UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
98th MEETING
(BY TELECONFERENCE)
WEDNESDAY,
MARCH 17, 2004
The
Advisory Committee met at 1:00 p.m. via a teleconference organized in
Conference Room C of the Center for Biologics Evaluation and Research, Building
29B, 8800 Rockville Pike, Rockville, Maryland, Dr. Walter Royal III, Acting
Chairman, presiding.
PRESENT: 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.
WALTER ROYAL III, M.D. Acting Chairman
NANCY J. COX, Ph.D. Consultant
MICHAEL D. DECKER, M.D. Industry Representative
WALTER DOWDLE, Ph.D. Consultant
THEODORE EICKHOFF, M.D. Consultant
MONICA M. FARLEY, M.D. Member
JUDY D. GOLDBERG, Sc.D. Consultant
RUTH A. KARRON, M.D. Member
PHILIP S. LaRUSSA, Ph.D. Member
PAMELA McINNES, D.D.S. Consultant
ARNOLD S. MONTO, M.D. Consultant
MARTIN MYERS, M.D. Consultant
PETER PALESE, Ph.D. Member
STEPHEN C. PHILLIPS, D.O., Consultant
M.P.H., LTC(P)
BONNIE M. WORD, M.D. Member
CHRISTINE WALSH, R.N. Executive Secretary
FDA REPRESENTATIVES:
WILLIAM EGAN, M.D.
ROLAND A. LEVANDOWSKI, M.D.
KAREN MIDTHUN, M.D.
DENISE ROYSTER
I-N-D-E-X
Agenda Page
Welcome - Chairman Royal 3
Introductions - Christine Walsh 3
Presentations
Roland Levandowski 11
Nancy Cox 14
Committee Discussion on Influenza B 26
Recommendations
P-R-O-C-E-E-D-I-N-G-S
1:03
p.m.
CHAIRMAN
ROYAL: Good afternoon. I guess it's good afternoon to most of
you. My name is Walter Royal. I am the Acting Chair for this
teleconference, sitting in for Dr. Gary Overturf. I would like to call this meeting to order. Today's agenda will deal with recommendations
pertaining to vaccines and related biological products.
We
will begin today's teleconference with announcements by Ms. Walsh from the FDA.
MS.
WALSH: Thank you, Dr. Royal. Good afternoon. I am Christine Walsh, the executive secretary for today's meeting
of Vaccines and Related Biological Products Advisory Committee. I would like to welcome all of you to the
98th meeting of this Advisory Committee.
There's a speakerphone for public participation located here in
Conference C of Building 29B on the NIH campus. This afternoon's session will consist of presentations and
Committee discussions that are open to the public, as described in the Federal
Register notice of February 19, 2004.
At
this time, I would like to introduce the Committee members and ask if they
acknowledge by saying, "Present," if they can hear me. The Committee Acting Chair, Dr. Walter
Royal, III, Associate Professor of Medicine Morehouse School of Medicine?
MS.
WALSH: Present.
MS.
WALSH: Our consumer representative,
Cindy Lyn Province, R.N., M.S.N., Associate Director, Bioethics Center of St.
Louis.
Our
non-voting industry representative, Dr. Michael D. Decker, Vice President,
Scientific and Medical Affairs, Aventis Pasteur.
DR.
DECKER: Present.
MS.
WALSH: Dr. Monica M. Farley, Professor
of Medicine, Department of Medicine, Emory University of School of Medicine.
DR.
FARLEY: Present.
MS.
WALSH: Dr. Ruth A. Karron, Associate
Professor, Division of International Health, Johns Hopkins School of Hygiene
and Public Health.
DR.
KARRON: Present.
MS.
WALSH: Dr. Philip S. LaRussa, Professor
of Clinical Pediatrics, Columbia University.
DR.
LaRUSSA: Present.
MS.
WALSH: Dr. Peter Palese, Chairman and
Professor, Department of Microbiology, Mt. Sinai School of Medicine. Dr. Palese?
Dr.
Bonnie M. Word, Assistant Professor of Pediatrics, Baylor College of Medicine,
Texas Children's Hospital Clinical Care Center.
DR.
WORD: Present.
MS.
WALSH: Now I would like to introduce
our consultants for today's meeting.
Dr. Nancy Cox, Chief Influenza Branch, Center for Disease Control and
Prevention.
DR.
COX: I'm present.
DR.
PALESE: Peter Palese joining. I'm sorry I'm late.
MS.
WALSH: Thank you, Dr. Palese. We just called your name. Dr. Walter Dowdle, Senior Public Consultant,
The Task Force for Child Survival and Development.
DR.
DOWDLE: Present.
MS.
WALSH: Dr. Theodore Eickhoff, Professor
of Medicine, Division of Infectious Diseases, University of Colorado Health
Science Center.
DR.
EICKHOFF: Present.
MS.
WALSH: Dr. Bruce Gellin, Director,
National Vaccine Program.
Dr.
Judith Goldberg, Director, Division of Biostatistics, New York University
School of Medicine.
DR.
GOLDBERG: Present.
MS.
WALSH: Dr. Martin Myers, Co-Director, Public
Health Policy and Education, Sealy Center for Vaccine Development, University
of Texas Medical Branch. Dr. Myers?
Dr.
Arnold Monto, Professor of Epidemiology, University of Michigan, School of
Public Health. Dr. Monto?
Dr.
Stephen Phillips, Director, Deployment Medicine and Surveillance Force, Health
Protection and Readiness, Office of Assistant Secretary of Defense.
