FOOD AND DRUG ADMINISTRATION
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CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
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VACCINES AND RELATED
BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
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MEETING
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WEDNESDAY,
FEBRUARY 28, 2007
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The meeting convened at 8:00 a.m. in Salons A, B, and C
of the Hilton Washington D.C. North/Gaithersburg, 620 Perry Parkway,
Gaithersburg, Maryland, Ruth A. Karron, M.D., Chair, presiding.
ADVISORY COMMITTEE MEMBERS
PRESENT:
RUTH A. KARRON, M.D.Chair
ROBERT COUCH, M.D.Temporary
Voting Member
NANCY COX, Ph.D.Non-Voting
Member
THEODORE EICKHOFF,
M.D.Temporary Voting Member
MONICA M. FARLEY,
M.D.Member
BRUCE GELLIN,
M.D., M.P.H.Temporary Voting Member
WAYNE HACHEY,
D.O., M.P.H.Temporary Voting Member
SETH HETHERINGTON,
M.D.Industry Representative
LISA JACKSON,
M.D., M.P.H.Member
PAMELA McINNES,
D.D.S.Temporary Voting Member
JOHN MODLIN, M.D.Member
CINDY PROVINCE, R.N.,
M.S.N., M.A.Temporary Voting Member
STEVEN SELF, Ph.D.Member
JACK STAPLETON, M.D.Member
MELINDA WHARTON,
M.D., M.P.H.Temporary Voting Member
BONNIE WORD, M.D.Member
This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly, the Food and Drug
Administration makes no representation as to its accuracy.
FDA PARTICIPANTS:
CHRISTINE WALSH,
R.N.Executive Secretary
NORMAN BAYLOR,
Ph.D.Director, Office of Vaccines Research and Review
SARA GAGNETEN,
Ph.D.Scientific Reviewer, DVRPA
RAKESH PANDEY, Ph.D.Division
of Vaccines and Related Products Applications
GALINA VODEIKO,
Ph.D.Division of Viral Products
JERRY WEIR, Ph.D.Director,
Division of Viral Products
ZHIPING YE, M.D.,
Ph.D.Division of Viral Products
SPEAKERS:
TONY COLGATENovartis
ANGELA OWENS, M.P.H.Air
Force Institute for Operational Health
ALBERT THOMASSanofi Pasteur
A-G-E-N-D-A
CALL TO ORDER AND OPENING
REMARKS ............. 6
Ruth A. Karron, M.D., Chair
ADMINISTRATIVE MATTERS
........................ 6
Christine Walsh, R.N., FDA
TOPIC 3: STRAIN SELECTION FOR THE INFLUENZA VIRUS VACCINE FOR THE 2007-2008 SEASON
INTRODUCTION ............................ 9
Rakesh Pandey, Ph.D., FDA
U.S. SURVEILLANCE ....................... 20
Anthony Fiore, CDC
WORLD SURVEILLANCE/
STRAIN CHARACTERIZATION ................. 29
Nancy Cox, Ph.D., CDC
VACCINE EFFECTIVENESS REPORT - DOD ...... 59
Angela Owens, M.P.H., DOD
VACCINE RESPONSES ....................... 68
Zhiping Ye, M.D., Ph.D., FDA
AVAILABILITY OF STRAINS AND REAGENTS .... 84
Galina Vodeiko, Ph.D., FDA
COMMENTS FROM MANUFACTURERS ............. 87
Albert Thomas, Sanofi Pasteur
OPEN PUBLIC HEARING .................... 100 Christine Walsh, R.N., FDA
STRAIN SELECTION OPTIONS/COMMITTEE
DISCUSSION AND RECOMMENDATIONS ......... 101
Rakesh Pandey, Ph.D., FDA
INFLUENZA A (H5N1) VIRUSES UPDATE ...... 165
Nancy Cox, Ph.D., CDC
TOPIC 4: INFLUENZA TYPE B STRAIN - DISCUSSION ON CIRCULATING LINEAGES
INTRODUCTION ........................... 179
Jerry Weir, Ph.D., FDA
BACKGROUND AND PRESENTATION OF
POSSIBLE VACCINE OPTIONS ............... 183
Robert Couch, M.D., BCM
REGULATORY IMPLICATIONS FOR
ALTERNATIVE VACCINE OPTIONS ............ 222
Sara Gagneten, Ph.D., FDA
COMMENTS FROM MANUFACTURERS ............ 227
Tony Colgate, Novartis
OPEN PUBLIC HEARING .................... 238
Christine Walsh, R.N., FDA
COMMITTEE DISCUSSION ................... 243
Ruth A. Karron, M.D., Chair
ADJOURN MEETING
.............................. 272
P-R-O-C-E-E-D-I-N-G-S
(8:12 a.m.)
DR. KARRON: If everyone would please take their
seats. We're going to begin this
mornings session.
Yesterday we heard mostly about
pandemic influenza and today we're going to hear mostly about seasonal
influenza.
Christine?
MS. WALSH: Thank you, Dr. Karron.
Good morning. I'm Christine Walsh, the Executive Secretary
for today's meeting of the Vaccines and Related Biological Products Advisory
Committee.
I would like to welcome all of you
to this meeting of the Advisory Committee.
Today's session will consist of
presentations that are open to the public.
I would like to request that
everyone please check your cell phones and pagers to make sure they are off or
in the silent mode.
I would now like to read into the
public record the conflict of interest statement for today's meeting.
"This brief announcement is in
addition to the conflict of interest statement read at the beginning of the
meeting on February 27 and will be part of the public record for the Vaccines
and Related Biological Products Advisory Committee Meeting on February 28,
2007.
This announcement addresses
conflicts of interest for the discussion of Topic 3, Discussion and
Recommendation on Strain Selection for the Influenza Virus for the 2007-2008
Season, and Topic 4, a Discussion on Circulating Lineages of Influenza B Virus.
In accordance with 18 U.S.C. Section
208(b)(3), waivers have been granted to:
Dr. Robert Couch, Dr. Lisa Jackson, Dr. Ruth Karron, and Dr. John
Modlin.
Dr. Seth Hetherington is serving as
the industry representative, acting on behalf of all related industry and is
employed by Icagen, Incorporated.
Industry representatives are not special government employees and do not
vote.
In addition, there may be regulated
industry or other outside organization speakers making presentations. These speakers may have financial interests
associated with their employer and with other regulated firms. The FDA asks, in the interest of fairness,
that they address any current or previous financial involvement with any firm
whose product they may wish to comment upon.
These individuals were not screened by the FDA for conflict of interest.
With regard to FDA's guest speaker
for Topic 3, the Agency has determined that the following information is
essential:
The following information is being
made public to allow the audience to objectively evaluate any presence and/or
comments.
Mr. Albert Thomas is employed as
Director, Bio-Manufacturing, Sanofi Pasteur in Swithwater, PA.
This conflict of interest will be available
for review at the registration table.
We would like to remind members and
participants that if the discussions involve any other products or firms not
already on the agenda for which an FDA-participant has a personal or imputed
financial interest, the participants need to exclude themselves from such
involvement, and their exclusion will be noted for the record.
FDA encourages all other
participants to advise the Committee of any financial relationships that you
may have with any firms, its products and, if known, its direct competitors.
Thank you. And Dr. Karron, I turn the meeting over to
you.
DR. KARRON: Thank you, Christine.
Our first speaker is Dr. Rakesh
Pandey from the FDA.
DR. PANDEY: Thank you, Dr. Karron.
Good morning, everyone. I welcome you all to this mornings meeting.
I am Dr. Rakesh Pandey from the
Division of Vaccines Applications at CBER's Office of Vaccines where I have
been a scientific reviewer and have been involved with the review of influenza
files for the last 12 years.
I'm going to introduce a topic for
today's discussion on the composition of 2007-2008 season influenza
vaccines.
This meeting has been an annual
activity for years. And around this
time, this Advisory Committee meeting is convened to get its recommendation on
the composition of the influenza virus vaccine for the next season in the
United States.
So why do we change influenza
vaccines annually? Influenza vaccine is
probably the most widely used human vaccine in the United States and millions
of doses are produced and used year after year.
Influenza vaccines do not give long
lasting immunity and generally do not protect well against the strains that are
not included in the vaccine. So as
listed on this slide, efficacy of the influenza vaccine is related to two
things:
The efficacy of the influenza
vaccine is considered to be related to vaccine potency. That's the amount of hemagglutinin antigen
present in the inactivated vaccine, which is measured by SRID, or a single
radial immunodiffusion acid. The antigen
content relates to the immune-SRID, which is measured by the immune response
seen in HAI assay.
Also, the efficacy is related to the
match of HA and NA antigens to those of the circulating strains. The HA and NA antigens keep on changing
continuously, and that is why influenza virus is considered to be a moving
target as far as the vaccines are concerned.
Influenza vaccines were licensed in
1945 for the first time in the United States.
And, in fact, within two years of their use, evidence came up for
reduced vaccine effectiveness because of the antigenic drift.
In order to ensure the effectiveness
of influenza vaccine from season to season, we review the antigenic composition
of the vaccine every year and change one or more strains as need, as and if
needed.
However, in order to come to a
conclusion that a change in vaccine composition is warranted, these are the
four questions that we need to answer.
First, we need to know if there are
new influenza vaccines out there that are antigenically different from the ones
in the vaccines. And for this purpose,
the WHO, CDC, and other agencies are involved in global surveillance, which is
a collaborative effort to monitor the emergence of new influenza viruses that
might be showing an antigenic drift or shift.
Then, we need to know if these new
viruses are actually circulating and spreading from one geographical location
to another in human populations. Are
such viruses confined to one geographical location only? Many times we may see that a new isolate may
appear in one location and then it might just simply disappear. So we may not have to worry about those
viruses.
Now, if an answer to these first two
questions is yes, then we need to know if the currently used vaccines work well
against the new isolates. So serological
studies are conducted to compare the inhibition of these isolates against serum
obtained from those vaccinated with the current vaccine. And this is to answer if the current vaccine
strain is well matched or whether it will work against the newly identified
strains.
Finally, if we determine that the
current vaccine strains do not match well against the new isolates, then we
need to ask, is a suitable vaccine candidate available for including in the
next seasons formulation.
So, if you make a recommendation to
include a new strain in the vaccine and it does not grow well in eggs, it would
not help much, since all the currently licensed vaccines in U.S. are made in
chicken eggs.
On this slide we have listed the
recommendations for 2006, 2006-2007 influenza season. Those are the vaccines that are currently
being used.
Last season was one of the few in
recent years when we had two strain changes, and those were the H3N2 and the B
strain. And as is shown on the slides,
you can see the ones in the red are the actual strains that were used by the
manufacturer of influenza vaccines in the United States.
Just a few years ago, the number of
influenza vaccine manufacturers with inactivated license vaccine had gone down
from four to two, leaving only Fluzone and Fluvirin on the market. This happened when King Pharmaceuticals and
Wyeth went out of the influenza vaccine business.
However, since then we have made a
lot of progress. We have overcome the
shortage situation of 2004 and we have two new inactivated vaccines available
for use.
Besides Fluzone and Fluvirin, which
have been on the market for quite some time, we have now GSK's Fluarix and ID
Biomedical's FluLaval licensed. GSK's
Fluarix vaccine was licensed in 2005, and last year we licensed FluLival.
Besides these four inactivated
vaccines, we also have MedImmune's live attenuated vaccine, FluMist, which was
licensed in 2003.
This slide shows the time line for
vaccine production, and it also highlights the activities relative to influenza
vaccine manufacturer, which go on for the whole year, in order for us to have
vaccine for use during the September to January time frame.
For the vaccines to be available for
use, one of the other production activities, as I said before, goes on for the
entire year.
New isolates are made available to
the manufacturers by CDC and CBER throughout the year, and the manufacturers
keep working on them to make sure they are usable in case they are recommended
for use in the vaccines.
Then from ordering the eggs to
making the monovalent strains for use in the vaccines in the U.S., the
activities go on from January and sometimes up to the late end of fall. And to that point, they will switch over to
the strains for making monovalent for use in the southern hemisphere vaccine.
So the formulation of trivalent
vaccines usually starts somewhere around June, and the activities related to
filling, testing, and release of the vaccine could continue until the end of
the year.
And finally, any, sometime around
July when the animal strain change supplements are approved, the distribution
activities begin, and they continue for the next few months.
Now, in order for all of this to
happen, the support activities go on for the whole year. Around this time of the year, WHO, U.S.
Public Health Services, and VRBPAC gives recommendation. Then towards fall, the Southern Hemisphere
recommendations come out.
And the whole process of
surveillance, identification of new relevant strain, and preparation of regents
continues for the entire year.
So basically, even though we
consider influenza vaccines as seasonal vaccines, they are seasonal only in the
sense of use. In the sense of
manufacturing, they are essentially a non-stop process with hardly a break in
manufacturing.
So time taken for the trivalent
vaccine lot to be available after a strain change, now since there can be a
significant impact of the Committee recommendations on the manufacturing
process, later in this session, the industry representative will go over this
thing in more detail.
As you can see from the slide, it
can take up to six to eight weeks for the manufacturers to optimize a strain
for production after it has been made available to them. So any delay in identifying the strains to be
used in the vaccine could delay the availability of vaccine in the fall.
Now, another great limiting step in
this process is the availability of reagents needed for the manufacturers to
standardize the vaccine and the assigned potency value.
Now, although the manufacturers may
start production of some of the vaccines monovalent at risk, a timely VRBPAC
recommendation is critical for trivalent vaccine to be available in fall, in
time.
Basically, it could take up to 18 to
20 weeks for the first trivalent lots to become available after the change in a
single strain and the recommendations.
If there is an additional strain change, it could delay the process by
another few weeks. And if all three
strains have to be changed, the situation could become really challenging.
The WHO held its meeting for the
2007-2008 Northern Hemisphere formulation from the 11 to 14 of this month,
where they reviewing the surveillance information and the information on
antigenic and genetic characteristics of the viruses circulating around the
globe. They also reviewed the
serological data as how the circulating viruses, isolated from different parts
of the world, react against the serum obtained from currently used vaccines.
Now, based n the discussions, WHO
gave the recommendations for the vaccine composition for the 2007-2008 season
for the Northern Hemisphere, and that's published on their website, which is
listed here.
And I also have that listed on this
slide, the recommendation basically reads, "It is recommended that the
vaccines to be used in the 2008 Northern Hemisphere winter contain the
following:
An A/Solomon Islands/3/2006
(H1N1)-like virus.
An A/Wisconsin/67/2005/(H3N2)-like
virus.
And a B/Malaysia/2506/2004-like
virus."
And out of these three, only the
H1N1 A/Solomon Islands is a new recommendation.
The other two have been from the last years vaccine.
Finally, the agenda for the
Committee would be to review the surveillance data on epidemiology and antigenic
characteristics, and the serological responses to the vaccine, and the
availability of candidate strains and reagents, which would be presented by the
next few speakers, and to discuss which strains should be recommended for the
antigenic composition of the 2007-2008 influenza virus vaccine.
So, at this point I will stop and,
unless there are any questions from me, I'll turn it over to the next speaker.
DR. KARRON: Our next speaker will be Dr. Anthony Fiore
from the CDC.
DR. FIORE: Hi, I'm Anthony Fiore from the CDC, Influenza
Division. I'm standing in for Joe
Bresee, and I am going to provide an update on the influenza surveillance for
this current flu season.
This depicts the various different
surveillance systems which come into CDC, are compiled, and then go back out
again to you, and the public, and healthcare practitioners, and so on.
We do conduct laboratory based
surveillance with strains coming into CDC from a variety of different sources
to be characterized.
We have Sentinel Provider
surveillance, which consists of a variety of different providers who provide
isolates and clinical information on patients that come in with influenza-like
illness.
Population-based hospitalization
surveillance, which is conducted in a number of different areas in the U.S.,
which were, those of you who went to David Shay's talk yesterday saw the map of
where our population-based hospitalization surveillance is conducted.
Assessments by state and territorial
epidemiologists about flu activity weekly from their states.
A pediatric mortality surveillance
system, which was setup in 2003-2004 after the early and fairly severe season
that we had that year.
And vital statistics and registrars
who provide us with data for 122 cities mortality surveillance for pneumonia
and influenza, and sorry, influenza, right.
And the next five slides are going
to sort of give you a time lapse version of this years flu season. The season started off in November with a
number of interesting small town, apparently school-based outbreaks in North
Carolina, some influenza-B outbreaks.
And over the course of the next few weeks, it kind of evolved to be a
southeast-U.S. phenomenon.
And again, mostly concentrated in
the southeast toward the end of last year, and then as we came into this year,
spread throughout other states.
And you can see by the color-coding,
regional activity as assessed by the state and territorial epidemiologists is
depicted in blue, and widespread activity in red.
And then this past week you can see
where we have a widespread or regional activity in most states.
This is the Sentinel Providers
surveillance system. And what you see
here is the last two years tracked by the solid lines, and this current flu
season by the red line with the diamonds on it.
And it predicts the percentage of visits to the Sentinel Providers for
influenza-like illness by week. And as
you can, there's a dotted baseline there which depicts what the average is
thought to be, the national baseline, and then over the course of the year the
people who come in for INI is shown by the lines.
And what you can see here is this
season, which is depicted up to about week seven or so, we have a fairly
typical percentage of visits for ILI. It
tracks more or less the same as the last two years.
Here is information from our
influenza hospitalization surveillance.
This is laboratory-confirmed influenza in the new vaccine surveillance
network, which is three sites around the U.S.
And it tracks hospitalizations due to lab-confirmed influenza among zero
to four year olds.
And this shows the last six seasons,
the previous five seasons by the solid lines, and this season by the incomplete
red line with the red circles on it. And
what it shows you is that this season is very similar to four out of the last
five seasons, that the blue line is the 2003-2004 season, which had early
reports of illness among children, severe illness.
This is the Emerging Infections
Program, this is, I believe, eight sites around the country. It again was shown yesterday by David Shay on
the map. Again, this is lab-confirmed
influenza vaccinations. This is just
shown for the last three years, sorry for the last four years counting this
one. And this shows not only 0 to 4 year
olds, but also 5 to 17 year olds. The
younger children are shown with solid lines, the older children with the dotted
lines. And you can see this season's
information, again with the red lines with the circles showing the 0 to 4 year
olds, and then right there on the x-axis the dashed red line showing the 5 to
17 year olds. And this is a cumulative
number of hospitalizations and that's why the number go up like that.
And then this is the pneumonia and
influenza mortality surveillance system, often called the 122 city surveillance,
showing the pneumonia and influenza mortality as reported by death certificates
and registrars around the country. What
is depicted by the black lines, the top black line is the epidemic threshold,
and the bottom, the bottom black line is the seasonal baseline. And then the actual reports are tracked with
the red lines. So you can see, we
haven't actually spiked up over the epidemic threshold in this flu season.
Now, I mentioned that in 2003-2004
we started a pediatric death surveillance.
And as of February 15 of this year, CDC has received 15 reports of
influenza-associated pediatric deaths.
Ten of these were among children five years of age or older. Three had underlying medical conditions. Five had no known underlying conditions. And two's previous health status are yet
unknown. Nine of these children were
unvaccinated, speaking strictly of the ten that were 5 years of age or older.
And then as compared to the last
couple of flu seasons, in 2004-05, 44 deaths were reported. In 2005-2006, 48 deaths, and then going back
to 2003-2004, 153 deaths.
This is the Collaborating
Laboratories Strain Surveillance Summary for 2006-2007. And what you see depicted here is, let's see,
yes, of the 10,458 viruses typed, 84 percent of them had been Influenza-A, 16
percent, B. Of the 28 percent of those
that have been sub-typed, 87 of the As were H1, and 13 percent of the As were
H3. And we've seen an increasing
percentage in the last couple of weeks of H3s.
Switching over to anti-viral
resistence data generated so far this year and as compared to last year, you'll
recall last year there was the identification of high levels of
adamantine-resistants among isolates, starting in 2005. And for comparison, in the last flu season,
two out of eight, or 25 percent of the H1s are adamantine-resistant. And 192 of 209 H3s tested, or 92 percent,
were adamantine-resistant.
There are fewer of these
adamantine-resistants, or the proportion of the adamantine-resistants is lower
this year, but there is still a considerable amount of it. And global surveillance so far, three percent
of the 199 H1s tested have been resistant.
Forty-four percent of the H3s tested have been resistant. Among U.S. isolates, the numbers are similar,
one percent of H1s and 33 percent of the H3N2s, although we don't have very
many of those tested so far.
As far as resistance to
neuraminidase inhibitors, oseltamivir or zanaminivir, among the isolates tested
so far since 2005, and that's 437 isolates, there have been none identified as
being resistant.
And just to update you on issues
that will come up in front of the ACIP over the next year, and also came up at
the meeting last week, of course the new vaccine strains, which we're here
today to discuss. The recommendation,
the ACIP recommended, as you would expect, that adamantine not be used in
treatment of influenza-A viruses.
We did make one change to the
recommendations. And this had to do with
harmonizing the American Academy of Pediatrics and the ACIP recommendations for
young children in a specific subset. As
you would recall, young children who are six months to less than nine years of
age who get vaccinated for the first time are supposed to get two doses. What, the disharmony occurred had to do with
children who only got inadvertently only got one dose in that first year. And what the ACIP recommendations have been
changed to, and what the AAP recommendations already were was that those
children who got one dose in their first year of being vaccinated in that age
range, in the second year of being vaccinated should go ahead and get two
doses.
Now, what was not changed was the
age groups or the risk groups that were recommended for routine
vaccination. And there is going to be
continuing discussion of advancing the recommendations to include other
age-groups or risk groups over the next several years. But for this coming flu season, the
recommendations have not changes as far as that goes.
And that's all I have to say. I can either take questions now or do you
want to wait after the session, either way.
DR. KARRON: We can take questions now if there are any.
Okay. Thank you, Dr. Fiore.
Our next speaker is Dr. Nancy Cox
from the CDC, who will tell us about worldwide surveillance.
DR. COX: Thanks very much. It's a pleasure to be here. And I'll try to make my presentation as
comprehensible as possible. For those of
you sitting in the back of the room, I know you won't be able to see the
slides, so there are plenty of seats in front if you would like to move up and
have a better view.
I'm going to be talking about what
we're seeing globally with respect to influenza activity and influenza viruses.
I will be talking about
hemagglutination-inhibition data, with post-infection ferret sera.
I will be talking about the genetic
analysis of the HA and the NA genes of the viruses.
And I will not be talking too much
about the serology, the post-vaccine serology unless you have specific
questions, based on the data in your packages, because I think that data will
be covered by Dr. Zhiping Ye later on.
Influenza H1 activity has been
relatively light, although influenza H1 viruses have predominated in the United
States and a few other countries, and in a few other countries have caused
moderate outbreaks, or moderate levels of activity. But really, H1N1 hasn't caused many problems,
except in the United States.
If we look globally at the number of
H1N1 viruses that were isolated within WHO's global influenza surveillance
network, we can see that for 2006-2007, which is shown in the blue line, we
really have relatively low numbers of H1 activities isolated worldwide.
What that means, of course, is that
we have a limited amount of data. If we
look at the viruses that are characterized in all of the WHO collaborating
centers, our own included here, we had the largest number of H1 viruses
characterized during this period from September to the current time. But there were also a significant number
characterized in Australia.
So, what we see is that we have, the
majority of viruses are still New Caledonia like, but there are a number of low
reactors. And they were seen
particularly at the WHO collaborating center in London, where they had a higher
proportion of low reactors.
I apologize for the HI table, but I
think it's important for us to go over carefully and to understand the kind of
data that we're looking at on a weekly basis.
All of the WHO collaborating centers
generate one or two HI tests per week on average, or at least we do. And we often have to retest viruses if they
appear to be low and we want to make sure that they're actually low reactors.
So what we have here are the
reference antigens, starting with New Caledonia, the vaccine strain, and we
have a number of other reference antigens, which we have put into ferrets to
develop post-reaction ferret serum.
So these across the top are the
corresponding reference ferret antisera.
And what we're really looking for is a lower level of reactivity than we
see with the homologous virus interacting with the homologous serum.
So here you see a number of viruses,
the Kentucky, the Virginia, and the St. Petersburg, which are very well
inhibited, equally well-inhibited by anti-serum to the New Caledonia vaccine
strain, as New Caledonia is itself.
Starting
here with the Hawaii/15/2001 strain, we see quite a marked reduction in the
ability of anti-serum to the New Caledonia virus to inhibit hemagglutination of
this virus.
And if we look across here, we can
see that it's true not only for the New Caledonia serum, but for the Kentucky
serum and the Virginia serum, as well.
So Hawaii/15/2001 was one of the
first viruses that we saw which had a specific amino acid change and a
corresponding difference in activity with the New Caledonia serum.
When we put the Hawaii virus into
ferrets, we got a homologous titer of 320 and viruses like it in having that
same amino acid change, which I'll talk about in more detail later, are
well-inhibited by anti-serum to this particular virus.
So we've, we've been able to really
distinguish viruses that have a change from lysine to glutamic acid at amino
acid 144. And that is antigenically
important area of the globular head of the HA.
So we can really group these viruses
into two groups, those that are well inhibited by the New Caledonia serum and
those that are not, but that when we make antiserum to these viruses, they
cover viruses with that 144 change.
So here we have a lot of test
antigens that have been isolated, many of them during the last couple of months
in December and January in the United States.
And really the majority of them are well-inhibited by the New Caledonia
serum. However, you can see this Texas
virus, which is not, is well-inhibited by serum to these viruses, including the
Solomon Islands reference strain, which I'll talk about later.
Likewise, if we look at viruses from
Asia, we see that there are some viruses that are still well-inhibited by the
New Caledonia serum, but we see a larger proportion of viruses from Asia, which
fall into this other group with the change from lysine to glutamic acid at
amino acid 144, and they're well inhibited by antisera to these reference
strains, including the first one, the Hawaii/5, and the Solomon Islands/2006,
which is the current reference strain.
I should note here that this is
Solomon Islands IVR 145, which is a high growth re-assortant, which has been
produced in Australia and circulated to the other collaborating centers in time
for us to produce antiserum against this particular virus.
So, in summary, while we still have
a number of viruses which are well-inhibited by the New Caledonia antiserum, we
see a growing proportion of viruses, particularly in Asia, which do have the
signature change and which are better inhibited by antiserum to viruses like
the Solomon Islands virus.
If you look at just our own CDC
data, you can see quite clearly that although the proportion of viruses that
are, that have a reduced titer to New Caledonia is really a moderate
proportion, and actually somewhat less than we saw during the period of April
to September. We have, we see viruses
predominantly from the United States during this October to February period,
but if you look at where we're seeing the low-reacting viruses, it's in Asia
and Central and South America. And so,
specifically, the majority of the viruses that have been sent to us from Asia
during this period from October to February, as well as the period from April
to September 2006, from Asia, are low-reactors.
