FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS AND EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE

MEETING ON INFLUENZA VIRUS VACCINE

FORMULATION FOR 2003-2004

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TUESDAY,

MARCH 18, 2003

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The meeting was held in Conference Room A on the 11^th^ Floor, 5515
Security Lane, at 10:30 a.m., Dr. David Stephens, Committee Chair,
presiding.

This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly, the Food
and Drug Administrations makes no representation as to its accuracy.

PRESENT:

DAVID S. STEPHENS, M.D. Chair

JODY SACHS, D.P.M. Executive Secretary

DENISE ROYSTER Committee Management

Specialist

MICHAEL A. DECKER, M.D., M.P.H. Member

PAMELA S. DIAZ, M.D. Member

JUDITH D. GOLDBERG, Sc.D. Member

RUTH A. KARRON, M.D. Member

SAMUEL L. KATZ, M.D. Member

DAVID M. MARKOVITZ, M.D. Member

AUDREY F. MANLEY, M.D., M.P.H. Member

GARY D. OVERTURF, M.D. Member

PETER PALESE, Ph.D. Member

JULIE PARSONNET, M.D. Member

WALTER ROYAL, III, M.D. Member

RICHARD J. WHITLEY, M.D. Member

CONSULTANTS PRESENT:

NANCY COX, Ph.D.

COLONEL BENEDICT DINIEGA, M.D.

WALTER DOWDLE, Ph.D.

THEODORE EICKHOFF, M.D.

BARBARA LOE FISHER

BRUCE GELLIN, M.D., M.P.H.

PAMELA McINNES, D.D.S.

MARTIN MYERS, M.D.

SPEAKERS:

ROLAND LEVANDOWSKI, M.D.

NANCY COX, Ph.D.

INDUSTRY PRESENT:

JOHN O\'BRIEN PowderJect

LISA BISSETTE PowderJect

KATHLEEN COOLING MedImmune

C-O-N-T-E-N-T-S

Call to Order 3

Announcements 9

Open Session

Strain Selection for the Influenza Virus

Vaccine for 2003-2004

Introduction and Review

Dr. Levandowski, FDA 11

Additional Information, H3N2

Dr. Nancy Cox, CDC 29

Committee Discussion

Open Public Hearing 49

Recommendations for Influenza Virus

Vaccine for 2003-23004 67

Adjournment 70

P-R-O-C-E-E-D-I-N-G-S

10:37 a.m.

DR. STEPHENS: That\'s great. Welcome, Pam.

DR. DIAZ: Hi. Thanks. I may not be able to stay long. I\'m sorry.

DR. STEPHENS: Just to get started, this is a follow-up to our meeting on
influenza virus vaccine formulation for 2003 and 2004.

As most all of you know, we delayed recommendations concerning the H3N2
components, and that\'s the subject, a major subject, of this conference
call and meeting. And I\'ll turn it over to Dr. Jody Sachs, who will
call the roll and give us announcements.

DR. SACHS: Good morning. I\'d like to go ahead and start with a roll
call. I\'ll read your name and your affiliation and just, if you\'re
here, say present. We do have a transcriber here, so this is for the
public record. Thank you.

I\'ll start with our chair, Dr. David Stephens from Emory University
School of Medicine?

DR. STEPHENS: Here.

DR. SACHS: Dr. Ruth Karron from Johns Hopkins University School of
Hygiene and Public Health?

DR. KARRON: Here.

DR. SACHS: Dr. Michael Decker from Aventis. And he will be calling in
later, so I\'m going to skip over. Dr. Pam Diaz from Chicago Department
of Public Health?

DR. DIAZ: Here.

DR. SACHS: Dr. Sam Katz from Duke University?

DR. KATZ: Here.

DR. SACHS: Dr. David Markovitz from University of Michigan Medical
Center?

DR. MARKOVITZ: Here.

DR. SACHS: Dr. Audrey Manley from \-- President Emeritus, Spelman
College?

DR. MANLEY: Here.

DR. SACHS: Dr. Gary Overturf, University of New Mexico School of
Medicine?

DR. OVERTURF: Here.

DR. SACHS: Thank you. Dr. Julie Parsonnet from Stanford University?

DR. PARSONNET: Here.

DR. ROYAL: Dr. Walter Royal, Morehouse School of Medicine?

DR. ROYAL: Here. Here.

DR. SACHS: Dr. Nancy Cox from the CDC?

DR. COX: Here.

DR. SACHS: Colonel Benedict Diniega?

COLONEL DINIEGA: Here.

DR. SACHS: From the Office of Assistant Secretary of Defense for Health
Affairs. Dr. Walter Dowdle, from the Task Force of Child Survival and
Development?

DR. DOWDLE: Here.

DR. SACHS: Dr. Theodore Eickhoff from the University of Chicago Health
Centers?

DR. EICKHOFF: University of Colorado. Here.

DR. SACHS: Yes. I\'m sorry. Dr. Pamela McInnes from the Division of
Microbiology and Infectious Diseases, NIH?

DR. McINNES: Present.

DR. SACHS: Dr. Martin Myers, University of Texas Medical Branch?

DR. MEYERS: Here.

DR. SACHS: And I\'m checking. Is Barbara Loe Fisher National Vaccine
Information Center on?

(No response.)

DR. SACHS: Okay. Hopefully, she\'ll call in. The following people have
told me that they will be calling in a little bit later, so we\'ll
acknowledge them when they come on: Dr. Michael Decker from Aventis, who
is our industry representative; Dr. Judith Goldberg; and Dr. Peter
Palese; as well as Dr. Richard Whitley.

I\'d also like to briefly say this welcome to the 95th meeting for the
Vaccine and Related Biological Products Advisory Committee. Where I\'m
talking from right now, there is a speaker phone for public
participation at the FDA, located at 5516 Security Lane in Conference
Room A on the 11th floor, Suite 1113 in Rockville, Maryland.

This morning\'s session will consist of presentations and committee
discussions that are open to the public as described in the Federal
Register notice of March 5th, 2003.

Should a committee member get dropped from the telephone lines, simply
call back at the number given, 1-888-655-9181, and ask to be connected
to the pass code VRBPAC. The operator is under strict instructions only
to connect committee members to this line. That number, again, if
you\'re disconnected, just hang up and call back. If you have problems
while I on the call, press star zero and the operator will help you.

I really wish that people would not use their hold button because if
you\'re calling from a clinical center that has background music, it
could be distracting to those remaining on the telephone line. If you\'d
like to use mute, please, I urge you to use star six. And if you\'d like
to speak, you have to press star six to get off the mute.

Since there are many lines connected, any background sound will decrease
the quality of sound for everybody.

I\'d like to remind everybody to please give your name before speaking.
And I\'d like now to introduce some of the FDA staff members who are
participating at today\'s meeting. They are currently not at this
location.

Dr. Karen Midthun is the Director of the Office of Vaccine Research and
Review. Dr. Norman Baylor is the Associate Director for Regulatory
Policy, Office of Vaccine Research and Review. Dr. Jerry Weir is the
Director of the Division of Viral Products. Dr. Roland Levandowski is
Medical Officer who will be presenting. Dr. Nancy Cox will also be
presenting. She will be from CDC.

And I\'d also for the record like to acknowledge the following people
who are on the call from industry: Dr. Sam Lee and Dr. Michael Decker
are both from Aventis. Dr. Lisa Bissette and John O\'Brien are from
PowderJect and Evans.

I\'d ask that committee members dock your cell phones, since it adds an
unnecessary background noise to the line.

And I\'d like to acknowledge Denise Royster. She is the Committee
Management Specialist who is responsible for pulling this meeting off,
and I am indebted to her.

At this point, I\'d like to ask if there are any other FDA members that
I left out. Please introduce yourself.

DR. EGAN: William Egan, Deputy Director for the Office of Vaccines.

DR. SACHS: Thank you. And Dr. Chris Mink, she\'s also from the FDA.

DR. MINK: I\'m here also.

DR. GAGVETEN: Yeha, and I\'m behind her. Sarah Gagveten from the \--

MS. McCRACKEN: Kathy McCracken from \-- also from \-- and FDA.

DR. SACHS: Thank you. Are there any others? Okay.

I have a meeting statement that I\'d like to read for public record.

The following announcement addresses the conflict of interest issues
associated with the Vaccine and Related Biological Products Advisory
Committee meeting on March 18th, 2003.