DR.
PHILLIPS: Present.
MS.
WALSH: Dr. Pamela McInnes, National
Institute of Allergy and Infectious Diseases, Deputy Director, Division of
Microbiology and Infectious Diseases, NIH.
DR.
McINNES: Present.
MS.
WALSH: Now I would like to introduce
the influenza vaccine manufacturers that will be participating in this
teleconference to answer any manufacturing questions. Ken Guito, Aventis Pasteur, Incorporated.
MR.
LI: Yes. Sam Li from Aventis Pasteur.
MS.
WALSH: Thank you very much. Peter McBride, Chiron Corporation.
MR.
McBRIDE: Present.
MS.
WALSH: Bill Turner and Kathy Coelingh,
MedImmune Vaccines, Incorporated.
MS.
COELINGH: Present.
MR.
TURNER: Present.
MS.
WALSH: Thank you. I would like to thank all Committee members,
consultants and manufacturers for taking the time to join us today. I also wish to thank Dr. Royal for agreeing
to step into the Acting Chair role for today's meeting.
I
just want to go back, if I may. Did Dr.
Bruce Gellin join us? Dr. Martin
Myers? Dr. Arnold Monto? Cindy Lyn Province?
(No
response.)
MS.
WALSH: Okay. There are also two other members that could not participate with
us today, and they are Dr. Gary Overturf, our Committee Chair, from University
of New Mexico Medical Center, and Dr. David Markovitz, University of Michigan
Medical Center.
Now
I would like to introduce some FDA Sieber staff members that will be
participating in today's meeting and are currently seated in the room. Dr. Karen Midthun, Acting Deputy Director
for Medicine; Dr. William Egan, Acting Director, Office of Vaccines, Research
and Review; Dr. Norman Baylor ‑‑
PARTICIPANT: No, he's not ‑‑
MS.
WALSH: Okay. Dr. Weir.
PARTICIPANT: No.
MS.
WALSH: Okay. Dr. Roland A. Levandowski, Supervisory Medical Officer,
Laboratory of Pediatric and Respiratory Viral Diseases, Division of Viral
Products, OVRR; and Denise Royster, Committee Management Specialist, VRBPAC
Advisory Committee, who actually helped pull this whole meeting together, and I
thank her for her hard work.
I
ask that all Committee members identify themselves each and every time they
speak. We do have a transcriber present
who will need your assistance in order to accurately transcribe all comments to
the appropriate Committee member. I
also ask that our Committee members not use cellular phones if possible since
that does add extra unnecessary background noise to the line. Should during the teleconference a noise
occur in your office, we would appreciate it if you would use the mute button
on your phone if you have that option.
We ask that you do not place us on hold, because many clinical centers
do have background music that can be very distracting.
I
would now like to read into the public record the conflict of interest
statement for this meeting. The
following announcement addresses conflict of interest issues associated with
the Vaccine and Related Biological Products Advisory Committee meeting on March
17, 2004. The Director for Biologics
Evaluation and Research has appointed Drs. Walter Dowdle, Theodore Eickhoff,
Bruce Gellin, Judith Goldberg, Pamela McInnes, Arnold Monto, Martin Myers and
Stephen Phillips as temporary voting members for this meeting. The Director of the Center for Biologics
Evaluation and Research also has appointed Dr. Walter Royal as Acting Chair for
this teleconference meeting. Based on
the agenda, it has been determined that there are no specific products being
approved at this meeting.
The
Committee participants have been screened for their financial interests to
determine if any conflicts of interest existed, the Agency reviewed the agenda
and all relevant financial interests reported by the meeting participants. The Food & Drug Administration prepared
general matter waivers for participants who require a waiver under 18 USC
208. Because general topics impact on
many entities, it is not prudent to recite all potential conflicts of interest
as they apply to each member. FDA
acknowledges that there may be potential conflicts of interest, but because of
general nature of the discussions before the Committee, these potential
conflicts are mitigated.
We
would like to note for the record that Dr. Michael Decker is a non-voting
industry representative for this Committee acting on behalf of regulated
industry. Dr. Decker's appointment is
not subject to 18 USC 208. He is
employed by Aventis and thus has a financial interest in his employer. In addition, in the interest of fairness,
FDA is disclosing that his employer, Aventis, is a manufacturer of a product
that could be affected by the Committee discussions.
Members
and consultants are aware of the need to exclude themselves from the discussions
involving specific products or firms for which they have not been screened for
conflict of interest. Their exclusion
will be noted for public record.
With
respect to all other meeting participants, we ask in the interest of fairness
that you address any current or previous financial involvement with any firm
whose products you wish to comment upon.
Waivers are available by written request under the Freedom of
Information Act.
That
ends the reading of the conflict of interest statement. Dr. Royal, I turn the meeting over to you.
CHAIRMAN
ROYAL: This is Dr. Royal. Thank you very much. At this time, we will move into our open
discussions and begin with our first speaker, Dr. Roland Levandowski from the
FDA.
MR.
MYERS: Hello. This is Marty Myers, I've joined you.
MS.
WALSH: Thank you, Dr. Myers.
MR.
LEVANDOWSKI: Okay. Thanks, Dr. Royal. I'll just go ahead and get started with a brief introduction
before we hear some updated information from Nancy Cox. Just to remind everybody and the Committee
members that we had our first meeting on February 19 to discuss strain
selection, and at that time we presented some fairly extensive information on
surveillance of influenza viruses, circulation of new strains, serologic
responses from people and strain availability for manufacturing.