Now, I apologize. This is going to be very difficult for you to
see in the back of the room, and I realize that your handouts are not color
coded. The color coding actually helps a
great deal because we've color coded the viruses by month of isolation so that
we could really depict where we're seeing, if we're seeing a trend toward more
viruses being in one group or another.
What you can see here is that the
H1N1 viruses genetically divide into two distinct groups, or clades, Clade 1
here and Clade 2 at the top. These
changes did not confer antigenic changes on the viruses, however. So we were not able to distinguish viruses
from these two groups until we started seeing the change 144, the lysine, oh,
this is the lysine to arginine, which is a different change, until we started
seeing the lysine to glutamic acid change pop up.
And it's a little bit, well, it's
really quite interesting actually, because we're seeing that this change is
occurring in separate subgroups. So we
see the change up here independently occurring, or so it appears to be
independently occurring, and in this group here, where the Solomon Islands
referenced strain and reassortant viruses.
And so no matter where the virus is
on the tree, if it has that lysine to glutamic acid change at 144, it is poorly
inhibited by the New Caledonia serum and well inhibited by antiserum to the
Solomon Islands.
And so what, when you see a change
that is occurring, apparently independently in different parts of the tree,
what you tend to think is there may be selective pressure in the population to
select that particular amino acid at that position.
If we look at the evolutionary tree
of the neuraminidase genes, you can see that we don't have as many strains on
this tree and we haven't really sequenced quite as many neuraminidase
genes. We'll be sequencing more in the
future because we'll be trying to do more high throughput sequencing, but
you'll see that the Solomon Islands virus here is in the Clade 2 just,
neuraminidase is in the Clade 2 just as the hemagglutinin was.
So there is correlation between
where in the tree the hemagglutinin is and neuraminidase. And you'll see that we do have a number of
viruses -- I should back up one and say that we do, we're still seeing quite a
few viruses from the U.S., recent viruses from the U.S., in this group down
here, which doesn't, and most of the viruses in Clade 1 do not have that 144
change.
So here is the old vaccine strain,
which I should point out is the 99-strain.
The Solomon Islands reference strain in Hong Kong/2652 is another of the
reference strains that has been important in our understanding of what's going
on with the H1N1 viruses.
So if we look, step back and
summarize what we've seen globally, we can say that H1N1 viruses have been
circulating at a low level, but sporadically in Canada, South America, and the
Russian Federation.
H1N1 viruses, however, predominated
in the United States. Many H1N1 viruses
have remained antigenically like the New Caledonia vaccine strain, but a
proportion of recent H1 viruses, particularly those from Asia, have been
antigenically distinguishable from the vaccine strain. And, as I mentioned, these viruses were more
closely related to early-Hawaii/15 strains and then these other reference strains,
specific, and I want to note the Solomon Islands/3/2006. And the majority of those viruses do have
this mutation that I spoke about.
Okay. We'll move on to the H3N2 viruses. H3N2 activity has been very moderate in many
parts of the world. We started out with
some H3N2 sporadic activity in a lot of the world, and then some increasing
activity in Scandinavia. And then by
January, we were seeing a number of European countries with slightly greater
intensity of H3N2 activity, and Canada was having quite a bit of H3N2 activity.
If we look at the number of viruses
that were H3N2 viruses that were isolated with the Global Influences
Surveillance Network, again looking at the blue line here, we see that there
really were not many viruses isolated globally compared to previous years,
where we had a lot more H3 activity than we had this past season.
And this is reflected in this table
here. If you look at the H3 table, you
can see that between February and September of `06, there were over 1,000
viruses isolated, between October `06 and January `07 we've only had, or had
only 319 viruses characterized by all of the four WHO collaborating
centers. And that was as of the second
week in February.
This is our most recent H3HI
table. And again, I'll walk you through
it fairly slowly and carefully. We have
included only one HI Table in our package this year because we felt that it was
the best summary of what's going on and includes the Ferret Sera from some of
the most recent viruses. And these data
were not even available from the WHO Meeting, so these are very fresh data.
So we'll look here, starting from
the left with the California/07. This is
an old vaccine strain. The current
vaccine strain, Wisconsin/67/2005 and its corresponding high-growth
reassortant, 161B, and its corresponding antiserum.
We have other viruses, including one
from the U.S., Kentucky, one from South America, Santiago, a Florida, and then
you'll see the last two antigens, Nepal/921 and Canada/1212, which I'll talk
about later.
The Canada/1212 was actually used as
a serology antigen, as was the Santiago virus.
And you'll see those data later.
Now, what we've been seeing over
time is that there's an increasing number of viruses that are poorly inhibited
by antiserum to the wild type Wisconsin/67 strain or the actual vaccine strain,
R161B. And you'll see that these
viruses, however, react quite poorly with all of the ferret antisera that we've
been able to generate.
Now, this table just shows a small
number of the failed antisera that we've been able to generate, either using
cell isolates or egg isolates. And I'll
talk more about how many egg isolates we've actually had in hand later on,
because that's increased significantly and I think it's important for the
Committee to know.
But what we can see here in this
reference panel is we don't get a great deal of differentiation. It's not like the situation that we saw for
the H1N1 viruses where you could see that clearly there were viruses which were
low on this side, and then a group of viruses that were high on this side, and
the antisera that corresponded to those viruses didn't inhibit the other
viruses very well.
So, we have here what is a much less
clear-cut situation. We have really
struggled with what these low-reactors mean.
And there is a tendency right now to think that these, many of these low
reactors are actually low avid viruses in the hemagglutination-inhibition
test. And the way that you can eyeball
this and determine whether they are low avid or not is to look at what the
difference is in the titer between the virus and the reference strain that
you're looking at, and it if a four-fold difference, just multiply everything
by four; if it's a 16-fold difference, multiply all these values by 16, and see
whether you get a pattern that's similar to that for the reference strain.
And what we've determined, and I'll
show you a graphic representation, is that many of these appear to be low-avid
viruses. Now, we don't really understand
as much as we would like to about avidity.
And we think that, well we know that the receptor binding properties of
H3 viruses have been evolving over time, and that some changes occurred a few
years ago that we believe have affected our ability to discriminate viruses
using the hemagglutination inhibition test.
Nevertheless, whether we're looking
at viruses from the U.S., Canada, Europe, or Asia, we do see viruses that are
well inhibited by the Wisconsin antiserum.
And if we look at these two most recent antisera, we see that while they
cover some of the low reactors somewhat better than the Wisconsin antisera, or
both that the antisera do, they really, you still are seeing a lot of viruses
which have a 4-fold or greater reduced titer against these strains.
The Nepal/921 is an
egg-isolate. And that was put into ferrets. And the Canada/1212, which is related
genetically is a cell-based virus put into ferrets. And whether you have an egg isolate or a cell
based isolate, you still see these low reactors.
So if we don't take avidity into
account and we just strictly look at the number of viruses that are, that have
a 4-fold or greater reduced titer to the antiserum to the vaccine strain, we
see that we have about 59 percent of viruses which are low reactors. And we do have relatively small numbers
compared to what we've had in the past, but these viruses are geographically
spread, so we're seeing low reactors around the world, but they are behaving
similarly in perhaps being low avid.
We have been trying very hard to
improve ways to look at the HI data, the ferret data, and these methods will be
extended to look at the human serologic data.
Derek Smith from the University of Cambridge, has developed a field
which he has called antigenic cartography.
He's pioneered this using data from the WHO Global Influenza Surveillance
Network. And basically what it does is
mathematically calculate different distances, antigenic differences between
viruses and then display this information graphically.
Well, if you're accustomed to
looking at HI tables and you look at them everyday, your brain is actually
doing a lot of it. It's amazing what,
how much your brain can actually do on its own, but it's nice to have a visual
display, especially when you're getting up in front of a group like this.
So Derek has, here is some of the
old vaccine strains, the Sydney, the Wyoming, the New York, here is our current
vaccine strain here in blue, and some virus strains that were used
previously. And we're starting to see
some outliers. You want to see some
viruses really clustering around your vaccine strain. And if you look over time, which I haven't
done here because we don't have enough time to review old data, but you would
see that for the time that the vaccine, this vaccine was used, that there were,
the majority of viruses were really clustering very closely around this. And each one of these squares represent a
two-fold difference in antibody title.
And then if you look at our CDC data
generated from viruses that were isolated in December, you can see a scatter
somewhat away from the list of Wisconsin/67 virus. And then if you look at January again, you
see the scatter.
Derek has written a program which
will account for avidity, and so he's incorporated into his program an avidity
correction, and so I'll just go through those same data. And what you see is that the viruses are
actually, when the avidity corrections are done, the viruses are actually
pulled closer to the Wisconsin/67 vaccine strain, although there are some
viruses which are fairly far away, getting to be 4-fold, or 8-fold, or
greater. But certainly the differences
are less for the July data.
For the December data, we are still
seeing viruses out here. This is the
Canada virus, Canada virus here, and Nepal virus here. So these viruses are really not being pulled
toward the Canada and Nepal.
And then for the few January viruses
that we've had in hand to analyze, we're still seeing this scatter over here,
but a few more viruses that are clustering around Canada and Nepal.
If we look at the genetic data,
we've actually sequenced a fairly large number of HA genes. Even in the last couple of weeks, we've been
able to sequence well over 50 HA genes from recent viruses. And we were very interested because we were
starting to see two primary groups emerging.
One here, which is represented by the Brisbane/9/2006 virus, which was
isolated in June during the Southern Hemisphere season, and another which is
represented up here by Nepal/921, which I pointed out on the HI table, and the
Canada/1212 virus, which was isolated in December.
I should mention that a lot of the
data on here has, the data have been provided, the sequence data have been
provided by some of the national labs.
The Canada lab provided us with sequence data. And we actually get data exchanged among the
four collaborating centers and as many of the National Influenza Centers as
possible. So we really have a lot more
data than I'm showing you on here, but I'm just really trying to demonstrate
what we're seeing.
Again, the most recent viruses are
shown in purple. The December viruses in
pink, November in orange. So you're
looking for the more intense red colors here to see where the trends are. And what we're seeing is that the most recent
viruses, and it is about 50/50, slightly more in this group than this group,
but about 50/50 distribution of recent HA's into this group here, which has
characteristic arginine to glycine change at 142, and then some additional
changes. You can see that there are
subgroups here with additional changes.
We do have a lot of viruses, and they are from Asia, from the U.S., and
Europe in this group as well.
Likewise, if we look at the NA
genes, here is our Wisconsin vaccine strain.
Here are the two groups that I was referring to before, the Brisbane
Group and the Nepal Group. And you can
see that the viruses, again, they're color-coded so that the most recent
viruses are shown in purple and pink, and the NA's are segregating along with
the HA's.
So, in summary, Influenza A H3N2
viruses have been difficult to analyze.
However, activity caused by H3N2 viruses was low, generally speaking,
around the world. However, there were
outbreaks during the period September to the current time in Madagascar, Canada
and a number of European countries.
Many of the viruses globally were
antigenically closely related to Wisconsin and Hiroshima. The Hiroshima virus is the vaccine virus used
in Japan. But an increasing proportion
of viruses was antigenically distinguishable from the vaccine virus,
viruses.
And increased heterogeneity was
observed in the HA sequences from recent viruses and no emergent antigenic
variant group was identified. And that
is, I think, the key to focus on. If you'll
remember, we really didn't see the same king of dichotomy in the ferret
antisera that we saw with the H1N1s.
Okay. We'll move on to Influenza B Viruses. Influenza B has also circulated at low
levels. There really hasn't been much
activity, except for sporadic activity in a few school outbreaks and so
on. But if we look overall, the
Influenza B viruses have circulated at relatively low levels, which is shown
very clearly here in the number of Influenza B viruses isolated in the WHO's
Global Influenza Surveillance Network.
And you see almost a baseline the number of Influenza B viruses.
So the total number of viruses that
we've had to look at is even smaller.
And we have them divided into two distinct lineages. And of course, this afternoon's discussion
will concentrate on the fact that we have these two distinct lineages of
Influenza B viruses.
So these are the four WHO
Collaborating Centers, and sorry that this didn't get, that it must've got
transposed. But you can see that in
Australia they had 95 percent of viruses being Victoria-lineage. In the U.S., we had more B viruses than any
other Collaborating Center to examine.
And 76 percent of the viruses that we examined were Victoria-lineage
viruses, thus matching the vaccine lineage.
But we're seeing some low reactors,
nothing really different than what we've seen before, as I'll show you in the
next table. Here, we have color-coded in
this yellow mustard color the viruses that are on the B/Yamagata lineage. And to the right we have the viruses that are
on the B Victoria lineage, including the Malaysia vaccine strain, which has
been used in all countries by all manufacturers.
These are the most recent viruses we
have. We have some from December, just I
think only one from January. We'll
expect to get some more later on. But we
have viruses from the U.S. and from Asia, and we see that if we look at the
homologous titer here of 1280, we do see a number of viruses that are reduced
in titer. But that has been something
that we have been seeing for a long time.
And what we know about the B
Victoria viruses is that once they are isolated in eggs, they lose an important
glycosolation site, which is right up at the tip of the hemagglutinin. And once they lose that glycosolation site
and are put into ferrets, they induce antibody that is not as broadly cross reactive
as the cell counterpart. And we have put
many viruses into eggs and have found that even if you retain a glycosolation
for one or two passages, if you pass it sequentially you eventually lose that
glycosolation site. So this has been
problematic for egg-based manufacturers.
So, if we look at what we are seeing
at CDC, we're certainly seeing the majority of viruses in the Victoria
lineage. That is, in the same lineage as
the vaccine strain. A smaller number,
which we're calling Florida-like, which would be a potential vaccine strain if
we were to move to the Yamagata lineage, but of course, globally and within the
strains that we've had from the USA, we've certainly seen a predominance of the
Victoria like viruses.
If we look at the HA genes, now
we're looking at the Yamagata lineage.
And this is just for full information, not really as pertinent to our
discussion today, but just to let you know that if we were to have, to move to
the Yamagata lineage, we have some very good vaccine candidate strains, which
produce antisera that do a very good job at inhibiting viruses on that
lineage. So this is the old vaccine
strain, so we do have contemporary egg run viruses that could be used, should
that become necessary in the next few years.
For the Victoria lineage, you see
that we really have much slower genetic change than we have seen for the H3N2
viruses. And this is typically what we
see. The HA of the Influenza B virus
does evolve more slowly.
So here we have the vaccine strain,
Malaysia/2506/2004, and then the viruses that are more contemporary that we've
been seeing. And you'll see some of the
viruses that are egg isolates. As I've
mentioned, they've all lost the glycosolation site. And we have a number of them. They are noted by the hatch mark, so you can
see that we really do have quite a lot of egg isolate.
The neuraminidase genes are also not
changing all that much. Here is the B
Malaysia vaccine strain. Here are a
number of the viruses, and again, you can see that we do have a number of egg
isolates shown here.
So, in summary, Influenza B viruses
have circulated in many countries; however, outbreaks or large outbreaks, apart
from institutional outbreaks, have not been reported since September 2006 and
January 2007.
Both lineages have continued to
circulate, but the Victoria lineage viruses have predominated. And if you look at the WHO data overall, it
was about 82 percent of viruses were of the B Victoria lineage.
The Yamagata lineage viruses were
closely related to those strains that I mentioned that were egg isolates and
could be used. And most B Victoria
lineage viruses were antigenic closely related to B Malaysia, taking into
account that we have an egg isolate that's gone into ferrets and we're looking
at mostly cell-based, cell isolated viruses.
Now, this is just to show you that
we've been working very hard to increase the number of egg-grown viruses. And this is shown by fiscal year. And our fiscal year and our influenza seasons
sort of start at the same time officially on October 1. So we have really increased the number of egg
isolates that would be available to manufacturers, should that particular egg
isolate look like it's an appropriate vaccine strain.
So, for the last fiscal year, which
ended September 30, 2006, we had 255 egg isolates distributed fairly well
across the different types and subtypes.
Now, I should mention that obtaining H3N2 isolates has been exceedingly
difficult. And if we put 100 clinical
specimens into eggs or into kidney cells and then pass on to eggs, we're likely
to get out five if we're lucky. So it
really does require a lot of work for the H3N2 subgroup of viruses.
I think I'll stop there and take
questions. If anyone has questions about
the human serology data that you see in the package, I can answer those
questions now because I have the slides available.
DR. COUCH: Just one quick question, Nancy, for
clarification to see if my assumptions are correct. When you say a low reactor, you spent a good
amount of time on the H3 antigens with the ferret sera, a low reactor would be
low reactor with say the Wisconsin antisera.
But with your other ferret sera, no reactions that gave it a different
identity? Is that --
DR. COX: That's correct.
DR. COUCH: -- what low reactor means?
DR. COX: So, okay, so when I say low reactor in my
table, I'm really talking about the number of viruses that have a 4-fold or
greater reduced titer to the antiserum to the vaccine strain. But when I was looking at the H3s, we were
looking very specifically because we're seeing this pattern of low reactors
across the board. So, in many cases,
your low reactor is a low reactor across the board and you don't see better
inhibition using any of the other ferret antiserum, or only moderately better
inhibition.
DR. COUCH: I guess being specific, that would count for
some of them, but when you say low reactors that reacted only with ferret sera,
or is a battery of ferret sera?
DR. COX: We always use a battery of ferret.
DR. COUCH: Only the Wisconsin -- a battery?
DR. COX: We always use --
DR. COUCH: So it's a low reactor across the board?
DR. COX: We always use a battery, but in order to
really be specific when we're talking of the WHO Meetings, we really are
looking at the number of viruses or the proportion of viruses that are low
reactors to ferret antiserum to the vaccine strain. So that's what is in those tables. But when we're looking more broadly, we're
looking for patterns of reactivity. And
so many, so for the H3s, the majority of the low reactors are low reactors
across the board to the battery of antisera.
And we never test viruses on their own.
We always test with a whole battery of ferret sera.
I don't know if that answered your
question.
Ruth?
DR. KARRON: Yes, two questions. One is so can you contrast these H3N2 viruses
where you say there is no emergent antigenic variant group, and I assume that's
based on the ferret antisera data, with say the situation we were in several
years ago with H3N2 Fujian. There we saw
an emergent new variant, is that correct?
DR. COX: We saw there an emergent new variant, which
we could clearly see using ferret antisera.
And we could see, we could see the two-way, 4-fold or greater
difference. So antiserum to the Fujian
strain didn't inhibit the old viruses as well, and antibody to the previous
vaccine didn't inhibit the Fujian strain.
So we had the two-way, 4-fold difference, which was very clear. And that also corresponded to changes that we
saw in the genetic data.
DR. KARRON: Thank you.
And then just a question either for you or for Dr. Fiore. Would you happen to know the school-based
outbreaks of B in North Carolina, whether those were Yamagata or Victoria
lineage. Is that something you would
know?
DR. COX: The North Carolina, and Tony correct me if
I'm incorrect, but the majority of those viruses were, they were Yamagata. And that was an early outbreak before the
season really got rolling. And so we
were feeling rather uncomfortable with the fact that they looked, that they
were Yamagata lineage viruses and we had Victoria. But then it didn't hold true for the rest of
the season.
DR. KARRON: Thank you.
I think we'll go on now to Angela Owens from DoD who is going to talk to
us about vaccine effectiveness and responses.
MS. OWENS: Hi. I
will also fill in for Luke Daum as well, as we provide the sequence analysis
overview.
Let me go back, sorry. We are actually part of an overall Department
of Defense Global Influenza Surveillance Program which is a WHO collaborating
laboratory and it has two parts.
One part is Sentinel site
surveillance that is managed at the Air Force Institute for Operational health,
and another part is a population based surveillance that takes base at eight
training camps and is managed at the Naval Health Research Center in San Diego.
For our Sentinel sites we have,
thank you, 43 medical treatment facilities that are located throughout the
service. We also have 22 sites
associated with four separate DoD Overseas Research Facilities. We provide naval wash kits, collection
material, education material, shipping supplies, so they can send us specimens
on a weekly basis. We contact them every
week. We expect six to ten specimens
every week from patients with a fever greater than or equal to 100.5 and/or a
cough or sore throat. We also request an
influenza surveillance questionnaire to be completed that describes vaccination
history, travel history, any additional symptoms other than cough and sore
throat.
We have so far collected about 1,200
specimens this season. Twenty-six
percent have been influenza positive by culture and the majority have been
Influenza A. We also test for
adenovirus, enterovirus, RSV, pair influenza, and HSV, which is a background
virus.
About 93 percent of our isolates
have been sub-typed at this time. The
majority have been Influenza A, H1, and the majority of B have been from the B
Victoria lineage.
This is Luke's portion, so let me
describe this. For Influenza B, the
hemagglutinin genes of over 40 DoD Influenza B viruses were analyzed from the
influenza strains obtained from summer of 2006 to present. Of these isolates, five strains were Yamagata
like, with the remaining isolates being B Victoria like.
B Yamagata like viruses are
antigenically and genetically distinct from the current vaccine strain, which
is the B Malaysia vaccine strain. These
five strains were collected from Peru, Maryland, and Illinois.
The remaining B viruses were B
Victoria and shared 99 to 99.6 percent sequence identity to the current B
Malaysia vaccine strain.
Depicted in this slide is a
phylogenetic analysis of influenza strains represented by 38 Influenza B
Victoria like strains and 5 B Yamagata like strains. As you can see, the B Malaysia indicated
within the red box is find within the cluster of B Victoria like filled strains
collected during the current season.
For Influenza A H3N2, the
phylogenetic analysis of Influenza A strains collected during the 2006 through
07 season have been the minority this year, taking a backseat to the H1
subtype. At present, we've collected and
sequenced about 70 strains, including a summary outbreak of H3N2 isolates in
Nepal depicted as a distinct branch, which is at the top.
Shaded in the circle is Clade of
Influenza A H3N2 Viruses that are forming a distinct branch in the current tree
of H3 viruses. These viruses show a
genetic variances in several nucleotides, inter-defined by the R142G mutation,
which forms the distinct branch point, I apologize, let me go back. I think every time I touch this -- I
apologize. I've been touching the
bottom. About 50 percent of our
isolates, including the July outbreak in Nepal are contained within this
branch, phylogeny. Indicated in the red
box is a current A Wisconsin strain and the older A California vaccine
strain. And as you can see from the
phylogeny, the A Wisconsin strain shows genetic variance from viruses belonging
to this Clade.
And this is the A H1N1 phylogeny of
the strains collected during the 2006 through 07 season. They've been the predominant circulating
strain, and two distinct Clades have formed with Clade II viruses showing
somewhat reduced titers according to the H1 analysis. While the two Clades are currently noted in
this phylogeny, isolates obtained in the U.S. are Clade I, which are the
current A New Caledonia vaccine strain.
Clade II isolates were obtained from South America, which are Peru,
Nepal, and one isolate from Saipan. Clade
II viruses are defined by several key amino acid changes, some of which are
located within the antibody combining isolates.
Again, we are a WHO collaborating
lab. All of our information is uploaded
to CDC's national surveillance system, and they also receive our isolates of
interest.
For vaccine effectiveness, this is a
descriptive preliminary review. We
looked at patients seeking care from U.S. Military Treatment Facilities from
October 1 to 12 February. This includes
active duty and DoD beneficiaries.
Our outcome was lab confirmed
influenza results by viral culture and isolation. We defined fully vaccinated patients as
patients who received the vaccine greater than 14 days prior to the clinic
visit date. Any of those patients
receiving the vaccine prior to August were defined as unvaccinated unless they
received another vaccine later.
Our vaccination data were gathered
form the Military Immunization Database, and our influenza surveillance
questionnaires. Those are completed at
the time of the clinic visit.
A total of 796 specimens were
included. 170 of these were
influenza. 65 of the 170 hadn't
identified vaccination status in the breakdown of FluMist versus the
injection. 23 of these patients has a
possible vaccine breakthrough, meaning they had the vaccine greater than 14
days prior to the clinic visit in which they obtained the isolate. All age groups were represented.
And the isolates obtained were
Influenza A, H3, from California, Texas, and South Korea. And the South Korea information is also
described in the sequence data that was mentioned before. H1 was identified in Alabama, Oklahoma, South
Carolina, Texas, and Antarctica. And our
Influenza B, one B was not sub-typed at this time. It was actually recently collected. And that was both identified from Alabama.
The Naval Health Research Center also
provided a vaccine effectiveness review at the eight training camps, which six
of them had influenza identified. All of
the trainees are vaccinated upon arrival, so their vaccination to identify a
fully covered vaccinated person is within the 14 days. They are not fully covered.
And they had 48 isolates. 38 of them of them were unvaccinated. And if you'd like more information regarding
this review, please contact NHRC. And I
have their information so afterwards I can get with you.
We did not, Geis, of course, is our
funding and guidance agency. CHPPM and
AMSA provided us with the vaccine information, and Pop. Health, CDC, and of
course all of our Sentinel sites. We do
expect a full review of vaccine effectiveness at the end of the season. This is a descriptive review. There is no random sample applied yet.
Here is our contact
information. And I do apologize that
Luke was not here.
Do you have any questions?
Yes?
DR. FARLEY: I was a little surprised at how often you did
not know their vaccine status in the first part. Is that because they really weren't all
enlisted military? It was families and
other people? Because otherwise I would
think your record keeping would be very tight.
MS. OWENS: Yes, for Sentinel site surveillance, our
population, it's gathered from family clinics, pediatric clinics, hospitals,
and ER's. The majority of our population
is DoD beneficiaries, and unfortunately for the Navy and the Army it's hard to
gather that vaccination status from DoD beneficiaries. That's where we come in play with the
influenza surveillance questionnaires.
That's why we actually look from the surveillance site, we request that
they all fill out that. And
unfortunately, a lot of these came from both Sentinel sites and non-Sentinel
sites. We had about 22 non-Sentinel
sites that submitted specimens this season.
But hopefully at the end of the
season also we'll get more information.
DR. KARRON: Any other questions?
Thank you very much.
MS. OWENS: Thanks.
DR. KARRON: Next on the agenda is Dr. Ye who will talk
about vaccine responses and availability of strains and reagents.
DR. YE: Thank you.
I think the whole purpose of doing
the human serological study is to see whether the HI antibody response to the
vaccine strain will confirm that the antibody response to the isolated, newly
isolated, viruses reach as Nancy mentioned in her talk.