The Director of the Center for Biologics Evaluation and Research has
appointed Dr. Nancy Cox, Dr. Walter Dowdle, Dr. Theodore Eickhoff, Dr.
Bruce Gellin, Dr. Pamela McInnes, Dr. Martin Myers and Colonel Benedict
and Ms. Barbara Fisher as temporary voting members for this meeting.

Based on the agenda, it has been determined that there are no products
being approved at this meeting. The Committee participants have been
screened for their financial interests to determine if any conflict of
interest existed.

The Agency reviewed the agenda and all relevant financial interests
reported by the meeting participants. The Food and Drug Administration
prepared general matter waivers for the Special Government Employees
participating in this meeting who required a waiver under 18 U.S.C. 208.

Because general topics impact on so many entities, it is not prudent to
recite all potential conflicts of interest as they appear to each
member. FDA acknowledges that there may be potential conflicts of
interest, but because of the general nature of the discussions before
the Committee these potential conflicts are mitigated.

We would like to note for the record that Dr. Michael Decker is
participating in this meeting as a non-voting industry representative
acting on behalf of regulated industry. Dr. Decker\'s appointment is not
subject to 18 U.S.C. 208. He is employed by Aventis and, thus, has a
financial interest in his employer.

In addition, in the interest of fairness, FDA is disclosing that his
employer, Aventis, is a manufacturer of a product that could be affected
by today\'s committee discussions.

In the event that the discussions involve specific products or firms not
on the agenda, and for the FDA participants have financial interests,
the participants are reminded of their need to exclude themselves from
the discussions. Their recusal will be noted for the public record.

With respect to all meeting participants, we ask in the interest of
fairness that you state your name and affiliation and any current or
previous financial involvement with a firm whose products you wish to
comment upon. Waivers are available by written request under the Freedom
of Information Act.

I\'d now like to turn the meeting over to our chair, Dr. David Stephens.
Thank you.

DR. EGAN: Jody, this is Dr. Egan. Is Dr. Gellin present?

DR. SACHS: He called me early this morning and said this morning and
said that he was at a \-- attending a conference that he was presenting
at. He will be calling in, but he said it may be after we begin, maybe
about eleven or so.

DR. EGAN: Okay. Thank you. I just wanted to clarify that.

DR. SACHS: And I\'d also like to remind people that there are additional
members calling in, Dr. Richard Whitley, Dr. Peter Palese, Dr. Judith
Goldberg, as well Dr. Michael Decker, who will be calling in later.

DR. STEPHENS: Thank you very much, Jody. I think we will \-- I want to
remind members and consultants to announce your name before speaking.
Otherwise, it\'s going to get real confusion. And I think we\'ll begin
with Dr. Roland Levandowski updating us and reviewing our positions.
Roland?

DR. LEVANDOWSKI: Okay. Thank you, Dr. Stephens. This is Roland
Levandowski. I\'m going to try to go over several things, and I\'ll just
\-- and actually both for Nancy and I just to get an idea of what the
agenda items will be, I\'m first going to give a brief statement about
the situation with H5 influenza A viruses and atypical pneumonia for
information purposes.

I\'ll then go on to review what\'s happened in terms of influenza strain
selections. And I\'d also like to restate what our question is for the
committee. I think it\'s pretty obvious that the question is going to be
what should be the H3N2 component of next year\'s influenza vaccines.
And I\'ll restate that.

And when I\'m done, Nancy Cox will provide the committee members with
some updated surveillance on epidemiologic data. And then I intend to,
and as usual, give information about \-- or just a summary of what the
options for recommendations could be at this point. And then turn it
back to you, Dr. Stephens, for committee discussion on the actual
recommendations.

So I\'ll just go right ahead and start getting in some information about
H5 and atypical pneumonia. Since the last committee meeting, and at
present time, of course there\'s been a lot of ongoing investigations
related about the avian influenza and atypical pneumonia in Asia.

You\'re probably all aware that in February the Chinese Ministry of
Health reported that there had been an ongoing outbreak of pneumonia in
the Guangdong Province of southern China.

OPERATOR: Ms. Loe Fisher has joined.

DR. LEVANDOWSKI: The pneumonia there in China in Guangdong Province was
described as being atypical, and it involved at least about 300 people,
and there were five associated deaths that were reported.

Subsequently, the Chinese Ministry of Health attributed that outbreak to
chlamydia pneumoniae, and they\'ve stated also that the outbreak has
ended there.

Because of that Chinese experience, the Hong Kong Department of Health
had also been making particular efforts to look at all the cases of
atypical pneumonia there to see if there was any type of pattern.

And initially, there was no particular etiology found in terms of
atypical pneumonia until the beginning of March. And there was nothing
that seemed to fit any particular clinical or epidemiologic pattern.

However, in February, in mid-February, there were two members of a Hong
Kong family who were demonstrated to have been infected with an H5N1
influenza A virus of avian origin. That family, just to remind you, had
visited relatives in Fujian, China, where the 8-year-old daughter of the
family, of the visiting family, became ill with an acute respiratory
disease and she died.

We don\'t really have any additional information on that family member,
but a 9-year-old son of the family and the 33-year-old father also
became ill, and when they returned to Hong Kong, the H5 influenza
diagnosis was diagnosed.

Now, the son in that case recovered, but the father developed pneumonia
and he died. And that death was \-- seems to have been related to avian
influenza.

The mother of the family also had an acute respiratory illness, but in
her case a pair influenza virus was isolated and she recovered
uneventfully.

Any relation between the atypical pneumonia in China and H5 is
uncertain, but there have been no additional cases of H5 documented
anywhere at this time.

Subsequently to discovery of the H5 influenza A virus and seem to be
similar to what occurred in China in February, there have been cases of
atypical pneumonia of an as yet unknown etiology in Hong Kong, Vietnam
\--

OPERATOR: Excuse me. Michael Decker is joining the conference.

DR. LEVANDOWSKI: And \-- but the epidemiology in those cases suggest
that there may be a contagious, infectious etiology.

The term that\'s being used by the World Health Organization to describe
this illness is severe acute respiratory syndrome. And I think they\'re
using that because it reflects the fact that the etiology is unknown,
even though we think there might be a microbial origin, and also the
fact that many of the individuals who have this illness do seem to have
some type of severe pneumonia, even if it\'s not fatal. In fact, most of
the cases, there seems to be some evidence of pneumonia.

The list of the countries that\'s affected by travelers who are coming
from those areas in Asia has been growing, and that\'s also listed now
by the WHO as including Germany, Canada, Switzerland and Thailand.

In the Thailand instances that were reported last week in Asia, there
really appears to be mainly a clustering of the cases in hospital
workers after they\'re exposed to an index case of a patient who has
severe pneumonia.

In those instances, a high proportion of the exposed people have become
ill and most of the instances of illness, the report is that there are
pneumonia symptoms, which I think in most cases is also documented by
X-Ray evidence of pneumonia.

The experience in Hong Kong, which is very well documented, also
suggests that family members and others who may be in close contact with
some of these patients may also be at risk and may develop symptoms.

The number of deaths, actually, however, related to this outbreak is
very small. There are four that have been documented during the past
week with the several hundred cases that are being investigated.

These cases are very \-- they\'re very similar in many aspects. Exposure
to the index case seems to result in symptoms in as short as two days,
but can be somewhat longer.

And the clinical signs and symptoms are described as flu-like, with sore
throat, fever, cough and, in many cases, this rapid progression to
pneumonia seen on chest X-ray. There are some other peculiar lab
findings, including thrombocytopenia and leukopenia.

And just one example of the index cases and here and what\'s happening
in Asian. For the businessman who visited Shanghai, passed through Hong
Kong on his way to Hanoi, when he arrived at Hanoi, became acutely ill,
developed pneumonia, required ventilatory support and subsequently was
transferred back to Hong Kong where he died.

In the meantime, in the hospital in Hanoi, approximately 40 of the
healthcare workers became ill. Some of them have developed pneumonia and
there\'s been at least death of a contact healthcare worker in Hanoi.

In Hong Kong, there have been many cases at one of the hospitals after
exposure to that patient who was transferred back. However, there have
been cases of illness with pneumonia symptoms at other hospitals and
clinics.

And at this point, it\'s not clear that all of this is related to the
same etiology, since there have been other cases of atypical pneumonia
occurring in Hong Kong. So there may be multiple etiologies that are
going on here, although there does seem to be a very distinct pattern
for this severe acute respiratory syndrome.