And
as a result of the information that was presented to the Committee, the
Committee recommended that for the 2004-2005 influenza vaccine that an A/New
Caledonia/20/99 H1N1 strain should be retained as part of the vaccine, that the
H3N2 influenza A component of the vaccine be changed to an
A/Fujian/411/2002-like strain. And the
recommendation for the B strain was made provisionally but with the ‑‑
the provision was that we would come back to the Committee with additional
information in the time between February 19 and the present to indicate whether
there would be a need for a change in the recommendation.
The
recommendation that was made based on the information that was available to the
Committee on February 19 was that the influenza B component of the vaccine
should be changed to be a B/Shanghai/361/2002-like strain.
In
the interim, other things that have been happening, manufacturing has been
continuing. The Committee heard in
February that manufacturers had already been manufacturing the A/New Caledonia
strain, and,subsequently, based on the recommendation, the manufacturers have
started working with an A/Fujian-like strain.
The actual strain that's being used for manufacturing vaccines is one
called A/Wyoming/3/2003. There are
high-growth reassortants of that that had previously been developed and were
available, and that manufacturing is going forward.
Manufacturing
for the B strain has not really begun in earnest yet. There have been several influenza B viruses that have been
distributed to manufacturers that fit the recommendation of
B/Shanghai/361/2002-like. Those are in
evaluation and we have some preliminary information that suggests that the
strains that are available seem to be moderate growth, but we don't have the
full information on that, and it's not clear of the strains that are available
which one might be the best one, but that work is going on too.
The
question that we would like the Committee to address today really focuses on
the B strain and finalizing that. And
the question is does the Committee confirm its recommendation of February 19,
2004 to change to a B/Shanghai/361/2002-like strain of the B/Yamagata
hemagglutinin lineage for vaccines to be used during the 2004-2005 season? I think, Dr. Royal, that's all I really had
to say as introductory remarks, and if you have ‑‑ you or the
others have any questions, I'll try to answer them.
CHAIRMAN
ROYAL: Thank you very much, Dr.
Levandowski. Do we have any questions
before we move on?
At
this time, I'd like to ask Dr. Nancy Cox to come forward.
DR.
COX: Thanks, Dr. Royal. I'm having a little bit of difficulty
hearing on my end. Either there is
quite a bit of wind or someone breathing into their handheld headset, so it's a
little bit distracting, a little bit hard to heard on my end. So if there's anything that can be done out
there, that would be very helpful.
MS.
WALSH: Excuse me, Dr. Cox. This is Christine Walsh. I would just ask that if you are not
speaking, if you do have a mute available option, if you would please use
that. Dr. Cox, go ahead.
DR.
COX: Okay. Before we start going through the package of materials that was
sent out, I'd first like to talk very briefly about surveillance data. And just as we were mentioning about a month
ago when we had our last meeting, activity was then winding down and has
continued winding down even more. So we
are now below baseline for influenza-like illness surveillance for sentinel
providers and for P&I mortality for the 122 U.S. cities.
Very
few influenza viruses have been isolated during the past month, but I'd just
like to remind you that overall the 2003-2004 season over 100,000 respiratory
specimens were tested for influenza.
Over 23,000 of those were positive for influenza, and this is a higher
proportion. This is about 22 percent,
and it's a higher proportion overall than we've seen in some years.
Of
these that were positive for flu, 99.3 percent were influenza A and
seven-tenths of one percent were influenza B.
For the influenza A viruses that were subtyped, 99.9 percent ‑‑
MS.
WALSH: Excuse me, Dr. Cox. I'm sorry, this is Christine Walsh. We're hearing a beeping sound. If somebody could ‑‑ oh,
okay. Are you there?
DR.
COX: Yes.
MS.
WALSH: Okay. The beeping sound stopped, so maybe that ‑‑ that may
help. I'm sorry, Dr. Cox, go ahead.
DR.
COX: Do I need to go back over
anything?
MS.
WALSH: If you please could.
DR.
COX: Okay. So I just mentioned that we had found below the baseline, both
for the influenza-like illness surveillance conducted by the Sentinel providers
and for P&I mortality for the 122 cities.
Very few influenza viruses have been isolated during the past month, but
overall for the season out of over 100,000 respiratory specimens that were
tested for a variety of respiratory pathogens, over 23,000 of those were
positive for influenza. Ninety-nine
point three percent were positive for influenza A, and only 0.7 percent were
positive for influenza B. Of the
influenza As that were identified, and not all of them were subtypes, but of
those that were subtypes 99.9 percent were H3N2 and only two were H1
viruses. So just as we had talked about
a month ago, we had a very heavily predominant H3N2 year.
At
the current time, only local activity is being reported in Mississippi and
Virginia. A number of states are still
reporting sporadic activity, which means they have influenza-like occurring and
an occasion sporadic isolates being reported to them. But activity, as I mentioned in my opening sentence, has really
declined. And, basically, we've been
looking for an upsurge in influenza B isolates or influenza H1 isolates and
absolutely have seen no sign yet that we're going to have a second wave of
infections this year. So in spite of
the fact that the H3N2 activity occurred early and actually declined very
early, we don't expect, based on our current data, to see a second wave.
Okay. If we could now turn to the CDC package of
information that was provided to the Committee members, I'd like to walk you
through this information. I hope you've
all had time to read the summary on Page 2.
I don't think I will need to go through that and read it to you, because
you've probably had an opportunity to do that.
