serologies. But, really, the
endpoint here was the illness.
Illness was supposed to be characterized
by symptoms that included abrupt onset fever,
myalgias, cough, sore throat, and nasal
symptoms. And
the cases were further categorized by illness
severity.
Those who had a temperature over 100 by
whatever the going criteria were, they were sent
to
the infirmary for hospitalization to get them
away
from the rest of the men in the barracks where
they
were staying.
They also, of course, did X‑rays when
they wanted to look for pneumonia.
There were some differences between the
multiple centers in terms of the way the actual
study
was run.
So that in some instances, hospitalization
could have been for lesser fever, but generally
this
is what was followed.
I am showing the two different studies
that were done here looking at influenza A and
influenza B.
Again, this was a clinical measurement.
It was clinical influenza that resulted in
febrile
illness that needed hospitalization. There were
approximately 12,000 individuals who were
randomized
to get either the vaccine, the trivalent vaccine,
or
somewhat identical placebo.
The number of cases that occurred was
substantially higher in those who got the placebo
than
those who got the vaccine. If you calculate
protective effectiveness from that, it works out
to be
about 69 percent protective effectiveness against
the
clinical febrile illness requiring
hospitalization.
A similar study was done for influenza B.
The numbers here are approximations because the
people
involved in these programs at the time were sort
of
going in and out. There was a lot of personnel
transfer in motion. So they did the best they could
to try to determine what the denominators were
here,
but it really is kind of an estimate.
The number of cases, it is firmer.
Again,
you can see that for the vaccine, there were
substantially fewer cases than in the placebo
group.
Translated, it would be a protective
effectiveness,
around 88 percent.
There were some subanalyses that were done
in this set of studies that have been published
also.
In one subset at the University of Michigan, they
tried to look at the effect on illness, different
levels of severity. They looked at people who had any
kind of respiratory illness. This included the common
cold or what they called the common cold. It was
illness that was obvious, but it wasn't severe
enough
to result in hospitalization. And it didn't have
other symptoms that they thought would be more
typical
of the syndrome that we call influenza with all
of
those symptoms that I listed early on.
We know very clearly that influenza
infection can cause what seems to be a common
cold in
some people, and we know just as well that other
viral
infections can cause what seems to be influenza
by its
clinical manifestations with fever, myalgias, and
so
on. So it
is a very nonspecific indicator.
For those that they thought were more
likely to have influenza based on the
symptomatology,
again, that is based on the clinical symptoms but
being more typical for influenza syndrome. These
inpatients had fever. Then, of course, they were also
looking at pneumonia.
What you see across the bottom here if you
try to figure out a protective effectiveness, you
can
see that there is increasing effectiveness of the
vaccine against the more severe forms of illness.
It is very difficult to show vaccine
effectiveness when it is diluted by many
different
types of respiratory viruses, none of which were
known
at the time.
They were identified specifically at the
time these studies were being done, but they
were, the
giants whose shoulders we stand on were, very
much
aware of the fact that there were other etiologic
agents out there that needed to be
categorized. You
can see that it is very difficult to show that.
If you go to the most severe forms of
illness, it is a lot easier to try to show that
there
is some effect.
They commented that throughout the
study, there were no cases of pneumonia in
anybody who
got the vaccine.
There were ‑‑ this is a relatively
small number ‑‑ only four cases of
pneumonia in the
recruits who got the placebo. That does fit, however.
These studies were done in 1943 and 1944, when I
showed that there was very low incidence of
pneumonia,
even though there was a high attack rate for
influenza.
So there were some other observations they
made from this.
One of them was that in these kinds
of studies, the placebo group was actually
diluted by
having an immunized cohort that may have been
able to
reduce transmission in the placebo group. This was in
one of the first thoughts about herd immunity.
The differences in the attack rates
between vaccine and placebo were really greatest
at
the peak of the epidemic. And as the epidemic
receded, it was harder and harder to be able to
show
anything.
One corollary to this part was that there
was at least one center where there was an
attempt to
immunize in the face of what seemed to be the
developing epidemic. And they noted that it was very
clear‑cut that during the first week, they
couldn't
really show any difference in the attack rate in
the
placebo or the vaccinated individuals, but after
one
week, it was very clear who had been
immunized. There
seemed to be a big difference, even after that
one‑week period of time.
I mention this just because we often talk
about needing two weeks after immunization,
somebody
who is immunologically primed. Of course, these
individuals all were immunologically prime by
previous
exposures.
But there may be protective effects that
are kicking in, even in an earlier period of
time.
So, to add a little bit of information
about some of the other studies that had been
done, I
wanted to concentrate on a few studies. These are
selected by me to make some points about the
effect of
vaccine when there is antigenic drift that is
occurring.
This first study that I want to talk a
little bit about was done in Texas in 1976. It was
the Houston family study for this particular
publication.
There were 37 families who had 155
members of different ages, ranging from infants
up to
about mid '40s.
The A/Port Chalmers/1/73‑like viruses had
caused an epidemic in 1975. And so these individuals
who were not immunized specifically had
antibodies
that were directed against or should have had some
possibility of having antibodies directed against
Port
Chalmers, but then the following year, A
Victoria/3/75‑like viruses caused an
epidemic. These
viruses, the A Victoria/3/75 viruses, are really
drift
variants of the previous strains.
At the time, it was noted that this was a
very dramatic difference in terms of antigenic
characteristics between these two viruses. I don't
know whether it is fair to say so, but it
probably was
at least as different as what we are seeing this
past
year with the Panama‑like strains and the
Fujian‑like
strains and possibly more because, actually, it
was
remarkable and there was a lot of comment about
how
different those strains were.
They were able to use virus isolation and
serologies to try to document infection. As I
mentioned, there was no vaccine used. Now, what I am
showing here are the preexposure hemagglutination
inhibition titers from the people who were in the
study.
They were able to get blood from 154.
They
tested them for antibodies to both Port Chalmers
73
and Victoria 75 strains.
What you can see here, I think, is that
there was some proportion who had, really, very
low
antibodies in both of these groups. These are the
same people, of course. So you see that some higher
frequency of those who they tested for antibodies
to
Victoria were more likely. They were more likely not
to have antibodies is what I am trying to say.
If you look at the distribution from low
antibody to high antibody, you can see that in
comparison to Port Chalmers, there is a shift
toward
lower antibody titers for Victoria strains. And that
is what we are usually dealing with when we are
looking at our serology. So this is very similar.
They were able to do some other things to
look at infection and illness. I think that what you
can see is that there is a relation between
antibody
presence and protection. As you get higher antibody
titers, there are fewer and fewer people who are
infected.
The same thing is true if you look at
clinical illness. Those who have higher antibody
titers are less likely to be clinically ill.
What this also says is that the number of
people who are infected who are relatively
asymptomatic is fairly high compared to the
numbers
that we would recognize as having had
influenza. So
it is something else to keep in mind in terms of
trying to make sense out of what is there.
So another study done by the same group in
1986.
Again, it was the family study, Houston family
study.
They had 98 families enrolled with 192
children who are between 3 and 18 years old.
These children were randomized.
I am not
sure that is quite the right word. They were groups
that got either placebo or inactivated trivalent
vaccine or a live attenuated bivalent vaccine.
Each of those vaccines contained an
A/Chile/1/83‑like H1N1 virus. These children all got
a single dose of vaccine. That particular year, the
H1N1 virus was a new one that had appeared only
in
March, was first identified in March.
And you might remember that that was the
year that there was a supplemental vaccine that
was
produced for A/Taiwan/1/86. It was not used in this
study, but it was recognized that the Taiwan/1/86
virus was substantially different from Chile so
much
so that it was thought that for younger people,
that
an A/Taiwan vaccine would be a good idea.
Again, they had virus isolation and
serology to try to document infection. What they
showed was both of these vaccines had protective
effect against infection with A/Taiwan/1/86. And this
is infection and not illness that we are looking
at
now. So
it is the measurement that would pick up more
individuals.
Anyway, you see this is fairly similar.
It was about 52 percent protective effect on this
drift variant from the live attenuated vaccine in
use
at that time and about 61 percent for the
inactivated
vaccine.
The authors commented that they thought,
actually, in the younger age group, the live
attenuated vaccine performed better than the
inactivated vaccine and vice versa for the
inactivated
vaccine, which you can see here. Nevertheless, both
of these vaccines were substantially better than
no
vaccine in terms of what happened to the placebo
group.
So, finally, one more drift variant story,
a nursing home in Colorado in 1987 during an
outbreak.
There was an outbreak that was caused by an H3N2
drift
variant.
The vaccine strain at the time was
A/Leningrad/6/86. The viruses that were being
isolated have names. They are Colorado, of course.
They were all similar to this reference strain,
the
Sichuan/2/87 strain. And that strain was different
enough that the following year, it was included
in the
vaccine for use.
So that there was some difference.
I am not sure that the difference between
Sichuan/2/87 and Leningrad/6/86 is the same as
the
Victoria/Port Chalmers difference, but there was
still
enough that it was thought a good idea to change
the
vaccine after those had appeared.
Not everybody in this nursing home was
immunized, but they immunized a very high
percentage
of them after the outbreak started. The outbreak
itself had a peak that occurred about two weeks
after
the immunization campaign.
This analysis was done retrospectively,
but they were able to get pretty good
documentation
from the nursing home records about who had
fever; as
measured by thermometer, who had illnesses, what
kind
of illnesses they were. Of course, pneumonia and
death were pretty obvious because the residents
needed
for the treatments. In a subset, they were able to
confirm that infection had occurred because of
H3N2.
But generally this again was a clinical
observation.
This just shows the epidemic, how it
occurred.
When it was first recognized, it was a
fairly sharp epidemic. There were about five of the
residents of the nursing home who were
infected. The
following week, vaccine was given to all who
wanted it
or could receive it. There were a number of
individuals who refused the vaccine, and there
were a
number of individuals who had other ongoing
illnesses
that were thought to be contraindications to
getting
the vaccine.
So the numbers peaked around week four
here on the epidemic. And then it kind of quickly
tapered off afterward. What you can see is that
although there are quite a few cases in both the
immunized and the unimmunized populations,
looking at
vaccine effectiveness, as calculated by the
authors,
they mainly were looking at febrile upper
respiratory
illness.
They excluded a number of individuals who
had been immunized in that two‑week
interval. From
the time they immunized until two weeks, they
excluded
those from their true analysis. And that was true for
both vaccinees and non‑vaccinees. There were some
other exclusions as well.
Looking at the incidence, these are
numbers and not percents here. Looking at the number
of febrile upper respiratory illnesses that
occurred,
the proportion was significantly less in those
who
received vaccine. And protective effectiveness
against febrile upper respiratory illness in that
group was calculated to be about 65 percent.
There were no pneumonias in those who got
vaccine and there were no deaths in those who got
vaccine; whereas, there were pneumonias and
deaths in
those who did not. This isn't really randomized
prospectively.
So there may be some other reasons for
that. But
if you look at all of the residents all
together, you can see that all together, the
residents
who got vaccine, there were no pneumonias and no
deaths; whereas, there was a substantial number
of
both incidence of pneumonia and death in the
residents
who were not immunized.
Some facts that I guess we could take from
those studies are that the vaccine protective
effect
is a lot more obvious for severe forms of illness
and
for complications that are related to influenza
and
infection.
The vaccine shifts the spectrum of disease
toward the less severe consequences and milder
illness.
Whatever you are looking at, they have to
keep that in mind. And higher antibody titers are
more likely to result in protection from clinical
illness.
Also, for infection, this is not an
absolute.
There is in my own mind not an absolute
number to use for this, but it is pretty clear
that
the more antibody you have, the better.
The vaccine administered in an ongoing
epidemic still may reduce illness, pneumonia, and
death, even when there is antigenic drift that
has
occurred.
Turning away from that at the moment,
these are the recommendations that were made by
the
World Health Organization for influenza vaccine
composition for the Northern Hemisphere for 2004‑2005.
The recommendations from there that are
based on the information that was available to
WHO
last week were to continue to use an A/New
Caledonia/20/99 H1N1‑like virus, to use an
A/Fujian/411/2002 H3N2‑like virus, and to
use a
B/Shanghai/361/2002‑like virus for the B
strain.
Again, the question for the
Committee,
"What strain should be recommended for the
antigenic
composition of the 2004‑2005 influenza
virus vaccine?
Should it be based on the epidemiology and
antigenic
characteristics of the viruses, the serologic
responses, and availability of candidate
strains?"
All the information that we are going to
be presenting apart from the vaccine
effectiveness
studies this morning will relate directly to
answering
this set of questions by the Committee. And I think
I can stop there and ask if there are any
questions.
CHAIRMAN OVERTURF: Were there
any
questions for Dr. Levandowski? Yes?
Please identify
yourself.
DR. MARKOVITZ: David
Markovitz. I am
speaking from the somewhat claustrophobic right
corridor of the table, where it is difficult to
see or
breathe.
So if you will excuse me, I am not
articulate.
My question is this. You showed
a graph
that implied that the vaccine manufacturing
process
was quite effective this year but, yet, also
alluded
to some early gaps, early in the season, which we
all
noticed just in our hospitals or reading the
newspaper.
What is your overall assessment of how the
manufacturing process kicked in this year?
DR. LEVANDOWSKI: Well, I am not
sure what
gaps you are referring to, but from the point of
view
of production and vaccine release this year, it
went
about as smoothly as it ever goes, which means
that
manufacturers were busy producing monovalent
vaccines
and busy producing trivalent vaccines and having
those
released and being able to get them into
distribution.
I don't know that I have any other
information.
From our perspective, things went
extremely well.
DR. MARKOVITZ: I guess at our
hospital,
in the fall, for example, people were not able to
get
vaccine.
I don't know what the cause of that was.
Was that just too early in the year? Did they strike
too soon or what? Is that just an anecdotal
observation from what I have seen? I believe I read
about that nationally, too, I thought.
DR. LEVANDOWSKI: Again, from our
perspective, I don't understand it. I don't have any
information that relates directly to
distribution. We
don't get involved with distribution per se at
FDA.
It is more understanding that the vaccines meet
their
specifications and that they are okay to go out.
What we saw was a steady stream of vaccine
preparation release. And maybe this is a question for
the manufacturers and not for me because I don't
know
what issues there might have been for them in
terms of
distribution.
DR. MARKOVITZ: I wasn't really
thinking
of distribution.
I was thinking more of manufacture.
DR. LEVANDOWSKI: Well, that is
an
important part of manufacturing: getting the vaccine
out to where it is supposed to be used. But, again,
that is not a part that FDA really interacts with
directly as the vaccine is being prepared. It is more
of the release specifications being met for the
vaccine and that all of the good manufacturing
practices have been met to make sure that the
vaccine
is ready to go.
Again, I would have to say that this year
‑‑ and the graph I showed I think is
an indication of
that ‑‑ all the vaccine that came
through FDA came
through at a very early time point.
CHAIRMAN OVERTURF: Dr. Myers?
DR. MYERS: Roland, the data
sometimes is
presented for children less than five and
sometimes
broken down by a year or less than five. The data you
showed is striking for the morbidity being for
children less than a year of age. Is there any
protective effectiveness data for that
population?
DR. LEVANDOWSKI: There is
relatively
little direct information. Again, I would have to ask
some of our other colleagues out there what they
know.
I don't know that there has been a specific study
to
look at vaccine effectiveness in children who are
less
than one year of age.
I think we do have some understanding that
immunogenicity may be decreased in the very young
children as well. I think that is partly reflected in
the setting, the cutoff at six months for use of
vaccines, if there is an understanding that maybe
the
vaccines won't be so immunogenic in those
children and
maybe the reactogenicity is a bigger concern than
any
clinical benefit that they might get.
There is, however, relatively little for
inactivated vaccines. There is more recently for live
attenuated vaccines. In children 15 to 72 months of
age, the studies that were done by MedImmune show
a
very high level of vaccine effectiveness,
efficacy
actually, in those children.
CHAIRMAN OVERTURF: Dr. Gellin?
DR. GELLIN: Well, two
questions. The
first is you made a comment in 1986 that there
was a
supplemental vaccine produced. Could you give us a
little more insight into what that was?
DR. LEVANDOWSKI: Right. The
vaccine was
made for the A/Taiwan/1/86 strain. That virus was
first identified, I believe, in March of that
year.
It was at a very late point in time. There was a
recommendation that a supplemental vaccine be
prepared.
And the manufacturers did that, but the
timing for it was not available until late
November
anyplace.
And because of the way it came out, there
was a lot of confusion, part of the confusion
because
I was in clinical practice at the time trying to
figure out what to do with the vaccine late
November
and early December. There was a lot of confusion on
the part of practitioners about what to do with
it.
Not much of it got used. Most of it was subsequently
discarded.
It had to be thrown away, basically.
That
strain was what was used in the vaccine, then,
the
following year for the trivalent vaccine.
DR. GELLIN: So it was a
monovalent
product?
DR. LEVANDOWSKI: Yes. Sorry.
It was a
monovalent supplemental vaccine, right, that one
year.
DR. GELLIN: The second question
was, in
your chart about the efforts, intensive efforts,
that
go into when they are changed each year and then
the
subsequent graph about the delay in production.
In 1992 to 2000, there were two changes.
And that was the year that there was a delay in
the
release of the vaccine that was used. I was wondering
if they were related.
DR. LEVANDOWSKI: It is partly
related.
Some manufacturers had some difficulty with
replication of the H3 strain early on, but that
was
worked out, as it usually is. Manufacturers are
actually quite resourceful at making things work.
If you will look at that chart that you
are talking about ‑‑ I am not sure I
can get to it
because of the touch pad here on the
computer. It is
not that friendly. If you look at that graph that you
are referring to, you can see that most of the
effort
actually goes into producing the H1 strain. And
although the H3 is the one that got all the
notoriety
for being difficult to work with, at least
initially,
the H1 strain took up more manufacturing time in
terms
of number of monovalents.
The way I presented that information, you
can't directly equate that with the overall
amount of
vaccine that is being produced because their
variability, lot sizes are variable from
manufacturer
to manufacturer and even within a
manufacturer. So it
is not like you have one box that has 100 units
in it.
You have a box that might have ten units. You have a
box that might have 150 units. It is not that direct.
But I just tried to give some impression
as to the overall effort. It is actually the H1
strains that have been more difficult the last
few
years in terms of overall manufacturing effort.
CHAIRMAN OVERTURF: Dr. Monto?
DR. MONTO: I would comment about
the
nursing home and how to interpret drift in terms
of
nursing home outbreaks. We have had a surveillance
going on in a number of Michigan nursing homes
for a
number of years now. Two years ago, with a rather
wimpy A/H3N2 outbreak with a non‑drifted
variant, we
had confirmed transmission in 26 percent of our
homes.
This year it is going to be higher.
And
we had an outbreak in December. It is going to be in
the 30 percent range, we think, once we finish
the
analysis.
What I am saying is that you really have
to look at what happens in nursing homes, even in
a
non‑drifted year, in terms of putting
things into
context because the vaccine really does not
protect
all that well against just influenza‑like
illness,
even laboratory‑confirmed, even in a non‑drifted
year,
in this population. Our nursing homes were typically
80 percent and many of them 90 percent
vaccinated.
CHAIRMAN OVERTURF: Dr. Farley?
MEMBER FARLEY: To me, one of the
most
striking features of this year's influenza
profile was
the early onset of disease. Given the manufacturing
timetable that you presented, if there were any
indication to attempt to begin immunizations
earlier
in the fall or late summer even, is it even
possible
within the constraints of the timetable?
DR. LEVANDOWSKI: I think the
answer, is
it possible, yes, I think it is. I mean, I think that
this year the vaccine was prepared at a very
early
point. If
you have that graph? Again, I am not
sure
I can get to it easily here because of the
computer
system.
There was a substantial amount of vaccine
in trivalent form. That graph that I was showing was
for trivalent vaccine. There was a substantial amount
that had been released for distribution, even in
the
summer months.
So it is possible that it could have
been.
This year, although there was an early
epidemic of influenza, although it started early,
there was a substantial amount of vaccine that
could
have been available around the country at that
point
based on the manufacturing timelines for this
past
year.
If we had made a strain change this last
year, I don't know that that would have been
true. I
am not sure that there would have been further
delays.
Given the timelines for preparation of seed
viruses
and so on this past year, I would assume that we
would
not have been seeing vaccine early in the summer
but
probably the first vaccines might have been
available
September, rather than in July.
So, again, from my perspective, I think
manufacturing went very efficiently and was early
and
on time with a total amount that was intended for
production for this year based on what the demand
parameters were that the manufacturers understood
for
all of the vaccines.
CHAIRMAN OVERTURF: Dr. LaRussa?
MEMBER LaRUSSA: Just to carry
that a
little further, can you just sort of estimate?
According to one of your slides, the high growth
reassortants were available in June for the
Fujian
strain.
If you had decided to go ahead and make a
monovalent vaccine, what would be the earliest
that
would have been available?
DR. LEVANDOWSKI: Well, that is
what I was
trying to get to with that other slide that I had
about manufacturing timelines, the 20 weeks. If you
take about six weeks for development of the
reference
virus at that point, what would that be? That is
about three and a half months.
So from June until sometime late September
probably by the time we would be seeing any
vaccine
produced that was trivalent; whereas, with the
manufacturing system as it was, the first
trivalent
vaccines were actually coming in end of June,
beginning of July.
CHAIRMAN OVERTURF: We have time
for about
one more question. Any other questions?
(No response.)
CHAIRMAN OVERTURF: I think we
will go
ahead and proceed, then, with the discussion
regarding
vaccine effectiveness. I guess Dr. Carolyn Bridges is
going to make that presentation.
VACCINE EFFECTIVENESS
DR. BRIDGES: Good morning. Today I am
going to be discussing some studies that have
been
done on vaccine effectiveness of the inactivated
influenza vaccine this year that CDC collaborated
on.
I will be discussing a little bit of
background about the flu season, most of which
Roland
has already covered. Then I will be describing two of
those studies, where we have preliminary results;
and
then listing some other studies that are
currently in
progress; and then end with some final remarks.
As Roland stated, influenza activity
started earlier than usual this year. And children
appeared to be disproportionately affected
compared
with recent years. There were widely publicized
reports of pediatric deaths that received quite a
bit
of attention.
There is also unprecedented demand for
vaccine more than in some recent years. And there was
discussion at the HHS level about additional
vaccine
purchase.
Although, as Roland says, the amount of
vaccine that was purchased or was manufactured
was
equal to the demand from the previous year.
In addition to these pediatric deaths,
there is also a drifted variant of influenza
H3N2,
which predominated, which was different from the
vaccine strain.
And influenza vaccine effectiveness
was questioned.
In order to assess the effectiveness of
this year's inactivated vaccine, several studies
were
initiated simultaneously using various age groups
and
looking at different outcomes.
Preliminary results are available from two
of those studies, which were conducted in the
State of
Colorado.
One of those studies was a retrospective
cohort study among health care workers. The principal
investigator for that study is Dr. Nidhi Jain.
The other one is a case cohort and
subsequent case control study among persons aged
50 to
64 years who have laboratory‑confirmed
influenza. And
the co‑PIs for that study are Drs. Marika
Iwane and
Guillermo Herrera.
This is some surveillance data from the
Children's Hospital in Denver, Colorado. And, as you
will look at the left scale, it goes from zero to
400.
This is a scale for influenza A viruses. On the
right‑hand of the graph, it is a scale for
RSV and
influenza B, which goes from zero to 40. So there is
a tenfold difference in the scales.
As you can see, influenza A activity began
early in November. It peaked towards the end of
November and then started on this decline. There were
very few influenza B viruses and very few cases
of RSV
that were identified at the Children's Hospital
among
hospitalized as well as outpatients.
This is the remainder of their
surveillance data. Again notice the scale, zero to
20. So
there also was very little in the way of
paraflu, adeno, rhinovirus, or pertussis that was
identified.
Incidentally, of the respiratory specimens
that were tested in the hospital laboratory, the
percent of specimens that tested positive for
influenza at the peak was around 60 to 70
percent. So
this is a very high percent positive rate from
respiratory specimens.
We decided to conduct a study among health
care workers at the Children's Hospital because
the
staff provided a large cohort for rapid
analysis. And
we knew that a large number was needed if we were
going to look at nonspecific outcome.
Also, this cohort has substantial
opportunities for exposure to influenza as they
had
many hospitalized patients who were influenza‑positive
and they had conducted the bulk of their
inactivated
influenza vaccine campaign in the month of
October.
Influenza‑like illness was the outcome.
This has been used, as Roland has described, in
many
prior studies, although we clearly understand
that
this underestimates the vaccine effectiveness
that
could be seen looking at more specific outcomes,
such
as laboratory‑confirmed influenza.
We thought that this may provide us with
a reasonable estimate or reasonable chance of
finding
vaccine effectiveness because influenza was so
predominant as the cause of flu‑like
illness in the
population based on the Children's Hospital
surveillance data. Preliminary results of this study
were published in the January 16th MMWR.
The objective of this study was to
estimate the effectiveness of the 2003‑04
inactivated
influenza vaccine in preventing influenza‑like
illness, or ILI, among adults working at the
Children's Hospital in Denver, Colorado.
This is a retrospective cohort study.
A
questionnaire was distributed via e‑mail
and also
paper surveys to approximately 3,100
employees. This
is an anonymous survey, and very limited
demographic
information could be collected. Information was
collected on age group, sex, whether they had
patient
contact, whether they had one or more high‑risk
conditions, whether they are vaccinated, and the
timing of their vaccination, illness onset and
symptoms, and whether they had physician visits
or
were influenza‑tested. We also asked about missed
workdays from flu‑like illness. The questionnaire was
distributed from December 11th through December
17th.
The ILI definition used was self‑reported
fever plus either cough or sore throat, which is
similar to the CDC surveillance case definition.
Illnesses were counted if they began on or after
November 1st or through the date of survey
completion.
We conducted two different types of
analysis, one a categorical analysis and the
other a
person‑time analysis. For the categorical analysis,
we estimated vaccine effectiveness against ILI
only
among persons who were vaccinated before November
1st
and compared those with those who were never
vaccinated.
We looked at two different vaccination
definitions for persons who became ill less than
two
weeks after being vaccinated. In one instance, we
categorized those persons as being
unvaccinated. In
the second analysis, we excluded them from the
analysis.
For the person‑time analysis, again, the
person‑time began November 1st and ended on
the date
of survey completion. We did not exclude persons who
were vaccinated during the illness period for
this
analysis, but an individual could contribute both
vaccinated and unvaccinated time if they got
vaccinated during the period of interest of
November
1 through survey completion date.
The outcome for this study was ILI
incidence density rate. And, similar to the first
study for those who became ill one to 13 days
after
vaccination, we either counted that time as being
unvaccinated time in one analysis or we excluded
those
person‑days from the analysis.
This graph shows the number of
influenza‑like illness cases among
staff. Those are
in the short light blue bars; the number of
laboratory‑confirmed influenza cases among
patients at
the Children's Hospital, which are the tall
purple
bars; and the line graph shows the percentage of
the
cohort that was included in the study, the
percent of
the cohort that was vaccinated by time.
So as of November 1st, 54 percent of the
persons who answered the questionnaire were
vaccinated.
An additional 24 percent were vaccinated
during the outbreak period of November 1 and
later.
So of 3,100 persons to whom the
questionnaire was distributed, 1,886, or 61
percent,
completed the survey. Half of those completed it
online and half of those completed it by paper.
Persons were excluded if they did not
report their vaccination status as being yes or
no or
if they did not report date of vaccination. We also
excluded persons who did not report whether or
not
they had an illness or if they did not report
date of
illness onset.
This is the demographic information from
the persons who completed the questionnaire. It
includes all persons vaccinated or unvaccinated,
regardless of the timing of their vaccination.
Persons who were vaccinated tended to be
in the older age group. And a higher proportion of
them, though not statistically significant, were
female.
In addition, physicians and nurses were
more likely to be vaccinated than persons in
neither
of those occupation categories. And people who had
patient contact also were more likely to be
vaccinated.
There is a considerable correlation
between these two variables.
As I mentioned, we asked people if they
had been tested for influenza and also what the
results of that testing were. Twenty‑eight people who
had influenza‑like illness reported being
tested for
influenza.
And of those, 13, or 46 percent, reported
that they were positive.
Now let's skip to the results.
This is
for the categorical analysis, where persons were
counted as unvaccinated if they became ill in the
less
than 14 days prior to vaccination.
So of the vaccinated persons, about 15
percent of them developed influenza‑like
illness
compared to almost 17 percent among the
unvaccinated.
The vaccine effectiveness adjusted for age group,
high‑risk condition, and patient contact
was
approximately 14 percent with confidence
intervals
that included zero.
If we looked at the additional vaccination
definition, where we excluded persons who became
ill
in the 14 days after vaccination, that eliminated
9
people from the analysis. This analysis, then, again,
15 percent of vaccinated were ill and
approximately 15
percent of unvaccinated were ill, with an
adjusted
vaccine effectiveness estimate of approximately 3
percent, again, with confidence intervals that
included zero.
In addition to the categorical analysis,
we conducted a person‑time or survival
analysis. In
this analysis, again, people were not excluded if
they
got vaccinated during the outbreak period.
Again, looking at the two different
definitions for vaccination, vaccine
effectiveness for
both of these, the point estimates were negative,
but
the confidence intervals were very wide and were
not
statistically significant from zero.
There are a number of limitations to this
study.
One, the response rate was only 61 percent.
And there was certainly a possibility for
responses by
us.
Secondly, vaccination and influenza‑like illness
status were self‑reported. And vaccination was
self‑selected. So there may have been some
confounding by indication for those two who were
vaccinated.
In addition, there was a high vaccination
rate among the respondents. And this decreased our
power to detect a lower vaccine effectiveness
estimate.
However, the vaccination rate that we found
in this cohort was very similar to what the
hospital
estimated for their entire population. They estimated
that they had approximately 75 to 80 percent of
their
employees vaccinated.
In addition, because the influenza season
was early, some persons were vaccinated during
the
peak influenza activity. In addition, we used a
nonspecific case definition, which likely
underestimated true vaccine effectiveness if one
were
to look at laboratory‑confirmed flu.
The conclusions from this study are that
we were unable to demonstrate vaccine
effectiveness
against ILI and this study when it drifted,
influenza
H3N2 virus predominated. However, vaccine
effectiveness is likely to be higher against
laboratory‑confirmed influenza and against
influenza‑related hospitalizations and
deaths.
The recommendations that were published in
the MMWR were to continue vaccination,
particularly of
high‑risk persons, their contacts and
health care
workers because H1N1 and influenza B may
circulate
later in the flu season and because based on
historical information, vaccine is expected to
protect
against influenza‑related complications and
laboratory‑confirmed influenza.
The study pointed out that retrospective
analyses and sort of on‑the‑fly
analyses are very
difficult to do during the middle of flu season
and
that prospective annual vaccine effectiveness
studies
against laboratory‑confirmed influenza are
needed for
more accurate yearly assessment of vaccine
effectiveness and to assess the impact of the
vaccine
program.
I am now going to move on to the case
cohort analysis for persons 50 to 64 years of
age.
This study was initiated to estimate the
effectiveness
of the inactivated vaccine against
laboratory‑confirmed influenza in persons
50 to 64
years of age.
And this was initiated at the same time
as the health care worker study.
For the cases, these all were
laboratory‑confirmed cases that were
identified
through the surveillance system in the Colorado
Department of Health. Colorado requires that persons
with laboratory‑confirmed influenza are
reported to
the state Health Department. However, they are not
required to report contact information. They report
age, gender, and name but not phone number or
address
or county many of the times.