What I\'d really like to emphasize is that although there has been a
high index of suspicion for avian influenza in the cases that have
occurred, and there\'s been a very large amount of work done to try to
identify an etiology, there\'s absolutely no evidence at this point that
this that this syndrome that\'s occurring now that\'s being reported in
the news media is related to influenza A of avian agency or in fact of
any origin. There\'s no evidence that influenza is playing a role in
that.

And maybe I should just stop there, Dr. Stephens, and see if you or
anybody else wants to add any comments of questions.

DR. STEPHENS: Comments, questions?

DR. KATZ: This is Sam Katz. I guess my question would be, have they used
any antivirals? I\'ve read about antibiotics. Have they used antivirals,
Ribavirin, Sotamovirin, any of the known antiviral agents in treating
these patients?

DR. LEVANDOWSKI: Our understanding is that a number of different
antimicrobial modalities have been used, including antibiotics for
bacteria and also a number of different antiviral agents.

I don\'t know that I can tell you the list of antiviral agents. It does
include also Tamiver and other anti-influenza agents. I\'m not clear on
what impact any of that has had. And I don\'t think I\'ve seen reports
that indicate what the outcomes might have been in any particular
individual treated with any particular agent.

DR. KATZ: Thank you.

DR. STEPHENS: Other comments, questions?

DR. LEVANDOWSKI: Just to clarify, somebody here was asking me about
being coy about saying that there was no evidence for influenza. It was
looked for very actively, and there is no documentation for influenza.
Again, very good laboratories that are involved in the investigation.

DR. MEYERS: Does that include serology, Roland? This is Marty.

DR. LEVANDOWSKI: I believe there is serologic studies going on as well.
I don\'t know what the status of those is and I don\'t know exactly what
is being looked for.

But I think that everything possible, any type of investigative
modality, electron microscopy, PCD techniques, serologic techniques,
histopathological examinations of tissues. All of those things are going
on.

DR. ROYAL: That leads to my question. This is Royal. Any other organ
systems known to be involved?

DR. LEVANDOWSKI: I am not clear on that either. It seems to be
predominantly a pulmonary issue, but I\'m not clear that there might not
be some other types of abnormalities.

As I mentioned, there is thrombocytopenia that\'s been identified. I
don\'t know what the implications of that would be. I don\'t believe
that there has been evidence for something like encephalitis or
hepatitis or renal disease.

But I\'m not sure \-- I\'m not clear on what the ultimate cause of death
is in the those people who have had the severe pneumonia. I believe
it\'s respiratory death, but there may be other organ failures as well,
as a part of that. And I don\'t know whether that indicates anything
about the etiology.

DR. OVERTURF: This is Gary Overturf. Have there been epidemiologic clues
in terms of index cases in particular, whether they have been primarily
rural lifestyle as opposed to urban? You mentioned that the businessman,
but I wonder if most of the cases have been rural as opposed to urban.
Do we know that?

DR. LEVANDOWSKI: I think that the outbreaks as they are occurring are
mainly in hospitals and involving healthcare workers, the ones that we
know about, at least.

There are also the family members who are living in urban settings where
these index cases are. And in the case of the businessman, I believe his
time was spent in cities, but I don\'t know for sure that he didn\'t
travel to some rural area. I\'m not sure that anybody can give us that
information at this point. A lot of these details are still being
collected.

DR. MARKOVITZ: David Markovitz here. I wanted to know, what happened
with the chlamydia aspect of this?

DR. LEVANDOWSKI: I believe that that might have been a serologic
diagnosis that was made in retrospect, but again, I don\'t have all the
information and I\'m not privy to all the information that may be
involved here. And I\'m sort of speculating a little bit.

I don\'t think that we have other evidence \-- I don\'t think we have
direct evidence for chlamydia as a cause of infection. I had heard that
there were some \-- there was at least one case of atypical pneumonia in
Hong Kong that might be attributed to a chlamydial infection, but I
think that also was a serologic diagnosis.

So I don\'t know \-- I don\'t believe that anybody suspects that that\'s
the cause of what\'s going on.

OPERATOR: Excuse me. Richard Whitley has joined the conference.

DR. COX: Roland, I can probably just mention one thing that would
clarify. The Chinese had looked extensively for a whole variety of \--

DR. LEVANDOWSKI: Is this Nancy?

DR. COX: Sorry. This is Nancy Cox. The Chinese have looked for a whole
variety of different pathogens in all the testing that they did. And
they had some autopsy samples, which they examined microscopically.

And they had some EM\'s and so on. And they were identifying from some
structures that they thought were chlamydia, but I think that folks here
at CDC would feel that that kind of a diagnosis for chlamydia would be
very difficult to make. And so \-- but it was an EM that the Chinese had
used, and that was the basis for they\'re saying it was chlamydia.

DR. PARSONNET: This is J. Parsonnet. Is there any \-- do you know when
the last new case was?

DR. COX: Today.

DR. PARSONNET: Today?

DR. LEVANDOWSKI: This is something that\'s still in evolution and I
think we\'re not able to give too much more information than we already
have. I don\'t think we actually \-- I personally don\'t have any
additional information that would be useful. And everything that we\'re
getting here at FDA is coming from the WHO and the Hong Kong Department
of Health website. And I think those who have an interest may find those
websites helpful in keeping track of what\'s going on.

I believe that both of those sites, as soon as they have information
that is credible and that they\'re confident in will put that \-- make
that information publicly available.

DR. STEPHENS: That\'s excellent. Why don\'t we go on, Roland, to the
influenza H3N2 question?

DR. LEVANDOWSKI: Okay. So thanks, Dr. Stephens. Just as review, just to
go over what the recommendations from the committee were in February
when we last met, the committee had indicated that it was recommending
that the H1N1 influenza A virus and the influenza virus B components of
the vaccine should remain the same as they were.

And for H1N1 influenza A, that\'s A/New Caledonia/20/99. And for
influenza B, that\'s a B/Hong Kong/330/01-like virus, which for us in
the United States would mean either B/Hong Kong/330 or B/Hong
Kong/1434/02 viruses.

For both of those strains, manufacturing has been in progress. And just
as further review of what happened in February, the H3N2 influenza A
recommendation was postponed because there was late breaking information
about a new variant of influenza A H3N2, which is represented by some
viruses forming a group that had signature amino acid substitutions at
positions 155 and 156 of the hemagglutinin.

These viruses were antigenically distinguishable from the current
strains. And we had information at that time that these new variant
viruses were identified in Asia, including China, and also in North
America and Europe.

We had information presented at the last meeting, which we won\'t review
again, but just to reiterate, it shows that current vaccines produce
antibodies that don\'t really inhibit many of these new viruses very
well.

And at the time we met last, there were no isolates that were \-- of
those new antigenic variant viruses that were suitable for use in
vaccine production.

After the postponement, we had some additional information through WHO.
And I think you all are aware that WHO had also postponed its
recommendation to try to identify whether it was possible to have a
response to the new variant.

In the interim, there\'s been a lot of work that\'s gone on to try to
find an isolate of one of these viruses that would be suitable for
vaccine production. That hasn\'t happened, in spite of a lot of effort.

And because of that, the WHO recognizing that time is limited for
vaccine production. And also the fact that many of the viruses have
continued to be A/Panama/2007/99-like, recommended that for the northern
hemisphere, that influenza virus vaccine should continue to have an H3N2
component that they would describe as A/Moscow/10/99-like. For us, that
would be the equivalent of A/Panama/2007/99.

OPERATOR: Peter Palese has joined, please.

DR. LEVANDOWSKI: Okay. The WHO recommendations have been \-- they were
first published on the WHO website at the end of February. And on
Friday, March 14th, the official weekly epidemiologic record publication
of those came out, so those of you who would like to see that
information directly also can access it at the WHO website.

Last week, early last week, the Committee on Proprietary Medicinal
Products for the European Union met to consider what their influenza
vaccine composition recommendations would be. And they announced at
their meeting that they would be publishing recommendations, official
recommendations, later this week that would be exactly the same as what
the WHO had recommended, which would include an A/Moscow/1099-like
virus, which again would mean A/Panama/2007/99.

So our main business today is really to complete the recommendations for
the United States. And the question for the committee really is what
influenza A H3N2 virus should be recommended for inclusion in the
vaccine produced for the 2003/2004 influenza season.