It seems the serum sample from human
was pre-selected to choose the antibody, positive antibody response. So the whole purpose of this study is not to
compare the antibody response from different vaccine string, but rather to see,
to use this serum to study, to compare the antigenic difference of the newly
isolated circulated viruses. Serum
sample actually comes from different centers worldwide. As shown on this slide, the serum sample
comes from, there are five serum samples that come from different centers. One is from Australia. The serum sample represent the human serum
which immunized, was the vaccine that contained New Caledonia for H1N1 and New
York/55/2004 for H3N2, particularly for the Austria serum samples.
Then the B strain is Malaysia and
that is the same for the rest of the serum sample.
And the other serum samples from
Europe, from Japan, and from U.S., the serum sample comes from the human serum,
from the human population that immunized the vaccine strain containing New
Caledonia for H1N1, and the Wisconsin like strain for H3N2. The actual vaccine strain contains Wisconsin
itself or Hiroshima for H3N2 for the European, and also for the Japan. The European contained two serum samples, two
serums, one is for Wisconsin itself, another one is for Hiroshima. But what I presented in this study is the
same sample for Wisconsin itself. And
also to have the same sample from a pediatric.
Okay. The antigen used for human serological study
has been carefully chosen. And one is,
of course, is the vaccine strain itself.
Here is New Caledonia/20/99 for H1N1.
And the representative or current vaccine, current strain used for
serological study, choosing according to antigenic and genetic characteristics
of the strain, but also the geographic characteristics of those viruses.
Here you can see that I have one
strain from New England, from Hiroshima, and from Fukushima, and from Asia,
also from European. And here I marked a
group of the antigen with the asterisk over here as it represents the signature
of antigenic differences in amino acid 144, substitution of amino acid from
lysine to glutamic acid as mentioned in Nancy's talk. So we will see what the main response of
those groups of viruses to the vaccine strain.
And here, this slide shows HI
antibody response to H1N1. And this
slide I choose a representative serum panels in one of the centers who did the
serological study. By the way, there are
four or five centers conducting the human serum study, and this is only one I
choose as positive representative for H1N1.
Here I chose from U.K study.
On the left column shows the serum
panel, where the serum panel comes from.
And here it shows the serum panel from adults and from European, which
immunized for Wisconsin. They solved for
H3N2, but here we're talking about H1N1.
And then the panel coming from Australia. Since Australia human serum sample comes from
human population immunize H1N1, so that's valid for this study. And here it shows the viral strain or
antigens that has been used in human serology study. And here is what vaccine strain is solved and
here is the representative circulating viruses.
And here I show the tradition of
things that shows the percentage of post-immunization, HI or eco to 40, 1 to
40. And it also shows the percentage
over 40, for the race.
But here I liked to focus on the GMT
reduction. Unlike the serum panel
studies in using ferret study, human serum we don't have the antibody of the
serum against the individual as related to viruses. So what we focus on is to see the GMT
reduction.
And I'd like to spend a few minutes
to explain how we summarized the overall study from different centers.
Here you can see the
post-vaccination GMT titer to the vaccine strain. Absolute number is not meaningful, but the
comparison of the GMT vaccine strain to the isolated virus is what you want to
focus on. Here you can see that the GMT
titer to the vaccine strain is 1 to 90, 1:90, where the GMT from the newly
isolated virus is a 36. What we want to
see is whether this reduction is a 50 percent reduction. Here you can see that's over a 50 percent
reduction. That's one layer of information
I'd like to you focus on.
The second one is the different
panels. This only shows the one panel of
this particular strain of 50 percent of reduction. And in the next serum panel, it's the same
thing. It's the GMT titer to vaccine
strain and it compares with the newly isolated virus. And here, again, it's a 50 percent
reduction. Now, we can see that there
are two panels and two out of two panels have a 50 percent reduction. And remember that because of that, the way
you translated to the summary data I will present later on.
And here is another two panels which
I show, which are shown in this slide.
So here is a panel from U.S. and Japan.
Again, you see that this GMT to the vaccine strain itself is 273, where
to this particular strain, England is 40.
So, it's a, one time, one panel, a 50 percent reduction. By the same token, the same thing happened to
the Japan group. The GMT is a 59, where
the GMT to this particular strain is a 22.
The reason I said even in the beginning of my talk, we're not to see
response to the particular vaccine strain, rather we see the difference. Since the serum sample from Japan was not
preselected to choose the high positive response of the post-serum sample, so
they are, the GMT is relatively low compared to the other centers.
So now, have this one in your mind
that I put the five different centers together to see the overall picture
because individual lapse of data, you know, may not be well represented of
overall data. And here is a summary of
the GMT, 50 percent of GMT reduction by composed the serological study from
different centers.
As I mentioned in a few slides back,
four of four panels for this particular strain have a 50 percent
reduction. So that indicates that there
is a strain which is different from the
vaccine strain. The same thing for
A/Fukushima. Here is like 12, in 12
serum panel, some of them have a reduction.
So now you can see, I can give you the sense of overall, of the strain
and composed from different centers, different centers of studies.
And here I have to point out that
the Solomon Islands/3/2006 in 19 serum panels, only two have the 50 percent of the reduction in this
serological study. But however, overall,
the representative circulating virus, the antigen that are used in serological
study, shows that in 55 panels, 30 of them had 50 percent GMT reduction. That indicates those viruses antigenically is
different from the vaccine strain. And
the last column shows the average 50 percent of reduction. And also, that gives you the sense of the
antigenic difference by using human serum.
And I apologize that the handout
that you have was typed and corrected over here, this 51 percent. So that's an indicator that the 50 percent of
GMT reduction isn't quite significant in this study. And it also shows that H1N1 newly isolated
circulating viruses is antigenically different from vaccine strain by using
human serum study.
And now we go on for the H3N2. And as I mentioned, the vaccine strain is
Wisconsin-like. So the actual strain for
the different vaccine components either is Wisconsin itself or Hiroshima. And again, this representative occurrence
strain, which we choose according to the antigenic and the geographic
differences. Here I like to emphasize
again that the Canada and the Lyon strain which is asterisks, indicates there
is a Canada or Nepal genetic group, as mentioned in Nancy's talk. So we want to see how this strain behaves in
the human serology studies.
And again here I choose the one of
the serum panels from the CDC to give you the sense of what's the antigenic
difference by using human serum studies.
I am not going to explain it again.
Here, like folks on the GMT reduction of the newly isolated viruses,
here in this column you can see that the GMT to the vaccine strains is a 101,
where the GMT to the Brisbane is a 65.
It's not quite a 50 percent reduction; however, the rest of the
circulation viruses that we used for antigen in the human serum serology study
included Canada antigen at more than 50 percent of reduction in a GMT. And something again, it's true to the other
different panels, such as from U.K. and also from Japan, and from Japan and
also from a U.S. serum panel.
And if we put the serum study from
different centers together, now here we show the summary of the viruses. We use a 50 percent of GMT reduction in
adults. And again here, we show the
Brisbane in the 16 serum sample, serum panels, 7 of them had 50 percent of GMT
reduction.
And another one is Sendai. And in 8 serum panels, 2 of them have the
GMT, 50 percent of GMT reduction.
However, the rest of the virus includes the Canada and the Nepal
variance here. We can see that every one
of them had a 50 percent GMT reduction.
And if we put the whole thing
together, as shown in here in 73 serum panels, 55 of them had 50 percent of GMT
reduction, as indicate that this virus really antigenically is different from,
from the vaccine strain.
And again, as a true for the
average, the average percent of a GMT reduction, 65 percent of reduction in the
summary. So, that is for H3N2.
Now, we go on for the B-strain. Again, the B-strain, everyone uses the
B/Malaysia, which is Victoria-like HA lineage.
And the representative current strain was a two group. One was Victoria itself, and another one was
the group that represent the viruses from the, represent the Yamagata lineage.
And here, again, I choose the serum
panel from the CDC. And here you can see
that the vaccine strain, here there are two vaccine strains, but I don't think
anybody used Ohio for their vaccine strain, for licensing the vaccine
strain. And here, as you can see that
the Malaysia has a 69 GMT and Ohio is 126.
And the rest of the strain you can see that the newly isolated viruses
from Victoria like, you can see that there's been no reduction. Include the Yamagata strain, they are not 50
percent reduction. Probably that's due
to adults that has been pre-immunized, immunized the previous year with Yamagata
vaccines. So this is true for the rest of the serum panel including from Japan
and U.S.
And here is a summary of the GMT
reduction in adults. So here you can see
that in 22 serum panels only four of them have 50 percent of GMT
reduction. Seventeen is the average percentage
of GMT reduction. So that indicates that
the circulating viruses that we used for serological study are antigenically
close to the vaccine strain.
And although the strain from
Yamagata had lower GMT reduction, but compare with Victoria and the reduction
is more than those with Victoria like strain.
So in summary of the serological
study, with the sera collected after immunization with current vaccines show
that:
With H1N1, the recent viruses was
not well inhibited compared to the current vaccine strain.
And the same thing with the H3N2,
the current viruses was not well inhibited compared to the current vaccine
strain.
Where the B, for B, the recent
B/Victoria lineage viruses generally well inhibited compared to the current
vaccine strain.
And I'll stop here if you have any
questions.
DR. COUCH: Again, just a question to be sure I
understand and have the data straight.
On your summary tables of GMT reductions and you say four out of four
panels, that's four out of four sources of sera tested at that particular
laboratory?
DR. YE: Yes.
DR.
COUCH: And that's their results. So we're looking at maybe CDC or CBER data
where you're looking also at the data from Japan, Australia, and Britain.
DR. YE: Right.
DR. COUCH: With that summary table?
DR. YE: I think do, as we discussed yesterday, the
HISA, the variations from center-to-center from lab-to-lab, so in order to se
the whole picture we have to use the serum from different centers. Here we have to use it from five different
centers to get the whole picture.
DR. COUCH: But your serum went to those laboratories and
they tested it. Is that correct?
DR. YE: Can you repeat your question please?
DR. COUCH: The FDA sera, the CBER sera, you have a panel
of 24 sera. Those sera went to
Australia, for example.
DR. YE: Right, okay.
DR. COUCH: And they tested. It went to Japan and they tested the same
sera. All this is a change of sera.
DR. YE: I should've explained it in my talk. Yes, we exchanged the serum sample from
center to center. Every single one of
the center had the same serum panels from all the centers. So all the centers used the same serum
samples. But the study may vary, such as
using different red blood cells or the way they diluted for the same samples.
DR. KARRON: John?
DR. MODLIN: You didn't show us the data from the
pediatric samples. I'm sure you've
looked at that, but probably the numbers are small. But I wonder if you could just summarize the
age range of which the kids with sera came from and maybe just give us a
summary of what they showed.
DR. YE: I know you going to ask this question. Actually I have a back slide for that but I
took it out.
DR. MODLIN: I'm getting to be that predictable.
DR. YE: I think although this same, okay, for this
pediatric serum, since the majority of them are naive, relatively, so you will
see the better picture. But in this
particular study --
DR. MODLIN: Oh no, I'm sorry.
DR. YE: So to answer your question that the
serological study from pediatric study more represent, for H3 for H1, is similar
to adults. Where the B, you can see some
difference between Yamagata and Victoria.
Did I answer your question?
DR. MODLIN: Yes, in general. That's fine.
DR. KARRON: Actually, I have an H1N1 question. The A/England/555/2006, I didn't see that in
the ferret sera panel or in the evolutionary diagram. But is that virus like Solomon Islands?
DR. YE: I'd like Nancy to answer this question. It should be there.
DR. COX: In your slides it should've been designated
if it had that change. Let me look at
that. I've got all the data here.
Could you mark it on your slide so
that he could go back and look at your slides and see?
So the England did not have that
change?
DR. YE: Right.
England has no change in, I think it should be 144.
DR. KARRON: I guess I was just trying to understand was
the England virus and H1N1 virus that is neither like the New Caledonia nor
like the Solomon Islands. I guess that
was just my question.
DR. COX: That wasn't a virus that we used in our
serology, sorry. What was the strain
designation again?
DR. KARRON: 55/2006.
DR. COUCH: What question are we trying to answer?
DR. COX: I'll get back to you. I'll find it and get back to you.
DR. KARRON: Thank you.
Other questions for Dr. Ye?
At this point, I think Dr. Vodeiko
--
DR. YE: Yes.
DR. KARRON: -- is going to speak?
DR. YE: Yes, talk to Dr. Vodeiko from the FDA, our
next talk.
DR. VODEIKO: Thank you again for this chance to present
the next part of information. My name is
Galina Vodeiko. And from the end of
2005, I am in charge of potency and reagent preparation in CBER with big help
from Christian Anderson.
Let me introduce you information
about availability from CBER on vital strains and for vaccine for reagents for
potency.
I think I go to four.
We start from Influenza A, H1N1
viruses. The currently available strain
is New Caledonia/20/99 and it's reassortant IVR-116, prepared in
Australia. Many of you know the designation
for many reassortant prepared in Australia started with IVR, and prepared in
New York Medical School, it's usually X with a number.
With three kinds of candidates for
new vaccine strain, one of them is A/Solomon/3/2006, and is available in high
yield reassortant, IVR-145. The second
strain is A/St. Petersburg/8/2006, and is available as a high yield
reassortant, designated as X-163. And
the third strain is A/Fukishima/141/2006, a high yield reassortant preparation
is ongoing in Melbourne. And it expects
to be available in late-February, so now.
Influenza A H3N2 currently available
vaccine strains, we have two of them.
A/Wisconsin/65/2005-like. One is
a high yield reassortant prepared in New York Medical School, designated as
X161B for A/Wisconsin/67/2005. And
another, A/Hiroshima/52/2005 is Australian high-yield reassortant IVR-142.
We have one candidate for strain
changes, it's A/Nepal/921/2006, and the preparation of high-yield reassortants
is ongoing in New York Medical School and expected to be available in
early-March.
For Influenza B, we have available
current vaccine strains, B/Malaysia/2506/2004 and B/Ohio/1/2005. There is no superior candidate strains
available by now.
Availability of potency reagents
from CBER, H1N1, A/New Caledonia/20/99 strain, we have available reagent
antigen and reagent serum. For H3N2,
A/Wisconsin/67/2005, reagent antigen and reagent serum. The same reagents are available from other
centers, in U.K. and Australia.
If new strain will be chosen, we
expect reagents, potency reagents available by the May of this season.
For viruses B, in CBER we have
reagents for both lineages. For Victoria
lineage it's a current vaccine strain, B/Malaysia/2506/2004, reagent antigen
and reagent antiserum. And for Yamagata
lineage, we have seen from the previous year, reagents for vaccine for the
previous year, B/Jiangsu/10/2006. The
same reagents are available from other chosen centers.
If new strain will be chosen, as it
is out of Advisory Committee work, the reagents are going to be available in
May of this season.
That's
it of what I wanted to say. Any
questions?
(No response.)
No questions.
DR. KARRON: Thank you very much.
At this point, we'll take a
break. And I think we're a bit ahead of
schedule. So instead of reconvening at
10:35, we'll reconvene at 10:30, when we'll hear comments from the
manufacturers.
(Whereupon, the above-entitled
matter went off the record at 10:07 a.m. and went back on the record at 10:36
a.m.)
DR. KARRON: We're now going to hear from Mr. Albert
Thomas, who will give us comments from the manufacturers.
MR. THOMAS: Good morning.
My name is Albert Thomas. I am
with Sanofi Pasteur.
I would first like to thank the
Committee for the opportunity to present the comments from manufacturers at
today's strain selection meeting, and would like to begin by discussing several
of the critical factors that are involved with influenza vaccine supply, and
how the strain selection process can impact each of those factors.
The first critical factor is the
growth potential of each monovalent strain seed virus. There are many factors that can impact the
total number of doses of influenza vaccine that can be produced, such as the
overall capacity that is available to each manufacturer, as well as the average
yield of all three monovalent strains, but most typically the number of doses
of vaccine that can be produced is limited by poorest growing or least yielding
monovalent string.
For example, a manufacturer may be
successful in producing 40 million doses of the H1N1 monovalent strain, 40
million doses of the B strain, but if only 20 million doses of the H3N2 strain
can be produced, there will only be 20 million doses of trivalent vaccine that
are available.
To evaluate the potential impact of
a low-yielding strain on vaccine supply, we only need to look to 2006, to last
year. Due to the initial low-yield from
the A Wisconsin/67/2005 strain, as part of the initial production, if it were
not for the greatly improved yield of the improved reassortant, the X161B, the
supply of trivalent influenza vaccine last year would've been significantly
reduced. Even though a record number of
doses of influenza vaccine were ultimately available last year, the late
availability of the much better yielding A Wisconsin X161B reassortant did have
a timing on the impact of vaccine supply.
The most critical overall factor is
time. The timing for influenza vaccine
manufacturing is limited at the beginning by the timing of the strain selection
meeting, and is then limited at the end to distribute and administer the
vaccine prior to the onset of the influenza season. Thus, the total time to develop production
seeds, manufacture the monovalent components, formulate the trivalent vaccine,
fill, package, release, and ultimately distribute is quite limited.
Also, please keep in mind that
production seeds typically require at least four weeks from time of receipt for
development and release prior to use in large scale manufacturing.
The potency of, the availability of
potency test reagents is another factor that must be taken into account. The potency or hemagglutinin titer of each
monovalent component lot must first be determined prior to formulation of the
trivalent vaccine. And as we've heard,
that's done via single radial immunodiffusion, which requires a strain specific
reference antigen and antiserum. These
two potency reagents must be manufactured and standardized for each new strain
prior to initiation of trivalent formulation.
The time to prepare and standardize the reference for reagents typically
requires 8 to 12 weeks.
The final critical factor is the
timing of the annual Biological License Supplement Approval. Since formulation of the trivalent vaccine
typically changes from year to year, a supplement to each manufacturer's biological
license must be submitted to and approved by the FDA each year. The license supplement includes changes to
the vaccine product labeling, such as updating the trivalent formulation with
the new strains. Large scale packaging
of the influenza vaccine does not typically begin until this approval is
received in the early-July time frame.
This next slide depicts a typical
time line for trivalent influenza vaccine manufacturing. There is an arrow listed here signifying the
time frame of today's meeting, the strain selection meeting.
The overall time line, as I
mentioned previously, for influenza vaccine is based on the requirements to
produce, and release, and distribute vaccine in time to support immunizations
for the upcoming influenza season.
The desired time frame to begin
distribution of vaccine is beginning in early-August with completion in
early-November, as depicted by the yellow bar on the time line.
The past several seasons have been
an exception to the typical timing in that distribution of vaccine has extended
late into November, actually even into December in several years.
In late-December to early-January of
the preceding year, time frame today, manufacturers typically begin production
of the first monovalent strain at risk.
This risk that the monovalent strain that is under production may not
ultimately be selected in the upcoming formulation. Production at risk is necessary because the
time to produce the monovalent component lots are limited. Again, as limited at the beginning at the time
of strain selection and limited at the end by the need to be able to distribute
and administer the vaccine prior to the onset of the influenza season.
Thus, at the time of the
mid-February VRBPAC strain selection meeting, manufacturers are looking to
begin production of the second monovalent string. Assuming the availability of an appropriate
production seed, manufacturing of the second strain typically begins
immediately following the strain selection meeting.
Due to the later scheduling of the VRBPAC
strain selection meeting this year, several manufacturers may have already
started the at-risk production of the second strain or risk over-production of
the first strain that they had underway.
This time line depicted here is
based on the fact that there would be one strain change, which is listed as
strain 3. Prior to beginning the
production of the third strain, the high growth reassortant would first need to
be developed, and then manufacturing working seeds would be developed form that
reassortant.
Please keep in mind that the
development of a working seed for manufacturing typically requires four weeks
from receipt of the reassortant at the manufacturer.
The final stage of production of the
monovalent lots involves strain balancing, in which manufacturers are targeting
the production of an equal number of dose equivalents of each monovalent string
to support trivalent formulation.
Balancing is required due to the difference in yield, per lot, of each
of the monovalent strings.
There are about 30 weeks available
from the beginning of the year until the early to mid-August time frame when
the monovalent production would need to cease.
The time that manufacturers produce at risk is typically six weeks, the
timing from the beginning of the year until the typical timing of the
mid-February selection meeting. So the
at-risk production time is 20 percent of the overall time that is available to
manufacturer the monovalent components.
If manufacturers were not able to
utilize this at-risk time, this 20 percent, the overall vaccine manufacturing
capacity would drop by 20 percent. So,
for example, assuming an industry capable of producing 125 million doses, that
would be a 25 million dose reduction from overall capacity if this at-risk time
were not able to be utilized.
In parallel with the production of
the monovalent component lots are the activities related to trivalent vaccine
formulation, filling, packing, and release.
The most critical element involved in this timing is the preparation and
standardization of the potency test reagents for a new strain.
The preparation of the potency test
reagents again typically requires between 8 and 12 weeks and begins once a seed
is available for the new strain.
Formulation of the trivalent vaccine begins following standardization of
the potency test reagents, which is then filling of the vaccine into vials and
syringes. Typically, a target for
beginning trivalent formulations is early-June.
Following approval of the Biological
License Supplement, packaging of the vaccine begins, and typically in
early-July. And following final release
of the vaccine, distribution of the vaccine would begin in early-August.
The greatest challenge that
manufacturers have had is achieving this time line. Specifically in the past several years it's
been related to when trivalent formulation can begin. The last year which manufacturers were able
to begin trivalent formulation in this desired early-June time frame was 2003. Due to numbers of strain changes, availability
of test reagents, or low yield, this has been delayed to the mid-June to
actually early-July in some years, which has pushed out the time frame for
vaccine distribution.
And please keep in mind this is a
typical or desired time line. The time
line again for each individual year will depend on the number of strain
changes, the yield of each strain, as well as the timing for preparation of
potency reagents.
The next slide provides an update of
current manufacturing status. As
previously mentioned, due to the limited time frame that is available for
production of the monovalent components, manufacturers have chosen to begin
at-risk production as soon as or at the beginning of this year.
Again, by manufacturing at-risk,
prior to strain selection, manufacturers gain additional time to produce the
monovalent component lots. In past
years, manufacturers have chosen to produce the A H1N1 New Caledonia strain at
risk. But with the greater potential of
this strain changing in this year's formulation, manufacturers have had to
select a different strain.
Based on the surveillance data
available at the beginning of this year, the manufacturers of the inactivated
influenza vaccine have chosen to produce the A Wisconsin strain at risk. MedImmune has recently begun production of
the B Malaysia strain at risk.
And again, based upon the timing of
this years strain selection meeting, several manufacturers may have also had to
begin the production of the second strain at-risk, or risk overproduction of
the first strain.
In conclusion, successful influenza
manufacturing and vaccination program is based upon cooperation among all the
parties involved. The consideration of
both antigenic match, availability of C candidates, including high growth
reassortants, as well as the potential growth of each candidate's strain is
necessary to ensure influenza vaccine supply.
A tangible example of these results
are the increased availability of egg-isolates and high growth reassortants,
which manufacturers are able to evaluate for potential growth characteristics
of strains that might be antigenically similar but do have significantly
different growth characteristics in large scale manufacturing. And I believe Dr. Cox had presented some of
that, some of the data listing the increased number of isolates that have been
available in recent years.
Another very tangible example of
this was during last year, when the initial yield of the A Wisconsin strain was
perceived to be very low. And obviously
that would have an impact on vaccine supply.
New York Medical College very quickly developed an approved
reassortant. That reassortant was
reviewed and ultimately approved, and it was able to be phased into
manufacturing. And a whole new set of
reagents were produced in a record time to ensure the nation's supply of
influenza vaccine in 2006.
So, in summary, it is necessary to
consider the various factors, such as the appropriate selection of strain,
based on antigenic and genetic match, as well as the availability of C-candidates
and high growth reassortants in order to best ensure the supply of the
influenza vaccines.
And once again, I would like to
thank the Committee for the opportunity to present the comments from
manufacturers at today's meeting.
DR. KARRON: Thank you, Mr. Thomas.
Questions?
DR. JACKSON: I wondered if you could comment on how
production of thimerosal free or reduced product interacts with your time line
that you showed us?
MR. THOMAS: Sure.
This may be different for each specific manufacturer, but particularly
the example of no preservative formulation for Sanofi Pasteur is essentially
the same time line, however we are not adding the preservative. The biggest constraint for the no
preservative formulations are that they are filled into unit dose vials and
syringes. So it's primarily a filling
constraint, both from the capacity point of view as well as the timing. For example, filling multi-dose, 10-dose
vials, you could essentially fill the equivalent of 10 times the number of
doses in a given time than you would for unit dose.
So the time frame is similar,
however you are limited on how quickly you can fill and package the product
because it's in a unit dose or single dose presentation.
DR. KARRON: Thank you, Mr. Thomas.
MR. THOMAS: Thank you.
DR. KARRON: Next, Dr. Pandey will present the strain
selection options.
Excuse me, Dr. Pandey, I apologize.
There is, next on the agenda is an
open public hearing.
Christine?
MS. WALSH: Thank you, Dr. Karron. As part of the FDA Advisory Committee Meeting
procedure, we are required to hold an open public hearing for those members of
the public who are not on the agenda and would like to make a statement
concerning matters pending before the Committee.
I have not received any requests at
this time.
Is there anyone in the room who
would like to address the Committee?
I see no response.
Dr. Karron, I turn the meeting back
over to you.
DR. KARRON: Okay, Dr. Pandey, now it's your turn.
DR. PANDEY: Thank you.
Now, I will be presenting the
options for strain selection for 2007-2008 season influenza vaccine.
As the Committee has heard before,
there are implications of strain selection, both in terms of vaccine efficacy
and availability. If the recommendations
match the strains that will likely circulate in the given season, then there
will be a great benefit to the public health.
However, if the recommended strain well for the manufacturers, we may
not have enough vaccine available for use or there might be delays.
So, as you can see on this slide,
despite two strain changes last year, the vaccine production went pretty well
and the vaccines were available almost on schedule.
The supply of the vaccine, despite
these two changes has, as in the previous presentation you heard, that we had a
record 110 million doses available. And
it shows that it definitely met or exceeded the demand.
So we must applaud the manufacturers
for a job well done considering all the problems one can face when there are
more than one strain changes.
And now coming to the options for
the vaccine composition, for Influenza A H1N1, we can retain the current
vaccine strain recommendation, which is in New Caledonia 2999 like virus.
Or the other option could be to
replace the current strain with the Solomon Island/3/2006 like virus, as the
WHO has recommended.
Or the option could be to replace
the current vaccine strain with something else, another alternative H1 isolate.
Now, of all these three possible
options there are pros and cons.
The
advantage of keeping the current strain, obviously, is that manufacturers have
worked with this strain for years. They
have the reagents available. But then
the disadvantages of keeping the current strain, obviously, we have heard that
it is a poor match.