Over 10,000 cases were reported to
Colorado by the end of December. And over 500 of
those cases were in persons 50 to 64 years of age.
However, more serious cases of influenza were
more
likely to be reported.
The cases were interviewed by phone.
And
they were excluded if they did not recall being
tested
for influenza or they denied being ill. In that case,
we may have had the wrong person when we tried to
hunt
down a phone number based on name only.
Information was collected on demographics,
illness onset, and duration, vaccination, and
timing
of vaccination, health care provider visits, and
hospitalization.
For the cohort, the cohort was considered
the Colorado population aged 50 to 64 years. To
estimate the coverage in Colorado among persons
50 to
64 years, we looked at the Colorado behavior risk
factor surveillance survey. This is an annually
conducted survey that is state‑based. And for a
number of years, the question has been asked,
"Have
you had a flu shot in the past 12 months?"
We looked at data from 2001 through 2003
for the limited 2003 data that was
available. We used
a screening method or case cohort method to
estimate
vaccine effectiveness, which was estimate to be
approximately equal to one minus the relative
risk.
The confidence intervals calculation included the
variance of the various aspects and coverage
estimates.
So the confidence intervals were
considerably wider.
Again, similar to the other study, we used
two different classifications of vaccination for
persons who were ill in the two weeks following
vaccination.
In one sense, they were counted as
unvaccinated.
And then they were also in a second
analysis excluded.
Vaccine effectiveness was calculated for
the different possible cohort coverage rates in a
sensitivity analysis. Because of the difficulty in
determining the vaccination rate of the cohort,
because the outbreak happened during the typical
time
where vaccine is administered, we have also
initiated
a case control study.
So controls are being recruited that will
be age group frequency matched. We are attempting to
recruit three controls per case. And they are being
recruited through random digit dialing. Hopefully
this will provide a more accurate assessment of
vaccine effectiveness.
So among the cases, there were
approximately 574 cases reported to the Colorado
Department of Health. Of those, interviews were
completed on 56 percent. Among those where there was
not an interview completed, for most of those
persons,
it was an inability to contract the person or for
most
of those inability to identify a telephone
number. If
there were 1,200 John Smiths in Colorado, it was
difficult to identify who that name and age may
have
belonged to.
However, those who were interviewed and
those non‑interviewed did not differ by
gender or age.
So this graph shows the number of cases by
week of their illness onset. As you can see, most of
these started again in early November and a
cumulative
percentage of these cases that were vaccinated,
which
is represented by the red line.
Of the cases, approximately 329 were
included.
As you may have noticed from the slide
earlier, there were 330, but the vaccination
status on
one of those persons couldn't be confirmed.
Of the 329, approximately 50 percent were
high‑risk and 50 percent were not high‑risk
using our
vaccination definition of counting them as
unvaccinated if they became ill less than 2 weeks
after the vaccination date.
Among all persons in this category, 42
percent were vaccinated, 52 percent of those were
high‑risk, and 32 percent were non‑high‑risk
who were
vaccinated.
A high proportion was hospitalized.
Forty‑eight percent of high‑risk
people were
hospitalized, and 17 percent of those classified
as
non‑high‑risk were hospitalized.
We found very similar numbers when we did
a second analysis and excluded people if they
were
vaccinated one to 13 days before illness onset.
Again, about 50 percent were high‑risk. And
vaccination rate was about 56 percent among
non‑high‑risk and 36 percent among
non‑high‑risk
persons.
And, again, high rates of hospitalization,
about a third.
I would like to look at the results of the
cohort.
So this is the overall Colorado population 50
to 64. We
had a number of different estimates.
The
middle estimate was using the 2002 BRFSS final
weighted data.
And the estimate, vaccine estimate, is
45 percent.
The high estimate may be the 2003
unweighted monthly data from BRFSS. So this is
preliminary data. And the December estimate was 52
percent.
A low estimate would be the 2002
Western
regional national health interview survey data
for
persons 50 to 64. That data would suggest that the
vaccination for high‑risk be 40 percent and
non‑high‑risk 32 percent.
However, we know that Colorado generally
has substantially higher vaccination rates in all
age
groups compared to most of the other Western
region,
particularly California, which tends to weight
that
estimate down quite a bit.
This is some preliminary results from the
controls that have been recruited from the case
control study.
Of 304 persons who have interviews
completed and data entered, 26 percent of those
have
high‑risk conditions. And vaccination rate for those
for this flu seasons, for 2003‑04, was 58
percent
among non‑high‑risk and 61 percent
among high‑risk, so
considerably higher than the previous behavioral
risk
factor surveillance survey estimates. We hope to have
recruitment through about 1,100 persons completed
by
early March.
So if one considers this range of vaccine
coverage estimates in the cohort, we then use the
screening method to estimate what the vaccine
effectiveness may be in the overall cohort of 50
to
64‑year‑olds.
If you look at the non‑high‑risk group,
where among the cases, the vaccination rate was
32.5
percent, assuming the vaccination coverage for
the
cohort ranges somewhere between 40 and 60
percent,
then the overall vaccine effectiveness may range
somewhere between 28 percent and 68 percent.
When you look at the high‑risk group,
there is substantially more content by
indication. I
think it is very difficult to assess these
results.
In general, it looks like vaccine effectiveness
is
lower. I
think that is very difficult to assess.
Again, looking at the second definition
for vaccination for cases being excluded if they
became ill in that two‑week period after
vaccination,
the estimates are somewhat lower, but the
non‑high‑risk, the estimate is
somewhere between 16
and 63 percent, and for the high‑risk,
again, most of
the estimates are negative. That I think is very,
very difficult to assess.
The limitation of this study is that these
lab‑reportable cases over‑represent
sicker and
hospitalized patients and certainly over‑represent
high‑risk persons. The case cohort method provided
for a very wide confidence intervals of the
vaccine
effectiveness estimate, which gives us quite a
bit of
degree of uncertainty.
However, overall the vaccination rate at
the time of onset of cases of illness is unknown
due
to the early season. So we don't really know what the
vaccination rate is, really, for the controls at
the
time of the outbreak. So use of the historical
vaccine coverage estimates would overestimate
overall
vaccine effectiveness.
So the case control study will help us in
determining what the vaccination rate was during
the
time of the outbreak. So that should give us a little
bit more confidence.
The conclusions from our case cohort study
are that vaccine effectiveness among the non‑high‑risk
is likely somewhere between 16 and 68
percent. It is
a very wide estimate.
The vaccine effectiveness among high‑risk
persons is difficult to interpret because of
content
by indication.
And further analysis is pending for
the case control study.
I would like to acknowledge our
collaborators at the Children's Hospital, the
University of Colorado, the Colorado Department
of
Public Health and Environment, and colleagues at
CDC.
I just wanted to show you some other
studies that are currently in progress on which
CDC is
collaborating.
As I mentioned, the Colorado case
control study, we hope to have some results from
that
by the summer.
There is also a cohort study being done
among children 6 to 23 months using Colorado HMO
database, which will look at ILI as an
outcome. In
addition, the vaccine safety datalink sites are
going
to be looking at vaccine effectiveness among 6 to
23‑month‑olds with outcome of
hospitalized
influenza‑like illness.
And in Georgia, a study is ongoing to look
at the effectiveness in children 6 months to 4
years
with laboratory‑confirmed influenza as
outpatients.
The new vaccine surveillance network in
Rochester, Cincinnati, and Vanderbilt will be
using
the case cohort method to look at vaccine
effectiveness for influenza, hospitalization, and
ED
and outpatient visits.
There is an ongoing study in Iowa among
college students, which is a cohort study to
estimate
effectiveness against influenza in outpatients.
Among all of these studies, one of the
issues has been for persons who are tested for
influenza.
What is the bias in terms of who gets
tested?
And are people being tested based on their
vaccination status.
The new vaccine surveillance network is an
active prospective surveillance system. And children
who come into that system who are enrolled, there
is
no bias in terms of their vaccination
status. So this
may provide us with one of the more accurate
estimates.
So our results, we feel, are compatible
with many prior studies and years with the
suboptimal
vaccine match, where low or no vaccine
effectiveness
against ILI can be demonstrated. However, there is
likely to be vaccine effectiveness against
laboratory‑confirmed influenza as our case
cohort
study suggests.
These studies also illustrate the
difficulty in estimating vaccine effectiveness in
retrospective studies.
Our resources should be devoted to annual
assessment of vaccine effectiveness and to the
vaccine's health impact. We hope to have a pediatric
assessment using the new vaccine surveillance
network.
And we would like to be able to use that system
for
yearly estimates in children.
I will stop there.
CHAIRMAN OVERTURF: Yes, Dr.
Myers?
DR. MYERS: Carolyn, I guess my
conclusion
is it is hard to do studies with vaccine
effectiveness
in the midst of the epidemic. So I think it is great
that the CDC is trying to do that.
On the first study, I am not so
troubled
by your using ILI in association with a lot of
clinical isolates of influenza as your endpoint,
but
I am troubled by the apples and oranges of the
groups
that you evaluated.
You showed a statistical likelihood for
people who are likely to be exposed to get
vaccine.
So the doctors and the nurses or people who had
patient contact were more likely to get the
vaccine.
So I would have liked to have seen and
maybe you have available of that subgroup looking
at
vaccine effectiveness for the people who had
patient
contact during that interval.
DR. BRIDGES: You know, we really
thought
a lot about asking questions about exposure, more
exposure, variables. But because there was so much
influenza circulating in the community, we
thought
that that was extremely difficult to do,
particularly
given that many people affected with influenza
may
shed virus but are clinically asymptomatic.
We did adjust in our analysis for patient
contact.
We adjusted for occupation in one analysis,
which I didn't present. And it didn't make any
difference.
We did a subgroup analysis.
Also, it
didn't make any difference in terms of being able
to
find vaccine effectiveness.
CHAIRMAN OVERTURF: Dr. Palese?
DR. PALESE: In terms of your
first study,
where influenza‑like illness is being used
as an
endpoint and there was no vaccine effectiveness
demonstrated, is it known what percentage the
Fujian
strain made up in terms of influenza activity?
In other words, what is the reason for the
ineffectiveness of the vaccine? Do we know that 80
percent was Fujian there? You said it was
predominantly Fujian, but do we know? Do we have
precise values in terms of how much Fujian was
and how
much H3 basically was occurring at the time in
that
location?
DR. BRIDGES: Very few isolates
were
antigenically characterized from Colorado by CDC.
They obviously characterized a huge number of
isolates
but relatively few isolates from every
state. Some of
those isolates have overworked Fujian. I think it is
very difficult to assess what the proportion of
H3N2
viruses in Colorado were Fujian based on the
small
number of isolates that were characterized.
DR. PHILLIPS: Wouldn't they be
interested
to know why the vaccine was not effective?
DR. BRIDGES: Nationally I think
Ann Moen
will present this. About 80 percent. Is that
right?
Seventy‑five or 80 percent of the H3N2
viruses were
Fujian‑like.
CHAIRMAN OVERTURF: Dr. Monto?
DR. MONTO: I want to
congratulate you all
for putting together the case cohort study in
Colorado.
I know how difficult it is in the midst of
an outbreak trying to identify the places where
you
can get useful data, which may have important
public
health impact.
I just want to recall that the multiple
studies that were put together during the period
when
HCFA questioned the use of influenza vaccine for
older
individuals, the 65‑plus, that there the
endpoint was
hospitalization for pneumonia, influenza
indications
in the course of an influenza season and not
laboratory‑confirmed influenza.
I would assume that many of your
confirmations here are in the more severe
individuals.
And controlling for confounding because we all
know
that the people with undermined conditions are
both
more likely to get vaccinated and more likely to
be
hospitalized, the effectiveness there was from 31
to
maybe 50‑55 percent, fairly wide.
And these were all non‑drifted
years. So
this really is not all that incompatible. You would
have a better endpoint here in terms of
laboratory
confirmation.
So it is all in the same ballpark and,
thus, suggests that there was some degree of
vaccine
effectiveness in the past year.
In terms of the other study, I want to ask
you a question and make a comment, namely since
the
outbreak was so abrupt and you have a fairly
large
population group, could you look at the peak
couple of
weeks of the outbreak in terms of the reported
illness
and also in terms of the ILI case definition?
We have done some studies which we are
going to be publishing suggesting that sore
throat
actually is a negative predictor in a febrile
individual of the isolation of an influenza
virus,
which suggests that it may be appropriate to
change
the very long used ILI case definition, but this
has
been present in two very large studies of
antivirals
in which laboratory confirmation was made before
treatment began.
Sore throat clearly predicts against
the presence of influenza virus.
DR. BRIDGES: Thanks, Arnold.
We also looked at analysis from just
November 15th on, which was more of the peak
week. We
didn't look at a two‑week interval, but we
did narrow
it down to about a four‑week interval and
still didn't
find effectiveness.
In addition, we looked at several other
outcomes that I didn't present today. One of those
was looking at a definition where persons had
fever
for three days, plus two or more respiratory
symptoms.
In addition, we looked at influenza
associated with loss of work, physician visits,
and we
also looked at days in bed to try and find a more
severe outcome.
And with none of those were we able
to demonstrate effectiveness.
CHAIRMAN OVERTURF: I will take
just two
more questions:
Dr. Karron and Dr. Goldberg.
MEMBER KARRON: Given information
that has
been available in the past about potential
increased
efficacy of live attenuated vaccine in children
against drifted strains, do you know of any
studies
that are currently being conducted, either
head‑to‑head comparisons to look this
year at the
efficacies or just live attenuated vaccine versus
non‑vaccinated children?
DR. BRIDGES: I don't know if
there is
someone from the manufacturers that could address
that
question, I think. I see Kathy Coelingh in the back.
Kathy Coelingh?
MS. COELINGH: I am Kathy
Coelingh from
MedImmune Vaccines. There are some ongoing studies
that are being conducted. None of those data will be
available for several months, head‑to‑head
comparisons
during the first year.
MEMBER KARRON: Did you do some
studies to
assess the effective coverage probabilities in
one of
these studies?
Did you look at different models to
try and assess the different levels of
non‑responsiveness in the different groups
and whether
you can model this out just to get an idea of
whether
that is what is causing the problem?
The definition problem you addressed in
several ways, but there is a whole other piece
about
what happened to the non‑responsiveness. You made
different classes of assumptions about them. Have you
done that?
MS. COELINGH: We haven't done
that, but
that is something that we easily can do.
CHAIRMAN OVERTURF: Carolyn, if
you could
just stay there?
I am going to have Col. Neville come
forward and go ahead and set up his
presentation. We
can take one more.
DR. DOWDLE: Thank you very
much. I will
congratulate you for some remarkable analysis in
a
very short period of time.
On the first study, in the 28 staff
members, as I recall, that reported being tested
for
influenza, which was considerably less than the
percentage among the patients, if I recall
correctly,
the question is, did you go further, do any
further
analysis, of those who had reported influenza‑like
illness and were tested?
By the way, was this serology?
Was this
isolation?
DR. BRIDGES: These were all
rapid tests.
As far as we know, it is anecdotal. We didn't ask
people to specifically to antidote. The hospital
epidemiologists and laboratories were testing
some of
the staff in the lab. And also physically they used
the staff for the advantage of testing.
We did look to see if we could find
something very different in terms of the vaccine
effectiveness point estimate among those 20
people.
And in looking at that, we have estimates of
zero,
point estimates.
DR. DOWDLE: Thank you.
CHAIRMAN OVERTURF: You get the
last
question.
MEMBER DECKER: And a couple of
segues, I
think.
First, I don't find your presentation and the
handouts.
Will it be made available to the Committee?
DR. BRIDGES: The case cohort,
the
information on the health care workers study was
published in the MMWR. And that is in the handout.
MEMBER DECKER: Right. The other one.
DR. BRIDGES: The other one is
very
preliminary.
So at some point, when we have more
analysis, we will be able to provide that.
MEMBER DECKER: All right. And the second
question is, if I understood your table
correctly, the
first availability of the data that looks at
hospitalization or mortality is by vaccination
status,
which I think is the real outcome of interest
because
I think that is why the country hires the
vaccines, to
prevent hospitalization and death and not
influenza‑like illness.
The first data on that will be available
at the end of this year at the sites? Is that right?
DR. BRIDGES: Right. The NVSN sites, we
want to have some data, hopefully by the end of
the
year. For
the case control data, because we have such
a high proportion of those persons who were
hospitalized, maybe also we are able to look at
hospitalization outcomes for the 50 to 64‑year‑olds.
CHAIRMAN OVERTURF: I think we
will
proceed at this time. Thank you very much.
Dr. Neville is going to make a
presentation from DOD.
COL. NEVILLE: Thank you very
much. I
appreciate the invitation.
I am here because the Air Force is the
executive agency in the DOD for influenza
surveillance.
And the Air Force has been conducting
systematic influenza surveillance since the late
1970s. In
1999, it became the DOD program.
My organization is the Air Force Institute
for Operational Health, Brooks City, based in San
Antonio.
We collaborate with the Naval Health
Research Center you see here in San Diego. In
addition the Army, this here, you will see in a
minute
conducts clinical and virology services at the
medical
centers.
And the DOD oversees labs participating in
febrile respiratory illness projects.
The overall program is conducted under the
auspices and guidance of the DOD global emerging
infections surveillance and response system, or
DOD‑GEIS.
Later you will hear from Linda Canas this
afternoon, who will present her annual summary of
the
data from the DOD lab‑based surveillance
program. I
won't present her data here, but, rather, my
intention
is to describe other aspects of the DOD's
involvement
in influenza surveillance with an emphasis on
tests to
meet vaccine effectiveness, which, of course,
received
attention this year.
DOD typically does not conduct influenza
vaccine effectiveness research, although this
year
several efforts were made, as I will describe.
I will briefly overview the surveillance
programs that exist in the DOD and describe some
of
the data that was available for estimating
vaccine
effectiveness.
Those include a Navy estimate, an Army
estimate, and Air Force estimate. These are the three
that I am aware of in DOD.
All three medical services and also the
Coast Guard contributed to influenza surveillance
in
the Department of Defense. The Air Force program is
laboratory‑based, radiology‑focused,
its main purpose
being the collection of respiratory pathogens
from
military populations around the world that are
considered good sentinel sites. Don't worry about the
map details here. You will see it again this
afternoon from Linda Canas.
Selection factors for several sites
include overseas location, major ports of entry,
and
the history of participation in the program. There
are 27 sites from all 3 services and the Coast
Guard.
In addition, the overseas laboratory
network supplies specimens from various countries
where those programs are active. Some of the overseas
labs sends isolates to us in San Diego. Some of them
process their own or ship to the regional health
organization labs.
AFIOH in San Antonio has the only
full‑service clinical virology laboratory
in the Air
Force.
The Navy's febrile respiratory illness
surveillance program is managed by the Naval
Health
Research Center.
It focuses on eight military
training centers.
On‑site investigators at FRI visits,
febrile respiratory illness visits, they all take
the
denominator data and collect specimens of
systematically health care‑seeking trainees
who meet
an FRI case definition, which is a temperature
greater
than 100.4 and a cough or a sore throat. we may have
to change that maybe. We will see.
Since these trainee populations are
well‑characterized and monitored, attack
rates can be
established with a high degree of
confidence. NHRC
has the name "Respiratory Virology
Lab."
U.S. Army has six regional medical
centers, each with clinical diagnostic virology
capability.
While there is no systematic influenza
surveillance program per se in the Army, clinical
results are characterized as needed. And local and
regional preventative medicine staff track FRI
rates
and etiologies as needed.
Special operating investigations also are
conducted as needed, more of which I will
describe
briefly here in a minute. I should mention that all
three services have agreements or a plan in place
for
sharing laboratory services in situations where
demand
outstrips capacity, such as how major febrile
respiratory illness operates.
I will briefly describe some of the
relevant data sources that have been identified
from
the DOD.
Certainly these are not all unique data
sources, but in the context of an urgent public
health
effort to estimate the effectiveness of the
vaccine in
the face of this nationally occurring disease,
these
are the data sources that we used both to monitor
disease activity and to attempt the evaluation of
vaccine effectiveness.
The first is the local public health
officer reports, which is a surprising part of
the
report.
The primary responsibility for response and
monitoring rests at the local level in DOD. Reports
include routine reports of reportable diseases
and
evidence of unusual patterns of disease or
outbreaks
which might require special responses or
assistance.
Our medical surveillance currently takes
advantage of data collection systems, largely not
designed specifically for surveillance
activities.
Among this existing data sources is familiar IC‑9
coding for ambulatory visits.
Many of you may be familiar with the
electronic surveillance system for the early
notification of community‑based epidemics,
or ESSENCE,
which monitors ambulatory visits at every DOD
health
care facility.
These data can be manipulated or used in
several ways.
Here this chart may be hard to see.
This data accumulates all of the Pacific Rim DOD
medical care facilities and the percent of visits
for
ILI, influenza‑like illness, which is
comprised of
about 30 different codes, IC‑9 codes, that
make this
ILI family.
So this can be monitored on a daily
basis.
Facility‑specific data can also be
monitored.
And a similar approach is used to monitor
diseases and non‑battle injuries for
deployed
locations.
Data collection at those locations is
often more lacking for a variety of reasons.
Laboratory specimens, submissions, and the
results can also be used to identify surges in
activity generally or at specific sites. This is an
example from last year where an outbreak occurred
in
the Tidewater region of Virginia. Percent of total
commissions gives a good indication of pathogen
activity as well as illness occurrence. This is
similar to data displayed by CDC.
Officers. This tracks
vaccination
delivery.
These here just show the Air Force's data
because that is what it was most able to meet.
Annual influenza vaccination is mandatory
for military members, barring contraindications,
of
course.
High vaccination rates are achieved fairly
quickly.
Again, this may be a little difficult to
see from the back reading from the handouts. Eighty
percent coverage was achieved by the 2nd of
December
in this past year, 2003 and by the 6th of
December,
2002.
Because influenza vaccination is mandatory
and it is a command program, it is not a medical
service program, it is a commend program,
analyzing
vaccine effectiveness among active duty personnel
during this time period would be a fairly complex
undertaking.
Because such a small portion of service
members remain unvaccinated comparing attack
rates
between vaccinated and unvaccinated groups is not
very
efficient.
Now to the vaccine effectiveness data.
First, the Navy's. As I described earlier, the Naval
Health Research Center in San Diego monitors FRI
illness, febrile respiratory illness, on basic
trainees of all three services. They have used
existing data here to estimate influenza vaccine
effectiveness.
Their calculation is based on data for
four representative centers, training bases: Fort
Leonardwood, Fort Jackson, Marine Corps Recruit
Depot
in San Diego, and Lackland Air Force Base in
Texas.
For the month of December 2003,
influenza‑specific attack rates were
calculated based
on culture‑proven influenza cases
identified in the
ongoing surveillance program.
All trainees are routinely vaccinated upon
arrival of basic training, especially during this
time, the early fall. For this analysis, they were
considered unvaccinated or non‑immune for
the first
two weeks after vaccination. So for an 8‑week
training course, for example, 75 percent of the
person‑time, they are considered immune or
vaccinated.
So just to display the data that NHRC
worked with, these numbers are for their overall
surveillance program, not just for the sites that
they
focused on.
Only influenza A has been identified so
far this season as a ton of data, which was about
a
week and a half ago. All of the isolates that they
sequenced were of the Fujian strain.
The dark red segments are influenza
isolates from trainees who had been vaccinated at
least two weeks prior to the onset of
illness. As you
can see, the number of influenza cases is
dreadfully
small, but there were no isolates segmented away.
This is the size of the calculation.
Because of the specific calculations they are
showing,
viewing the vaccine effectiveness estimate of 9.9
percent, it is basic trainees. These data are not yet
published.
I don't have other parameters, like age
ranges and gender and so forth, at this time.
The Army's Fort Lee is an Army post,
design post, in southeast of Richmond,
Virginia. It
is home of the Army's quartermaster center and
school.
It is not a basic training base, but it is a
basic.
And that is specialty training.
At any one time, there are a little over
3,000 students present. And courses at that school
are of varying length, from 4 to 12 weeks. Students
arrive weekly for different courses. They are
organized into companies of 200 or so
trainees. They
are housed in dormitory rooms of three to four
people
each. And
so it is a fairly complex model of exposure
in populations at risk.
An influenza outbreak began on the 31st of
October to find out it was in the students and
staff
of the 23rd quartermaster brigade, which was a
training.
Also, that epidemic occurred here.
So the
31st of October, that is when that outbreak
began.
Massive vaccination campaign began.
EPICON is the term for epidemiology
consulting team, the Army's Center for Health
Promotion.
So the next outside team came and did some
work here.
A team came back later in December to get
more information to try to evaluate this vaccine
effectiveness.
Fort Lee had just done their routine
annual influenza immunization campaign. And few were
immunized when the outbreak started. So the medical
personnel on the post responded with a rigorous
case
isolation protocol and mass immunization campaign
that
reportedly reached about 95 percent of the target
population, which in this case is the trainees.
Data for two different cohorts were
analyzed, primarily based on data
availability. One
cohort arrived early November, and the other
cohort
arrived later in November. These two different case
definitions now that we see, in a minute we will
see
four different analyses.
There are two case definitions.
The loose
case definition and any ILI‑related IC‑9
code, a
visit, a health care visit, with a diagnosis of
an ILI
code, and also a tight case definition that
documented
febrile illness with sore throat or cough or
lab‑confirmed influenza infection.
There are few limitations here for us.
One of those is that it occurred right after an
epidemic, an influenza epidemic, in that training
post, which means that the threat of a subsequent
outbreak may have been modified somewhat by the
population on the study, being surrounded by
people
who had achieved the natural immunity grasp.
So two different cohorts are listed,
population size for each, 67 and 463 there. The
vaccine effectiveness point estimates range from
40.5
to 100.
And here there were no cases among the group
considered to be immune. Obviously those confidence
intervals are pretty well. And we put zero. So it's
hard to reach any conclusions of effectiveness
evaluation.
Now, the Air Force is here. The
Services
Branch of AFIOH has a retrospective force underway
using telephone surveys to collect data on
household
contacts of influenza‑infected index
cases. They
identify influenza‑exposed cohort by
identifying index
cases, who are persons whose cultures have tested
positive for influenza in our own lab.
We included only Air Force personnel for
simplicity and excluded persons from the Air
Force
Academy and those who are deployed, in deployed
locations, because our real target is household
members.
We contacted the sponsor of each positive
culture, which may be the person with the culture
or
in post housing, and sought voluntary
participation in
the survey and took some surveillance within two
weeks
of the index case as well as vaccination status.
The secondary attack rate among vaccinated
and unvaccinated is used to estimate vaccine
effectiveness or is being used to estimate
vaccine
effectiveness.
There are almost 2,500 specimens in our
lab this year as of a couple of weeks ago. Of those,
859 were positive for influenza. And of those, 114
were considered eligible for this. Among those
eligible, there should be about 400 family
members of
those.
So as of February 12th, last Thursday, we
had collected data on 219 of these family
members.
And the preliminary estimate of vaccine
effectiveness
is 40.1 percent.
We feel this could be a greatly
recurring annual study because it is relatively
efficient to do.
Plan B, we would like to do the same study
with a little more effort to validate some of hte
data, like looking at medical records, linking
the Air
Force's immunization tracking, electronic
tracking,
system to validate vaccine delivery and so on.
So, to summarize, NHRC had a vaccine
effectiveness of 91 percent. CHPPM's vaccine
effectiveness was 40.1 percent, although our
concern
was pretty wide.
It included zero. Our vaccine
point
estimate in the Air Force was preliminary point
estimate is 40 percent, but that it gave us
collections that were none.
With that, I will be happy to answer any
questions.
CHAIRMAN OVERTURF: You didn't
mention,
out of those 240 isolates, what the type was.
COL. NEVILLE: Every isolate we
got was an
A, an influenza A. And every one that we have
sequenced is consistent with Fujian strain. I don't
know that we sequenced, but it might be something
like
20‑30 percent.
CHAIRMAN OVERTURF: Are there any
more
questions?
DR. MYERS: I missed it, the NHRC
Fujian
portion.
COL. NEVILLE: Every one that
they
sequenced as well as those after the first
isolate
that they sequenced ‑‑
PARTICIPANT: They have sequenced
about 20
percent, sir.
COL. NEVILLE: Pardon me?
PARTICIPANT: They sequenced
about 20
percent.
COL. NEVILLE: About 20 percent.
DR. GELLIN: Can you comment
about the
regularly recurring annual study?
COL. NEVILLE: Well, competing
interests,
I suppose, supplies and manpower and stuff like
that.
We were able to achieve pretty rapid IRB
permission to
do this next year. It's on the chart. We
will do it
again.
And it is relatively easy and cheap.
But there is another operator, another war
somewhere and competing priorities, then
yes. We plan
to, sir.
CHAIRMAN OVERTURF: Dr. LaRussa?
MEMBER LaRUSSA: Would you just
remind me?
The Air Force study, was it everyone who had the
influenza culture?
COL. NEVILLE: The sampling is
designed
primarily for collecting pathogens. So not every
person who shows up at a clinic, even if the
symptoms
are right, is sampled. It's just the clinician in the
local public health system.
We try to get them to send us six a week,
but that is the target. So if they have not much
disease, they don't get that many out of
these. And
we may get a lot more than that.
So I don't know what portion of people
presenting to a clinic with febrile respiratory
illness is sampled. It is variable.
CHAIRMAN OVERTURF: Any other
questions?
(No response.)
CHAIRMAN OVERTURF: We are on
time. We
will hear the INSERM presentation.
DR. FLAHAULT: Ladies and
gentlemen, first
of all, I would like to thank the adviser very
much
for inviting me to present this work. This work is
followed by INSERM in France, which is the
national
institute, the French NIH, I will say, and by the
Universite Pierre et Marie Curie, which is a
university of Paris.
Of course, I will not come back too long
to the strain selection for the influenza
vaccine,
just to say that in Europe, that was, of course,
the
same recommendation. And vaccine which was not
created in Europe also used Panama strain, rather
than
the Moscow, and used several other strains of the
B
virus for the epidemic current season. Eventually it
is a main circulating strain. As you say, it was also
in Europe, the Fujian strain.
So it is a question of which of those is
during, at the beginning of the epidemic, and not
after the epidemic was, how effective was the
vaccine
against clinical disease? So it was nearly impossible
to try to provide some answer due to certain
difficulties but also to measure it for sure
during
that time in Europe as well as in the U.S.A.
Also in Europe, we had a very early
epidemic.
It was just above the man, the average,
epidemic, but as an early epidemic, it was not so
easy
to determine.
The question you had in the previous talk
was about the particular rates you found in your
revised studies and also in the comprehensive
review,
which was done by Roland at the first talk.
So what is an appropriate protective rate
is difficult to answer. It has been proposed by the
weekly epidemiological record of the WHO that
against
ILI, clinical disease, at least, that should be
between 15 and 80 vaccines.
How can we measure vaccine effectiveness
in the flu season? We have seen several methods also,
of course, particular efficacy, which is mainly
used
for trial vaccines. And the clinical effectiveness is
usually observed by the so‑called screening
methods in
the cohorts that are the case controls and the
case
cohorts and all of these kinds of models, which,
in
fact, try to compare attack rates in vaccinated
versus
unvaccinated.
The vaccine effectiveness with the
so‑called screening methods is this
formula, which is
1 minus the ratio of attack rate in vaccinated
population and of the attack rate in unvaccinated
population.
