UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL

PRODUCTS ADVISORY COMMITTEE

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94th MEETING

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THURSDAY,

FEBRUARY 20, 2003

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.

The Advisory Committee met at 8:30 a.m. in the Versailles Ballroom of
the Holiday Inn Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr.
David S. Stephens, Chairman, presiding.

[PRESENT]{.underline}:

DAVID S. STEPHENS, M.D. Chairman

ROBERT COUCH, M.D. Temporary Voting Member

NANCY COX, Ph.D. Temporary Voting Member

MICHAEL DECKER, M.D., M.P.H. Non-Voting Industry Representative

PAMELA S. DIAZ, M.D. Member

COLONEL BENEDICT DINIEGA, M.D. Temporary Voting Member

[PRESENT]{.underline}: (cont.)

WALTER DOWDLE, Ph.D. Temporary Voting Member

BARBARA LOE FISHER Temporary Voting Member

BRUCE GELLIN, M.D. Temporary Voting 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

PAMELA McINNES, D.D.S. Temporary Voting Member

MARTIN MYERS, M.D. Temporary Voting Member

GARY D. OVERTURF, M.D. Member

PETER PALESE, Ph.D. Member

JULIE PARSONNET, M.D. Member

WALTER ROYAL III, M.D. Member

JODY SACHS, D.P.M. Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

CARL FRASCH, Ph.D.

ROLAND LEVANDOWSKI, M.D.

KAREN MIDTHUNE, M.D.

RICHARD WALKER, Ph.D.

ZHIPING YE, M.D., Ph.D.

[ALSO PRESENT]{.underline}:

LINDA CANAS Department of Defense

SAMSON LEE, Ph.D. Aventis Pasteur

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

Call to Order 5

Dr. David Stephens, Chair

Introductions 5

Administrative Matters 7

Dr. Jody Sachs, FDA

[Session 1 - OPEN SESSION]{.underline}

[Strain Selection for Influenza Virus]{.underline}

[Vaccine for the 2003-2004 Season]{.underline} 11

Introduction 11

Dr. Roland Levandowski, FDA

U.S. Surveillance

and

World Surveillance and Strain Characterization

and

Molecular Characterization of Strains 22

Dr. Nancy Cox, CDC

Additional Surveillance Reports 65

Linda Canas, DOD

Vaccine Responses 80

Dr. Roland Levandowski, FDA

Availability of Strains and Reagents 106

Dr. Zhiping Ye, FDA

Comments from Manufacturers 108

Dr. Sam Lee, Aventis

Options for Strain Selection 127

Dr. Roland Levandowski, FDA

Committee Discussion and Recommendations 170

Vote Taken 174

H1N1 174

H3N2 177

C-O-N-T-E-N-T-S (Continued)

[Section 2 - Open Session]{.underline}

[Laboratory of Bacterial Polysaccharides]{.underline} 192

Overview of Division of Bacterial,

Parasitic, and Allergenic Products 192

Dr. Richard Walker, FDA

Overview of Laboratory of Bacterial

Polysaccharides 206

Dr. Carl Frasch, FDA

Open Public Hearing 214

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

8:36 a.m.

CHAIRMAN STEPHENS: Good morning. Welcome to the first meeting, the 2003
meeting, of the Vaccines and Related Biological Products Advisory
Committee.

I would like to start by going around the room and introducing our
members and consultants. Dr. Katz, would you like to begin?

DR. KATZ: I\'m Samuel Katz from Duke University.

DR. COUCH: I\'m Robert Couch, Baylor College of Medicine in Houston.

DR. MYERS: I\'m Martin Myers from the University of Texas in Galveston.

DR. McINNES: I\'m Pamela McInnes, National Institutes of Health,
Department of Health and Human Services.

DR. COX: I\'m Nancy Cox, CDC, Atlanta.

DR. GELLIN: Bruce Gellin, National Vaccine Program Office, Department of
Health and Human Services.

DR. DOWDLE: Walter Dowdle, Task Force for Child Survival and
Development, Atlanta.

DR. PALESE: Peter Palese, Mt. Sinai School of Medicine, New York.

DR. MARKOVITZ: David Markovitz, the University of Michigan Medical
School.

DR. DINIEGA: Ben Diniega, Department of Defense, Health Affairs.

DR. ROYAL: Hi. My name is Walter Royal, Morehouse School of Medicine,
Atlanta, Georgia.

DR. GOLDBERG: Judith Goldberg, New York University School of Medicine.

DR. OVERTURF: Gary Overturf, University of New Mexico.

DR. KARRON: Ruth Karron, Johns Hopkins University.

DR. PARSONNET: Julie Parsonnet, Stanford University.

MS. FISHER: Barbara Loe Fisher, National Vaccine Information Center.

DR. DECKER: Michael Decker, Vanderbilt University and Aventis Pasteur.

DR. DIAZ: Pamela Diaz, Chicago Department of Public Health.

DR. LE: Zhiping Le, CBER, FDA.

DR. LEVANDOWSKI: Roland Levandowski, the Center for Biologics.

CHAIRMAN STEPHENS: And I\'m David Stephens from Emory University in
Atlanta, where it was 60 degrees yesterday and we\'re expecting our
first flowers.

(Laughter.)

I want to thank everyone for coming and braving the weather.

We\'ll begin with Dr. Sachs, who has some introductory comments.

DR. SACHS: Good morning. I\'m Jody Sachs, the Executive Secretary for
today\'s meeting of the Vaccine and Related Biological Products Advisory
Committee.

I would like to welcome you all to the 94th Meeting of the Advisory
Committee. This morning\'s session will consist of presentation and
Committee discussions that are open to the public. Then in the afternoon
we\'ll go into a Closed Session until the meeting is adjourned, as
described in The Federal Register notice of January 21st, 2003.

I ask that all our Committee members identify themselves each and every
time they talk, since we have a transcriber present who will need your
assistance in order to attribute all the comments to the appropriate
Committee member.

I also ask our Committee members and the public to place your cell
phones on mute since this adds a distraction that is unnecessary to the
meeting.

I would like to list the following individuals as not present today: Dr.
Richard Whitley, Dr. Theodore Eickhoff, Dr. Dixie Snider, Dr. Audrey
Manley.

There are two presenters that will not be present today, so there will
be a change in the agenda. The two people from CDC, Dr. Alexander Klimov
and Dr. Keiji Fukuda.

I would like to read a statement for the record. \"The following
announcement addresses the conflict-of-interest issues associated with
the Vaccine and Related Biological Products Advisory Committee meeting
on February 20th, 2003.

\"The Director of the Center for Biologics Evaluation and Research has
appointed Dr. Robert Couch, Dr. Nancy Cox, Dr. Walter Dowdle, Dr.
Theodore Eickhoff, Dr. Bruce Gellin, Dr. Pam McInnes, Dr. Martin Myers,
Dr. Dixie Snider, Colonel Benedict Diniega, and Ms. Barbara Fisher as
temporary voting members of 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 conflicts of
interest existed. The agency reviewed the agenda and all the relevant
financial interests reported by the meeting participants.

\"The Food and Drug Administration prepared general matters waivers for
the special government employees participating in this meeting who
required a waiver under 18 USC 208.

\"Because general topics impact on so many entities, it is not prudent
to recite all potential conflicts of interest as they apply to each
member. FDA acknowledges that there may be potential conflicts of
interest, but because of the general nature of the discussions before
the Committee, these potential conflicts 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 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 the
manufacturer of the product that could be affected by today\'s Committee
discussions.

\"In the event that the discussions involve specific products of firms
not on the agenda, and for which the FDA\'s participation have a
financial interest, the participants are reminded of the need to exclude
themselves from the discussions. Their recusal will be noted for the
public record.

\"With respect to all other meeting participants, we ask, in the
interest of fairness, that you state again your name and affiliation and
any current or previous financial involvement with any firm whose
products you wish to comment upon.\"

I now wish to turn the meeting over to our Chair, Dr. David Stephens.
Thank you.

CHAIRMAN STEPHENS: I want to issue a welcome to two new members of the
Committee, Dr. Karron, welcome, and Dr. Royal. We appreciate very much
your service.

I also want to welcome back Ms. Fisher, who was on the Committee for
four years and is back for this meeting.

With that, I think we will begin the program. Our first session deals
with strain selection for influenza virus vaccine for the 2003-2004
season. Dr. Levandowski will give our first presentation.

DR. LEVANDOWSKI: Thank you, Dr. Stephens.

I hope everybody can hear me. I hope this microphone\'s okay.

Good morning. Welcome to Bethesda. I\'m glad to see everybody here.

Actually, before I begin my introductory remarks for the session, I
wanted to bring to the attention of the Committee and others that
yesterday and today, many of you already know actually that the Hong
Kong Department of Health and the World Health Organization made press
releases indicating that there has again been evidence of avian
influenza viruses causing human infection in Hong Kong residents.

These press releases indicate that the influenza A virus is of the H5N1
subtype, and it has been isolated from a 9-year-old boy who became ill
early in February. There\'s also evidence of H5N1 in the lung of the
boy\'s father, who died on Sunday.

The source of this H5 virus isn\'t determined, but there has been
continuing H5N1 influenza activity in waterfowl and other birds in Hong
Kong during the past year, and in particular during December, when there
were a number of deaths of waterfowl in some of the parks in Hong Kong.

Investigations involving the family and the family\'s potential exposure
to the H5 viruses in this particular instance is continuing. It is
expected that there is going to be more information available in the
near future, and we expect to bring a lot more information at a later
date, but today we will need to defer those discussions with the
Committee until we\'ve had an opportunity to really review and to verify
the information.

So I would like to make sure, I would like to encourage that since our
primary task is strain selection, that we spend most of our time dealing
with those issues, which are really going to be quite interesting, I
think.

So, as always, that is our business today, which is to make the
recommendations for the influenza vaccines to be used in the 2003 and
2004 season coming up. This is the basic question that we ask the
Committee every year, what we need to address here: That is, what
strains should be recommended for inclusion in the influenza vaccines
for the 2003 and 2004 season?

This Committee has been charged with the responsibility for making the
influenza composition recommendations on behalf of the U.S. Public
Health Service, but the recommendations also have implications for the
Department of Defense, since the same strains are used both for the
civilian vaccine and also for production of vaccines that are used by
the military.

The basis for the recommendations really comes from information that
we\'re going to supply this morning in these areas that are shown on the
slide. Most importantly, we need to know if new influenza viruses are
evolving in nature, and there is an extensive international network
that\'s supported by the World Health Organization and its collaborating
laboratories to collect and analyze information on influenza throughout
the year, as we will be hearing from our colleagues from CDC and from
the Department of Defense.

In addition, we\'re going to be hearing a significant amount of new data
that has only been developed within the last couple of weeks. When new
variant influenza viruses are identified, the extent of the geographic
distribution of those variants helps to judge the urgency, and changing
the composition of the vaccine, often antigenic variants appear, but
sometimes these represent just dead-end branches on the evolutionary
tree.

As we have seen in the case of influenza B in Asia in the recent past,
there could be some very significant differences in antigenicity of
viruses that can spread in one geographic location, but may stay there
for a number of years. Our experience was that for 10 years we didn\'t
see the strains in Asia spreading to the rest of the world, but that
happened last year.

Of course, we have also seen just the opposite occurring. With
significant new influenza variants, sometimes there\'s very rapid
spread. A recent example of that would be the A/Sydney/5/97 virus. That
virus was first isolated in Australia during our summer months, but by
winter of that same year it was very widespread in North America. That
was after it had first appeared in August amongst passengers on cruise
ships that were touring the maritime provinces of Canada.

If these new strains do appear to be disseminating widely, it\'s useful
to know whether or not antibodies are induced by the current vaccines
and whether those are likely to inhibit these recently-circulating
viruses. For this, we rely on information from serologic studies that
are gathered from persons who have been immunized with current
inactivated influenza vaccines.

Finally, if the new variants arise, disseminate, and appear to be poorly
inhibited by current vaccines, practical matters still need careful
consideration. For the inactivated influenza viruses there\'s an
increasingly pressing question about whether enough vaccine can be made
to meet the demand that\'s out there. The wild-type strains often grow
very poorly, so that high-growth influenza A viruses need to be prepared
to facilitate large-scale manufacturing of inactivated vaccines.

In formulating an answer to the question, it is helpful to review a few
facts about the currently-approved inactivated influenza virus vaccines.
We know that inactivated vaccines act primarily to induce the production
of antibodies, mainly to the hemagglutinin. The hemagglutinin and the
neuraminidase of influenza viruses incorporated in the current
inactivated vaccines are concentrated, and they\'re partially purified
to remove extraneous materials that are derived from the eggs in which
the vaccines were produced.

But, as part of the production, the inactivated vaccines are only
standardized for the content of hemagglutinin, and, therefore, we place
the great emphasis on the viral hemagglutinin. However, we do consider
the neuraminidase because it, too, can add to the protective efficacy of
vaccines. Where possible, we have tried to match those up.

Since the use of the first inactivated vaccines in the 1940s, it has
been very clear that one of the most important predictors of vaccine
protective efficacy is the match of the vaccine viruses with the
influenza viruses that are currently causing infection.

What we have seen also is, however, that every year there\'s the
possibility for a lot of antigenic diversity, some of which may be
important and some of which may not be so important.

We will talk about antigenic drift. Mainly, that refers to the ongoing
random mutations that are occurring in the hemagglutinin and in the
neuraminidase. But, occasionally, there is introduction of an entirely
new gene for either hemagglutinin and neuraminidase, and that\'s
referred to as antigenic shift.

In this slide I\'m giving a very brief overview of the timelines for
preparation of influenza vaccines. The emphasis in this slide is on the
use of the vaccine, which generally occurs in fall months. But if you
look at that and work backward through the preparation and the support,
you see that there\'s a lot that has to happen at certain times in order
for everything to go forward.

A number of times the surveillance information has not been ‑‑ although
it\'s going on all the time, we get new surveillance information always,
and the influenza viruses, of course, don\'t always cooperate with us in
terms of this timeline. They show up whenever they do in terms of the
natural evolution.

A new concern that we have this year in terms of this vaccine use in the
fall is that we now have only two manufacturers of inactivated vaccine
supplying the United States. Those two manufacturers are Aventis Pasteur
and Evans PowderJect. You probably have seen press releases to know
this, but Wyeth announced at the end of the 2002 influenza vaccine
production campaign that it would no longer produce inactivated
influenza virus vaccines.

Although the current manufacturers have given us assurance of their
intent to fill the gap that\'s left by Wyeth\'s departure, we can be
certain that any shock to the system is more likely to be evident for
all of us in terms of what happens.

When there are multiple manufacturers, it\'s possible that if one
manufacturer experiences a temporary problem, then others can pick up
the slack and help out. That\'s been true often in the past. However, if
one of the two remaining current manufacturers experiences a problem,
the probability is now a lot greater that there will be a delay or a
shortage of vaccine during the vaccine preparation period.

That\'s not to say, however, that the vaccines don\'t need to remain
current. They do, in order to maintain effectiveness. Of course, we do,
and the manufacturers do too, anticipate change on a regular basis, but
each one of those changes represents a certain amount of risk to the
vaccine supply, particularly when we don\'t have all the details to
support manufacturing worked out well in advance.

So this slide shows the most recent recommendations from both this
Committee and from the World Health Organization. The recommendations on
the left are the ones that were made by the Committee for this current
production year that we\'re using the vaccine from.

The recommendation last year included one change to the trivalent
vaccine, and that was for the new influenza B strains, which are shown
at the bottom of the lefthand column. Actually, during the past year\'s
campaign, two different influenza B viruses meeting the recommendation
have been in use, and those actual strains in the United States are the
Hong Kong/330/01 strain and the Hong Kong/1434/02 strain.

The recommendations on the right are those that have just been made by
the World Health Organization for 2003 production in the Northern
Hemisphere. I would ask you to note that those most recent
recommendations, which were made on Friday of last week, include the
very unusual postponement of recommendation for the H3N2 strain. That
postponement relates to the fact that there was late-breaking
information about influenza A H3N2 viruses. We will be presenting some
of that information this morning, along with a lot of other data.

I think I will stop there, and if there are any questions at this point,
take them.

CHAIRMAN STEPHENS: Questions for Dr. Levandowski\'s presentation?

(No response.)

Roland, just can you comment further on the WHO decision not to include
currently a recommendation for an H3N2?

DR. LEVANDOWSKI: I can try a bit, but there are others here who may want
to add to that. I believe it really is that only in the last couple of
weeks was it well-recognized that there are some new H3N2 viruses that
are becoming more predominant or appearing at a greater frequency than
they have been. I don\'t think I want to go into all the detail because
that\'s what Dr. Cox is going to present for us in her presentation.

DR. COUCH: Could I make just a quickie? Couch here.

I just want to highlight the fact that WHO is willing to be flexible on
these decisions because, while I\'ve never participated in that to my
knowledge, that may be a precedent for WHO. You may want to comment on
that, but the flexibility has been a characteristic of this Committee to
be sure as much as possible that we hit the right target.

DR. LEVANDOWSKI: WHO tries, at all cost, to make its recommendations
when it has its meeting in February, but they do, and they have in the
past, postponed their recommendations. It happens about once every ten
years. You, Dr. Couch, have made that comment on a regular basis about
how we need to be sure we\'ve got all the right epidemiologic
information collected.

Of course, sometimes the influenza seasons are a little bit late
developing. I think our concern is somewhat like it was with the
A/Sydney strain, which was a very markedly different antigenic virus in
1997. It was only recognized very late. It was recognized too late
really to make any changes for the vaccine that year.

We think that the vaccine probably was reduced in its effectiveness by
not being a very close match with the strains that circulated that were
A/Sydney, like that following year. I think that\'s reflected by WHO\'s
decision to postpone this until some additional information could be
obtained as well.

DR. COUCH: Just an informational comment: For those of you who don\'t
worry about flu, the language that has been coined for this is the
\"herald wave.\" So the herald wave is the prelude to the epidemic virus
the following year. So it is important to try to search for those herald
waves. That is what Roland is suggesting may be going on right now that
delayed that decision. That, of course, is important to make the right
antigen decision.

CHAIRMAN STEPHENS: Thank you, Dr. Couch.

I think we\'ll move on now to Dr. Cox\'s presentation. Dr. Keiji Fukuda
is not available, and Dr. Cox will do the next two presentations.

DR. COX: Thanks very much, and thanks for the introduction, the
introductory material, Roland. I do want to convey regrets from Drs.
Klimov and Fukuda, who are back in Atlanta handling a variety of
activities related to the announcement by Hong Kong of the H5 viruses.

I\'m going to present U.S. surveillance data. I would first like to
preface my remarks by saying that the season that\'s ongoing now can be
characterized as mild to moderate. We really haven\'t seen a lot of
influenza activity except with respect to influenza in young children,
and there have been a number, quite a large number, of school closings
reported to us. Most of those school closings were associated with the
isolation of influenza B viruses, but influenza A viruses have also been
isolated.

Roland, is there a pointer?