So then the option for A Solomon
Islands, if we were to switch to that, the reagents are going to be available
in May. The manufacturers have already
gotten some experience with this vaccine, and based on what I have heard, that
it is reasonably, it goes reasonably well.
And we don't have another option at
this time, I guess, for if we were to change to a different strain.
Now, the option for Influenza A
H3N2. Again, we have the similar
options. You know, either we can retain
the current strain, which is A Wisconsin/67/2005 like virus, replace with an
alternative H3N2 isolate, or another option that manufacturers definitely don't
like is to defer the decision to a later date, in case there is more data going
to be available in helping make that decision.
So, if the recommendation again, as
I said, is to retain the strain, we have the reagents available and we have the
manufacturing experience.
But if we were to change the
recommendation to another strain, the availability of reagents is an issue that
won't be, as Galina mentioned before, it won't be available before May.
For Influenza B, either we can
retain the current B/Malaysia/25/06/2004 like virus, which is of B Victoria 287
lineage, or our other option could be to replace it with an alternative virus
from B/Yamagata/16/88 or B/Victoria/2/87 like lineages.
Now, if you were to retain the
B/Malaysia like virus, which was in last years recommendation as well, and also
has been recommended to be retained by WHO, we have the experience with this
strain and the reagents are available.
But if we were to change, then
currently there are no better strains available and the availability of
reagents could also become an issue, and also how it would out for the
manufacturers.
So, finally I come to my last slide,
which is basically the question every year for the Advisory Committee is that
what strains should be recommended for the antigenic composition of the 2008,
2007-2008 influenza virus vaccine based on the epidemiology and antigenic characteristics
of the influenza virus strains circulating in the human population that the
committee has heard, the serological responses to circulating influenza viruses
of persons immunized with the current influenza virus vaccines, which was
presented earlier, and also the availability of suitable vaccine candidate
strains, which also the Committee has heard.
So I'll turn it over to Dr. Karron.
DR. KARRON: Thank you, Dr. Pandey. At this point I'll open it up for discussion.
But I actually want to ask one, can
I ask you one specific question, which is, if you go back to your H3N2 slide
and you talked about the possibilities being A/Wisconsin or something else,
would you, based on the data you've heard, if there were a something else,
would you think, for example, it would be a Nepal-like strain?
DR. PANDEY: Well, that definitely came up as a possible,
you know, option. But I don't know at
this time and I think that's for the Committee to discuss if that could be a
good option.
DR. KARRON: Thank you.
So at this point I'd like to open
the strain selection up to discussion, questions, and if there are additional
questions for Dr. Pandey or the manufacturers.
Everything is very -- oh yes, I'm
sorry.
Dr. Wharton?
DR. WHARTON: Given that we now have a number of, we've got
the wonderful privilege in the United States now of having multiple influence
of vaccine manufacturers producing for the U.S. market, but some of them do not
exclusively produce for the U.S. market.
A couple of them do have major production facilities outside this
country. And presumably those production
facilities are not only, will be having to deal with recommendations from other
national authorities. What is the impact
of that on realistically if this Committee were to make a recommendation
different from the WHO recommendations on how we would get vaccine from those
facilities that have to deal with potentially two different sets of
recommendations?
DR. KARRON: So this is a question for the manufacturers?
MR. THOMAS: Maybe I can sort of answer and maybe some of
the other manufacturers would also like to participate. But a selection of two, for example, H3N2
strains, different one say for the U.S. and possibly a different one for the
WHO recommendation would be extremely difficult. Manufacturers who produce vaccine for several
markets would have to produce four strains.
So there are inherent inefficiencies in doing that. The overall number of doses of vaccines would
be reduces, as well as the additional complications of preparing another set of
reagents and having to test the different strains. So that would have a significant negative
impact on vaccine supply.
And I'd also like to point out with
the discussion here of the H3N2 that there is currently no other production
seed currently available other than the A/Wisconsin/67. I know there was a potential there for
evaluating another strain, but currently no other seed exists today.
DR. KARRON: Thank you.
Yes?
DR. MCINNES: So, I think I heard that it would be very
difficult but not impossible. And I'd
like to probe a little bit more about what would be the feasibility of actually
getting a high growth, or using a high growth reassortant for H3N2 that could
be used for production. And I don't know
who wants to comment on that.
DR. COX: As soon as we realized that the so called
Nepal Canada group of viruses was increasing, we went back and looked and found
that we had a Nepal egg isolate, which didn't grow particularly well during
initial passaging. However, on
subsequent passage it seemed to pick up a little bit. That virus has been distributed to a number
of individuals, including to Doris Boucher at New York Medical College. And I know that she's been working on making
a high growth reassortant for that particular virus. Of course we have no idea how it will grow or
what its antigenic properties will be because, of course, after going through a
number of passages to select for high growth in eggs, we often do see
changes. So I think there are a number
of unknowns. But maybe Doris would be
willing to make some comments about when the high growth reassortant might
possibly be available to distribute to manufacturers.
DR. BOUCHER: I can only say it's under development. So far everything is proceeding according to
plan, but we don't have it as of now. We
are trying, we would like to ship it off to the CDC for them to begin analysis
next Wednesday, a week from today. But
we don't know what will happen with the testing. And as Nancy said, we don't know how it's
going to grow.
DR. KARRON: Nancy, I wonder if I could ask you to comment
on some of the ferret antisera data, Nepal, and the Wisconsin strains, and the
differences that you see. And some of these
are the tables that we looked at, in trying to discriminate between the Nepal
strain and the Wisconsin strain.
DR. COX: Yes, I think that the H3 table in the CDC
package is actually fairly instructive.
We were hoping to see a different pattern. That's on page 19.
What you see here is the Nepal
antiserum on the right, which has been made to an egg grown virus. So that was the virus that was sent to Doris
to make a high growth reassortant. As
well as antiserum made to the Canada/1212, which is a cell isolate. So we tried to control for the fact that, you
know, sometimes you see a little bit different results for cell and egg-grown
isolates that are genetically similar, or at least in the same general and
genetic group.
And what we see, if you look down
the rows, if you compare the Wisconsin/67 wild type titers, as you look down
the table, and then the Nepal, the titers against the Nepal and Canada/1212,
you will see that you have the same viruses being low reactors for all three
antisera.
So you may get a two-fold higher
titer for the Nepal and Canada antiserum, but you still get the same low
reactors. And so that has been the real
issue.
And as I mentioned in my talk, there
have been some studies done that indicate that the receptor binding pocket of
the H3 viruses has evolved. And of
course the shape of the receptor binding pocket can have an impact on what you
see in an HI test. So antibody could
still be binding to the hemagglutinin, but not inhibiting the, if the pocket is
lighter, not inhibiting the ability of the virus to agglutinate to red blood
cells.
So I think that what we are going to
be doing in the future with the H3 viruses is to look at virus neutralization
tests for a small number of viruses.
It's a very labor intensive test, but I think it might really help us to
discriminate exactly what is going on here.
DR. KARRON: Right, so I guess also to summarize what
you're saying, we don't really see a difference in, or much of a difference,
more than a two-fold difference when we look at the HI test, Wisconsin and
either the Nepal or the Canada strain?
DR. COX: That's correct. So we were hoping to see that the Nepal and
Canada antisera would cover the viruses that are in the same genetic group
better than the Wisconsin virus does.
But really there doesn't seem to be that much difference.
DR. KARRON: Right.
And there's certainly, going back to some of the human data, there's
certainly a difference when you look at the human sera. But I would think that the problem is really
that we don't have the reverse experiment in humans. We don't know what would happen if you
immunize a person with A/Nepal or A/Canada strain. We don't, we of course don't have that
information because that's not what we do.
We can only look at responses once you vaccine.
Yes?
DR. FARLEY: As a follow-up to that, is there a way of,
because I guess if I'm reading this correctly, the Canada and Nepal
cross-protect for each other that they seem to have, am I reading that
correctly if you go down further? Now, I
guess the question is, is there a way of knowing among these low-reactors what
proportion the burden of disease that is taken up by Canada and Nepal isolates
as opposed to these various others that are listed here, with mostly U.S.
designations?
DR. COX: We, because we really can't discriminate
between viruses that are in the Nepal group and in the Brisbane group using the
antisera that we have, we've done a lot of sequencing. And so, what we're seeing, I think I
mentioned, so for the 91 H3N2 viruses that have been sequenced, and those are
viruses collected since October of 2006, we found that 48 percent were in the
Brisbane group and 45 percent in the Nepal group.
So we're seeing an almost equal
distribution of viruses in those two groups.
And it doesn't seem, it, I would say that the Asian viruses are
predominating in the Nepal group. But
that, for example, there was a fairly, the National Influenza Center in Seoul,
Korea had sent us quite a number of H3N2 viruses from an outbreak that occurred
in November and December. And those
viruses were distributed in the two groups.
So even if you look at a particular country you can see that viruses
fall into both the Brisbane and the Nepal Canada groups.
DR. KARRON: Dr. Couch?
DR. COUCH: I would, if you permit, I think it's probably
worth pursuing H3 because that's the one that's bothering us. We started there and Dr. McInnes indicated
that we've already heard that follow-up too.
If you look at the ferret sera and the H3 strains, you know, there's no
big differences there anywhere, as Dr. Cox has pointed out. If you pick all these various isolates now,
you can say well, you know, it looks like there's maybe a little shift toward
the right side over there of which Nepal can just be one example.
So I make my little chart each time
on this one, so antigenic change I ended up saying well, probably zero
here. No big antigenic changes we can
hang our head on, you see, as part of the decision making. Epidemiology always comes with a question
mark and wait to see what Dr. Couch tells us.
And we had no major problems with H3 anywhere in the world so we don't
have the benefit of viruses that dominate in an outbreak that would help us
decide that one is about to move there.
And then the final one I always look
at is the human sera. And the human sera
results for H3 is quite bothersome because some of those strains that are out
on that side there's not very much in the way of cross-reactivity. And Dr. Ye pointed out, you know, that the
reduction that you deal with GMT's for the H3s, with these various
laboratories, is comparable to the H1, which is a little bit of a discussion
item, but less so maybe than this one, you see.
And the final statement to make at
H3, around this table and every time we do this, you know, that is the most
important decision we make because that still is clearly the most common
epidemic virus with the most, the most serious impact against humans, with
attack rates and in hospitalizations and disease.
And so I came around here bothered
about the Wisconsin decision that we were told had been made by WHO, but we all
accept the fact, the position that was pointed out to us by the industry
representative. If we talk about doing
something different, we are really tampering with vaccine supply and perhaps
significantly. So I feel like we're in a
bind here this year on H3. And some
other people may want to comment on that as well. That one is my tough one.
DR. KARRON: I'll say that I am particularly bothered by
this sort of discordance, if you will, between the ferret sera and the human
sera. And I was wondering do you want to
comment on that, Bob? Does that bother
you too?
DR. COUCH: The differences between the two? Yes, that bothers me. I mean I think a ferret, you know, if I want
to try and biologically do something with this, I say well let's look at, and
you've expressed here, let's start seeing more pediatrics here. Because if we say those ferrets are helping
us differentiate these, then the most comparable individual for humans, which
is our primary interest not the ferrets, is going to be how those children
do. And the children, what we have this
year, their Wisconsin antibody didn't like the strain either. So the ferrets maybe didn't agree with the
children very well here. Now, so what
data do you like for your decisions? I
like to see them all fall into place, but maybe that represents what I do and
my strongest interests. I want to be
sure those antibody responses to that antigen cover the ones that may be coming
out in the future in humans. I'm a
little more concerned there than I am whether the ferrets manage to pick up a
difference or not. But we'd like to see
both of them.
DR. KARRON: John?
DR. MODLIN: Right.
Ruth, I don't think I got an answer to my question earlier, and that is
the age range for the pediatric sera. I
mean it's a big difference whether they are two-year-olds or whether they are
nine-year-olds.
And it may be that is the entire
range, but Dr. Ye, do you know what the age range for those panels?
DR. YE: Yes, the age range is 6 months to 36
months. So they are quite young.
DR. MODLIN: Indeed, as Bob said, they could be very
useful, particularly if we had larger numbers.
So I think the recommendation might be, you know, in future years if we
could look at a larger number of pediatric panels that would help, at least
with this particular conundrum.
DR. YE: Yes, I think this year, normally we send this
to CDC ourselves, so probably we should send it to different centers to give,
you know, more confirmative data from it.
We're limited to the limits of this sera sample, so sometimes it's
harder to share with other centers.
DR. KARRON: Pamela?
MS. MCINNES: We started a little bit of this discussion at
the break, but I need to, I'd like to look at page 23 in the CDC. And I need to just have somebody explain this
to me. So the A/Wisconsin was our
vaccine strain, right? And the A/, wasn't
A/Hiroshima an alternative?
DR. COX: Yes.
DR. MCINNES: So I'm confused about the data.
DR. COX: Oh, this is a different Hiroshima.
Thank you.
DR. COUCH: I'm with you.
I looked at it on the chart. It's
right next to Wisconsin, Hiroshima/33, so I assumed that was the same one we were
talking about last year. But I had the
same problem with that that Pamela is talking about.
DR. COX: It's a 2006 strain. And in the old one was a 2005, so there's
something wrong with it.
DR. COUCH: Something wrong with it?
DR. COX: Yes.
DR. COUCH: I see, okay.
DR. COX: Yes.
DR. COUCH: If you look at table 21, I think Sasha has
got it. Hiroshima may not be 33, but
down at the bottom lists the, should've been 2005. It's a different Hiroshima.
DR. COX: It's an old, the one in the vaccine is an
older strain.
DR. MCINNES: So I can be just a little less worried.
DR. COUCH: I hate to tell you how long I spent worrying
about that particular one.
DR. COX: I apologize.
DR. KARRON: Is there more discussion? Are we ready to select our strains, as ready
as we're going to be?
(No response.)
Okay, I'm going --
DR. MODLIN: Ruth, I'm sorry. Just maybe a little bit more discussion about
the H1 strain and then the recommendation for a WHO. I mean it sounds like to me that the
experience here in the U.S. is a little bit discrepant from what the rest of
the world has been this past year and so it's easy to see why the WHO made
their recommendation. I guess we haven't
had any discussion about what this really means for us for next year. My assumption would be that it would be
presumptuous to think that we were going to experience the same H1 activity as
the rest of the world is over a period of time, at least that one could
predict, they would be more likely to predict that. But we haven't had that discussion and I
would just be interested to what other people think of that.
DR. KARRON: Nancy?
DR. COX: I think what we have to take into
consideration is we've had a predominantly H1N1 year this year. So that, generally speaking, brings up the
antibody levels in the population. And
so, we hadn't had so much H1N1 activity before, so just in looking at what
might come next, I think it's more likely to be something different next time.
DR. COUCH: Do you want to talk H1? I've got my table on H1. The ferret data here said we've got different
viruses. And so I was waiting for the
epidemiologic data on that one, and it's a U.S. epidemic. It's, you know, scattered around a little bit
in Asia, but presumably it's different and the antibody results are
erratic. Instead of a yes and a no that
New Caledonia was the highest growth, and I might of gambled on keeping that
one. But WHO voted to go for another
one, you see, and I said well, we had a significant year and Influenza A
viruses drift. And we've got pressure,
as Nancy said, you know, that we have to have some drift coming up here. So H1 has got to change, if not the coming
year the following year. And New
Caledonia has been there a long time.
So I rationalized my way into a week
support for changing H1.
DR. KARRON: While you're at it Bob, do you want to
comment on the B? There's not too much
probably to say there?
DR. COUCH: B's are actually easier. Maybe if somebody wants to redo it after we
have our discussion this afternoon that might be different, but no, no
discussion on B, no problem.
DR. KARRON: Pamela?
DR. MCINNES: So let me return to the H3N2 dilemma and also
I am very troubled by the sort of lack of concordance, the comfort that we have
that the ferrets are compared with the human serum. You know, we can say well maybe the HI test
is not the best way for us to do this, but in effect, the reality is we do
have, I think, some troubling data here.
And the question on the table would be, I'm aware of what WHO Committee
recommended, I'm going to throw out the idea of two H3N2s.
DR. KARRON: Nancy?
DR. COX: I think that it would be wise for us to have
comments from the manufacturers about that.
MR. THOMAS: I guess some of the questions would be,
initially, what would it replace, first of all?
And again, we're into the same is this a, how different of a product is
this from the licensing aspect? Does
this require clinical trial, that whole aspect.
So there are a lot of questions on defining what the product actually is
and ultimately deciding is it the H1 strain that is removed and there are two
H3s. I'm assuming it's still a trivalent
formulation, based upon the question. So
I think there are a lot of questions on definition of the product, licensing
aspects.
Now, specifically for the
manufacturing point of view, the concern that I mentioned before about
manufacturers producing the A/Wisconsin at-risk, obviously you would alleviate
that because a lot of that product is already produced, but we're still
introducing another H3 strain that today a production seed does not exist. There is no yield date available for that
seed, nor do we have a definitive time line of when that see would be
available, which could impact overall vaccine supply as well as the timing of
when reagents could be prepared and when vaccine would ultimately be available
for distribution.
DR. KARRON: I was just going to say sort of back in
response, I'm, what's troubling me the most is I don't, is trying to understand
low responders and what those viruses are, and what it means, and how we interpret
the tests. I think despite all the
manufacturing caveats, if I had seen that there were really good responses to
the ferret, the ferrets had very good responses and they were clearly these
were very different viruses I would've said, you know, maybe we should be
postponing our decision until March until we have, until we know if we can get
an isolate that represents the H3N2 strains.
My concern in looking at this data is I don't know that a new H3N2
strain would do better. And if you gave
that to children that that would induce a better HI response, or whether there
is something about these low responder viruses that's different and that we
have the, you know, we need a different test to really understand this.
So that's what's, that's what I think
is troubling me the most.
DR. COUCH: And I would hope that when you do those HI
tests that you've got controls in there to indicate that you're not dealing
with a low responder antigen. And when
you run these HI, these HI batteries, see we don't have all these ferrets here
in my lab.
DR. COX: We have controls.
DR. COUCH: But you're suggesting a low responder. I would think that ought not be a question of
the --
DR. KARRON: But if you give a ferret A/Nepal and look for
their HI titers to A/Nepal, they're relatively low. Correct?
I mean there's something about this virus that induces low levels of
antibody as we currently measure them in HI tests.
DR. COX: Actually, Nepal does find, there are some
viruses that are, will give you a homologous titer of 80, and that really
indicates to us that that's a low avid virus.
But these viruses, both Nepal and the Canada/1212, when put into
ferrets, elicit titers of 640 or so. So
I think that we have sort of the, we really have a contradiction in the
data. And I honestly have wrestled with
this and have lost sleep over this data, these data.
DR. COUCH: I thought you were talking about the humans
here not the ferrets here. Because the
ferrets here, I've been hearing problems with them.
One more and I quit. And you can end up, the antigens don't all
agree. I mean that was part of, somebody
talked about the HI yesterday. But we've
got three of them for H3, Santiago, Canada, and Hiroshima and they're
uniform. That's, see, if you look at the
H1 data there's an erratic one in there every now and then. I can bypass erratic results, but all three
of them?
DR. MODLIN: Could I ask a very basic question, and I'm
embarrassed I don't know the answer to this.
But for a particular antigen, if a human already has a high titer of
antibody and a relatively high titer and receives an inactivated antigen, how
much of a boost do we expect, or does that high titer actually inhibit a boost
like it does with other inactivated antigens?
And if that's the case, then it seems to me that if we have a
discrepancy between our animal sera and our human sera that perhaps the human
data may be a little less reliable in terms of making these types of
decisions. Am I way off base, Bob or
Nancy?
DR. COUCH: One of the things you'd like to know to fully
understand the data, which is maybe what you're driving at, is I would like the
battery to each time say is that the same group of individuals? Were they vaccinated last year? And the industry might not prefer that, but
I'd like to know which of those vaccines they received as well. Because if you look at some of the data, I
don't mean to be picking on my friends, I worry about some of those antigens in
the Japanese vaccines, if you just look at the comparisons of the battery of
sera there. But we don't know that, you
see.
And your point would be that if
they're already high from Wisconsin and you re-vaccinate them and they're high,
then you're going to have less likelihood of finding a cross-reactivity to one
of those other strains.
DR. MODLIN: Exactly.
DR. COUCH: I guess I think that's probably correct but I
don't know that for sure.
DR. KARRON: Zhiping?
DR. YE: Dr. Couch already answered the question.
I just want to comment on that. Because of the serum in humans, especially
for adults, previous years may expose them to the same antigens or different
antigens, so their responses is kind of order than the children's one or the
ferrets studies.
DR. COUCH: You could follow that up with saying well if
that's the case and that antigen does change, we want that new antibody and we
better give him that antigen to get it.
DR. KARRON: Dr. Eickhoff?
DR. EICKHOFF: A question for the manufacturers. Would, if we try to put 60 micrograms of
hemagglutinin in a vaccine, wouldn't that automatically equate to a 25 percent
reduction in the amount of vaccine available?
DR. HETHERINGTON: Yes, I think that is the point that there is
a maximum capacity for total antigen that gets produced in the U.S. And you can cut it up anyway you want to, but
a trivalent vaccine you get "x" does and quadravalent vaccine you're
going to get 25 percent less. And also
the increased risk of delay in
production because you have yet another antigen, another seed stock you need to
get up and go, so timing is at risk as well.
So you're really taking two hits on going to a quadravalent vaccine.
DR. KARRON: But as maybe a follow-up question, you can
answer both of these, Mr. Thomas, is what percent of the vaccine produced this
year did we actually use total, of the vaccine that was made available by
manufacturers because we have increased our capacity significantly.
MR. THOMAS: So the first question regarding the increased
formulation, the answer exactly would be an equivalent to a fourth strain, in
terms of monovalent requirements, so you'd have that 25 percent decrease.
And I'm assuming the question for a
vaccine that wasn't administered, was produced last year in this current
season, the biggest impact there was the timing of the vaccine. The fundamental feeling is that the timing
was available, the vaccine was available in a time frame that everyone desires,
the September/October time frame into early November, then there wouldn't be,
there would be much less vaccine unused.
A great deal of distribution of
vaccine this past year, due to issue of yield with the A/Wisconsin, which then
created a delay in the reagent preparation shifted a great deal of vaccine
supply into the late-October, November, into December time frame. So based on what we see from immunization
programs, obviously the sooner we can get the vaccine as available, the success
of the immunization program will increase greatly.
DR. KARRON: But actually, just to follow-up on, I
understand that timing can be critical, but do you actually know what percent
of the vaccine manufactured this year was actually administered?
MR. THOMAS: I don't have any data on that.
DR. KARRON: Do you know that?
DR. COUCH: I think most of us understand and appreciate
that problem that would relate to an individual decision like say a decision
this year to put two H3s in there, you see, and you cut the supply by 25
percent, perhaps more, depending. If
we're talking about changing and having new concepts, and we're going to talk
about one this afternoon, you're talking about it evolving slowly so that the
industry can adjust to that. And they've
adjusted to providing, you know, I remember the time in which you were lucky if
20 million doses were made and used. Now
we're talking about over 100 million, you see, so that with time and the desire
to make it and sell it, the industry can adjust, but not just like that. I think that's what we're hearing in the
answers.
DR. KARRON: Lisa?
DR. JACKSON: It seems like there could be costs and
purchasing implications that might not be insignificant as well.
DR. COUCH: Could you say that again?
DR. JACKSON: I'm sorry, my usual clarity. It seems like -- that's even worse -- there
could be costs and therefore purchasing implications if four-valent vaccine
were say more expensive than a three.
And you know, as you were saying, the ability to adapt quickly to that
kind of change, you know, may cause additional problems with distribution and
purchase.
DR. KARRON: Pamela?
DR. MCINNES: I mean I think we're cognizant of all of
these factors. The risk, I mean to just
say because of all these issues we're just pragmatically going to go along with
something bothers me. I mean I think the
data are worrying. And this is, whether
we like it or not, this is a collective effort.
This is not someone is just the recipient and just marches along. It's not in anybody's interest to have a
vaccine that isn't, you know, the best decision we could've made with the data
that are on the table. So I am going to
think about all those other factors and the balancing of them, but I first am
going to wrestle with what I think is the best, what I think is the best
decision based on this data.
DR. KARRON: Steve?
DR. SELF: Ultimately, it seems to me the tradeoff is
one of coverage versus efficacy. So
adding a component may make the vaccine a little more efficacious, it will
probably reduce coverage due to timing and supply. And those tradeoffs are very hard to make
even when you've got modeling results in front of you. We have none of that and, you know, I listen
to this and I honestly have no sense at all about how much an improvement in
efficacy we could obtain, what the impact on coverage would be, and how at the
end that would balance out in the population impact. I mean this is, this is a very interesting
discussion, but I find it informed by very little.
DR. COUCH: We have made, and I'm straightforwardly
honest with you, as you might say the wrong decision in past years, and the outbreak
that succeeded with the vaccine that did not have a good match, on occasion,
has really been severe. But that was an
innocent error. We couldn't help it, you
see, that was the only information we had at the time, you see, when the
decision was made. So that concern is
there. I guess my only point was you
were suggesting well you lose a little bit.
No, we've got the risk of losing a lot.
That's our concern.
DR. KARRON: Monica and then Nancy?
DR. FARLEY: I wonder if those who, Dr. Ye and Dr. Cox
perhaps, is there anything that we would gain, or you won't know for sure, but
can you comment on whether a delay of the decision on H3 has much chance, if
any, of clarification for us over the coming number of weeks. Is there anything that we can do with the
current strains that we have, in terms of additional testing that we think
might help us sort out the low responders, or will additional strains coming
in, is there much chance that the volume of additional input would be there
that, you know, to help inform us, given the fact that we know it's a big
tradeoff, a negative tradeoff, from the manufacturing perspective?
DR. YE: I think if we wanted to have more data
probably the best we can do is to conduct human serology study using the Nepal
strain. But I don't think that will be
reality, because we'd have to send it to the different centers to do a similar
study. This precedent we are doing this
to give more data.
DR. COX: I can't, can't really add very much. I was just conferring with Dr. Klimov and he
thinks that we probably have several dozen H3N2s that haven't yet been analyzed
that are just coming in. We know they
are coming in and haven't yet been analyzed.
We are able to generate sequence
data very, very quickly, which will tell us which of the two groups the viruses
are falling in genetically. It takes a
bit longer to generate the HI data because we have to grow the virus and do the
HI test. But there would be limited
additional information. There would also
be limited additional information on how the high growth reassortant that Dr.
Booker is producing grows. But again, in
a three week period of time, the additional data would be limited.