To assess vaccine effectiveness in real
time in France, we used the screening methods
because
they are efficient, because cases are drawn from
our
sentinel system, which is a very clinic
surveillance
system, which provides some figures in real time
or
close to a real‑time basis. I say "closely" because
we have all of the consolidated figures each
week.
We chose the controls of the cohort from
a regular poll which had been collected by the
French
Social Security using a private company
specializing
in these kinds of polls for studying and
estimating
the vaccine coverage in France for years.
It had been set up in our communities 20
years ago in November '84. It continues on the clinic
surveillance of 12 conditions: ID, of course, but
also acute diarrhea, measles, mumps, chicken pox,
spinal meningitis, viral hepatitis, and also
other
infectious conditions, such as asthma.
It can hold a network of 1,200 sentinel
GPs, which are virtually unpaid and all private
practitioners, as they provide information on a
numbering basis.
As I told you, we have re‑created a
ton of information which is widely available on
the
internet, including the vaccine effectiveness.
So cases are ILI reporting ID cases, which
are only clinical cases with high fever and
myalgia,
upper respiratory symptoms, as you
mentioned. What is
at work is in each case is individually described
with
the age in year, either in months for children;
gender; vaccine status. That is the trademark, only
the vaccine or not, during the preceding four;
and
also hospitalization, the case of and with many
details of hospitalization, such as condition
dates
and so on, in the case of. It is a mix for France.
Controls. As I told you, we
conducted a
poll, which has been done annually for estimating
in
terms of vaccine compliance. This is a national
survey.
It was a representative sample of the French
population.
We obtained data until ten years ago
conducted by a private organization.
As I told you, we have to make
assumptions.
These are the figures which were 65
years or less, between 60 persons and 70 persons
now.
Of course, we did not have the level of the
cooperation of the current season. So we assume it
was constant, it was the same as the year before.
For the others, the illness in 50 and 64,
there is a rate of conditions being low in
France. It
is assumed to be 11 percent for the current
season as
it was for the preceding season.
This slide is just to show you some
existing tools for monitoring that we have in
France.
We have an early warning system based on
accepting
what it takes to detect epidemic in time and to
measure the excess morbidity of influenza.
Also, we have a set of predictors.
The
size of influenza epidemics prior to its
occurrence
has been presented in our application 5. It predicted
fairly well the level of influenza activity in
last
September for the current system. We predicted a
sweep on two million cases. And eventually the size
was Sweden in person‑time, which is a
country of 16
million persons.
We also have set up a forecasting
time‑space dynamic of influenza epidemics
broadcasted
on French TV, which was for broadcasting three
weeks
ahead the times of influenza. These maps are
broadcast on the French TV each week now during
the
epidemic, of course. It was actually this content in
France.
As I told you, we have now set up a field
vaccine effectiveness, which is run for years for
measles.
It has been published in 1993 and which is
on the routine basis since 1998 in France for
influenza and clinical disease. We also have some
maps showing the current evolution of the
epidemic
week after week in the country.
So the available material for influenza
effectiveness assessment is to have this
contingency
table for each age strata and each age group
strata.
We need to have the number of vaccinated ID
cases,
vaccinated ID cases, and say which coverage in
the age
strata.
In fact, we did not choose the screening
methods as it was presented because it is too
simplistic.
If we want to adjust an age group, we
need to use this for vaccine efficacy which has
been
proposed by Greenland in statistics medicine in
'86
and which also is used to compute the 95
confidence
interval, which is very easy to meet demands in
our
system.
The results of these measures, the ongoing
measurements, are this one. You have here the figure
of this year, which is vaccine
efficacy/effectiveness
of 60 percent, which computes along with the
score to
77.
Of course, the confidence interval may be
large.
And if the point estimate, the confidence
interval, which is very important, which was very
important to our public health authority, is to
see
that in 2003‑2004, the level of vaccine
effectiveness
was pretty similar to that of the other years
with the
exception of the year '97‑'98 where when
the H3N2
Sydney strain was circulating and it was very
well‑known that this strain was not
included in the
vaccine and the vaccine was clearly not
protective
against this strain and the vaccine effectiveness
using the same methods was 26 persons developed,
13 to
39.
We presented this measure on the first
week of the epidemic. And we completed this series
during the whole epidemic using two relative
figures,
but it did not vary a lot. Of course, the confidence
interval was much larger at the beginning of the
epidemic, but the vaccine effectiveness was about
the
same.
We put all of the data each week on the
Web site, which is now available also
available. Many
things are in French. We have set up for WHO since we
have been designated five years or six years ago
as a
collaborating center for epidemic disease
surveillance.
We have set up for them the FluNet
System, which is still based in Paris, our unit,
but
we put the move, really, in 2004 for Geneva. It was
set up in 1997 trying to connect all of the
network of
412 centers and also the center between WHO,
which was
very important.
Because of that, it is possible to have
some very interesting findings. The first thing is
that there are similar patterns in the Northern
Hemisphere in terms of morbidity. It really begins in
the U.S. early.
It begins also in Europe very early.
The duration of epidemics was the same in '98 and
'99
presenting the figures, but also for the four
following winters.
The virus circulation with the FluNet,
which is reported in FluNet, you can see that in
the
Southern Hemisphere, not for Hong Kong, which is
more
a subtropical area, but in the temperate zone of
the
Southern Hemisphere, you have a very good
coherence of
time occurrence of isolates reported in the
hemisphere.
Of course, in the Southern Hemisphere,
there is a lag of six months, which is also very,
very
good evidence.
We have tried to study the mortality in
France, in the U.S., and in Australia. We have seen
that the average duration of activity with the
same
kind of model organization using a periodic
regression
model for estimating the size of epidemics to
show
that the average is really very, very similar in
France and in the U.S. It is a little shorter in
Australia.
Excess mortality is highly correlated
between France.
So we can say between Europe and the
U.S. It
is not correlated between the South and the
North Hemisphere as in Europe or in the U.S. The
correlation between France and hte U.S. was open
to 60
to 66.
To understand if the peak is happening
here the same date in France and in the U.S. and
also
in Australia, we can see this is a way to get the
analysis.
We show very, very high coincidence in the
phase of rapidity.
And we can see also a high correlation
between the peak date in the U.S. and the peak
date in
France, showing that the peak occurred at the
same
time in both countries. So we see a peak between the
U.S. and France in the last 20 years. It was opened
five weeks, so very, very short.
There is a strong coherence in Northern
Hemisphere, the temperate zone at least. It may
suggest the starting date, date of peak, duration
of
influenza epidemic are similar in the U.S. and
Europe.
Also size and severity of influenza incidence are
proportionally similar in the U.S. and as for
Europe.
So we can probably assume that virus circulation
and
probably also vaccine effectiveness among
clinical
disease as we see in France is probably
similar. And
this is going to be around 60 persons in the U.S.
as
well as Europe.
That was around 60 persons using the
method reviews, the general practitioners, the
clinical nurse, and so on.
So I want to take this opportunity to
thank all of my team, which worked with us on
this
thing.
Tank you very much for your attention.
(Applause.)
CHAIRMAN OVERTURF: Are there any
questions?
Yes, Michael?
MEMBER DECKER: I just wanted the
same
question I had for Dr. Bridges. Will you make a copy
of your presentation? Will it be available?
DR. FLAHAULT: Yes, of
course. I just did
not provide that. In fact, I was a little embarrassed
because we wanted to publish the material. And we
know that FDA will publish it on the Web
site. So we
will wait for the presentation to provide all of
the
figures and charts with that.
CHAIRMAN OVERTURF: Dr. Farley?
MEMBER FARLEY: Yes. I am wondering what
predicts an early onset of a flu season.
DR. FLAHAULT: In fact, we did
not try to
predict.
We did not include that in our predictions.
So we only predicted the size in terms of
morbidity
and mortality of the epidemic in France.
We did not predict the onset. We
only
predict the onset with the other model, which has
been
very recently published in the American Journal
of
Epidemiology by Cecile Viboud, a nurse, which is
predictions three weeks ahead. So that is providing
a very big warning for the beginning. And after we
predict three weeks.
CHAIRMAN OVERTURF: Yes, Dr.
Monto?
DR. MONTO: I think your studies
show the
idea of long‑term ability to study
influenza vaccine
effectiveness from year to year because then you
really can put what you observe into context.
What I would like to ask you about is the
variation in peak time in influenza incidence in
various countries in Europe. I had better be careful
what I say.
France is a relatively small country.
And the peak occurs over a reasonably short time
period in the entire country.
I understand there were different times,
just as there were different times of peak occurrence
in Europe.
And we have the same situation in the
United States.
How well does your model predict
occurrence of peaks in western and central
Europe, for
example?
DR. FLAHAULT: It is not so easy
to have
precise data and available data on that. In fact, we
felt that the distribution of the peak was much
wider
than it was, effectively, either in France,
within
France.
We used to say that the peak was moving from
a region to another one. The reasons were so that, in
fact, there is a good coincidence everything is
done
within ten weeks.
So ten weeks may be not exactly
coincident, but all activity is done in ten
weeks.
And all of the peaks are done within three weeks,
so
very, very short. So within Europe, we need to have
the same kind of system or at least the same
kind, not
the same system but to know what we know, if
anything,
about the peak.
And in terms of mortality data, when we
have them, we can say that the peak of mortality
is
really, really coincidental. And so I don't know what
is your experience in the United States between
the
states of the United States, but I am not so sure
it
is a very wide distribution of peak in your
country,
too.
CHAIRMAN OVERTURF: I assume that
the
reason for no breakdown in the age group from 15
to 60
or 65 is because there is no recommendation for
vaccine routinely to be given. I assume that the
rates of immunization in 50‑year‑olds
is the same as
it is in 15‑year‑olds, which is 10
percent. Is that
true or not?
DR. FLAHAULT: Yes, not completely true
but approximately true. That is right. In France,
it
is free of charge to be immunized after 65 and
plus,
and it is not reimbursed before. It is not completely
exact because in several companies, you may have
free
of charge vaccination. And because of that, in the
same age group, in some particular situation, you
may
have some higher figures, but in children at
least,
the figure ‑‑ not in children. It is very low, but
between 15 and 30 is very low, too.
CHAIRMAN OVERTURF: There are no
European
countries that are considering immunization of
children that you know?
DR. FLAHAULT: All of us are
considering
immunization of children, but we are still
waiting for
the product, which is still not yet marketed,
also to
have some recommendation of regulatory authority
with
work on that in the future, we are sure.
CHAIRMAN OVERTURF: Dr. Gellin?
DR. GELLIN: We are enlightened
by this
series of vaccine‑effective studies. Do you or does
anybody know if there are similar studies in the
Southern Hemisphere?
DR. FLAHAULT: I am sorry. Can you repeat
that?
DR. GELLIN: Does anyone know if
there are
vaccine‑effectiveness studies in the
Southern
Hemisphere?
DR. FLAHAULT: No, I am not aware
of that.
CHAIRMAN OVERTURF: Yes, Dr.
LaRussa?
MEMBER LaRUSSA: Do you plan to
have any
data on the importance of influenza‑like
illness in
children?
DR. FLAHAULT: We collect
influenza‑like
illness in children. In France, general practitioners
are taking main charge of the presence of the
children
in terms of immunization, in terms of like
illness.
So we have these down. They are not immunized at all.
So we did not compute any vaccine
effectiveness. So
the measurement of the coverage, vaccine
coverage,
only concerns age 15‑plus.
CHAIRMAN OVERTURF: Any further
questions?
(No response.)
CHAIRMAN OVERTURF: Well, I would
like to
thank all of the presenters thus far. We have a
little extra time for a break. We are to be back here
by 11:30.
And we will hear about U.S. surveillance.
(Whereupon, the foregoing matter went off
the record at 11:15 a.m. and went back on
the record at 11:36 a.m.)
CHAIRMAN OVERTURF: Ann Moen is
going to
present the data on the U.S. influenza
surveillance.
U.S. SURVEILLANCE
MS. MOEN: Good morning. I am going to
spend about the next 20 minutes giving you an
overview
of the U.S. influenza surveillance data for the
current 2003‑2004 season.
This first slide depicts the general
schematic of the U.S. influenza surveillance
season
and the major components of that under which CDC
collects data on a weekly basis from October to
May
each year.
There are four major components that we
collect data on weekly. The first is virologic data,
which we collect from the system of laboratories
in
all 50 states.
And then there are sentinel providers
that we collect influenza‑like illness on
throughout
the 50 states.
That is data reported weekly to CDC.
Each week, the state and territorial
epidemiologists in each state report to CDC the
level
of influenza activity in their state based on
defined
criteria.
And then the 122 cities' mortality system
we receive vital statistics, registrars' reports
to
CDC on a weekly basis, reporting influenza
mortality
due to P and I.
There are some other various forms of data
that come in sporadically, such as institutional
outbreaks and sometimes cruise ships. This year we
had some extra data we collected on pediatric
mortality, which I will talk about later.
All of this information flows into CDC
through the state health departments. And we work
very closely with our partners in the
states. Then
the data is analyzed weekly at CDC and then
published
in reports that go back out to public health
officials, physicians, the medics, and the
public.
This slide shows the virologic data that
is collected through the WHO and national
respiratory
and enteric virus surveillance system
collaborating
laboratories.
There are approximately 120
laboratories throughout the United States that
collect
virologic data.
They report to us weekly the number
of respiratory specimens that they tested and the
percent that were positive for influenza.
This graph shows just the positive
samples, and the yellow bar shows the influenza A
viruses, which were unsubtyped. And that smaller
subset, which were subtyped, the influenza
A(H3N2)
viruses, are shown in red. There is a smattering of
B viruses down here, just a small handful, shown
in
green that you may or may not be able to
see. And
then the blue line shows the percent of overall
respiratory specimens that tested positive for
influenza.
To give you an idea of the magnitude of
the data collected through that system, of the
viruses, the total specimens tested by the WHO in
NREVSS laboratories in the U.S. for the week
ending
February 7th, there were over 92,000 respiratory
specimens tested for influenza. And of these, 22,419
were positive for flu.
All of the laboratories in this
surveillance system type the influenza
viruses. Of
those positive for influenza, 22,286, or 99.4
percent,
were influenza A viruses. And then there was a small
handful of influenza B viruses, just 133.
Now, a smaller subset of these 120 or so
labs also do subtyping of influenza viruses. And of
the 22,000‑some viruses positive for
influenza A,
5,862 were subtyped. Of those, 99.9 percent were
influenza A, H3N2, viruses with just one
influenza A,
H1 virus, which was detected from a military base
in
Virginia, I believe, and was probably associated
with
travel.
So of all of these viruses collected
through this system, a subset is sent to CDC for
further characterization. This afternoon, you will
hear about the antigenic and genetic
characterization
in detail.
In reference to an earlier question about
the percentage of Fujian‑like viruses, I
believe for
the week ending February 7th, approximately 82
percent
of them were antigenically similar to Fujian
viruses.
And 18 percent were Panama‑like. You will hear those
details later.
So this slide shows the percentage of
estimates testing positive for influenza. The red
line shows this year's data. You can see that it
peaked at about 36 percent positive around week
51‑52.
For comparison here, I have shown the data
from the 1999‑2000 season in green, which
is the most
recent moderately severe influenza AH2 H3N2
season
that we have had. And then, for further comparison,
the purple line shows the percent of positive
specimens tested through this system of labs for
the
2002‑2003 season.
What this slide does a very good job of
showing is that the season did come earlier this
year
and started very early and peaked earlier than
most of
the previous seasons. The 1999‑2000 season was
considered early at the time. And this season was
even earlier than that.
This slide showed the percentage of visits
for influenza‑like illness reported by
sentinel
providers through our national system of sentinel
providers.
Each week, a series of sentinel providers
in the U.S. report the total number of patients
seen
in their practice and then the total number of
patient
visits for influenza‑like illness using a
case
definition of fever of greater than or equal to
100
and cough or sore throat with no other known
cause of
illness.
The smooth white line across the center at
2.5 percent is a national baseline. And you can see
that this season that started early peaked around
eight percent.
And it has currently come back down
under the baseline. We are currently at the end of
last week around 1.5 percent.
Again, for comparison, the 1999
season‑2000 season is shown in green. And then the
much milder season that we had last year is shown
in
purple, where there wasn't that much time spent
above
the national baseline.
Just to give you an idea of the numbers of
sentinel physicians in this program, we currently
have
1,931 sentinel providers that are enrolled in
this
program.
And they voluntarily report this information
to CDC on a weekly basis. Of the providers enrolled
in this program this year, 1,141 of them have
been
regularly reporting so far, which is considered
reporting more than half of the weeks.
From these sentinel physicians, we
received almost 20,000 reports to the end of last
week, which was for over 5 and a half million
patient
visits.
And of these, about 170,000 of them were for
reports of influenza‑like illness.
This slide shows the third major component
of the influenza surveillance data collected at
CDC.
It represents the pneumonia and influenza
mortality
data for the 122 cities. Each week the vital
registrars in the 122 cities report the total
number
of death certificates filed and then the number
of
death certificates that have either pneumonia or
influenza listed somewhere on them so that we can
get
a percentage of deaths due to P and I.
This data represents about a third of the
mortality data for the U.S. The 122 cities represent
about a third of all deaths in the U.S. On this
slide, you can see the bottom smooth line is the
seasonal baseline that is calculated using a
mathematical modeling method. And the upper smooth
line is the epidemic threshold, which is 1.645
standard deviations above the seasonal
baseline. Then
the red jagged line shows the influenza mortality
due
to pneumonia and influenza.
You can see for the current season that we
have peaked at about 10.3 percent and just for
the
week ending 2‑7 came down to about 8.7
percent is
still above the epidemic threshold. Any time the red
line crosses the epidemic threshold, then we
consider
that there is excess death due to influenza and
pneumonia.
For comparison on this graph, you can also
see last season, which was much milder and barely
up
above the epidemic threshold. Then you can also see
the 1999‑2000 H3N2 season, which peaked at
11.2
percent over here. So it would sort of show that this
season wasn't greater in magnitude in terms of
mortality than previous H3N2 seasons.
This slide shows the fourth major
component of our influenza surveillance system,
where
we have received weekly influenza activity
estimates
reported, as assessed and reported, by state and
territorial epidemiologists.
The white color shows no report.
The
yellow color is no activity. Green represents
sporadic activity. Purple or the light purple
represents local activity. Blue is the regional. And
red represents widespread.
This is the very first week that we have
started reporting data for this season. And you can
see that already in Texas, local activity was
being
shown.
The next series of slides is going to take
you on a quick trip through the weekly reports as
reported and assessed by the state and
territorial
epidemiologists.
You will see how the season
progressed.
By the middle of November, there was quite
a bit of activity reported, especially in the
western
half of the United States. And by the beginning of
December, there was widespread, lots of influenza
activity throughout the United States, where we
peaked
about the middle of December or towards the end
of
December.
Then you can see the activity continued to
decline, and there is still as of the week ending
February 7th some activity or relatively a bit
more
activity in the East, where the outbreaks and the
epidemics started just a bit later.
This year we made some changes in the
activity reports from the state and territorial
epidemiologists.
In previous years, the activity
levels were assessed at four levels: none, sporadic,
regional, or widespread. These were based on a
percentage of the population and counties. And then
the criteria used was either outbreaks of
culture‑confirmed influenza or influenza‑like
illness.
In response to some comments from states,
we worked closely with our partners in the states
to
make the criteria by which reporting was done
more
defined so that it could be more uniform from
state to
state.
So for this current year, five levels of
activity reported: none, sporadic, local, regional,
or widespread.
And this was based on state‑defined
regions within the states. The defined criteria used
a combination of influenza‑like illness and
outbreaks
and laboratory data. There were specified time frames
for which the lab confirmation needed to take
place,
though hopefully we will be able to assess this
at the
end of the season and see if states are happier
with
this local new definition for providing activity
reports.
So, just to take you back to the peak
week, though, for the week ending December 20th,
351,
there were 49 states reporting either regional or
widespread activity in contrast to the previous
1999‑2000 H3N2 season, when there were 45
states
reporting either regional or widespread activity.
You can see that that season peaked about
three and a half weeks later than the current
season.
This is in contrast to last year, where at the
peak of
the epidemic, there were 34 states reporting
regional
or widespread activity. And that peaked at the
beginning of March.
I also want to spend a couple of minutes
talking about influenza‑associated death
among
children less than 18 years of age. Because of the
early attention that pediatric mortality
received, CDC
requested reports of influenza death in children
by
sending out health alert networks, publishing in
the
MMWR and Epi‑X.
As of the end of last week, we had 134
influenza‑associated deaths that were lab‑confirmed
reported to CDC.
The median age was 3.36 years with
the range of 2 weeks to 17 years.
Of these, 82 children were less than 5
years of age, 36 children were 6 to 23 months of
age.
And of the 134 children, 32 of these children had
underlying medical conditions.
Of the available vaccination
histories, it
is shown that 76 children were unvaccinated, 38
had
missing or unknown vaccination histories, 20 had
some
sort of vaccination, but only 3 of these were
vaccinated according to the recommendations. It was
pretty much equal opportunity with about half and
half
male and female.
This slide shows the epidemic curve by day
and week of the influenza impact in
children. You can
see or you will see that the peak here correlates
with
the peak of the nationwide aggregate data.
So the question is, is the 2003‑2004
different in impact among children? Well, this has
not been a normal part of our regular
surveillance
systems.
The influenza‑associated deaths are not
reportable conditions in the U.S. So the average
annual number of influenza death is unknown. There is
no baseline data.
There was a study that looked at ten
years, from 1990 to 1999, and estimated the
annual
average of 92 deaths, respiratory and circulated
deaths, occurring among children less than 5
years of
age. This
estimate is based on mathematical modeling,
and it is not counting laboratory‑confirmed
fatalities.
Studies to determine if hospitalization
increased in children are ongoing. And discussions
are underway with our state partners to consider
making laboratory‑confirmed deaths in
children or
reportable conditions.
This slide, in summary, shows some of the
main components of our influenza surveillance
system
overlay so you can see how they correlate. The red
line shows the percent of visits for influenza‑like
illness.
The blue line shows the number of states
reporting widespread or regional influenza
activity.
The yellow line shows the pediatric deaths. And the
green line shows the percent of positive isolates
as
tested by the WHO collaborating and NREVSS
laboratories.
You can see that the ILI, the state
reports, and the influenza mortality, pediatric
mortality all nicely correlate and peak around
week
51. The
virologic data seems to precede the other
indicators a bit. And it may be due to some early and
very heavy reporting by some of the states who
tested
a lot of respiratory specimens in the West and
submitted a lot of specimens that were positive.
I think I will stop there and take any
questions.
CHAIRMAN OVERTURF: Are there any
questions?
Dr. Myers?
DR. MYERS: Ann, in those
pediatric
deaths, particularly the ones in young children,
were
there risk factors other than age? And did you look
specifically under one year of age?
MS. MOEN: They have got age data
on all
of the children.
The data are being analyzed. The
form that they used is to collect as much
information
as they could on children.
But some of the information was hard to
collect because we had reporting of a lot of
death
before they decided to collect certain
information.
They are going back and trying to fill in some of
that
information.
Hopefully more full information will be
published.
CHAIRMAN OVERTURF: I believe from the
published data already, about 50 percent of the
children did have underlying illness,
though. Isn't
that correct?
MS. MOEN: That was through a few
weeks
ago. This
is the most current data as of the end of
last week.
So the underlying illness for this is a
bit lower.
CHAIRMAN OVERTURF: Dr. Monto?
DR. MONTO: One of the questions
we are
always asked is whether the deaths in children
that
have been in the newspapers, et cetera, and
locally is
something new or is something that has been
around for
a while that we haven't recognized.
One thing that was striking to us in
southeastern Michigan is that we had several
deaths of
children last year. And some of them were type A H1.
And some of them were type B. And none of them were
A H3N2, which is the subtype we generally
associate
with severity.
My question is, how much is the use of
rapid testing to identify influenza virus
associated
with the correlation between children's deaths
during
an influenza outbreak and identification of
influenza
as the etiologic agent?
MS. MOEN: I am not sure how many
of these
children were tested by rapid test or influenza
culture.
So I can't answer that question.
CHAIRMAN OVERTURF: There is a
question
from the audience. Yes?
DR. RUBEN: Fred Ruben of Aventis
Pasteur.
I just wondered, Ann. We would
normally
think of deaths during influenza periods as
associated
with pneumonia and influenza. My understanding from
a presentation by Tim Uyeki was that these
weren't all
pneumonia and influenza‑like type deaths,
that there
were other attributes, like neurologic conditions
and
so forth.
Could you comment on that?
MS. MOEN: I think that is
true. Some of
them were sudden. It runs the gamut. There
were some
that were quite rapid and not associated with
long‑term pneumonia illness.
And there were definitely some excess or
additional cases of pediatric encephalopathies
associated with some of these cases. And we
additionally have been collecting information on
other
severe cases of influenza associated with
encephalopathies that may not have resulted in
death.
CHAIRMAN OVERTURF: Dr. Gellin?
DR. GELLIN: Ann, you commented
early on
about the surveillance, the virologic
surveillance,
system. I
don't have a context for how many samples
normally go through that system. I guess the question
is akin to the rapid diagnostics. With the increasing
availability of rapid diagnostics, is there a
problem
in the system with getting enough viral cultures?
MS. MOEN: I think right now it
is
something we remain concerned about. We know there is
a good useful rapid test on occasion, but we also
need
to maintain viral isolation so that we can
characterize the viruses.
I don't know what percentage of these
tests were rapid positives, but those are also
reported.
An in some cases, say in a year like this
year, when there weren't very many B's, if we're
just
getting mostly rapid test reports of B's, that
doesn't
leave us very many isolates.
But so far, I mean, the 92,000 that have
been year to date this year is almost equivalent
to
the total number of respiratory specimens that
were
looked at last year. So I think we are getting more
isolates so far this year.
CHAIRMAN OVERTURF: Dr. Myers?
DR. MYERS: I guess after the
presentation
we had just before the break, the obvious
question is
to ask, as the numerator data, the case selection
method that France is using, is available to us
through our sentinel physician system, has CDC
considered the possibility of doing an electronic
surveillance analogous to what is done in France,
which, really, I was impressed by the fact that
it
gives real‑time data?
MS. MOEN: Yes, their system is
impressive.
Right now our sentinel physicians don't
collect vaccination data or patient‑level
data. We
get only age data on the sentinel
physicians. So we
can't look at vaccination right now.
And on a wide scale, I don't know how well
we would be able to convince all of these
providers to
report that level of detail gratis, as they are
doing
now.
But it would be great if the U.S. could
implement some way to have annual estimates of
vaccine
effectiveness based on surveillance data.
CHAIRMAN OVERTURF: Yes?
DR. ROYAL: Are you able to
comment more
specifically on what is known about some of the
neurologic complications these children have
developed, either pathologic findings or other
autopsy
abnormalities?
MS. MOEN: No. I wouldn't be the best
person to comment on that.
CHAIRMAN OVERTURF: Is there
anyone
present who can comment on that?
(No response.)
CHAIRMAN OVERTURF: Are there any
further
questions for Dr. Moen?
(No response.)
CHAIRMAN OVERTURF: We only have
three
minutes left before the scheduled break for
lunch. I
think Dr. Cox was going to go early, but I don't
think
we have time for Dr. Cox. So I think we will just
wait until after that time.
We are scheduled to reconvene at 1:00
o'clock.
So I will adjourn the meeting until that
time.
(Whereupon, at 11:59 a.m., the foregoing
matter was recessed for lunch, to
reconvene at 1:00 p.m. the same day.)
DR. FREAS: I think we're ready
to resume
the meeting.
CHAIRMAN OVERTURF: At this time
of the
meeting, there's time set aside for public
comment.
We've heard of nobody who wants to make public
comment, but at this time I would encourage
members in
the audience or others who want to make public
comment
to step forward to a microphone, identify
themselves.
Before you comment, I need to make one
statement which I need to read for the FDA. "Both the
Food and Drug Administration and the public
believe in
a transparent process for information gathering
and
decision making.
To ensure such transparency at the
open public hearing session of the Advisory
Committee
Meeting, FDA believes that it's important to
understand the context of an individual's
presentation.
For this reason, the FDA encourages
you, the open public hearing speaker at the
beginning
of your written or oral statement to advise
Committee
of any financial relationship that you may have
with
any company or any group that is likely to be
impacted
by the topic of this meeting. For example, the
financial information may include the company's
or
group's payment of your travel, lodging or other
expenses in connection with your attendance at
the
meeting.
Likewise, the FDA encourages you at the
beginning of your statement to advise the
Committee if
you do not have any such financial
relationships. If
you choose not to address this issue of financial
relationships at the beginning of your statement,
it
will not preclude you from speaking."
MS. BARR: Thank you. My name is Geeta
Barr. I'm
with the National Vaccine Information
Center.
And I have no financial conflicts of
interest.
And this question is addressed to Ann
Moen.
During the question and answer period after
your presentation, something came up regarding
flu
related deaths in children, especially in regards
to
neurological complications, encephalopathy and
you
mentioned encephalopathy has been associated as a
cause of complication with these flu related
deaths.
Is there or will there be available data
on how many of these children were vaccinated?
MS. MOEN: I gave the vaccination
data for
the kids that were vaccinated. I believe it was 76 or
78 of the children were unvaccinated and then
there
was missing data on I believe it was 38 of the
children and vaccinated children were
approximately 20
with three of them vaccinated according to the
recommendations.
MS. BARR: Thank you. And I had one other
comment.
Dr. Levandowski mentioned in his
introduction that protection from being
vaccinated has
been noted as early as one week following vaccination
and considering this point, is it really
appropriate
in many of the effectiveness studies since they
have
considered subjects as unvaccinated for the two
weeks
following vaccination?
CHAIRMAN OVERTURF: Dr.
Levandowski, would
you like to address that issue?
DR. LEVANDOWSKI: All right, I'll
try. I
was just ‑‑ I think I was trying to
point out in that
early study in 1943, it was commented that they
could
tell the difference between the people who were
vaccinated and unvaccinated as early as one week
later.
Traditionally, we think about protection
as taking two weeks, mainly because it takes at
least
that long for peak antibody titers to be achieved
after immunization and somebody who has been
immunologically primed and we believe strongly,
at
least for the inactivated influence of vaccines,
it's
the antibodies' direction against hemagglutinin
and
that they are the most important of the
protection.
I'm sorry if that seems a little confusing, but I
don't think we actually know exactly when
protection
kicks in for any one person and on a population
basis,
we would, I think, normally be expecting it
should be
at least within about two weeks, but there may be
some
effect earlier or it might be later in some
individuals.
MS. BARR: Thank you.
DR. FREAS: Mr. Chairman, just
for
clarification, I would like to say that the open
public hearing, it really is to address the
Committee
and make comments before the Committee. We would
appreciate you holding questions until the end of
the
discussion or the end of all presentations just
in
case those questions may be answered in
subsequent
presentations.
Thank you.
CHAIRMAN OVERTURF: Are there any
additional public comments?
(Pause.)
I think we will proceed then.
Dr. Cox
will present the information on the world
surveillance
of strain characterization.
DR. COX: Okay, I want to start
out my
presentation by reminding you that CDC houses one
of
four WHO collaborating centers for influenza and
one
of our responsibilities that we fulfill for WHO
is to
receive influenza viruses from the National
Influenza
Centers located around the world and we
characterize
those viruses both genetically and antigenically
in
order to provide data for vaccine strain
selection to
WHO.