Okay, we have data for the week ending February 8th, during which
approximately 20 percent of the isolates that were tested by the WHO and
NREVSS labs were positive for influenza. I would like to point you to
the color-coded legend here. We\'ll see that influenza B viruses are
represented in green. You can see that the majority of the strains so
far this season that have been reported are linked to influenza B
isolates, but we also have an increasing proportion of influenza A
viruses.

We have incomplete information, of course, for recent weeks, where not
all the viruses have been subtyped. But, of the influenza A viruses that
have been subtyped, about 80 percent are H1 ‑‑ that is, they are either
H1N1 or H1N2 ‑‑ and the remainder are H3N2 viruses.

I should also note that almost half of the influenza B viruses have been
reported by the States of Texas and Missouri. So they\'ve had very
significant outbreaks there, and that\'s been reflected by school
closures.

This slide shows the percentage of the total patient visits to the
influenza sentinel physicians that are for influenza-like illness, or
ILI. So during week six about 3 percent of the total number of patient
visits were for influenza-like illness. This is above the national
background. These are national data, and the results for the last three
weeks are above the national background of 1.9 percent. It certainly
appears that influenza activity may be continuing to rise.

This map shows influenza activity which was reported by the state and
territorial epidemiologists. We had a total of 13 states reporting
widespread activity and 21 states and New York City reported regional
activity.

You will see that the western part of the U.S. is reporting sporadic
activity, and that\'s been characteristic of all the indices that we
have for influenza. The western part appears to be relatively spared so
far.

Now we\'ll move on to pneumonia and influenza mortality. This is the 122
cities reporting system. You can see that for this season we haven\'t
actually gone above the baseline levels, the baseline or the threshold
levels, with respect to excess deaths. So we\'re looking for deaths that
might be above this top threshold level. These are deaths as reported to
CDC by the vital statistics offices of 122 cities.

I would like to mention that this season, where we had a very
significant peak of excess mortality due to pneumonia and influenza, was
caused by H3N2 viruses.

Now we\'ll move on to influenza H1 viruses, and I should mention that in
this category we have both H1N1 and H1N2 viruses. Reassortment had
occurred between the circulating human H1N1 viruses and the human H3N2
viruses at a point in the past, and we had quite a bit of discussion
about this event last year at our meeting. The H1 and 2 viruses have
continued to circulate.

I have really tried to distill the information that was circulated
earlier into some simplified tables. Hopefully, I can walk you through
these tables and they won\'t be quite as confusing to some of you who
aren\'t accustomed to looking at these tables as the ones that were
circulated.

So I\'ll walk you through the table. We have our reference antigens.
These are well-characterized viruses to which we have raised
post-infection ferret serum. We then conduct hemagglutination inhibition
tests with these ferret sera.

We have homologous titers for these reference antigens and their
corresponding ferret antiserum, shown in red, across the top here. What
we are really looking for are differences of fourfold or greater between
the homologous titer and the titer obtained with additional strains.

I would like to focus your attention on column B, where we have
antiserum, antiserum to the current vaccine strain, New Caledonia/20/99.
You see there\'s a homologous titer of 320, and the majority of the test
antigens which have been isolated in recent months are well-inhibited by
antiserum to the New Caledonia serum. This has been true of the most
recent viruses. I\'ll show a frequency table later, but the vast
majority of the most recent viruses are very well-inhibited by antiserum
to the vaccine strain.

We\'ve also seen a few viruses with reduced titers. Particularly, we saw
viruses from Chile last summer during the circulation of influenza in
the Southern Hemisphere, which were reduced in titer with the Nanchang
serum. We\'ve put a couple of those viruses into ferrets.

For this particular strain that you see at the bottom, where the titers
are really quite dramatically reduced, we see that we got a low
homologous titer and that we get low titers against the
currently-circulating strains. This is probably an indication that this
is a low avid strain. I\'ll talk more about the sequencing results and
additional results, but this virus is certainly not typical of the
majority of strains that are circulating.

We do have a couple of strains at the bottom, the Peru/3090, which was
used in the post-vaccine serology tests that Roland will talk about
later, which has a profile somewhat similar to that of the Hawaii/15
virus. Sorry, the Peru/3064 has a profile more similar to this virus,
and the Peru/3090 is also a low reactor.

You\'ll see down the far right column an indication of which
neuraminidase these viruses contain; that is, whether they have an N1
neuraminidase or N2 neuraminidase. You can see that we have a number of
viruses, a couple of viruses, from Canada. We have actually tested more
which have N2 neuraminidase. We have from the United States both N1 and
N2 neuraminidase among the currently-circulating strains. I will give
frequency information as well, but the take-home message is the vast
majority of the most recent viruses are well-inhibited by antiserum to
the New Caledonia strain.

I also should mention that there\'s been very little H1 activity outside
of North America. So the majority of viruses that we have tested, and
that have been reported anywhere in the world, are actually either from
Canada or from the United States.

As I mentioned before, of the most recent viruses ‑‑ that is, viruses
that were isolated between October 2002 and February ‑‑ over 95 percent
are well-inhibited by antiserum to the New Caledonia strain and only 3
percent, two of the viruses, were low reactors during that period.

I had mentioned that during our summer months, the winter in the
Southern Hemisphere, there were a number of low reactors, and those
viruses, many of those viruses were actually from Chile.

Here we have a frequency table which shows us the proportion of H1N1 and
H1N2 viruses that we characterized that have been isolated between April
and September and then between October and February. You can see that
about 30 percent of the viruses from the most recent period are H1N2,
the majority being H1N1.

This reflects viruses that we have characterized at CDC. A large number
of H1N2 viruses have been identified in Canada, which have not been sent
to us. The ones that have been sent are reflected here, and they really
have a vast majority of H1N2 viruses, which is a little bit different
from what we\'re seeing.

We are, of course, tracking these viruses in terms of the evolution of
their hemagglutinin and their neuraminidase genes. We\'ve tried to
simplify the tree that we had in the package and to just focus on a few
points here in this tree.

The first point I would like to make is that the hemagglutinins of the
H1N2 viruses cluster together, and they\'re shown here in blue. In spite
of this clustering, we do not distinguish these viruses antigenically
from the vaccine strain or from each other. So when you raise antiserum
to one of these viruses and test it against viruses in this clade, you
can\'t detect antigenic differences on a reliable basis.

Some of the low-reacting strains from Chile that were isolated in the
summertime are down here, and they are not so similar to current
activity in North America.

I should also mention that we have shown here on this tree viruses that
were tested as serology antigens, the viruses that were isolated in
eggs, in case we needed to have a change in vaccine strain, and low
reactors to the New Caledonia antiserum.

I would like to mention ‑‑ I\'m not sure that it is so obvious in this
pared-down tree ‑‑ but we didn\'t have any real clustering of low
reactors. That is to say, we had low reactors scattered throughout the
tree, so there was no indication that we had a growing genetic group
that had reflected any antigenic changes that could be correlated with
genetic changes, and that\'s always what we\'re looking for. When we put
the antigenic and the genetic data together, we are looking for a
correlation in molecular changes with the differences that we see with
our post-infection ferret serum.

At the request of a number of different people and groups, we have been
spending a bit more time on the neuraminidase. We had been sequencing
neuraminidase for a number of years, but we\'ve also been looking at the
antigenic properties of neuraminidase. Sometimes this is a bit
confusing. I hope not to confuse you today.

I think the H1N1 data are pretty clear. We have ferret antisera which I
should mention are not ideal because they\'re made against the virus
itself; they\'re not made against a reassortant which has been a
relevant hemagglutinin. So these results are the best that are available
anywhere in the world, but in some senses they\'re not ideal because
ideally you would make a reassortant that has an irrelevant
hemagglutinin, so you could be sure that you\'re not looking at any
stearic hindrance that might occur by antibody to the hemagglutinin
binding and inhibiting the neuraminidase.

What we see here with these H1N1 viruses, which are recently isolated,
is that we really can\'t tell much difference in their neuraminidase. So
the N1 neuraminidase are quite stable.

When we expand our table and begin to look at H1N2 viruses, we see a
slightly different pattern. We can distinguish N2s. For example, we have
antiserum to this Hawaii/10 H1N2 and we can see differences down here
with some of these currently-circulating strains. Unfortunately, we
don\'t know the full significance of this difference that we are seeing
because, as I mentioned, these antisera are not the ideal ones, but
there is some indication that there are differences in the N2
neuraminidase.

The evolutionary relationships among the N1 genes are pretty
straightforward. There hasn\'t been very much variation in the N1
neuraminidase genes since 1999, when the vaccine strain was chosen. So
we really have fairly homogenous viruses and neuraminidase genes, and I
don\'t think there\'s anything really very remarkable about the sequence
data for the neuraminidase genes.

So, in summary, for the influenza H1N1 and H1N2 viruses, these H1
viruses have been reported primarily from the Americas, and I would like
to particularly point out Canada, Chile, and the United States. Greater
than 95 percent of the most recent H1 viruses have hemagglutinins that
are antigenically- and genetically-similar to that of the current
vaccine strain, A/New Caledonia/20/99, and the neuraminidase of the
current H1N1 viruses are similar to the vaccine strain.

The neuraminidase of the H1N2 viruses are similar to those of
currently-circulating H3N2 viruses, and I\'ll show you some genetic data
when I get to the H3N2 neuraminidase.

So now I\'ll be talking about the influenza A H3N2 viruses. Of course,
this is the vaccine component. This category of viruses is represented
by the vaccine component that WHO deferred.

So I need folks to really pay attention to this simplified table. Once
again, we have post-infection ferret serum to a number of reference
strains, which are shown here, our antigens here. We have post-infection
ferret serum to the old Sydney vaccine strain, to the Moscow
WHO-recommended strain, and to the Panama vaccine strain itself.

In addition, we have reference ferret antisera for a couple of more
recent viruses, one of which was isolated in Hong Kong, one from New
York, then the ferret serum against this reference strain
A/Fujian/411/2002, which I\'ll be talking about quite a bit. So I\'ll be
mentioning the Fujian/411 virus.

I\'m sorry, there\'s a mistake here. This actually should be Fujian. It
was a mistake in the editing.

What I would like to mention is that, until about January 31st, the
majority of the viruses that we were analyzing looked like the viruses
at the top of this table. On January 31st, we had a number of new
viruses that we had just received from Asia in a test, and we had
antiserum to the Fujian virus that we could test for the first time.

The Fujian strain was actually not well-inhibited to antiserum to Moscow
and Sydney, and it is not reflected as much in this particular test, but
we have done a number of additional HI tests. Typically, the Fujian
virus is reduced in titer by about fourfold.

So, as of about the end of January, we\'re seeing that viruses were
really pretty well-inhibited by antiserum to the Panama vaccine strain.
Then we started seeing an increasing proportion of viruses which were
poorly, relatively poorly, inhibited by antiserum to the vaccine strain.

I\'ve shown a number of these viruses in green here, and I will be
mentioning them later because all of the viruses shown in green here
have two amino acid changes that we have been watching very carefully.
They have changes at amino acids 155 and 156. These amino acids are
located in antigenic site B of the hemagglutinin.

So, just to emphasize a couple of points, we have viruses that are low
reactors and have these signature sequence changes from the United
States, from Japan, from Korea, and from China. So we have a number of
isolates from the United States. It started out that we had isolates
from the West Coast and from Hawaii, and now we\'ve got isolates from
other parts of the U.S. as well.

This is a frequency table for the antigenic analysis that we\'ve done.
You\'ll see that we\'ve so far characterized, antigenically
characterized, a total of 110 influenza A H3N2 viruses that were
isolated between October 2002 and the present time, and approximately 33
percent ‑‑ sorry, 30 percent ‑‑ of these viruses are reduced in titer by
fourfold or greater with the Panama antiserum as compared to the
homologous titer.

If we look back at the previous period ‑‑ that is, April 2002 to
September 2002 ‑‑ about 11 percent of the viruses were low reactors. We
haven\'t done this, but if we were to split this time period out even
more finely, we would see an increasing proportion in the most recent
months, but the numbers are relatively small compared to those shown
here.

Now we\'ll move on to the evolutionary tree for the hemagglutinin genes
of the H3N2 viruses. Please note that the sequence for the Panama
vaccine strain is located here on the evolutionary tree. I neglected to
mention before that, when you see amino acids and numbers, when you see
letters and numbers like this, this means that an amino acid at this
particular position in the hemagglutinin has changed, in this case from
malinin to valine. We look at both the number and the types of changes
that are occurring along the evolutionary pathway of these strains.

What I would like to mention is that the viruses that I mentioned that
have both the 155 and 156 changes are shown here at the top of the
dendrogram in red. They are clustering together, and you\'ll see that we
have a number of viruses from China, from Korea, from the U.S.,
Washington, Georgia, Tennessee, Massachusetts, and so on, all of which
have this particular change.

Please also notice that there is a tendency, but not an absolute
finding, that viruses that have both of these changes are low reactors.
So we do occasionally see viruses that are in this genetic group that
are well-inhibited by antiserum to the Panama strain, but, generally
speaking, these viruses are poor reactors with antiserum to the Panama
strain.

I would also like to mention that this group has really developed out of
a group that was identified about two years ago as it emerged in China.
We noticed that there were viruses with a number of conserved amino acid
differences from the previous strains that were conserved among this
group.

So we were watching this so-called China group quite carefully. It
wasn\'t until at the end of January when we saw that there was really
much more consistency in viruses that were within this genetic group
overall, but then had this additional change, but we were seeing that
they were low reactors.

We still do have viruses that are located in this part of the dendrogram
that are without these changes here, but there really are a striking
number of changes between this part of the dendrogram, a striking number
of amino acid changes between this part of the dendrogram and this part
of the dendrogram. Of course, because of the fact that H3N2 viruses
cause more significant mortality than viruses H1 or B viruses, we always
watch these changes particularly carefully.

I have simplified the neuraminidase inhibition test that we have for N2.
I\'ve really focused on the H3N2 viruses here. We haven\'t tested a lot
of strains, but these are the results that we have that demonstrate that
H3N2 viruses, these two viruses can\'t be distinguished from our
reference here.

These viruses are inhibited well by all of our reference sera that we
tried. Again, I would like to provide the caveat that these ferret sera
are not ideal sera for this type of testing, but this is the best that
is available worldwide.

So now we look at the N2 dendrogram. So this dendrogram shows the
relationships among the N2 neuraminidase genes, and you can see that
there are two different groups here. What I would like to mention is
that the viruses that we are seeing with the 155/156 change are also
clustering in terms of their neuraminidase. This is a simplified tree
that doesn\'t have many of the recent strains on it, but we actually
have sequenced them and they\'re clustering together in this portion of
the tree.

So, in summary, I should mention that H3N2 viruses haven\'t circulated
terribly widely in North America. However, they have caused significant
recent outbreaks in Japan, Korea, and China. An increasingly proportion
of the most recent H3N2 isolates are not well-inhibited by
post-infection and post-immunization antiserum, and Roland will be
presenting the post-immunization results.

H3N2 viruses with amino acid changes at both 155 and 156 in site B tend
to be poorly inhibited by antibodies to the vaccine virus, and
low-reacting viruses with these changes have been detected in Asia,
Europe, and the Americas.

I should also probably mention that our colleagues in the UK have
similar findings in that at the WHO Collaborating Center in London they
found that the most recent viruses that they had received from Europe
are really quite poorly inhibited by antiserum to the Panama virus.

Okay, so now we will be talking about influenza B viruses, which are
also complex but perhaps not so troubling as the H3N2s. We have here a
simplified HI table for influenza B viruses. Please recall that we have
two very distinct lineages of influenza B viruses circulating in the
world. This has been true now since 1989, and we have been tracking
these two separate lineages.

Our vaccine virus represents this lineage here on the right where we
have the Shandong/7, Hong Kong/330, and Brisbane/32 strains. The
previous vaccine strain was Sichuan/379, and we really don\'t see very
many Sichuan/379 strains circulating worldwide. In the most recent tests
we do have a few viruses. We have here two from China and from Texas
that belong to this older lineage that\'s almost been displaced in North
America by viruses from this lineage.

I will show you a little bit more about the evolutionary relationships
between these viruses, but suffice it to say that antigenically these
viruses are very easily distinguishable. There is not a great deal of
cross-reactivity when you look using post-infection ferret sera. So they
are very easy to distinguish.

Because these viruses represent a really minor part of the influenza B
viruses that are circulating, we\'ll concentrate most of our time
discussing viruses on the right. What I would like you to note is that
Shandong/7 and Hong Kong/330 and Brisbane/32 are all actually Hong
Kong/330-like viruses.

So if you look at these viruses, there really are not any more than
twofold differences. When you look at these viruses themselves across
the row, and it doesn\'t matter how many antisera we put in there, you
probably noticed this from your tables, but you can\'t distinguish these
three viruses using any of the post-infection ferret sera that we have
developed. So these are really antigenically indistinguishable from each
other.

But when you test the antisera to these viruses with
currently-circulating strains, you do see some differences. This is
something that we noted starting last year in about April or May, round
about that time, as more and more influenza Bs came in to be tested.

And we noticed that there were a number of these viruses that are
circulating that weren\'t as well-inhibited by the antiserum to these
reference strains, Shandong/7 and Hong Kong/330, even though these
viruses couldn\'t be distinguished among themselves. We noticed that the
Brisbane/32 antiserum really inhibited most currently-circulating
strains well.

I need to call your attention to this column on the right. I don\'t know
if you recall or not, but we had noted that many of the influenza B
viruses that were circulating late last season were actually
reassortants between the two different lineages, and it becomes a little
bit confusing, but I hope that we can clarify any questions that you may
have about the HA-NA combination of the viruses that are circulating.

The bottom line is that the majority of the circulating strains have
Victoria lineage hemagglutinins and Sichuan lineage neuraminidase. Our
current vaccine strain has a Victoria/Victoria combination. It\'s even
getting me confused.

So if we look at the frequency table for the antigenic characterization
of the viruses that have been isolated most recently, that is, October
2002 until the present time, we see that we do have a number of viruses
which are low to the ferret serum made against the Hong Kong/330
reference strain. However, those viruses were all well-inhibited by
antiserum to the Brisbane reference strain. We have been calling these
Brisbane-like viruses, but please remember we couldn\'t antigenically
distinguish the Brisbane virus from the Hong Kong/330 virus. So it is a
bit of hairsplitting that\'s going on here.

We saw only a small proportion of viruses, about 6 percent of viruses,
that were Sichuan-like, and that\'s down just a bit, you know, probably
not significantly from the 8 percent that we saw during the Southern
Hemisphere influenza season.

So I just wanted to give you some of the overall topography of how the
hemagglutinin genes of viruses from the Sichuan or Yamagata lineage and
the Victoria lineage are related. So the hemagglutinins are really quite
distinct antigenically and genetically. They are really quite distant
when we\'re talking about genetic distances.

But we\'ll first focus on the viruses that are on the Sichuan or
Yamagata lineage. There are two subclades. We won\'t need to spend a lot
of time on this, but there are two subclades. We\'re seeing that the
most recent viruses are peppered through both of these subclades. But,
remember, this is a very, very small proportion of viruses that have
circulated recently.