And then there would be difficulty
but a possibility of conducting microneutralization tests in the interim. So that would be, that would be difficult to
do within a three week period but it could be done.
DR. KARRON: Bob?
DR. COUCH: Well, just to extend on that one because I'll
be entirely straight with the Committee, I'm waffling. I don't want to say no. I'm waffling between abstain and defer. But if we defer, and that was going to be one
of the questions, you asked about more strains, but if we defer and the FDA
just now is looking for the reassortant, once you have the reassortant you have
to know that it works well and then you've got to make the antiserum. And then you've got to distribute that. We're probably talking about really almost
May or June before you can even, the industry can even begin to work with a new
H3.
DR. WEIR: I think that's correct from what Dr. Ye said
that it would be probably unlikely that we could generate more serology data
very fast.
But just to clarify one other thing
from Dr. Cox, would you not also after
the high growth reassortant is made, would you not need to generate ferret
antisera to that before you test it to the isolates to see how well it would
cover, to really give some useful data about whether that would be a candidate
or not?
DR. COX: We always test the high growth reassortants
to be sure that they have similar antigenic properties to the wild type
strain. However, it doesn't preclude our
distributing it to see how it grows for the manufacturers.
DR. WEIR: But I thought the high growth reassortant for
the Nepal was not available yet.
DR. COX: That's right.
It's not available.
DR. WEIR: So what I'm saying is after it is available,
then you would have to generate ferret antisera to that before you saw how well
it would really cross-react?
DR. COX: That's correct. But that wouldn't preclude its being
distributed.
DR. WEIR: Okay.
But it would still take time to generate that additional data?
DR. COX: Two weeks.
Two weeks. Two weeks to make the
serum and then the test could be done almost immediately after that. And one other thing that I need to say that
needs to be emphasized I think every year, we are really limited by what the
epidemic does, you know, what certain viruses circulate, where they circulate,
and how many of them circulate. And
we're also limited, to some extent, to the timing of when they get sent to
us. But the season was a very mild
season generally and that is true worldwide.
And it really didn't takeoff terribly early, except for some of the
school outbreaks that we had in the United States.
So this is one of the situations
that we often face where we would like to have a lot more data, but the
majority of, the concerning data that you've seen here today was generated in
the last three weeks or so. So it's,
we're really racing with the virus, and it is a moving target, and it's a very
difficult business.
DR. KARRON: First Steven, then Bob.
DR. SELF: Yes, so that's a perfect segway to a question
about the epidemiology. So I see that
within the H3, the low reacting viruses are sort of on the rise. But I don't see what the best current data is
for the balance between H1 and H3. I see
last year based on the plot was predominantly H1. Am I, is there current data sort of on the
balance of H1 and H3 infections?
DR. COX: Are you talking about in the United States?
DR. SELF: In the U.S.
DR. COX: Tony, I think that because there are so many
unsubtyped viruses that have been recently identified in the United States,
it's difficult to say. But as Tony
mentioned, there appears to be an increasing proportion of Influenza As that
are H3s. But they were predominantly H1s
this year, whereas last year that was not true.
DR. COUCH: But it is --
DR. SELF: You're right.
It's on page 4. Yes, so we're
arguing about, for the H3 problem, what this year may be a pretty small
fraction of the total cases. Is that
correct?
DR. COX: Yes.
So basically this year we've had predominantly H1s. So we wouldn't expect to have predominantly
H1 next year, although influenza is not predictable. And I always have to say that over, and over,
and over again.
So when H1 circulates in the United
States again, we might expect to see a different virus because the New
Caledonia viruses have been around for so long.
With respect to the H3s, we've had relatively
less disease caused by H3s, but H3 activity appears to be picking up somewhat
relative to H1 activity.
Did that make any sense?
DR. SELF: Yes, it did.
I'm still trying to get a handle on just the magnitude of this subset of
H3 viruses, what the likely magnitude of that problem for next year.
DR. COX: That is totally unpredictable.
DR. SELF: Okay.
DR. COUCH: There is such a thing as the Harold-wave,
which as been popularized by a group from Houston, suggesting that late phrase
like that, that that was the proceeder for the epidemic the following
year. And there are at least three or
four clean examples of that, where that's been the case.
I'm willing to take us off dead
center, if you want, unless there is more open discussion.
DR. KARRON: I do just want to ask a question and go back
to the H3N2. So my sense, however, is
when it comes to making a decision about that the only, the two options really
are to retain the current strain or really to defer, because at this point we
do not have a Nepal strain. I mean we
don't have a high growth reassortant. So
we couldn't, as a Committee, make that recommendation. We could say that we would defer our
decision. I just wanted to put that out.
And with that, I think it is
actually, unless there is anyone else who wants to make any comment, question,
I think it's time to actually talk about the individual strains.
And I am actually, first we'll start
with H1N1. The three possibilities, as
outlined by Dr. Pandey, are to retain the current vaccine strain, which is
A/New Caledonia, to switch to A/Solomon Islands, or to replace the current
vaccine strain with an alternative strain.
Dr. McInnes, I'm going to start with
you?
DR. MCINNES: I was looking also at the decision from WHO,
and I sort of do take a little bit the same view as Dr. Couch in this about
concurrence with it or having difference or non-concurrence with that.
And looking at the H1 data, I would
support changing that strain, the vaccine strain to the A/Solomon Islands, the
H1N1-like virus for this upcoming season.
DR. KARRON: Thank you.
Dr. Hachey?
DR. HACHEY: I would also support replacing the current
vaccine strain to the A/Solomon Islands-like virus.
DR. KARRON: Dr. Stapleton?
DR. STAPLETON: I would also support changing the current to
the A/Solomon Islands.
DR. KARRON: Ms. Province?
MS. PROVINCE: I too support changing the current strain to
A/Solomon-like.
DR. KARRON: Dr. Jackson?
DR. JACKSON: Yes, I agree with the change as previously
stated.
DR. KARRON: Dr. Word?
DR. WORD: I would agree with the changes as previously
stated.
DR. KARRON: Dr. Hetherington, do you want to comment?
DR. HETHERINGTON: I agree with the comments so far.
DR. KARRON: Dr. Wharton?
DR. WHARTON: I concur with my colleagues in changing to
the A/Solomon Islands.
DR. KARRON: Dr. Eickhoff?
DR. EICKHOFF: I concur with updating the H1N1 strain to
A/Solomon Islands.
DR. KARRON: Dr. Self?
DR. SELF: I agree.
DR. KARRON: Dr. Farley?
DR. FARLEY: I agree.
DR. KARRON: Dr. Couch?
DR. COUCH: I already said I had a weak agreement, but I
agree.
DR. KARRON: Okay.
Dr. Modlin?
DR. MODLIN: Yes.
DR. KARRON: Okay.
And I also agree with changing to the A/Solomon Islands.
Please Christine?
MS. WALSH: Just to summarize that vote, it was
unanimous, 13 votes in favor of replacing the current vaccine strain with the
A/Solomon Islands.
DR. KARRON: Can we actually go to the next slide?
So there are actually three options
listed up here for H3N2, but I think we have concurrence among the panel that
really there are only two options that we can realistically consider.
One is to retain the current strain,
which is A/Wisconsin.
And the second is really to defer a
decision to a later date, pending the potential availability of a Nepal-like
high growth reassortant.
So this time, Dr. Modlin, we're
going to start with you?
DR. MODLIN: Well, obviously we're in a box. I'm very much concerned about the fact that
these new strains have appeared so recently.
And obviously the question is does that predict increased activity for
these new strains next year. And I think virtually everybody has acknowledged
that we don't know what the predictive, the likelihood is here.
I would point out that this
represents obviously a major problem for the manufacturers and this would be a
second new strain if we were to defer a decision, with the possibility that
there would be a second new strain. That
would be the reason why we would be deferring a decision in the first
place. And that creates real issues with
respect to concern about supply and cost, as Dr. Jackson pointed out.
I'm also, I recognize that we have
this discrepancy between this data from ferrets and data from humans that
bothers me a little bit. And I suppose
if I had to make a choice between the two, I would probably come down on, based
on the discussion we've had and also recognizing the fact that I'm not a
respiratory virologist or an expert in this area and I'm new to this sort of
decision making, but it seems to make sense that maybe putting a little bit
more weight on the ferret data as opposed to the human data, recognizing the
pitfalls there.
So yes, I come down with a
recommendation to retain the current strain based on all this, weighing all the
information that we have. It seems to
be, to me the better or the lesser of two evils I guess, would be a better way
to state it.
DR. KARRON: Dr. Couch?
DR. COUCH: I agree.
I've sort of already said my piece on this one I guess. But I had a weak support of H1. I have a very weak support, but I would vote
with going with A/Wisconsin. And for two
reasons, primarily one is you heard me say that I think vaccine and some
antibody is better than no antibody. And
that even if we miss, we'd have some benefit there and we'd have plenty of
doses of vaccine. Plus, the fact that I
think if I could afford the luxury, my vote would've been to defer. But I don't think defer is likely to gain us
anything in this decision.
So I guess what I say is I vote yes
to go ahead, but I would like to add a qualifier to that and ask CDC and
whoever else is appropriate to continue to monitor this one, and maybe these
new strains you're seeing, very closely.
And I don't propose this as an option, but to just at least point out
that in the past when this has happened, and these new strains have appeared,
we have made supplemental vaccines, the last one being A/Taiwan when we missed
on the H1 decision and then we added an A/Taiwan supplemental vaccine that was
given to us as a special supplemental vaccine.
So I would not propose that now, but I would hold that out as an option
in case we miss on this one and we still have some time.
So I do have concern about the H3
decision, but I'll vote with going with WHO recommendation. And somebody tell them we're not happy with
what they did.
DR. KARRON: Thank you.
Dr. Cox, would you like to offer an opinion?
DR. COX: I'd rather abstain. Thank you.
DR. KARRON: Okay.
Dr. Farley?
DR. FARLEY: Well, I'm reluctant in my answer as
well. I'm particularly concerned that
deferring this year would be more problematic than it always is to defer. And that is that the manufacturers have
almost uniformly chosen to do their at-risk production of this particular antigen,
and so that not only be potentially be asking for a two component change, but
we would have lost the two months of production that have already gone into
it. So given all of that, but in light
still of the concerns, I agree with whatever we can learn about these, this
emerging issue, both from a testing standpoint of how best to look at these
things when there are questions, are there additional tests that we can do and
is there way that they can be done in a timely fashion given all the constraints
of how it happens, how the epidemic unfolds, which we can't control. But continuing to study them so that we will
understand where it is going is very much, I think, is something I would concur
with.
And, in addition, then my vote would
be in favor of keeping the Wisconsin component.
DR. KARRON: Dr. Self?
DR. SELF: I vote to retain the current strain.
DR. KARRON: Dr. Eickhoff?
DR. EICKHOFF: Well, I was always taught by my mentor,
Gordon Meiklejohn, to pay more attention to human data than to ferret
data. And in this case the ferret data
looked reassuring to retain A/Wisconsin but the human data did not, and I am
puzzled by this.
If there were a likely, a good
likelihood that we could come up with additional useful information not at a
later date but by some date certain, call it mid-March, call it the end of
March, that would favor an updating to A/Nepal.
That likelihood does not seem to me to be great. And yet at the same time, I think while I'm
sympathetic with Nancy's reluctance to make any predictions for next year,
looking at the mortality data for the last several years makes me concerned
that next year is going to be a pretty significant H3N2 year. And the question is what virus will predominate.
Given, however, that the likelihood
of additional information is not good, I would vote to retain
A/Wisconsin/67/2005. If something
dramatic happened in the month ahead, I hope we could reconvene on sort of an
emergent basis, but I don't think the odds favor that at all.
DR. KARRON: Thank you.
Dr. Wharton?
DR. WHARTON: I would concur with retaining the
A/Wisconsin, but have to say that I really feel like between the at-risk
production the manufacturers have already done and the WHO recommendation,
which presumably will be affecting the U.S. suppliers who are located in
Europe, we simply have no choice. I
think those two things together would provide such a hit to supply that
whatever benefits might accrue from a better match were we to wait, and all
these other things that might happen do happen, that we simply would be in a
very unacceptable situation regarding the influenza supply.
That is a really place to be. And I don't know what kind of signals the
manufacturers look for when they make these decisions about at-risk production. I am sure good efforts are made to have those
be the most informed decisions possible, and I do not know if there is any
signal that could have been detected regarding these potential issues of the H3
strain at the time those decisions were made, but I hope there can be some
consideration of making sure that the at-risk decisions are the best ones
possible, because at this point I feel like we don't have any choice.
DR. KARRON: Thank you.
Dr. Hetherington, would you care to offer an opinion?
DR. HETHERINGTON: Well, just briefly. The Committee obviously is faced with a very
difficult decision, but I think it's all about coverage and delivering the
vaccine in a timely manner to get what positive benefits we know will exist out
of this, as opposed to putting more, excuse me, putting more at risk because of
the timing and trying to gain an additional benefit that really is not
quantifiable with the data we've got, unfortunately. And hopefully that situation will improve,
but you're stuck with the pragmatic.
DR. KARRON: Dr. Word?
DR. WORD: I guess as I sit here I listen to many of my
colleagues who have more experience in influenza and, you know, we keep hearing
about issues with manufacturing, you know, they've started things up. Then I keep saying why are we here. Because if you are presented with the
information and you're here to make a decision, I know that the WHO has made
theirs, but then if because of, you know, various constraints from other areas,
we're not going to be able to make the best decision that we think is best for
this particular country, then I'm saying I'm not sure why I sat here and
listened to all this. I mean so many
people here felt uncomfortable with moving forward, yet they're saying I can't
get this information quickly enough, and I guess with that I'm not as
comfortable moving on with the A/Wisconsin.
Even though I'm struggling and I'm still trying to figure out the best
way to phrase this because I know you're saying you may not get additional
information in a timely fashion, we should get some vaccine out to people, but
then I'm going to say we're going to revisit this every single year, aren't
we? I mean wouldn't that be the same
discussion every year if something happens?
So, I'm going to extremely reluctantly
agree too. I don't know, I'm torn. I want to say no.
DR. KARRON: Are you saying retain, defer, or abstain?
DR. WORD: I don't want to abstain. I have a thought. I would defer in good faith.
DR. KARRON: Okay.
Dr. Jackson?
DR. JACKSON: Well, I agree. I mean the concerns voiced are very
concerning. And if we have a significant
mismatch here that's obviously something we want to avoid. But I agree with Dr. Wharton that it seems
we're in a box and we don't really have much of a choice. And, you know, delays in vaccine supply
really impact vaccination programs, of course, but in particular, vaccination
of children which is an area of increasing emphasis. And what we find where I am is if we don't
have vaccine by, at the latest, early November, we really don't get children,
interest wanes, and they certainly don't get two doses. So we just really are dealing with a
situation which we have really limited good options. So I would vote to retain.
DR. KARRON: Ms. Province?
MS. PROVINCE: I echo Dr. Word's sentiments. It seems that, not every year, but every year
we face these same kinds of questions since I've been on the Committee. We're driven, understandably, by limitations
of the manufacturer, but I don't want to be driven, I don't want my decision to
be completely driven by limitations of the manufacturer. Although I know what the realities are, I
understand those, but I think we need to look at the processes that we are
going through, examine those, and figure out sort of from year-to-year how can
we get out of this box that we seem to be in more and more frequently, and
maybe make better decisions and have data available at a time where we can act
on it and still accommodate manufacturing schedules.
So reluctantly, I too vote to retain
the current strain, but with those caveats.
DR. KARRON: Dr. Stapleton?
DR. STAPLETON: I think Dr. Word's comments, I would perhaps
argue that this is somewhat unusual to have the difference between the human
the ferret data. And the timing of the
isolates coming in late and having a late epidemic in the U.S. is part of it,
and contributes to a complication that we couldn't really predict.
And I have to say that being on this
Committee is fun because I hadn't though of children being more like ferrets
than humans, although I'm thinking about it immunologically I understand
that. But I think that getting children
immunized is important, and if they're more like ferrets then I'm reassured by
that.
So I vote to retain, but I echo Dr.
Couch's comments that I think it's important to monitor and to keep the option
of a monovalent supplement as an option if indeed we find there's a serious
mismatch.
DR. KARRON: Dr. Hachey?
Dr. HACHEY: I'm going to agree that the problem is we
just don't have a good fit this year, as far as the current vaccine. But I really don't see a clearly superior
strain that we have an option to pick.
And any delay is associated with clearly some substantial risk in
regards to production, supply, and delays.
More data would be nice, but that doesn't look like it's going to
happen, at least data that is substantial enough to have a high likeliness of
altering the decision.
So I vote to retain the current
strain.
DR. KARRON: Dr. McInnes?
DR. MCINNES: I'm not comfortable with retaining the
current strain. I think there are some
additional data that could come to the table.
I think we would, we have a potential within the next month, 4 weeks, 3
and a half to 4 weeks to understand about this potential, this reassortant, how
it's going to perform. I think CDC has
indicated that they do have some additional viruses to look at and I want to
acknowledge the extraordinary amount of work that they do, and that they have
put on the table, and that they continue to be willing to do. And I would vote to defer.
DR. KARRON: Thank you.
I am going to vote to retain the
current strain. With all of the
concerns, both voiced by I think many of the people around the table, I'd
actually, two points that I'd like to make.
One is I'd really like to echo what Dr. Wharton said. I think that if, for example, the B strain
had been made at-risk instead of the H3N2 strain, this would've been a very
different discussion. And I realize the
manufacturers are working with the best data they have, but I don't know how
those decisions were made and I would urge them to review them carefully each
year, as I imagine they do.
The second thing is I would like to
have some kind of mechanism for dissemination of the additional data that will
become available in the next month or so from the CDC and from other centers to
members of this Committee. Not
necessarily because it will have an impact on any decision-making, but because
I think all of us are concerned about this decision and we would like to be
able this data as they become available.
And Christine needs to summarize the
vote. And then did you have a comment
John? But I'll let her summarize.
MS. WALSH: To summarize the vote on the options for
H3N2, there were 11 votes to retain the current strain, A/Wisconsin, and 2
votes to defer the decision to a later date.
DR. KARRON: John, did you have a comment?
DR. MODLIN: Well, just one comment. I guess we're now in a post-hoc position of
second guessing the decision to go with A/Wisconsin for the first strain, as
opposed to say the B-strain. And I guess
the question is when that decision needed to be made did we have anymore
information at that time that we would be seeing this shift in the H3 strain
compared to a similar change in the B-strain?
I haven't seen that we have and so I just would question. Obviously you roll the dice and was there
anymore information that would've been informative when the dice were rolled a
couple of months ago compared to what we have now. And I haven't see that we have it. So that was the only thing that I would
raise.
DR. COUCH: I guess we're saying the same thing, but when
the industry has told us repeatedly that they have to commit before we sit
around a table and make a decision, I guess what I'd say is if your commitment
is H3N2 be very thoughtful that is the one of greatest concern to us. And if you cannot make that one, we'd prefer
it.
DR. KARRON: Norman?
DR. BAYLOR: I just wanted to make a comment. I guess Bob, the commitment has already been
made. They have committed. They have started, many of them already. We do have the march, you know, as we
follow-up VRBPAC, which we usually have sometime in March, and that is the time
that we could review the data from CDC.
We can arrange that meeting anytime in March if that data would suggest
that we need to have a further discussion.
So that's open, although, again, the commitment, I think the
manufacturers have already started, and they can correct me if I'm wrong, how
far they've gotten. But if the data are
so impressive that we need to make a change, we can have that discussion at the
March meeting.
DR. KARRON: Did you want to make a comment, Mr. Thomas?
MR. THOMAS: Yes, I could provide a little insight into
the timing or the decisions making for at-risk production. Just bear in mind the decision to produce the
A/Wisconsin strain at-risk was decided over seven weeks ago. And that was based upon the best available
surveillance data at the time. And if
you recall, based on some information already presented here, at that time both
B/Yamagata and B/Victoria strains were co-circulating. There was still data on both. So the B-strain was uncertain. There was indications that the New Caledonia
strain, which is what had been selected in years past, would be changing, based
on the availability of the Solomon Islands.
So there was a new egg isolate.
The B-strains were co-circulating.
And at that point we all realized that the H3N2 strain is the one that
has the most potential changing year-to-year, but again it was the, essentially
our only available production candidate.
And at that time there were no additional egg isolates available, nor
did the surveillance say that there was going to be a grouping of an antigenic
drift that was currently identified.
But the manufacturers would
completely support another method here of looking at how we would begin that
decision for producing at-risk.
DR. KARRON: Thank you.
Dr. Choeling?
DR. CHOELING: Kathleen Choeling for MedImmune. So I think maybe I should explain just for
transparency why we made the decision to go ahead with B, having the same
information. And I think maybe the
timing was a little bit different when we made our decision. It could've been. But the other thing that the Committee
probably may or may not know is that we make our own reassortants. So the CDC supplies us new isolates in a very
timely manner. So when we got the
A/Nepal H3N2 strain, we were aware that there was a possibility that that
strain could change.
So I think it's, there are a number
of different reasons for that difference in our deciding to go ahead with the
B/Malaysia at-risk.
DR. KARRON: Thank you.
And speaking of the B, that's our one decision left to make.
Christine is going to put up that
slide.
And Dr. McInnes, we're going to
start with you?
DR. MCINNES: I would vote to retain the current
B/Malaysia/2506/2004 like virus, B/Victoria 287 lineage.
DR. KARRON: Dr. Hachey?
DR. HACHEY: Vote to retain.
DR. KARRON: Dr. Stapleton?
DR. STAPLETON: Vote to retain.
DR. KARRON: Ms. Province?
MS. PROVINCE: I also vote to retain.
DR. KARRON: Dr. Jackson?
DR. JACKSON: I also vote to retain.
DR. KARRON: Dr. Word?
DR. WORD: I vote to retain.
DR. KARRON: Dr. Hetherington, do you have any opinion?
DR. HETHERINGTON: No other comments.
DR. KARRON: Okay, thank you. Dr. Wharton?
DR. WHARTON: Vote to retain.
DR. KARRON: Dr. Eickhoff?
DR. EICKHOFF: Vote to retain.
DR. KARRON: Dr. Self?
DR. SELF: Retain.
DR. KARRON: Dr. Farley?
DR. FARLEY: Vote to retain.
DR. KARRON: Any, no, okay. Dr. Couch?
DR. COUCH: Retain.
DR. KARRON: Dr. Modlin?
DR. MODLIN: Concur.
DR. KARRON: And I also vote to retain.
Yes, Christine, please summarize.
MS.
WALSH: For the option, options on
Influenza B, there were 13 votes, unanimous decision to replace -- I'm sorry,
retain, retain current, the B/Malaysia virus.
DR. KARRON: Thank you.
This concludes our morning
session.
It is about 12:15 and I would like
to propose that we reconvene at 1:15 instead of 1:30, unless does this pose any
particular hardship for anyone?
Yes?
DR. WEIR: I thought we were getting an H5 update?
DR. KARRON: Oh, I apologize.
Nancy, an H5 update, of course.
DR. COX: Gosh, I thought I was going to be let off the
hook.
This is not the right presentation.
Okay. This should be easier. This is just for information only, but I
thought it would be very useful to update the Committee on what's been going on
with the H5N1 viruses that are circulating.
I'll just give you a bit of history
and recapitulate what's been going on since 1997. Currently there are two discreet lineages of
H5HAs that have descended from the A/Goose/Guangdong virus. And the A/Goose/Guangdong virus is really
then ancestral virus of all of the H5 viruses that we have. That is that it's the nearest to the ancestor
of the `97 strains that caused the 18 human cases with 6 deaths.
In `97, I should remind you that
there was evidence for direct avian to human transmission with limited, very
limited, and rare human-to-human transmission documented. That has remained true since then.
Then we didn't hear very much about
H5N1, although we thought that it was probably continuing to circulate in South
China. And then in late 2003, there was
a sort of an explosion of reports of activity in Southeast Asia. And actually, that was at the end of 2003. Earlier in 2003, there had been two human
cases with one death in Hong Kong that was from a family that had traveled to
Fujian Province to celebrate the Chinese New Year.
And then retrospectively, it was
determined that there was a death in Beijing that was thought to be SARS at the
time but it was one of those SARS-negative patients who then subsequently was
tested for H5N1 and found to be H5N1 positive.
So since the end of 2003 until
today, we have cases in 12 countries.
The latest country to be added is Laos, and I didn't get it on this
slide. I'll have it on the next slide. But Nigeria and Laos are the two latest
countries, there it is, Laos and Nigeria are the two latest countries to report
human cases of, and Laos reported the first human case yesterday, or WHO
reported it.
So we have 275 cases, 167
deaths. It's a 60 percent case fatality
ratio, and you can see where the cases are occurring. The current hotspot is really Indonesia. And then there's a lot of activity going on
in birds in Africa as well. And we've
heard of recurrence of H5N1 in birds in a number of a different countries, and we
heard quite a bit about what was occurring in the U.K. while we were in Geneva
a couple of weeks ago. And we also have
heard about bird outbreaks in Bangladesh and a number of other countries that
hadn't previously reported outbreaks in birds.
So, with respect to what we're doing
globally, there are some basic principles and practices that the WHO undertakes
when there is a newly emerging strain.
And developing of H5N1 vaccines is
one component of WHO's overall strategy for pandemic preparedness. And there are four WHO Collaborating Centers,
as you know, with an additional four H5 reference laboratories. And we share the H5N1 antigenic and genetic
data very frequently. It's actually put
into a share compartment, which allows us to really compare what is going
on. And then WHO convenes periodic
teleconferences of these reference labs to discuss the data and apportion tasks
require for vaccine candidate reference virus production.
And we really have to have
integration of antigenic, genetic, and
epidemiologic data from both the human and veterinary health sectors in
order to make the best decisions about which viruses to select as potential
vaccine strains.
And consequently, the candidate
reference viruses are really chosen on the basis of all of these
considerations.
So, as I've mentioned the HA
sequences divide into two distinct phylogenetic clades. Clade 1 viruses have circulated in Cambodia,
Thailand, and Vietnam and caused human infections during 2000 and through 2005. And then subsequently caused two cases in
Thailand in 2006.
In contrast, clade 2 viruses were
circulating in birds in China and Indonesia during 2003 and 2004, and then
spread very dramatically westward after the very well known outbreak of H5N1 at
Qinghai Lake in Western China. And it is
postulated that migratory birds did assist in the spread of the virus to the
Middle East, Europe, and Africa.
Clade 2 viruses have caused the
majority of human infections since late 2005.
And there are multiple subgroups, genetic subgroups, in the so called
clade 2. And they can be distinguished
both genetically and antigenically, and some of them have very discreet
geographical distribution.