We have a number of additional
responsibilities, but that's the main
responsibility
that is relevant to my presentation today.
So I'll be talking about influenza H1
viruses first.
Hopefully, the blood hasn't all gone
to your stomachs and you'll be able to go through
some
of this rather dense laboratory data with me.
Influenza A (H1N1) and (H1N2) viruses have
continued to circulate globally although at very
low
levels during this past six months. Here is the
first hemagglutination inhibition table which
I'll
show you and I'll walk you through this first one
fairly slowly and fairly carefully. I know there are
new members on the Committee and some of these
data
presentations may not be totally familiar to you.
When we're looking at the antigenic
characterization of influenza viruses, we do so
by
developing a post‑infection ferret serum
against
viruses that are part of our reference
battery. So we
have our reference antigens listed across here
and we
have the corresponding reference ferret antisera
listed across here. And so the homologous titers,
that is the titer, the inhibition titer for the
Beijing/262 antiserum against the Beijing/262 antigen
is 640.
Now when we are looking for differences,
we're looking for at least fourfold reductions in
titer compared to this homologous titer. What we
tried to do is to develop post‑infection
ferret sera
to viruses isolated over time and with a
reasonable
geographic distribution and in particular, if we
find
a virus that is reduced in titer to the vaccine
strain, for example, the Peru/3135 here show
where the
vaccine strain, New Caledonia/20/99 has a
homologous
titer of 1280, we have a titer against the Peru
virus
of 80.
Whenever we see a virus with a low titer,
we retest that virus in order to make sure that
it is
actually reproducibly low in an HI test.
For any viruses that are put into ferrets
and for a selection of other viruses that have a
good
geographic distribution, a good temporal
distribution,
we also sequence the hemagglutinin. As Roland pointed
out, antibodies directed against the
hemagglutinin are
the most important determinants of protection
against
influenza and then we also look at a subset of
the
viruses for which we sequence hemagglutinins and
characterized their neuraminidase as genetically.
We also do some neuraminidase inhibition
tests to characterize the neuraminidase.
Okay, having said that, what I can say and
you can see very clearly is that there are a
couple of
viruses which are variants from the vaccine
strain,
New Caledonia.
One of them is the Peru/3135 shown
here and the other is the Hawaii/15/01 shown
here.
Those are really outliers. We have seen them, seen
viruses like these viruses relatively rarely.
What you have here are the test antigens
8 through 14.
They have been isolated from a variety
of continents including Europe, Asia and North
America.
And you can see very clearly here that all
of the titers for these viruses are within
twofold, at
least within twofold of the homologous titer for
the
New Caledonia.
Although we haven't determined the
neuraminidase subtype for these viruses shown here,
what I can tell you from past experience is that
it
doesn't matter if the virus is an H1N1 virus or
an
H1N2 virus.
The HA pattern looks very similar.
So the hemagglutination inhibition pattern
looks very similar for H1N1 and H1N2
viruses. You
really can't distinguish them by doing an HI
test.
You have to look at neuraminidase specifically.
So in summary then, what I'm showing here
is the antigenic characteristics of viruses, H1
viruses that were isolated between October 2003
and
February 2004, rather ‑‑ yes, their
isolation dates
were between October and February. We only have 10
viruses that were H1 viruses and only one of the
10
was low to the New Caledonia vaccine strain.
If we look back at the previous period,
April to September during the time when influenza
viruses were circulating in the Southern
Hemisphere,
we have a larger number of viruses to look at, a
total
of 130.
And likewise, for that period we had
relatively few, 5 percent or so which were low
reactors to the New Caledonia serum.
Just to amplify a bit with data on the
subtype of neuraminidase, we have 126 viruses for
which we had determined the neuraminidase subtype
isolated between April and September of
2003. And you
can see that roughly half of them were H1N2
viruses.
And for this current interval, we're also
talking about co‑circulation of both H1N1
and H1N2
viruses, although our numbers are very small.
When we look at the sequence of the
hemagglutinins and I've got a much simplified
dendogram on the screen, you can see that there
are
two subgroups; one, which represents the H1N1
hemagglutinins and the second of which represents
the
hemagglutinins of H1N2 viruses. I mentioned before
that we could not distinguished these two
subgroups
antigenically.
We can tell them apart genetically,
but not antigenically.
Here is the N1 neuraminidase gene tree and
you can see that here's our vaccine strain down
here
and there's really relatively little change in the
N1
neuraminidase since 1999. So I can point out that the
Peru viruses that had a bit of antigenic
difference
among them also have a few changes on the
neuraminidase and I should also point out that I
had
pointed out the Peru 3135 virus on the HI table
and
this virus was a low reactor and like other low
reactors it has a K144E change. But those viruses are
really in the minority.
So in summary, I can say that relatively
few H1N1 viruses have been isolated during the
past
six months and relatively little influenza
activity
has been associated with circulation of these
viruses.
No new antigenic or genetic variance of H1HA have
been
detected.
And in HI tests using post‑infection
antiserum to the A New Caledonia vaccine strain,
these
recently isolated H1 viruses are well
inhibited. The
NA genes of both N1 and N2 subtype viruses are
similar
to those of viruses circulating a year ago.
That was the easy one.
(Laughter.)
Now we'll go into influenza A H3N2
viruses.
On the screen you'll see a simplified
table and I'll lead you through the simplified
table
which was developed for last year's meeting. And I
just wanted to remind you what we were actually
seeing
last year at this time for H3N2 viruses.
We have on this particular HI table, the
old Moscow/10/99 reference strain as well as the
Panama/2007/99 vaccine strain. We also have antisera
and antigens representing Fujian/140, Chile/6416,
Hong
Kong/1550 and a number of other viruses.
What you can see is that last year at this
time we were seeing a number of viruses isolated
from
different continents which were well inhibited by
antiserum to the Panama strain. There were some
viruses which had reductions fourfold or greater
reductions in titer against the Panama, but the
majority of strains really were well inhibited.
We did, however, have antiserum to this
Fujian strain which we can see if we look at this
table carefully we can see that there was at
least a
fourfold reduction between Moscow homologous
titer and
the Fujian titer and in this particular case
there was
only a twofold reduction, but in some other tests
there was a greater reduction. And there were some
other similar strains that gave a difference that
was
at least fourfold in both directions.
And that's really what we're looking for
when we're looking for a variant. We're looking for
a variant that has a fourfold reduction in both
directions.
So basically, we were seeing a pattern
where there were viruses with reduced titers, but
for
many of the strains, for example, this one, you
didn't
see the reduction with the Panama and Moscow
older
strains, neither did we for the New York/55 nor
for
this particular strain from Asia which had
somewhat
reduced titers with Moscow and Panama.
This is a simplified table that was
developed for this year's meeting and what you'll
see
here is that in contrast to what we were seeing
last
year, we have many more viruses that have a
fourfold
or greater reduction in titer compared to the
homologous Panama titer. We have our Fujian 411
reference strain here and you can see that in
spite of
the fact that all of these viruses are Fujian,
when
you look at their genetic characteristics there
are
some viruses which are not as well inhibited by
this
antiserum and actually we were seeing that last
winter
as well.
Here's another Fujian‑like virus, the
Korean/770 and we have a homologous titer of 1280
and
there are a few viruses down here at the bottom
that
have a fourfold or greater reduction in titer
compared
to the homologous.
What we have tried to do here is to
represent different genetic groups that we have
observed through our sequencing data by
developing
ferret antisera to these viruses and then looking
to
see what kind of patterns we get. So we have this
recent virus from Texas. This was from the Texas
outbreak.
This is actually a virus that was isolated
in October and you can see that there really
aren't
significant differences in the patterns that we
get.
If we have a virus that tends to be a low
reactor, it
tends to react rather low to all of the different
ferret antisera, indicating that we may have low
avid
viruses.
So I think in summary what I'd like to say
here is that we have a lot ‑‑ we've
analyzed a
tremendous number of viruses during this current
influenza season from a number of different
continents
and antigenically they are somewhat
heterogeneous.
There still have been quite a number of viruses
that
were very well inhibited by antiserum to the
Panama
strain and this is not like the pattern that we
had
when the Sydney virus emerged back in 1997. We very
clearly had two‑way fourfold or greater
differences
when we looked at HI tests. So every virus that was
Sydney‑like genetically was also Sydney‑like
antigenically.
There were very, very clear cut
differences.
For the Fujian variant, we haven't seen
that kind of clear‑cut antigenic
difference. And so
we've really tried extremely hard to understand
what
is going on with these particular viruses and why
are
they slightly different from other ‑‑
why is the
emergence of this variant slightly different from
the
other variants we've seen over the past few
years.
Here is a summary slide for the antigenic
characterization of the H3N2 viruses that were
isolated between October and March, October 2002
and
March 2003, last influenza season. You can see that
there were some Fujian‑like viruses, I
think it adds
up to a total of about 28 percent that were
Panama‑
like (low) of Fujian‑like.
Likewise, during the summer months that
there were actually increasing numbers or
increasing
proportions of Fujian‑like viruses. If we look at the
data for the current influenza season, we see
that of
a total of 720 viruses that we've analyzed in
this
extensive reference battery, a lot of different
post‑
infection ferret antisera that we have about 70
or 80
percent, close to 80 percent being Fujian‑like
and a
proportion of those are low to Fujian, give lower
titers with the Fujian antiserum and that's what
we
would expect as well. We always see a proportion of
viruses that are low.
Once again, I've simplified the dendograms
so that I could walk you through it more
efficiently.
If you look at the dendogram in your package,
you'll
see that viruses that have been isolated in eggs
are
shown in blue color, if you have color ‑‑
no, sorry.
But you'll notice that we have more egg isolates
this
year than we did last year because we put a
tremendous
amount of effort into this endeavor.
Last year at this time we were seeing
quite a number of viruses in this the Fujian part
of
the graph, but we were also seeing quite a few
viruses
down in what we call the Chili genetic group and
it
wasn't entirely clear which of these two genetic
groups would win, so to speak. In Europe, they were
actually seeing a higher proportion of viruses at
about this time last year in this particular
group
than in this particular group. We all know that the
Fujian‑like viruses won out and we then, as
I
mentioned, were monitoring the changes in this
group
of viruses very closely.
And you can see that there's a subgroup of
viruses that have changes, these viruses have
changes
of amino acids 193 and 227; a separate subgroup
that
has a change in amino acid 140; and then this
group up
top which really constituted the majority of the
strains that circulated in the United States
which has
a change in amino 126. In that previous slide with
the H1 table I had represented viruses from this
genetic group and this genetic group and we
really
can't see distinct antigenic differences for
these
groups, but we've been looking actually very
carefully
to make sure that if we choose a virus that's a
little
bit older like the Wyoming/03 virus and the
Kumomoto
virus which have been actually ‑‑
actually, the
Wyoming strain was used to prepare vaccine for
the
Southern Hemisphere season that's upcoming, so we
wanted to be sure that we didn't need to go even
beyond these strains.
The neuraminidase genes of the N2 subtype
are really quite heterogeneous. The Panama
neuraminidase gene is represented back here and
there's been a lot of genetic change in the N2
neuraminidase since Panama. And we've really got a
couple of different groups that I'll tell you
about.
The N2 genes of the H1N2 viruses all
cluster together right here. The N2 gene of the
Chili‑like strains that I pointed out that
had been
circulating in Europe last year cluster down
here.
The N2 genes of the majority of the viruses that
had
been circulating were clustering up here.
Many of the new viruses that we ‑‑ the
neuraminidase genes of the most recent viruses,
for
example, some of the Texas viruses that we had
looked
at cluster down here and this indicates that
there's
been genetic reassortment between H3N2 viruses in
the
Chili and the Fujian genetic group, so this is
fairly
interesting and it just shows how promiscuous
influenza viruses are. They're out circulating in
populations and reassorting all the time.
Now I'm only going to show one slide with
data about the H1N antibody response to the 2003‑2004
vaccine, maybe two slides. But I wanted, in
particular, to show this slide because this
Committee
has asked for data on children who had been
vaccinated
and we had been able with Chris Turley and Marty
Myers
to do a study that would allow us to look at the
immune responses in children 6 to 23 months of
age.
And here we have the immune responses to the
Panama
vaccine strain and then to some representative
strains
that were circulating this year.
And you can see that there was, from a
pre‑vaccination, geometric mean titer of
5. We went
up to a post‑vaccine, geometric mean titer
of 50 in
this population of children, and we also were
able to
detect antibodies to the Texas/40/2003 and other
representative viruses that had been circulating
this
winter.
And of course, we can see that there are
lower titers, but still there has been an immune
response to these other viruses.
I mentioned that we had been looking very
carefully at our HI tables and really wonder
whether
we had something slightly different going on this
year
and perhaps our hemagglutination inhibition tests
weren't telling us the whole story. So if you'll look
at the bottom half of this particular slide,
you'll
see that we have done microneutralization tests
using
a variety of different antigens and again using
post‑
infection ferret antisera.
So this is more of a functional assay
where we're looking at the ability of antibody
against
the Panama virus to neutralize these other
strains and
we can see a bit more of a clearcut
differentiation
between the Panama and these Fujian‑like
reference
viruses.
But you can see there is quite a bit of
cross reactivity and you get some inhibition in
both
ways.
We also used microneutralization tests to
look at the antibody responses among students who
were
vaccinated with the 2003/2004 influenza vaccine
and
these sera were collected by Arnold Monto and I'd
like
to thank him for those sera. So we were looking at
the neutralizing antibody titer rises to Panama,
Fujian/411 and Fujian/455 and Fujian/444‑like
virus
and the Christ Church/28 strain.
And you can see that although the post‑
vaccination geometric mean titers were reduced,
we
still did have neutralizing antibody to these
other
strains.
So in summary, H3N2 viruses have
circulated really quite widely during the past
year
and have been responsible for most reported
outbreaks
of influenza in Europe and North America during
this
past season.
A Fujian/411/2002‑like viruses have
predominated.
Viruses that are well inhibited by
post‑infection antiserum to the A Panama
vaccine
strain do continue to circulate, however.
Genetic heterogeneity among current H3N2
viruses has been observed, but we haven't found a
correlate when we look at the antigenic
properties of
these viruses and I'd also like to mention that
reassortment has occurred among H3N2 viruses so
that
some of the viruses with Fujian‑lineage HA
have a
Chile‑lineage neuraminidase.
So now I'll move on to Influenza B virus
characterization and I'd like to remind you there
are
two very distinct sublineages of Influenza B
viruses
that have circulated, as Roland mentioned, for at
least the past 15 years. One lineage is called the
B/Victoria lineage. The other is called the
B/Yamagata lineage and I'll try to point out so
that
you don't get too confused which viruses belong
to
which lineage.
Here's a slide which shows two B/Yamagata
lineage viruses, the B/Sichuan/379/99 strain
which was
the prior vaccine strain before we moved to a
Victoria
lineage strain.
And then we also have
B/Shizuoka/15/2001 which was a referenced strain
which
was an updated virus, but was in the same genetic
and
antigenic group with Sichuan.
These viruses from reference antigen
number 3 down to 9 are B/Victoria lineage viruses
and
what I'd like to point out right away is that you
really see very little cross reactivity between
the
Yamagata lineage and the Victoria lineage
viruses.
Likewise, these Victoria lineage viruses induce
antisera that do not inhibit the B/Yamagata
lineage
viruses at all well. And remember, we're working with
ferret antisera.
We make sure that the ferrets are
clean of any antibodies to influenza so the
ferrets
behave more like a naive human, like a child, for
example, who has never experienced influenza
before,
but you do get these very clear, clean reactions.
We had been seeing viruses that were on
the B/Victoria lineage. Last year we had a lot of
Influenza B activity, a lot of school closings
caused
by Influenza B viruses. There were some Influenza B‑
related pediatric deaths and all of those viruses
would have looked similar to these Hawaii viruses
down
here at the bottom.
We had relatively few Influenza B viruses
and really had to beat the bushes to get viruses
sent
to us.
There were relatively few, only somewhat over
a hundred that were isolated in the United States
and
so we have been very actively soliciting those
viruses.
Most people were concerned about the H3N2
vaccine component and were concerned about the
large
outbreaks that were occurring due to H3N2, so we
really haven't had as many viruses as ‑‑
Influenza B
viruses as we would like. But of those that we've
had, the majority have been represented by the
B/Yamagata lineage and we noticed that the
majority of
the viruses had reduced titers to the old
Sichuan/379
vaccine strain.
So in response to those findings, we very
aggressively pushed ahead to develop some
additional
ferret antisera to newer strains. So here on this
slide we have some new strains. Once again, these
viruses here at the top are the B/Yamagata
lineage
viruses.
These two are the B/Victoria lineage viruses
and you can see that we developed ferret
antiserum to
Shanghai/361/2002, to this Jilin 2003 and Ulan
Ude
2003 viruses.
And in this particular test we've put in
viruses from North America, primarily, but we
also
have some viruses from the Middle East and from
Asia.
We can see that the antiserum to the Shanghai 361
virus does inhibit these viruses quite well and
as
does the antiserum to the Jilin, although we have
a
fairly low homologous titer, a little bit lower
than
we normally like.
So in summary, what we can say is for this
last most recent time interval, we have 17
Influenza
B viruses that we've analyzed. Of those, 15 are in
the Yamagata lineage and the majority of those
are low
to the Sichuan antiserum, that is, the older
B/Yamagata lineage vaccine strain.
We only have two viruses that are in the
B/Victoria lineage and data developed in Japan
and
also in Europe very much reflect what we found in
our
WHO collaborating center, that is that the
majority of
the viruses that they have received are likewise
of
the B/Yamagata lineage.
So I haven't actually put the HA sequence
data for both the Yamagata and the Victoria
lineage
viruses on the same dendogram. I have an old slide
that I had hoped to put into my presentation last
evening, but my computer had an encounter with
some
water and so it really wasn't very happy about
that.
So you'll just have to take my word for it that
these
two lineages, HA lineages are very distinct and
so if
we were to have them on the same slide, we'd have
very, very small tip branches and we'd have a
long
line and then it would be connected to the other
lineage.
So first of all, we'll look at the
Yamagata HA gene relationships. Here is the old
Sichuan/379 vaccine strain that was used
previously as
a representative of the Yamagata lineage and the
viruses that are currently circulating are
primarily
related to an older reference strain that some of
you
will remember, Harbin/7/94. And that is the lineage
that's really taken off and has become
predominant.
I'd like to point out here up at the top,
the Jilin/20/2003 reference virus. We had developed
antiserum to that virus. There's the Shanghai/361
virus right there. It was a low reactor and that was
one of the other reference viruses. So we have a
number of egg isolates. We have Jilin/20/2003,
Shangdong/22, Jiangsu/10, and then of course, the
Shanghai/361.
Just for reference, we'll go back and look
at the B/Victoria HA gene relationships. Here's our
reference virus here, Hong Kong/330/2001 and the
current vaccines are B/Hong Kong/330‑like.
And the majority of the viruses that have
been circulating actually have HAs that are up
here.
The viruses that have HAs up here are not
antigenically distinguishable from those that
have
their HAs fall on this part of the tree.
And now we'll move on to the genetic
relationships among the neuraminidase genes of
the
currently circulating Influenza B viruses. The
B/Victoria lineage viruses started out having
their
neuraminidase genes down here, but genetic
reassortment occurred and so what happened was
the
majority of the viruses that had B/Victoria
hemagglutinins actually had neuraminidase genes
from
this group up here last year. So during our outbreak
we had viruses not this current year, but the
previous
year where we had a significant amount of B
activity,
the viruses had HAs down here and neurominidases
up
here.
You can see that the neuraminidase genes
for some of the viruses that I have pointed out,
Jilin/20, for example, and Shangdong/22, Ulan
Ude/6
and so on have their neuraminidase genes
here. So
these are viruses that really have both the Yamagata
HAs and the Yamagata lineage NAs.
So in summary, viruses both the B/Yamagata
and B/Victoria lineages have continued to
circulate.
However, although the numbers are fairly small,
B/Yamagata viruses have predominated over all.
Relatively little influenza activity has been
attributed to Influenza B viruses in recent
months and
most recent Influenza B viruses from the U.S.,
Europe
and Asia are most closely related antigenically
to
B/Shanghai/361/2002 and B/Jilin/20/2003. I apologize
for the typos.
Influenza B neuraminidase gene sequences,
they also form two separate lineages and the
majority
of recent viruses have neuraminidase genes from
the
Yamagata lineage as well as their HA from the
Yamagata
lineage.
I think with that, I will close and if
there are any questions, I'll be happy to answer
them.
CHAIRMAN OVERTURF: Are there any
questions for Dr. Cox?
Yes.
DR. MARKOVITZ: David
Markovitz. Nancy,
I wanted to ask you about the microneutralization
assays.
So those were done with human sera, right,
did I understand correctly?
DR. COX: We had
microneutralization
assays done both with ferret antisera and with
human
sera.
DR. MARKOVITZ: Both.
DR. COX: Both. So the bottom part of the
table was an assay done, actually a compilation
of
five assays done with the ferret sera and the top
part
of the table was with the human sera from the
Montose
study.
DR. MARKOVITZ: And do you have
an
estimate, if you wanted to put a percentage of
efficacy on ‑‑ in terms of ‑‑
if you look at the
microneutralization the Fujian being neutralized
by
the current vaccine strain, what ‑‑
can you put a
percentage on how effective that was?
DR. COX: No, no. We wouldn't really want
to extrapolate from the laboratory tests to what
happens in humans. I mean the laboratory tests are
done with post‑infection ferret sera, the
ferrets have
never seen influenza before, so we're really
looking
at very clean results without much cross
reactivity
because the ferrets are unprimed when they're
given
the virus.
And so I think extrapolating and also we
don't really know what level of cross reactivity
in
this laboratory‑based test would correlate
with
protection in humans, so even with the human post‑
infection or post‑vaccination sera, we
don't know and
at this point wouldn't like to predict what
efficacy
we would expect.
It's an index of cross reactivity.
It tells us that there is antibody there that's
reacting, but we wouldn't really ‑‑
it would be very
dangerous to try to extrapolate to protection in
human
beings.
DR. MARKOVITZ: So it's just an
index of
cross reactivity, so you're just trying to show
that
there are ‑‑
DR. COX: That the antibodies
that are
there are neutralizing the virus.
DR. MARKOVITZ: Yes.
DR. COX: In a laboratory
assay. So if
you take the virus and add the antibody that's
developed to that vaccine, you have
neutralization of
the virus and that's what we're talking about.
DR. MARKOVITZ: What would you
like the
take message of that slide to be then in terms of
picking vaccine antigens?
DR. COX: The take ‑‑
DR. MARKOVITZ: Or how the
vaccine‑picking
in the past ‑‑
DR. COX: The take home message
is that
clearly there is cross reactivity between
antibodies
developed to the Panama vaccine strain and the
currently circulating strains. I can ‑‑ so there is
neutralizing antibody there.
How that level of neutralizing antibody
translates into protection in a human population,
I
really can't extrapolate, but it clearly is
there.
DR. MARKOVITZ: Okay, thanks.
DR. KARRON: Ruth Karron. Nancy, do you
think that the greater difference that you've
seen
with microneutralization versus HAI has to do
with the
divergence of the neuraminidase in these H3N2
viruses?
DR. COX: I don't think so, but I
don't
have concrete evidence, but I really don't think
so.
DR. KARRON: And also as a follow‑up
question, first I wanted to thank you for
including
the sera from the pediatric population. I know it was
something that the Committee brought up last year
and
it's good to see it. Do you think it's useful if sera
were available in this pediatric population to
look at
microneutralization in this population also?
DR. COX: I suspect that we would
see very
similar results.
We've looked at microneutralization
tests in the past and really had expected to see
a
much more dramatic difference between HI and
microneut
data.
Nevertheless, when there is a situation
where there a lot of questions being raised, you
know,
the data just aren't falling out the way we think
they
should or there are questions about vaccine
efficacy
or something, we like to do the more labor
intensive
microneutralization tests as we've done for the
H3
here, but generally speaking, we don't get any
more
information from a microneut test than we do from
an
HI test, but it does provide confirmation that
there
is functional cross reactive antibodies so that's
basically what we're looking for.
DR. HJORTH: Richard Hjorth,
Aventis
Pasteur.
Nancy, you mentioned that there are a number
of egg isolates of the B types, B/Jilin related
and I
wonder if you've kind of looked at yield at all
and if
they're winding their way to the manufacturers?
DR. COX: Good question. We have not
looked at yield and our way of looking at yield
is
much less sensitive than your way of looking at
yield,
so I don't know really what to tell you about
their
ability to grow.
I know some of the manufacturers
have the B/Jilin/20 virus and others will be
forthcoming.
CHAIRMAN OVERTURF: Are there any
other
questions from the Committee members or the
audience?
It must all be perfectly clear, Nancy.
(Laughter.)
If there are no more questions, we'll
proceed then.
Thank you.
The next report is from Linda Canas from
DOD.
MS. CANAS: Good afternoon. It's always
a pleasure to come to this meeting. The Department of
Defense has long recognized the threat of just
influenza illness and the possibility of a
pandemic is
something we take very seriously.
In fact, as you've heard before,
vaccination is a mandatory procedure for all
active
duty military personnel. We give this to them for
their own health, but we don't make the decision
on
what's going to be in the vaccine. And since we are
out in the world, and carrying on public health
surveillance, we find it important that we share
with
you what we find so that perhaps it can help make
your
decision somewhat easier.
This has been an on‑going procedure for
the Air Force since the 1970s where we've
collected
influenza surveillance data from our facilities
around
the world and it was a very successful
program. So
when the Global Emerging Infection System came
into
being in the 1990s, we joined forces and it's now
a
tri‑service program and funded by the
Department of
Defense.
This actually takes place in two different
arenas.
The one I'm reporting on today is the Global
Influenza Surveillance carried out in San
Antonio,
Texas from military installations of all three
services and the Coast Guard around the world.
Another area is carried out in San Diego from the
Naval Health Research Center and they do baseline
surveillance, population‑based at the
recruit centers.
I will, of course, be reporting on the
Global Program and how we work this, just as a
quick
overview, we have our annual meeting which is
overseen
by GEIS.
The laboratory and the epidemiologists work
very closely.
We get together and decide what our
surveillance site should be. You saw the map earlier
that we've had.
We choose our sites on mission,
people that are going to be out in the world,
that
could be traveling in areas that could be
infected,
coming in and out of the country, training sites
and
those that have historically participated.
We supply them with all of the materials
they need to do surveillance, the collection kits
and
all the instructions and I would point out that
this
takes place in the context of a full service
reference
laboratory.
This is not an operation all on its own.
We are receiving medical samples from these
medical
treatment facilities around the world, so it's
very
easy for them to add respiratory samples to the
FedEx
box that's coming to us. So daily, we get samples in,
sometimes one or two samples, sometimes in the
middle
of an outbreak, it could be 50. But it makes it much
more low cost than if we were trying to do this
all on
our own.
Conventional laboratory methods.
In our
laboratory, we only do isolation. We don't work with
any rapid tests because we want an isolate. We want
to be able to examine what that influenza sample
is
like.
These reports go back to the facility as a
patient report.
This is a medical treatment that
we're carrying on. We're doing kind of a dual duty
with surveillance and with medical surveillance. We
have our sentinel sites, but we get samples from
other
facilities also.
So in order to be able to track for
reports, we work with the epidemiologists and
they
report back to the facility that you do have
influenza.
This lets them know they have it and also
facilitates them to go back and do follow‑up
work on
vaccination status and be able to do reports like
Colonel Neville reported earlier on vaccine
efficacy.
Meanwhile, back in the laboratory, we're
taking selected samples, subtyping them, perhaps
sending them on for molecular sequencing and
characterization and then some on to CDC for
further
characterization and then meetings like this
today
where we can actually decide on the sites.
This is our map for this year.
It's hard
to see the map on your handout. You have them listed,
but it's hard to read. We do have 27 sentinel sites
that cover all three different services and this
year
we got the Coast Guard, up in Ketchikan, Alaska.
Cruise ships come in there. They had some very early
outbreaks, so we were able to get set up with
them for
samples to come in.
We also work with the Army and Navy in
areas of the world where they have research
protocols
going on, particularly in South America. There are
several sites.
And they've been very proactive.
In
fact, we've just last week received another box
with
115 samples.
These are all from Peru. We do
get them
also from Ecuador, Bolivia, Colombia and more
recently
we got some from Nicaragua.
Over in Thailand, the Army collects
samples from Thailand, Nepal and Cambodia and I
have
a report that we're going to get some from
Maldives in
a shipment that we should be receiving fairly
soon.
So you have a list and I'd be glad to go over it
with
you some time if you really want to know what
they
are.
When we look at our results over all for
everything, everything we got for the year, this
is
from the beginning of October until now. We've seen
quite an increase in our recovery from last year
and
of course a lot of that has to do with the fact
that
there was a lot more influenza. But we operate, as
everyone else has said, on a case
definition: fever,
equal to or greater than 100.5 degrees and cough
or
sore throat.
Well, that's what we say we collect.
But there was some question last year, I mean the
sample comes into our laboratory. We don't know if
somebody just said oh, I'm low on my quota, let's
collect samples.
So we've been a little bit more proactive.
We have a questionnaire which we're encouraging
them
to fill out at the time the sample is taken and
we're
collecting that data. Also, in one of the facilities
that had sent us quite a few samples, a team of
epidemiologists actually visited and did a
limited
records review and found that, in fact, the
majority
of what we were getting did not meet our case
definition.
If it did, if there was fever of greater
than 100.5, more than 40 percent of those samples
were
positive for a respiratory virus. If it did not meet
the case definition, only about 20 percent was
positive.
AUDIENCE (OFF MIC): Eight
percent.
MS. CANAS: Okay. Excuse me.
Also,
another thing we found in our overall work this
year
is the role of the rapid‑flu kits. We don't use them
in our facility, but we know that many of our
bases
did. And
one of our big concerns and it's been
brought up is if these become more common, are we
going to have fewer isolates to examine.
What we found this year, in years past, we
have battled the mindset of I know what flu looks
like, I don't need a result. But now we have rapid
tests out there and what we were getting in our
lab in
very large numbers were those that were rapid
test
negative and those tests are very good. They're very
specific, but they are not as sensitive,
somewhere
around 65, 75 percent sensitive. So many of our
isolates, the majority of our isolates this year
were
from rapid flu test negatives. So we are still
getting many results and probably more because
now
people want a result. They're used to having
something and they want a result. And that presented
somewhat of a problem for us this year because we
were
so overwhelmed, we were afraid we were going to
run
out of materials and we were also getting urgent
requests of laboratories who were afraid they
were
going to run out of rapid tests so they were
going to
start sending everything to us. We had to do a lot of
negotiating on you know what's going on in your
facility, let's concentrate on the people who
might
really benefit from the testing. We didn't want to
miss those that were particularly important.
And down below, you can see that we're
still getting quite a variety of other viruses
along
with the influenza. I will say here, talk about
everything, 46 percent of our positives were
subtyped.
One was an H1N1, everything else was H3 and 2 of
the
As. We
did isolate 5Bs. They were widely
dispersed
throughout the season and throughout the
world. We
had two from Hawaii, one from Korea, one from
California and one from Okinawa. One was very recent.
We haven't subtyped it. We had three that were
B/Sichuan in the B/Yamagata family and one that
was a
B/Hong Kong.
The H1N1, we were curious about, because
even though it was early, we knew it was
rare. I
asked our epidemiologist to do a travel history
and
was, in fact, from a dependent wife whose
Filipino
family had just been visiting and some of those
family
members had been ill.