Nancy Cox from CDC will be presenting some additional information on
surveillance and epidemiology.

And again, before Nancy goes on, I should stop and see if you or any of
the committee members have any questions about anything I\'ve mentioned
here.

DR. STEPHENS: Questions for Dr. Levandowski?

DR. MEYERS: What seems to \-- this is Marty. What seems to be the
problem in identifying the seed virus?

DR. LEVANDOWSKI: There aren\'t any seed viruses. And the problem is that
it\'s not been possible to isolate a reference strain in eggs from one
of the \-- that is one of these new variant viruses. All of the isolates
that we have to work with at this point are derived from tissue cultures
of uncertain origins. They\'re the regular laboratory tissue cultures
that are used for recovering viruses. And for the most part, that\'s MD
\-- laboratory grade MDCK virus tissue cultures.

DR. PALESE: Peter Palese. Can I ask \-- well, maybe we should wait until
Nancy has presented her data. But there \-- I realize that there some
New York strains. And wouldn\'t there be some throat washings available
from these patients?

DR. LEVANDOWSKI: Maybe what I can say is that CDC and other WHO
influenza centers are obtaining the original secretions to try to
re-isolate these viruses. And as sometimes happens, these are \-- they
do not seem to replicate that well at all with at all in eggs. Even the
tissue culture isolates are sometimes problematic.

DR. PALESE: I mean, clearly, I mean, I will say that I haven\'t seen an
influenza virus which doesn\'t go in eggs, basically. I mean, it\'s
difficult for me to understand that there are no throat washings
available, particularly from American strains.

DR. COX: This is Nancy Cox. There are throat washings available, and we
have very actively solicited the original particle specimens from our
collaborating laboratories in Hawaii and military labs that have good
access to very good specimens.

And we\'ve actually inoculated approximately 20 or more of those into
eggs, and have not been able to recover any, when normally we would. And
we\'ve also tried primary kidney cells, and we put fewer in because we
just didn\'t have those going as long.

But we were not so far able to recover any in primary kidney cells. I\'m
sure if we had more time, that might be possible.

In addition to the work going on here, work has been proceeding at the
other WHO collaborating centers with some of the national influenza
centers, and it\'s just not been fruitful, and none of us really
understand why. But I think there are probably some answers in the
receptor binding area.

DR. STEPHENS: Nancy, I think \-- why don\'t we go on with your comments
at this point?

DR. COX: Okay. I\'ll try to be quite brief. The influenza activity in
the United States is declining. It\'s pretty apparent from all of the
graphs that we generate on a weekly basis that activity peak during the
sixth week of the year, it comes \-- but there still is a bit of
epidemic level activity going on.

But certainly the intensity has declined, and our sentinel physicians
data indicates we\'re almost down to background with respect to visits
to the sentinel physicians for ILI.

Forty-five percent of the viruses that have been identified this season
are influenza A isolates.

And 46 percent of those subtype, 82 percent of the subtype viruses are
H1 and only 18 percent are H3. And of course, 55 percent of the isolates
are influenza B.

I should say that influenza B predominated during the early part of the
season, and now there are more influenza A isolates being identified
during recent weeks.

But I think that the season has been unremarkable except for the
outbreaks in schools, and those were primarily associated with influenza
B viruses, but we also know that influenza A isolates were obtained from
some of the school outbreaks.

The only \-- and finally, the other thing worthy of mentioning \-- and
I\'m sure some of you have seen some of this in the newspapers and
various other places \-- there have been a number of severe illnesses
associated with influenza infections, and a number of deaths in children
and others.

It\'s not so surprising to us here at CDC because we know that happens
every year, but I think the number of reports has increased a bit
because of the attention on \-- by our peers and then the much greater
efforts that are going into diagnosing various illnesses in this country
now.

But there have also been some reports of encephalopathy associated with
influenza infections in children. And those are all being followed up
and investigated. And I\'m sure you\'ll hear more about those in the
future.

DR. WHITLEY: Nancy, excuse me. This is Rich Whitley. Children in the
United States?

DR. COX: Yes, children \-- I\'m talking specifically about \--

DR. WHITLEY: Okay.

DR. COX: So I think that really sort of covers what I would like to say
about the activity in the United States.

I\'d like the committee members to look at the frequency table, which is
titled Influenza A(HSN2) Isolates Characterized by CDC.

And you saw a similar table during my presentation in February. And we
simply updated this to have the most recent figures for viruses that
we\'ve tested here.

The thing that I\'d like you to note is that we now have about 25
percent of the isolates, H3 isolates that have been \-- that were
obtained between October and March \-- that is to say they have
isolation dates between October 2002 and March 2003 \-- that have
reduced titres to the Panama strain.

If you look more closely at where those viruses have come from, they\'re
predominately from Asia. And that reflects the viruses that we were
talking about. That number of 35 low reactor \-- viruses that we were
discussing at the meeting in February, where we were focusing on some of
the viruses from China, Japan and Korea.

DR. KARRON: Nancy, this is Ruth Karron. I have a question about this
table, and actually how it relates to the previous table that we
received in this packet, that has sera/anti-sera data on it.

The A/Fujian-like viruses would not be low reactors, is that correct?
They seem to have very high homologous titres but equivalent HI titres
to the A/Panama-like viruses.

DR. COX: No, that\'s not correct.

DR. KARRON: Okay.

DR. COX: Some of the Fujian-like viruses have very low titres to Panama.

DR. KARRON: Oh. So my question is this a \-- can we then assume \-- does
this table indicate what proportion of Fujian-like or \--

DR. COX: No \--

DR. KARRON: Not at all?

DR. COX: This table does not. This table is looking overall at the
number of viruses that are reduced fourfold or greater in titre to the
Panama antiserum, compared to the homologous titre to the Panama.

We haven\'t sequenced all of those viruses, that we don\'t know \-- I
don\'t know off the top of my head what proportion of those viruses
would have the 155/156 changes.

DR. MEYERS: Nancy, this is Marty. Given the difficulty in recovering the
variant in both primary kidney and in eggs, do you think the proportion
might be higher, that this may underestimate? It\'s a difficult one to
culture?

DR. COX: We don\'t really know if this is difficult to culture in MDCK
cells. That\'s where the original isolations are typically done
nowadays. And we don\'t really have a feeling that they\'re hard to grow
on MDCK. Their titres are a little bit lower, but the isolation seems to
be fine. The isolation rate seems to be fine.

DR. PALESE: Nancy, you would still say that the \--

DR. STEPHENS: Is this Peter?

DR. PALESE: Peter Palese. Yeah, sorry. That the Fujian-like virus is
represented as a heralding virus at the end of this year, and most
likely, if you wouldn\'t have a problem in terms of having an isolated
virus, you would recommend A/Fujian-like to be the next strain, is that
correct?

DR. COX: If we were able to isolate a virus, and if we had an egg
isolate with the right property for production of vaccines, then yes, we
probably would recommend that strain for the next vaccine. And we would
probably think that would be a good way to go.

DR. PALESE: Thank you.

DR. COX: I think that it isn\'t quite as clearcut. I mean, influenza HI
tests are not quite as clearcut as we would like them to be. And we do
have isolates that have the 155 and 156 change that are well inhibited
by Panama, and we have a large number of them which are not well
inhibited by Panama.

I think that the other issue is that when the lab in the UK has tested
the viruses coming in from Europe, and they have been having increasing
H3 activity over the past several weeks in Europe.

Alan Hayes, who is the WHO Center Director there in London, has said
that a fairly significant number of those viruses are in fact not so
well inhibited by the Fujian antiserum as he would have expected.

And so I think that we felt because a lot of the H3 activity in North
America has been late, we still don\'t know what the significance of the
Fujian variant is.

DR. PALESE: The other \-- Peter Palese again \-- if we look at the table
you gave us, in New York, Alaska, Missouri isolates, they are, in terms
of the ferret antiserum, they are at least ten times better with the
Fujian ferret sera G, for example, as compared to the Moscow.

So that would indicate, you know, that these American ones here, I mean,
we would have tenfold less vaccine than we could have, as compared to
changing the \-- not changing the strain.

DR. COX: Yeah. I think that there are a lot of different ways to
interpret these tables, and I don\'t want to get into too much detail. I
mean, what we\'re really looking at is the homologous titre for Panama,
and then we\'re looking down \-- we\'re looking to see how many \-- what
proportion of viruses have a fourfold reduction in titre, or greater
reduction.