On
the second ‑‑ Page 3 of the handout, you will see an hemagglutinin
inhibition table for influenza B viruses that we tested most recently. And as we discussed in February, we have the
two groups of viruses. The Victoria
lineage viruses are represented on the right hand side with blocks of yellow
color, and the Yamagata lineage viruses are represented on the left hand side
of the table, represented in green. We
have here a number of viruses from North America, including viruses from
Canada. The most recent virus I think
that we have is one from Alaska that was isolated in mid-February. Then we have a number of viruses from ‑‑
one from South America and then some from Asia. Those are all Yamagata lineage viruses.
At
the bottom of the page for test antigens 25 through 33, you will see a block of
viruses from Paraguay that were actually isolated in October and November. When we got a recent shipment, didn't know
these viruses were coming, but they were sort of cleaning out their season at
the end of their year, and what became apparent in terms of looking at the
isolation dates of the whole package of viruses that they had sent us the
viruses were actually ‑‑ they had a late influenza season that
started ‑‑ you know, normally, they're having their season during
our summer months, and they had a late B outbreak starting mainly in September,
going into October and just a couple viruses in November.
And
those ‑‑ so that was their previous ‑‑ these are the
tail-end of their South American season, and the question always comes up as to
whether viruses that are circulating in different places in the Southern
Hemisphere indicate what viruses are going to circulate the following season in
the Northern Hemisphere. Clearly, in
this particular case, for these Paraguayan viruses, they did not predict what
was going to happen in terms of B circulation in North America because they
were Victoria lineage viruses whereas in North America, both in the U.S. and in
Canada, Yamagata lineage viruses predominated.
Okay. I think unless there are any questions on
that page, I'll just mention that the viruses that we talked about before,
namely the Shanghai/361 and the Jilin/20 strains, have antisera that
covers a currently circulating strain on the Yamagata lineage well.
DR.
PALESE: Peter Palese. Can I ask you a question, please, Nancy?
DR.
COX: Yes, certainly.
DR.
PALESE: These Paraguayan strains, have
they been associated with unusual virulence or are they ‑‑ is
anything known about that? In other
words, are those more vicious viruses than what we have seen?
DR.
COX: We can't say for sure, but,
certainly, whenever there have been unusual outbreaks in Latin America, we have
had calls from our colleagues at PAHO and they have ‑‑ there's
something unusual going on. And so, for
example, when there was the outbreak El Salvador back in September we actually
sent an EIS officer to help investigate that particular outbreak because there
was reported increases in pediatric deaths.
So because ‑‑ I can't say with 100 percent certainty, but because
we had no information that there was anything unusual going on either from our
sources in Paraguay with our email contact or with PAHO, we, I think, could
safely assume there was nothing very unusual about these.
DR.
PALESE: But it was ‑‑ I
mean the first isolate is from October 9, and the last one ‑‑
DR.
COX: There were isolates from September
but because the cutoff here ‑‑ because we're talking about ‑‑
we're presenting data for the period October onward. So what we can see from looking at the whole package of
information they sent is that this was the tail-end of their activity. So the outbreak started earlier and this was
the end of it. But it went on in to November
as evidenced by the two isolates from November. So we can say that that may be somewhat unusual, just like our
season this year was somewhat unusual because it started so early. But it's certainly not out of bounds with
what we know about Southern Hemisphere activity where in Australia or New
Zealand or any of the countries in the Southern Hemisphere there can
occasionally be outbreaks that go beyond the normal winter ‑‑ that
go on into their spring. Peter, does
that help?
DR.
PALESE: Thank you. Thank you very much.
CHAIRMAN
ROYAL: Thank you very much. This is Dr. Royal. Are there any other questions for Dr. Cox?
DR.
COX: Okay. So then I'll go on to Page 4, and what we have encapsulated on
Page 4 is a result that we have for influenza B viruses that are actually
antigenically characterized by us here at CDC.
We have now slightly different proportions of viruses that are Yamagata
lineage and Victoria lineage because of some additional viruses that have come
in and particularly the viruses from Paraguay.
But you can see that 65 percent of the viruses tested here at CDC are on
the Yamagata lineage and 35 percent are on the Victoria lineage, shown in the
green color.
If
we look then at the map on Page 5, and we were just ‑‑ we realize
that this map isn't perhaps the more informative piece of information in the
package, Page 6 is somewhat more informative, but we really wanted to try to
give the Committee an idea of the countries where we've had either no reports
of B isolates, where we have no data whatsoever for Bs or where we have B but
we don't know ‑‑ and that's shown in orange ‑‑ which
they are, whether they're Yamagata or Victorian, and that's because some of
these countries actually do serology or use rapid tests and then they report
based on that or they've been having a virus isolate that they can use for testing.
The
blue color indicates the countries where the Yamagata viruses only have
circulated or where they have predominated.
This color shows where the Vic viruses have circulated only or have
predominated. But I think we should go
on quickly to Page 6 because the impression that you get from Page 5 is that
Yamagata strains are circulating more widely and predominating in more
countries than the Vic viruses. But to
get the actual numbers, you can see on Page 6, and we did quite a bit of
beating the bushes to get this data.
So
you can see that there were a couple of surprises in terms of B Victoria
viruses circulating. We had the 12 that
we got from Paraguay from October onward, and, once again, these are viruses
with isolation dates October 1 through March 10. Okay.