This Victoria lineage dendrogram really represents the majority of what
we\'re seeing. One of the things that I would like to emphasize is that
we\'re seeing actually very little genetic differences among the
currently-circulating influenza B hemagglutinins. So whether we\'re
looking at viruses from Texas or Argentina or Thailand, there really are
not great differences and sometimes no coding difference, only silent
mutations, among these strains.

So the Victoria lineage hemagglutinins are really remarkably stable when
we compare them to the other virus groups that we have been looking at,
but I should mention that our vaccine strain is on this lineage, on this
clade here, and the majority of viruses are here. We can\'t distinguish
those two subclades antigenically, however. I should mention also that
low reactors are peppered through, and those are all the viruses that
are well-inhibited by the Brisbane antiserum.

In order to really keep up fully with what is circulating, we do a lot
of restriction analysis of the hemagglutinin and neuraminidase genes of
influenza B viruses, just as we do for the H1N1 and H1N2 viruses,
because we really want to have a full picture of what\'s circulating.

So we\'re able to separate the Sichuan-like viruses, the viruses that
are Sichuan-like antigenically, into two genetic groups, and they are
reflected here. Then we have the Hong Kong/330 lineage and what we call
Oman or the Shandong lineage. So those are just those two subgroups that
I showed you on the dendrogram that I just got done showing you.

We have also been doing neuraminidase inhibition tests on the influenza
B viruses, and the bottom line here is that we can distinguish the
neuraminidase of the viruses that have the Victoria lineage
neuraminidase basis from those that have the Sichuan lineage
neuraminidase. That is shown quite clearly here with the blocking in
color.

So these are viruses that are in the Sichuan, that have neuraminidase in
the Sichuan lineage, ferret antiserum against viruses with Sichuan
lineage neuraminidase, and vice versa. So we can distinguish the
neuraminidase of these two lineages.

Here is how the neuraminidase genes of these two lineages are related to
each other. So these are the Victoria lineage neuraminidase. These are
Sichuan lineage neuraminidase, and there are a number of conserved amino
acid changes in these two groups.

So, in summary, I would like to say that influenza B viruses are
predominating in the U.S. and much of Europe. Influenza B viruses on the
Victoria lineage have predominated worldwide, and viruses on the Sichuan
lineage have continued to be isolated, but relatively infrequently.

The most recent influenza B viruses have neuraminidase that are most
closely related antigenically and genetically to that of the Sichuan
reference virus, and influenza B viruses have remained quite stable
since last September, when we had the WHO vaccine consultation and
recommendations for the Southern Hemisphere, which Roland already
mentioned to you. At that time the WHO recommended a Hong Kong/330-like
virus.

Okay, I think I\'ll close there and entertain any questions.

CHAIRMAN STEPHENS: Thank you very much, Dr. Cox.

Questions? Dr. Couch?

DR. COUCH: I have more questions. Nancy, would you explain to me why the
A/Johannesburg H1N1 is on our chart? Is there some background of that
one that\'s worth knowing? A/Johannesburg was at 96?

DR. COX: No, those viruses have been displaced, as far as we can tell,
completely by the Beijing ‑‑ sorry, by the New Caledonia viruses. So, in
other words, the H1N1s had diverged. There were two very distinct
lineages, one of which was circulating in China and the other in the
rest of the world. The Johannesburg virus was an old vaccine strain, and
it represents a group of viruses that has not been detected for probably
a year and a half or two years.

DR. COUCH: So it\'s just being carried as a reference strain? It\'s
quite different from New Caledonia?

DR. COX: It\'s just carried as a reference strain. That\'s right. We
extracted it from a larger table.

DR. COUCH: I see. Well, it stood out, so I wondered why we needed to
know that.

DR. COX: Yes, sorry. It went quietly by the wayside.

DR. PALESE: Peter Palese.

Basically, I think a major issue today will be in terms of the choice of
H3N2 virus. There it really depends on knowing what has happened over
the last recent past.

One of your first slides actually shows a number of strains which have
been obtained from the collaborating laboratories. If you look at the Y
axis, there are about 500 isolates. A large percentage of those are
unsubtyped, or at least that\'s what I understood, if there was a yellow
part of that column.

So you mentioned that a large percentage is B now, and maybe you can
show it. I think it was the second slide you had.

So the creation really is, since we don\'t know what these unsubtyped
viruses are, and you called them A viruses, how difficult would it be to
find out what kind of H3N2 viruses these are, and would that be helping?
These are quite a lot of viruses ‑‑

DR. COX: Right.

DR. PALESE: \-- which are unsubtyped.

DR. COX: Yes, that\'s true. The viruses come in to us from state health
laboratories and a number of other hospital laboratories, and so on. The
percentage of viruses that are subtyped depends on the capacity of those
local labs to subtype.

I would just like to make mention of the fact that CDC has been
providing funding to the state health departments and other
collaborating labs to increase the percentage of viruses that are
subtyped. Now what we have been doing at CDC is to actively call the
states that have H3N2 viruses reported, and we have solicited viruses
from them.

DR. PALESE: So this is exactly the ‑‑

DR. COX: So when I left, yes, when I left yesterday, I had a log-in
sheet stack, a stack of log-in sheets this thick (indicating) of viruses
that had come into CDC since last Monday or Tuesday. So we have received
a large number of viruses from the U.S. and also some from abroad that
have not even been inoculated yet. So we will have data as quickly as
possible, and there will be additional data forthcoming.

So I hope that answers your question.

DR. PALESE: Yes, because if you look at the tip which is red, we are
supposed to make a decision on H3N2 viruses of very few isolates, which
is the H3 and which are the H3N2 viruses, but there is still a large
percentage out there over the last several weeks, which are yellow, and
I think they should have given some more information probably.

DR. COX: I think, as I said, that we will have some additional
information. I would like to emphasize that we also pay a lot of
attention to viruses that come from other parts of the world. These are
just from the U.S., of course.

In addition to the viruses from the U.S., we want to put those viruses
in context with the larger global picture of what\'s going around. So
what we\'re trying to do is place these viruses in the context of the
viruses that have been obtained from Korea, Japan, and China, where
there have been more significant ‑‑ I won\'t say ‑‑ probably more
significant outbreaks of H3N2. Then we\'re trying to, of course, analyze
as many from the U.S. as we possibly can.

It\'s a very good point, and we are doing the utmost to try to assist
the states, so that they can subtype efficiently. So the kinds of
support that we\'re providing includes support for personnel to actually
do the lab work.

CHAIRMAN STEPHENS: Dr. Dowdle?

DR. DOWDLE: Nancy, I wonder if you have information on the newer
strains. Many of them are not inhibited very well with the reference
strains. But, on the other hand, how many of these actually have low
homologous reactions as well, or have you had a chance to look at them?

DR. COX: We don\'t know. We have three more viruses in ferrets. We\'ll
have the testing done next Monday, either Sunday or Monday.

What I can say is that the Fujian virus had a very nice homologous
titer. It had a homologous titer of 1280, and that\'s reflected nicely
in the package of information that you got, which is more complete than
what I showed in my slide.

But I think the fact is that we had a very nice homologous titer, and
that when we looked down at the titers against the Fujian antiserum for
those viruses that had the 155 and 156 changes, we saw that there were,
generally speaking, quite good titers. There were other viruses that we
knew did not have those changes that were low.

I think the thing that perhaps really was a red flag to me as well was
the fact that, if you look at the Fujian homologous titer and then look
at the ability of that antiserum to inhibit the older viruses, you see
that the ability just has fallen away and there are very low titers to
those old viruses, indicating that we may well, indeed, have a new
antigenic variant.

But, as you mentioned, we have to confirm that by using viruses,
additional post-infection ferret sera to well-characterize viruses, so
that we can really get a complete picture and we will be doing
retrospective testing of the viruses that we sequence, so that we can
really get a very, very good handle on what\'s going on with respect to
the antigenicity of these newer strains.

DR. DOWDLE: And those data would be available when?

DR. COX: We are going to have data available next Tuesday for sure,
probably Monday afternoon, definitely ‑‑ not probably ‑‑ Monday
afternoon definitely, because we have a WHO conference call on Tuesday
morning at 6:30 a.m.

CHAIRMAN STEPHENS: Ms. Fisher and then Dr. Myers.

MS. FISHER: Dr. Cox, I have two sort of generic questions. This handout
that we were given, there\'s a statement that says, \"Since September
29, WHO and NREVSS laboratories have tested a total of 33,901 specimens
for influenza viruses and 1,195, or 3.5 percent, were positive.\"

Doesn\'t that seem like an awfully low percentage there that were
positive for influenza virus? I assume that means that these individuals
were sick with other things that looked like the flu.

I guess my question is, in your statistics, when people report flu, how
do you know that is actually reflecting flu and not something else?

DR. COX: Right. There\'s not a really short answer to this question,
but, first of all, I would like to mention that what we had circulated,
what had been circulated to the Committee previously, was a week older
data than what I talked about today.

What I talked about today is the figures for week six, which is the
figures for the week ending February 8th. During that week, which is
actually during the influenza season, 20 percent of the respiratory
specimens tested were positive for flu. This is what we will expect
during the influenza season. The numbers that are in that report reflect
all of the respiratory specimens that have been collected since October,
when influenza viruses were not circulating.

Now these respiratory specimens are collected from people with
respiratory illness, and there are many other pathogens that cause
respiratory illness. So we don\'t report on those pathogens because this
Committee is really focused on influenza.

MS. FISHER: The second question is, why do you think there was such a
predominance of influenza B virus in children that caused the schools to
be closed?

DR. COX: I\'m speculating a bit, but probably not sticking my neck out
very far. The influenza B viruses that are circulating this year are
different from, quite distinctly different from, the influenza B viruses
that had circulated in the United States for the previous ten years.

What we knew is that a cohort of young children had absolutely no
antibody to these newly-circulating strains, and we had a very
susceptible population. I think that was part of our discussion and
consideration last year, when we choose the Hong Kong/330-like vaccine
strain for inclusion this year. So we were on the mark in terms of
updating the vaccine to include a Victoria lineage virus because that\'s
what actually happened in the U.S.

MS. FISHER: Thank you.

CHAIRMAN STEPHENS: Dr. Myers?

DR. MYERS: Nancy, I know we\'re concentrating on H3N2, but in your table
on the H1 there were two recent isolates that were very different,
A/Texas/02 and A/Michigan/208. I just wondered if you would comment on
those because those were both recent isolates.

DR. COX: Texas? Oh, they must be on another table. They\'re not on this
table.

DR. MYERS: Line 15 and 17.

DR. COX: Oh, sorry. So you\'re saying that Texas/02 is different? It\'s
actually very well-inhibited by the New Caledonia serum.

DR. MYERS: I see.

DR. COX: So it\'s not as well-inhibited by the previous vaccine, serum
to the previous vaccine strain.

DR. MYERS: Right. Nancy, thank you.

DR. COX: Okay.

CHAIRMAN STEPHENS: David? Dr. Markovitz?

DR. MARKOVITZ: Yes. Nancy, I was curious, just so I make sure I
understand this completely, it seems that the H3N2 vaccine is the one
that is going to be the difficult choice, but yet there\'s been this
reassortment with the neuraminidase with H1 viruses. So how much
attention will we have to be paying to the neuraminidase component
vis-a-vis its protection for the H1N1 or H1N2 when we\'re trying to pick
a vaccine? I hope that\'s clear.

DR. COX: I think that\'s a good question. I think that Roland may want
to say something about this as well.

What we have tried to do is provide the Committee with as much
information as possible about the match and the differences that we\'re
seeing, but I would like to remind the Committee that the neuraminidase
component of the vaccine is not standardized. So at this point in the
United States a certain amount of hemagglutinin is required to be in the
vaccine, and neuraminidase is there, but it\'s not standardized in terms
of the quantity that\'s actually contained, because of the fact that we
have considered antibody against the hemagglutinin to be the primary
determinant of protection.

So what I would say is that it\'s always prudent to have a good match
with the neuraminidase, but certainly we need to focus the most on the
hemagglutinin.

Roland, did you want to make an additional comment or clarify what I
said?

DR. LEVANDOWSKI: No, I think you stated it very well.

DR. COUCH: Well, I want to be sure we don\'t lose the question that Dr.
Markovitz brought up because it is one that has been on this table many
years, and I almost feel like to continue the plea ‑‑ I\'ve inherited Ed
Kilbourne\'s mantle, which is, of course, not the case.

But neuraminidase is an important antigen. Nobody questions the fact, as
Dr. Cox has said, that the paramount antigen is the hemagglutinin, and
CDC is to be congratulated, maybe partly as a result of the urging of
this Committee to start including more neuraminidase data, the
relationship, the changes that are going on, in their data that they
present to this Committee because it is an important antigen.

They have responded in that regard. It doesn\'t approach the amount of
data we get on the hemagglutinin, but the closer you get to it over a
period of time, the better off we will be, I think.

One of these days, hopefully, it will be pointing toward that being a
component of the decision of the strain, so that we be sure that the
neuraminidase behaves properly. But the major problem Dr. Cox pointed
out is that right now there is no antigenic requirement for the vaccine
antigens themselves, for incorporating into the vaccine, and that\'s a
whole different topic, as to if there would be one, what should it be
and what kind of confidence should you have about how it should be made.

But it\'s an evolving subject that we certainly don\'t want to lose and
this Committee should keep hearing about every year, and the kinds of
questions that Dr. Markovitz has raised should continue to be raised.

DR. COX: I might be able to clarify things just a bit more. The
neuraminidase of the N1 viruses are very homogeneous. So that just kind
of puts the N1 to rest, I think, unless the Committee feels differently.

The N2 viruses ‑‑ sorry, the neuraminidase of the H3N2 variants are in
that little cluster that I pointed out. We don\'t have a lot of data on
the antigenic relationship of viruses in that group versus viruses in
other groups. So I think that, because we just got the Fujian ferret
antiserum very recently, and haven\'t really done a lot of testing, I
think that it would be difficult for us to base our decision very much
on the N2 neuraminidase.

We are relying, of course, on the N2 component of the H3N2 virus to
provide the neuraminidase that would be actually the component for all
of the N2s, whether the H1N2s or H3N2s, if you see what I mean.

DR. COUCH: Again, could I just make an additional phrase? I guess if I
state ‑‑ maybe Nancy and Roland will agree with me that where we stand
right now with neuraminidase data is being reassured that there\'s not
some major difference in that neuraminidase that we should have taken
into account with a decision.

CHAIRMAN STEPHENS: Well, that raises ‑‑

DR. COUCH: Using it positively for making a decision.

CHAIRMAN STEPHENS: The question I had regarding the neuraminidase story
has to do with the B strain, and where we\'re using a vaccine strain
with Victoria/Victoria, yet the neuraminidase is different. Can you
comment or, Roland, can you comment on that difference and its potential
meaning?

DR. COX: Roland, you\'re going to be presenting the post-immunization
data. I don\'t know if you want to comment or not.

DR. LEVANDOWSKI: Well, I think the comment would be very similar to what
Nancy Cox said related to the H1N1/H1N2. Here again, I think we do have
a concern about the neuraminidase. It is an antigen that may lend some
protection.

We don\'t standardize the vaccine for that, however, and we don\'t
really know to what level the protection is. We don\'t have sufficient
data, I think, from clinical studies to understand how much of an impact
that has.

The studies that we do have in the past looking at efficacy and
effectiveness for the most part would have been matching up both the
hemagglutinin and the neuraminidase. I think it\'s something that,
obviously, we do need to have consideration about, and there is a lot of
work that\'s going on to look at what the benefit of both manufacturing
vaccines where the neuraminidase is emphasized and also on ways to be
able to standardize both of the components in a way that would not
interfere with production of the vaccine altogether.

Just to re-emphasize, all the studies that I am aware of, if you have
both hemagglutinin and neuraminidase, it is the hemagglutinin that is
predominantly responsible for the protective immunity, and antibody to
the hemagglutinin alone is protective. That may be true for
neuraminidase also, but I think there is some reassurance in knowing, in
emphasizing the hemagglutinin, and we are not ignoring a very important
feature of the virus and an immunity to it.

CHAIRMAN STEPHENS: Thank you.

Additional comments? Dr. Katz?

DR. KATZ: I would like to go back to Mrs. Fisher\'s comment, because as
I look through the agenda, this Committee is obviously focused,
appropriately, on the selection of strains or the vaccine. But what
doesn\'t get discussed here is who is going to receive the vaccine.

When you talk about why you\'re seeing school absenteeism, and we\'re
seeing enormous numbers of children in our clinic with B influenza virus
infection because we don\'t immunize children ordinarily, and there is
an increasing interest at least on the part of the various advisory
committees of including young children, particularly infants, in the
first two years of life as recipients of influenza virus vaccines.

So you might see a major shift in the epidemiology if we protect the
younger children, both among them and among the parents and day care
teachers and others to whom they are exposed during the course of their
illnesses.

CHAIRMAN STEPHENS: Dr. Dowdle?

DR. DOWDLE: Thank you.

Nancy, on this discussion of neuraminidase, though, I think you pointed
out, quite rightly, that you really need sera that were produced with
viruses with irrelevant hemagglutinins. What are the plans? Do you have
plans to do that?

DR. COX: Yes, that\'s a great question. We have produced some of those
antisera, and we haven\'t in the last perhaps two years, but we had
previously. We did run a comparison and we didn\'t see differences when
we expected to. I think based on the results that we have for this year,
we would probably see them if we had the reassortants for the
currently-relevant viruses.

We are really considering a number of different approaches to this
problem. It can be, as you know very well, difficult to get out of the
mix the reassortant that you want. So we are going to be using reverse
genetics to produce the reassortants. We also have some very embryonic
plans underway to express the neuraminidase as in vacuo viruses or other
expression systems, and to then hyperimmunize rabbits or other animals
to produce the sera.

So we are definitely thinking along those lines. It is just difficult to
get everything done.

CHAIRMAN STEPHENS: Dr. Diaz?

DR. DIAZ: I just wanted to comment that I, likewise, with Dr. Stephens,
was more curious about the neuraminidase in the B strains and the
changes that we\'re beginning to see. Although we do tend to focus on
the hemagglutinin, I think we do have an opportunity, and we should
really work towards, increasing our surveillance of comparisons not only
of vaccine failures and also of disease occurrence, but also looking at
the differences in disease severity, if there are any, in individuals
who have similar B hemagglutinins but different neuraminidase, the
Victoria versus the Sichuan.

I think it would be important to know if there is, likewise, a
difference in severity that might be yet another reason to think harder
about the neuraminidase components of the vaccine.

DR. COX: I think those are very good questions, and they are relevant to
H1N2 as well as H1N1 viruses. We have actually tried to devote a
significant amount of time to looking at viruses, influenza viruses,
whatever the subtype might be, that were isolated from severe or fatal
cases of influenza.

To date, we really have found for those viruses that we have examined
that the viruses simply reflect what is going around, and that we\'ve
not been able, in spite of a lot of effort and looking, to pinpoint any
consistent differences between viruses that cause severe infection and
complications in those that don\'t.

CHAIRMAN STEPHENS: Bruce?