When we look at just those that came from
Asia and the Pacific and we do concentrate on
that
area, again, we had pretty much the same kind of
percentages, 40 percent of everything we received
was
positive; 71 percent of the positives were
Influenza
A and again, these were all H3N2. And when we did
sequencing data they were all of the Fujian
subtype.
This was also true in North America.
Of
course, North America makes up the bulk of what
we do
receive.
Again, we were seeing the same kind of
percentages, 47 percent were positive, 71 percent
of
the positives were Influenza A. This was consistent
throughout everything we did. Again, one of those was
an H1N1, probably having been imported everything
else
H3N2.
We do get samples in from South America.
This, of course, being more their summer
season. This
particular shipment represented pretty much
exclusively Peru. We did not have any from other
areas. We
get more from them later on. We had a
much
bigger variety of respiratory viruses in this
sample,
too. They
also were seeing the same H3N2.
In Europe, it started very early,
especially at our base in the United Kingdom at
Lakenheath Air Base there. It started early and
continued on, probably one of the longest lasting
outbreaks that we saw. Again, they were H3N2.
They
came through very nicely. We also got samples there
from Germany, Italy and Turkey, all of them being
the
same.
Very important for us, I'm not sure it's
as important for international surveillance was
to be
able to establish surveillance sites in deployed
areas
because again for the Department of Defense,
sharing
this data is important today, but public health
of the
troops is one of the main reasons that we carry
out
this surveillance and being able to get
surveillance
in deployed areas is very important. This was spurred
on, actually, last spring when SARS outbreak hit,
right about the same time when we were moving
into
this area of the world.
We haven't gotten big numbers, but the
system is in place and being able to have a
system
that we can rely on has made it very
important. One
of the bases is in Afghanistan. It's fairly large.
There seems to be a good bit of interaction from
various groups of people, so this could represent
some
isolation from that area. From the base in Kyrgystan,
this is much more remote. There is not as much
interaction and I don't know if this is what we
have
isolated there, if it's just the people coming in
and
bringing it or if there's some from the
area. But
since everybody seems to have the same virus,
it's
probably both.
If we look at a different graph of the
same information, again you can see very clearly
that
Influenza A has been the most important isolate,
respiratory isolate this year. We target for it and
we get it.
If we take that out of the picture, and
for the military, adenovirus is a very big
player,
especially in the recruit centers. We've had a
vaccine for adenovirus before. We lost it.
We're in
the process of getting it back. So it's very
important for us to track this and have an idea
of
what's going on.
This is our dendogram. This
actually was
supplied to us from the CDC from isolates that we
had
sent to them.
A little hard to see, but they're all
very closely related on this graph. You can see that
we have sequenced 90 of our isolates. We do tend to
target those that are overseas, but we try to get
some
from each area, each base that we get samples
from.
We target to get some of those samples so that we
can
have an idea.
All of them were showing the amino acid
change 155/156 which is consistent with the
A/Fujian
virus.
And we also found a good number that had the
substitution of 140 amino acid.
So this is a good summary of what we have
done this year.
It's an exceptional year because it
has been pretty much the same thing. The last few
years we've seen a variety of different
viruses. This
was especially true last year. This year was very
consistently H3N2 with just a few of the
Influenza Bs
and in our case only one H1N1.
We, of course, are poised, like everyone
else waiting for the H5H7 that we hope not to
see.
But everything that we have analyzed has been
consistent with the variant, the A/Fujian.
Thank you. Would there be any
questions?
CHAIRMAN OVERTURF: Are there
questions?
Yes?
DR. McINNES: (off mic)
MS. CANAS: Would our Quatar
specimens
have captured Iraq?
MAJ. GOULD: No, those would have
been
patients in Qatar.
MS. CANAS: Just in that area in
Kyrgyzstan.
MAJ. GOULD: No, in Qatar. Qatar is in
the Gulf.
There was a mislabeling.
Afghanistan
should have read Kyrgystan.
DR. McINNES: So do we have Iraq
troops
data?
MS. CANAS: No. We're still working.
Shipping is a problem, getting the lines
open. We
don't have a lot of priority over there.
CHAIRMAN OVERTURF: Questions?
MAJ. GOULD: Just a comment. Major Gould
from AFIOH.
On that study it was about 42 percent of
those patients who met the ILI case definition
had a
virus present and only 8 percent in those that
did not
meet the ILI case definition. So about a five fold
difference.
CHAIRMAN OVERTURF: Were there
other
questions for the speaker?
Thank you.
(Pause.)
The next speaker is Dr. Maria Zambon from
HPA from the UK.
DR. ZAMBON: Good afternoon,
ladies and
gentlemen.
Thank you for inviting me to speak.
I'm
here today to summarize the experience of United
Kingdom influenza surveillance from last winter
season
and I do so on behalf of the Health Protection
Agency
which is a newly formed agency and comprises what
many
of you will be familiar with, the Public Health
Laboratory Service which has been amalgamated
with a
number of other government agencies to give an
overall
health protection agency.
In common with many developed countries
and the United States, we have a comprehensive
national influenza surveillance system which looks
at
a number of different aspects and indices to try
to
give the best overall picture of the impact of
influenza.
And within our surveillance system, we
monitor various different aspects. We monitor what
goes on in primary care, particularly through a
sentinel general practitioner network which I'll
talk
more about later.
We monitor through secondary and tertiary
care hospitalization. We monitor obviously deaths
through our Office of National Statistics. And we
combine elements of our primary and secondary
care
surveillance system wherever possible linked
pharmacological sampling.
The entire surveillance outputs, if you
will, are integrated within the Health Protection
Agency in Colindale which comprises both
laboratory,
centralized laboratory reference facilities and
the
epidemiological work, so in other words, the
Colindale
site is, if you will, the equivalent of the
United
Kingdom and CDC.
So our GP surveillance comprises a
sentinel network of about 80 practitioners which
cover
a population of about 1 million. Health care
provision in the United Kingdom at primary care
level
is denominator based and we can therefore get
very
good population estimates of morbidity. And GPs
record the incidents of new cases of
influenza. In a
subset of those GPs, actually take samples for
virological analysis from the population under
surveillance.
As a consequence of our general
practitioner influenza‑like illness
monitoring, we
have very good historical data and we have
learned, we
think how to interpret it, to give a picture of
overall morbidity and impact of influenza. We set
somewhat arbitrary the level of baseline activity
at
a consultation rate of 50 per 100,000. When
consultation rates rise about that, we describe
that
as normal seasonal activity in the sense that we
recognize the circulation of influenza viruses
every
year, year in, year out, although the timing and
duration and magnitude of the epidemics may
actually
vary.
So to orient you somewhat, if we take Year
1989/90, we recognize that as being the last very
major epidemic year in the United Kingdom and if
I
were to orientate you further and put 1968 which
you
will recall is a pandemic year, that would be
around
about a thousand consultations per 100,000.
If we look at 2004, you can see that it is
really overall quite a moderate year and
certainly
fairly similar to the last few years of influenza
surveillance.
I'd like to draw your attention to
1989/90 because I'll come back to that. As I will
also to 1995/96 which was the year in England
that we
saw the emergency of the Wuhan/395/95(H3N2).
And also here, in 1999/2000 where we saw
the emergency of the A/Sydney virus. So all of those
years here were pure H3N2 virus years, 1989/90,
1995/96 and 1999/2000. And I'd like you to contrast
that with this current year.
Now there's been a lot of indication about
the impact of influenza in children and that's
one of
the main concerns this year. I think as has been
pointed out by a number of previous speakers, the
influenza season began early in the United
Kingdom and
we see from our consultation data which are
broken
down by age that the peak of consultations was
indeed
in the youngest age group with relatively little
impact in the elderly age group.
Influenza watchers who have been around
the block a few times will know that season to
season
influenza is a very unpredictable disease. And if we
look over a number of years, one of the things
that is
characteristic about influenza epidemics is that
they
can impact differently and in different age
groups in
the population.
If we take 1969 which was the pandemic
year, this was primarily an epidemic which
affected
the working age population. If we look at 1989 which
I pointed out to you previously, this was in
contrast
an epidemic which was particularly hard on the
children with peak consultations in the naught to
four
age group.
If we look at 1999/2000, we saw that this
was an epidemic which was particularly affecting
the
older age groups and that, of course, can
translate
into the mortality figures, but my point here is
that
it is important to recognize that each influenza
year
is different in terms of its impact and it's
therefore
not always possible to predict what's actually
going
to happen.
If we look at the death statistics for
this year, these are total deaths from all causes
reported to our Office of National
Statistics. We've
taken the last four years and plotted them in
this
particular graph and there's one feature I would
like
to point out.
You will see that the baseline here for
1999/2000 is somewhat higher than the three
subsequent
years and that actually reflects and overall
change in
reporting practice so that there are some
differences
in the way that deaths are actually registered as
being due to the respiratory system.
If we look at this year's death data, the
thing that we notice particularly is this early
peak
in deaths.
And one point I should make is that we did
have an earlier influenza season which peaked
really
between about weeks 46 and 52, as you will see,
but we
do have an excess, a very small excess of deaths
here
which is noticeable against an otherwise flat
background.
Now to come back to the virological data,
our virological data is derived both from
community
and hospital sources and community sampling takes
place from GP practices throughout the United
Kingdom.
What you see here is the clinical index of
morbidity,
here it is, rising above the threshold of 50 for
a
number of weeks, so peaking between about weeks
45 and
50.
In the pink, we have the number of samples
coming in from GPs and in the green, we have the
percentage positive. Our surveillance system is
somewhat susceptible to external influences, for
example, here a postal strike meant that many
samples
were sitting in the post for weeks, leading to
somewhat reduced recovery. But importantly, we look
also for RSV in this surveillance data and one of
the
things that is interesting is that our flu peaked
before the RSV started to kick in and normally
it's
quite difficult to disassociate them since ‑‑
and
that's particularly important in assessment of
morbidity and mortality in the younger age is to
know
when flu is circulating relative to RSV.
One of the ways that we analyze our
strains, particularly from community sources, is
we
analyze them genetically first, so we PCR samples
and
then once we have a PCR positive we attempt to
grow
virus which is slightly the wrong way around, but
gives us a very rapid turnaround and gives GPs a
quick
answer as to whether or not flu is positive in
the
samples that they've submitted.
Rather than try to characterize a lot of
our data antigenically, we developed and RFLP
which
just allows us to distinguish between Panama and
Fujian‑like viruses, so here, for example,
use of
different restriction enzymes allows you to pick
out
Panama viruses versus Fujian viruses.
So my point here is that this is a typing
method which isn't dependent on antigenic
analysis,
but is consistent with the antigenic data that we
have.
And by using this sort of genetic
approach, it's allowed us to look at the analysis
of
our influenza strains over the course of
2003. Here
is the start of 2003, so the last winter season
was
for us primarily Influenza B, but with some H3
influenza activity and a little bit of H1.
So during last winter season we saw some
H3 viruses of which over 90 percent Panama‑like. We
had a couple of low reactors which turned out to
be
Fujian‑like.
SARS came towards the end of the last
influenza season. We had an enhanced surveillance
program in the United Kingdom for returning
travelers
and this allowed us to characterize rather more
viruses over the summer than we would have got a
hold
of. And
we could see the proportion of Fujian‑like
viruses changing in here. The viruses that we
recovered from returning travels were almost
entirely
H3N2.
And just over half of those viruses, up
until the 1st of September were Fujian‑like.
Following the 1st of September, all of the
viruses
that we've received were H3N2, this current
winter,
having been Fujian‑like with just one or
two Panama‑
like viruses.
So my point here is that this influenza
season has been almost entirely pure H3N2 and
also
Fujian‑like, so evidence of a new drift
variant in the
population.
If we look at the distribution of the
isolates, in general, from either the community
or
from hospital cases, the vast majority of the
isolates
that we've had have been from young people with
relatively few from the elderly population. I think
that's important because that certainly does
contrast
with other years.
In terms of respiratory outbreaks, we
would say it was a fairly quiet season with 13
major
outbreaks reported. Eleven of these were in schools
or nurseries and 10 out of 11 were associated
with
Fujian‑like viruses. Two outbreaks occurred in
elderly homes, one of which was associated with
Fujian.
Now, this winter one of the reasons
there's been a lot of interest, particularly in
influenza, has been I think heightened awareness
of
the existence of a new drift variant, heightened
awareness I think because of SARS and the impact
of
emerging viruses.
Across the United Kingdom, we had 17
laboratory confirmed associated deaths. They were
laboratory confirmed either by PCR detection and
sequencing or by virus isolation so that would
usually
be detection in more than one laboratory so
confirmation by reference laboratory
ourselves. So
those are, if you will, rock solid laboratory
confirmed influenza associated deaths in
pediatric
cases.
For us, we would call that under 18.
And we
saw those deaths throughout really our influenza
season.
We obviously did have some deaths in the
older populations too which were laboratory‑
associated.
What I can say about these 17 deaths that
we had is that none of them were vaccinated and
only
two of them would have fallen into the risk
categories
for vaccination anyway. So the majority of these were
children not perceived to be at risk of severe
influenza.
Now in common with United States, we have
attempted some modeling work based on excess
mortality
calculations to allow us to get at the question
of
whether the number of deaths which we saw this
year in
children was consistent with what might be
expected.
It's been pointed out previously that in the U.S.
there is no formal mechanism for getting at laboratory
confirmed pediatric deaths and we have exactly
the
same problem in the United Kingdom. We don't have a
way of referring back, but what we do have is
good
enough data which allow us to calculate excess
morbidity with reference to knowledge of when
influenza is circulating and therefore a way of
estimating mortality in different age groups.
I think many of you will be familiar with
the papers put out in New England Journal of
Medicine,
I think it was or perhaps JAMA from Bill Thompson
at
CDC who's used a modeling approach to derive
excess
mortality.
My point here is that if we look at
1989/90, 1995/96 and 1999/2000, all of which we
know
to be H3N2, pure H3N2 years, virologically, if we
look
at the estimates of excess mortality in the young
age
groups that we have, the observations that we
have
this year are consistent with those
estimates. I
think that doesn't say exactly why those children
have
died, but what it does say is that the numbers
that
we've seen are consistent with previous years.
Let me move on now to virological
characterization of our data. Nancy has already
explained much of the hemagglutination inhibition
difficulties of this year. One of the things that we
noticed in our strains was quite a wide range of
HI
reactivity to the Fujian antisera and this strain
here, Scotland/50 is a strain recovered from a
fatal
case which does have reduced reactivity, although
we've seen this reduced reactivity of other
strains
and we do not think there's anything particularly
unusual about that.
When we put our sequences into more
limited dendograms based only on England strains,
we
also see two genetic groups which we've just for
the
sake of rather arbitrary reasons called it Group
1 and
Group 2.
These ones have the N126D substitution which
have already been mentioned and this Group 2 is
consistent with the other genetic groups that's
been
previously discussed.
The cases here in blocked out, represent
some of our preliminary sequence data from the
fatal
cases which suggest that the fatal cases fall
into
both genetic groups, but importantly are closely
related to other similarly circulating strains,
at
least on the hemagglutinin sequence that we've
developed so far.
Our N2 data, neuraminidase data from the
H3N2 also demonstrates the phenomenon which Nancy
has
alluded to, the fact that the neuraminidase of
the
recently circulating strains is closer to Panama
virus
than to Fujian‑like viruses which is
consistent with
a reassortment event and here is the
neuraminidase
from a fatal case, closely related to two other
nonfatal cases, also from young children.
With respect to Influenza B, we've had
only two isolates of Influenza B this season,
both of
which reacted well to Harbin and Sichuan serum,
placing them clearly in the Yamagata lineage and
distinct from Influenza B isolates that we had at
the
end or during the season of 2002/2003. So this
evidence is certainly suggestive of a resurgence
of
the Yamagata lineage in the United Kingdom, but
based
on a sample of two, I'm not sure how much we can
infer
from it.
And that is consistent also with the genetic
data which places these closest to the Harbin
lineage
here.
With respect to Influenza H1, we've had
one Influenza H1N1 detection which has a somewhat
reduced reactivity to New Caledonia, but again,
with
a sample size of one it's hard to know how to
interpret that information. We do know that it was an
H1N1 and it sequenced, clustered very closely
with
H1N1s and H1N2s which were circulating over the
last
year in the United Kingdom.
So in conclusion then, the 2003/04
influenza season in the UK could be summarized as
being early, young and low. The majority of viruses
were H3N2 and of those H3N2, it was almost
exclusively
A/Fujian‑like viruses with some evidence of
both
genetic and antigenic heterogeneity.
The neuraminidase sequences of the viruses
which we sequenced were certainly more closely
related
to Panama, suggesting reassortment events. And so far
our data suggests that the laboratory confirmed
deaths, the number of deaths are consistent with
previous estimates, but they do not act ‑‑
that
statement doesn't imply anything about the
susceptibility of those individuals. And the
Influenza B isolates which we've got suggest that
they
belong to the B/Yamagata lineage which is
consistent
with data elsewhere from Europe.
I think I'll stop there and ask for
questions.
CHAIRMAN OVERTURF: Are there
questions?
DR. MYERS: I'd like to ask Dr.
Royal's
question from this morning on the pediatric
patients.
Were these all pneumonia‑related deaths or
were some
of them neurologic?
DR. ZAMBON: The laboratory‑associated
deaths, all the subject of the public health
inquiry
in English, we should have the full, if you will,
pathological data available on those towards the
end
of March.
The evidence so far is that there's a range
of syndromes involved. There is definitely one with
post‑mortem findings consistent with encephalopathy.
There are others which have occurred as sudden
deaths
without antecedent illness and there are others
which
have had antecedent respiratory illness
recorded. So
I think there's a spectrum of illnesses in there
and
our propriety at the moment is to college
together in
one place the pathology findings with all of
those
deaths so that we can try to make some sense of
it,
but I don't think what will come out of it is a
single
unified pathology description of those deaths.
DR. MYERS: And just to be sure I
heard
you right, none of those children had been
immunized?
DR. ZAMBON: That's correct. What I can
say about immunization in the United Kingdom is
that
it is age‑related. The policy is age‑related, 65 and
above and we know from monitoring of immunization
uptake which occurs mandatorily that there is a
70
percent coverage in our over 65 population. The at‑
risk population below 65 is much less well
covered
than that of the order of 30 to 40 percent and
perhaps
lower and immunization of at‑risk children
is probably
lower than that still. It's of the order of 10 to 15
percent.
CHAIRMAN OVERTURF: Are there
other
questions for Dr. Zambon?
May I missed it. What was the
actual
number of children that were analyzed for this
year
were pediatric deaths?
DR. ZAMBON: Sorry, the number of
pediatric deaths was 17.
CHAIRMAN OVERTURF: Okay, thank
you.
DR. ZAMBON: The number of
children
analyzed and indeed the number of deaths which
came to
light was somewhat higher, but what we focused on
are
those which are definitely laboratory confirmed.
One of the questions that I see keeps
coming up in my mind and I haven't heard an
answer to
it today is ‑ and actually what we're
seeing in terms
of the higher morbidity and mortality seemingly
in
children this year, brings up the question again
about
what influence, particularly this year where
there was
so much heterogeneity in the Fujian strain, what
influence repetitive immunization, yearly
immunization
has in increasing or decreasing protection. Does
anybody have data on that, the effectiveness of
the
vaccine?
Because one of the things that has
occurred over recent years is that we have
certainly
increased our immunization rates, particularly in
elderly populations and many of those persons are
likely who have been ‑‑ obviously,
they've lived a
long time, but they've also ‑‑ and
been exposed, but
they've also been immunized many times. So is there
data on that?
Dr. Eickhoff?
DR. EICKHOFF: The data I'm aware
of such
as it is, comes largely from Houston. I think Bob
Couch and his colleagues have collected data in
several settings showing or studying the efficacy
of
influenza vaccine in a group of adults who have
been
sequentially immunized on an annual basis over a
number of years.
And as I recall the data, there was
really no difference in vaccine efficacy among
those
who were repeatedly immunized as opposed to those
who
were relatively new to influenza vaccination.
That's my recollection of the data.
In
other words, while we think those were repeatedly
immunized are immunologically somehow different,
the
data do
not seem to support that.
CHAIRMAN OVERTURF: Dr. Monto?
DR. MONTO: The group in the
Netherlands
have been much interested in the so‑called
Hoskins
phenomenon which actually doesn't relate to older
individuals at all, but to children in a boarding
school who were repeatedly vaccinated. They've
reanalyzed those data. The third year, clearly, was
wrong in terms of the conclusions that were
reached
and they've done a fair amount of modeling
recently
which is a little difficult to describe
succinctly
because it suggests that if you ‑‑
for some people if
you don't have an exact match, you do better in
terms
of long‑term protection than if you do have
an exact
match, but the bottom line is that there really
is no
evidence that repeated immunization is bad for
you
which is really what the Hoskins study was
talking
about, that if you were going to make antibody to
the
older strain, invoking the law of the original
antigenic sin which really doesn't apply in this
situation anyway, but saying that this was
certainly
bad for you and the conclusion is that repeated
immunization really is good for you.
CHAIRMAN OVERTURF: Dr. Decker?
DR. DECKER: Yes, Aventis Pasteur
conducts
annual studies of flu serum when it's first
released
in the market.
In a single small location where
there's a tendency for people to participate year
after year and we had caused recently to look at
the
data from most recent year and analyze it by how
many
times previously those participants have been in
the
study in prior years and thus, were known to be
repeaters and found no clear predictive effect on
their antibody response.
On the other hand, that doesn't tell us
how many of them that weren't in the study in
prior
years picked up their flu vaccine elsewhere, so I
can't rule out the possibility, but my impression
is
the same as you just heard.
But the other thing is that my
understanding of the overall epidemiology,
particularly in pandemic years is that there
tends to
be some evidence of protection from the severe
consequences of influenza and age cohorts old
enough
to have been around when that strain last
circulated,
so my own hunch in the absence of rigorous data
supported is that you do get some protection
against
death, but you don't particularly get any higher
antibody titers as measured in a lab.
CHAIRMAN OVERTURF: Were there
other
questions for any of the speakers in the
afternoon
session?
We are about 15 or 20 minutes early so
what I would suggest we do is we adjourn at this
time.
We are scheduled for a half hour break at 3
o'clock
and instead of that, we can be back at 10 minutes
after 3 and we'll begin at that time.
Thank you.
(Whereupon, the proceedings went off the
record from 2:40 p.m. to 3:14 p.m.)
CHAIRMAN OVERTURF: On the
record. So
we'd like to begin the second half of the
afternoon
with Dr. Levandowski who is going to give us a
rundown
on vaccine responses.
DR. LEVANDOWSKI: Okay, thank
you. I'll
try to be informative and clear and brief on
influenza
vaccine responses. This is always a task.
I'm afraid
people way in the back are not going to see
what's on
the slides because it's going to be tables of
results.
But I tried to do a better job this year. I hope it's
going to come across, at least color coded, that
you
can tell where the hot zone is on the serology.
First of all, I should mention that the
material I'm going to present here comes from a
number
of different laboratories. There are a number of
serum panels that are available to us from
different
parts of the world. These are shared between
laboratories.
There are some sets of sera for adults and
elderly that are shared between five different
laboratories.
All of them test these sera against
some of the same antigens and some different
antigens
to try to get some estimate or some gage on how
close
or different the currently circulating strains
are
from the vaccine influenza viruses.
So on this first slide, there are three
serum panels shown here that come from Australia,
from
England, and from Japan. These are for adults and
elderly.
You can see ‑ you probably can't from the
back ‑ but the vaccines are pretty much the
same.
They fit the recommendation from last year that
vaccines have an A/New Caledonia/20/99‑like
strain for
the H1N1, an A/Moscow/10/99, or in our case an
A/Panama/2007/99 (H3N3)‑like strain, and
then a B/Hong
Kong/330/2001 influenza B strain which is
represented
in the first two serum panels here by
B/Shangdong/7/97
and on the subsequent slide represented by B/Hong
Kong/1434/2002.
Serum panel number four, the first one on
this slide, is one that was made available to us
that
included not only adult and elderly serum, but we
had
a small number of sera from a second study in
children
that I'll talk about a little more as we get to
that
point.
The amount of serum obviously for pediatric
studies is relatively limited so those sera are
not
necessarily shared with all the other
laboratories.
But those first four serum panels are shared
amongst
all the laboratories that were involved in
looking at
serologies.
There's another serum panel from children
which Nancy Cox talked about. She presented some of
that information. I may be redundant and go over that
again if that's okay with you. Then because the
B/Yamagata/16/88‑like viruses seem to be
predominant
again, to try to get some information about
previous
vaccine strains that were similar, whether those
would
give us any coverage, we went back and tried to
find
some sera.
Our lab and John Wood in the UK tried to
go back and find some sera from some old panels
that
would have had a B/Yamagata‑like strain as
the vaccine
strain.
These would have been the most recent ones
from 2001‑2002. In our case, the B strain was
B/Victoria/504/2000. In the sera that John Wood was
able to examine, the strain was
B/Johannesburg/5/99.
Those two are antigenically similar to the
recommended
strain for that year which was B/Sichuan/379/99.
That's probably more than you want to know.
The antigens that were used for the H1N1
serologies are shown here. They are representative of
currently circulating strains and include H1N1
viruses, shown up at the top. The first three here
are H1N1 viruses. And the last four viruses on this
chart are H1N2 viruses. I don't know if it was
mentioned before but of course the H1N2 virus has
the
hemagglutinin from the H1N1 strain as it was
originally existing and has all the internal
genes and
the neuraminidase from the H3N2 strain.
The most important part for us however is
that the H1 here, actually as Nancy mentioned,
they
are very similar between these representative
strains.
So you can see we have them from a number of
different
continents, from Africa, from Asia. Does Iceland
count as Europe?
I think it does. And from the
Americas.
You won't be able to read this I'm sure
even at the back of the table. But what I have here
are an exemplary panel of anti‑sera. These are
adults.
Actually it's three different panels of anti‑
sera; adults from the United States, from Europe,
and
from Japan and tests that were done at CDC on
these
sera and the antigens that they looked at. In blue on
every one of the slides, if you can see the blue,
you
can tell what the vaccine strain is.
But A/New Caledonia/20/99 was the vaccine
strain that was used here. Then there were a number
of newer antigens; the Minnesota/18/2003,
Virginia/20/2003, and Belem/84066/2003. These last
two are H1N2s.
That one is an H1N1. I mentioned
that
I would show in red where there are significant
differences.
What I would like to try to do, although
I have all the information on these panels that
you
normally see in serologic tables, I would like to
focus your attention more on the geometric mean
titer.
This is probably the most non‑arbitrary
measurement
that we can look at. We're interested in determining
whether in the post‑immunization sera there
are
changes that would result in reductions in
antibody
responses.
We have arbitrarily chosen a 50 percent
reduction which would be a two‑fold
reduction in our
geometric mean titers. I think you can think of that,
if you will, similar to what Nancy Cox was
talking
about as a four‑fold reduction with a
ferret serum.
But it's another way to try to get to how
different
are the strains that are circulating.
In this case, you can see from all of
these serum panels I don't have anything colored
red
so there's nothing here that has a major
reduction, as
much as a 50 percent reduction from the vaccine
strain.
All of these strains, the H1N1s and the H1N2s
seem to be inhibited very well by the anti‑sera
from
people who are immunized with current vaccines in
three different places.
This is a similar table for the H1 for an
elderly population. In this instance, the serologies
were performed at NIBSC. There are sera from Europe,
from the United States, and from Japan again
here.
There are some different antigens shown here on
these
tables; Dakar/85/2003, Virginia/20/2003 what we
have
seen before, Iceland/123/2003, and
Nagano/1328/2003.
Again, we have strains that are representing the
H1N2
and also representing the H1N1.
Again, calling your attention the post‑
immunization geometric mean titers, I think you
can
see that in all of these serum panels from these
different locations that all of these strains are
inhibited very well in this elderly population by
the
anti‑serum in response to the New Caledonia
vaccine
was pretty good.
I should also point out that there
are going to be differences in the absolute
numbers on
these tables.
What I would really again want you to
focus on is the relative differences between the
vaccine strain and the new test antigens and not
worry
so much about the level of the antibody
responses.
That's really not the point of this
exercise. It's to
see if this can tell us anything about how
similar the
current antigens are in terms of their
recognition by
the anti‑sera from vaccines.
So now, there are pediatric sera as well.
These are studies that were done either at CDC or
at
the Center for Biologics. The CDC, as Nancy Cox
mentioned, had the panel of anti‑sera from
children
who were six to 23 months. I have already forgotten.
Someone told me what the mean age for the
children
was, but they were very young, around a year old
I
think on average.
Also there were some children who were six
to 38 months with a mean age of 21 months. Here
again, we're looking at the vaccine antigen in
blue
and then some of these newer antigens. Again, what I
think you can see is even in these very young
children
the antibody responses against these newer H1N1s
was
very similar to what was seen with the
vaccine. So it
suggests that children immunized with that
vaccine
would have very good responses. I should mention the
sera were collected after two doses of vaccine so
they
got the full immunization.
To try to pull this all together from all
of the data that we have, because not all of the
different groups tested all of the antigens and
we had
a number of different antigens that were tested,
I
have tried to summarize in the table here showing
where there was a 50 percent reduction in the
geometric mean titer of the test antigens as compared
to the vaccine antigen which here was A/New
Caledonia/20/99.
By gestalt, I think you will see
that there are very few instances in which there
was
as much as a 50 percent reduction in any of the
serologic tests that were done.
There was some reduction. We
always see
that.
There's always some amount of reduction in the
actual titers as compared to the vaccine
strain. But
for the most part, these are very minimal and not
very
indicative of much of a difference in terms of
what we
might expect from this kind of serologic testing.
So moving on to the H3, again, the vaccine
strain was Panama/2007/99. There are a number of
representative strains here. The Chile/82660/2003
strain is in the New York/55 group or Chile group
if
you want to use that terminology that Nancy Cox
was
mentioning that's different from the Fujian group
that
has been developing. All the rest of these strains,
and there are quite a few of them represented
here,
are all Fujian/411/2002‑like strains.
Here again, this is for adults. These are
sera that were tested in Australia at the WHO
center
there, European, U.S. and Australian sera. The
vaccine strain again is shown in blue in each of
these
panels.
Now what I think you can see, because there's
lots of red there, is that there are reductions
in the
antibody titers in a number of these panels.
It's as much as 50 percent for the
Wyoming/3/2003 in all three of the panels. It's not
quite reaching 50 percent for some of these other
antigens.
But you can see that somewhat consistent
with what we're seeing here that there is a
reduction.
On a different day perhaps that absolute titer
would
be a little bit less than it was there.
Again, from these sera, you can see that
all of these antigens, Victoria/584/2003,
Texas/584/2003 and the Chile/82660 which was in
the
other lineage Fujian‑like strains, all of
those are
relatively poorly inhibited by anti‑serum
from the
current vaccine.
And that's true with the Australian
sera here as well.
Again, looking at the elderly sera, CDC
did these tests, sera from the United States,
from
Japan, from Australia. The vaccine strain is shown in
blue.
Again, you can see that in the majority of
instances there's as much or more than a 50
percent
reduction in the antibody titers. That's not always
true.
There are some of these panels where the
antibody titers seem to be a little bit
higher. But
the general trend seems to be that there are
reductions.
This is looking at children.
Again, the
serotested at the CDC and the serotested at the
Center
for Biologics.
These are two different separate
panels.
Here, the Chile/82660 strain showed a 50
percent reduction. I think I have the numbers right.