The
second surprise was that we got an email from the WHO Collaborating Center in
London, from Alan Hay, and they had
shortly after the WHO and FDA meetings received a package from South Korea that
contained 19 B/Vic lineage viruses. South Korea had a very, very heavy H3N2 season last year. They had very little influenza-B last year
and a heavy season with mainly H3, sort of like the season that we had in the
U.S. this year. So, anyway, that's what
they were seeing.
We
were also able to get data from China, Thailand, Malaysia and Hong Kong and
then some updated information from Japan.
Now, in all of the other Asian countries besides South Korea, you can
see very clearly that the Yamagata lineage viruses are predominating. So we do have a mixed picture as sometimes
happens for influenza B viruses with these two different lineages circulating,
but when we look at the numbers globally, we have 80 percent of the viruses on
the Yamagata lineage, 20 percent on the Vic lineage, and when we look at the
distribution on the somewhat simplistic maps that we presented on Page 5, there
are more countries now, and we know the numbers are low for all, there are more
countries, there's a greater geographic distribution of countries that have a
predominance of the Yamagata-like viruses.
So the picture hasn't changed, it's changed a little bit, but overall
the message is the same as it was a month ago.
Now,
just for completeness, we did include updated evolutionary trees for the HAs of
viruses on the Yamagata lineage and the Victoria lineage and also the
neuraminidase genes of viruses on both lineages. I don't think it's really necessary for me to go through these
dendograms in very much detail if you were able to print them out in
color. I just would like to note that
the viruses that have the little hatchmark, the pound sign after them, are egg
isolates and they also show up in blue if you printed it out in color so you
can see where the egg isolates lie on the dendograms.
So
I think with that I will close and see if there are any additional questions.
DR.
EICKHOFF: This is Ted Eickhoff. Nancy, could I ask you an additional
question?
DR.
COX: Certainly.
DR.
EICKHOFF: On Page 4, the color code
doesn't seem to be quite the same as the color code on Page 3 since the
Paraguay isolates are shown there in blue ‑‑ or green, rather,
which on Page 3 represents the B Yamagata lineage.
DR.
COX: Green? I'm sorry, so the Paraguay viruses are shown in green on Page 4 ‑‑
oh, Page ‑‑ no, the color code isn't the same. No, the color code ‑‑ it's mixed
around. So I apologize. We should have kept the color code the same
on Pages 3 and 4. I'm with you now. I'm sorry, I apologize for that.
DR.
EICKHOFF: No, it was just confusing me
a little bit. So the color code is
reversed on Page 4?
DR.
COX: Correct.
DR.
EICKHOFF: Okay.
DR.
MONTO: Nancy, this is Arnold
Monto. The South Korea isolates seem
rather out of line in many respects. Do
we know for sure that these were isolates from this past winter, and how does
this compare with China over the border, because I know you get specimens in
from Mukdin and places like that?
DR.
COX: Yes. These viruses were from this season. Their isolation dates were November and December of '03. The earliest one it was isolated in, let's
see, toward the end of November, and then the rest of them are thread all the
way through December. And we just don't
have any explanation for why South Korea has different strains than China,
Thailand, Malaysia and Hong Kong, and Hong Kong, Japan and Mainland China all
have data that corresponds very well, and Thailand as well. So we just don't have an explanation for why
South Korea is kind of sticking out there like a sore thumb.
DR.
LaRUSSA: This is Phil LaRussa. I have a question for you. Do you get any information about whether the
isolates are spread around the country or whether they're from a single
outbreak?
DR.
COX: The isolates from Korea are
actually from six different cities.
DR.
LaRUSSA: Okay. Good.
CHAIRMAN
ROYAL: Are there any other Committee
questions for Dr. Cox at this time? If
not, we will move on to Committee discussion.
Does anyone have any comments or questions regarding questions for
today? Can everyone hear me, this is
Dr. Royal.
DR.
COX: Yes.
CHAIRMAN
ROYAL: I hear some, I guess, airport
noise around there. At this time, we'll
move on to the open public hearing. Is
there anyone from the public who would like to make a statement concerning
matters addressed today? Okay.
MS.
WALSH: Dr. Royal, this is
Christine. I don't see anyone in the
room.
CHAIRMAN
ROYAL: Okay. Well, thank you. Well, in
that case, ahead of schedule we will move on to specific Committee discussion
concerning the recommendations for influenza B virus and also for ‑‑
I guess we need to address how to confirm our recommendations for the influenza
A virus vaccine.
MR.
LEVANDOWSKI: Dr. Royal?
CHAIRMAN
ROYAL: Yes.
MR.
LEVANDOWSKI: This is Roland
Levandowski. I don't think we were
asking to have confirmation for the influenza A recommendations. I think we had already had very good input
from the Committee on that. It was
really to confirm the recommendation for influenza B today.
CHAIRMAN
ROYAL: Okay. Thank you for that correction.
Any discussion from the Committee?
DR.
KARRON: Yes. This is Ruth Karron. I
was just wondering if the industry representatives wanted to say anything more
about the availability of the B/Shanghai/2002-like virus, as we heard a little
from Dr. Levandowski, but I didn't know if they had any other specific
comments.
CHAIRMAN
ROYAL: Are there any comments from
industry at this time? Okay. Well, if not ‑‑
DR.
PALESE: Dr. Royal, Peter Palese. Can I ask one other question, please?
CHAIRMAN
ROYAL: Yes. Go right ahead, please.
DR.
PALESE: Okay. Looking at the B/Shanghai in terms of its ability to interact or
to neutralize the most recent B virus, there's actually quite a drop in terms
of hemagglutination inhibition activity from the 2002 to the 2003 virus. It looks actually that the Jiangsu/10/03
might almost be a better ‑‑ I'm just concerned because it looks
like that the B/Shanghai may not be the best one.