And then because some of these Fujian-like viruses, which would be the
viruses represented by antisera G, H, I, J and K, because they have
higher homologous titres, they tend to look much better down the row.
But if you take into account the higher homologous titres, there are \--
you can see that there are significant reductions in titre for some of
these viruses down at the \-- these antigens down at the end of the
table.

I\'m sorry. I probably wasn\'t very clear on that, but I think you can
probably get what I mean.

DR. STEPHENS: Are there other questions for Nancy?

DR. KARRON: This is Ruth Karron again. I just had a question about
whether we know anything about the severity of illness associated with
A/Fujian-like strains?

And specifically, do we know anything about the cases of encephalopathy
this year in children, and what strain of influenza those were
associated with?

DR. COX: Yeah. We know that the H1N1, H1N2 and B viruses have all been
associated with severe influenza cases and with some of the
encephalopathy cases.

DR. EICKHOFF: This is Ted for Nancy. Is there any data in human sera,
people immunized with the A/Panama and how well A/Fujian viruses are
inhibited?

DR. COX: I\'ll turn that over to Roland, actually.

DR. EICKHOFF: Okay.

DR. LEVANDOWSKI: Yeah. The question is about current vaccines, I
understand, right? About whether they produce antibodies that cross
react well with these Fujian-like strains?

DR. EICKHOFF: Correct.

DR. LEVANDOWSKI: And it\'s not perfect, as it never is when you\'re
looking at serologic results. But there are a number of strains that
were looked at in different laboratories, in which there seem to be
significant reductions in antibody responses to these viruses that have
the 155, 156 amino acid substitution.

It wasn\'t perfect, but as I said, it usually never is. But there is \--
we did see several strains that seemed to have reduced antibody titres,
or that antibody titres against those were reduced as compared to the
vaccine strain.

DR. EICKHOFF: Yeah. Thank you.

DR. STEPHENS: This is David Stephens. A further question about options,
Roland, and potentially Nancy. It sounds like from a practical
perspective, there really isn\'t an option at this point, in the sense
that we don\'t have A/Fujian-like strain that can go grow in eggs.
That\'s correct? And therefore, we\'re a bit stuck at this point.

What about the issue of a supplemental vaccine?

DR. LEVANDOWSKI: This is Roland. I\'ll try to address that. That\'s been
tried in the past. There was an experience in 1986. The A Taiwan/186
H1N1 virus was recognized only very late in the year ads a new variant.
It was about March, I believe.

There was a lot of work that was done to try to make a supplemental
vaccine to target certain populations. Actually, it was young people who
were the biggest concern.

And the problem there was that the vaccine, although manufacturers
worked very hard to produce it, it was only available very late toward
the end of November. And therefore, there wasn\'t a lot of use of the
vaccine.

There was a little bit of confusion on the part of providers \-- and I
know that because I was one of them at the time \-- on who actually
should be immunized.

And so overall, I\'d say the experience was not very positive in terms
of the turnaround time and getting the vaccine to those who needed it.

But the fact is, the positive aspect of that was that it was possible to
do that. Of course, that was at a time when there was quite a lot less
vaccine being used. There were about 20 million doses of vaccine being
produced per year at that point, and a lot less vaccine at use as
compared to today.

We had that discussion earlier in February, about what the implications
of an additional strain would be. And because manufacturers currently
are \-- for the amount of demand they have \-- working pretty much up
until September or October to get the number of doses produced, to add
another strain into that mix at a late time would, whatever number of
doses of that additional strain were produced, would take away from the
total number of doses that could be made in the regular trivalent
vaccine that might be already in production.

Any other questions about that, Dr. Stephens?

DR. STEPHENS: Well, I guess, the concern, certainly my concern, and I
think many of the committee members, is are we going to see the
emergence of the 155, 156 variants and how can we potentially deal with
the possibility.

Obviously, there will be continued work, as I understand it, to try to
get these strains to grow, which is the first step.

It\'s \-- given the issue of SARS and this issue of the emergence of a
new H3N2 \-- I think we\'re all \-- I mean, I think that\'s certainly a
concern of me and many of the other members of the committee.

DR. PALESE: Peter Palese. Can I just ask one question? As we\'re saying,
concerns, you know, that they are not doing the bets \-- that they are
not recommending the best solution in terms of the efficacy of the
vaccine.

The New York Strains, like 2003 and the Hawaii one, et cetera, what
happens \-- they be isolating MDCK cells \-- when they are being put
into eggs, do they grow sufficiently high?

DR. COX: Yes. If those MDCK isolates are subsequently packed in eggs,
they grow okay. It\'s just a matter of not being able to get the
original clinical material to grow an egg.

So we very carefully inoculated both the amnion and the allantoid
cavity, and we used the same techniques that have been used previously
with great success. And it\'s just not working this time. And as I said
before, we don\'t know why.

DR. PALESE: But you have good growing viruses of the Fujian \-- of
Fujian kind?

DR. COX: They grow quite well in MDCK cells, and if you put those
subsequently into eggs, they will grow.

DR. PALESE: Let me then ask sort of the \-- this is posed to Dr.
Levandowski, sort of a challenging question. So the viruses would be
available. They would grow. And the problem is that they have been in
the MDCK cell line, where we don\'t know exactly what the \-- they\'re
not approved cell lines.

However, I mean, what happens if we have a virus isolate which was from
a presentation to have HIV, hepatitis B, hepatitis C and three other
unknown viruses, and we would then still accept that this is being
purified for an \-- egg passage? And would allow it for vaccine
production?

I mean, I\'m not really convinced that just because it was the MDCK
cells, we should make 80 million doses where we know that the H3 is not
good. And just because \-- I mean, we have the unknown of a patient.

I mean, there may be all kinds of isolates in a patient. And just by
having it filled in an \-- egg, rather than purifying it afterwards ten
times, I just \-- I mean the regulatory people have to make the final
decision, and they don\'t have to accept our recommendation.

But for me, it would look that this \-- that we are sort of not making
the best vaccine decision, if we don\'t allow the Fujian type to be part
of this new formulation.

DR. LEVANDOWSKI: Well, if you\'re asking for a response \-- this is
Roland \-- I think that we\'re not alone here in this respect. I think
we\'re in concert with most of the other \-- in fact, all of the other
regulatory authorities that I\'m familiar with.

The concern that you\'re expressing, that we don\'t know necessarily
everything there is to know about every donor of every virus, I think is
true. Many of these viruses do come from otherwise healthy people, but
we never really know what all they might have.

And you\'re right. We have put some sort of hope in use of eggs over the
years that a lot of mammalian type advantageous agents might not
replicate.

But I think the concerns about MDCK and in particular MDCK as they exist
in laboratories that are doing the isolation, there are other concerns
related to other materials that might be introduced. If the materials
are used to support the tissue cultures, the possibility of cross
contamination with other agents and so on.

I don\'t think I\'m answering you entirely, but I think I\'m expressing
what all the regulatory agencies worldwide have been concerned about in
terms of MDCK and in non-qualified cell lines in the laboratories that
are using those.

The historical artifact is that eggs were the first way that influenza
viruses were isolated and we\'re kind of still living with that.

DR. STEPHENS: Okay. Other comments, questions, for Dr. Levandowski or
Dr. Cox?

DR. MEYERS: One other question. This is Marty, again. One of the
questions that came up at the last meeting was the timetable for
reagents and \-- which is of course not dependent upon eggs replication.
What would be the timetable on having reference reagents available if
there was opportunity to continue to find a more appropriate feed virus?

DR. LEVANDOWSKI: Well, the reference \-- this is Roland again \-- the
reference reagents are dependent upon the actual feed virus. They need
to match up with whatever is going to be displaced, as much as possible.

And in fact, the reference antigen that\'s used to preparation, the
comparison is really a vaccine that\'s produced in eggs. We still are
somewhat dependent there.

It is true that it would be possible to consider influenza virus in some
other manner for use as antigen, but the fact is that it requires a
large volume, a very large volume of antigens, so it\'s not really
practical to think about setting up tissue culture flasks in order to
get enough virus to have \-- to produce the antigen.

The timeframe is still the same, from the time we have the strain at
hand until the reagents could be made, if everything was already set to
go. It would be about two months.