It's not as much as a 50 percent reduction for
these
other representative Fujian‑like
strains. But there
is some reduction there.
Similarly, this group of children, the
Kumamoto/102/2002 strain which is a Fujian‑like
strain
was not really reduced in this one test. I'm not sure
how many conclusions we can draw from that. But there
were reductions that were fairly substantial with
the
other Fujian‑like strains.
To try to do the summary again for this
with the 50 percent reductions, here you can see
looking at the overall scope of testing that very
many, in fact the majority of the serological
testing
indicated that there were some substantial
reductions,
more than 50 percent reductions, in the geometric
mean
titers of the test antigens versus the vaccine
antigen.
Here, you also see that for the most part
the mean percent reduced is over 50 percent
overall
with some of these in some instances having
almost no
cross reactivity with the test antigen in the
particular test that was done.
There are some differences. You
see that
not always do all the laboratories pick things up
quite the same way. This partly relates to the fact
that we're using this arbitrary cutoff of 50
percent.
It doesn't mean that there wasn't some reduction.
It's just that it wasn't that severe.
Now, finally, coming to the influence of
B serologies, this is a little more complex. The
current vaccine strains are Hong Kong/330/2001‑like
strains.
Then these serologic panels are represented
by Shangdong/7/97 and Hong Kong/1434/2002. In that
same HA group, we have B/Sichuan/259/2003. That's the
only strain actually that's amongst these that
was
included in the test. Partly this reflects that fact
that there have been so few recent influenza B
viruses.
But there were more that were in the
Yamagata/16/88 lineage. Some of the time we're
calling them Shanghai/361‑like. They are represented
by a number of different strains from different
locations including the United States, from North
America, from Asia several, and from Europe. As I
mentioned before, we have the older vaccine
studies
which I'll get to at the very end with older
Yamagata/16/88‑like vaccine strain.
These are adults who the sera were tested
at NIBSC from Europe, Australia, Japan. I think they
give pretty much the same picture. The vaccine strain
is shown in blue. The Sichuan/259/2003 strain is
similar to the vaccine strain. You can see that in
all these serum panels there's very little, if
any,
reduction as compared to the vaccine strain.
But in this case the B/Jilin/20/2003 is
one of the Yamagata‑like strains. It's related to
Shanghai/361 and there are some fairly
substantial
reductions, 50 percent or more, in all cases
here.
DR. FARLEY: Excuse me for interrupting.
Several people were asking for hard copies of
your
slides.
Apparently they were stapled by mistake to
the next speaker's presentation. So if you look at
the next speaker's presentation, page two, three,
and
four are really for Dr. Levandowski. Sorry for the
interruption.
DR. LEVANDOWSKI: Okay, do you
want me to
start over?
(Laughter.)
DR. LEVANDOWSKI: So moving on,
elderly
tested at the CDC, serum from the United States,
from
Europe, and from Japan. Here the vaccine strain or
what was representative of the vaccine strain in
these
serologic panels was B/Hong Kong/1434/2002. We have
the vaccine‑like strain, the
Sichuan/259/2003, and
then some other representatives of the
Yamagata/1688
lineage.
In this case, it's somewhat variable, but
again I think it shows that there are reductions
for
people who are immunized with the current
vaccines.
There are reductions against these Yamagata‑like
strains, most marketably shown in this serum
panel by
the Jiangsu/10/2003 strain. But that's true again you
see for B/Jilin/20/2003 and
Washington/3/2003. You
see that there are some reductions in the titers
here
as well for those strains.
Pediatric populations pretty much tell the
same tale.
These are children who for the most part
have not been immunologically primed. Therefore, if
they haven't been exposed to both of the strains,
we
would predict from all past experiences ‑‑
And we have
had a lot of them looking at this kind of data
although not in the past two or three years.
We had quite a lot of experience with it
in the early 1990s when the strains seemed to
have
diverged.
It's pretty clear that there's a big
difference between the Hong Kong‑like
strains up here
and the Yamagata‑like strains. Maybe it should say
the Victoria/287‑like strains up here and
the
Yamagata/1688 strains down here. There's essentially
no responsiveness of these children to the other
HA
lineage.
That's true in this panel down here.
You
see a large difference between the vaccine and
the
Yamagata‑like strain, the B/Jilin/20/2003.
So the last thing I'll cover here are some
studies that we did with an older vaccine,
vaccines
from 2001‑2002. These studies were done at NIBSC for
some European sera or in the United States. We had
sera from adults in this instance. We had a small
number of sera from adults and elderly in the
other
instance.
Again, the vaccine strains are in blue here
in each case.
Although there was some reduction, it
wasn't as dramatic in this particular instance
between
the vaccine strain and the test strains which are
all
in the same HA lineage so it isn't too
surprising.
But here in this particular panel ‑ and
it's only one
and it's a small number of sera so it's hard to
draw
too much conclusion from it ‑ there was
more than a 50
percent reduction.
This is a little bit difficult to
interpret because the pre‑immunization
titers in our
serologies here were different. So this was about
two‑fold higher to begin with. It's hard to know
whether that just represents something about the
technique in that particular instance. Here again, in
this particular panel, there's not much of a
difference between the older vaccine strain and
B/Jilin.
Going back to the main part of the
serology, here again, it's trying to sum it up
with a
50 percent reduction for these newer
strains. All of
these at the top are in the Yamagata/16/88 or
Shanghai/361 family. You can see that there are
reductions.
If you add this up, that the majority of
instances there's some reduction in titer. Although
it's not quite 50 percent on mean, there is a
tendency
for these to be higher. They are in between what we
saw with the H1N1 and the H3N2 but there is
somewhat
of a difference there.
But if we looked at the viruses that are
in the same HA lineage as the vaccine strain,
actually
the coverage would look pretty good. There's a
divergence here coverage good for the vaccine
strain,
coverage not so good for the currently circulating
strains in the other HA lineage.
So to try to summarize then, studies with
the sera that were collected after immunization
show
that representative influenza H1N1 and H1N2
viruses
are very well inhibited. Many of the
A/Fujian/411/2002 (H3N2)‑like viruses are
less well
inhibited than the vaccine strain. The B/Hong
Kong/330/2001‑like viruses are well
inhibited by
current anti‑sera.
But the Shanghai/361/2002 and similar
viruses are less well inhibited than the vaccine
strains.
That's most marked in the instance of young
children who have not been immunologically primed
for
both strains.
I can just stop there and take
questions.
CHAIRMAN OVERTURF: Are there
questions
for Dr. Levandowski?
DR. ROYAL: This sort of reflects
my
ignorance about how you look at the data. But when
you look at a 50 percent reduction, that's not
exactly
what you are doing in analyzing your other
neutralization data in that you are looking at at
least a four‑fold change in your
neutralization or
your titer.
Here, you are looking at a 50 percent
reduction instead of at a range of 25 to 75. Could
you explain that to me?
DR. LEVANDOWSKI: Yes, in terms
of the
ferret sera, we're looking at individual ferrets.
There, you have a one time test basically. But here,
we're looking at pooled data. We were looking at more
than one serum at a time so the geometric mean
titer
is from whatever the number is we happen to have
in
the serum panel.
You can see that that was variable
for this time.
It's an arbitrary measurement.
The four‑
fold of course in the ferret serum is because
when you
do two‑fold dilutions, you have the
possibility of
having one two‑fold dilution error. To try to factor
that out, you take four‑fold to make sure
it wasn't
just the crossing. With the geometric mean titers,
it's actually a little bit firmer.
Although, on any given day, I think we
could be two‑fold off on our geometric mean
titer. I
wouldn't put it beyond the scope of imagination
for
that to happen.
I think that's less likely to be
true.
When we were looking at a two‑fold difference,
when we're looking at the geometric mean titers,
it's
not quite the same as looking at the four‑fold
difference.
But I tried to sell that. If you
don't
buy it, okay.
(Laughter.)
CHAIRMAN OVERTURF: Yes, Dr.
Palese.
DR. PALESE: We heard that we
have
basically no influenza B or in H1 this year in
the
United States.
What is your assessment in terms of
the B lineages worldwide, particularly in terms
of the
B/Yamagata and B/Victoria, this season and the
summer
season on the Southern hemisphere?
Basically we would like to get some
feeling which one of these lineages, Victoria ‑‑
And
I know there have been many names given to these
different lineages. But let's stick with Victoria and
Yamagata.
So what is your feeling in terms of
worldwide distribution of these two lineages just
in
terms of B?
DR. LEVANDOWSKI: I think I'm
going to
have to defer that question to Nancy Cox
probably.
But I guess I could take a stab at it and give
you a
quick answer.
The majority of the strains that are
appearing are in the B/Yamagata lineage. There are
very few that seem to be in the B/Victoria/287
lineage.
Thinking back to a similar experience,
although someone said that influenza is totally
unpredictable and what happened in the past is
not
necessarily likely to happen in the future. But the
situation was somewhat similar in 1989. All the
strains that were circulating that anybody had
seen
were really Victoria/287. B/Yamagata/16/88 itself was
identified just that first winter in Japan. It hadn't
been seen any place else.
Interestingly enough, in many countries in
the world the following year it was the
predominant
strain.
In some countries, it was still a 50‑50
spread of those two. But it was a fairly ramped
spread. I
don't know if that was because of a
susceptible population. I tend to think that it was
because there was a big difference in the percent
of
people who had antibodies that cross reacted with
both
of these strains.
It depended on whether they were
immunologically primed or not. Again, we're really
referring to children. So I'm rambling off the
question that you asked. But I think we have a
similar situation where there is a susceptible
population that's been developing for a couple of
years.
The current strains that have spread to a
number of different areas, because they have been
identified on several continents, have the
opportunity
for spreading further.
DR. PALESE: Do we have in our
handouts
precise numbers?
Looking at 115 isolates, how many of
them are Victoria and how many are Yamagata? Do we
have that in our handouts?
DR. LEVANDOWSKI: Nancy, can you
help me
here?
DR. COX: Okay, if you look on
the
influenza C isolates characterized in the CDC
package
which is the second page after the influenza B
viruses
start, you'll see just the influenza viruses
characterized by the CDC. But these are really
reflected of the overall global data as well.
You can see it divided up by time
interval.
So if we look back at the time interval
from April 2002 to September 2002, you see that
approximately 90 percent of the viruses were Hong
Kong
or Victoria lineage viruses. Likewise, the following
time interval, October 2002 to March which was
our
last winter season, we had a large number of
influenza
B isolates.
Over 90 percent of them were B/Victoria
lineage viruses.
Then if you look to the next time
interval, Southern hemisphere influenza season,
you'll
see that it starts to change slightly and we have
smaller numbers.
But we had a higher proportion of
viruses that were actually Yamagata lineage. It's
represented here by Sichuan/379‑like and
Sichuan/379‑
like (low).
Then admittedly for the most recent
period, we have a small number of influenza B
viruses
that we analyzed at CDC. But the proportions here are
reflective of similar numbers and similar
proportion
of viruses that were analyzed by two other WHO
Collaborating Centers; one in the UK and one in
Tokyo.
DR. PALESE: Do we have those
numbers
because 11 is very little and very low?
DR. COX: I don't have those
numbers at my
fingertips.
But it is similar numbers.
DR. PALESE: But again, in order
to make
some informed prediction, one would like to have
some
statistical ‑‑
DR. COX: I'll get those for you
at the
break.
CHAIRMAN OVERTURF: Are there any further
questions for Dr. Levandowski? Okay, we'll go on
then. The
next issue is the availability of strains
and reagents by Dr. Ye.
DR. YE: This presentation is
related to
the status of candidates vaccine strains and
potency
reagents for production and the standardization
of the
influenza vaccine. Current influenza vaccine contains
three antigenic components, two type A which are
H1N1
and H3N2, and one B component.
New Caledonia/20/99 is a current vaccine
strain for H1N1.
IVR‑119 is a reassortant between New
Caledonia/20/99 and A/Puerto Rico/8/34 or PR8
which is
a high growth virus. This reassortant gives moderate
to high yield in A. Additional research of this virus
from NIBSC in the UK is available for evaluation.
However, currently we do not have any candidate
strains for this virus for distribution.
A current H3N2 is A/Panama/2007/99 which
is A/Moscow/10/99‑like strain. IVR‑17 is a
reassortant between A/Panama/2007/99 and PR8. This
reassortant gives a high yield in A. The candidate
strains are Fujian/411/02‑like
strains. There are two
strains right now. One is Wyoming/03/2003 and
Kumamoto/102/2002.
IVR‑134 X‑147 or X‑149 are the different
reassortants between Wyoming/03/2003 and
PR8. They
all have moderate to high growth in A. IVR‑135 is a
reassortant between A/Kumamoto/102/2002 and the
PR8.
This reassortant has moderate to high yield in A.
The current vaccine for B components are
B/Hong Kong/330/01‑like strain. It's been mentioned
that there are two HA antigenic lineages for
influenza
B viruses.
They are the Victoria lineage and the
Yamagata lineage. The current influenza vaccine is
B/Hong Kong/330‑like which is Victoria
lineage. There
are three viruses; B/Hong Kong/330/2001, B/Hong
Kong/1434/2002, and the B/Shangdong/07/97 that
all
have moderate yield in A.
The candidate strain on the other hand is
B/Shanghai/361/2002‑like strain which
belong to the
Yamagata lineage. There are two strains.
One is
B/Shanghai/361/2002 itself and another one is the
B/Jilin/20/2003.
The growth characteristics of those
two viruses is still in early development. But in our
hand it seems likely Jilin/20/2003 gave us a
reasonable year in A.
Now I'll move on to the potency reagents.
The anti‑sera and antigens for A/New
Caledonia/20/99
and for Panama/2007/99 are available in CBER for
distribution.
Since Fujian/411 has been recommended
for the Southern hemisphere, the anti‑sera
and antigen
for A/Wyoming/03/2003 are available from NIBSC in
the
UK and TGA in Australia. CBER has anti‑sera for
Wyoming/03/2003.
Both anti‑sera and antigens for
A/Kumamoto/102/2002 are available in TGA in
Australia.
However, they only have a limited amount of both
antigens and anti‑sera for
distribution. However, if
other strains are chosen, specific reagents will
be
available in May at the earliest.
The current reagents for B are B/Hong
Kong/330/01, B/Hong Kong/1434/2002, and the
B/Shangdong/07/97. Both anti‑sera and antigens are
available in CBER. If we decide to switch from
Victoria lineage to Yamagata lineage, the anti‑sera
and antigens for previously used vaccines are
available in CBER which could be used for initial
potency tests.
However, if a new strains are chosen,
specific reagents will be available in May at the
earliest.
Thank you.
CHAIRMAN OVERTURF: Are there
questions
for Dr. Ye?
DR. DOWDLE: Walter Dowdle. Would you
remind us again about the recommendations from
the
Southern hemisphere for B?
DR. YE: For B, I will refer to
Roland.
DR. LEVANDOWSKI: The
recommendation
currently is the same as it was for the Northern
hemisphere.
It's B/Hong Kong/330/2001‑like strain.
It includes several different strains just as it
does
here. So
there was no change in the recommendation
for the Southern hemisphere this past season.
CHAIRMAN OVERTURF: Are there
other
questions regarding reagents or potency? Thank you.
At this time, we'll have comments from the
manufacturers and Greg Slusaw.
DR. SLUSAW: Thank you for this
opportunity to address the committee today and
chair
the manufacturer's perspective on flu vaccine
manufacturing.
I would like to talk about a couple of
things today.
First is a brief discussion of some of
the time lines we face and some of the
constraints
when manufacturing flu vaccine and also to
emphasize
some of the activities that have to come together
to
ensure a successful flu vaccine manufacturing
cycle.
I'd like to start with just a brief overview of a
high
level view of the process. This is where we are right
now in February.
As mentioned several times earlier today,
manufacturers often will begin production of one
of
the vaccine strains prior to this meeting, taking
the
risk of doing that vaccine in advance but basing
the
decision on some of the early available
surveillance
data that's out there then of course soon after
that
manufacturing the monovalent component of the
second
strain and then the third strain preferably with
a
period of the end where all three strains may be
manufactured intermittently to balance off
equivalent
amounts of the three antigens to support
formulation
of the final bulk vaccine which of course leads
to the
production of the final vaccine doses which are
distributed at the end of July through October.
A couple of key things I would like to
emphasize here are first of all let me put some
dates
in your mind for beginning manufacturing of the second
and third vaccine strains. For the second strain, for
us at least, that's right about now, in February,
where we have manufactured large amounts of the
first
vaccine strain, the New Caledonia H1N1. We need to
begin production of the second vaccine
strain. Also
a reasonable time frame would be April or so at
the
latest to begin manufacturing the third vaccine
strain.
A few messages though that I would like to
leave with this slide to keep in mind is although
these may be the dates for beginning
manufacturing of
the strain, as Dr. Levandowski mentioned this
morning,
there's some pre‑work, some ground work
that needs to
be laid before we can actually start
manufacturing.
That's making the working vaccine seed to use in
production as well as making the high growth
reassortants which are really critical to
supporting
the number of doses that we're manufacturing the
last
few years since the production yields are two to
four‑
fold higher than they would be for the
corresponding
wild‑type virus.
So again, although we're looking at these
time frames to start, remember that we had to
make a
decision back here a little bit earlier that a
new
isolate was unique enough that it was something
that
we wanted to look at for making a reassortant and
considering it as a potential vaccine candidate
strain
for this year.
Another point I would like to make is
in order to produce the number of doses we did
last
year, we need to keep this manufacturing pipeline
full
from the December/January timeframe up until all
the
monovalent components are manufactured in August
or so
without any gaps or delays in production.
One of the consequences if we do have a
brief delay in production, for example, if
there's a
delay in selecting the third strain and the
second
component is completed being manufactured, is
that
will push everything out that period of
time. But it
will still take the corresponding number of days
to
complete manufacturing.
So delaying monovalent manufacturing due
to a delay in strain selection or availability of
the
seed virus will ultimately push out the
distribution
of final vaccine doses. I think as the manufacturers
have learned from previous years, vaccine doses
which
are made available much after the end of October
or so
are generally not saleable doses and they often
end up
being destroyed.
Something in the manufacturing time line
that Dr. Levandowski mentioned this morning that
I
would like to amplify a bit is we're often asked
"Why
does it take you so long to make flu
vaccine?" That
question usually comes internally from our
marketing
departments.
But I've laid out a hypothetical process
here from the first eggs going into the pipeline
to
the first vaccine doses coming out.
We really don't have to pay attention to
all the details in the process throughout
here. But
just distilling it down into the basic
operations, I
wanted to emphasize that only about 15 percent,
ten
days or so in this scenario, is actual
manufacturing
time where there is processing of vaccine going
on.The
rest is quality control testing, release document
review and so on and all the quality checks that
need
to go into ensuring the quality characteristics
of the
vaccine.
So that's something to keep in mind.
There
really aren't a lot of opportunities to expedite
the
time line here at least by streamlining the
manufacturing process itself.
So an update on the current status, where
are we now?
I just wanted to mention this has been a
subject of discussion in previous years, the
critical
nature of egg supply and ensuring that enough
embryonated eggs are available for vaccine
production.
I think we have undertaken major efforts over the
years to enhance the reliability of the supply to
the
point where it's really become almost a non‑issue.
We currently have a reliable egg supply
that will fully saturate our available
manufacturing
capacity.
This supply is available virtually all year
long in part because the manufacturing cycle has
become so long but also because several
manufacturers
manufacture vaccine for the Southern hemisphere
as
well. So
there's a second flu campaign going on each
year.
We have supplemental back‑up flocks
available to replace any birds that are lost
throughout the year. We have undertaken efforts to
make sure the flocks are geographically
dispersed,
particularly getting some of the flocks away from
other commercial chicken production areas
too. Then
of course, we put biosecurity precautions in
place.
This includes limiting access to the flocks as
well as
disinfection procedures for people, equipment,
vehicles, and so on.
I'll run through this really quickly.
This is basically the same information that Dr.
Ye
just presented.
As I mentioned, as a manufacturer, we
took a risk last year. Although, we normally begin
early production. We have manufactured virtually all
of the New Caledonia H1N1 that would be required
for
this year's vaccine.
That was partially a response, trying to
be proactive to the unique situation we had with
the
perceived vaccine shortage last year and looking
at
the best available surveillance information that
was
available in December. We undertook the risk to make
that monovalent component at that time.
Among the H3N2 candidates, of course we
have last year's vaccine strain and a number of
A/Wyoming/03 reassortants which we have
evaluated.
The X‑147 seems to be the best one in your
hands right
now.
Another possible candidate would be the
A/Kumamoto.
The B strains, of course we mentioned the
Hong Kong strains from the current vaccine
formula,
the 1434 and the 330. We have limited information
with the B/Jilin. The early data indicates that this
one is also a moderate grower. But that's very early
in the initial stages of seed preparation right
now.
But it looks like a potential candidate strain if
the
decision is made to switch B strains.
Okay, so for the ten minutes or so that I
have the soap box here, this is my wish
list. Step
one, choose the right strains and also in a time
frame
that's appropriate for vaccine manufacturing so
we can
ensure that we can make the maximum number of
doses in
the time frame that's required. But that's what
today's meeting is all about.
Also the timely availability of seed
viruses.
That includes again those steps that have to
be undertaken in preparation of starting
manufacturing
such as making high growth reassortants and
giving the
manufacturers time to make the working seeds for
vaccine production.
Not directly related to this committee but
something we also have to keep in mind which is a
collaborative effort between the manufacturers
and
regulatory agencies is timely availability of the
potency reagents. Finally, an opportunity for
manufacturers to participate in this process and
evaluate the growth and purification
characteristics
of candidate strains before the final selection
takes
place.
Thank you. Any questions?
DR. MCINNES: Greg, I wonder if
you could
describe how you characterize a reassortant as a
medium grower or a high grower? What are you
measuring when you say that?
DR. SLUSAW: That would be the
actual
hemagglutinin yield based on when we have the
official
homologous potency test reagents. So that translates
directly into two to four times more vaccine
being
available.
DR. GELLIN: This is Bruce
Gellin. Is the
maximum availability of vaccine related to what
you do
on a given day or how long you extend the
process?
DR. SLUSAW: Could you be more specific by
what we do in a given day?
DR. GELLIN: Are you running at
100
percent capacity on April 12?
DR. SLUSAW: Yes, virtually.
DR. GELLIN: So to make more
vaccine, you
just have to make more monovalents and more over
time.
You have to extend the period by which you
campaign
each monovalent run.
DR. SLUSAW: Right, I think the
important
thing is that we keep the manufacturing queue
full by
manufacturing every given day without a break of
time
in there waiting for strain selection, for
example.
But now of course as in this case, we have
manufactured virtually all of the H1N1 that would
be
required.
So we need a second strain to move on or we
will have a gap in manufacturing.
DR. GELLIN: I don't know the
situation.
But assuming that you had bulk from last year,
would
you be able to use bulk H1N1, or do you have to
make
fresh bulk?
DR. SLUSAW: Generally we haven't
been
carrying over bulk material from previous
years. It's
made fresh annually.
DR. GELLIN: Generally, okay.
DR. SLUSAW: Currently we don't
carry
over.
CHAIRMAN OVERTURF: Dr. Eickhoff.
DR. EICKHOFF: If I recall
correctly,
there was one year perhaps in the mid‑80s
that avian
influenza decimated the manufacturer's flocks
such
that they had to stretch very hard to find enough
chickens who were free of avian influenza where
the
eggs from which could be used to make
vaccine. To my
knowledge, and please correct me if I'm wrong,
this
has not been a problem for the last 20
years. Is that
threat the reason for the biosecurity precautions
that
you mentioned?
DR. SLUSAW: Yes, I think the
reason for
the biosecurity is people's memory of the events
of
the mid‑80s as well as the sporadic annual
outbreaks
of avian influenza that we experience. Realizing
again how critical the egg supply is, we put
these
measures in over the last five or ten years or so
to
ensure the flocks are isolated and to protect
them to
the extent we can. Of course, nothing is completely
iron clad.
But the measures that are in place today
are much more sophisticated than they were ten
years
ago or during the mid‑1980s, for example.
DR. GELLIN: This is Bruce Gellin
again.
I'm going to push you on the eggs. You said it was a
non‑issue.
I would like you to qualify which parts
are non‑issues. You just talked about biosecurity.
Given the situation this year where there was a
high
demand and no one knows how that will translate
into
next year and should there be an increased demand
by
X percent next year, do you have enough eggs to
meet
such a demand?
I can give you numbers. But I
was
wondering what not an issue means.
DR. SLUSAW: Okay, let me clarify
that.
Eggs are an issue in that they are an absolutely
critical raw material for our process. However, they
are not really an issue for expanded
manufacturing
capacity because we already have an adequate
supply of
eggs to max out the available plant
capacity. So
really to produce substantially more doses we
would
need more physical manufacturing plant.
DR. GELLIN: So you have enough
eggs to
maximize your existing capacity year round.
DR. SLUSAW: Potentially year
round if
there were a demand for doses produced outside
that
July to October window.
CHAIRMAN OVERTURF: Dr. Farley.
DR. FARLEY: What would be the
impact of
pandemic strain emerging or having to shift
gears? Or
is that just opening a can of worms in terms of
having
to manufacture two kinds of vaccines I guess is
what
I'm asking?
DR. SLUSAW: Well, clearly if we
were
going into full scale manufacturing of a pandemic
strain it would be an either/or situation, either
the
conventional trivalent vaccine or the pandemic
strain.
So they couldn't produce the full normal doses of
a
trivalent strain in addition to pandemic vaccine.
CHAIRMAN OVERTURF: Dr. Myers.
DR. MYERS: There's obviously a
lag
whenever there's a change in strain. But it sounded
from what you described as if there would be less
of
a delay in the changing to A/Fujian than for the
Yamagata strain of B. But are they directly additive
if you change two strains? I know we do this every
year.
Would the impact of that be directly additive
or not?
DR. SLUSAW: Not directly
additive in that
a lot of the activities involved can be done in
parallel and done concurrently. But you are also
correct in noting that we're in a closer position
to
begin the A/Wyoming H3N2 production before we are
the
B/Jilin production because we still have seed
development to do and things to prepare for
there.
DR. MYERS: The other
manufacturers, are
they similarly positioned?
DR. SLUSAW: Would any of my
colleagues
like to comment?
DR. HJORTH: I'm from Aventis
Pasteur as
well, Richard Hjorth. I just wanted to add to
something Greg was saying. It might have less to do
with the number of strains that are changed as it
would with the amount of time we have had to work
with
them.
We've had the X‑147 for quite a while.
We've been able to get that ready to go. The other
reassortants we just received recently. So it would
be a lot harder to use them. Now, if we had the X‑47
and the B/Jilin back in September, I think we
could
pretty easily make that change. But since we're just
getting the B/Jilin and similar kinds of strains,
there would be a lag because we need to do at
least a
month's worth of work and probably more.
CHAIRMAN OVERTURF: Dr. LaRussa.
DR. LARUSSA: Relative to last
year, are
you planning on making more or less or the same
number
of doses of vaccine?
DR. SLUSAW: I think the
manufacturing
forecast ‑ and Dr. Decker, you can correct
me if I'm
wrong ‑ is similar to last year.
DR. DECKER: You keep looking at
me so
I'll comment.
Ultimately we make what you order.
If
you want vaccine, put in an order. The expectation is
that demand for vaccine in the upcoming year will
probably be higher than the average for prior
years
because of the stimulus everybody got from the
events
of this past fall. But in truth, it's the orders that
come in that determine the amount that everybody
makes. I
would predict that we'll end up making at
least as much as we did last year. But that's just my
prediction.
CHAIRMAN OVERTURF: Dr. Myers.
DR. MYERS: Can I ask a question
that goes
back to Roland and Nancy probably?
CHAIRMAN OVERTURF: Yes, they're
fair
game.
DR. MYERS: Roland quite
correctly noted
there was a difference in the age groups in the
two
pediatric populations so there were differences,
both
magnitude of serologic response as well as the
demographics of the populations, particularly
with the
B strains.
And they were tested in the same
laboratories.
I understand all those copy ads.
But the sera that we supplied to CDC were
much younger children. Their mean age was 11 months.
All but two of the children were less than 15
months.
I think the other panel of sera were from
children
that were on the average of two years of
age. The
geometric mean titers are very different between
those
two groups of children for the B strain.
Like Dr. Royal, when I think about
geometric mean titers, I understand that what
we're
doing with these sera pools is looking for the 50
percent reduction because that's how we look for
a
drift.
But if you look at the 50 percent reduction in
those young infants, they have no response to the
other strain, to the Jilin strain.
So 50 percent reduction to them is no
response at all in the young infants. I think we need
to keep that in mind that the young infants are
not
being primed.
Whereas if you look at the older
infants and the adults, a 50 percent reduction
doesn't
take them down to zero.
CHAIRMAN OVERTURF: Did you have
a
question for Dr. Levandowski?
DR. MYERS: Well, we're supposed
to be
looking at this as a reduction in geometric mean
titer.
But I wonder about the effectiveness of the
vaccine if there's no immune response in the
young
infants and how that should weigh in on our
consideration of strain selection.
CHAIRMAN OVERTURF: Yes, Roland.
DR. LEVANDOWSKI: Okay, I can add
some
information from older data again from a study
that we
collaborated with CDC on. We had some young children,
some of whom had been immunologically primed and
some
who were quite clearly not. They were young children.
They were immunized with the Victoria vaccine
strain. We looked at both HI and
neutralizing antibodies in those children. There was
a perfect correlation between the
hemagglutination
inhibition and the neutralizing antibodies. It
indicated that there were good vaccine responses
but
it was really zero, as Marty is pointing out,
against
the other HA lineage. This is something we've seen
going on for a long time so that's no surprise.
There, we really don't need to talk about
50 percent reductions because there's really no
antibody response to the antigen for which
there's no
priming.
I think I probably ought to point out that
there is a bigger difference between the two
influenza
B lineages, as Nancy showed on her slides with
the
ferret sera, than there is between the H3N2
strains
we're talking about.
CHAIRMAN OVERTURF: For those
very young
children we're talking about, these children
receive
two doses.
DR. MYERS: Yes.
CHAIRMAN OVERTURF: Yes, Dr.
Decker.
DR. DECKER: I want to go back and finish
addressing a couple of things that got left
dangling.
One was the question about the impact of changing
two
strains versus one. Greg gave you most of the answer
to that.
The other thing that I would comment though
is that there's always a hard to quantify risk
involved in a strain change.
There's the unpredictable risk of having
unexpectedly low growth. In fact, in 2000 when we had
such a debacle, much of that was traceable to the
fact
that we had not only low growth but because we
had no
reagents available until late in the spring. We
didn't know we had low growth. By "we," I mean the
industry, not just Aventis Pasteur.
So it looks this year there is a decent
chance I would guess we might change two strains
and
that's not to say that would not be the right
thing to
do. But
every time we think about that, we have to
recognize we're doubling the risk that something
unexpected like this will happen and interfere
with
supply.
So it's important to keep that in mind.
The second thing is there was a question
raised whether Greg's comments were applicable to
all
of the manufacturers' situations or just to
Aventis
Pasteur.
In the break just now, I had the chance to
put my head together with my colleague from
Chiron and
confirm that their situation is, as far as I can
tell,
identical to ours in that we must leave this
meeting
with the ability to begin production of strain
two if
you want optimal timing and supply of vaccine. And it
would be very good to know what strain three is
so
that the work can get hard going in an aggressive
fashion on being ready to manufacture that.