DR. GELLIN: Nancy, can you comment a little on your response to Dr.
Palese\'s question? It got back to the surveillance and the state
laboratory network of doing the strain detection. I got the impression
it wasn\'t as robust a system as I thought it might be, and a sense of
what the volume is and how reliable the states are and whether or not
you routinely confirm everything that comes in or you just take their
reports?

DR. COX: The reports of the numbers that you see, for example, in the
first few pages, that is based on data that is supplied to us by the
states. We only confirm the results for a small subset of viruses
because we couldn\'t possibly characterize all the strains that are
detected in the United States.

So, of course, we take the words of the states. We train them from time
to time and provide reagents for them to do this kind of analysis.

But it is very clear that the states need more assistance even than we
have been able to provide, and that, especially with respect to pandemic
planning and detection of novel subtypes of influenza, they have a way
to go. So this is something that we have been emphasizing in our efforts
to improve surveillance in the United States. We have some goals, but
we\'re, clearly, not there yet.

DR. GELLIN: So that implies that particularly the novel strain, they may
be likely to miss something?

DR. COX: Well, when you look at the numbers and you see that they are
subtyping 70 to 75 ‑‑ or not subtyping 70 to 75 percent of the strains
as they go through the season, yes, it could certainly be possible that
they would miss something. I think most of the time that\'s not so much
of a concern, but if there are new problems emerging, we really want to
do everything that we can to make it possible for them to subtype as
many viruses as possible.

That\'s been one of our goals in terms of improving surveillance. As I
said before, that\'s been very much on the table in our discussions with
the states.

CHAIRMAN STEPHENS: I think we\'re going to take our 15-minute break now.
I really appreciate Dr. Cox filling in and thank the panel for the
active discussion this morning.

So be back in 15 minutes. Thank you.

(Whereupon, the foregoing matter went off the record at 10:09 a.m. and
went back on the record at 10:31 a.m.)

CHAIRMAN STEPHENS: Let\'s go ahead and get started.

Our next presentation is by Linda Canas from DOD.

MS. CANAS: Good morning. The Department of Defense recognizes the
potential for severe disruption of mission and training programs if
influenza illness becomes epidemic within the troops and, in fact, has
led the effort for vaccines in the early days of the influenza vaccine.

The Air Force in 1976 developed a surveillance program, partly for
public health of the troops, and recognizing that we need this influenza
vaccine and we don\'t manufacture it. So if we help provide information
that we may have gathered from our own surveillance programs, it would
help those of you decide what should go into it.

This program has been very successful. In 1997, under the Global
Emerging Infection System, this became tri-service, and it\'s now
handled in that regard.

There\'s actually two parts to this program. The first is
population-based surveillance. This is conducted in San Diego from the
Naval Health Research Center, and they have all of the recruit centers
from each of the services. They know the population. They establish a
certain number of samples that should be collected weekly, so they can
get a baseline of what\'s going on healthwise in those individuals and
will be able to tell if there are outbreaks.

The second part of the program is etiology-based, and that takes place
in San Antonio in my laboratory. We\'re out there; we kind of look for
anything that might be there. We don\'t really care what the population
is. We fondly say, \"We\'re trolling for bugs.\"

And how this works, basically, it is funded by DOD GEIS. They give us
program guidance, and in San Antonio we have the clinical laboratory; we
have the epidemiologists, and together with the rest of the GEIS members
in the spring at our annual meeting we decide on who the sentinel sites
will be.

The epidemiologists make sure they have all the information to know what
they\'re supposed to do, and the laboratory provides all of the supplies
that they need and instructions on getting the specimens to us.

Now I need to explain that one of the reasons this program is successful
is the laboratory does not exist for influenza surveillance. We are
actually a clinical reference laboratory for all of the DOD services,
and we are based in San Antonio. We have FedEx contracts that bring in
diagnostic samples daily to our laboratory. So it is very easy for each
of these sites to put throat swabs into the boxes that are coming to us
with PSAs, hepatitis studies, whatever other clinical diagnostic tests
they are.

We handle these as clinical samples in our laboratories. So we are
getting samples from other places besides our sentinel sites, but these
are the ones we are especially tracking. We don\'t disregard any other
data. Any flu specimen is fair game for us, but we especially target our
sentinel sites.

When they get into our laboratory, we set them up the day they arrive,
handle them as clinical samples, according to traditional laboratory
methods. We will report back to the laboratory, submitting laboratory,
anything that we isolate, but we are particularly interested on
influenza.

When we get influenza, besides that information going back to the
provider, we also give it to our epidemiologists, who then send out an
e‑mail to the Public Health Officer at the base, so they have real-time
information on what\'s going on in their facility. That gives them
knowledge, public health knowledge, of what they\'re doing.

It also means they can go to their commander and talk about how well the
influenza vaccination program is going. All active-duty military are
required to be vaccinated for influenza annually.

When we work up our samples in the laboratory, we do hemagglutination
inhibition subtyping in our lab, and anything from overseas and anything
interesting that we see, we send on to CDC. We also have our molecular
department that does some other sequencing work, and then I get to come
here today and talk to you.

Now this year we\'ve added another level, and that\'s ESSENCE. That\'s
the Electronic Surveillance System for the Early Notification of
Community-Based Epidemics, kind of one of those intuitive acronyms like
VRBPAC.

ESSENCE, in two sentences, to explain a big program, when a military
member or his dependent visits a provider, they are diagnosed according
at this point to seven syndromic groups, one of which is respiratory
illness. That is entered into a computer and is fed to a secure website.
This is tracked across the various MTFs in the country.

Baselines have been established for each of these syndromic groups. If
something should spike, it should be picked up. Ideally, real-time at
this point in time it\'s about a two- to four-day lag, as I understand
it.

We actually saw this happen last week in Ohio. Wright Patterson Air
Force Base suddenly peaked respiratory illness there, not one of our
sentinel sites. They were contacted and asked to send us samples for
characterization. We just got those into our lab just before I left. So
we will see what we get.

As it stands now, our sentinel sites, how we choose those, we look for
training sites. These are people that are being sent from many different
areas. They are going to one place. They may be bringing their own virus
with them. Sometimes they are very stressed, depending on what they are
training for. We want to know real-time what is going on public
health-wise, and it is also a good opportunity to possibly pick up a new
virus.

We use those bases on each of the coasts, again, people coming into and
leaving the country, maybe bringing in viruses. Often those are bases
that have missions overseas also. Then all of our overseas bases are
sentinel sites.

Now in the past few years, under GEIS, we have been able to partner with
the Army and the Air Force to get more remote laboratories. These are
laboratories that are doing outbreak investigations in foreign
countries, and they have been able to add protocols to surveil for
influenza-like illness in the local populations.

This is an added benefit, but it is also an added challenge because, of
course, we are not doing diagnostic studies and we don\'t have FedEx
arrangements with them. So it is much more problematic getting the
specimens to us.

We did, two weeks ago, get 190 samples in from South America. About a
fourth of those were collected within the last two months. So we\'re
making some real progress in that.

You have listed in your handout the various sites. We do try to cover as
much of the area of our responsibility as we can.

In looking at this year, now this data is based on week collected, and
that\'s significant because, of course, we\'re getting them from all
over the world. While most are coming to us within two to four days, as
you see, we have some unfinished specimens clear back here at the
beginning of the seasons. That\'s what we got in from Peru just
recently.

So most of them are finished. We\'ve had a very busy year. It started
out from the very beginning, and we\'ve been getting influenza most of
our season.

Most years we talk about a flu season as being an A season or a B
season, an A trailing to B. In our program, which of course is global,
you can see that in virtually every week since we began surveiling this
year, we\'ve had A and B somewhere in the world.

We break this down into regions. Dr. Cox alluded to the H3N2 over in
Asia, and we saw that very early. It came up and it has continued and is
increasing. You never know if it\'s increasing in numbers or if our
participants are just increasing, but we\'re getting more and more
specimens each week. So it\'s certainly not trailing off.

In the United States we started out early with the B in Texas. Of
course, we\'re in Texas, and we have several bases in Texas. But Texas
has been one of the hardest hits.

It has characterized very nicely with the B/Hong Kong in our studies. We
don\'t put our efforts into subtyping into those isolates in the United
States because they are characterized also at other places, and we have
so many coming in from Asia.

We try to do the first few that come in from any location, and then if
it continues, as it still is in Texas, we go back periodically and pick
it up, just to see if we see any changes there. But our efforts are
spent in those from overseas.

In Europe and the Middle East ‑‑ now this graph looks fairly dramatic,
but you can see the numbers aren\'t real big here. But this is changing.
We just started getting samples in recently. Last week we got in 30
samples from UK and Germany, and it looks like about a third of those
are positive, most of them for B at this point in time. They just
started coming in. But we do have the B/Hong Kong and the A that we
haven\'t been able to subtype too much. We do have one now as an H3N2.

If we look at this about how our season developed, these are areas that
we\'ve actually gotten isolates from this year. It started out in
October again in Asia with the H3N2 and then from South America.

This is an interesting point and probably another strength of the
program. We have this one A/H3N2 hanging out in New Jersey, which we
sent off to CDC because it was so unusual. In fact, it was so unusual I
called and asked for a travel history and found out the patient had been
in China two days earlier. So this is probably a China isolate rather
than a U.S. isolate. We started, then, picking it up in Texas, which
continued.

Most of our early work was in Asia, and almost all of it has been H3N2
continuing, and in the United States we started seeing the H1N1. We\'ve
had two H3N2s in the continental United States. Everything else has been
the H1N1.

That continued through until actually the present. I don\'t have any
February data on this map because it\'s still being compiled.

Because ours is a clinical program and we\'re getting many different
isolates, and because I know this question comes up, we like to include
what else we get. Of course, it\'s a virology lab, so we\'re only
looking for respiratory viruses. Many providers will send viral and
bacterial. So with strep throat, Bordatella pertussis, we\'re not
getting any of those in this kind of a study.

Now I need to comment on adenovirus, which of course is nearly 50
percent of the pie here. That\'s strictly a military phenomenon. The
recruit centers have a real problem with adeno. Generally, at this point
it\'s adeno Type 4. It is a problem in that population, but it\'s not
spilling out into the general population.

So if we take that out, and I\'ve taken it out entirely, there is, in
fact, adenovirus background in the population as a flu-like illness,
mostly what we get after ‑‑ of course, we\'re looking for influenza. Our
case definition is fever greater than 100.5, cough or sore throat, and
radiographic evidence of pneumonia or a provider feeling there\'s
influenza-like illness. So we do mainly get influenza.

But the parainfluenzas, of course, it\'s like flu, mainly in the fall or
the spring, we\'ll pick that up. Enterovirus RSV, if this were a
hospital-based program or a pediatric population, RSV would be a huge
part of this pie, but it\'s not. We\'re not looking for it. It doesn\'t
transport well. So unless someone specifically asks for special tests,
we don\'t even look for it.

It is interesting because one of the problems with flu, of course, and
you all know this, is flu-like illness describes virtually everything.
We saw this last year when we had these reports of going out to test for
flu, and if it is not flu, maybe it\'s anthrax. Well, that is a little
far-fetched.

Our sequence studies this year were really quite interesting. This
represents all of the sequences from Asia that were performed in our lab
last year. These are \'02.

This is the A/Panama H3N2 vaccine strain, and from Asia the H3N2 viruses
from our laboratory this year. So there has been a change, and I think
Dr. Cox went over those changes very nicely, of what they have been,
some amino acid changes in that virus.

Our program this year has been really quite exceptional. I heard that it
was a moderate year.

Success breeds success. So our participants know that they\'re going to
get results back if they send us specimens. So we\'ve already done
almost 2,000 specimens in our lab alone for this year since October.

We\'ve had many isolates, most of them coming initially from Asia, and
Asia has had the H3N2 with only a few H1N1s, contrasted in the opposite
with the continental United States being almost exclusively H1N1, with
the Hong Kong everywhere, often in the same place.

It is not at all unusual; we test everything that comes in for A and B.
We have actually had one isolate that has had both. We have tested every
way we can, and it has both in it. There has been, we are showing the
hemagglutinin variation in those specimens out of Japan and Korea that
we have tested.

Would there be any questions?

CHAIRMAN STEPHENS: Thank you very much, Ms. Canas.

Questions? We\'ll start at the end down there, Dr. Katz and then Dr.
Myers.

DR. KATZ: This is an influenza virus meeting, but you show 49 percent of
your respiratory isolates were adeno 4. Until a few years ago, the
military had an excellent vaccine for adeno 4 and adeno 7.

Can you tell us whether there\'s any prospect of a new vaccine?

MS. CANAS: I will refer that to Dr. Diniega.

DR. DINIEGA: That\'s a very good question. As you well know, the
manufacturer for adenovirus vaccine types 4 and 7 ceased production in
the mid-nineties, and we ran out of any vaccine in about 1998. Since
then, last fall, in September we let another contract with a new
manufacturer. It is estimated that it is going to take four to five
years to get to vaccine production and licensure.

DR. KATZ: With the intention of reinstating the previous vaccine
program?

DR. DINIEGA: In fact, the previous vaccine program, it was being used by
two services. All the services will be using it the next go-round in all
recruit centers.

CHAIRMAN STEPHENS: Dr. Myers?

DR. MYERS: When you look at your dependents, does that change the
distribution of Bs? Are a lot of those Bs coming out of Texas in
dependents?

MS. CANAS: I don\'t know that we\'ve looked at that specifically, but
glancing through it ‑‑ I mean, I can\'t give you statistics, but out of
Texas, yes, they have mainly been dependents.

CHAIRMAN STEPHENS: Dr. Palese?

DR. PALESE: I just wanted to know how many of your isolates ‑‑ the H3N2,
we have Fujian-like. Of all the isolates, it looked to me like it was 40
percent on that one slide you had in terms of the 2002-2003 isolates, is
that correct?

In other words, the question is: Can you guide us? Can you help us in
terms of making a decision whether there should be a change and whether
that should be an H3N2 Fujian-like virus for the next year?

MS. CANAS: We do kind of a first cut in our laboratory. We use the
rabbit antisera, which does not merely give us the breakdown. So we\'re
only looking, as far as H3 goes, from Panama and Sydney, I think. Then
we send them on to CDC, where they put them in a ferret antisera. So I
can\'t answer the Fujian question.

DR. PALESE: But you said you had sequences.

MS. CANAS: We have sequences that show there has been this change, and I
believe that\'s probably consistent with the Fujian.

DR. PALESE: Have you sent all your isolates on to CDC?

MS. CANAS: Yes.

DR. PALESE: So they have all your samples?

MS. CANAS: As of last week.

DR. PALESE: But they haven\'t analyzed them, is that correct?

CHAIRMAN STEPHENS: Dr. Cox?

DR. COX: Yes, perhaps I can help out with that. We communicate very
frequently with Linda and folks in her group. They have provided some
very, very useful information to us.

For example, you might have noticed on some of my slides that we are
sharing not only viruses, but sequences, and so on. So in my sequence
slides I had B as B/Brooks Air Force Base. That indicates the sequence
that was shared with us by Linda\'s group. So we\'re compiling that data
together. Yes, indeed, viruses obtained through military surveillance in
Japan and Korea have those changes, the 155/156 changes.

Did you say we just had another shipment? I mean, we\'re working on ‑‑
we\'ve had a number of shipments from Linda, and we\'re working on some
additional strains.

MS. CANAS: Yes, last week was the last one we have sent so far.

DR. COX: Right.

MS. CANAS: We try to get those out as quickly as possible, for obvious
reasons.

CHAIRMAN STEPHENS: Thank you. Thank you very much.

We\'ll move on now to a return appearance from Dr. Levandowski.

DR. LEVANDOWSKI: Okay. Sorry, but these are going to be overheads. I
hope they are going to project well enough that you can see them. There
aren\'t too many people all the way at the back of the room, but I will
try to describe what is up here.

What I\'m going to attempt to do is to really summarize the information
we got from a number of different centers. We haven\'t distributed all
of the raw data from the centers because that seems to be a little bit
overwhelming sometimes. What I am going to try to do is distill this
down into some manner that might make some sense about what\'s going on
with current vaccines.

This first overhead that I\'ve got here shows the serum panels that we
have available to us for serologic studies. You can see that there are
four separate sets of serum panels from both adults and elderly from
different continents. We have them from Australia, from Europe, from
Asia, and also from North America. That\'s represented by countries,
Australia, Japan, the United States, and several countries in Europe.

The vaccines used for the immunization are shown here, and I mainly
would want to call your attention to the differences in the B components
of these vaccines. There have been three different strains actually used
for a B/Hong Kong/330/01-like strain, including actually the B/Hong
Kong/330, the strain itself. That\'s not represented in these
serologies. The surrogate strains are B/Shandong/7/97 and B/Hong
Kong/1434/02.

In Australia, the vaccine that was being used there at the time these
studies were performed was their previous vaccine. They now also are
using a B/Shandong/7/97 strain in their vaccine, but these sera were
collected last summer, before that was available. So it\'s the previous
year\'s vaccine strain, which was, if you remember the term that Nancy
used about a B/Sichuan/379/99. I am going to try to be consistent with
these names to try to help make a little bit of sense out of all that.

All of these vaccines, no matter where they were, include the New
Caledonia/20/99 H1N1 and the Panama/2007/99 H3N2. The laboratories that
participated in testing these sera include the WHO Influenza Center in
Melbourne, Australia; the National Institute of Biological
Standardization and Control in London; the Centers for Disease Control
and Prevention in Atlanta; the National Institute for Infectious
Diseases in Tokyo, and our lab at the Center for Biologics in Bethesda.
These labs all share these sera, and they represent about 200 pairs of
serum from different people.

They have been used to ‑‑ the sera actually are very valuable, and the
quantity is not infinite. These have been used to support both Northern
and Southern Hemisphere influenza vaccine recommendations. Generally, it
means testing somewhere between 10 to 20 new antigens by each of the
laboratories, to the extent that that\'s possible to do for each of
these cycles of recommendations.

So, wherever possible, the potential vaccine candidate strains have been
used for testing, and that really means some emphasis on egg isolates,
but there\'s also an emphasis placed on strains that appear to be
different by their antigenic characterization using the monospecific
ferret sera. Of course, when there are that number of antigens,
logistics, and everything else, it is not always possible for every
laboratory to test every strain, but there is an attempt to share at
least some of the different influenza viruses so that there can be some
comparison made between the results at different laboratories and get a
measure of confirmation.

Can we get the next overhead? This overhead shows the H1N1 antigens that
were used for serological testing. As I mentioned, not every one of
these antigens was used in all laboratories. That\'s, again, because the
amount of serum that\'s available needs to be conserved somewhat, and
more emphasis was placed on testing the H3N2 and the B strains this
year. So there are relatively few antigens that we were testing at this
point for the current set of recommendations.

As Nancy Cox has already mentioned, most of the H1 strains were actually
H1N1, and they are very similar to the vaccine strains. So that we
tested fewer antigens that would fall into the sort of typical category
and more antigens that fall into the less common category.