And if you\'re asking if \-- are we within that timeframe now, we are
today, but shortly, we will not be. In past years, our recommendations
had been finalized in March. That doesn\'t mean that reagents weren\'t
in preparation prior to that.

I think we started as late as early April in making reagents and still
been able to provide them by the time they\'re necessary for testing the
potency of the third strain of the vaccine, so that the formulation can
begin.

But until we have the actual strain, we really aren\'t able to do much
of anything.

DR. DECKER: This is Michael Decker. You know, it\'s very frustrating to
be in this situation, and I hear that from everybody on the committee,
because it\'s obvious that we would prefer to make the switch if we
could. But it\'s also clear to me that trying to do so is likely to
cause more problems than it will help.

In terms of the best protection for the United States population, the
perfect vaccine, arriving in insufficient quantities and late, will
protect fewer people than the less perfect vaccine arriving abundantly
and on time. And that\'s exactly the situation I think that we have.

The match between the Fujian strains and the A/Panama is not ideal, but
it\'s not bad. And we\'re probably better off at this point, given the
fact that there is no commercially usable, industrial strain, but just
going ahead, sighing, and taking the Panama.

DR. PALESE: Peter Palese. I mean, I can see from a commercial standpoint
of view, it is sort of easier and probably less complicated to stick
with the old formulation. But this is now 1998. This is a five years old
strain, the \-- and I feel that for safety, in terms of purifying it
through egg passages \-- I mean the weighing of a slight risk versus a
much better vaccine.

And I\'m not sure that I really agree that we should just forget about
the H3. And there are ways, I believe, with some \-- I mean, that we
have much better technology now to look whether there are adventitious
agents, one, and I don\'t see a real problem in having one MDCK passage.

I mean, it\'s a tradition from the regulatory people, but on the other
hand, I mean, why we could even make it from \-- viruses now. And I just
don\'t feel that we should \-- if we have the technological abilities to
make better vaccines, then we should make them, rather than sticking to
old regulatory rules.

DR. DOWDLE: This is Walter Dowdle. Could I ask Nancy to give us some
sense of the urgency in the network for isolating such a virus and
growing such a virus in eggs? Because I would assume that the same
issues are going to be coming up very shortly for the southern
hemisphere as well.

So I would assume there\'s a considerable amount of urgency, but if you
could sort of relate that to us, I\'d appreciate it.

DR. COX: Certainly, Walt. This is Nancy and thanks for that question.

There is a lot of urgency, and so there\'s been a lot of \-- with the
National Influenza Center. And I know from speaking with Allan Hayes the
other say, that he\'s been trying to work with all the European labs,
and some of those are very good.

And we have been thinking ahead to the southern hemisphere decisions, of
course. And so we\'re continuing to work as, you know, as intensively as
we possibly can on this issue.

And a lot of discussions have also gone into trying to use reverse
genetics to make vaccine strains that would be \-- that would have the
Fujian-like hemagglutinin neuraminidase.

That brings up a lot of additional intellectual property issues and so
on. But I think there are laboratories which are going ahead and trying
to make these vaccine strains and qualified cell lines, and they would
be suitable vaccine strains.

And, you know, certainly here at CDC, we\'re going to continue our
efforts to isolate appropriate viruses, both using tissue culture, the
primary kidney cells, and eggs.

And, you know, I just can\'t \-- you know, it\'s hard to \-- we all feel
very \-- that this is a very urgent issue. We\'ve all been working on
this very intensively for what seems like a very long time. We\'re very
disappointed that we haven\'t been able to obtain an egg isolate or an
appropriate isolate. So I don\'t know what to say.

The other centers are doing the same. Our colleagues in Japan had felt
that they had what would be an appropriate egg isolate, but it turned
out that that virus had an earlier passage in MDCK cells, and so that it
was not deemed to be appropriate in regulatory terms.

So there\'s been really, you know, very \-- you know, I don\'t want to
say frantic \-- but a very intensive effort around the globe to try to
solve this problem.

DR. DECKER: This is Michael Decker again. Let me remind the committee
that the issue is not simply obtaining an isolate. Even if that could be
done, that is hardly the end of the issue. The goal is not to have an
isolate in the laboratory but to have millions of doses of vaccine.

In 2000, when we had the flu supply debacle, we already had the isolate
by this point in time. If we had the isolate today, we would still have
to obtain a high growth reassortment. We\'d have to be able to take that
into egg production. We would have to await FDA\'s producing the
reagents to test potency.

In 2000, those reagents became in May. Production was already ahead of
the point where it is this year. And when the product was tested, it was
found that the yield from the industrial process was much lower than had
been anticipated. And volumes of available vaccine would only be half to
two-thirds of what had been planned.

All those pitfalls still lie ahead of us this year. And if you elect to
try to go for this new strain, even if you could snap your fingers and
make an isolate tomorrow, you haven\'t removed the risk of those other
pitfalls.

And I just have to wonder: A strain that can\'t be isolated in the
world\'s best labs, are you sure it\'s going to be easy to grow in
industrial volumes in eggs?

DR. STEPHENS: Okay. I think we need to move now to at least having a
brief \-- or if there\'s any open public discussion. Jody, do you want
to introduce that?

DR. SACHS: Sure. At this part o 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 who 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 at this time?

DR. STEPHENS: I would like to hear from the PowderJect/Evans Group, if
they want to make any comments about this issue.

DR. O\'BRIEN: (Poor connection) Actually \-- Michael Decker\'s concerns
\-- difficulties in flu production. The earlier start we get, obviously
the better. This will be a significant delay, and therefore it would
jeopardize the number of doses which could be made available for a year.

I think I\'ve mentioned before, it\'s got to be a balance between the
total number of doses that can protect a certain number of people and
that they are effective. And someone\'s got to find that balance,
obviously.

DR. STEPHENS: Are there other comments, other questions?

DR. SACHS: I would like to thank the participants at the open public
hearing. And at this time, if there\'s no other comments in the open
public hearing, I\'d like to turn the meeting back over to you, Dr.
Stephens. Thank you.

DR. STEPHENS: Okay. I think that we\'re now coming to kind of final
discussion and recommendations for the vaccine. I would like to make
sure that there are no additional questions.

I just have one further question from a regulatory standpoint. And
Roland has given his comments, but are there other FDA comments about
the use of an MDCK variant for vaccine production?

DR. MIDTHUN: I guess \-- this is Karen Midthun, FDA. I just think that,
you know, it is a tumorigenic cell line. It\'s not previously used in
any vaccine production.

That\'s something that would really have to be very closely considered
and characterized to determine, whether that was an acceptable cell
substrate for something to have been passage through.

DR. STEPHENS: The practicalities, though, make that a long-term process,
I would guess?

DR. MIDTHUN: I\'m sorry. Could you \--

DR. STEPHENS: I\'m sorry. The practicalities of making those
determinations are a \-- not something that can be solved quickly?

DR. MIDTHUN: That\'s correct.

DR. STEPHENS: Okay. Roland, I think it would be helpful just to restate
the question for the committee at this point and your opinions about
options.

DR. LEVANDOWSKI: Okay. I\'d be happy to restate the question. It\'s very
straightforward. The question for the committee is what should be the
H3N2 influenza component of the influenza vaccine to be used in
2003/2004.

And if you\'d like me to, I\'d just \-- I can give a sort of a summary
about the information. And I think it covers some of what has already
been discussed.

But I think it probably is worthwhile reiterating some of the points in
terms of what the options are that are available to us at this point, if
that\'s okay, Dr. Stephens?

DR. STEPHENS: Yes, that\'s fine.

DR. LEVANDOWSKI: Okay. So, you know, as we\'ve talked about or as we\'ve
done typically in our meetings, there \-- actually, there are probably
three options.

The first one here is that we could keep the same strain. We would
continue to use A/Panama/2007/99 strain as the vaccine virus. And
actually in favor of that, still the majority of the viruses that are
being isolated are A/Panama/2007/99-like characterization of their
hemagglutinins.

We know that manufacturing is worked out and the yield is very
predicable. And as we also heard, some \-- what would be against
continuing to use the same strain for the vaccine would be that there is
an increasing proportion of recent H3N2 viruses that are not well
inhibited by post-infection or post-immunization antisera.

Highly consistent between the strains. There is some variation, as I
mentioned. Many of these recent viruses, however, do seem to have
signature amino acid changes, which suggest that a variant is
developing.