CHAIRMAN
ROYAL: Thank you. Dr. Cox, do you have any comments?
DR.
COX: Yes. Peter, I'm glad you're looking at all of these carefully. One of the things that always happens when
we're working with a variety of strains is that we get different homologous
titers with the sera and respective antigens.
So the homologous titer for the Jiangsu is higher and in that sense is
more satisfactory and gives nice titers with some of the recent viruses. The Shanghai has a twofold lower homologous
titer than Jiangsu and the titers are correspondingly lower. And so it's hard to know if that really is
significant or not. The viruses that
are egg isolates have been circulated to the manufacturers, and so we're very
keen to hear on the relative growth properties and the ability to manufacture
to use the different egg isolates that have been circulated for
production. So I think going back to
Ruth's question, it would be helpful to hear more from the manufacturers.
DR.
PALESE: Yes. But even the Jiangsu is also an egg isolate, so I mean the
question is‑‑
DR.
COX: That's why we need to hear from
the manufacturer.
DR.
PALESE: But if they never got the
virus, they can't get any data.
DR.
COX: They did.
MR.
LEVANDOWSKI: This is Roland
Levandowski. We have distributed those
viruses. Some of them the manufacturers
haven't really had enough time to work with yet to give us a lot of feedback,
but just, Dr. Royal, if it's okay with you to comment on the question Dr.
Palese's raising about the cross reactivity of the anti-sera. They're actually looking down the Jiangsu
column on Page 3 of the CDC handout, and it looks to me like it may not be as
good in terms of cross reactivity as the Shanghai/361 anti-sera. If you're looking at the homologous titer
and the reductions there, I see two strains, antigens 13 and 14, which show a
fourfold reduction with the Jiangsu serum, and I don't see that with the
Shanghai/361 serum. But I'm not sure
that that even in and of itself means a lot, as I think Nancy Cox was trying to
say. I'm not sure that I would negate
the use of Jiangsu because there are a couple of strains that seem to have a
somewhat lower cross reactivity in this particular test.
DR.
COX: Yes. I guess, Peter, what I was trying to say is that when you look at
the homologous titer it kind of is a toss-up between the two.
MR.
MYERS: Nancy, it's Marty just following
up on Peter's question. When we look at
a cross reaction in a human sera, what do you see?
DR.
COX: Well, we haven't had any people
who've been immunized with either of these viruses, so we really don't have a
comparable way to look at it.
MR.
MYERS: Well, I mean with last year's.
DR.
COX: With last year's vaccine, we
tested ‑‑ I'm going to have to flip back ‑‑
MR.
LEVANDOWSKI: Well, Nancy, this is
Roland again. To help you out, last
year's vaccine had a Hong Kong/330/2001-like B/Victoria/281 lineage
hemagglutinin, and the cross reactivity, as I recall, was somewhat low for
these B/Yamagata lineage strains, as you would expect. I don't exactly recall what we saw with the
use of the B/Victoria/504/2000/Yamagata-like strain from sera that we had from
a couple of years ago, but I seem to recall that there was some reduction in
antibody responses against the current B/Yamagata-like strains probably because
there's been antigenic drift going on in those strains as well.
DR.
COX: So the bottom line is that the
serologies that we did are really not that informative, because we had the
Vic-like antigens and we had tested Jilin and Jiangsu and there was not a good
response. They were equally poor, but
it was not the right lineage vaccine strain to be able to say anything.
MR.
MYERS: I understand.
DR.
EICKHOFF: This is Ted Eickhoff. Another question for Nancy. You may have mentioned this but I simply
didn't pay attention. What were the
dates of isolation of those South Korean strains?
DR.
COX: South Koreans, yes, the dates of
isolation were November and December.
DR.
EICKHOFF: Of 2003.
DR.
COX: Of 2003, correct.
DR.
EICKHOFF: Thank you.
DR.
DECKER: This is Michael Decker. I've got a question for Roland and for
Nancy. And the question really relates
to what level of detail do you want the Committee to go into? I'm a little confused because I had the
impression before the meeting started that our primary job today was to either
reconfirm the tentative decision to go with the B/Yamagata lineage or to
reverse that tentative decision and switch to a Victoria lineage, and I hear us
now discussing fine details of specific strains, which is a conversation I
wasn't expecting because in prior years what we've told the companies is ‑‑
we've told them what general type to go and we've allowed them to pick the
specific production strains based on the performance of the candidate strains
in their hands. It sounds like now
we're trying to pick the exact strain they're going to use for production, and
is that what you really intend us to do?
MR.
LEVANDOWSKI: Dr. Royal, this is
Roland. Should I respond to that?
CHAIRMAN
ROYAL: Yes, please, go ahead.
MR.
LEVANDOWSKI: Okay. Well, as Dr. Decker is pointing out, in past
years we have had from the Committee a general recommendation for a strain of
which we should try to have an isolate that would be suitable for manufacturing
that would meet the antigenic characterization for that particular strain. And we have usually be successful with that
strategy for finding a strain that will be a reasonable one for manufacturing
and still meet the antigenic characteristics.
You're probably aware that most years we don't have the exact name
strain from the recommendations in the vaccine, although occasionally that
happens. But the reason for that is
that we do try to make sure that the manufacturers get a strain that's going to
be useful for their purposes in terms of getting good yield.