So the majority of the H5N1 virus
detected in Africa, Asia, and Europe in birds, which have been associated with
sporadic human infections are in clade 2.
Clade 2.1 viruses circulated in
poultry and caused human infections in Indonesia. And as I mentioned, Indonesia is somewhat of
a hotspot.
Clade 2.2 viruses have caused
outbreaks in birds in Africa, Asia, and Europe.
And these are the Qinghai Lake viruses.
And these were most recently associated with human infections in Egypt,
Nigeria, and we're not sure yet about the virus from Laos.
Viruses in clade 2.3 cause poultry
outbreaks and human cases in China.
And then there are viruses outside
this classification, the 2.1, 2.2, and 2.3, which have been isolated from
domestic poultry in Asia. And there are
two emerging clades, which are represented by A/Goose/Guiyang/06 and A/Chicken/Shanxi/2006. And the virus A/Chicken/Shanxi/2006 is
particular interest because it was mentioned at a meeting in Beijing in early
December that birds that were well vaccinated with the current inactivated
vaccine using the A/Goose/Guiyang strain were having breakthroughs caused by
this particular virus.
So this is the way we, you can look
at my next, unfortunately will not be quite oriented like this, but these are
the clade 1 viruses. And we had the
vaccine candidates, Vietnam/11/94 and 12/03 about which you heard a lot about
yesterday that were developed using reverse genetics to take the multi-basic
cleavage site out of the HA, and then they were put on a puree backbone, safety
tested extensively, and then subsequently used to manufacture the vaccines that
you've heard about yesterday.
Clade 2, subclade 1, so 2.1,
consists of these Indonesian viruses which have been fairly homogeneous
antigenically with the exception of the viruses that were isolated from the
Karo cluster. This was the large family cluster
that occurred in Northern Sumatra. And
those seem not to be the predominant viruses circulating in Indonesia.
And then we have Clade 2.2. I mentioned these were viruses that actually
descended from the bar headed goose Qinghai Lake virus. We have a number of vaccine candidates that
have been made by reverse genetics that are in this group.
And then clade 2.3 here, which is
circulating primarily in China, and the majority of the Chinese human cases
fall into this group. And we have to
vaccine candidates here, the Anhui/1/05, which was isolated from a human
infection, and then the Japanese white-eye/Hong Kong/06 was obviously isolated
from a bird.
When we look at these virus
antigenically, there is also good differentiation. So we have the clade 1 viruses, which inhibit
each other well but don't inhibit the clade 2 viruses, so the antisera don't to
the Vietnam/11/94 virus really don't do very well in inhibiting viruses in
clade 2.
These are viruses in clade 2.1. The antiserum to these viruses don't inhibit
clade 1 viruses very well and tend not to inhibit viruses in clades 2.2 and
2.3, although they do better with 2.3 viruses.
Viruses in clade 2.2, likewise, in
antisera inhibit to these viruses and inhibit each other pretty well but there
is differentiation, good differentiation.
And the same is true for viruses in
clade 2.3.
So, we can see very clearly here
with color coding, clade 1, clade 2.1 in green, 2.2 in yellow, and 2.3 in
blue.
If we look at the profiles of these
viruses in terms of their resistence and susceptibility to anti-virals, with
respect to resistence to amantadine and rymantadine, the M2 channel blockers,
we see that clade 1 viruses are resistant and there's a particular amino acid
change in the M2 protein that confers resistence.
Clade 2.1 viruses are a mixed
bag. About 80 percent are resistant and
there are two different resistence changes that are seen among those viruses.
Clade 2.2 viruses have been
sensitive.
And Clade 2.3 viruses also have been
sensitive.
If we look at susceptibility to the
neuraminidase inhibitors, we see that clade 1 viruses are generally sensitive
but there have been several resistant mutants isolated from treated patients.
Clade 2.1 are sensitive.
2.2, again, generally sensitive but
moderately resistant viruses were detected from patients from Egypt that were
treated with Oseltamivir.
Clade 2.3 viruses are sensitive.
I won't bother going through that
particular HI table because I think you've seen enough HI tables.
I just wanted to point out the two
new subgroups here that I had mentioned before, Shanxi virus, and you can see
the horizontal distance is the distance that really counts on these trees. And the Shanxi virus is out here from the
backbone, the consensus. And then also
we have another group that appears to be emerging. There are a number of 2006 viruses in this
group, and these are isolated mainly from Guyang. So these viruses are being sought from our
Chinese colleagues to be used, possibly used to make candidate vaccine
viruses. And we really haven't
characterized these in terms of their antigenicity or their susceptibility to
the anti-viral drugs.
So, in conclusion, I want to make it
very clear, and I think everyone in this room certainly knows that H5N1 viruses
remain a pandemic threat but have not yet developed the ability to be
transmitted efficiently from person-to-person.
We've seen some changes in the
viruses. In particular, occasional
viruses around the receptor binding pocket, but those viruses have not
persisted.
We're not able to predict which, if
any, H5N1 antigenic or genetic variants might acquire the ability to be
transmitted efficiently. We see distinct
geographical distribution of the H5N1 genetic and antigenic variants, and
therefore we really find ourselves as a group, global WHO group, unable to make
specific recommendations for use of one particular group or subgroup of viruses
because it's not possible to predict which of the viruses in the distinct
antigenic or genetic groups might acquire the ability to become officially
transmissible.
Instead, we are taking the approach
that we should provide potential vaccine viruses and that we should encourage
the regulatory authorities to produce the reagents that would be needed to make
vaccines, both for experimental purposes and for stock piling purposes.
So, as you know, the Vietnam strains
have been available for some time. The
Indonesia/5/05 clade 2.1 is available from CDC.
Antigen and serum should be available soon from CBER, and Dr. Ye may be
able to comment on that.
The reverse genetics, modified
Turkey/Turkey/1/2005 clade 2.2 is available from the NIBSC in London. And they also have the antigen and chief
serum available.
The Qinghai Lake, clade 2.2 is
available from St. Jude. Reagents are
not yet in production. And that's true
also for the Whooper Swan/Mongolia.
The A/Anhui/1/05, clade 2.3, virus
is available from the CDC. This virus
was made during the visit of post-stock from the National Influenza Center in
China to CDC and was made together with our staff. Reagents are not yet in production.
I'd like to acknowledge all of the
many, many collaborators around the world, without whom I could not have made
this presentation.
Thanks very much.
DR. KARRON: Thank you, Nancy.
Questions or comments at all?
Now, it's lunch time. We will reconvene at 1:30.
(Whereupon, the above-entitled
matter went off the record at 12:30 p.m. and went back on the record at 1:35
p.m.)
A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
(1:38 p.m.)
DR. KARRON: If everyone would please take their
seats. We're going to begin the
afternoon session.
We're going to go ahead and start
with an introduction by Jerry Weir with the FDA.
DR. WEIR: Is it on?
Thank you.
I'm Jerry Weir, the Director of the
Division of Viral Products and I am going to give a very brief introduction to
the last of our four sessions for this Vaccines and Related Biological Products
Advisory Committee.
The topic of the fourth session will
be a discussion of the circulating Influenza B strains that you have already
heard about today and yesterday somewhat.
As you know, Influenza B viruses are
not divided into subtypes, and currently vaccines contain a single B
component. There are, however, two distinct
antigenic and genetic lineages of Influenza B, which co-circulate. They are designated by their reference
strains that correspond to them, and they're referred to as the B/Yamagata
lineage and the B/Victoria lineage.
Influenza viruses from each of these
lineage periodically become dominant as they circulate. And one of the main reasons that we're here
this afternoon is because today and in previous VRBPAC discussions, the
question has come up as to whether there should be some consideration given to
some alternative vaccination strategy in order to address this issue of having
two distinct lineages circulating.
Just to remind everyone, this slide
shows the composition, the B-component composition in the vaccine for the last
few years. And if you look to the far
right you can see in parenthesis the lineage that each strain comes from. And you'll see that what's happened is we've
actually alternated every couple of years with a strain from the Yamagata lineage
and the Victoria. And of course, we just
recommended that we keep the Victoria lineage for one more year.
So, the reason we're here today, the
agenda is as follows.
Besides this brief introduction that
I'm giving, our colleague, Dr. Robert Couch, who is on the Committee, has
agreed to provide a background to this issue.
And then following Dr. Couch, Dr.
Gagneten from CBER will discuss briefly the regulatory implications of any of
the alternative strategies that are brought up and that will be presented by
Dr. Couch, as well as yourself.
And then we have the manufacturers
scheduled to give comments, to get their view points.
And then we have an open public
hearing scheduled after that so that anyone else in the audience that is
interested can put in their two cents.
And then what we would hope to have
is a discussion among the Committee that will discuss this issue.
So what the goals of the afternoon
are, are as follows:
We want to review the available data
regarding the Yamagata and Victoria lineages of Influenza B. Discuss the genetic and antigenic
relatedness, epidemiology, cross-protective responses to vaccines derived from
each strain, as well as the morbidity and mortality associated with Influenza
B.
And then have, the speakers will
assess the various options to provide vaccine coverage for strains of both
lineages.
And then we'll examine the
regulatory and manufacturing considerations for these options.
And what we would like to see the
Committee focus their discussion on after everyone has had their input is the
following three items, which we can I guess put back up there at the end:
Please discuss the medical
significance and concerns presented by the two circulating lineages of
Influenza B, and whether such concerns can be addressed by means of an
alternative vaccination strategy.
Second, please discuss the
feasibility of the various options for expanded vaccine coverage of the two
lineages of Influenza B. And you'll see
as the speakers go through their data that these could, some of these options
will include types of quadrivalent vaccines, supplemental vaccines, as well as
some other options.
And then finally we would like you
to discuss the possible future steps for both manufacturers and the public
health agencies, keeping in mind of course the context of the global nature of
influenza vaccine recommendations and production.
And so that's all I have for an
introduction and I guess we can, unless someone has a question, we can move on
to our background.
DR. COUCH: All right.
Thank you, I'm Robert Couch, Baylor College of Medicine. I was introduced earlier yesterday but not
again since then.
I have three introductory comments
first. One is I'm your third choice
speaker. When Jerry asked me to do this, I said look this needs to be either
Nancy Cox or Roland Levendowski because year after year they've presented this
data on the lineages and immune responses.
And he came back to me and said well Nancy has got a big assignment for
the morning, which I think everybody would agree she did have. And he thought Roland had an assignment for
H5 yesterday, so I'm not sure what happened to that one. I said, all right, I think I'm probably a
reasonable third choice. So you got the
third choice for this one.
Now, the second is I said, he said
how much time. I said give me 30
minutes. He gave us 40. So what I did was to add a little bit more,
you might say, on the biology of Influenza B, epidemiology, and so forth before
we go into the lineage data, which is what we'll have to wrestle with, with
regard to discussions.
And one other comment I want to make
is my purpose is to provide the background and the options. I won't take a stand. Maybe we'll come to that later on, but the
options are for the discussions of the group afterwards. So that's what's coming to you.
And the final comment is in that
regard, this has been going on for some time.
And I've brought it up on occasions in the past, but I'm more
comfortable saying, not calling this a problem, but calling this a concern. And it has been a concern, and it still is,
and it may continue to be a concern that I think needs to be addressed. And that's what Jerry said as part of the
introduction here.
All right, with kind of an
introduction then, let's go into the subject.
Some of this, this is repetitious obviously, but the classification of
the human influenza viruses is, and we've already heard A, B, we don't talk
about C. It doesn't exhibit that kind of
variation that gives us concern. These
are our medical problems, A and B, and as you know, subtypes. And within those subtypes, and for B we
drift, and that's what the task we have every time we meet here is trying to
identify that drift, prepare for it, make the vaccine decisions so it has
control.
Now, our current concepts are that
these are bird viruses. And they crossed
that species barrier and established themselves in man and that's what we're
getting as a problem out here. Whereas,
our current concept is that this is a human virus that had our animal origin;
we still don't know what it is. So
Influenza B are human viruses that we have to live with but share a lot of
characteristics with the Influenza A.
And I've chosen to take that tact
and a little bit of the background information in contrasting Influenza A. First, just some comments about the
virogy.
These viruses have a similar
structure. They have the same component
parts. They have the same replication
sequence. There are some differences,
but they're not major ones. But the
Influenza B and A have unique nucleoprotein antigens, and that defines them as
Influenza A or B, the nucleoprotein antigen, and they are different.
Now, that follows a lot of other
differences that are associated with that.
They both exhibit drift, as we said, but Influenza B do not exhibit
shift and therefore no pandemic and no subtypes.
Antigenic drift is at a lower rate
than that that has been described for Influenza A. And this is from one of Nancy Cox's
manuscripts, the evolutionary rate for the HA1 gene and the protein, H1N1,
H3N2, and B, and over a lot of years, from 1943-94 here, for the Influenza B,
nucleotide changes per site, per year.
You see the As are about the same and the Influenza B is a little less
than half of that.
Amino acid changes per site, per
year, up around five and down to a little over one and a half. And that clearly accounts for some of the
differences in the epidemiology between the A viruses and the B viruses as we
know them.
Now, a few comments about infection
and disease, and in that contrast. There
are some differences in substrate preference.
Those that you have worked with these know that B likes tissue culture
less than A. A does pretty well with
eggs, those vary with time. And the SA
performance, whole virus for HI for Influenza B, split products, more
sensitivity, A doesn't have that problem.
So there are some differences here, but they're all in the laboratory
set. But those relate to differences in
the infection in the laboratory.
As we know it to have a similar
transmission, a similar pathogenesis, a similar infection pattern, and a
similar illness pattern, and the same basis for immunity. And it's that we use for the basis for our
decisions on an annual basis for the vaccines.
There are some differences in
complications but there's a lot of overlap.
Both viruses can produce pure viral pneumonia, and both produce, induce
secondary bacterial pneumonia. Both
produce otitis media or lead to otitis media in children, sinusitis in older
individuals. Acute myositis is thought
to be more common in Influenza B than in Influenza A, more in children than in
adults, but described for both.
Acute encephalitis or encephalopathy
is thought to be more common for Influenza A.
The Japanese problem may be a good example, and it's very acute in
association with the illness.
Reye's Syndrome, originally thought
maybe to be a complication only of Influenza B, it turns out it's a
complication, just a little bit more common, it appears, for Influenza B. And both produce various neurologic disorders
that we'll call one of the myelitis disorders and there are quite a number of
them.
Now, an anecdote on the side. And the reason I like this one, Influenza B
and Parkland Hospital 7677. This has Jim
Luby's mark on it. Some may know
Jim. He's a great physician. He was a CDC EIS Officer and I have a lot of
respect for what his beings, for what was done here and what was said. And this was their experience in that
hospital: 15 confirmed cases, three
secondary bacterial pneumonia, two with a severe chest disease disorder, and
I'm not giving you details on these, high fever and rhabdomyolysis, two
cases. Three of Reye's Syndrome, I guess
it preceded the aspirin knowledge. Two
with neurological syndromes, again, not giving you the details. One Steven Johnson Syndrom. One thyroid dysfunction. One pregnancy with toxemia and two
deaths. All Influenza B.
And this is the conclusion out of
that, "Quantitatively rare but qualitatively severe, complications and
sequelae outside the respiratory system may be the most significant
contributors to Influenza B, morbidity and mortality." And I don't think we have a good quantitative
understanding for how true that may be, but clearly that is true, just the
uncertainty is the overall significance.
Now, Influenza B is associated with
mortality. Here is the data from
Thompson, which most of us do. H1N1,
H3N2, and B, look at H3N2, you see P&I Mortality estimate, 6,600, 28,000,
all causes over 40,000. Influenza A
here, H1N1. B is in between. You see 1,100, 5,200, and 8,300, less than
H3N2 and greater overall than H1N1.
And this is one of the, this is a
period of the epidemiology descriptions in a CDC publication of a ten year
period. And it shows the circles, which
they sometimes use. The size of the
circle was the magnitude of the epidemic.
And the viruses are the pieces of the pie. The slash marks are Influenza B. You see, here is about three quarters of
them, Influenza B, a small number, and Influenza B epidemic, a sizeable
one. Mostly Influenza B, but a small one.
Influenza B almost half of a big epidemic.
Influenza B, three quarters of a major epidemic. So that was actually four out of the ten
years there, which is a little more common than most of us think of it, but a
significant cause of epidemics for influenza.
These are age distributions. I know, and I think most people that
Influenza B is more common in children.
This is the kind of data that is the source of that generality. This is data out of Houston. Two successive epidemics, A/Victoria and the
next year we had a B/Hong Kong epidemic.
1,100 isolates in this one and 670 isolates in this one. See, 0 to 6 months, 7 to 12 months, 1 to 4, 5
to 9, so on down the line, 45 to 64 and greater than 65.
If you look at Influenza A, you see
that this is what gets you right away.
It's all running about the same.
Seven, six, seven, two, and this seven if four, versus the distribution,
100 percent is the total obviously. This
one, and here is nine and five, which you see thirteen percent, eight percent,
and then when this 30 percent grabs you.
So if you look at five to fifteen, half of the isolates in the Influenza
A, in the Influenza B outbreak are in that age group, a much higher frequency,
lower and higher, and a greater distribution for the Influenza A epidemic.
That's the kind of data that leads
to the association that it's more of a problem, not more of a problem but a
major problem among children.
This is also, I experience in
looking at, these are low-income clinics, charity clinics and private hospitals
and private physicians offices. Just
looking at the children, look at the low income. You see I put the distributions to the total
here, 12 percent, 3 percent, 30 percent, 15 percent. 38 and 46, so it goes up here, and it's high
down here. I dropped this one just
because you can argue in the low income groups that we're getting an age group
where it's hard to control the children, even get them to the doctor. But if you just go up to age 9 and take this
group, you see, three quarters of those isolates in this group, a quarter of
them under age five, whereas half of them are in the low income age group under
age five.
That's been not an unusual
characteristic, and it's also true to the certain extent to Influenza A. But they spread more and the rates are higher
among low income groups. We can
speculate as to the reason for that.
Hospitalizations for influenza virus
infections, 1969-1995, and this is Simonsen's data. Only 1 H1N1 epidemic, but hospitalizations,
you see, look at H3N2, 12 epidemics, estimated 85 to 220,000 in excess. Influenza B isn't the highest, didn't even
get close to the lowest. So a much lower
hospitalization rate.
On the other hand, if you get put in
the hospital, this is the data out of DC Children's Hospital over a number of
years, 131 Influenza As H3N2 isolates, 54 isolates of the children admitted to
the hospital. Syndromes, upper croup,
bronchiolitis, and pneumonia. And you
see they overlap. They're both
here. So you get croups a little
higher than Influenza A, and other
people have pointed that out. But if the
child gets sick enough to put in the hospital, it's the same disease that you
can see in an Influenza A infection.
And then go back to another age
group so we don't forget the elderly. An
outbreak in Influenza B nursing home, 1979.
This represented an antigen change.
I didn't look it up, but I presume it's probably the B/Singapore/79
change, which was one that was recognized.
Nursing home, 359 cases, 129 yield a 36 percent illness rate, 5 hospitalized
and one death. 93 percent of the
individuals had been vaccinated, but there had been a significant change in
Influenza B that caused that outbreak and then related to this occurrence in
the nursing home.
So I would summarize the features of
the Influenza B epidemiology as we know them today here. The major cause of an annual epidemic, about
every two to four years. Infections
occur in all age groups. Illness is most
prominent among older children and young adults. Illness in infants and young children appears
to be more common among the low income groups.
Infections are prominent in the elderly in some epidemics, with excess
mortality, but not in all epidemics.
Overall impact is less than H3N2, but greater than H1N1. I think that's a fair statement that we would
all agree with. But overall, Influenza B
is a significant cause of absenteeism, clinic visits, hospitalizations, and
deaths. And that's a reason Influenza B
is in the vaccine and one of our considerations that we addressed this morning.
Now, if move on to the lineage
subject, this is a, Nancy showed you one this morning, this is one from last
year, but just to remind year that there are pretty clear cut change and
differences in ferret sera. And you see
here is a B/Yamagata lineage and a B/Victoria lineage. And we're coming up here, I'm not, I chose to
just stay away from all these strain names.
So what you're going to see is the lineage, B/Yamagata, B/Victoria, not
the particular strain that represented that lineage in any given data. So I think it'll be a little bit easier for
you to follow that way.
And this is a description of the
sequence as it's generally known now.
Now, before the 1980's, Influenza B was considered to be a single
dominant strain in the epidemics, each year and in epidemic years.
In the mid-80s and early 90s,
B/Victoria/87 like strains were dominant.
B/Yamagata was present, however.
It was recognized, some of it in retrospect recognition.
In the early 90s to 2000, B/Yamagata
like strains were dominant, except for Asia, where they had both of them,
B/Yamagata and B/Victoria.
2000 to the present, both lineages
worldwide. That's the major reason for
our addressing the topic today.
And another example, this was
presented to this Committee in early January, at the January meeting in 2000,
and I'm sure it was probably was Cumiac Nairomi. But they had had a major problem with B in
two previous succeeding years, and this was the example of what we're seeing in
Asia.
Here is the Yamagata derivative. That was their vaccine. Here was their outbreak two successive years
with the B/Victoria. And they were,
basically as he described it, smashed with Influenza B infection and disease.
And his summary and recommendations
I thought were interesting. For the B
components, should we consider B/Harbin, that's a B/Yamagata strain, B/Beijing,
a B/Vic strain, or a third strain which efficiently covers the above two
strains. You see if we had that, we
wouldn't be having that discussion at all and our decisions would have been
easy every time the subject comes up. So
the question was raised but we don't have the solution to it, unfortunately.
And I like this recommendation from
1999-2000 recommendations from WHO. For
Influenza B, either B/Yamagata or Victoria depending on your local
conditions. They just putt and left it
up to the individual countries to decide what they were going to do. They've not done that every year, but they
sure did it that year.
And this is the circumstance before
we started getting a little more concerned of this problem. Here is a geographic distribution, October
`97 to 2000. This is one of Nancy's
maps. And here we are in the Far East
for Influenza B, you see, and the rest of the world blank. And then in late-2000 going over into 2001,
then it started changing. Here is
Asia. Here is Italy. It began to show up in parts of Europe and in
North America. So then we began to see
the Victoria lineage appearing. It was
here around the late-80s and 90s, but reappearing in the Western Hemisphere.
And this is my table of the
distribution of the lineage starting in `98-`99. Now, this comes from that stack of things on
my filing cabinet behind my desk. And
there are differences in the numbers here, and the reasons are, for a number
like this, for example, I had the report from the full season. From a number like this, I only had a report
that was given out at this meeting, for example, you see, in February. So they're smaller numbers. But when I had both, while the percentages are
different, the patterns were the same.
So I think we're all right with pattern thinking rather than necessarily
the harder percentages.
And I chose to star those in which B
was equal to or greater than 20 percent of the isolates. Well, that's a little bit arbitrary but in my
mind when you get over 20 percent now, that's a significant contribution to the
epidemic. So you can see the ones that
are starred here.
So we go up here to 1998-1999, 100
percent Yamagata, and the vaccine that year was Yamagata. The next year, 100 percent. The following year, 100 percent. And then a B/epidemic, a B/contribution of
significance and Yamagata vaccine. And
then you can see then, then the B/Vic, we're talking about U.S. now, then the
B/Vic appeared. And it was not
significant that year, so we switched to a B/Vic vaccine, but we had a
B/Yamagata dominant. And then we go with
a B/Yamagata dominant the subsequent year and went back to a B/Yamagata
vaccine, and now we have a significant contribution from Influenza B, and most
of the isolates matched the vaccine.
B/Yamagata the following year, but
now we have a Victoria predominance. And
so this year it doesn't reach that 20.
It's running around 17 percent, but two-thirds of Victoria, so at least
yes, no. It's Victoria vaccine, but I
didn't get it starred, that's it. But
the Malaysia is matching at this particular point. So when it started circulating, we got two
right and we missed on two.
And this slide does a good
example. Nancy gave this one to us last year
again. And I like to use this to say
that this is a good example, I think, of the fact that these two lineages are
jocking for dominance, and it comes and it goes in different parts of the years
and has been coming and going at different parts of the world.
Now, what's going to happen? Is this temporary and will go away or
not? Well, we don't know the precise
answer to that, but this manuscript relates to that question.
Multiple Genotypes of Influenza B
Virus Circulated between 1979 and 2003.
This is an article out of the Memphis Group. And they completely sequenced 31
viruses. The lineages, according to
them, were established somewhere around the mid-80s. It had been suggested by the CDC folks
earlier that it was around 1983. There
is other data centers, probably was close, sometime in the 70s, at least
1975. It may have been even earlier than
that in which the lineages started separating and both started occurring. But by 1980, or shortly thereafter, it was
pretty clear.
And they used as a parent a Russian
strain showing the two lineages clearly are moving away from that. And calculated again evolution rates. This is, this is, this is a little bit higher
than the one that had been seen by Dr. Cox, a little bit low, but see, at least
suggested B/Yamagata, it may be a little bit more commonly changing than the
B/Victoria and the same for the amino acids.
And you could get the impression,
when you look at this data, that B/Yamagata looks like it's a little more
likely, a little bit more of a dominant lineage, and this would be compatible
with that but certainly not in enough data for you to make any kind of
conclusions or any kind of planning on that basis.
And they agreed with other
individuals looking at the same subject that the Influenza B had been
undergoing a great deal of reassortment, mixing up all kinds of genes. And out of those 31 sera types, 31 viruses,
they had 15 genotypes. I mean basically
one out of every two was a different genotype.
Unrestricted mixing of lineage genes,
they could find no paired relationship basis for them and so their conclusion
had to be no survival advantage to either one of these lineages. So we don't come out of that with a feeling
that one is about to move and replace the other, or any kind of our feeling or
thinking we sometimes use for Influenza A.
And here are the genotypes, the 15
genotypes. Here is the Russian. Here is Victoria/87. There was an 85 virus that was identical. Here is Yamagata. That has a shared nuclear, a non-structured
gene here. And there was a virus in
Memphis that has all eight that appear clean.
That's somewhat later. But you
don't need to go, you can look at the stripes just are all mixed up there. It didn't appear to be any preference for any
of these sorted out with any of the others, so they just concluded we can't, we
have no idea what kind of virus is going to be showing up with the future. And that included the hemagglutinin genes,
which of course is our focus.
Now, the problem with this is only
31 viruses. And this, I think, is
important to be followed, in my view, as to what, is this prediction and
anything that would say it's not right so that we would say these co-lineages
are likely to continue.