And there\'s evidence that that new variant can spread. It\'s been
identified in Europe and Norway and the United Kingdom, there are
isolates.

There may be others that are coming because we\'re not entirely finished
with the surveillance and epidemiology. There are isolates from Asia,
from China, Japan and Korea. And there are also isolates from North
America, both the United States and Canada.

And as has been pointed out when we see new strains, they often tend to
spread rapidly in susceptible populations when there\'s a herald wave
phenomena, in particular where there\'s a large increase in the number
of the new variants. Sometimes that following year, we see those
becoming the predominant strains.

And, of course, are concern is that the H3N2 influenza viruses are
highly associated with morbidity and mortality.

That brings me to the second option, of course, is to try to change the
vaccine strain. And in favor of that would be that these new variants
are spreading geographically and they have been causing illness, and
that a large portion of the population may be susceptible to those
strains.

We would like to suspect that a new strain would provide a closer match
with the hemagglutinin and neuraminidase of the contemporary strain.

But the fact is that we don\'t always known whether a new strain, even
if it is supposedly a better antigenic match, will provide any superior
coverage to the current strain. We only find that out in retrospect,
after the vaccine is produced.

And of course, also not in favor of trying to make a change is the fact
that we really do not have a suitable influenza virus in hand that could
be used for manufacturing, and there\'s absolutely no information about
what difficulties might arise in manufacturing.

The third option usually is to postpone the decision, but we\'re at that
point in time where there will probably not be a lot of additional
helpful information that we\'ll be able to provide. And manufacturing
really does need to proceed at this point in time.

I guess I can stop there, Dr. Stephens, and ask if there are questions
or comments.

DR. STEPHENS: Questions, comments?

DR. MEYERS: Well, it\'s probably not answerable, but I\'d just like to
ask Nancy about the serology and other tests that have been run on these
\-- on this severe acute respiratory syndrome, and whether she is
comfortable that this is not an H3N2 that is just being difficult to
cultivate in vitro?

DR. COX: Okay. I think I can address that very efficiently. We\'re sure
\-- we don\'t have a lot of appropriately collected sera yet. More is
coming in. But a lot of work on \-- and again, some of the best labs in
the world looking by PCR, culture and using a whole variety of different
antibodies that are pegged to different groups of influenza. And so far,
everything is negative for flu.

DR. MEYERS: Thank you.

DR. STEPHENS: Okay. Well, I think there doesn\'t sound like there\'s
further questions at this point. And I \--

DR. PALESE: Peter Palese. Can I ask one other question?

DR. STEPHENS: Yes, please.

DR. PALESE: So what would happen, for example, if the committee
recommended change? And the FDA doesn\'t have to accept that
recommendation, is that correct?

DR. COX: Yes, that\'s correct. You\'re advisory to us.

DR. PALESE: Okay.

DR. STEPHENS: Okay. Well, I think, if there are no further comments, we
will take \-- I think this is correct, Jody \-- a roll call vote on this
issue.

DR. COX: Yes, that\'s correct. But you need to present which question
you\'re asking for the vote.

DR. STEPHENS: The question is what strain, what H3N2 strain, should be
recommended for antigenic composition of the 2003/2004 inactivated
influenza virus vaccine. I think that\'s correct, isn\'t it, Roland?

OPERATOR: Karen Cox is joining.

DR. LEVANDOWSKI: Yes.

DR. STEPHENS: I think we\'ll pretend like we\'re having a similar
seating chart to what we had on the 20th of February, and would start
with Dr. Katz. Doctor, I\'ll put you on the spot today. Sam? Is he still
\-- is Sam Katz still here?

DR. COX: He might be on mute. Well, we can move on and try to pick him
up later.

DR. STEPHENS: Right.

OPERATOR: Excuse me. Bruce Gellin has joined the conference.

DR. COX: Great. Thank you.

DR. STEPHENS: Dr. Meyers?

DR. MEYERS: Well, I\'m very uncomfortable in \-- in that I really think
we have an emerging new clave and we don\'t have a seed virus. And so I
guess we\'re better to have an H3N2 in there. And so I guess I would
vote to stick with the same strain.

DR. STEPHENS: And so you\'re voting for a A/Panama/2007/99
recommendation, is that correct?

DR. MEYERS: Correct.

DR. STEPHENS: Okay. Dr. McInnes?

DR. McINNES: A pragmatic recommendation for me was, I think, less than
ideal, but I would go

A/Panama/2007/99.

DR. STEPHENS: Dr. Eickhoff?

DR. EICKHOFF: Well, I will cast my vote as did Marty Meyers, retain the
present strain. But for the first time in many years of participating in
these deliberations, I must add I am very uncomfortable with that
recommendation.

DR. STEPHENS: Is Dr. Gellin here?

DR. GELLIN: Yeah, I just dialed in. I think \-- I don\'t think I can
weight in, since I didn\'t benefit from the discussion.

DR. STEPHENS: Okay. David \--

DR. KATZ: This is Sam Katz. I stepped out of the door to grab a quick
other call when you called my name, but \--

DR. STEPHENS: Well, we called you first.

DR. KATZ: I know, that was what I was afraid of. You did that through
all the last meeting, too.

DR. STEPHENS: Well, you were at the end of the table on the chart, so
I\'m just following protocol.

DR. KATZ: I just wanted you to know I was here for the whole call and I
missed that last 30 seconds when you called me. But I would have to go
along in \-- reluctantly, but with \-- I don\'t see a practical
alternative \-- voting to stick with the Panama.

DR. STEPHENS: Dr. Cox?

DR. COX: I agree with what Sam said. A/Panama, but, you know, I think we
all have concerns.

DR. STEPHENS: Sure. Walt Dowdle?

DR. DOWDLE: Panama.

DR. STEPHENS: Peter Palese?

DR. PALESE: I feel very strongly that we should change the strain to the
Fujian-like. And it\'s based on the fact that, one, there is a herald
wave. It\'s a good indicator that this will be the next strain.

And two, that I feel that the slight risk of the egg passage, I think
can be, with scientific means, can be gauged or estimated by passaging
it five, six times through embryonated eggs. I feel that it is better in
the long run to have a good vaccine or a better vaccine, where the H3
component is really effective, then having just a potential very, very
minimal risk in terms of a formaldehyde treated vaccine. So I would like
to vote for a change.

DR. STEPHENS: Knowing that there is no current candida at this point?

DR. PALESE: I \-- okay. I disagree with \-- I mean, this virus \-- this
virus are going well in embryonated eggs. We were told by Dr.
Levandowski that the timeframe, if we had a virus on March 18th, that
this will be enough to get all the reagents.

Otherwise, I mean, there was no point in delaying it. I mean, our
February meetings was predicated on the fact that if there is some more
evidence in three weeks later, that we would have a choice of what we
\-- a good, a better reason to choose one or the other.

And I just feel that one passage of MDCK cells is not necessarily where
we should jeopardize 80 million doses and also give the influenza virus
vaccine a bad name because many people may get sick.

DR. MIDTHUN: This is Karen Midthun \-- I would just like to reiterate
that at this point, it really would not be possible to qualify whatever
MDCK line has been used.

And so in that the issue that Dr. Stephens raised before, you know,
it\'s not that there isn\'t something that, you know, we can\'t
consider. It\'s just that one really needs to know a lot about the cells
that were used. They need to be qualified, characterized, to really
address the different safety issues that we feel need to be addressed.

So I just thought that might be helpful to others, to have that
information.

DR. PALESE: Look, I mean, that\'s sort of a decision on the FDA \-- I
mean, I think one can make a reasonable argument that we don\'t know
what kind of adventitious agents are in human isolate as well, and that
we are perfectly happy to accept that.

I mean, we\'re not asking for manufacturing vaccines in MDCK cells, but
rather be sure that what is put into embryonated eggs is as pure as be
free from adventitious agent as we can, with the best of our technology,
assure at this point.

So I think the question whether it\'s an FDA approved cell line or not,
I mean, is sort of \-- I mean, we are not \-- I don\'t think anyone use
MDCK cells to produce 80 million doses.

DR. STEPHENS: Okay. I think that your position is clear. Let\'s move to
Dr. Markovitz.

DR. MARKOVITZ: Yes. I would have to vote for retaining the A/Panama.

But I also would like to go on record as urging that we have an
exploration of these issues that Dr. Palese has raised, so that if we
have this in the future, perhaps we\'ll be able to move more
expeditiously.