In
this particular situation, I guess, from my point of view, I see that there are
several strains that are available.
Those have been distributed to the manufacturers, and if everybody is
okay with that, we would certainly like to give the opportunity for the
manufacturers to pick from those strains that have the right antigenic
characterization, which of those would be the one that give us the best yield
so that we can use that for vaccine manufacturing.
MR.
LI: This is Sam Li from Aventis
Pasteur. I think that process of
selecting a prototype strain now and then working later to come back and decide
what the actual vaccine strain would be is very suitable to our time
frame. We have candidates for at least
three different strains, the B/Jilin, the B/Jiangsu and the B/Shanghai, that
we've began initial work on.
Unfortunately, at this point, the data is still pretty early, so we
don't have enough to make an actual determination of which one would be the
best yielding. So if we could follow
that path, that would probably be the best for us.
DR.
PALESE: Peter Palese. I mean, clearly, I think there should be
some understanding that not every B/Yamagata strain should be ‑‑
could be used. For example, if I go
back to the Page 3, we have the Sichuan/379 and that is also green and also
posing for the same lineage, but, clearly, I mean that has tenfold lower
interaction with the more recent one.
MR.
LEVANDOWSKI: Dr. Palese?
DR.
PALESE: Yes.
MR.
LEVANDOWSKI: Let me answer that. We don't have any intention to go back in
time to an older strain of a different antigenic characteristic. As you're pointing out, the Sichuan/379/99
strain is an older strain, and we don't actually think that would
representative of the strains that we're talking about now, which I think we're
characterizing generally as B/Shanghai/361/2002-like. And Nancy may want to answer that too.
DR.
PALESE: True, but I mean I just wanted
to sort of clarify and maybe disagree with Dr. Decker in terms of what can be
used or should be used by industry.
DR.
MONTO: This is Arnold Monto. According to what we've heard, industry now
has three different B/Yamagata lineage viruses. Can't we assume that the recommendation is going to be
B/Shanghai-like and one of those will be the candidate for vaccine?
MR.
LEVANDOWSKI: This is Roland again. That would certainly be our ‑‑
what we would have anticipated doing.
That's what we would intend to do, yes.
DR.
COX: And just if I could pipe in one
more time, the viruses that we sent to Roland for distribution, the new B
strains are all ones that we believe are acceptable, that fit into that
B/Shanghai/361-like category, and we would not at all think that going
backwards to the old Sichuan/379/99 strain would be sensible.
MR.
LI: This is Sam Li again. I also want to say to the Committee that
based on the initial data we're confident that one of these strains that we're
working with would be acceptable, so I just wanted to make sure the Committee
felt comfortable that one of those three probably would be used for the
vaccine.
DR.
DOWDLE: Nancy, this is Walter Dowdle,
and I'm sorry I don't have access to the tables, but if I could ask, would it
not be fair to say that if you have a ‑‑ if all three of those
viruses grow well, it is quite possible that they may not show the difference
that you see as this sort of one shot HI test.
In fact, they could indeed be closer on later tests than they perhaps
are now, and this could be within test error.
DR.
COX: That's true, and ‑‑ I
mean that is true. Based on their
genetic properties and the antigenic properties and the tests that we've done
thus far, we believe that they are antigenically equivalent, the ones that
we're talking about.
DR.
DOWDLE: Right. So I think we're talking about differences
here that may turn out to be minimal if at all.
DR.
COX: Right. Correct.
DR.
DOWDLE: Yes. Thank you.
DR.
COX: Yes.
DR.
DECKER: This is Michael Decker
again. Correct me, Roland, if I'm
wrong, but I believe is it not true that also in at least some prior years
different manufacturers have had differing success with different strains, and
the vaccine that's marketed is actually not always been the same strain from
each manufacturer, but they've always been in the same antigenic group
here? In other words, we may find of
the three strains you've recently distributed one manufacturer has their best
success with one, another with another, and those manufacturers' specific
choices all fall within the domain of choices that was approved by the
Committee.
MR.
LEVANDOWSKI: Yes, that's true. In fact the current vaccine from this past
year of the two manufacturers, each had a different influenza B, actual
influenza B strain. Aventis used B/Hong
Kong/1434/2002, and Evans/Chiron used B/Hong Kong/330/2001. I guess I should mention that Medimmune used
B/Hong Kong/330/2001 as a strain for the live vaccine. So, yes, we do anticipate that that may be a
necessity, and if it will help manufacturing, if it significantly helps
manufacturing, we're prepared to support that.
DR.
DECKER: Then, Mr. Chairman, I would
suggest that perhaps the question before us is whether we wish to reconfirm our
B/Yamagata choice of last month or wish to move instead to Victoria, and if we
wish to stay with Yamagata, do we wish to authorize FDA to move ahead with these
three strains they sent to the manufacturers and allow the appropriate
officials in the companies and at FDA to agree on the final choices.
CHAIRMAN
ROYAL: Do we have any discussion
concerning that recommendation? Is
anyone ‑‑
PARTICIPANT: Do we need a second?
MS.
WALSH: Yes.
PARTICIPANT: I'll second.
CHAIRMAN
ROYAL: All in favor?
(Committee
members vote aye.)
CHAIRMAN
ROYAL: Okay. So we now change the question.
Could you please restate that question, Dr. Decker?
DR.