Among those recent isolates ‑‑ this may not be entirely reflected in the
information that we have presented to this point ‑‑ there are some
differences between the laboratories working with these strains, but I
have tried to indicate strains that have been identified as being H1N2
strains with an exclamation point and strains that have been at least in
some of the laboratories low reactors in the ferret antiserum testing
shown here.

So if we can go to the next overhead? What I am going to try to do is
give you some examples of the serologic results, and then at the end I
will try to summarize kind of overall findings, if I can do that.

This overhead shows results that were obtained with a panel of sera from
adults in Australia, and the testing was done with the same sera at
either CDC or the Center for Biologics. This table and the other ones
that I\'m going to show that are like it will include data on geometric
mean titer pre- and post-immunization, the percent of the individuals
who had titers greater than 32 or 40 between the pre- and
post-immunization and the percent of individuals who had fourfold rises.
I\'m really going to concentrate mainly, however, on the geometric mean
titers and comparisons of those.

The strain, the vaccine strain, for these studies, of course, was the
IVR‑116 reassortant New Caledonia virus, and that was also used for
testing the antigens in these particular serologies. Generally, I think
we could say that the vaccine used was immunogenic and it produced a
reasonably good, homologous antibody response.

You will notice that there is variability in the actual absolute titers
from laboratory to laboratory and also between the different subtypes.
That relates somewhat to some differences, technical differences, in
performing the hemagglutination inhibition antibody test, but I think
you will also see that we often have, in spite of that, have fairly good
correlation between the results, as shown in this particular instance.

Although the more typical strains here are represented by
A/Massachusetts/5/02, there were some strains that were less
well-inhibited in testing done at CDC. For example, the Canada/649/02,
this was an H1N2 strain, and the Peru/3090/02, which is a low-reactor
strain.

You can see that in this instance the Canada strain seemed to be
reasonably well-inhibited by post-immunization after sera, but the Peru
low reactor was not. We didn\'t see that in testing at the Center for
Biologics, but, again, as I mentioned, we sometimes see some differences
between the laboratories.

If I can get the next overhead, this next overhead is going to show
results from serum that were obtained from elderly individuals in
Europe. Testing was done at the WHO Influenza Center in Melbourne and at
the National Institute of Biological Standardization and Control.

Here again, in this instance, in testing in Australia, the
A/Massachusetts strain looks pretty similar to the vaccine strain, but
there\'s a quite substantially reduced response to both the Canada H1N2
and the Peru/3090 low-reactor strain. That\'s reflected for the Canada
H1N2 strain in testing done at NIBSC.

This strain, Dakar, is one that was more typical, but, again, there was
some reduction that was seen in testing in that laboratory. That\'s
actually the only laboratory that did testing with that strain. So we
don\'t have a way to confirm that. So I will cover in a more general
sense summary information from serologies for H1N1 in a few minutes.

The next overhead, I\'ll move on to H3N2 influenza viruses, and you see
there were a lot more strains that were tested here. These include a
number of strains that are more representative of the current vaccine
strain, the A/Panama/2007/99 strain, and it also includes viruses that
were circulating in both the Northern and the Southern Hemispheres
during the last year.

I\'ve tried to indicate, and I\'m not sure I\'ve been entirely
successful because I\'m a little bit confused about which of these
strains have a single amino acid substitution at position 155 in the
antigenic B site and which have two. I believe this is probably
incorrect. Nancy will have to help me out. The Shiga/41, is that 1 or 2?

DR. COX: One.

DR. LEVANDOWSKI: One? That\'s one, okay. So maybe I\'m okay.

But there are some strains that have only a single amino acid
substitution in that general site, and then there are a number of
strains that represent the H3N2 viruses that have both of those amino
acid substitutions that Nancy Cox was telling us about, and I have
indicated those with two exclamation points.

So next overhead, please. This one shows the results, again, from a
panel of sera from adults in the United States testing at the Centers
for Disease Control and also at the National Institute of Biological
Standardization and Control.

There are a number of antigens that were used here. A/Panama is the
vaccine strain, and it was also used for serologic testing at CDC.

I think this asterisk is wrong at NIBSC. I believe that they were using
the wild-type strain for their testing. I\'m not sure that that\'s
really critical.

The A/New Jersey/4/02 strain is one of those that had the single amino
acid substitution, and these others, Korea ‑‑ let\'s see, Guam I think
also is a single amino acid substitution, but Korea, Beijing/301, and
Fujian/411 are all strains that had the double amino acid substitution.

I think what you can see here is that, as compared to Panama, these
double substitution and some of the single substitution strains are
showing reductions in inhibition by current vaccines, as seen both at
CDC and at NIBSC. Although the reduction here isn\'t quite as marked,
there still is something different as compared to the vaccine strain.
This Paris/207 strain is, again, another one of those more typical
Panama-like strains.

So next overhead, please. This overhead shows results from elderly in
Australia, testing done at the Center for Biologics and WHO, Melbourne,
and some of the same strains here.

We\'re not showing much of a difference between the single amino acid
substituted strains and the Panama strain, and A/England, again, is
another recent, I think it\'s a recent Panama-like strain. I\'m not
entirely sure that I\'m correct on that, but I believe that it is.

Other recent typical strains like Hong Kong/1550 have been quite good
antibody responses as compared to the vaccine strain, but, again,
looking at these strains as tested at WHO Melbourne for those strains
that had the single or double substitution, I guess Osaka/70 and
Korea/770 are the double substitution, amino acid substitution; Shiga is
the single.

You can see here that they are also picking up reductions in antibody
titers for those strains. So I\'ll cover that again more in summary form
toward the end.

So now the next overhead will show the antigens, the B strains that were
used for serologic testing. You will recall that there are two
hemagglutinin and antigenic lineages that are circulating. The older
vaccine for us was the B/Sichuan/379/99-like, and strains that fall into
that category are indicated by exclamation points. For the serologic
testing we\'re currently using a typical strain. The Shanghai/361 was
chosen.

The rest of these strains would fall into the category of being B/Hong
Kong/330/01-like, and there were a number of those that were picked up
again from fairly diverse geographic locations for testing.

All of these serologies that I am going to show you will have been done
with ether-extracted antigen.

The next overhead, this one will show some studies for sero collected
from adults in Australia and testing at CDC and the Center for
Biologics.

In this particular instance, the vaccine strain was the
Victoria/504/2000. I think you can see that reflected ‑‑ I only put this
up as a reminder of what we were seeing last year. You can see reflected
that, using that as the vaccine, you get very good responses to the
Sichuan/379/99-like strains, when it is tested, but you get very low
results to the B/Hong Kong/330/01-like strains. This is something we
have been seeing for quite some time. So this is just sort of a reminder
and not real critical information.

So in the next overhead, looking at another serum panel from the United
States in the elderly, and again looking at different laboratories with
these sera and a battery of antigens, the top three here actually
represent the going vaccine strains. The particular vaccine strain used
for these studies was Hong Kong/1434/02, which is underlined, but there
were some other more recent strains that were tested.

Actually, it appears from these studies that, for the most part, the
responses against the more recent strains, including B/Brisbane/32/02,
are reasonably well-maintained against the hemagglutinin. I think that
fits with what Nancy was saying about not being able to distinguish
those strains so much. Plus, here the results are a little bit different
from ferret serology in that individuals had been exposed on multiple
occasions either to vaccine or to wild-type viruses.

So these individuals also have pretty good responses to the other
lineage of HA lineage, partly because of their ‑‑ well, because of their
previous responses or their previous experiences with influenza B
viruses. This, too, we had seen before with some other clinical studies.
So that is not really news.

Let\'s see, we can move on to the next overhead. So I\'m going to try
now to summarize a little bit about what was found at all the different
laboratories contributing, to the best of my ability.

These tables that I\'m going to show you are going to try to give you a
frequency where new test antigens were 50 percent or greater reduced in
geometric mean titers compared to the vaccine strain. We used 50 percent
as a somewhat arbitrary measure, but it is quite a substantial
difference, and a twofold difference on a geometric mean titer is a
pretty reasonably big difference in this kind of study.

What I have also tried to do here is to emphasize, as best I can, where
there are multiple labs tests, but sometimes that\'s not possible. So
I\'ve also included some representative viruses that were tested maybe
only in one or two of the laboratories.

So all of the viruses here again are New Caledonia-like, and the
A/Massachusetts strain is the one that represents the 95-plus majority
of all the H1N1 strains that have been isolated, and I think you can see
that really there is very little, if any, difference between the results
that were found for that particular strain and the current vaccine
strain.

For the Canada H1N2 strain, however, the majority of the serological
tests were reduced. More than half of the tests done by the different
laboratories were reduced. On average, this reduction, looking at all
the information from the laboratories, looking here, it was more than 60
percent reduction, which, again, is quite substantial. But it was a
fairly wide range between approximately 40 and 80 percent reduction in
the individual tests done by the laboratories.

For the other H1N2 strain, this Yokohama/22, the one laboratory that was
testing it found it to be very similar to the vaccine strain. I put that
up there just to give you some idea that there may be differences also
between these H1N2 strains and how they perform and the human
serologies.

Results for this low-reactor Peru was done in multiple labs. Again,
there was some variability, but a fair number, almost half of the tests
done, showed more than a 50 percent reduction in the post-vaccine
geometric mean titer. But, again, there was a fairly large range, and
overall you would say that, if you just would be willing to take this at
face value, it\'s kind of a moderate difference.

For the A/Yamaguchi/12/02 strain, that was tested by a single
laboratory. Again, it showed substantial reductions in that laboratory,
possibly consistent with it being one of these low reactors, which may
not be typical of the majority of the strains.

So on the next overhead, trying to summarize the results with the H3N2
viruses, and the more recent strains shown in this table with the single
amino acid substitution at position 155, the New Jersey and the Guam
strains appear to be relatively well-inhibited by the current antisera
as compared to the vaccine itself. The Hong Kong strain is one of the
more typical Panama-like strains, and it also seems to be
well-inhibited.

Amongst these strains at the bottom, which have this double ‑‑ or that
have the amino acid substitution at both positions 155 and 156, they
appear to be much less well-inhibited. Here, again, the majority of
these results from all the laboratories that were testing ‑‑ and, again,
we sometimes have only one lab that tested ‑‑ but it seems to be
consistent across those strains and also pretty much across the
laboratories that the current vaccines don\'t seem to cross-react all
that well with significant or substantial reductions in antibody
responses to those newer antigens.

So I will move on. So the overall picture for the H3N2 viruses is really
different from what we are seeing with the H1N1 viruses, and I guess
these results would suggest, where there is this clade developing for
the amino acid substitutions at position 155 and 156, we might expect to
see a lack of inhibition with the current vaccines.

So this final overhead shows some summary results for influenza B
strains. Again, the B/Shanghai/361 strain belongs to the Sichuan/379/99
HA lineage, but all the other strains that are shown here are part of
the current vaccine lineage. They\'re Hong Kong/330/01-like.

Interestingly enough, all things considered, most of these viruses
appear to be pretty similarly inhibited by antisera from the current
vaccines. I\'m not showing that the current Sichuan/379/99 vaccines do
not go back the other direction. There\'s not a cross in the back
direction. The Sichuan/379/99 strains do not produce an antibody
response that cross-reacts well with Hong Kong/330-like strains. I think
I have already mentioned enough about that. So we can take the overhead
off.

In summary, I would say that the vaccines used for these clinical
studies appear to be immunogenic in the populations that were tested. As
usual, the serologic studies are consistent with antigenic drift that\'s
occurring. I would say that the results are most suggestive of antigenic
drift for the H3N2 virus strains, particularly for those strains in the
cluster that had the substitutions at position 155 and 156.

I think I can stop there and take any questions, if there are any.

CHAIRMAN STEPHENS: Thank you very much.

Dr. Decker?

DR. DECKER: I have two questions. The first, the simplest one, could you
just refresh what Nancy might have said earlier? When is the WHO having
their next meeting to consider H3N2 selection?

DR. LEVANDOWSKI: Right. The WHO has indicated that it is going to
reconvene on February 26th to make their determination of what direction
they Are going to be going in terms of the H3N2.

DR. DECKER: Thanks. And the second ‑‑

DR. COX: Maybe I just need to clarify that a bit. I think that there\'s
going to be a couple of points at which a number of the WHO consultants
touch base. The final recommendation from WHO will occur on March 14th.
I think it is going to be published on March 14th.

DR. LEVANDOWSKI: I think that\'s the publication date, but ‑‑

DR. COX: Right.

DR. LEVANDOWSKI: \-- I think the press release also mentioned doing
something on February 26th.

DR. COX: We\'ll have a conference call and we\'ll be touching bases
about additional data that are available from all of the WHO
collaborating labs on Tuesday, February 26th, I guess it is.

But the recommendation won\'t be issued at that time. The manufacturers
and others will have an update at that time, but the recommendation
won\'t be necessarily finalized at that time.

DR. DECKER: The timing of our meeting today was moved a month back from
last year\'s in order to ensure that we had available WHO\'s
recommendations when we made ours. With that in mind, what date are you
suggesting this Committee could make a recommendation on H3N2, if it
elected not to make one today?

DR. MIDTHUNE: Karen Midthune, FDA.

We have been working with our Exec. Sec., Jody Sachs, to find out what
date we could have the poll, Dr. Decker, and I know that Jody\'s been
working on that. I\'m not sure exactly whether we\'ve nailed down a
date.

CHAIRMAN STEPHENS: I think we\'re going to come to this later.

DR. SACHS: I think this is a little premature. I mean, there are two
possibilities, March 14th and March 17th, which after the vote we could
query the members and the consultants to see which is best for them, but
I didn\'t know the public disclosure wasn\'t going to be until March
14th. So it makes more sense to me maybe March 17th, but, again, this is
premature to our vote and our discussion.

DR. DECKER: That\'s good enough. I was just trying to get a sense, are
we talking February, are we talking March, are we talking April?

DR. SACHS: Okay, but we\'re going to do what we can for you today, okay?

DR. DECKER: My second question, Roland, is more directly on your
presentation. When I look at the minutes from last year\'s meeting for
the flu section, I note that Item 5 in my summary says, \"The Committee
requested in the strongest possible terms that future antibody response
data include a pediatric cohort in addition to the present adult and
elderly cohorts.\"

So, in follow up to Sam\'s earlier question, I would like to ask, what
steps have been taken to implement that request of the Committee?

DR. LEVANDOWSKI: I think it requires resources in order to get those
things to happen. The Committee ‑‑ and thank you for reminding us. We
have been reminded about this every year for probably the past ten
years, and we agree strongly that it\'s something that we need to
undertake.

It is not a lack of enthusiasm for doing that, I would say. It is
difficulty in making sure that our resources are used for the things
that have the highest priority, and I would have to say that that has
not really gotten the priority that I think it deserves, and that I am
sure that you think it deserves, in terms of being able to do those
things.

We need to have someone out there who can give us some support in terms
of identifying sites where some of the studies might be going on. If we
can tag onto some of those other studies in a way that doesn\'t
interfere with them, that would be one route that we could anticipate
taking.

We haven\'t been able to find those kinds of studies going on, however,
on a regular basis, and that is a difficulty for us.

DR. DECKER: Has Stefen Gravenstein been unable or unwilling to
incorporate pediatric populations into his routine annual testing that
you rely on?

DR. LEVANDOWSKI: Well, I guess we haven\'t really approached it that
aggressively with that group. They, of course, have been doing studies
for someone else for a different purpose. The funding for that, I guess
if that other source could contribute to that some more and would make
those sera available, we would certainly like to have them.

DR. DECKER: That resource, we\'d probably love to talk about that.

DR. LEVANDOWSKI: Stefen Gravenstein, I guess he\'s mainly involved with
geriatric medicine as his background, but I don\'t see any reason that
it wouldn\'t be possible at his university to be able to identify and
immunize the population and acquire that, and we would certainly like to
have that, if it were available. I have to say I have not really
aggressively pursued that with that group.

CHAIRMAN STEPHENS: This was a conversation at the break, a fairly
extensive one.

Nancy, any comments on the pediatrics?

DR. COX: We are very keen to get our hands on pediatric sera. So it\'s
really a matter of having some kind of a collection of specimens, and
we\'ll be very happy to test them, as we did in the past, when they were
available. We feel that it is a high priority.

DR. LEVANDOWSKI: Well, could I just make one more comment about our role
in this? We had at one time at the Center for Biologics a contract for
immunizations that included a pediatric population, and it was a very
unusual pediatric population and very informative.

It was unusual in that it was very young children. It was children who
were in the range of six months to about three years old. The
information that came from that source was, we thought, extremely
valuable because it was very much ‑‑ because this population is
immunologically naive, it was very much cleaner information and gave a
different kind of instruction for these deliberations.

But, again, that contract was ended because of funding issues that have
impacted FDA and other government agencies generally over time for what
our resources should go for.

CHAIRMAN STEPHENS: Dr. Markovitz?

DR. MARKOVITZ: Yes, I was wondering, just to go back to the basics of
these things, all the data you present are hemagglutinin inhibition.
I\'m wondering what the current view is on how well that actually
correlates with protection, and do you do some neutralization assays
also?

DR. LEVANDOWSKI: Well, the correlation with protection is what\'s
published. There are a number of studies that were done in years past.
Those studies haven\'t been repeated on a very regular basis, but there
is some information along those lines also. I think I\'m going to ask
Dr. Couch to comment on this because his group is involved in doing some
of those studies to try to correlate antibody responses to protection.

But years past, the classic information is probably 30 years old or
longer, and was with a few strains, not very well-generalized but with a
few strains, that suggested that this antibody titer of 1 to 32 or 1 to
40 might be correlated with protection.

You\'re asking about neutralizing antibody. There are also some studies
that were not part of those same studies that suggest that a detectable
neutralizing antibody titer might be correlated with protection.

We have studies also where there has been an attempt to correlate the
neutralizing antibody with the HI. You can show that there is some
general correlation between the two, although it\'s not perfect, but
that hasn\'t been altogether correlated to protection.

We\'re not generally using neutralization antibody testing because it\'s
a much more ‑‑ when we\'re trying to test 15 to 20 new antigens, it\'s a
very daunting task to begin with just to do hemagglutination inhibition,
much less to try to do all of that with all these strains with
neutralization. We\'re not actually doing that in our laboratory. Some
of the laboratories may be and others may want to comment.

DR. COUCH: I guess I don\'t really have much to add to that except that
the correlate to the anti-hemagglutinin and antibody in serum is, I
think it\'s well-established. It\'s decades old. Its first demonstration
is back in the forties, and it\'s been, if not annually, almost
annually, demonstrated in studies. So I don\'t think there\'s any
question about the correlate.

Actual cause-and-effect data comes a little bit from animals, but if you
start reasoning ‑‑ and I won\'t do that now ‑‑ about what we know about
the physiology, the accumulation, the challenge, and things like that,
all of it falls together being sera anti-hemagglutinin and antibodies as
the paramount protective mechanism for influenza. I don\'t think
there\'s a whole lot of difference of opinion among individuals about
that.

As Roland said, we have been continuously involved in studies, and each
time we do a study, I mean just off the top of my head, how many times
have we found that correlate in individual studies? Twenty or 25 at
least, I would say, and it\'s not just us; it\'s everybody. So that\'s
well-established.