CHAIRMAN OVERTURF: Yes.
DR. MARKOVITZ: I wanted to
follow up with
something else you said, Mike. The question was posed
as to the ability essentially of industry to
continue
to ramp up.
I understand industry has ramped up
considerably over the last years. Your response was
well, it depends on what you order. But my question
is it depends what who orders and when do they
order
it and when does that come relative to your
decision
about how much to make and how reversible is that
decision if subsequently it becomes clear that
more is
needed?
DR. DECKER: The answers are a
little
complex so recognize anything I say is a
simplification.
Pretty much production facilities
like this are in use year round. So in response to
Bruce's question, I would simply say eggs are not
the
right limiting step.
Now, if you want us to now make flu
vaccine for the Southern hemisphere because you
want
for some reason for us to continue making it for
the
Northern hemisphere when we should be making it
for
the Southern hemisphere, they both take
eggs. It's
just a matter of what we use the eggs for.
If there's a crisis that would force us to
stop using that facility to make some other
vaccine
that's otherwise considered important in order to
use
those eggs in that facility for flu, then that
can be
done. But
the facility is pretty much in use year
round.
The eggs are going into it everyday.
So eggs
aren't the issue.
Can we build new facilities?
Sure, we can
and we do.
Do you build factories to make stuff
nobody wants?
No, you don't do that. U.S.
Public
Health Service has set a goal for Healthy People
2010
of 150 million Americans immunized. Last year we had
the greatest uptake ever and we got 85 million or
something.
That's a pretty big gap.
If tomorrow 150 million people wanted a
flu vaccine, the industry would certainly be
panting.
But if you ramp that up, as everyone hopes you
do,
smoothly over the course of a decade, I'm
confident
we'll all be right there with you.
DR. MARKOVITZ: I know you are
speaking a
little bit figuratively. But when do you actually
know how much people are likely to want from you?
When is that relative to other decisions like
today's
decision and other decisions in the future?
DR. DECKER: Well, we open the
ordering
lines in December for the vaccine that will be
distributed late summer or early fall this
year. I'm
not sure.
Maybe one of the other guys here knows when
the ordering lines will close down. But typically
they close down around April or May or something
like
that. As
you have seen from the charts, if you don't
finish your monovalent production by May or June,
you
are not going to have stuff ready on time.You
have to
pretty much finish by then. It's not to say you can't
push all of it forward. If we have the orders in the
spring to know that there's going to be more
demand
for flu, we can extend the production cycle at
that
point in time pretty easily. If you come back in
November and say we want more flu, we're already
working on some other product in that
factory. It's
just not feasible.
DR. MARKOVITZ: So you do at
least have a
pretty good early indication of what people
anticipate
they want when you make those decisions.
DR. DECKER: Yes, and then we
always over
manufacture.
I will use mythical numbers for the
point of example. If we had orders for 40 million
doses, we might make 50 million doses. In fact, in
the year that just ended, we over produced by a
larger
margin than we ever had before because we thought
the
orders looked a little light and we were worried
people would want more. Well, they sure did.
CHAIRMAN OVERTURF: I guess what
I'm
trying to clarify is what you told Dr. Gellin
regarding the egg supply. If you make a decision that
you're going to make 50 million doses, then you
start
by making that first monovalent quantity in 50
million
doses. If
you have to ramp up, it wouldn't be eggs
that would be the problem. It would be whether you
could grow enough of each of the monovalent bulk.
DR. DECKER: Ramp up isn't an
applicable
consideration.
Once we know how to make it, your turn
around time, if the facility is not busy doing
something else ‑‑ For example, let's
suppose we finish
a campaign for one strain. We can be back in full
scale in the campaign for another strain very
quickly.
The eggs are available. Once we know how to do it,
it's just a matter of walking in and doing it.
Greg, if I say something wrong, you
correct me here because it's your factory. But
basically it's not a ramp up. Ramp up is
applicable
right now where you are talking about introducing
a
new strain and we don't know how to make it.
We have to figure out how to make it.
FDA
and others have to go through and create the high
growth reassortants. We have to adapt them to the
industrial process and so on. Once we have all that
done, once the cookbook is written, it's just you
want
a pie in the morning and a cake in the afternoon,
no
problem.
CHAIRMAN OVERTURF: Dr. Cox.
DR. COX: Yes, I thought before
we go onto
other topics or have a break I would go ahead and
provide the committee and particularly Peter with
the
data from the other WHO Collaborating Centers for
the
influenza B viruses. I'm sorry I don't have a slide
but I can give you the numbers fairly slowly and
clearly I'm sure.
For the WHO Collaborating Center in Tokyo,
they had a total of 26 influenza B isolates that
they
analyzed.
Twenty‑six of those 26 were Yamagata
lineage viruses.
It's from October to the present
time. So
what I have here I think is comparable data
for all three centers.
For the WHO Collaborating Center in the
UK, six influenza B isolates were analyzed, five
of
which were Yamagata lineage and one of which was
Victoria.
Our WHO Collaborating Center in Atlanta had
17 influenza B viruses of which 15 were Yamagata
lineage and two were Victoria lineage.
So we have a total of 49 influenza B
viruses of which 46 are Yamagata lineage and
three are
Victoria lineage. There just hasn't been that much
influenza B activity globally. So these are all the
data that we have.
DR. MONTO: Nancy, were the
specimens, the
viruses from Tokyo mainly from China?
DR. COX: They were mainly from
Japan but
there were a few viruses from China as well. We had
some from China as well.
CHAIRMAN OVERTURF: Are there any
further
questions for industry? Yes.
DR. ROYAL: Maybe I could just
make
another comment about supply. As Mike was saying, we
produce full bore and then we have to decide when
to
stop at the end of the season. That's based on our
early orders, how many orders we have in
hand. We
asked everyone to order early. But we're the
manufacturers, and I'm not sure that carries a
lot of
weight.
But I think if other groups and bodies
were to encourage early ordering of vaccine, I
think
that would do something to reduce the ups and
downs of
vaccine supplies and the shortages. We realize that
some people don't know they want it until
late. But
there are other people who might just
procrastinate or
might not think it's that important. If there were
some neutral bodies advocating early ordering, I
think
that would help as you can see.
CHAIRMAN OVERTURF: Dr. Gellin.
DR. GELLIN: I have a question
for
somebody over there about this ordering. Are these
binding orders?
Do you know for sure that the people
who order are actually going to pick it up at the
end
of the line?
Particularly after the seasons when
there were some mismatch between supply and
demand,
whether or not the health professionals or
organizations might want to hedge their bets and
order
multiply.
Is there a system in place that keeps a
check on that?
DR. DECKER: Yes, honestly I
can't tell
you and I can't tell you for sure if the answer
is the
same for all the manufacturers. I know from
historical experience at least through some of
the
manufacturers it's possible to cancel your order.
Whether that currently remains true for any of
the
manufacturers, I'm just not sure because I don't
personally handle that stuff. I think everybody has
a policy right now of once you receive your
product
it's nonreturnable. That's to reduce gaming of the
system and so on. I shouldn't speculate. I
just
don't know.
CHAIRMAN OVERTURF: Are there
further
questions or clarification needed? We are scheduled
for the H5 update at 5:00 p.m. Are the people who are
ready to do that here now? I think I would suggest we
go ahead and proceed with that rather than take a
break.
There's no break scheduled. I'm
getting a
request for a five minute break. Why don't we take a
15 minute break and come back at 20 minutes till
5:00
p.m. which is 15 minutes? Off the record.
(Whereupon, the foregoing matter went off
the record at 4:27 p.m. and went back on
the record at 4:44 p.m.)
CHAIRMAN OVERTURF: On the
record. We're
going to put aside the issue for just a moment of
selecting the strains for this year's
vaccine. The
votes and the discussion on that will be
continued
tomorrow morning. Right now, we're going to discuss
and get an update regarding the H5 strains. Dr. Cox
will begin that discussion.
DR. COX: Thank you. So you've probably
discerned from the previous presentations that
although this year influenza activity started
very
early, it really wasn't that unusual
overall. But we
were scrambling to figure this out. A lot of people
thought there was something really unusual going
on.
There was really an unprecedented amount
of attention devoted to influenza during the
normal
influenza season. But just as things were winding
out, influenza threw us another curve ball. Influenza
A (H5N1) activity was detected in Asia. So I'm going
to try to give you a brief summary of what we
know
about the viruses and the activity that's going
on in
Asia.
There's also been quite a bit of media
attention devoted to what's going on in
Asia. This is
one of my favorite headlines, "Killer Bird
Flu
Rampant."
I think it depicts how people are reacting
to the information coming out of Asia which
indeed is
really quite frightening.
This is a slide that had been made about
a year ago.
Some of these photographs here were
actually taken by one of our CDC investigators
who
went to Hanoi and set up some surveillance
studies to
look at whether or not viruses that were present
in
the birds in Vietnam in the live bird markets
were
transmitted to poultry workers who were selling
the
birds, caring for the birds, and so on. So these are
actually very timely slides.
In addition, I have a clipping showing
that this is a problem that affects the United
States
as well.
You will remember about a year and a half
ago there was an outbreak of influenza A (H7N2)
in
Virginia poultry farms. So it's a problem that is
universal.
But there are different viruses
circulating in different parts of the world.
I just wanted to remind you of the
virologic and epidemiologic criteria for a
pandemic.
First of all, we're looking for a novel subtype
of HA.
It can be accompanied by a novel neuraminidase or
NA
subtype but it's not necessary. In 1968, we had a
novel HA, the H3, but we still had N2
neuraminidase
which had been circulating in the hema population
previously.
Along with that, we have populations that
are immunologically naive. The viruses that emerge
must cause morbidity and mortality in
humans. In
order to really have a pandemic, the viruses must
be
easily transmissible from person to person.
Fortunately we have not had viruses that are
readily
transmissable from person to person during the
direct
interspecies transmissions of influenza A, AB,
and
influenza A viruses to humans that were exposed
to
infected poultry over the last seven years or so.
I would just like to refresh your memory
about what happened back in 1997. There were 18
documented cases of human respiratory illness
caused
by highly pathogenic avian H5N1 viruses that are
related to the current strains. Among those 18 cases,
there were six deaths in Hong Kong.
In 1998 and 1999, there were at least
eight documented cases of human respiratory
illness
much milder caused by H9N2 avian influenza
viruses
with no accompanying deaths. Those illnesses were
documented in Hong Kong and South China. H9N2 viruses
circulate widely in the bird populations in Asia
and
the Middle East.
In 2003, at just about this time last
year, there were two additional cases of
H5N1. Again
high path viruses were isolated from two humans
with
one death.
These individuals had traveled to mainland
China from Hong Kong. Their illnesses were diagnosed
after they returned to Hong Kong. There was an
additional death in a member of that same family
that
occurred while they were in China. That death was
never diagnosed.
Then in 2003 in the spring, there were
more than 80 cases of infection by high path H7N7
viruses in humans with one death in the
Netherlands.
So we see that there have been cases where
influenza
A viruses of the H7, H9, and H5 subtypes have
jumped
from birds to humans and caused disease and even
very
serious disease and death.
Now in 2004 ‑ actually I need to update my
slide ‑ there have been 29 cases of human
respiratory
illness caused by high path H5N1 avian viruses in
Vietnam and Thailand. Of those 28 cases, there have
been 20 deaths.
There might even be an update on the
Internet as of today. I haven't had an opportunity to
check that.
I just wanted to give you an idea of
extent of circulation of the H5N1 viruses in
birds.
This slide just shows in this yellow amber color
the
countries that have reported outbreaks of H5N1
virus.
Then in red, I have shown the countries Vietnam
and
Thailand which have both avian cases and human
cases.
So you can see that a tremendous area has been
affected.
Not all provinces in China, not all
provinces in some of these other countries have
reported outbreaks in birds. But we know that
provinces from the very south to the northern
parts of
China and all the way into the west and even
Tibet
have reported outbreaks in birds.
So we were very keen to get our hands on
some of these viruses and to find out how similar
they
might be to the strains that had caused illness
previously.
In particular, we were very interested to
find out if the vaccine candidates, the vaccine
reference strains that had been made using the
viruses
isolated from humans in 2003, those most recent
H5N1
cases, would be similar to the currently
circulating
strains.
Last year at about this time of course the
SARS virus was emerging. In the background, we had
H5N1 cases in people who lived in Hong Kong but
had
traveled to China. So there was concern about there
actually potentially being some H5N1 activities
smoldering in the background. So it was decided that
we would go ahead and see if we could produce a
candidate vaccine strain.
This particular candidate strain, A/Hong
Kong/213/2003 by A/PR8 was produced at St. Jude
in Dr.
Rob Webster's laboratory. So we had this virus. We
developed ferret anti‑serum to it. We wanted to see
if the anti‑serum to the wild‑type
virus into the
vaccine reference strain would cover the
currently
circulating strains.
So you can see we have nice high
homologous titers here for both ferret anti‑sera
and
their corresponding antigens. Here, we have test
antigens 8 through 19 which are viruses that were
isolated from a variety of birds in Vietnam. Then
down at the bottom, we have antigens 20, 21, and
22
which are isolates from human cases. Unfortunately,
these anti‑sera did not inhibit these
viruses
particularly well. So it was a great disappointment.
There is some cross reactivity here. But it's not at
the level that we would have wished.
The only other thing that I would like to
point out in this slide is that there is some
indication of antigenic heterogeneity (PH). If we
look at, for example, this column here with
ferret
serum to the Hong Kong/156 virus, which was the
prototype 1997 strain, it was isolated from the
very
first case of H5N1 in 1997. Anti‑serum to that virus
does inhibit some of these viruses pretty
well. But
other viruses are extremely poorly inhibited by
anti‑
serum to that virus.
So there was indication that there was
some heterogeneity (PH) among these strains. That
proved to be true when we ‑‑ And I
apologize. I don't
think that shows up nearly as well as it does
here on
the screen.
I think I'll go on to this one.
When we
looked at the evolutionary relationships among
the
neuraminidase genes of those viruses that I
showed you
on the previous slide, you can see that they fall
into
two groups.
These viruses down here are the viruses
that had higher titers to the Hong Kong/156 anti‑
serum.
These viruses up here in blue are also
isolated from birds. All these are bird viruses.
These are really in a separate genetic
group. All of
these bird viruses are grouped together with the
viruses shown in red which are the human
influenza
isolates.
Now there are a number of markers for
these two groups. This particular group does not have
an amino acid deletion in the stark region of the
HA
while all of these viruses have a 20 amino acid
deletion.
Then there are a few additional viruses
that have a 3 amino acid deletion in addition to
the
20 amino acid deletion. You can see the signature
amino acid changes that are characteristic of
this
particular group.
We have analyzed not only the
hemagglutinin and neuraminidase genes but also
most of
the other genes of most of these viruses.
Interestingly, the viruses that fall into this
group
have an amino acid change in the M gene which
confers
resistance to the adamantanes, amantadine and
rimantadine.
When viruses in this group are then
tested in a phenotypic acate (PH) to look to see
whether they are susceptible or resistant to
adamantanes, they behave as one would expect from
the
genetic characteristics in a resistant manner.
We have also recently received some
viruses that were isolated from birds in
Laos. Those
sequences fall right up here with this group of
viruses. (Indicating.) I should also point out
that
there is one virus right here which was isolated
from
one of the cases in Thailand.
So we'll just go back to the HA slide.
One of the things I would like to point out is we
have
a number of sequences that are marked St. Jude
here.
We've had really excellent sharing of information
among all of the WHO Collaborating Centers, both
the
human WHO Collaborating Centers and the avian or
animal influenza Collaborating Centers. We have been
able to really put these current viruses in the
perspective of what was going on in Hong Kong
during
their outbreaks in 2002 and 2003.
I would just like to mention a couple more
things.
All of these viruses are really descendants
of the Goose/Guangdong/96 strain which was
isolated
during an outbreak in geese in Guangdong in 1996
of
course.
These are the human isolates from Hong Kong
in `97.
So you can see that there has been a lot of
evolution up to the point where these viruses are
now
the viruses currently circulating it looks like
in
Vietnam, in Thailand, and probably in Laos.
I would just like to go over a few of the
things that we've been involved in doing over the
past
few weeks as the situation has developed in Asia.
First of all, we have needed to develop an
updated WHO
kit for identification of H5N1 viruses. In order to
do that, we have to have an anti‑serum with
high
antibody titer against the currently circulating
H5N1
strains in Asia as well as an inactivated antigen
that
can be put together in a kit and sent out to the
National Influenza Centers and others who need to
identify or potentially need to identify H5N1
viruses.
In addition, we have been developing rapid
detection methods for H5 viruses using real‑time
PCR.
A lot of different laboratories have been asking
us
for positive RNA controls and for primer
sequences so
that they can get the method up and running.
Others will talk about this as well.
In
addition, we have been involved in H5N1 vaccine
development.
That is to say we've been trying to
develop a reference strain that could be used for
a
safe manufacture of influenza H5 vaccine should
that
be needed.
We're using reverse genetics, a Modified
Fodor Vector system which probably doesn't mean
too
much to some of you. Basically it's an eight plasmid
approach.
We have cloned and characterized the HAs
and we have removed HA and NA. We have removed the
polybasic peptide that makes these H5 viruses
highly
pathogenic in birds. We want to remove that cleavage
site so that the viruses, the vaccine strains
don't
pose a threat to the poultry industry and the
birds in
this country.
Of course, we're hoping to produce a
strain that would meet regulatory requirements.
This is just a schematic of the plasmid‑
based reverse genetic system. So we take the HA and
remove the polybasic amino acid cleavage site and
then
rescue it into a PR8 backbone. Hopefully the PR8
backbone will give the vaccines a reference
virus, the
ability to grow to high titers in eggs. Then we're
hoping to rescue this reassortant with the
modified HA
and the neuraminidase of the H5N1.
Once the virus has recovered, well
actually, it has to be recovered and certified
cells.
In this case, we're using certified Vero cells
and
certified cell culture medium. Then the rescue virus
is amplified in eggs. Of course, the virus has to be
characterized and we have to make sure the HA and
NA
of what comes out is actually what we want.
Once the virus is rescued, we have to test
it for safety and immunogenicity in animal models
before it can be given to the vaccine
manufacturers.
Of course, we expect that after the modification
the
virus would no longer be lethal to chick embryos
and
that it would no longer be lethal to
chickens. We
would look to see if the virus is attenuated in
mice
and ferrets.
These H5N1 viruses have been really highly
pathogenic in mouse models as well as in ferrets.
Then we'll be looking at the immunogenicity just
in
terms of looking at the HI cross tests using post‑
infection ferret serum to see how closely related
the
vaccine candidate virus is to the previous
strains.
Then additional protective efficacy studies can
be
done in mice if necessary.
So I'll try to briefly summarize what we
know about the avian influenza outbreak in
Asia. We
know that poultry outbreaks caused by these
highly
pathogenic avian influenza H5N1 viruses have now
been
reported and confirmed in Cambodia, China, Hong
Kong,
Laos, Indonesia, Japan, South Korea, Thailand and
Vietnam.
There are low path viruses circulating in
other countries.
But here, we're really concentrating on
the outbreaks caused by high path H5N1 viruses as
these are the viruses that appear to really pose
the
threat to human health. I had mentioned that there
were cases in Vietnam. Now this count is up to 21.
I think the count in Thailand is still eight with
six
deaths.
No human cases have been reported in other
countries.
But it's expected that where there is a
lot of exposure of humans to the sick and dying
birds
there might be cases.
Most of the cases have documented exposure
to sick or dead birds. But there have been some
family clusters.
Whenever there are family clusters,
questions are raised about the potential for
person to
person transmission. But that has not been documented
thus far.
I showed you in the dendrogram that the
H5N1 viruses from birds and humans in Vietnam are
genetically and antigenically closely
related. The
human isolates from Vietnam and Thailand and one
group
of the Vietnam avian isolates are resistant to
the
adamantanes.
I neglected to mention that we've done
the phenotypic testing to see if all of the
viruses
are sensitive to oseltamivir, one of the
neuraminidase
inhibitors.
Indeed they are sensitive.
So obviously there are treatment
implications for the findings that a number of
these
viruses are resistant to the adamantanes. I also
demonstrated that a candidate vaccine reference
strain
produced with the 2003 H5N1 virus is not an
optimal
antigenic match to the 2004 H5N1 viruses. But I also
want to mention that based on some preliminary
neutralization data, there might be some cross
protection provided.
The construction by reverse genetics of a
new vaccine reference strain is being undertaken
in
two U.S. labs and one in the UK. I think that the
subsequent speakers will be talking about their
results.
We actually need genetic and antigenic
comparisons of H5N1 viruses for more countries so
that
we have a better understanding of the spread and
a
better understanding of whether one vaccine
strain
would really cover all of the viruses that are
circulating.
It's been very difficult to get viruses
from birds in some of the countries that have
been
affected.
What we have found and we have known for a
long time is that there's often a silo approach
to
animal health and human health. There's really not a
lot of cross talk. It's getting much better now, but
it still is sometimes difficult to get influenza
viruses that might have an implication for human
health from the agricultural side in some countries.
Culling infected birds and their proper
disposal is really necessary to reduce the risk
of
human infection.
But culling efforts have been
somewhat limited in certain countries. Human exposure
does continue in developing countries where
backyard
flocks really constitute a majority of the
poultry.
This is a recent statistic that I have
heard. China
has about 13 billion birds and three‑quarters
of the
farms have 100 birds or less. So we're talking about
a lot of human exposure to chickens and ducks.
I also need to mention that there's poor
or nonexistent human influenza surveillance in a
number of these countries that are affected by
the
poultry outbreak. So if something is happening in
humans, we may not hear about it. So we do have
unprecedented human exposure to highly pathogenic
H5N1
viruses.
There is a threat to global health.
There
is close circulation of avian H5N1 and human H3N2
viruses in the region. So reassortment is possible.
Of course, I'm sure all of you have heard about
and
have read in the newspapers that one of the
things the
influenza experts are concerned about is that
reassortment might occur. So then the H5N1 virus
would acquire the ability to spread from person
to
person by gaining some of the internal genes, the
replication machinery from the human influenza
virus.
Therefore, the virus would be more easily spread
from
person to person.
Another thing that influenza experts are
concerned about is that if these viruses have the
opportunity to jump to humans, to replicate in
humans,
and possibly even to be transmitted at very low
levels
from person to person, they have an opportunity
to
adapt to replication in humans through
mutation. It
seems unlikely that H5N1 viruses can be
eradicated
from that region very soon.
A number of the countries are approaching
control of the virus in that they are talking
about
culling and also use of vaccine. But I think
eradication is not very likely. Of course,
eradication of backyard flux is very difficult.
The farmers aren't being compensated so
they don't want to cull their birds. Furthermore,
infections have been documented in wild
birds. Some
of these are migratory birds which potentially
are
spreading the virus from country to country and
region
to region.
Now, there are large international efforts
coordinated by the World Health Organization and
the
Food and Agricultural Organization. They have been
assisting in culling, in surveillance, and in
disease
control efforts.
But there's really a lot more that
needs to be done. So as the outbreak continues, I
think there will be a need to consider H5N1
vaccine
production, to consider what the trigger points
might
be, what the target populations might be, and
what the
quantities of vaccine that might be needed would
be.
I'd like to acknowledge both for this talk
and for my previous talk all of the members of
the
Influenza Branch who have worked extremely hard
this
past year and whose work I have presented today,
along
with the WHO National Influenza Centers, the WHO
Collaborating Centers in London, Tokyo and
Melbourne,
as well as the WHO Center in St. Jude, Memphis,
the
WHO Regional Offices, and of course the WHO
Headquarters in Geneva. Thank you.
(Applause.)
CHAIRMAN OVERTURF: While we're
setting up
the next presentation we can take some questions.
DR. DOWDLE: Walter Dowdle. I think we
sometimes forget in the H5 era that in the pre‑1977
era there were a considerable number of cases of
transmission of transmission of swine influenza
from
swine to humans.
This occurred not only with
illnesses but also with a few deaths. There were a
number of these sporadic reports. Of course, there
was also Fort Dix at the time.
But pigs have also figured rather
prominently in the potential transmission of new
influenza viruses from animals to man. I just wonder
in this area, are there now surveillance studies
going
on looking at the pig populations and seeing
what's
going on?
We know for example there are continuous
introductions from man to pigs. But what's happening
at this point from chicken to pigs that we know
of?
DR. COX: It's a very interesting
question.
I'm sure many people have heard reports of
pie die‑offs in the Mekong Delta and all
kinds of
things in the press. So it was a great interest to
try to find out what was going on.
Rob Webster has done a fairly extensive
study.
Although it was short in duration, it was a
window looking at what was going on in a
particular
two or three day interval. Linda may want to say more
about that.
But as I understand it, he wasn't able to
find evidence or at least not very much evidence
of
replication in pigs. I think that what we have heard
from people who have gone to the field to look
for
sick pigs is that they have seen healthy pigs.
So we don't really know about the reports
in the Mekong Delta. Those are of great interest.
I
think the studies are ongoing. There's a lot of
interest in Vietnam and some other countries in
the
region to find out if pigs are affected. I think Rob
and Malik Peiris will have some interesting
information over the next few weeks.
DR. KARRON: Ruth Karron. Nancy, are
there any invitro data regarding the
compatibility
between the H5N1 avian genes and the human
internal
genes.
DR. COX: There aren't at this
moment, at
least none that I know of. We had looked at the 1997
viruses in this respect but have not looked at
the
current viruses.
CHAIRMAN OVERTURF: Any further
questions?
Okay.
DR. MINOR: Well, Nancy mentioned
two U.S.
labs and one UK lab but I am a UK lab. I'm head of
the division of NIBSC. We send out reference reagents
and strains to manufacturers to play with so we
have
a considerable interest in terms of vaccine
reagents
in general if you like. That's from the point of view
of looking at the quality of vaccines and
standardizing vaccines for the UK government and
so on
and so forth.
One of the things that we do is
occasionally we will actually make the strains
that we
send out to manufacturers. The conventional way of
doing this is by inoculating an egg with a wild‑type
strain you are interested in plus a high growth
lab‑
adapted strain like PR8 for example. You then sift
through the harvest to find a virus which will
grow
well which will normally have the core genes from
the
PR8 high growth lab strain, if you like, plus the
surface antigens from the wild‑type strain
that you
put in.
This works insofar as you get a high
growth strain out of it. Sometimes it doesn't work
because you don't get any strain out of it that
grows
well.
Sometimes you get the hemagglutinin and the
neuraminidase reassorting separately so you wind
up
with the wrong strain coming out of it
altogether.
So if you are good you can do this.
The
people I have in the lab are very good and they
can do
this. But
it would be quite good in addition to have
a actually rather more direct way of doing this
so
that you know exactly what you are doing and you
can
predict what's going to happen. The advantages of
reverse genetics are of course that you start
from
nucleic acid and work on from there.
So you can start off with your six core
genes from the lab‑adapted strain and you
can put on
your wild‑type genes on top of that. It's a very
precise process.
At least in principle, you can do it
very clearly and precisely. It's very directed. You
will get out what you want in terms of the actual
genetic structure. That's the first point here.
It's
a directed approach to reassortment.
The second thing is you can get an
increased scope for reassortment. You could do this
now with B strains which you can't do at the
moment
for reasons I won't go into. We can talk about it
later if you want. There were issues to do with the
origin of isolates in the field which is
something
I'll be talking about tomorrow.
We'll be talking about cell grown viruses.
You can get rid of any other virus that happens
to be
there that you don't know about which you may be
concerned about simply because you're going
through
the nucleic acid. Finally, you can engineer the
hemagglutinin.
As Nancy said, you can make a pussycat
out of a tiger.
So these are the reasons why reverse
genetics is attractive anyway. Now the reason why we
particularly at NIBSC would want to get involved
in
this is because of the fact that we supply
manufacturers with strains. No matter where these
strains eventually come from we really want to
know
how robust the system is. Is it really possible to
take any two hemagglutinin and neuraminidase
genes and
graph them onto this high growth core if you
like?
Secondly, how quick is it? You
have heard
from the manufacturers already that when a strain
decision is made, they really want the strains
yesterday.
We really want to make sure you can do it
rapidly and robustly as much as possible.
Finally, because we are involved in the
regulatory process to some extent, we are aware
that
there are certain regulatory beefs that come up
from
time to time.
So we can maybe try and cope with those
maybe rather better than perhaps some academic
labs
might be able to do. We have that kind of background
to it.
So for the last three years, I have been
very keen on my lab getting this going. I have to say
they now have it going. The work I'm going to
describe is by Carolyn Nicholson who works with
Jim
Robertson.
She does the work and he gets the credit.
Well, not here though, she's getting the credit
here.
Nancy has already gone though this a
little bit.
I'll go through it again. The
current
events in Vietnam are H5N1. There was another event
last year in 2003 in Hong Kong. Before that, in 1997,
there was another one in Hong Kong. There was also a
strain called Duck/Singapore which is another H5
virus
from ducks as the name implies which looked very
much
like the 1997 Hong Kong strain.
When the Vietnam 2004 isolates are
compared with these three preceding H5N1s, they
are
clearly very antigenically different. Nancy showed
some data.
We have data in house from post‑infection
ferret sera which there's really very little
reaction
at all between the 2004 isolates and the 2003
isolate.
There is a major problem there. It does seem to me
that if you are presented with this, you wouldn't
say
that was a vaccine strain.
We also have some evidence of the three
isolates we have, which are 1194, 1203, and 1204,
1203
is slightly different from 1194 and 1204. Again, this
is not unprecedented. It also happened in 1997.
So
what we have gone with is 1194. That's the one you
are going to see data on for all it's worth.
The final thing is again Nancy mentioned
the need for post‑infection ferret
serum. To my
knowledge, currently there are no post‑infection
ferret sera for the Vietnamese isolates as of
yet.
The reason for that is this is an extremely nasty
virus.
As far as I'm informed at least ‑ maybe
people can correct me if I'm wrong ‑ the
only living
ferrets who have actually been infected with the
stuff
are currently at NIBSC in high containment. All the
other ferrets have died at around day six or
seven.
So there are no post‑infection ferret sera
which are
suitable for characterizing a strain. I'll come back
to that later.
This again is the technique that's used to
get rid of the polybasic sequence which makes the
virus lethal.
Again, I won't go through the details
of this except there are some very clever
features of
this. The
polybasic sequence has been taken out.
The
point mutations have been put into the sequence
to
prevent the polyadenolation (PH) signals acting
to
reintroduce those polybasic sequences.
The thing has been cloned and sequenced.
There are about three or four clones of this
which are
now available which Carolyn has prepared and
sequenced
through the actual region to show that she's
taken out
what she meant to take out. This is the overall
strategy which has been followed. To cut a long story
short, we actually have a strain here which is
currently being tested for safety at the moment.
The idea is to recover Vero cells which
are a cell line which is pretty much approved for
vaccine production. The original recoveries were done
on 293 T‑cells which are slightly suspect
if you like.
The idea then is that the harvest is put into an
egg.
Then it's put into another egg. Then that's the seed
which would be characterized further.
We got to the second egg passage for
this
particular material. It's called NIBRG 14. The
titer
of this in the second egg is 1,280 HA units which
is
actually quite good. That's actually quite a high
titer.
That is quite promising. That's
British for
very promising actually.
(Laughter.)
DR. MINOR: The basic structure
under
which this has been done is some attention was
paid to
the quality of how this was done. The first thing is
the cell is a Vero cell which was donated by
Aventis
for pandemic use. I think the issues to do with IP
are perhaps something that maybe one could have a
little discussion about. But nonetheless, very
generously donated by Aventis for pandemic use.