DR. STEPHENS: Dr. Diniega?

COLONEL DINIEGA: This is Ben Diniega from Health Affairs. I vote to
retain the A/Panama, but agree with the need to continue efforts to try
to get the Fujian-like strains grown on eggs.

DR. STEPHENS: Dr. Royal? Dr. Royal? Dr. Manley? Hello? Walter?

DR. ROYAL: Yes, I\'m back.

DR. STEPHENS: All right.

DR. ROYAL: I guess my mute was on. I agree with the comments with
respect to the Fujian strain. Again, I\'m forced to cast my vote for
retaining the A/Panama.

DR. STEPHENS: Dr. Manley? Is she on the line?

DR. MANLEY: I am. I would vote to retain the A/Panama.

DR. STEPHENS: Dr. Goldberg?

DR. GOLDBERG: I vote to retain the A/Panama. However, I do believe that
we have to make plans for a strain change and do everything that Dr.
Palese is suggesting, and my other colleagues.

DR. STEPHENS: Dr. Overturf?

DR. OVERTURF: I would also vote to retain the A/Panama \--

(Line feedback.)

DR. STEPHENS: Okay. Well, that was fun.

(Laughter.)

DR. STEPHENS: Gary?

DR. OVERTURF: I would also vote to retain A/Panama-like agents. But I
think that it\'s really very clear that we are going to have to plan
contingencies, which may include certifying other cell lines for culture
to produce other strains. Because that may be necessary, because I think
we\'re going to have to change this next year.

DR. STEPHENS: Dr. Karron?

DR. KARRON: I vote very reluctantly to retain the A/Panama and would
like to ask in future meetings that we hear updates about ability to
isolate appropriate A/Fujian-like viruses, so that hopefully we\'re not
in this position next year.

DR. STEPHENS: Dr. Parsonnet?

DR. PARSONNET: I agree with the last comment and also would love to hear
updates. So I vote for Panama, but I \'d also love to hear updates about
our ability to explore other tissue culture systems for growing viruses
in the future.

DR. STEPHENS: Dr. Fisher?

DR. FISHER: Well, because there are an increasing number of cases of new
variant H3N2 viruses causing flu, I feel uncomfortable voting for
inclusion of an A/Panama-like virus, when what may really be needed is
an A/Fujian-like virus.

So I\'m going to abstain and urge that the public be informed that next
year\'s flu vaccine may not be protective against an emerging strain.

DR. STEPHENS: Okay. Dr. Diaz?

DR. DIAZ: I\'m still here. I would prefer that we move to an
A/Fujian-like strain. However, it seems from a regulatory standpoint and
from a practical standpoint, in terms of manufacturing, we somewhat have
our hands tied.

So I would agree that we need to maintain the A/Panama strain in next
year\'s vaccine.

OPERATOR: Excuse me \-- has joined.

DR. DIAZ: I would also give the same urgency to looking at manufacturing
processes in particular and new strain lines \-- or new cell lines to be
able to be used. I don\'t think this will be the last time that we will
be faced with this issue.

DR. STEPHENS: Okay. Rich Whitley? Is he still on the line?

DR. WHITLEY: I\'m here, Dave. I don\'t think \-- obviously, practically,
we have to maintain A/Panama, but I want to reiterate what Peter said.
And that is, if we\'re not prepared to have Fujian-like strains
incorporated into next year\'s vaccine, we\'re making a mistake, number
one.

And I\'d like to make one other point. And Nancy alluded to it earlier
in this conference call. And this is, this issue of encephalopathy in
children can\'t be swept under the carpet. And we need to know more
about that as quickly as possible.

We need to know whether it\'s in vaccinated individuals or
non-vaccinated individuals, and we need to know the strain type, not
that it\'s just globally associated with all three.

We know what happened in Japan. We know what\'s happening in Japan. And
if this is a potential cofactor in immunization, we\'d be making a
mistake not to know more.

DR. STEPHENS: Thank you. Anyone that I\'ve missed?

DR. SACHS: Dr. Decker needs to state his opinion for the record, please.

DR. STEPHENS: Okay. Mike?

DR. DECKER: My opinion is that the ideal strain would be a Fujian, but
neither regulatory nor industrial circumstances permit us to pursue that
this year. And I\'m confident by the time we have to pursue it next
year, we\'ll have appropriate isolates.

Meanwhile, I think the public health is best served by proceeding with
the A/Panama because it gives adequate cross-protection. Not ideal, but
adequate.

And widely immunizing the population with an adequate vaccine will
better serve the public health than immunizing them with a somewhat
better vaccine only a fraction of the same population.

DR. SACHS: Dr. Stephens, the next vote is yours.

DR. STEPHENS: Okay. Well, I share the majority\'s of the committee\'s
reluctance about accepting A/Panama, but I really don\'t think we have a
choice at this point. I certainly would like to see a change, if we
could do that, to A/Fujian, but that\'s currently not possible.

I would like to continue to have this, as has been suggested by others,
as a topic for \-- in our future meetings.

I would also urge continued consideration of the supplemental idea. And
although it has not been that successful in the past, it certainly is
something that as we get strains that do grow in eggs, that it\'s
something that we may want to continue to consider.

DR. SACHS: This is Jody Sachs. I\'d like to just sum up the vote, if I
may. It looks like 17 have voted to retain and keep the Panama \--

DR. MIDTHUN: Can you speak up?

DR. SACHS: Sure. This is Dr. Sachs. I\'d like to sum up the results. It
looks like 17 have voted to retain the current strain. And it looks like
two have abstained and one has stated that they would like a new strain,
the Fujian-like strain replacing the old strain.

DR. STEPHENS: Okay. Other \-- any additional comments at this point?

DR. KATZ: I have a question, David. This is Sam Katz. At the last
meeting, in answer to a question that I submitted, someone said that
there was a vaccine licensed in Holland that was prepared in tissue
culture and not in eggs. Can Nancy or Roland or anyone tell us more
about that? I think it was a vero cell.

DR. LEVANDOWSKI: This is Roland Levandowski. There are two vaccines that
are registered in some country, at least one country in Europe. I don\'t
believe that they\'re widely registered at this point.

The two companies that have registration for a tissue culture vaccine or
what used to be called \-- are they have an MDCK tissue culture vaccine
that they have in registration. The other vaccine is from Baxter
Healthcare. Their vaccine is produced in vero cells.

So there are those two tissue culture vaccine products that may be
available there.

You should know that those companies are also dependent upon egg
isolates. The regulatory authorities in Europe, under the current
conditions with the tissue cultures that are used, laboratories for
collecting viruses are still recommending that an egg isolate be used
for that manufacturing, until issues related to getting availability of
appropriate tissue cultures for isolation can be worked out.

DR. KATZ: Thank you very much.

DR. MEYERS: The tissue culture derived vaccine in Canada, I believe.

DR. LEVANDOWSKI: This is Roland again. There are companies that have
products in development in a number of places. And you are correct that
the company that used to be called Biochempharma \-- I guess it\'s now
Shire \-- are developing a tissue culture vaccine and has published
about their vaccine. That one, too, was an MDCK vaccine that was being
developed. But it\'s not in use anyplace and it\'s not in use in Canada,
as far as I know.

DR. MEYERS: And just one other thing, Sam, was that at the APIP meeting,
I believe somebody from Baxter and that\'s \-- that it was their
intention to enter the U.S. marketplace.

DR. KATZ: Thanks.

DR. STEPHENS: Okay. If there are no further comments, Jody, any comments
about future meetings?

DR. SACHS: Yes, I\'d like \-- to remind everybody that the next meeting
is scheduled for May 8th and 9th. And I\'ll shortly have additional
information regarding that meeting that I\'ll send out to everybody. But
I just wanted to say please save the May 8th, 2003 date, because that is
the next date coming up. Thank you.

DR. STEPHENS: Jody, are you implying that May 9th may not be used, or
did you know?

DR. SACHS: Yes. I am implying that May 9th may not be used. Officially,
I\'d like to wait another week or so, but I\'d like you to save the May
8th and reserve that date. And shortly, I\'ll be sending you details on
the next meeting.

Thank you and thank you all for participating. I appreciate your calling
in and participation.

DR. STEPHENS: Thank you very much.

(Whereupon, the meeting in the above-entitled matter was adjourned at
12:05 p.m.)