But neutralization you asked about. We are probably one of the few
groups that\'s routinely done neutralization tests in addition to
hemagglutination inhibition tests, and it was also a correlate that
follows the same pattern that the hemagglutinin does, depending a little
bit on how you do the test, and I won\'t get into that.

You can measure pure hemagglutinin and anti-hemagglutinin in antibody.
We do it because we find it to be a somewhat more sensitive test in
general, and we find it to give us an additional test, and it gives us
more detailed data about what\'s going on in a particular population.

With regard to the neutralization test, the European group is currently
involved in considering the possibility of instituting neutralization
tests into their programs of surveillance and decisionmaking, and they
have had at least one meeting, and there is another one scheduled, to
try to move forward to consideration of neutralization and whether there
is value there that should lead to incorporating those tests into the
types of discussions that we are having here. But at the moment it\'s
just under consideration.

CHAIRMAN STEPHENS: Dr. Cox?

DR. COX: I\'ll just comment very briefly. I think I can really
corroborate what Bob has said. We find that the neutralization tests are
more sensitive than hemagglutination inhibition for detecting antibody.
So you get higher titers when you look for neutralization antibody,
neutralizing antibody.

Where we have looked for differences between strains, we would think
that the neutralizing antibody test might be more sensitive, but we
haven\'t in the past found them to be so. Nevertheless, we\'re going to
examine the current H3N2 viruses in neutralizing antibody tests. I\'m
not sure exactly when we\'ll have those data available, but I believe
it\'s sometime next week.

DR. COUCH: One of the problems is that there are different ways to do
neutralization tests, and you can do them to make them very sensitive
and then you worry a little bit about specificity. You can increase the
specificity, and then you worry a little bit about sensitivity. It
relates to your substrates, your dose, how you picked your antigen.
There are a whole lot of variables that go into that to begin to be as
well-standardized as the HI test.

CHAIRMAN STEPHENS: Okay, I think we\'ll move on to our next presentation
on availability of strains and reagents by Dr. Ye of the FDA.

DR. LE: I\'m going to present the status of candidate vaccine strains
and their related potency reagents. Current trivalent inactivity in
lines of vaccine strains contain the antigen of two type A strains which
are subtype H1N1 and the subtype H3N2, and one type of B strain.

A/New Caledonia/20/99 is a current H1N1 vaccine strain. IVR‑116 is a
reassortant between New Caledonia/20/99 and A/Puerto Rico/834. This
reassortant has a moderate to high yield in eggs. At this time we do not
have a new candidate strain for H1N1 influenza A.

A/Panama/2007/99, which is a Moscow/10/99-like virus, is a current H3N2
influenza A strain. Resvir‑17 is a reassortant between A/Panama/2007/99
and the A/Puerto Rico/8/34, which has high yield in eggs.

Again, at this time we do not have a new candidate strain for H3N2
influenza A. However, A/Fujian/411/02-like strains, we just substitute
HA amino acid 155 and 156 were isolated in the middle of February and
are being distributed to collaborating labs this week for development of
high-growth reassortants.

Moving on to influenza B strains, the current vaccine strains for B as a
virus are B/Hong Kong/330/01-like. There are three strains currently in
use, including B/Hong Kong/330/01 itself, B/Hong Kong/1434/02, and a
B/Shandong/07/97. All three strains had moderated growth in eggs.

B/Brisbane/32/02 is a strain with B/Hong Kong/330/01-like HA, but
B/Sichuan/379/99-like HA in eggs. Brisbane appears to be low to
moderated growth in eggs.

Now let\'s focus our attention on the potency reagents. Antisera and
antigen for the current influenza A vaccine strain, A/New
Caledonia/20/99 and A/Panama/2007/99, are available from CBER from
manufacturing. However, if another influenza A strain should be chosen,
new reagents will be needed, but they will be available in May at the
earliest.

For the current B vaccine strain, both antisera and antigens for B/Hong
Kong/330/01, B/Hong Kong/1434/02 and B/Sichuan/07/97 are available from
CBER. However, if a new strain is chosen, specific reagents will be
available in May at the earliest.

Thank you.

CHAIRMAN STEPHENS: Okay, questions for Dr. Ye?

(No response.)

Okay, moving to comments from Aventis, one of the manufacturers, Dr. Sam
Lee from Aventis.

DR. LEE: Thank you, Dr. Stephens. I want to thank you also for the
opportunity to share our manufacturing perspective on influenza vaccine
strain selection, and I want to thank the members of the Committee for
taking time to review all the data and facing a very difficult challenge
today.

Certainly you have to review a lot of data from the strain surveillance,
but also you need to decide whether the need to change a strain
outweighs the risk of making that change. So, certainly protecting the
public\'s health against influenza means not only selecting a vaccine
strain that antigenically protects against circulating influenza
viruses, but also allows us to produce enough vaccine to protect the
public. In the U.S. it\'s up to 70 to 80 million doses needed each year.

The manufacturers have developed processes that are quite robust, and we
have successfully produced sufficient quantities of vaccines for the
U.S. market in most years. But I do want to remind you, for the recent
experience in 2000, when we had a strain, A/Panama, that was expected to
be high-yielding, but when put into full production, turned out to be
low-yielding.

So over the next several months manufacturers did respond to that and
made improvements. However, it did cause a delay in vaccine distribution
over the next two months.

What I plan to share with you today are the key factors involved with
manufacturing influenza vaccines and how your decisions can help assure
a sufficient and reliable supply.

Of course, the primary objective of this Committee today is to select
the vaccine strains that will protect against the circulating strains,
and you have reviewed and seen the data for hemagglutinin inhibition and
also cross-reactivity and similarity for the different strains.

I have also described to you that there\'s a secondary objective that
may or may not be as apparent, and that is to select strains that
propagate well enough in eggs to allow manufacturers to produce vaccines
needed for the U.S. market. Certainly the best way to ensure this
predictability of supply is not to recommend any changes, but, of
course, it is not always possible because we must protect the public
against the circulating strains.

A second best way is to minimize the number of strain changes. Each new
strain can yield anywhere from 50 to 120 percent of the average strain.
So one low-yielding strain could mean as much as 20 million doses fewer
for the market. Two low-yielding strains would certainly make even less
available.

So while manufacturers have been fairly successful at supplying the
market with sufficient quantities of influenza vaccine, each change does
infuse more risk.

If a change is necessary, there are two factors that are important to
consider. First is that the strain propagates well in eggs, and a second
is that the new strains need to be identified as early as possible. The
reason for this will become more apparent in my next response.

But, simply put, early strain selection allows manufacturers more time
to understand the growth characteristics of the new strain and to make
adjustments, if needed. So there is a real balance between optimizing
vaccine strains and making your selection early enough to have the
vaccine available.

Certainly there are many factors involved in manufacturing a vaccine,
but I want to review some of the critical components. First of all, the
vaccine is manufactured in eggs, and so we must ensure that there is a
reliable supply of eggs. Several hundred thousand eggs are used daily,
and traditionally we have been able to have a sufficient quantity and
quality of the eggs and a reliable supply, but we do have to monitor any
diseases such as avian disease that could threaten the flocks, and we
also have to look at weather for delivery. I\'m glad to say that the
recent snowstorms and all have not impacted our manufacturing at all and
we did not lose any production days.

The second critical component is the seed virus. Certainly the
availability of the high-growth reassortants in a timely fashion is
critical and also that the yield in general is predictable, but it is
really not fully understood until we have reference reagents available.

So that leads to the last critical component, which is the availability
of the potency test reagents. These are specific to each strain, as you
know, and are required prior to formulating the vaccine.

My final slide is to show you a timeline for manufacturing that
encompasses the time we order chicks for producing the eggs all the way
through distribution of the vaccine. In order to ensure that we have a
reliable supply, we order chicks as early as a year in advance. We\'ll
order then starting in January of the previous year and then move them
into the houses for the laying of the eggs in October and November.

The other component is the seed viruses, and we\'ll receive candidate
seed viruses in the fall and in the early months of the year. Along with
CBER and other laboratories, we will prepare the high-growth
reassortants, and we also have internal passaging that we can perform in
order to improve our yields.

So, typically, those seeds are produced and continual yield improvements
are made throughout the spring, and we will begin production as early as
January each year.

I do want to point out that, by starting in January, manufacturers take
a risk because they are producing before the strains are actually
selected, but we do this in discussion and collaboration with CBER and
other laboratories and other agencies.

Typically, we do produce the first strain starting in January. We\'ll
look at the second strain starting in February at some point and move
into a third strain as it is selected.

However, this year the timing of the strain selection is a little
different in that we are making it probably in the middle of when we
would typically be starting the second and third strains.

So the last piece is the preparation of the test reagents during this
time period. Really, this piece cannot start until the strains are
selected. I know CBER does begin work in preparing the purified HA
antisera and also preparing the reference antigen, but until that is
available in May and into June, we cannot begin formulating the vaccine.

The main consideration here is that the vaccine is typically distributed
September and October and into November. Because of this limited time
window for distribution, all product must be formulated, filled, and
tested in a very short time period, roughly about 17 weeks.

So any delay in strain selection or availability of test reagents does
delay the beginning of this point, and all this work must be compressed
in a shorter time period.

At this point that basically summarizes what I wanted to say today. I
wanted to kind of give you an understanding of the decisions and the
timeliness that\'s needed, and I am open at this point for any
questions.

CHAIRMAN STEPHENS: Thank you very much, Dr. Lee.

Open for questions, comments. Dr. Katz?

DR. KATZ: What progress has been made in getting out of eggs and into a
cell culture system?

DR. LEE: I\'m not familiar with all the research that has been done with
that. I know that it has been looked at for several years, and I believe
there was a cell line that was licensed in Europe to perform this.

My understanding at this point is that the yield in cell culture is
still extremely low, and that production capacity would not be there to
supply the entire vaccine supply.

DR. KATZ: Thank you.

DR. COUCH: I know, just by hearsay, that Aventis in Europe was pursuing
a cell culture vaccine as a possible product. Is that still being
pursued by the company, do you know?

DR. LEE: My understanding is that we are still looking at it, but at
this point it is probably still too early to say when it would be
available.

CHAIRMAN STEPHENS: Other questions, comments, for Dr. Lee?

(No response.)

Any other manufacturers who would like to make any comments? Evans, I
guess, or maybe Medimmune? Anyone else want to make comments on these
issues? Okay.

DR. ROYAL: Walter Royal.

Given that there\'s always the risk that your vaccine may not work, what
sort of in-house R&D takes place to try to reduce that risk, and what
sort of information might be passed onto some of the agencies that are
doing the various antibody and neutralization testing?

DR. LEE: I\'m not sure I fully understand your question. Could you
repeat that?

DR. ROYAL: Well, what I am wondering is whether what\'s done is that the
information that\'s given to you regarding the candidate viruses,
presumably, there\'s, as you said, a risk that your vaccine may not
work.

DR. LEE: Uh-hum.

DR. ROYAL: So I would assume that there are some in-house steps that are
taken to reduce that risk, or are there?

DR. LEE: Okay, I assume you\'re talking about new candidate strains ‑‑

DR. ROYAL: Yes.

DR. LEE: \-- for any new strains that may be selected?

DR. ROYAL: Or even once you get to the vaccine formulation step.
There\'s always a chance that your vaccine will be ineffective, but are
there steps that you take to reduce that risk?

DR. LEE: I guess I\'m trying to understand. It seems like there\'s two
different issues. One is effectiveness in terms of protection and the
immune response?

DR. ROYAL: Yes.

DR. LEE: Okay. At that point I guess I can\'t speak too much about that,
but in terms of productivity, we are in constant discussion with
Roland\'s lab to let them know what our responses are from various
candidate strains that we have been given and working with. Then once a
strain selection is made, we do continue to crop, passage the seed
viruses in eggs, and to try to improve the yields. New seeds are made
available and sent to Dr. Levandowski\'s for approval for use in
production.

CHAIRMAN STEPHENS: Dr. Decker and then Dr. Levandowski.

DR. DECKER: Yes, Dr. Royal, let me help answer your question. You caught
Sam offguard because he\'s just focused on manufacturing.

The simple answer is nobody can do anything to address that. Everyone
has to take it on faith that the strains selected, if grown properly and
inoculated, will produce the relevant antibodies and they will not only
work against that strain, but they will, hopefully, work against
whatever circulates.

All that has to be taken on faith, because by the time you produce it,
there\'s no time left to do any testing. Were there any time to do
testing, there would be no time left to manufacture anything.

So from the manufacturer\'s point of view, their obligation is to
produce whatever this Committee tells them to produce. Whether or not it
works has to be based on the faith that the data collected by CDC and
FDA and presented to this Committee will be relevant and accurate.

CHAIRMAN STEPHENS: Dr. Levandowski?

DR. LEVANDOWSKI: Yes, I just wanted to add a little bit to that also.
Our Committee is charged with making the recommendation, and in itself,
that\'s why we emphasize, I think, the practical information, to try to
avoid a situation where a recommendation is made that can\'t be
implemented.

We do need to take a look at the practical side of things here and make
sure that strains that we\'re recommending are strains that have some
likelihood of the manufacturers being able to develop things.

Probably, we don\'t emphasize it, but there\'s a lot of work that goes
on behind the scenes in advance of this meeting to look at new strains,
and when they are available, they are sent to the manufacturers at the
earliest time point.

We\'re in a little bit different situation here today. As you have
already heard, these new H2N3 strains have not even been distributed to
all of the laboratories that would be involved in preparing the
reference material, the reassortants, and so on, that the manufacturers
need to support them to be able to do what we ask them to do.

And then just further to the clinical side of things, we don\'t really
ever know how immunogenic any particular strain is going to be before a
vaccine is manufactured, and there really isn\'t time to do the kind of
clinical trials you would anticipate for any other kind of vaccine.
Influenza virus vaccine is different from every other one in that it is
changed almost every year and it\'s a new experience with each one.

I think we can say from experience that there is variation in the
inherit immunogenicity of individual viruses. Sometimes it\'s higher and
sometimes it\'s lower. We\'re always hoping that it\'s going to be
higher, but there may be instances where a strain is chosen that does
turn out to have lower immunogenicity.

I think, fortunately, it seems to be that in most instances where it has
been examined, when there is a good match between the vaccine strain and
the circulating strains, then efficacy is usually shown. Of course, the
vaccine itself, the efficacy of the vaccine is not a hundred percent.
It\'s probably 79 to 90 percent in adults, and it\'s quoted as being 30
to 50 percent in the elderly. We\'re really talking about preventing
illnesses, predominantly trying to prevent the serious consequences of
influenza infection.

But your questions are very good ones, and we\'re struggling with that
issue about what the implications will be when we make a change. We\'re
very concerned about both the practical manufacturing and also the
clinical implications.

CHAIRMAN STEPHENS: Ms. Fisher?

MS. FISHER: Well, I think that Dr. Royal\'s question is extremely
important, but is there a systematic surveillance after we use a flu
vaccine in any given year to measure how many of those who are getting
the flu have been vaccinated? I mean, what is the followup? How big is
the population you\'re following up, or is there any followup?

DR. LEE: Yes, I was going to say probably the CDC does most of that
surveillance.

Dr. Cox, do you want to respond?

DR. COX: There is no systematic followup to see, to document whether the
general population who receives flu vaccine actually is infected by flu
virus because it\'s an impossible task. I mean we have 80 million doses
or 70 million doses given, and it would be impossible to follow up.

Where vaccine efficacy studies have been done in the past, vaccine
efficacy has been found when there\'s a good match between the
circulating strain and strains in the vaccine. The only ongoing
surveillance for vaccine effectiveness that I know of was done, I think,
for about five years, up to last year.

What investigators were doing was to look at the Medicare population,
the elderly population, and look at vaccinated and unvaccinated
individuals who are 65 and older and see if there were reductions in
respiratory hospitalizations and death among the vaccinated compared to
the unvaccinated. And effectiveness, vaccine effectiveness, was
definitely shown.

There you are using a very high bar because there are a lot of other
respiratory infections that are going around at the same time as
influenza, but, nevertheless, effectiveness was demonstrated in this
high-risk elderly population.

MS. FISHER: I just think that, from a public confidence standpoint, I
think that there needs to be some thought given, particularly as we move
to recommend flu vaccine for infants and virtually everyone in this
society, that there be some mechanism for measuring and also in
consideration that many things can look the flu, that we somehow try to
measure how many people get the flu who have already been vaccinated. I
mean I think that is sort of elementary as we move into this universal
use of flu vaccine.

CHAIRMAN STEPHENS: Thank you. Dr. Decker?

DR. DECKER: Well, just a quick response or followup to what Dr. Cox
said: Although there are not routinely systematic, ongoing studies of
the type that you\'re wishing for, in fact, there are so many efficacy
and effectiveness trials done with flu by various research groups and
universities every year that, despite the fact there\'s no single,
ongoing systematic study, the literature for almost every year is that
efficacy or effectiveness data, because this is such a rich area of
research.

I mean I know the hospital immunology literature, I can guarantee you
that every year there will be a half a dozen studies submitted in the
literature in the hospitals about how effective the vaccine was in their
health care workers, and so on.

So, despite the absence of an ongoing, systematic, centralized study,
there is actually an area of very rich data.

CHAIRMAN STEPHENS: Okay, a couple of questions.

DR. GELLIN: I want to go back to a manufacturing question. You highlight
the risk that the manufacturers take by getting out in front of the
recommendations. You have also, since this is your graph, you could put
the arrows wherever you wanted, and it looks like you put two arrows
ahead of where we are currently.

Historically, have you, your company or other companies, missed on that
guess?

DR. LEE: Well, I can speak for Aventis. Perhaps the other manufacturers
would like to comment.

The strains that are selected for early manufacturing are done under
discussion. We certainly make the decision ourselves to go ahead at
risk, but in terms of the strain selection, that is made under
discussion.

In the past we have not missed, to date. So we\'ve been fairly fortunate
that the available data was there for us to make that decision.

This year we have not gone into production for the second strain because
there\'s been a big uncertainty about the second and third strains. So
while I do have the arrow for the second strain there starting in
February, this year is an exception to that, and it\'s pretty apparent
why we made that decision.

CHAIRMAN STEPHENS: Dr. Katz?

DR. KATZ: My question may be for Dr. Lee but also for Dr. Decker or
whoever else can answer it. We heard that from four companies we have
gone down to two in the United States. I don\'t know; is Evans a United
States company? Do they manufacturer? I thought they were English.
Aventis is French, but they make it at Connaught in Swiftwater,
Pennsylvania.

I guess my question was, who makes vaccine for the rest of the world?
Who uses vaccine other than the United States? Western Europe I assume
does. Who are the other companies involved?

DR. LEE: There are actually quite a few companies around the world that
are involved. To name a few: GlaxoSmithKline is a large player. There\'s
also Chiron, Sorbet Dufar. Up in Canada there\'s Biochem Pharm, I
believe, and certainly Evans Vaccine and PowderJect are involved with
that.

So it is not an exhaustive list of other suppliers, but ‑‑

DR. KATZ: No, but several of the companies that you mentioned do
distribute other products in the United States or they don\'t do flu.