Now, we just had a press release
that NIAID had now completed the sequencing of 2000 influenza viruses, of gene
sequences. And we sent 50 Influenza B
strains over a ten year period to them for that purpose and I'm sure a lot of
other people did as well. Somebody needs
to examine that data bank now, and if that confirms the conclusions from here,
then you would have to conclude these co-circulation is indefinite, in the
indefinite future. And that's an
important bit of information that would relate to any decisions that we'd want
to make. So that would be one of my
recommendations on data if we get to that point.
So here's a summary slide of the B
Lineage surveillance data. Two distinct
antigenic lineages of Influenza B have circulated at least since the mid-80s,
probably before that.
Both lineages have circulated in
Asia since emerging.
The B/Yamagata lineage predominated
in North America during the 90s. The
B/Victoria lineage was essentially absent but was in Asia.
Co-circulation of two lineages has
been present in North America since 2001 with varying dominance.
And the available data currently
suggests that co-circulation is likely to continue. And as long as we have co-circulation, we are
no better off and we can't predict which it will be I think. It will be a guess.
Now, let's look at some of the
antibody data that relates to the decision-making to this body. Serum HAI antibody after an inactivated
influenza vaccine, and this is data presented at this Committee. Rather than present all these different
strains, I did make selections. And I
will say, I will claim they are only representative because you look at them,
the titers and frequencies differently when you use them with different
strains, but the patterns are the same.
B/Yamagata 1988-`89, adults and
elderly, you see, the number, somehow this group seems to like 24. I'm wondering why not 25, but any rate they
like 24.
B/Yamagata like, you see, percent
rise, GMT, and percent equal to or greater than 40. So if you just look at this one, you see, 75,
178, 97 percent equal to or greater than 40.
Elderly, somewhat lower, 97, 67.
Somewhat to be expected.
Now, go over to the Yamagata, we
follow the same thing. If you just look
at the last column, it displays the problem, 100 percent, 75 percent to the
elderly, 8 percent, 75 percent for the elderly.
Now, if you look at the opposite
lineage not in the vaccine, you see, let's just, let's me, let's just take the
equal to or greater than 40. It
illustrates the data. 97 percent equal
to or greater than 40, down to 59 percent.
67 percent down to 25 percent for the opposite lineage. Same here, 100 percent, 33 percent, 75
percent down to 17 percent. 88 percent,
38, 75 down to 50. See, a significant
drop in the coverage for the opposite lineage.
Now, here's a B/Victoria vaccine, in
which we've got 88 percent here, 75 percent, slightly lower in the
elderly. You look in the reverse
direction, now it's 88. I dropped to 64. 75 and I dropped to 63. So the patterns worked in both
directions. And the reason for showing
this one separate, the 2004 and 2005 vaccines is this one now has children
stated, children sera.
Adults again, and we see the same
pattern, you see, a B/Yamagata vaccine, 94 percent, 57 percent in the
elderly. You go to the opposite lineage,
it drops 94 to 46, 57 to 40. The same
down here if you do the adults, 96 percent drops to 38 percent with the
opposite lineage, both the Yamagata vaccines.
Now, let's look at the
children. 264 sera, I wondered myself
how they all of a sudden had that many in one year, but 264 sera. 79 percent rise, pretty good for the 5 to 8
year olds. 48, GMT, 64 percent, not bad
at all, you see, we think, most of us think of these as less than a normal adult
and elderly less, children are less. And
that fits with that generality.
But if you look over at the opposite
lineage, it's a much more of a drop, 8 percent.
If you look at those, half, 6 months to 2 years of age, see we're
looking at only 9 percent got equal to or greater than 40, and 0, nothing
basically measurable to the opposite lineage in that particular age group.
And these children I don't know the
ages of them, but you see the same general pattern here is 40 percent equal to
or greater than 40 to the vaccine antigen and nothing measurable, presumably in
any, among the children to the opposite lineage at all. So it really looks terrible for very young
children.
Now, I'm sorry that the rest, the
other half is not available for this data, which I put in and might not have if
you hadn't sent us these articles. I had
forgotten about Jan England and the two articles out of Seattle. But one of the points to make is that that
previous one, see this one right here, 10, 9 percent, 0 percent. That is the same vaccine you're looking at
here, which is now 62 percent GMT and 88 percent equal to or greater than
32. It's a different group of children,
maybe a different vaccine, a different laboratory; in fact, we all ought to
contract with that laboratory to test our serology maybe. But again, some of the variability that you
can get in things.
Not quite as good with the B/Vic
strains, but not bad for very young children.
And these were very young children.
They were all between say 6 and 23 months. So it's not always bad, but we don't have the
opposite lineage data from that particular one.
And this last one is the summary of
the work data that I had from the WHO reports, `98, Al missed a year too
here. But four Yamagatas, a Vic, and a
Yamagata. And if you look at equal to or
greater than 40 and equal to or greater than 40 from Vic, which is the way to
express your data, here is the drop across the board in the elderly, which you
expect to see. And B/Vic, you see, now
we're 79 percent to 39 percent. It drops
to 30 percent or so in the percent of individuals what some people call
protective titers. And children only in
this last one, 13 percent equal to or greater than 40 to the vaccine lineage,
and 40 to the opposite lineage.
So a little inconsistency, but by
and large, very young children get very negligible benefit for the opposite
lineage of the Influenza B that's in the vaccine.
And this is another. We heard from, Dr. Ye showed us that I've
sort of gotten used to seeing some of this data now. What percent lower in those GMTs, you see,
and most of us think in terms of roughly a two-fold different in GMT is getting
at the area of significance. And they
quoted in percentages, you see, so these would each be 50 percent or greater
reduction for that opposite lineage for that particular individual. So those are the kinds of figures that we
have to deal with.
Now, the summary of Influenza B
antibody responses. Antibody responses
among healthy adults to the vaccine like strains are generally good.
The antibody responses among the
elderly to the vaccine like strains are reduced compared to young adults, but
that is data we're custom to seeing.
Antibody responses among children to
the vaccine like strains are reduced compared to adults, particularly in young
children, again data that we're used to seeing, but maybe particularly, but
particularly among infants.
Antibody responses to the lineage
not in the vaccine are significantly reduced in all age groups. That's my judgment of significance, not a
statistician's judgment. But I would
consider it clearly clinically significant compared with the vaccine strain
responses, and they appear to be minimal responses in very young children.
Now, one of the questions I ask is
if we use the live vaccine in children, FluMist, does it do better at crossing
that lineage. And I can only give you a
little bit of information. I know Kathy
Choeling is in the audience and I spoke to her a little bit earlier, and I
think she can elaborate on these. But I
got Arnold Monto to send me his data, this recent publication in the New England
Journal of Medicine. And these are young
adults, or 18 to 46, with a mean of 74, got live or inactivated, 278, 273,
equal to or greater than four-fold increase with the Yamagata lineage, which
was the vaccine, or the opposite lineage, equal to or greater than 1 to
32. And you can see the kind of data we
just got through looking at for the inactivated vaccine, 85 percent, 30 percent
for the opposite lineage, 98, 73.
Now, if you look at the live vaccine
to only 12 percent had a response to the vaccine lineage, but four percent
against B/Vic. And these ratios are
basically the same.
If you look at these, this one is
down about 25 percent. This one about 20
percent. But those are in the same
pattern so that doesn't support any particular advantage for the live vaccine.
And this is the other source of data
that I have, and that's the recent publication by Bob Belshe in the group on
basically -- but the huge multi-center, multi-country study. And now, was the virus well-matched, no placebo
in this study, you've either got live or inactivated. Here is the attack rate. Virus-positive illness was inactivated, live,
and at 27.3 percent reduction. Not
statistically significant, but reduced when the vaccine, when the infection
virus matched the vaccine virus. Now,
their definition of non-well matched is the opposite lineage or a B/Yamagata,
which is significantly different. It's
not defined in the manuscript what significantly different consisted of. But it probably doesn't really matter because
when you look at that whatever poor cross-benefit you got from inactivated,
which would be our concern, live is no better.
So this is, there is no data here to support the live vaccine being
better at crossing that lineage than was true for the inactivated vaccine.
So, with that as a background of
information now, let's move on to consider the options. And the options were handed out to the
Committee, and I added one to that list of options, which seems to me is fairly
obvious, as I told you earlier, really we should've stuck it there probably to
begin with.
And that is, don't change
anything. So that is the first one up
here. Continue the annual trivalent
vaccine and do the best we can, which is what we got through doing this morning.
The advantage of that are a system
is in place for each step to delivery of the vaccine. A single strain selection is made, reagent
preparations, and manufacturing, and the delivery of that vaccine is, and the
manufacturing and everything would be unchanged. See, once you have something in place it is
tempting to leave it alone.
The disadvantages of that would be
co-circulation would leave a proportion of persons unprotected. We've already talked about that. Children and elderly perhaps at the most risk
for being unprotected. A major mismatch
then would result from selection error, not from a novel virus emergence, which
is the way we usually think, that we miss when a novel virus emerges like we
had the discussion a little bit of H3 this morning. Those have been the -- in this case we might
just make a bad selection. You hate to
think that way. And then you end up
missing and have significant disease that cause dyslexia.
Option two, and I added this one to
the list, alternate annually the lineage strain in the vaccine. And the way I said that to Jerry, that's why
I had a little less concern this past year or this current year than I had the
previous year because we changed lineages.
And the advantages would be it would
ensure protection to both of the lineages, at least to some degree, a little
quantitative uncertainty there, among those who are vaccinated yearly, because
you're switching yearly, your prime, you're boosting. It requires only one antigen selection, where
we are right now. Reagent preparation,
manufacturing would continue the same system we have at present. We'd be switching Bs every year, but we'd be
close to the same system we're working with at present.
The disadvantages are we have the
potential from reduced protection from a mismatch. We'd have to concede that. We have that now when we miss, when we don't
guess correctly. And we'd have the
potential for the reduced protection for those skipping a year. A number of individuals don't get their
vaccine every year. You see, if you've
got the two lineages, this one and one in the middle, you might be in trouble
for that lineage. Not a half frequency,
I don't think, but it clearly occurs.
Options now, here's a third
option. Quadravalent vaccine with 15
micrograms of each lineage.
The advantage to that would be the
expected responses to both lineages should ensue. And it should provide the expected protection
for both lineages.
The disadvantages would be the
possible increased reactogenicity. The
total dose would be 60 micrograms. I
think that would be negligible as my personal opinion, and certainly not a
reason it, it could be evaluated, but not a reason for serious concern.
It requires a selection of two
strains now and the reagent preparations yearly. So that compounds the problem at the decision
level where we were this morning and at the reagent preparation at CDC. And the manufacturer, if he doesn't tell me
that going to create a problem, I'll be terribly surprised. The lack of data on responses to a
quadravalent vaccine, we would always consider that something of a deficiency
though we would think it should be good.
And my, this one is personal, I personally have a little problem with
Influenza B then becoming the dominant vaccine component with 30 micrograms
when the dominant vaccine component consideration should be H3N2. It's a little bit of the same idea that we
heard this morning.
And I thought there was a third
example, but whatever I had in my office I couldn't find it anywhere.
Vaccination with two strains,
1956-57, both B/Lee and B/Great Lakes were added to the vaccine. 63 and 64, both B/Great Lakes and
B/Maryland. 73-74, B/Mass/71 and an
additional monovalent B/Hong Kong/72 was made.
I had no idea when it showed up, how well it was used, or that thing,
but was added when this change antigenically occurred, which caused a major
B-epidemic the subsequent year. So that
supplemental vaccine was added.
The fourth option, a quadravalent
vaccine with seven and a half micrograms of each lineage.
The advantages were if the response
to both lineages should ensue. The
overall B dosage would be unchanged, 15 micrograms. The reduction in immune responses and
protection, versus 15, should be minimal.
The disadvantages are that it would
reduce the usual dosage of the single most-likely antigen, which is a fix, to a
great extent in our thinking. Some
reduction in immune responses would occur and some responses in protection is
possible. It would require the yearly
selection of two strains and reagent preparation. Would this give the manufacturer problems or
less so than 15. And lack of data,
again, on the quadravalent vaccine.
Now, this is data to support that
perhaps being okay. This is John
Treanor's publication. And groups
getting the full dose and half dose, and this is Influenza B, 2002, this
must've been five years ago, the actual state, one of those shortage years when
the half dose study was done.
The vaccine group, prior vaccinated
group and no prior vaccinated increased four-fold you see. A significant increase, just 10 percent
significant for a four-fold increase.
And the same here, the 84 versus 73 percent. No differences in the GMT. No differences in the percent equal to or
greater than 1 to 40. And if you look at
this reverse accumulation of individuals, here I even forgot which one was
which. But here is the full dose and the
half dose among those who had previous vaccine.
We do see decreasing numbers of 1 to 40, 1 to 80, 160 and so forth, and
of those with no previous vaccine. So in
that study, in healthy adults, there's a negligible difference between some
slight reduction if you only gave a half dose if it's minor. The children, the data you'd like to have
for more confidence are, however, is young children, and we don't have that
data.
Now, the fifth option, both a
trivalent and a quadravalent vaccine, so to reduce the magnitude of what you're
proposing be made would be the reasons for this.
The advantage would be that there's
a greater need for children and probably the elderly in which the quadravalent
would provide that. The expected
responses to both lineages should follow the quadravalent. The quadravalent should provide expected
protection from both lineages.
The disadvantages to this would be
that those given the trivalent may have reduced protection against the opposite
lineage. And the available data suggests
that all ages would benefit from that quadravalent, including those healthy
adults. There were possible increased
reactogenicity. You've already heard me
for the quadravalent, I think, would be highly unlikely. It requires yearly selection of two strains,
manufacturer problems, lack of data on the quadravalent, and again, an awful
strong emphasis on Influenza B rather than H3N2, which I personally have a
little problem with.
And the final option is production
and delivery of a supplemental B, 15 micrograms it would be for the other
lineage.
The advantage would be again the
expected response you should get to both lineages should provide the expected
and desired protection.
The disadvantages would be required,
again, two strains to be done. The
manufacturing problems for the supplemental vaccine, delivery problems, it
makes Influenza B again the dominant antigen, rather than H3N2. You keep hearing that from me. But this would complicate delivery too,
particularly for the unprime. Now we're
talking about three doses, maybe even four injections depending on what you
need from that opposite lineage. And it
brings up the question of having to now really seriously consider adding spring
vaccination, which has been proposed as a way to shorten what we have to do
right with two doses in the fall. So
there are some disadvantages associated with that one too.
Well, that was my assignment and the
preparation I presume for the discussions.
DR. KARRON: Thank you very much. Next will Sara Gagneten from the FDA.
DR. GAGNETEN: Hello.
I'm Sara Gagneten. I'm a
Scientific Reviewer in the Office of Vaccines.
And I didn't request for an extension of my presentation. I'm going to very briefly give you an
overview of some of the regulatory considerations for the alternative vaccine
options that Dr. Couch talked about just now.
The biology of Influenza B, Dr.
Couch just went through it briefly just now, went through it very, in detail,
and just wanted to mention in this slide the problems of coverage.
Starting in 2002-2003, as Dr. Couch
mentioned, the vaccine, it was recommended that the vaccine contained strains
from the B/Victoria lineage.
That year the majority of Influenza
B viruses isolated in the U.S. were from that lineage, so the strain was
retained the following year in 2003-2004.
But that year, as you see, the majority of the viruses isolated in the
U.S. were from the B/Yamagata lineage.
So for the following year,
2004-2005, there was a switch to the B/Yamagata lineage. And then that year things worked well and the
virus was retained in 2005-2006.
But then the following year, the
majority of the viruses isolated were from the B/Victoria lineage. And so this, as you can see, this slide
illustrates problems of coverage that we've been talking about every two years,
well, I mean, it's been happening every two years but that's coincidence.
So some of the, okay, I'm
sorry. So I will talk to you briefly
about the alternative vaccine formulations to expand coverage for circulating
strains. And I will discuss the
regulatory passageways for licensure of alternative vaccine formulations,
manufacturers using this license process.
Just as a refresher I wanted to
mention that each year after selection of the strains, manufacturers submit a
BLA supplement to their licenses and that supplement does not contain chemical
data.
Also, as a refresher, their license
vaccine contain influenza viruses from two type A strains, one type B. They contain 15 micrograms from each strain
for a total of 45 micrograms of hemagglutinin per adult dose.
So some of the alternative
vaccination strategies were just mentioned.
I'm just mentioning these three that would require some kind of
licensing action.
So the option, one option would be
to include, to develop a quadravalent vaccine with two type-B strains and two
type-A strains at 15 micrograms HA for each one of the strains and a total of
60 micrograms HA per dose.
An alternative would be to develop a
quadravalent vaccine with half the amount of HA, or 7.5 micrograms HA for each
of the two B-strains and 15 micrograms hemagglutinin for each of the A-strains,
for a total of 45 micrograms hemagglutinin of the monovalent Influenza B
vaccine that would be administered with seasonal trivalent vaccine.
Now, for the regulatory
considerations for alternative vaccine formulations. When you factor using a license process, I
wanted to mention that at the clinical level the quadravalent vaccines would
require clinical immune response and safety data. And the monovalent Influenza B vaccine
administered with seasonal trivalent vaccine would require clinical immune
response data for administration to address issues of possible immune
interference.
At the manufacturing level, the
applications would require data for each virus strain as it is done
annually. And in addition, we would need
data for steps that differ from the license process, the manufacturing steps, such
as formulation that would differ.
Lastly, administratively, the type
of application that would be required, there could be a clinical supplement to
an existing BLA or a new BLA is under discussion in CBER. And options related to trade, a change in trade
name, surveillance, considerations impact the type of application that would be
required.
Lastly, we would require revision of
the labeling.
I will conclude, and this is just to
mention a few of the advantages and disadvantages. Dr. Couch went through it in detail, but
generally, these options would represent an improved coverage against
circulating influenza strains. They
would also contribute toward preparedness of possible introduction of
previously circulating strains, such as H2N2.
And the important disadvantage is,
as you've heard from this morning, formulations that contain four influenza
strains may cause manufacturing constraints that may affect the timing
availability of vaccines.
So with this, the topics for
discussion will come after the next topic.
DR. KARRON: Thank you.
I think we'll move on now to comments from manufacturers.
Dr. Colgate.
DR. COLGATE: Good afternoon. My name is Tony Colgate. I'm from Novartis Vaccines based in
Liverpool. And I was nominated by the
former working group to give this presentation on behalf of the industry. And although you see the Novartis logo on the
slides, it's not totally a Novartis presentation. There was input from all of the U.S.
manufacturers, and indeed you'll see that the presentation is actually based on
the presentation that was given by Al Thomas from Sanofi this morning. So basically I'm building on his
presentation.
I really just want to set the scene
initially. I personally find the
influenza vaccine the most stimulating vaccine to manufacture. The main reason for that is it's a seasonal
product. It's invariably a new product
every year and, therefore, a new challenge.
We have a liberty production period, so you get your product to market
on time or you don't sell it. And it's
changed by the next year, so it's lost.
And at present, all the influenza
vaccines are derived from virus inflated in eggs. So basically that's all I'm going to talk
about today. And the majority of FDA
approved influenza vaccines are inactivated.
And that's for all except for the MedImmune cold adapted live virus
vaccine.
And many of the issues that I'm
going to talk about here actually don't apply to that vaccine, but I'm not
going to address those, but I think Kathy is here if you want to talk about
them.
You saw this this morning. Basically, I put it up and you're going to
see it twice more later on to emphasize that we have this fixed period really
from somewhere at the beginning of the year, manufacturers start manufacturing
at-risk, to the strain decision time, to August, in which we have to produce an
antigen. And this again is assuming that
in fact we have two, two seeds, or two strains that are known and only one
working seed was to be produced.
A number of things are outside our
control. One is the virus reference
strain, which we have to, we have to get from WHO-approved laboratories,
reassortant production, and also reagents.
So basically it's not totally under our control. And really getting the vaccine out is a
collaborative effort between industry, and WHO, and the WHO-labs. And in general, it works very well.
So we have to produce our three lots
of antigen in this period, produce reagents, and then we have to fill, and
formulate, and distribute.
Now, I put on the top here just to
kind of remind you it's a seasonal product, new product every year, and limited
production. So there's pressure on all
the time.
Now, the growth potential of the
seed virus, as Al said this morning, the quantity of monovalent influenza
vaccine that can be produced is limited by the least product of the monovalent
strains selected. So basically if you
put an extra strain in there, we've got another constraint.
And each working see requires at
least four weeks from receipt of the seed to develop prior to using in large
scale manufacturing. Now, every
monovalent that we produce has a minimum quality assurance requirement. We have to do virus inactivation validation
qualification on each strain, process validation qualification, assay
validation qualification, and we also, one of the manufacturers has to produce
a purified antigen for the single radial immunodiffusion reagent.
Now, the potency test reagents are
most important to us, as you've heard before.
We can't formulate trivalent vaccine until we have some way of
standardizing the vaccine. So they're
required to determine the potency of the monovalent.
And, again, as I've said before,
this is not under our control entirely.
We are relying upon control agencies, CBER, in this case, to produce,
standardize and supply reagents for all new strains. So basically not only will there be more
pressure on industry, there will also be more pressure on CBER.
And as we've said before, production
begins at-risk prior to the mid-February decision. If we don't do this, we are endanger of not
producing sufficient doses. And as we
already know, one strain is usually produced at-risk. I don't think I need to dwell on that. We covered that well this morning.
So I've got a look at a couple of
scenarios and I don't think I've covered all the scenarios that Bob Couch
suggested, but I think I've got some of them.
Basically, the brief I had was to look at a vaccine containing 45
micrograms, which is basically what the trivalent vaccine contains now, and the
vaccine containing 60 micrograms.
Now, for 45 micrograms, there are
two options. One is 15 micrograms of the
A-strain and seven and a half of each of the B-strains. I've heard that discussed many times in the past,
but I was interested to see actual clinical results. I didn't know there was any clinical data on
that.
And the other is, could be to put in
approximately 11 micrograms of HA of each strain, but between 15 and 20 years
ago the vaccine actually used to contain 10 micrograms of hemagglutinin, but
that was changed in preference for 15 micrograms. And I'm not sure that anybody will want to go
back on that.
And both of these formulations I
thought may have clinical challenges with lower HA content per strain.
The other alternative is a
vaccine containing 60 micrograms in
total, 15 micrograms of each strain.
And another alternative we have is
to reduce a monovalent B-strain in addition to the trivalent vaccine.
If we look at the first scenario,
the good thing is that we could potentially produce the same number of doses as
the trivalent manufacturer. But again,
as I've said before, it's subject to the growth characteristics of the fourth
strain, or the strain which is the lowest yielding. But what we would have to produce is initial
B-strain seed and that would require manufacturing and testing. And as I said before, there would be the
additional testing for the fourth strain regarding virus inactivation, process
validation, assay validation, and production of the purified antigen for the
reagents. And this of course would, as I
said before, give additional work to control agencies.
Possible difficulties that certainly
our policy control people perceived when I was discussing this with them, they
were worried about the accuracy of the assay with two B-strains. They have not looked at that before. They were worried that there might be
symbiosis during the two B-strains and that it would be difficult to accurately
measure them. But this presumably would
be down to specificity of reagents. And
that's something that we would need to consider if we're going ahead with this.
So basically this is the same
picture as before, except we divided the third, or divided the third part into
a three and a four. So basically we're
using the B-slot to produce two halves of the B-strain containing seven and
half micrograms instead of 15.
The second scenario with a
60-microgram HA total vaccine is a different situation. And assuming that there were no changes to
manufacturing capacity and timing of strain notification, we could only produce
75 percent of the doses compared with trivalent vaccines. So this has a significant impact.
And as you'll see when I put the
chart up again for the third time, you'll see it may require productions of two
strains at-risk because of the shorter periods.
We may have finished, run out of steam on the first at-risk production
before the strain decision is made. And
also balancing of the four strains would be more difficult at the end.
There would be the additional work,
as for the first scenario, which is the production of the new strain,
additional testing, validation, qualification, more work for CBER and possible
difficulties for two B-strains to be assay.
And here we are, as you can see,
with a smaller slot here, we may be in a situation where we are looking for the
second strain to manufacturer before the first one. There may be ways around that, but I guess
that would require some pre-notification of A/B strain before the February
decision.
Now, again, assuming no changes to
manufacturing, and capacity, and timing of strain notification, if you try to
produce an independent B-strain, this has even more adverse effect if you're
trying to vaccinate everybody with a trivalent and a monovalent because it
requires two vials of, one of the trivalent vaccine, one of the B- for every
vaccination. And that would reduce
filling capacity by 50 percent if a second strain is not identified very early.
If only subjects were to receive the
monovalent B-vaccine, i.e. children, then the impact on monovalent strain
manufacturing depends on the size of the population selected. You need to identify timing for vaccination
of the selected populations, still a potential impact on filling capacity and
therefore, a potential impact on the number of those who supply.
All I'm considering here are really
basically the mechanics of doing this operation. I haven't considered any clinical
requirements, regulation, or legal pathways, which I think have been covered
previously.
And it may require a timing of
strain recommendations for all the four strains. An earlier recommendation may be required if
we're going to get the required doses and number of doses. But you suggested that maybe we could produce
the fourth B-strain out of season. That
would require some kind of decision in advance of which strain that should be.
In addition, as we heard yesterday,
most manufacturers are now actually producing H5 antigen during the closed
season. And in Europe, vaccine
manufacturers are actually producing for the Southern Hemisphere in the down
season. So that suggestion is a little
bit limited, but it's worth discussing.
Just to mention, we, obviously, cell
culture is the flu product of the future.
And multiple manufacturers are working on cell culture influenza
vaccine, but at the moment none is approved in the U.S. or I don't think
anywhere else either. But it's getting
close, I think, in Europe.
Cell culture has production
attributes that may facilitate manufacturing of a tetravalent vaccine, but that
has not yet been established.
So in summary, all of the scenarios
that I've discussed increase the workload and complexity of a season of
product. That potentially changes other
year and is subject to exactly manufacturing time constrains.
The second scenario, the 15
micrograms of each strain, the 60 micrograms of HA total would reduce existing
production approximately by 25 percent, assuming no changes are made to
manufacturing capacity and the September release, because the release date is
dependent on the date the virus seed is supplied, growth rates, and yields, as
already described. But this could be
overcome with a corresponding increase in production capacity, but that means
planning and time.
Production with addition monovalent
vaccine B-strain is also likely to impact on vaccine supply.
So, in conclusion, influenza vaccine
manufacturers is complex, increased complexity with a four vaccine strain, and
the balance between the supply and timing to deliver with additional strains.
Having said that, if desired by
health authorities on the basis of public health need, the vaccine industry is
prepared to try to resolve the many issues together with health authorities.