They have been grown in a facility at
NIBSC which is involved in the UK stem cell bank
and
which is more or less under GMP. I'm not totally
convinced that it's been inspected by the
competent
authority yet.
But it's more or less GMP. It's
certainly aimed at that particular level.
The media is prepared in a GMP
compliant
consistent facility. The DNA is basically done away
in a nice clean safety cabinet. We have always been
fairly obsessed with TSEs at NIBSC as everybody
else
has. The
components, as far as we can tell, are
consistent with BSE guidelines. The intention at
least is to get the dossiers (PH) off to people
that
we know who look at these things and say what do
they
think about it or we think they are pretty good.
Finally, it's all been rescued in high
containment.
There's a Category 4 unit that we have.
It's basically been rescued in there. There's no
other viruses in there at the same time. So we
believe the documentation we have on this is very
good. So
if you consider the bits in green, those are
the bits that are definitely done.
The quality assurance, we have very good
lab records here about how this is done and
documented
procedures by which the whole thing is actually
produced.
The quality control now begins.
The
pathogenicity testing is something that has to be
done
before it comes out of high containment. What we have
to do is inject our recovered material into
ferrets
and compare that compare that to what happens
with the
wild‑type ferrets.
Now the wild‑type ferrets went in a week
ago last Monday.
We had a phone call from John Wood
who is in Geneva on Friday saying that everybody
else's ferrets were dying and could we do
something
about this please? They were dosed with Tamiflu which
is one of these chemotherapeutic jobs on
Friday. On
day six which was Saturday, one of the ferrets
was
looking extremely sick. But by day seven with
repeated doses of this stuff, he became better.
As far as I know, they are still alive.
They are due to get another boost with the same
virus
today. So
they should actually get a bit of a crank
up there.
With a bit of luck, what's going to happen
is that we'll get post‑infection ferret
sera which are
specific for the Vietnam isolates probably by
next
Monday or maybe a bit after that.
What then has to be done is we have to do
the proper pathogenicity study which involves
putting
wild‑types into ferrets, putting the
recovered strain
into ferrets.
We have to do the same thing with
chickens.
This is a requirement of the UK Department
of Agriculture equivalent if you like. So then we
have to do a pathogenicity test there.
We also have to do an egg embryo test to
show that this is no longer lethal for egg
embryos.
The original was you could slaughter them right
away
which is why you get no virus out of an egg
that's
infected with the original Vietnam strain. The
recovered strain so far at least has not killed
the
embryos.
So that's actually also quite an encouraging
observation that we've done something proper to
this.
But you have to do that formally.
There are, as I said, no sera yet.
But
there will be probably by next Monday or next
Friday,
who knows?
In which case, the antigenicity can be
looked at.
The sequence is being done at the moment.
And away we go.
So all of this will be carefully
documented.
What we've managed to set up at NIBSC over
the last two or three years is really routinely
rescuing things in Vero cells which are approved
for
that kind of use. We have used the Aventis materials
for the potential pandemic strains. We also have our
own Vero cells which we play with. So we can recover
H5s, H1s, and H3s. There doesn't seem to be much of
an obstruction to it.
Now, when Carolyn was doing this for
A/Fujian, which some of you may be familiar with
as a
strain that possibly raised a little problem last
year, it was 17 days from the time when the virus
came
into the building to when she actually had the
reassortment strain in her hand. That's actually
quite slick I think.
For what it's worth, with respect to the
H5 construct, it was 19 days between when the
virus
actually arrived and when we actually had the
stuff
recovered as the first egg passage. So again, I think
that's really quite slick. I think she has done quite
a smart job on this. And it does seem to be quite a
robust system that she has going on over there.
This finally is the acknowledgment phase
here. We
got the plasmids, which is a 12 plasmid
expression system, from Ervin Fodor and George
Brownlee who were at the University of Oxford at
the
time. The
Vero cells came from Aventis Pasteur.
Thank you very much. Hema Patel does the cell stuff.
There are people who do the animal work in NIBSC
and
take their life into their hands which is when
you are
handling an angry ferret.
Some people do chick pathogenicity tests.
We do that with the veterinary lab at Weybridge;
Diane
Major, Jim Robertson, and John Wood. Jim Robertson
and John Wood, some of you may know, are the PhDs
who
stand up and talk about this stuff. Diane does the
antigenic characterization. The big letters in yellow
at the bottom is Carolyn Nicolson who actually
does
the work and God preserve her.
What she has been doing is dealing with
the technical aspects of this. Can you actually do
this in a robust manner? Can you get it out quickly?
What do you do?
What's the time scale over which
we're actually going to have something we can
send
out. The
time scale is going to be probably around
the end of March when the pathogenicity studies
are
actually finished and it can go out.
I think what happens to it then is really
a matter for some concern and debate
perhaps. I think
there are IP issues which are still outstanding
about
these issues.
In Europe, at least, there are
genetically modified organism regulations which
are
also an issue.
There are all sorts of issues to do
with the Department of Health and the Ministry of
Agriculture and the Health and Safety Executive
and
the European Commission and the regulatory
framework
within Europe.
We have had discussions about the
regulatory framework in Europe. Just as a final
little lighthearted comment, the main concern
seems to
be what language the package insert should be
written
in. This
seems to be the main obstacle to getting
this stuff actually on the market. Thank you.
(Applause.)
CHAIRMAN OVERTURF:
Questions? Dr. Myers.
DR. MYERS: Just given what we're
going to
talk about tomorrow morning, I was curious as to
the
strategy to go back into eggs from the Vero
cells. I
wondered if you could comment.
DR. MINOR: Right, egg cell
vaccines are
licensed.
I think there are huge obstacles to doing
anything but a pandemic strain. I think if you can
make sure that you are still using eggs to grow
it in,
that may be one obstacle that you don't have.
Having said that, I think there are also
major logistic attractions at least from the
outside
to go into a cell grown culture system because
then
you don't worry about chicken flu taking out your
chicken flocks and things like that. We went back
into eggs because it will be eggs that the
manufacturers will be using to grow it in. But it's
a very fair comment.
DR. BUCHER: Yes, hi, Doris
Bucher from
New York Medical College. I would just like to make
a few comments about the dirty way of making high
yield reassortants. Last Thursday we were very
excited and we felt that we had satisfied all of
the
characterization of our high yield B reassortant,
the
B/Hong Kong/1434 high yield reassortant.
I think we just shipped it off the CDC,
and someone told me it was now B/Jilin. However, the
reason we were able to do this is because we have
gone
to enhanced techniques of selection using anti‑sera
to
the purified surface antigens and kicking up
selection
to the neuraminidase. We can very nicely pull out the
high yield B reassortants. We hope we can do B/Jilin
as soon as we get the stuff.
The other reason why we shouldn't throw
out the approach to high yield by selection is
that if
you think about it, when you do reverse genetics,
you
do one pattern.
Kathy Coelingh will be relieved to
hear that I have gone over to her system of six
PR8
genes and two of the target.
When you do it by the old fashioned but I
would say now with enhanced selection, you can
allow
the other six genes to vary. Of course you have to
have the right hemagglutinin neuraminidase. So that
would be two to the six possible outcomes. You have
64 different variants that you are testing.
Now, going even further, if you look in
the past, I reviewed the gene composition of what
was
available in the literature. Maybe only about half
have six PR8 genes and the two current
genes. If you
also consider maybe dirty isn't necessarily bad,
one
person's dirty is another person's quasi‑species.
If you consider variants of each gene that
may exist, maybe you have five variants for each
of
those six genes both from PR8 and from your
target.
I'm being generous perhaps. Then you are talking
about ten to the six so you are testing a million
possible high yield reassortants which sounds
incredible.
I didn't believe it until I looked at the
numbers.
Ed Kilbourne reminded me that with the X‑
53, X‑53A ‑‑ I know maybe we
don't want to be reminded
about X‑53, X‑53A, the high yield
swine. But it was
just a single amino acid difference between X‑53
and
X‑53A that made a difference of maybe eight‑fold
increase in yield. That's what the manufacturers use.
Perhaps unfortunately we had a swine flu vaccine
because of that.
And they could not be distinguished
anogenically.
So anyway, let's not forget about
selection.
DR. MINOR: I don't think
anybody's
forgetting about selection. We've been trying to brew
these things up for years. The fact is that mostly it
works.
When it doesn't work, you are really stuck.
What happens with reverse genetics appears to be
that
you tend not to get stuck. I find that a very
attractive option as somebody who has
manufacturers on
the phone screaming in my ear saying when can we
have
it, you see.
Nobody I don't think is going to go over
to reverse genetics full time. Apart from everything
else, there's the patent IP issues and all the
other
issues that I was mentioning at the very
end. So
nobody is going to abandon it at all to begin
with.
But I'm not sure it has the advantages you say it
has.
DR. BUCHER: Just one more quick
comment,
when Barbara Pokorny, who has been Dr.
Kilbourne's
chief assistant all those years, went back to her
record books, she made X‑53 in nine
days. She made a
high yield reassortant in nine days so it can be
done.
DR. MINOR: It can be done. She was
lucky, wasn't she?
(Laughter.)
CHAIRMAN OVERTURF: Additional
questions
or comments?
DR. GELLIN: Yes, Phil, can you
comment a
little bit about how you are going to navigate
through
the genetically modified quagmire?
DR. MINOR: Right, well, what a
very good
question.
This is being discussed in the regulatory
circles in Europe. Until you have been in a
regulatory circle in Europe, you don't know what
a
circle is.
(Laughter.)
DR. MINOR: They will come out as
contained use GMOs. So if manufacturers wish to use
them, they will have to have approval for
contained
use. I
don't think that's terribly difficult to get
but I'm not sure. But it does require manufacturers
to do it if they so wish.
So there's an element of do the
manufacturers want to go down this road
anyway? It's
not a question of free release which would be
extremely difficult to deal with. Maybe one could
actually persuade the European ‑‑
No. I was going to
say maybe you could persuade them to change it a
little bit.
I don't know if you could do that.
But I think to do contained use is
probably not quite such a challenge as to make an
organism ‑‑ But it does require
effort. I'm not sure
the manufacturers necessarily have the incentive
to
make that kind of effort. But those are the kinds of
discussions we're having. What would it actually
take? And
that's not the least of the quagmires I
don't think.
CHAIRMAN OVERTURF: Other
questions?
Thank you very much, Dr. Minor. The last presentation
is by Dr. Linda Lambert.
DR. LAMBERT: All right, I would
first
like to thank the organizers of this meeting for
giving me the opportunity to update you with the
current activities that NIAID is supporting as we
address the H5N1 outbreak in Asia. My talk this
afternoon will be really broken into two parts.
The first part will be the research
resources or really the response capacity put in
place
by NIAID to ideally prevent or as a fall back
prepare
for the reemergence of H5N1. Then as Nancy already
alluded to, I will provide you with a little bit
of
data about why we may be where we are in this
current
situation.
The second part will then specifically
update you on NIAID activities that are ongoing.
So as you heard now twice that there was
the first direct human transmission from an avian
H5N1
to humans in `97. That happened late in `97 when we
first had the tally about what was going on with
the
total number of deaths. In early `99, the NIAID
awarded a contract for pandemic preparedness in
Asia.
That was to St. Jude Children's Research Hospital
in
Memphis.
The PI on that contract is Robert Webster.
He participates with the WHO animal influenza
surveillance centers. Much of what I present today to
you will be work that is done in his laboratory
in
Memphis with Richard Webby, Elena Gorbakova (PH),
Scott Kraus and then his collaborators at Hong
Kong
University which include Malik Peiris and Yi
Guan.
So the scope of this contract when it was
put in place in `99 was to establish an animal
influenza center, a center of excellence in Hong
Kong
at Hong Kong University. The dynamic of what's going
on in Hong Kong is that there are on average
about 26
million birds that are imported into Hong Kong
each
year. So
to try to get a sense of what was really
coming in from mainland China as well as what was
being propagated on farms in Hong Kong, one of
the
high priority programs was to establish this
animal
influenza center.
On average again anywhere from about
15,000 to 20,000 samples each year get assessed
through this contract and to try to keep a pulse
on
what's happening in the live bird markets, what's
happening in swine slaughter houses, what's
happening
with wild birds, pet birds, and essentially all
types
of avian species. Another objective was to try to
determine the molecular basis of transmission;
how
these viruses were spreading from one species of
poultry to another and what would really
potentially
lay the groundwork for how they could get into
humans.
Another key provision of this contract was
to identify and provide characterized viruses
that
could be suitable for vaccine development,
support
training of new laboratory personnel, and it
seems
very timely to tell you that through this
contract the
NIAID is supporting a WHO animal influenza
training
class that will be the first week of March.
It was originally scheduled for last year
but was derailed for SARS. So that will be held for
the Pacific Rim students, if you will, in Hong
Kong
the first week of March. And finally, to produce
selected reagents as needed for the research
community.
So you have also heard about some of these
results from the previous two speakers. But these are
really key findings that this contract has
delivered
over the last few years and really lead us to
understand why we are faced with what we are
right now
in Asia.
So following the cull of all of the poultry
in Hong Kong in 1997, these investigators in Hong
Kong
detected the first reemergence of H5N1 in the
live
bird markets.
The Hong Kong public health authorities,
looking at that data, made a very proactive
decision.
In the absence of any confirmed clinical cases in
humans, they decided to prospectively kill 1.2
million
birds.
They have also instituted a rest day in the
market. I
think it's gone from one day to two days to
try to clean out everything.
Unfortunately what we know though is while
the markets get cleaned within a couple of days,
surveillance tells us that these avian influenza
viruses are back in within a few days. In 2001, there
was another significant finding. These researchers
really identified a particular species of land‑based
poultry, and that was the quail, as the likely
mixing
vessel for the spread of avian influenza viruses
from
aquatic birds to land‑based birds such as
chickens and
pheasants.
Again, looking at the data, the public
health authority in Hong Kong, which have worked
very
closely with the group at Hong Kong University,
made
a very bold and proactive decision to ban the
sale of
live quail from bird markets in 2002. Again,
beginning two years ago, the second reemergence
of
H5N1 was detected through ongoing surveillance in
this
contract.
This time it wasn't limited to just a few
farms.
There were more than 20 farms that were
infected.
As Nancy alluded to, there's something
going on with these viruses. There were at that time
more than seven different H5N1 genotypes that
were
identified.
So the message is very clear.
We're
continuing to hear that message which is the H5N1
viruses are not in evolutionary stasis and they
are
continuing to reassort.
At the end of the 2002, the Hong Kong
Agricultural Fisheries Department was alerted to
dead
ducks, geese, and swans in Kowloon's Penfold
Park.
This park is just a few blocks in Kowloon from
Victoria Harbor so it's not far from a very
densely
populated area.
The Hong Kong U team went in and
identified highly pathogenic H5 as the cause.
Again, there was also a dead migratory
waterbird, a heron, that was found on the border
of
Hong Kong and mainland China. This really sounded an
alarm for influenza researchers because it was
really
the first time since 1960 that a highly
pathogenic
avian influenza virus was identified to kill
aquatic
birds.
So at the end of 2002, we were left with
the question of knowing this and wondering if
aquatic
birds will then turn around and start spreading
these
H5N1 viruses throughout Asia. The second question was
what is the potential for the spread of this
virus to
other animals including humans?
So Nancy and I think Phil have also
basically told you that in early 2003 in February
there was a family that traveled from Hong Kong
to
mainland China to Fujian Province. At the end of the
day, there were two confirmed cases of
fatality. As
both have also described, the laboratories that
had
the capacity to do so around the world
essentially
raced to develop a suitable vaccine reference
strain
using reverse genetics.
At least two candidates were created.
There may be more. Reference reagents were produced.
Essentially if what we're dealing with now had
turned
out to be very close to 2003, we would be much
further
ahead.
Then just within a month or two after that, we
were dealing with SARS. Now looking at 2004, H5N1, as
you have also heard, there are studies that have
shown
that the 2003 candidate may not be optimal.
There is one ferret study with preliminary
results have come out of St. Jude where ferrets
were
vaccinated with a laboratory produced and
activated
vaccine against the 2003 H5 virus and challenged
with
the 2004 H5.
Those animals appear to be protected.
But certainly those results would need to be
confirmed.
So in response to a question someone asked
about animal surveillance and specifically pigs,
I am
just going to tell you briefly about some of the
data
we have.
Again, it's very preliminary. It
was a
report that just came in a few days ago. At least in
Hong Kong what we know is that since the middle
of
2003 in the avian species, poultry, there's been
no
H5N1 viruses that have been isolated. Again, they are
very rigorously looking for this.
These are studies that are ongoing
collaborations with Dr. Robert Webster and Malik
Peiris and the Department of Agriculture in
Vietnam.
In Vietnam, they have looked at approximately 200
pigs
from epidemic areas of Hanoi and have not
cultured any
influenza viruses from them. They have also done
serological tests on approximately 450 pigs again
near
an epidemic area in Hanoi and have shown that one
of
the sera is positive for H5N1 by both HI and
neutralization studies.
The take home messages at least at this
point is it's one animal. This H5N1 virus appears to
be able to infect pigs but is not at this point
spreading in the area that is tested. In addition, it
appears that the avian H5N1 viruses that have now
been
identified in Vietnam are genotypically like the
human
isolates ‑ and I think Nancy alluded to
this as well ‑appear to be derived from a genotype that was
detected in Hong Kong at the end of 2002.
Reagent production, a very important
component for researchers and those thinking
about
developing vaccines, a reagent grade reverse
genetics
H5N1/Vietnam/1203 PR8 reassortant was produced by
St.
Jude. As
Phil indicated, it was rescued in 293 T‑
cells which is not suitable for vaccine
production.
But it is available as material that can be used
to
generate an antigen for those who have the
appropriate
biocontainment facilities.
Production of purified recombinant HA from
wild‑type Vietnam/1203/04 is underway by
Protein
Sciences.
The CDC provided the starting material.
The NIH is supporting the production. As soon as that
material is ready to go, the FDA will receive
some of
that material and start producing sheep anti‑serum.
Production of monoclonal antibodies against 2004
H5N1
is underway.
I briefly want to tell you about some
animal studies at St. Jude. I suspect that what Phil
said is true for St. Jude, that there's no living
ferrets that's been challenged with 2004
H5N1. What
St. Jude has seen is lethal infection,
neurological
symptoms, hind leg paralysis.
The virus is recovered in nasal washes out
to day seven and detected in all organs; brain,
olfactory bulb, lungs, heart, spleen,
intestines. So
it's very bad for ferrets. My understanding in
talking to Richard Webby this morning, maybe it
was a
BlackBerry email, was that it appears to be a
similarly nasty virus in mice as well.
So where we are and frankly where St. Jude
is that St. Jude is one of the laboratories
around the
world that is participating with generating a
vaccine
reference strain. They have prepared a reverse
genetically engineered H5N1 Vietnam/1203 that was
generated using the PR8 as the backbone. It was
rescued in St. Jude qualified Vero cells. Additional
plaque purification of that candidate is planned.
Pathogenicity studies of the first
material that was rescued is ongoing in chickens
and
mice. As
Nancy and Phil both alluded to, there are an
additional battery of tests that will need to be
done.
Additional vaccine reference strains that are
planned
and supported by the NIAID is the generation of a
live
tenuated vaccine reference strain. This is also
planned via collaboration with NIAID's Intramural
Laboratory of Infectious Diseases and MedImmune. The
PI is Dr. Kanta Subbarao.
My last slide is to tell you where we are
with vaccine development. We are currently having
technical discussions with manufacturers who are
interested and who have questions about
production of
small pilot lots of investigational vaccine that
can
be produced and used in clinical trials.
The NIAID, as most of you know, supports
a clinical trial network called the Vaccine and
Treatment Evaluation Units. We also support a Viral
Respiratory Pathogens Research Unit. Both of these
can support phase one and phase two clinical
trials.
The NIAID has also initiated discussions with the
clinical investigators of these units to identify
points to consider and are involved in the design
of
clinical protocols which is ongoing. With that, I
will end and be very happy to answer any
questions.
CHAIRMAN OVERTURF: Are there
questions
for Dr. Lambert?
DR. MARKOVITZ: Yes, I was
curious if you
or anyone else could comment. What's the extent of
the number of laboratories do you think that are
actually working on this type of vaccine?
DR. LAMBERT: Generating the
reference
strain?
DR. MARKOVITZ: Yes, in other
words, labs
that are either academic, government, or
industrial
that are working on H5 vaccines, do you have any
ballpark idea?
DR. LAMBERT: Let me try to list
them.
Nancy can jump in if I miss anybody that she
knows of.
In the U.S., it is St. Jude in Memphis, CDC in
Atlanta.
It soon will be Kanta Subbarao in Bethesda
at NIAID.
You have heard from Phil so the NIBSC
group.
There's also a group in Japan.
That's the
extent that I know of. Nancy, do you know of any
others?
DR. COX: No, I think that the
group at
NIID, the National Institute of Infectious
Diseases,
in Japan has also begun some work.
CHAIRMAN OVERTURF: Any further
questions?
DR. WHITAKER: Linda, can you
comment on
some of the challenge grants that may also be
working
on this type of H5 or related H5?
DR. LAMBERT: Thank you, Charlie,
for
bringing that up. In 2000, the NIAID awarded three
challenge grants. It was the first time the NIAID had
ever been given challenge grant resources. It's
matching dollars so we were able to make awards
to
companies for a certain amount of money provided
they
put at least the same amount of money into the
project.
So there were nine awards that were made
in 2000.
Three of them were made for influenza.
One
went to Aviron.
One went to Aventis which is the one
I'm going to expand on. One went actually to Novavax
in Rockville.
So I think, Charlie, that all of the goals
of those grants were to develop first of all
vaccine
candidates, reference strains, master seeds. At the
end, the end result of those grants was to and is
to
get clinical trial material that can be tested
either
by the company if they have the resources or the
NIAID
through the Clinical Trials Network. Specifically,
they basically said up front which viral
reference
strains they wanted to work with or they got
feedback
from a collaborating interagency group that we
had put
together.
At the end of the day, those grants are
still ongoing so they just turned three I think
at the
end of last year. Some of them have had difficulties.
I'll be very clear. But that's science through
grants.
Some of them have done very well.
We suspect
that one or two of them will be able to produce
clinical trial material sometime in 2005.
Now, whether that's material that
addresses the 2004 H5 or another H5, the bottom
line
is none of them had planned for what is going on
now
because we weren't faced with this scenario when
the
decisions were made. They have all invested a lot of
time and energy on picking their particular virus
and
really making progress. So I think it's fair that for
those particular projects that they can continue
to
make the clinical trial material that they set
out to
do a couple of years ago. Does that address your
question?
CHAIRMAN OVERTURF: A question
from the
floor.
DR. RUBEN: Fred Ruben,
Aventis. Linda,
I have a question about animal models of the
avian
strain.
Are there any studies that have looked at
priming animals with an H5 and then challenging
them
with some of these antigenically drifted or
changed
strains?
I think if you are getting a primary
infection, we see that influenza is very lethal
in
some instances in children who are not primed at
all.
I'm wondering if the same situation might not
apply to
animals.
DR. LAMBERT: Yes, the only one
that I can
tell you right now, Fred, and it's very relevant
today, is the preliminary study that was just
reported
by St. Jude.
They made an activated laboratory
developed vaccine. They immunized ferrets.
They came
back and now have challenged those ferrets with
the
2004 H5.
So even though what we're seeing
antigenically shows that those two viruses may be
significantly different, this one study is what
we
have right now with these viruses. I'll tell you the
punch line.
Those ferrets were protected. So
I think
there's much more work that has to be done.
CHAIRMAN OVERTURF: Walter.
DR. DOWDLE: Walter Dowdle. Linda, is
there any additional work going on with H7 and
H9?
DR. LAMBERT: Anything else we're
supporting?
DR. DOWDLE: Yes, anything else
you are
supporting in H7 and H9 or is that all lumped
under
the St. Jude's?
DR. LAMBERT: Yes, there's a
lot. But I
guess most of what we have in place to rapidly
respond
to scenarios that are unfolding like the one
that's
happening now is a lot of our response capacity
is
with St. Jude and the team that they have
established.
Following the outbreak of H7N7 in the Netherlands
‑ I
think Nancy touched on it ‑ that killed one
and I
guess infected more than 80 other individuals,
St.
Jude also generated an H7N7 reference virus with
reverse genetics and rescuing it in the St. Jude‑
qualified Vero cells.
The H9N9, we are currently conducting a
study of an activated H9N2 vaccine. It was a staged
phase one, phase two study. So what we can tell you
is that it's being conducted in healthy
adults. There
was a phase one study that was completed through
the
end of last year.
We're about to start in early March the
phase two.
It's focusing on safety and immunogenicity
of increasing dosage levels of an H9N2. But that's on
the vaccine front. There's lots going on with animal
surveillance of H9s and H7s and swine
surveillance.
But those are key things with the vaccines at
this
time.
DR. FARLEY: Monica Farley. Can you or
perhaps someone else clarify what level of
clinical
trials would be necessary for approval if a
pandemic
strain vaccine were made using the traditional
methodologies?
I'm just wondering about the emergency
response capacity. Will it have to go through a full
traditional review process in an emergency
setting?
DR. LAMBERT: I am going to turn
this to
Roland after I comment. I think at the end of the day
we sit here waiting and we have to identify
trigger
points to make decisions. So at NIAID, we have framed
the parameters of a clinical protocol.
It's aggressive. It's in
multiple
populations, multiple different age groups. It steps
down from older to younger. The numbers of those
subjects are best guess at this time. We anticipate
fully developing it and submitting it as part of
an
IND package when vaccine candidates are available
and
vaccine material is available.
But I think your question as to what the
numbers would have to be to satisfy regulatory
agencies or other public health officials that
you
would want to start producing a vaccine at a
particular formulation, it's going to be a
balance of
a number of things that are unfolding at that
moment.
So what we plan to do is to have a progressive
program, gear up as though we're focusing on
getting
clinical trials underway as fast as possible
knowing
that things could change drastically in a matter
of a
few weeks, and then know that other people would
get
involved in making much bigger decisions about
vaccine
production.
So Roland, anything to add?
DR. LEVANDOWSKI: No, if the
question is
about the licensing process, I think that we're
envisioning that for a manufacturer that already
has
a license, a current license manufacturer, that
we
would approach this, at least from the paperwork
side
of things, as more or less a strain change
amendment
which we do every year for current vaccines. That's
what was done I guess pretty much for the return
of H1
in 1978.
But the question about what the dose and
what the schedule would need to be I think would
have
to be addressed as it was during those clinical
trials
that were done during 1976 and 1977 with swine
flu and
then the Russian flu strains to try to understand
whether people currently have antibodies that
would
permit one dose or if they don't have antibodies,
if
they are immunologically unprimed and it's very
clear
that they are going to need two doses.
Those kinds of clinical trials would have
to be worked out and would be needed to support
use of
the vaccine.
But I think we see the licensing aspect,
at least for current manufacturers, as being more
of
a straightforward road with just the current
strategy
of changing the strain once we understand all the
other aspects of the process that goes into
making the
vaccine.
CHAIRMAN OVERTURF: Dr. Monto.
DR. MONTO: Including the reverse
genetics
and production in Vero cells?
DR. LEVANDOWSKI: I think we're
prepared
to address those things, yes.
DR. EGAN: Yes, Bill Egan from
the Office
of Vaccines, if I could just add one thing to
what
Roland said.
After the pandemic or while the pandemic
is coming, we're hopefully not going to be doing
these
trials about what the dose should be and how many
times, seven and a half or 15 micrograms, whether
it
should be with an adjuvant or not with an
adjuvant, do
you need two doses? Those can be done up front.
For example, there's the trials that the
NIH are sponsoring now or considering now so that
we
can get that information about how many doses and
what
that dose should be, getting that information up
front, and then if the pandemic does come, to use
that
information for the vaccine and then, as Roland
said,
with a licensed manufacturer just treat whatever
that
pandemic strain is as one of these strain
changes.
CHAIRMAN OVERTURF: Marty.
DR. MYERS: It's a little unfair given
where I've been historically. But there's the obvious
question and that is that manufacturers are not
likely
to go at risk for the production of a vaccine
that
might never be used. What are the trigger points that
will cause the department to initiate the
production
of vaccine in bulk and in what time frame is that
likely to occur?
DR. EICKHOFF: I guess that's not
an FDA
question but perhaps somebody from the National
Vaccine Program could answer that.
(Laughter.)
CHAIRMAN OVERTURF: Bruce.
DR. GELLIN: Well, Marty used to
be in the
National Vaccine Program and he didn't have an
answer
to that.
So why should I have an answer now?
(Laughter.)
DR. GELLIN: You waited until now
to ask
the question.
This is all in the transcript, right?
I think it's safe to say, as Linda had talked
about,
that there are discussions now going on about
evaluating clinical grade material to begin that
process.
The trigger points aren't clear.
But the
discussions are in place recognizing that you
can't
buy a newspaper without seeing something about
the
bird flu in Asia.
CHAIRMAN OVERTURF: I think that
was an
answer.
(Laughter.)
DR. GELLIN: If the trigger
points were
clear, I could tell you. But as you know, they are
not entirely clear. I think that we're sensitive to
the situation and trying to advance the ball as
quickly as we can. But as Linda has highlighted, the
first step is the one of getting these evaluations.
The other thing that's going to be
important is trying to understand how a vaccine
like
this might be used. With the situation in Asia, you
can envision ‑ and I heard Klaus Stohr from
WHO
talking about this on NPR last week ‑ that
there might
be endemic uses of this vaccine in Asia. In which
case, it becomes a question larger than just an
HHS
question.
CHAIRMAN OVERTURF: Any other
questions or
comments?
DR. HJORTH: Richard Hjorth with
Aventis.
I was just wondering and I think it would be
great if
we could have a model vaccine as NIID is doing to
reduce some of the time after pandemic is
announced.
But I guess I was just concerned that the
pandemic
strain would behave the same as the model
strain. I
presume if it was H5 it would probably be the
same.
But if an H13 or something came along or
whatever, I
don't know.
What's the thinking? Would that
be a
good enough model?
DR. LAMBERT: You know, Richard,
if you
had asked me in `98, when I was relatively new in
this
position, if we were going to be set, if we had
one
H5, one H6, one H7, made one prototype vaccine
reference strain for each of the HA subtypes, I
would
have said yes.
So we had H5 in `97. The two
subsequent H5s have been different from `97 and
different from each other.
So what this tells us is that we can't
wait to start making these things and testing
them.
We have to get the information about novel HAs in
vaccines and clinical trials and immune response
safety profiles.
I think at the end of the day if you
haven't made the right one ‑ you hope you
have but now
I presume we won't because what's happening now
could
be drifted and very different six months from now
‑
but you have to keep doing it.
If we dodge this bullet, a year from now
we will still probably be in the same scenario if
an
emerging H5 happens. If it's different, we go back
into the drill; production of investigation lots
of
vaccines, clinical trials, and hope that there's
enough time, as Bruce said, to get it done before
it
comes. That's what I've learned in the last six
years.
CHAIRMAN OVERTURF: Any further
comments?
I'm sure this is clarified in everybody's mind.
(Applause.)
CHAIRMAN OVERTURF: Tomorrow
morning we
will begin at 8:30 a.m. The meeting is adjourned this
afternoon.
Thank you for all of your attention.
(Whereupon, the above‑entitled matter
concluded at 6:07 p.m.)