DR. LEE: That\'s correct.

DR. KATZ: GlaxoSmithKline has a large market for a lot of different
things, but they haven\'t chosen to do flu. I guess the question is, how
important is it that we have an augmented source? If H5N1 came along
next year, who could make enough vaccine to protect us?

CHAIRMAN STEPHENS: It doesn\'t sound like there are any direct takers
for that.

(Laughter.)

DR. COUCH: That\'s going to be left on edge.

(Laughter.)

CHAIRMAN STEPHENS: Dr. Decker, and then we have got to move to Dr.
Levandowski and the options.

DR. DECKER: Well, I will just give you a very general response, Sam.
That is, availability of flu vaccine in this market is determined by
market forces, frankly. You have had two companies leave it because they
can\'t make enough money to pay for the buildings that they need to make
the stuff.

As flu prices have risen in the last couple of years, driven by the
companies that want to stay in the business and who raised prices so
they could, then we have seen foreign-based companies devote more
efforts to bringing flu vaccine here. For example, Evans is sending a
much larger proportion of its production to the U.S. now that U.S.
prices are approaching European prices. Those are the types of market
forces that one presumes the other companies will eventually respond to.

DR. KATZ: Thank you.

CHAIRMAN STEPHENS: Okay, Dr. Gellin.

DR. GELLIN: Let me comment from the HHS perspective, and I didn\'t bring
with me the budget, the \'04 budget, that was released a few weeks ago.
But what was highlighted in there was a piece on pandemic flu, and it
was really recognizing some of the issues that Sam has alluded to on the
need to have a greater manufacturing base to be able to produce a
sufficient supply of flu vaccine in such an event.

So I think the details of that are being worked out, but at the highest
levels that I get to see in the Department there is sufficient interest
in making sure that that capacity is there.

I\'ll also highlight, if you look at the language, it focused on the
domestic capability because of the recognition that, in the event of a
pandemic, it is probably where the vaccine is produced is going to be
the most important in the country that receives it. So, again, these are
details that are now being discussed, but they put that out there to
emphasize the Department\'s interest in making sure that we\'re thinking
forward about this.

CHAIRMAN STEPHENS: Thank you very much.

Dr. Levandowski, I think it would be appropriate for at least our
thinking at lunch to introduce the options for the vaccines.

DR. LEVANDOWSKI: All right, I\'ve got overheads.

CHAIRMAN STEPHENS: Being prepared for PowerPoint failures is good.

DR. LEVANDOWSKI: Am I permitted to complain a little bit? I couldn\'t
get my Microsoft Word document to go into PowerPoint directly, so we
tried a different route.

Okay, while we\'re waiting, let me just summarize some information. I\'m
going to try to go through some options for recommendations for the next
year\'s influenza vaccine. I would like to start, and I\'ll just
summarize. I\'m actually going to steal the summary that Nancy Cox gave
you earlier. So if you have that, you could just read along with me.

But for H1N1 viruses or H1 viruses, including both the H1N1 and the
H1N2, since last winter, H1N1 and H1N2 viruses have been reported
primarily in the Americas, which means Canada, Chile, and the United
States. That means more than 95 percent of the recent H1 viruses have
HAs that are antigenically and genetically similar to those of the
current vaccine strain, the A/New Caledonia/20/99.

The neuraminidase of the current H1N1 viruses are similar antigenically
and genetically to the N1 of A/New Caledonia/20/99, and the
neuraminidase of the current H1N2 are similar to those of the
currently-circulating H3N2 viruses, meaning predominantly, I think, the
strains that are more like A/Panama.

So in terms of what our options might be for next year, first of all,
there\'s always the opportunity to maintain the current vaccine strain,
which is A/New Caledonia/20/99. In favor of that, manufacturing is very
well worked out and the yield is very predictable now, after several
years of using this strain.

Also, more than 95 percent of the viruses that have been analyzed this
year are A/New Caledonia/20/99-like by their antigenic characterization
of both the HA and the NA. Against that, however, there are some, a
small percentage, less than 5 percent of the viruses analyzed this year
are low reactors.

If I could get the next overhead? The second option would be to change
that strain which came from what we first had in 1999 to a more
contemporary H1N1 strain. In favor of that, some of the viruses analyzed
this year have been low reactors. But, against that, the low reactors do
seem to be scattered throughout the genetic dendrogram, which doesn\'t
suggest any particular common mutation occurring.

There is no broadly representative strain that has been identified, so
that none of the manufacturing issues that would need to be addressed
have even been investigated at this point. Then there is always the
possibility that we were discussing earlier, that a new strain might not
provide any superior coverage to the current vaccine strain.

So there is always the possibility to postpone, but in this case we
don\'t see that there is any advantage to postponing a recommendation,
mainly because there is not going to be any real significant new data
that will be appearing in the near future.

So moving on to the H3N2 viruses, again, the first option ‑‑ let me just
first go through a review of a summary. Sorry.

The H3N2 viruses have been causing, as has been mentioned, recent
outbreaks in Asia, and in particular in Japan, Korea, and China. An
increasing proportion of the recent H3N2 isolates have not been
well-inhibited by post-infection or by post-immunization data.

The H3N2 viruses that have the amino acid changes at positions 155 and
156, which is in antigenic site B on the hemagglutinin, tend to be
poorly inhibited by antibodies to the vaccine virus. These low-reacting
viruses with these changes at 155 and 156 have been detected not only in
Asia, but also in Europe and also in the Americas.

So the first option for the H3N2 would be, again, to maintain the
current vaccine strain, which is A/Panama/2007/99. In favor of that,
again, the manufacturing is very well worked out. Although the yield
might have been low for this strain at one time in its early days, it
has become a very good, reliably high-yielding strain for manufacturing.
Many of the viruses that have been isolated this year actually are still
A/Panama/2007/99-like by their antigenic characterization of the
hemagglutinin.

Against maintaining the current vaccine strain, there is this increasing
proportion of recent H3N2 influenza A viruses that are not
well-inhibited, and many of those viruses seem to be in the clade that
has the amino acid substitutions at positions 155 and 156.

This strain, as mentioned in the summary, has been ‑‑ the new H3N2
variant has been identified in Europe ‑‑ I guess there are strains from
Norway and UK ‑‑ in Asia, China, Japan, and Korea, and also in North
America and the United States.

What we do know is that sometimes new strains may spread very rapidly in
susceptible populations. We also know that H3N2 influenza virus has
often caused significant morbidity and mortality, and they are most
often associated with those epidemics where there is a large amount of
excess mortality.

So the second option would be to change the current vaccine strain to
something that\'s more representative of these newly-circulating
viruses. In favor of that, these are all just the things that were again
on the previous slide, but the new variant does appear to be spreading
geographically and causing disease. When new strains appear, they may
spread very rapidly.

A more recent strain might provide a closer match for the hemagglutinin
and the neuraminidase of the contemporary strains. Again, the H3N2
viruses are often responsible for significant morbidity and mortality in
all age groups.

Against changing would be that information about the newest strains is
not yet completely analyzed, and we are at a fairly late date. There
aren\'t any new strains that have been distributed for evaluation for
manufacturing issues, although that is happening.

New strains may cause difficulties in manufacturing, as has been pointed
out, until all the process parameters can be optimized, and we don\'t
minimize that possibility.

A new strain, again, may ultimately not provide superior coverage
compared to the current vaccine strain. We won\'t know that until we see
results from the vaccine.

So the next overhead. A third option here would be, again, to postpone
the decision. In favor of that, postponing that decision today would
provide time to further analyze these newly-collected strains and gather
information that would be relevant to manufacturing and would also tend
to keep the process parallel in the United States and elsewhere in the
rest of the world.

A more recent strain might provide the closer match with the
hemagglutinin and neuraminidase of the contemporary strains. So if it
turns out that these strains, once they have been completely analyzed ‑‑
and we don\'t know whether they will be suitable or not, but when
they\'re completely analyzed, we may be in a better position to
understand what that likelihood would be.

The H3N2 viruses, they are a cause of morbidity and mortality, and I\'ll
keep saying that. But there may be a fallback position to consider also
as part of the postponement, which is that, if we\'re not able to do
something about these new strains as they\'re circulating, a possibility
would be to maintain the Panama current vaccine strain as a necessary
resort.

And then against that, again, we don\'t know what\'s going to happen
with manufacturing. By postponing, the manufacturing issues are still
not resolved and they are not likely to be easily resolved, and those
activities are very time-critical.

We do know that if there are manufacturing delays, that that will reduce
the amount of vaccine that is in use for a lot of different reasons. One
is because of the manufacturing itself, but also the social implications
of when people expect to receive the vaccine and be immunized.

Okay, so moving on to influenza B viruses, in summary, again, the
influenza B viruses have been predominating in the United States and in
much of Europe during this current season. The influenza B viruses that
have been predominant worldwide really are in the current vaccine, our
current vaccine lineage, the B/Hong Kong/330/01 lineage, although there
are a few of the older lineage which are still persisting.

Most of the recent influenza B viruses that are in the Hong Kong/330/01
lineage, however, have neuraminidase that are more closely related to
the neuraminidase of that other hemagglutinin in lineage influenza B
virus. But what we have seen is that that has remained fairly stable in
terms of the overall antigenic composition of the strains as they have
been appearing over the last several months.

So moving on to this, again, options here: The first option, of course,
is to retain the current vaccine strains. Again, we know manufacturing;
it\'s well-defined; it\'s very predictable. Most of the viruses that
have been isolated this year have hemagglutinin that by antigenic
characterization is very similar to the B/Hong Kong/330/01 vaccine
strains. But against that would be the concept that most of the
currently-circulating strains have their neuraminidase from
B/Sichuan/379/99.

A second option for influenza B would be to change to another strain,
and, of course, we would do that because of the vaccines might provide
better coverage for those current influenza B viruses, but, again, we
don\'t really know anything, we don\'t know very much about what the
difficulties in manufacturing might be.

I guess what I could say, or just to repeat what we know from limited
experiences, that the B/Brisbane strain, for example, is a moderate- to
low-growing strain, which would make it less yielding for manufacturers
than the current strains. Of course, also, manufacturing delays, again,
would reduce vaccine availability and use.

And, again, a third opportunity or possibility would be to postpone the
decision, but, again, there doesn\'t seem to be any advantage. Although
there will be some additional data, because I guess there are still lots
of influenza B viruses coming in; it\'s not clear that that will help to
inform whatever the decisionmaking is.

So I would stop there and see if there any questions before I sit down.

CHAIRMAN STEPHENS: Thank you very much. We\'re going to continue this
discussion after lunch, but I want to have the opportunity at this point
to have Roland respond to any questions.

Dr. Gellin?

DR. GELLIN: Roland, is there ever, or how often are there, differences
in the strains that are selected for the U.S. versus the ones that WHO
selects, and what implications does that have on confusion and
everything else?

DR. LEVANDOWSKI: Well, all the strain names are confusing. So any
differences in the names is confusing, even within the United States.

In terms of being consistent with the recommendations, the WHO
recommendations are worded in such a way and actually say that national
authorities should make their own choices for what the strain should be,
but they recommend the strain that is \"like.\" And generally it\'s
possible to meet those recommendations, even using some slightly
different individuals strains; they still fit the overall
recommendation, but there could be different strains that are used. As
we have in the United States for influenza B right now, there are two
different influenza B viruses that are being used.

CHAIRMAN STEPHENS: Julie?

DR. PARSONNET: I guess I just have a very naive question that sort of
relates a little bit to the previous question, which is, you know, if we
could put infinite numbers of viral strains in each vaccine, we would
probably try to do it. We would probably put the number in that we
thought were really going to be circulating or guess. If we could put
five or six in, we might try to do it.

So the other way to do that is to allow manufacturing companies to make
some differences in the ones that they produce. So you might have
different companies but be different, maybe one virus, different
vaccines.

The advantage of that might be that you would have herd immunity and a
wider variety of vaccines in the population, and also that you might
have a vaccine that\'s already prepared that you could use if you
guessed wrong on the third virus, for instance.

So I guess this is a naive question because I\'m sure companies think
about this, and people think about this all the time, but what are the
possibilities, since there are at least two, and actually FluMist, a
third company that produces flu vaccines in the United States, to allow
those companies to make a decision where there are areas of uncertainty
and so that we can have actually broader coverage possible?

DR. LEVANDOWSKI: I think we try to build flexibility into the system. As
I was mentioning, it is already possible for manufacturers to use
different strains that would fit the \"like.\" For inactivated vaccines,
the real issue, as we have discussed, is predominantly the
hemagglutinin, although we\'re concerned about the neuraminidase.

There could be instances ‑‑ you mentioned FluMist ‑‑ there could be
instances for a vaccine like that, where it would make sense for a
completely different strain to be used that would be pertinent to their
own manufacturing issues that need to be worked out.

The issues are different there. It would be an attenuated vaccine.
They\'re more worried about maintaining attenuation and matching up as
best possible the hemagglutinin and neuraminidase, but there would
probably be, there probably will be, we would expect and anticipate that
flexibility is necessary for overall manufacturing. We\'re trying to
show that now.

I thought you were going to ask, why not a quadravalent or a pentavalent
vaccine or something like that?

DR. PARSONNET: I\'ve heard before that wouldn\'t be possible. So can we
do the equivalent by having two different trivalent vaccines?

DR. LEVANDOWSKI: Okay, well, the manufacturers themselves may want to
address that concept of having different strains possibly, because if
you are the manufacturer who has the strain that nobody wants, where
does that leave them for the following year, if they can\'t sell their
product?

I think we\'re trying to make sure that, as best we can, all of us, that
there\'s plenty of vaccine to go around and that manufacturers all have
an even chance at being able to have their product used, and that it\'s
a good one.

CHAIRMAN STEPHENS: We have had the discussion about multi- or additional
components. Could you just comment on that? I\'ll put you on the spot.

DR. LEVANDOWSKI: All right, I had to open my big mouth.

There are a couple of issues. One of them is very practical. There\'s
only a certain number of egg days available or tissue culture days.
Whatever you want to look at in terms of manufacturing, there\'s only a
certain amount of time for production.

Whatever gets used for ‑‑ if you have three components and you\'re going
to make 90 million doses, okay, you need 30 million of each. If you want
four components and you can make 90 million, then you are going to
reduce the amount, the total number of doses that you can produce within
that period of time.

The issues about the yield of these different strains also is an
important one within that context. The poorest-yielding strain is going
to be the one that pretty much determines or it drives how much vaccine
the manufacturers will ultimately be able to produce.

I don\'t know if anybody wants to comment on that from a manufacturing
point of view before I go on, but I could say some more things.

DR. DECKER: Well, you said it well. Let me just correct one thing. If
Aventis, for example, wants to have 50 million doses on the market, to
pick a round number, that means we\'ve got to make a minimum of 150
million doses, 50 of each strain. If you want four strains, that\'s 200
million. We can still only make 150. So you just very arithmetically cut
the availability.

On top of that low-yielding issue is a roll of a dice with every strain.
As you said, whatever is the lowest yield for that caps your production.

With respect to whether companies would want to offer different strains,
I rather doubt it, not only for the reason you mentioned, but with
current technology ‑‑ and this isn\'t likely to change anytime soon ‑‑
you\'ve got one roll of the dice to make vaccine for the year. You have
to start right now. In fact, we started a month ago, just gambling that
we\'ve made the right choice.

So by the time you know what\'s the right strain, you can\'t do anything
about it. Today, and over the next couple of weeks, people are going to
make the best possible choice. Once this group has articulated the best
choice, why would any company want to go with what\'s not the best
choice?

DR. PARSONNET: My comment would be that it may be that we will come out
and say, well, we\'re not sure what the best choice is. With the A3 and
2, I think there\'s a question about what the best ‑‑ we may have a
question at the end of what the best strain is.

That\'s the issue for me. It\'s not the other two. You know, no company
would want to do differently.

But when there\'s a question about the third strain, for instance, and
we are not sure which one to put in, the question is, should we be
encouraging people to do both, so that in either case, if there is an
incredible outbreak of one, or the one that we didn\'t expect, or the
one we didn\'t predict, there\'s another source of vaccine to cover
that?

DR. DECKER: There is one more answer to that, which is the big risk for
production is not a couple of weeks\' delay to get better data. The big
risk is making the decision to make a new strain.

The delay plays into that a little bit because if it turns up, it\'s
harder to grow it; you\'ve lost a few weeks of your time.

But, generally speaking, you\'re far better off, if you have to, to wait
a few weeks, make the best decision and go with it, even if it involves
a change, than to make a change now that perhaps you don\'t need a much
higher risk.

So, again, for that reason, companies aren\'t likely to do what you say,
unless their choice is, let\'s just keep making what we made before.

CHAIRMAN STEPHENS: Okay, I would like to have one last question from Dr.
Karron, and then we\'re going to break for lunch and resume the
discussion at 1:15.

DR. KARRON: I guess just a comment about the issue of different
companies manufacturing different vaccines: One is that manufacturers
can probably comment better on this distribution than I can, but my
understanding is that in this country Aventis still makes the majority
of the vaccine. It\'s certainly not an even distribution between Aventis
and Evans.

Then also just to mention that, in fact, for children under four there
is one manufacturer of influenza vaccine, and that is Aventis. So there
would not be a distribution.

CHAIRMAN STEPHENS: Okay, we\'ll continue this discussion at 1:15. Thank
you very much for all the presenters and the comments from the panel.

(Whereupon, the foregoing matter went off the record for lunch at 12:17
p.m. and went back on the record at 1:19 p.m.)

A F T E R N O O N S E S S I O N

1:19 p.m.

CHAIRMAN STEPHENS: Okay, let\'s go ahead and get started.

If I could ask Dr. Levandowski come to the podium with the options,
we\'ll continue that discussion.

We have a session on open public hearing, if anyone would like to make a
statement from the public.

(No response.)

Okay, seeing no one, Dr. Jody Sachs has a statement to make.

DR. SACHS: Well, as part of the FDA Advisory Committee meeting
procedure, we are required to hold an open public hearing for those
members of the public who are not on the agenda and would like to make a
statement concerning the matters pending before the Committee.

I have not received any requests at this time. If there is anyone in the
room that would like to address the Committee, please come forward to
the mike and this is the opportunity.

(No response.)

I would like to close the open public hearing at this time because I
don\'t see anybody who is approaching the mike. So I\'m going to turn
the meeting back over to Dr. Stephens. Thank you.

CHAIRMAN STEPHENS: Okay, Roland, I think we cut you off a little bit,
but this is the heart of the matter, in a sense, and it may be helpful
to review these options very briefly and ask for further discussion on
the options.

DR. LEVANDOWSKI: Okay. Well, I\'m not quite sure how brief I should be,
and I don\'t think I probably need to belabor all of the pros and cons
again, but just to maybe indicate the highlights of what the options are
that were laid out here.

Okay, so the first, starting with the H1N1, of course, the first option
is always to keep the vaccine strain the same. Here we have a strain
that we have had in the vaccine for several years, so it is getting a
little bit old, but still it represents the majority of the viruses that
are circulating.