Thank you.
DR. KARRON: Thank you, Dr. Colgate.
Next on the agenda is the open
public hearing.
Christine?
MS. WALSH: As part of the FDA Advisory Committee Meeting
procedure, we are required to hold an open public hearing for those members of
the public who are not on the agenda and would like to make a statement
concerning matters pending before the Committee.
I have not received any requests at
this time.
Is there anyone in the room who
would like to address the Committee?
(No response.)
Dr. Karron, would you read the open
public hearing statement please.
DR. KARRON: 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 at the Advisory Committee Meeting, FDA believes
that it is important to understand the context of an individual's presentation.
For this reason, FDA encourages you,
the open public hearing speaker, at the beginning of your written or oral
statement to advise the Committee of any financial relationship that you may
have with any company or any group that is likely to be impacted by the top 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, 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.
DR. CHOELING: My name is Kathleen Choeling and I'm an
employee of MedImmune. What I wanted to
do is just follow-up on, to provide a little bit of additional information on
the immune response, the cross-lineage reactivity following vaccination of
children with FluMist because there have been a lot of questions, I know,
following some of our findings that show we have broad cross-reactivity against
drift strains within a lineage.
There were some question whether
that would extend across the lineage. So
what we did is look at a few different pieces of pertinent information. And to summarize it before I tell you, it
basically agrees with everything that Dr. Couch summarized so nicely
earlier. But I wanted to just reinforce
that.
The first thing we look at was the
response in ferrets. And when you
vaccine ferrets with FluMist containing one Influenza B lineage, there is no
immune response developed in the ferrets to the opposite lineage that's not in
the vaccine. If those ferrets are then
challenged with either lineage of B-virus, there's complete protection against
the lineage that's contained in FluMIst, but not any protection against challenge
with a strain that's in the opposite Influenza B lineage. So that's what you would expect.
Then we also looked at the immune
response in young children, 6 to 36 months of age, who are vaccinated either
with FluMist or with an activated vaccine.
And they got two doses of vaccine.
And we looked at their serum antibody responses following vaccination,
after their one dose or two doses, and if you look at the HAI response in these
children, you can see a very nice vigorous antibody response, as measured by
HAI to the B-lineage contained in the vaccine.
And also if you look at drift
strains within that lineage, you see a good antibody response that is highly
actually than what you see with an activated vaccine in that age group.
If you then test those same sera
using a microneutralization assay, you can then see a vigorous immune response
to the B-lineage contained in the vaccine, a good response to the drift
strains, but absolutely no microneutralizing antibody detectable to the
vaccine, to the non-vaccine lineage.
So I think those data all would
agree with what Dr. Couch told us earlier.
And then finally we, Dr. Couch
presented the head-to-head study that we just completed, the Belshe
publication, and showed that you couldn't draw any conclusions based on the
wide confidence intervals between the two vaccine strains. And as Dr. Couch mentioned, the way that
study was analyzed was that the not well mapped strains consisted of a bucket
of strains containing Yamagata, drift strains, and also the non-vaccine lineage
of the Victoria strains.
So there is no way you can sort that
out looking at those data, the immune response to the vaccine lineage or the
non-vaccine lineage.
I looked also back at some previous
years in which vaccine efficacy studies had been done with FluMist, when
fortuitously the circulating strain was of the opposite lineage as contained in
the vaccine. And again, all those
studies were analyzed in the same way where the non-matched strains consisted
not only of the opposite lineage, but also of drift strains within the vaccine
lineage. So, it was very difficult to
make any conclusion based on these data that we have any reason to think that
you would achieve cross-lineage protection from FluMist anymore than you would
from an inactivated vaccine in this age group.
Thank you.
DR. KARRON: Thank you.
At this point if there are no other people who would like to make a
comment during the open public hearing, we'll move to Committee discussion. And what I'd like to do is put up the slides
that Dr. Weir had up at the beginning with some of the discussion points.
Okay. While he's actually putting those slides up,
I have a question of my own. I think
maybe they're for Dr. Cox or Dr. Couch, just something of interest to me, which
is this has to do with drift among Influenza B strains. And I was wondering within the B/Victoria
lineage or within the B/Yamagata lineage, how much drift do we see over the
years as compared with A-strains?
DR. COX: Oh, okay.
Antigenic drift is slower just like the genetic changes are slower in B
than in A. And we don't really know the
reasons why, but it's, I would say roughly half to a third of the rate,
genetically, and antigenically, probably about the same.
DR. KARRON: So just I guess to sort of understand, when
we have switched back and forth over the years between Yamagata lineage and
Victoria lineage, with each switch are the viruses very different? You know, a Victoria that we chose lineage
virus that say we chose this year as opposed to two, or three, or four years
ago? I'm just trying to get a sense of
that.
DR. COX: It probably, you know, I would have to go
back and really look at it analytically, but if there's a significant time
interval then there would be a difference.
If not, then you know, if it's only, for example, we've seen in the
Yamagata lineage we've seen B/Florida, which was one of our reference
strains-like viruses for a number of years.
And we don't see a change really from those B/Florida-like strains in
the Yamagata lineage.
And like -- right, but when we
hadn't had circulation of the B/Victoria strains for a period of time, then we
had a big change between the previous B/Victoria strain that had been in the
vaccine prior to that, resurgence of the Victoria.
DR. KARRON: Thank you.
Dr. Farley?
DR. FARLEY: Well, I had a follow-up to that and a couple
of other questions. But in looking at
the, it was slide number 3 on our handout from Dr. Gagneten. It almost looked like, which was kind of
showing the percentage of Yamagata versus Victoria in one year, and what the
vaccine was, and then what happened the next year. We, for the last four or five years, we've
been in the pattern of going two years with one and it's almost, if you looked
at that, if you had just alternated years rather than done two years in a row
for each one of them, it seems like we would've been closer to the mark. And I wondered, I mean if we went back and
kind of re-analyzed it, would there have been something near the end of the
previous season, the season that was a good match, the last things that were
isolated, would that predict the reversal that you'd see the following
year.
And I just wondered if one of the
other options to discuss was just that automatically we assumed we were going
to alternate years and can we come up with a system where it would give us an
early option, in terms of the strain, so that could be the first thing they work on the next year,
whether the off season or at the very beginning of the following season.
So that's one of my questions. And I guess the other is much more
hypothetical. But it seems like with
this kind of stable 2 lineages that it's a perfect candidate for molecularly
constructed antigen, where you would put the key parts of both of those
together. And it seems to me that,
again, the idea of trying to modernize the process that this, the Bs, would be
the first good candidates for trying to work on that option, that approach, and
get it incorporated into our thought process.
I mean I know that will take years to go through the regulatory issues,
but it seems like this one would be a good one to put in the two stable
antigens.
DR. EICKHOFF: Well, actually my comment sort of takes off
from what Monica just said because of the several options that Bob Couch
spelled out. The one that I found most
intriguing was simply to alternate between the two lineages year-to-year,
pretty much irregardless of what one expected to be predominant that year. And that was the one option that Mr. Colgate
had no comment on, did not consider it, and so I wonder if Mr. Colgate might
comment about that option in particular.
DR. COLGATE: That would cause us absolutely no problems at
all.
DR. KARRON: Actually as a follow-up question to that,
would there be a potential advantage in terms of, an actual advantage in terms
of vaccine production? That is to say if
you could make the Influenza B strain every year at risk because you would know
it's either going to be Yamagata --
DR. COUCH: Every year you would know one strain you
could start with in B-strains.
DR. COLGATE: If you could tell us that, we'd be very, very
happy, yes.
DR. KARRON: But just because then you would never be in a
situation of potentially not having, you know, if there were going to be say,
as we talked about this morning, the H3N2 change --
DR. WEIR: I was going to say --
DR. KARRON: Anyway, yes?
DR. WEIR: -- and I think Nancy is too, you still have
to pick the right strain.
DR. KARRON: Right.
DR. WEIR: Okay.
DR. KARRON: Right.
And Nancy, yes?
DR. COX: I think that it's also important when you're
thinking about, when you're thinking about the big picture you have to know not
only what proportion of Yamagata and Victoria lineage strains are circulating
in the U.S., but what proportion they made up of the entire influenza activity
that was ongoing. And that's, you know,
in some years it can be a big problem if you have a mismatch. In another year, if you have relatively
little B-activity and very few outbreaks, if you have a mismatch, it really
doesn't have the clinical impact.
And so I think that looking at it
simply, you know, in this dichotomous way over-emphasizes the problem that we
sometimes face when we have a mismatch.
Sometimes it really isn't that important clinically because we have very
little B-activity.
The other thing is that if the U.S.
decides to do this, would decide to alternate, I just want to emphasize we
would have to choose the right strain.
There wouldn't be an automatic okay, go ahead with the old, whatever it
was before, Victoria lineage or Yamagata strain. But also, the U.S. could be out of sync with
the WHO recommendations very easily. So
that would be a potential disadvantage for the manufacturers that Tony didn't
bring up.
So, and what sometimes happens is
that globally you'll see one picture where a certain lineage will predominate,
whereas, in a particular country or particular region of the world you'll see
another picture. And that was very true
because Victoria viruses, I'm sure you covered this while I was out of the
room, but Victoria viruses continued to circulate in China, specifically in
Southern China, co-circulate with the Yamagata lineage viruses. Well, they caused very little activity, if
any, elsewhere, anywhere else in the world.
DR. KARRON: Right.
And I assume that it was issue like that that led to the recommendations
that Bob talked about, which is use whatever is appropriate in your region.
DR. COX: Exactly.
DR. KARRON: So in those sort of years you would not be
out of sync because I assume that everyone was manufacturing differently and
according to the needs of the region.
I wonder actually if this kind of
issue has every been discussed at WHO or ever come there as an issue, this
issue of a problem with B.
DR. COX: It has not been presented in this formal way,
where pros and cons of the different alternatives were really spelled out and
discussed. So this is a really good way
to look at the problem.
I had one question for FDA. If a tetravalent vaccine, including two
B-strains and two A-strains were to be licensed, would you have to go through
the same regulatory process if you were to have three A-strains, that is two
H3s and 1 H1, and a B-strain. Or would
the fact that you have 60 micrograms or whatever number of micrograms would be
decided be, and you looked at that quantity of antigen and found it to be safe,
and effective, and not to be interference.
Would that be sufficient data for you to be able to generalize and say
you could have two H3s, instead of two Bs if, for example, the B/Victoria
lineage did circulate only in China, as it did in the past for a period of
time?
DR. WEIR: Okay, I think I got it. So you're saying if we license the
quadravalent with, in this case, two As and two Bs, then could we switch and As
and Bs in any sort of combination in the future without --
DR. COX: Yes, yes.
So that say we were facing a year like this year where the As --
DR. WEIR: So, in other words, two H3s the next year if
that became?
DR. FARLEY: And just to add a little complexity, more
complexity, could H5 be one of the antigens?
DR. WEIR: Okay.
So we haven't thought about this that much. I think that, I'll just speak off the cuff
and then let Norman correct me. I think
that the simple example, if you really had four and you licensed it and it was
safe and effective, probably strain changes would probably be pretty easy to
manage. Now, I haven't thought about the
H5 possibility.
DR. BAYLOR: And I think that adds to the complexity
because an H, unless you take it even further, an H5 we're gaining experience
on H5. So in the near future, H5 may not
cause as many problems, but you could take it out to an H7, an H9, and there
where we may not have had a lot of experience, I think it would be much more
complicated.
DR. WEIR: Yes, I guess the other scenario is a little
simpler because we would at least be assuming the 15 micrograms is effective as
well, whereas if we don't know that with the H5. But as Sara pointed out, I mean we are
talking about clinical data to support the, you know, not only the safety but
the efficacy, you know, to make sure no interference from one strain to
another, the addition.
DR. KARRON: Dr. Self and then we'll take a comment from
the audience.
DR. SELF: I'd like to go back to this point about the
antigenic variability within and between lineages. I mean my read of this data and some of the
comments was that most of that variability is between lineages. And the slow rate of evolution would sort of
support that idea. If that's true and
variation within lineage is fairly slow over time, then the selection earlier
of a strain within a lineage would be much easier. And that would have some important
implications about manufacturing.
However, Nancy, you indicated and I
was getting, you know, vigorous head bobbing across the way that selection of
strain within lineage would still be a very important. Where, which is it? Would selection of strain within lineage be
able to be done reliably sooner if lineage was set?
DR. COX: That's a very, very difficult question to
answer. If we were looking at switching
to the Yamagata lineage, we have strains that we've had basically, one strain
we've had in our back pocket for a number of years. So given the fact that we are very actively
pursuing egg isolates and characterizing them more vigorously than we have in
the past, I would say that on balance, because the B-viruses do tend to evolve
more slowly, it would be easier but it wouldn't be guaranteed that we could
come up with that earlier selection. But
it would certainly be a lot easier than trying to do that for the H3s.
DR. SELF: So then the strategy of alternating years,
which I find sort of theoretically fascinating, but I'm not sure is the best
solution, or maybe a quadravalent but would split those. I was impressed at how similar the data
looked for the seven and a half would make that total B-component able to,
manufacturers to start that process at considerably less risk earlier. Is that fair?
DR. COX: I do, I think that's fair with the caveat
that those data were derived from immunization of young, healthy adults.
DR. SELF: So one of the down sides, one of the cons
listed by Dr. Couch in the option with the quadravalent half dose was the lack
of data --
DR. COUCH: The half dose data was healthy adults. And I'm told, this is hearsay, but there is a
large study done by the military of basically the same thing, but it was all
much larger numbers, all healthy adults and found the same thing.
And the data we want are the two on
each end, preferably the children. But
we don't have that data.
DR. SELF: But lack of data in the cons distinguishes
from all the other cons in that you can remedy that. Most of the other cons you can't do
that. You just have to live with that.
DR. COUCH: I want to ask just for my information and
maybe help a couple of questions of Tony.
If you took the scenario of I don't care seven and a half or fifteen,
you can comment on the two, but two of them, see, and let's take the seven and
a half I like best, you only have to make half as much but you have to make two
of them, what does that do to the time frame?
You know, do you have to close down and a long time to start up again
and use the rest of your eggs and so forth?
DR. COLGATE: Not really because we're changing between the
H1, the H3, and the B anyway, especially at the end when we're trying to
balance the strains. So it's really a
matter of having a reference strain early and being able to get the reagents so
that we can formulate. So it is really,
again, things which are, to some extent, out of our hands. As I was trying to explain before, we have to
work in cooperation with everyone else.
So if we have the strains early enough and the reagents are there, then
it's just more hassle basically is putting four strains together in a season.
DR. COUCH: And then if you went for a full 15, could you
then slide that back instead of starting in December, why, we give you one of
the, I mean in January we give you one of the antigens and you start in
December?
DR. COLGATE: That's a possibility. But as I said before, some, the problem is
that some manufacturers in Europe are producing for the Southern Hemisphere as
well. So their production, and also H5
production goes in that time. I guess
the only answer really to 15 micrograms of each is to increase capacity. And I mean that can be done with sufficient
notice, basically, and investment. I
mean all these things can be done if it's done in a controlled, planned way.
DR. COUCH: No question about hassle, but some of them
are a little easier and doable than some of the other options that we talked
about.
And my last question, I'm not sure
whether it's for you or for FDA is I don't know, and maybe somebody else does,
where do we stand with regard to development of cell culture vaccines in the
pipeline and that sort of thing? Can
comments be made on that because everybody is waiting for that other option to
come into the considerations for flu vaccines.
DR. COLGATE: I don't know.
MR. TSAI: I'm Ted Tsai.
I'm an employee of Novartis Vaccines.
Novartis has an MBCK cell culture vaccine that for which an application
has been submitted to the EU and for which we have some plans for the U.S.,
including a manufacturing plant that's been, for which construction is already
underway in Holly Springs, North Carolina.
So there is a cell culture vaccine based upon MBCK cell production that
is emerging very soon.
DR. COUCH: You may not be able to say it, but you've got
to have some sort of time line. Is that
three years from now, five years from now, or can't you say?
MR. TSAI: We can't predict what the EU regulatory
authority will say.
DR. COUCH: Well, assuming they're cooperative.
MR. TSAI: Well, they have the application. And as I said, we have plans to submit an
application to the U.S. And there are
other manufacturers with cell culture vaccines in the work as well for the U.S.
DR. KARRON: There is someone who has been waiting very
patiently in the audience.
MS. CAVANAUGH: Nancy Cavanaugh, MedImmune. I just had a clarifying comment, I guess,
about the quadravalent vaccine, and in particular the regulatory and clinical
pathways that were described by Dr. Gagneten, and whether those would be
similar for the live attenuated vaccines.
Those were specifically described for the inactivated vaccines.
DR. GAGNETEN: Those, I'm sorry. Those ones would hold for licensed
products. So it would hold for MedImmune
also.
MS. CAVANAUGH: Thank you.
And actually before you sit down, could I just ask in terms of as we're
talking about this half dose, seven and a half microgram, obviously you don't
measure your doses in micrograms, but does that have relevance when you're
considering FluMist or is that then just a quadravalent vaccine and it almost
doesn't matter whether it's ten, 7.5, or it's half that, which is not
much. I mean how would you interpret
that?
DR. KARRON: Right now we're considering both
options. You know, the same dose for
four vaccine strains or yes, half of each.
MS. CAVANAUGH: Okay.
Thank you.
DR. KARRON: Dr. McInnes?
DR. MCINNES: I'd like to push the envelope on the amount
of antigen that can be manufactured as opposed to reducing the dose that we're
delivering. And I say that because I
don't think we have ever optimized the amount of antigen we've delivered, to
optimize for immunogenicity and deficacy.
And even though we did see very similar responses in the study that was
for healthy young adults. So I'm a
little reluctant to just assume that, you know, moving towards a half dose,
half strength concentration on each of the Bs is the solution.
So in trying to push again about the
amount of antigen that could be manufactured to produce, at a minimum of 60
microgram per unit delivery, however that be divided up, I'd like to ask about
the life of the manufacturing facility.
I've only ever visited during the day.
Does it work round the clock? Is
it possible to push the amount of time that can be in a 24-hour period? I mean do you work all night?
DR. COLGATE: Basically, it really depends on your
manufacturing. But the limiting factor
is the number of eggs that you can incubate basically. So it's the number of eggs that you can
handle in a working day. And that
working day, I guess, could be 24-hours.
But really, the simplest way would
be just to increase the size of your facility to buy 25 percent, I guess, and
operate that way, rather than try to hot-bed everything. I mean if you try, if you stress the facility
too much by running it 24-hours a day, it's going to crash. And there have been examples of that.
DR. MCINNES: Talking about the same period working
24-hours a day. No, I'm serious.
DR. COLGATE: No, the facility as well. I mean you basically, you have to allow time
for cleaning and preparation and make sure everything is done in an orderly
way. If you try to compress too much in,
eventually you fall over. It's really
better to do it in an orderly way and just increase your capacity for
processing eggs to the amount that is needed to go out at the end of the day.
DR. MCINNES: Tony, I'm sorry, so I'm pushing you
here. So I'm hearing that in fact we
work a traditional daylight time. There
may be some cleaning and campaigning going, but you're not loading eggs in, in
what could constitute the other half of the clock, right? There's not a night stock that works the same
kind of work as the day stock?
DR. COLGATE: We have an evening staff who actually do the
cleaning in preparation for the rest of the day.
DR. MCINNES: Okay.
DR. COLGATE: And certainly in the downstream processing,
we are actually working a 24-hour shift.
DR. COUCH: Am I correct that basically what you're
saying, Tony, is we're going to increase dosage, you know, and I'm interested
in antigens besides B, you have to have increased facility capabilities? Is that what you're saying?
DR. COLGATE: That's it basically. Do it properly or you get no vaccine in the
U.S. one year.
DR. KARRON: Dr. Jackson?
DR. JACKSON: Just regarding the half dose. I mean I guess, I think we do know some
things. We know in the elderly the
response to the 15 microgram is diminished and that there is clearly a very
strong dose response, you know, in Dr. Kyle's studies and others. If we give more antigen, we get a better
response. And we think more is better in
that regard. And then when we go down to
the other end of the age spectrum, particularly infants, you know, Dr.
Englund's studies and other work that's been done indicate that the response,
in particular, to B after a single dose of vaccine is very poor. And even after two doses, in some cases,
doesn't seem to be great.
We also know that in a good year
only about half of children who are supposed to get two doses actually get two
doses. So I'd be very concerned about
cutting the amount of antigen in half in those two groups for fear of what
might happen assuming of what we know what a correlation there might be between
antigen, antibody level and true protection.
DR.
KARRON: Dr. Farley?
DR. FARLEY: This is a question for the
manufacturers. I'm wondering, from a
practical standpoint, given this discussion, and if we were to choose to go
down the route of quadravalent vaccine with say this 60 microgram total, so not
making the compromise on the antigen
content, what would be the time table of when this could even possibly
happen? I mean are we talking about two
years down the road, or more, or less?
DR. COLGATE: That's a difficult one really. I mean it normally takes two to three years
to get a new plant up and running.
Increasing capacity by 25 percent would really depend on the individual
circumstances of the company. If they have
space just to increase the size of the facility, then I guess it could, may be
done earlier.
But I think also the regulatory
hurdles are probably going to be the constraining issues basically. And I think we, I think we need some kind of
clear directive about that. That is, is
it required and there is a regulatory pathway and what kind of clinical
requirements are also there. I think it
would need to be spelled out to us very clearly exactly what is required and
the mechanism for doing it. And if
that's done, I'm sure, as we have done in the past, we would respond.
DR. KARRON: Dr. Wharton?
MS. BAXTER: Marguerite Baxter with Novartis
Vaccines. I just wanted to add to Tony's
comment to sensitize the Committee. The
other factor that would have to be considered is it would actually be necessary
to enact tax legislation to include a quadravalent vaccine in the vaccine
injury compensation program. Because the
way the law is written now, it only covers trivalent influenza vaccine. So that would also need to be a step in the
process that would need to be factored in.
DR. WHARTON: Yes, it seems like given that this is likely
to be a somewhat long range process that is being really the follow-up from the
last couple of annual VRBPAC meetings on influenza strain selection with some in-depth
discussion this afternoon would be for FDA to, you know, to be able to define
for us, or to be able to define what the regulatory pathway is that such
products would have to go through. And
I'm sure there are some clinical studies that would need to be done so that we
all would be sure we understood what a quadravalent vaccine would mean.
And so given that we are on a
journey here, I think. I think we're not
planning on getting there this afternoon that those are some steps forward that
would move this process forward, just as this discussion has as well.
DR. STAPLETON: Yes, I think just as several people have
eluded to, it would be interesting and should be feasible to retrospectively
look at drift within different B-lineages and come up with some confidence
intervals with how likely you are to have a major mismatch, based on previous
years, which might actually improve the at-risk manufacturing process.
DR. COUCH: I just wanted to add that I tried
dose-response data to Influenza B in infants and very young children. I couldn't find anything. None.
DR. KARRON: One other question I have and I don't know if
this would be useful or not, but we're also, we're in a changing era with
regard to influenza vaccination. We're
vaccinating more children than we ever did before and we're increasing the age
range in which we vaccinate children.
And I guess I was also wondering as part of this journey, if you will,
whether it's useful to do any kind of modeling to look at the various options,
taking into account the B-lineage strains that have circulated, the rates of
vaccination, if you alternated strains in a vaccine what would it do? If you had a quadravalent vaccine, let's say
of 60 micrograms, what would it do? We
may not know enough about half doses to
really be able to model that, but whether it would be useful to do some of that
as part of the thinking process.
Are there other comments, thoughts
form members of the Committee, or FDA, or from the audience?
Yes, Dr. Eickhoff?
DR. EICKHOFF: As part of this process, could we formally
ask CBER and/or CDC representatives to take the issue of alternating strains
year-to-year to WHO for their consideration next year?
DR. KARRON: I don't know --
DR. COUCH: Well, since you're at the hand, this is
almost to the side, sorry. But I almost
did it up there but I forgot. I wanted
to, I think we've done it before, let's thank CDC, and Nancy, and Dr. Klimov,
and Dr. Ye for that presentation this morning because that's a huge amount of
work that they bring to these decisions for us.
And one of my reactions was that if they'd just give us less data,
they'd probably have much less discussion, and the decisions we'd make would be
much simpler, but we wouldn't encourage that.
DR. KARRON: Absolutely.
Of course, I think we should thank all of the people who've worked very
hard on our behalf.
I do though want to follow-up on Dr.
Eickhoff's question and ask whether these deliberations could be brought back
to the WHO?
DR. COX: Yes, I think it would be very important to
bring these deliberations back to WHO.
We do often spend extra time; we even started our meeting on Sunday
afternoon this past year so we could spend half a day deliberating about H5
vaccines and going over that data. So we
do find time for special topics and I think it would be very useful to invite,
and we can invite outside experts. And
it would be very useful to have the same kind of deliberations and really get
feedback, because on that one occasion or two occasions, as Dr. Couch pointed
out, we did have to say within the WHO recommendations, either B/Vic or
B/Yamagata lineage virus, whichever is most appropriate, because the
distributions were very different.
I think that it would be extremely
useful to begin thinking about clinical trials.
And exactly what it would take to put together a clinical trial that
involved 15 micrograms of each B, and seven and a half of each B, that would
really help answer some of the questions that have come up today and give us a
lot more substance to deal with as we move forward with some of the difficult
decisions.
DR. KARRON: Norman?
DR. BAYLOR: I just wanted to say, I mean, what we'll do
as far as the FDA, I mean we look forward to working with the manufacturers and
probably pursuing this discussion a little further. We have meetings with the Influenza
Manufacturing Group Pharma, and this is something I think we can bring up as an
agenda item and discuss the feasibility of this. And what we can do internally is we can do
some, create some scenarios on what kind of clinical trials we would need or
develop to answer some of these questions, you know, using, you know, with all
the options, looking of the options of alternating, or a quadravalent, what
would it take. We can actually outline
what we think would be a likely clinical trial to design.
I think also, Ruth, your comment
about the modeling I think would be important because I really, I think we need
to know among the options what do we really gain. I mean it would really be helpful to say if
we go this route we gain this much. And
that way we'll have a better idea of which one of the options to pick, or do we
pick any of them. I mean, as Bob had
indicated in his first option, do you stay the course. And I think it's important to evaluate all of
those.
DR. COUCH: My last slide which I didn't use said data is
needed.
DR. KARRON: Any other comments?
In that case, I'd like to thank
everybody for attending this VRBPAC meeting and we're adjourned.
(Whereupon, the above-entitled
matter went off the record at 3:30 p.m.)