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]{.underline}: 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]{.underline}:

WILLIAM EGAN, M.D.

ROLAND A. LEVANDOWSKI, M.D.

KAREN MIDTHUN, M.D.

DENISE ROYSTER

I-N-D-E-X

[Agenda]{.underline} [Page]{.underline}

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.)