DECKER: It was a two-part. Number one, does the Committee wish to
reconfirm its tentative recommendation of last month that the influenza B
component be changed to a B/Yamagata/1688 lineage, a B/Shanghai/361/2002-like
strain? That's part one. And assuming that that question is answered
in the affirmative, does the Committee then wish to authorize FDA and the
companies to make appropriate choices among the candidate strains that have
been circulated as to the specific strains used by each company for
manufacture?
CHAIRMAN
ROYAL: Are we prepared to vote? First, I'd like to check to see if anyone
new has joined the teleconference since we checked the roster?
DR.
MONTO: Arnold Monto has joined.
CHAIRMAN
ROYAL: Okay. Great. Dr. Gellin? Dr. Myers?
MR.
MYERS: Yes.
CHAIRMAN
ROYAL: Mrs. Province? Okay.
With that, I believe we are prepared to vote. We'll start with Dr. Dowdle.
DR.
DOWDLE: My vote is affirmative. Do you want to do both ‑‑ do you
want to consider both 1 and 2 as one or do them separately?
CHAIRMAN
ROYAL: I think Number 2 will be
contingent upon the outcome on 1, so if ‑‑
DR.
DOWDLE: Okay. Number 1 would be, yes, I agree.
Yes.
CHAIRMAN
ROYAL: Okay. Dr. Goldberg?
DR.
GOLDBERG: Affirmative for Question 1 to
change to the strain.
CHAIRMAN
ROYAL: Okay. Great. Dr. Karron?
DR.
KARRON: Yes, I agree that we should
change the strain.
CHAIRMAN
ROYAL: Okay. I'm next, Dr. Royal, I do agree to change the strain. Dr. Farley?
Are you still with us, Dr. Farley?
Okay. We'll move on to Dr.
McInnes.
DR.
McINNES: I vote to confirm the
recommendation made on February 19 to change the flu component to
B/Yamagata/1688 lineage.
CHAIRMAN
ROYAL: Okay. Thank you very much. Dr.
Phillips?
DR.
PHILLIPS: Yes. I vote to the confirm the recommendation.
CHAIRMAN
ROYAL: Okay. Dr. LaRussa?
DR.
LaRUSSA: I also vote to confirm the
recommendation to change.
CHAIRMAN
ROYAL: Okay. Thank you. Dr. Myers?
MR.
MYERS: I vote to confirm the
recommendation.
CHAIRMAN
ROYAL: Dr. Word?
DR.
WORD: I vote to confirm the
recommendation.
CHAIRMAN
ROYAL: Dr. Peter Palese?
DR.
PALESE: Yes.
CHAIRMAN
ROYAL: How do you vote?
DR.
PALESE: Yes.
CHAIRMAN
ROYAL: Thank you. Dr. Monto?
DR.
MONTO: Yes.
CHAIRMAN
ROYAL: Okay. And Dr. Eickhoff?
DR.
EICKHOFF: Yes, vote to confirm.
CHAIRMAN
ROYAL: Thank you very much. Did we miss anyone? Any further comments from the Committee or
from FDA or CDC? If not, we can adjourn
today's teleconference.
DR.
KARRON: Don't we have a second
question?
CHAIRMAN
ROYAL: Oh, the second question I
thought was contingent upon the first.
Okay. Well, we will do that
separately. Okay, the second question,
that is to ‑‑ Dr. Decker, I did not write it down verbatim. Could you go ahead and state the second
question for us, please?
DR.
DECKER: Does the Committee authorize
FDA to work with the manufacturers to settle for each manufacturer on the final
strain to be used within the guidelines that we just authorized?
CHAIRMAN
ROYAL: Okay. Great. Okay. Dr. Dowdle?
DR.
DOWDLE: Yes.
CHAIRMAN
ROYAL: Dr. Goldberg?
DR.
GOLDBERG: Yes.
CHAIRMAN
ROYAL: Thank you. Dr. Karron?
DR.
KARRON: Yes.
CHAIRMAN
ROYAL: Dr. Royal, yes. Dr. Farley?
Dr. McInnes?
DR.
McINNES: Yes.
CHAIRMAN
ROYAL: Dr. Phillips?
DR.
PHILLIPS: Yes.
CHAIRMAN
ROYAL: Dr. LaRussa?
DR.
LaRUSSA: Yes.
CHAIRMAN
ROYAL: Dr. Myers?
MR.
MYERS: Yes.
CHAIRMAN
ROYAL: Dr. Word?
DR.
WORD: Yes.
CHAIRMAN
ROYAL: Dr. Palese?
DR.
PALESE: Yes.
CHAIRMAN
ROYAL: Dr. Monto?
DR.
MONTO: Yes.
CHAIRMAN
ROYAL: And Dr. Eickhoff?
DR.
EICKHOFF: Yes.
MS.
WALSH: Excuse me, this is Christine
Walsh. Can you please repeat the
Question Number 2 again?
DR.
DECKER: Question Number 2 was does the
Committee authorize FDA to work with the manufacturers to reach final agreement
on the specific strain to be used by each manufacturer for manufacturing the B
component of the 2004-5 vaccine in accord with or consistent with the
recommendation that we just adopted that it be a B/Yamagata
B/Shanghai/361/2002-like strain.
MS.
WALSH: Thank you.
CHAIRMAN
ROYAL: Okay. Thank you very much. Any
further comments? Christine, anything
else?
MS.
WALSH: Nothing that I know.
CHAIRMAN
ROYAL: Okay. Well, with that, we will adjourn today's teleconference. Thank you all.
MS.
WALSH: Thank you very much.
(Whereupon,
at 2:04 p.m., the FDA Teleconference was concluded.)