Certainly the manufacturers have had enough time to really get to know
it well. A concern might be the small number of viruses that have been
low reactors in some of the serologic tests, but we also know that those
low reactors are not clustered in any particular genetic branch, so that
they probably represent independent kind of mutations and maybe not the
development of a specific clade that\'s going somewhere on its own.

The other main option here for H1N1 would be to change the strain, and
the main reason to do that would be to try to have better coverage for
some of those strains that look like they\'re low reactors, but, again,
we just don\'t really need ‑‑ those low-reactors by themselves are not
forming any kind of group. They really are not representative of the
mainstream of activity which we have seen mostly in the United States
during this year in terms of the H1N1 strains.

Although the Committee could consider postponing the decision, we really
don\'t think we would see an advantage from the point of view of what
information could be made available to do any better than what we\'re
presenting today.

CHAIRMAN STEPHENS: Comments or questions on the H1N1/H1N2 options?

(No response.)

Okay, go ahead.

DR. LEVANDOWSKI: Okay. So the H3N2 is a little complex, as pointed out.
You probably noticed I had a lot more pages to go through on that one
than on either H1N1 or the B.

Here again, one choice would be to maintain the current vaccine strain,
the A/Panama/2007/99. Here again, in favor of that, we really know quite
a lot about this strain. It has been in the vaccine for several years.
Most of the viruses that have been identified up until about two weeks
ago look very much like A/Panama/2007/99 by their antigenic
characterization for the hemagglutinin.

But not in favor of maintaining the current vaccine strain, there are a
number of issues, most of them relating to the fact that there appears
to be a new clade of H3N2 developing that has some very specific
signature, amino acid changes in one of the important antigenic sites of
the hemagglutinin.

Not only does that strain appear to be coherent in the sense of its
evolutionary background, it seemed to have spread quite a bit. We\'re
seeing most of the strains, I guess, from Asia, but there are also
isolates from Europe and a couple of countries and also in the United
States.

As I have belabored before, we do know that new strains can spread very
rapidly. We have had that experience with an H3N2 strain in the past.
Once it got seeded, it really got going. We are maybe early in seeing
this, but, you know, we don\'t know for sure.

The H3N2 viruses also tend to be those that cause or that tend to be
associated with more morbidity and mortality than the other strains. So
one of the other options, or the main option, or one of the main options
here, the second main option is to change the current strain to a
different strain that would be more representative, and really all the
pros here are basically like the cons for not changing the strain.

So I don\'t think I will spend a lot of time going through them, except
to say that these new variants have appeared and that they seem to be
spreading widely, or they have spread somewhat widely already, and that
we would normally take that seriously in terms of the consequences, if
it did become seeded and cause widespread infection.

Against making a change, however, we don\'t really have a lot of
information about the newest strains because they haven\'t been
available to work on. In this sense, I don\'t mean the epidemiologic
work. I mean strains that could be used for manufacturing.

I guess predominantly we have not had the opportunity to get those
strains distributed, evaluate them, make sure they have got the correct
antigenic characteristics and genetic characteristics, and then be able
to optimize the manufacturing process.

We do know that, as we have heard, if manufacturing is not smooth, then
delays and shortages are likely to occur. We ultimately don\'t really
know whether we would get better immunogenicity out of a new strain.

So the third option here ‑‑ I guess this one is probably still as strong
as the other two ‑‑ is postponing the decision in order to get some more
information to make a better ‑‑ or to have more information to inform
the decision in terms of these strains that are just being distributed
right now.

Again, the concerns always are the tradeoff between being able to
manufacture the vaccine or to have some vaccine of some sort that may
still provide some level of protection, even if it\'s reduced because
there\'s not a good match between the vaccine and the circulating
strains.

So, as mentioned here, a fallback position might be considered as
maintaining the Panama strain, if it turns that we\'re not able to
provide a practical response to what we\'re seeing in terms of the
surveillance and epidemiology.

I guess I can probably stop there and don\'t need to go through those.

CHAIRMAN STEPHENS: Questions? Dr. Dowdle? Dr. Couch?

DR. COUCH: It is just a reassurance question because I had carried
A/Fujian/411 as one of the possibilities, looking through these, but it
wasn\'t on the amino acid sequence list. Did you say it\'s also that
155/156 set of strains?

DR. COX: Yes.

DR. COUCH: It is?

DR. COX: It definitely has those strains.

CHAIRMAN STEPHENS: Dr. Dowdle?

DR. DOWDLE: Thank you.

Roland, just a little clarification on how you see a fallback position
of A/Panama actually working. I mean, what you\'re saying, that a
certain amount of time could be allowed to look for a high-yield strain,
let\'s say the new H3N2 strain. But at some point then you would have to
make a decision of go/no-go and fall back to Panama. Is this what
you\'re referring to?

DR. LEVANDOWSKI: I think that is a very important, practical
consideration, yes. The manufacturers, if it is a low-growing strain,
the manufacturers will be unable to really respond anyway, even if they
get the strain. In order to produce a high-growth reassortant, that in
itself takes several weeks, probably in the range of six to eight weeks
by classical methods, if that\'s what we\'re doing.

Manufacturers, once they have that strain in hand, require about a month
to develop their seed viruses. So we will be talking about manufacturing
with such a strain probably two to two-and-a-half months from now at the
earliest, if everything went smoothly from here on.

So there are some of those sort of considerations in terms of the
timelines that would have to be there. Even if a recommendation were
made to implement such a change, now or later on, if those things don\'t
work out, and they might not be completely worked out in the next week
or two, then we would have to have some sort of an idea as to what
direction we ought to take. Should we keep going and I guess risk very
low vaccine supply or should we try to maximize what the coverage for
the vaccine would be?

DR. DOWDLE: May I? I would think the last thing we would want to do is
get caught in a very low vaccine supply situation, as we have had
before. At the same time we always have the competing goal of wanting
the best possible strains in the vaccine.

But I have a pretty good feel for what happens, what needs to happen, in
order to incorporate a new strain, but it is still not clear to me
exactly when the drop-dead date is, I mean when the decision has to be
made. That\'s still quite nebulous. Are we talking about a month? Are we
talking about two months?

DR. LEVANDOWSKI: By precedent, we have gone into mid-March in finalizing
recommendations in the past. When we have done that, we have usually had
quite a lot of information that has been developed subsequent to our
January meeting and even subsequent to the WHO meeting in February.

So, in some sense, although this isn\'t what we would like, in some
sense we are in a similar situation to what we have had in past years,
when we had planned on having a meeting in January and a meeting in
March. That was not necessarily what we would desire.

We would hope that we could make sure that all these recommendations are
completed by this time, but I think we are still in a situation, except
for being somewhat later, several weeks later than we would normally
have been with getting some work done on developing a new vaccine
strain, I don\'t think that the timelines have bent that much. I think
that if we maintain that kind of timeline, we would still be consistent
with what has gone on in the past, although we would like to be better.

CHAIRMAN STEPHENS: I believe, Dr. Myers, did you have a question?

DR. MYERS: No, it\'s been answered.

CHAIRMAN STEPHENS: Okay. Dr. Diaz?

DR. DIAZ: Just a real quick question: In following along the theme of
that fallback possibility, if in fact something would happen and a
recommendation would be made to make a change, and yet it couldn\'t be
and the fallback was the Panama strain, if the H1N1 and B strains remain
the same, we would be at that point facing using the exact same vaccine
that we used for this current year. And I am wondering if the
manufacturers keep or have on hand vaccine from the current year that
doesn\'t get used that is viable for use in a subsequent year, if in
fact that were the case.

DR. LEVANDOWSKI: If you\'re asking ‑‑ I\'m addressing this one? Okay.
The manufacturers may want to address this also, but generally the
manufacturers produce as much as they think, or close to as much as they
think they are going to need for any given campaign. It\'s not really to
their advantage to have monovalent bulk vaccines carried over, but that
does happen sometimes, but we\'re usually talking about a very limited,
small amount of vaccine that might be available for subsequent years. It
usually would only be carried over from the end of one season to the
beginning of the next one.

DR. DIAZ: It could provide a jumpstart in that kind of a situation
potentially?

DR. LEVANDOWSKI: I don\'t ‑‑ what do you consider a jumpstart? It\'s a
very limited amount. It would maybe be one, or at the most two,
monovalent bulk vaccines from a manufacturer. So we\'re not talking
about an amount of vaccine that would really help them out in any way.

DR. DIAZ: That would be very useful, right.

CHAIRMAN STEPHENS: Dr. Decker, you have a question, but you may want to
comment on this issue as well.

DR. DECKER: No, I don\'t have a question. I was going to give a response
to Dr. Dowdle\'s question, and I\'m not sure if we have segued from
questions to discussion or not.

CHAIRMAN STEPHENS: Well, I think we\'re going through a discussion of
the issues as he\'s presenting the options.

DR. DECKER: Then let me go ahead. Dr. Dowdle was asking about how much
time do we really have. My belief is that a delay for a couple of weeks
that was talked about earlier would be inconsequential as long as the
Committee makes a decision on two of the strains today because,
particularly in the face of no manufacturing strain identified, let
alone reassortants generated, even if we picked an A strain today, it
wouldn\'t make any difference for at least a couple of weeks and maybe
more.

In all likelihood, if it would help improve the decisionmaking, a delay
towards even the end of March would be valuable to improve the
decisionmaking and would not interfere with the timelines, if we were
going to make a change.

Beyond that, you\'re really eating the timeline. I emphasize again that
the gamble is making the change, because once you do that, it will be
some time. When we had a problem in the year 2000, it took several
months to know that things weren\'t working well.

We heard earlier today that the reagents will not be available until
May. It is not until the reagents became available in May of 2000 that
anyone knew that the strains were not growing adequately. You inoculate
the eggs; you harvest the product, but you can\'t titer it until the
reagents become available. When you titer it and discover there\'s only
half as much there as you thought, you suddenly realize that you\'ve got
a real problem.

So that\'s where the gamble is, and the delay of this Committee\'s
decisionmaking for two weeks or three weeks or four weeks, if it will
improve the chances that we can actually produce vaccine after that
decision is made, is worthwhile. The question is, and this kicks right
back to FDA and CDC, and the data they think they might have, will we
improve the decisionmaking by that?

The other question that was raised is, can we make any advantage for
next year of this year\'s production? As Roland indicated, the answer to
that basically is no.

DR. ARCURI: Yes, my name is Ed Arcuri. I\'m Senior Vice President of
Manufacturing Vaccines for Medimmune.

The only comment that I wanted to make is the discussion of A/Panamized
backup strategy which is reasonable to look at, but one has to realize
what we\'re talking about is proceeding in parallel with going after a
new strain that will put us probably in all likelihood in a situation
where the manufacturers would have to take on more risk to manufacture
A/Panama in case the second strain does not work out. So there\'s that
piece of this that has to be put into the puzzle also.

As has been pointed out, the manufacturers have already taken on A level
risk, manufacturing bulks in preparation for the season.

CHAIRMAN STEPHENS: Thank you.

DR. DECKER: If I can just add to that, and correct me if I\'m wrong
about this, but the way you phrase it implied that the two would be made
simultaneously, but that\'s basically not what happens. I think what
would happen is that there would be the attempt ‑‑ perhaps some
production of Panama might go on while waiting for manufacturing strains
of the new choice. Once those become available, the focus would be on
using the eggs to try to make, and only once you\'ve realized that it\'s
failed would you then abandon that and go back to making Panama.

DR. ARCURI: Yes, but the problem could be that could be way too late for
a backup strategy of Panama to really work.

DR. DECKER: That\'s right. You chew up a lot of time.

CHAIRMAN STEPHENS: Dr. Gellin?

DR. GELLIN: Related to that, is there a way to quantify by week what
that risk is, if you go down one of these parallel tracks and then have
to reverse it later on?

DR. DECKER: Not really, because what you don\'t know is how hard it will
be to get the new guy to grow and how much time it will be judged
reasonable to invest in that. Maybe you can make an arbitrary decision
right now. You can say, all right, we\'ll give it until June 17th; on
that date we give up, but that\'s not sensible.

All I can do is point to historical experience, which is that sometimes
it can take as long as a couple of months, 10 weeks, to figure out how
to make something grow. Right now we\'ve got Panama that we could make
beaucoup tomorrow, but if it doesn\'t cover, that wasn\'t the best
choice.

DR. GELLIN: I guess you answered my question. If you could make beaucoup
of it tomorrow, what does it cost you to make that? And then if in a
month you find there\'s a decision not to go that route, what does that
cost?

DR. DECKER: Well, that\'s a different question than you asked a minute
ago.

DR. GELLIN: Yes. The real cost, and the opportunity cost isn\'t entirely
clear, either, because you\'re going to do these somewhat sequentially
because you have to wait for the strain to come around anyhow, the seed
to come around to grow.

DR. DECKER: I can\'t tell you dollar cost, but I don\'t even know if
that\'s a critical thing because it\'s resource consumption that\'s the
critical thing: the A\'s, the time on the manufacturing line, and so on.

DR. GELLIN: So to do parallel tracks, there are not enough eggs?

DR. DECKER: Well, you don\'t do parallel tracks. Yes, one manufacturing
line, and you\'ve got a bunch of eggs coming every day and you make
something. Whatever you make today ‑‑

DR. GELLIN: But if you made a bunch of Panama, you would use up all the
eggs?

DR. DECKER: Well, right now we\'re making something else. So we have to
stop making that something else to make the Panama. We\'re making the
H1N1 strain.

CHAIRMAN STEPHENS: Okay, Dr. Katz, then Dr. Myers, then Dr. Dowdle, then
Dr. Couch I think.

DR. KATZ: I agree we need to rely on Nancy Cox for this or Bob Couch
because Cagey isn\'t here, but it seems to me one of the reassurances,
which will probably fail this year if we don\'t have it, that even
though we anticipate flu in November-December, it has always come later
in the United States. It has been December, January, February. So that
there is a margin at least of error as far as, okay, we don\'t get
vaccine out as expected in October; we get it out in November/December
instead. There is at least that margin. Michael doesn\'t like that one.

DR. DECKER: Nobody buys it. You not only throw away 10 million ‑‑

DR. KATZ: They buy it if there\'s an epidemic occurring.

DR. COUCH: Granted, it hasn\'t occurred often, but it has occurred. We
had ‑‑ I can\'t remember the year; if I stop, I may ‑‑ the major
outbreak period for H3N2 was November. Now that is an exception, but
almost as a rule the H1N1s and the Bs will start early in December,
sometimes in late November, and you\'ve already heard we had outbreaks
of B in Texas, I think ‑‑ I got called; I should remember the date, but
I think it was mid- or late November. It was before Thanksgiving. So,
yes, you just can\'t predict flu that clearly, Sam.

CHAIRMAN STEPHENS: Dr. Myers?

DR. MYERS: It seems to me that what we really care about is what\'s in
that yellow bar and how small the red piece is in Dr. Cox\'s graph.
Monday afternoon ‑‑ it seems to me there are a couple of scenarios we
could paint, is that many of those will move from yellow and will be
155/156 deleted. I think we would all think at that point that this is a
pretty easy decision because we don\'t think this is a herald. If we\'re
suddenly seeing in geographically-diverse areas a new strain that was
predominated, I think we would say we should go to a new strain.

If, in fact, they are mostly A/Panama-like, we\'re still in the same
conundrum we are now because we don\'t have any sort of guidance, and
we\'ll all be still very nervous. So it seems to me that if we had that
information, this would be a much easier decision.

CHAIRMAN STEPHENS: Dr. Dowdle?

DR. DOWDLE: Does Nancy want to respond to that?

CHAIRMAN STEPHENS: Do you want to respond?

DR. DOWDLE: Do you want to respond, Nancy?

DR. COX: I probably could say a couple of things about the information
that\'s going to be available over the next few weeks. When we have our
conference call with WHO next Tuesday, we will be getting not only ‑‑ we
will have not only the data that we have generated, but also the data
that has been generated by the other WHO collaborating centers during
the past week, since actually it is about a week and a half since the
time that we all departed for Geneva, and between that time and next
Tuesday.

So there will be quite a bit of additional information, particularly
with respect to H3N2 viruses that are circulating in Asia and in Europe,
as well as the U.S. So we will have that information.

We will also have some additional information derived from testing some
ferret sera that we\'re producing with three other of those viruses that
have the double mutations, the 155/156 changes. So you only have the one
ferret antiserum, the Fujian/411 antiserum, at the moment, but we\'ll
have three more that we will have generated to see how consistent the
reactivity is with post-infection ferret sera and these
currently-circulating strains.

In addition, we should have had a bit of an opportunity to work with the
two egg isolates that the Japanese WHO collaborating center had
isolated, and, hopefully, we would be able to report on the growth
properties, at least in our hands. It doesn\'t translate into what the
manufacturers can do, but sometimes it gives us a little bit of an
indication.

Those viruses are going to be distributed as soon as possible to the
labs in the UK and the U.S. and Japan that make the high-growth
reassortants, and we\'re going to all be working on those
simultaneously. Of course, we\'ll go with whatever succeeds and comes up
first.

DR. DOWDLE: That\'s okay. That took care of it.

DR. COX: Okay.

DR. DOWDLE: That\'s okay. Thank you.

CHAIRMAN STEPHENS: Dr. Palese?

DR. PALESE: Will it be an option to make a recommendation for the H1 and
the B only and wait for the H3, or is that not what we can do in terms
of the Committee?

CHAIRMAN STEPHENS: I think the Committee can do that. We\'re going to do
these independently.

DR. PALESE: They will be independent?

CHAIRMAN STEPHENS: Yes.

DR. PALESE: Okay.

CHAIRMAN STEPHENS: Yes. Is there discussion? Dr. Karron?

DR. KARRON: Just another question from the manufacturing perspective: Am
I understanding this right, that if we decided on two strains and
deferred the decision on a third strain, say for a month, that from a
manufacturing perspective that wouldn\'t make a difference, given that
these are made sequentially? Is that correct?

DR. DECKER: Yes, based on the information I have right now, I believe
that that is correct.

CHAIRMAN STEPHENS: Dr. Lee, you have a comment?

DR. LEE: Yes, I was going to respond to that as well. We introduce one
strain at a time. If we do get two strains selected, then we shift to
the second strain, and we are producing that for a while.

I do happen to recall that to do a third strain is not just a matter of
when we could start production but that we would be preparing seeds in
preparation for that manufacturing. So even though we won\'t be starting
manufacturing for another two months, we still can be preparing the
seeds for that.

DR. KARRON: But if we were to switch strains, let\'s say, for H3N2
virus, you wouldn\'t be able to start preparing the seed right now
anyway because we\'re not at that point with the new strain, right?

DR. LEE: Right, that\'s correct.

DR. COUCH: Well, unless it happens to be Fujian/411, which was already
distributed to you, wasn\'t that correct?

DR. LEE: My understanding is that that there are no high-growth
reassortants for that particular strain. So we would need it.

DR. ARCURI: I would just like to repeat ‑‑

CHAIRMAN STEPHENS: Just identify yourself again for the record.

DR. ARCURI: Sure. Ed Arcuri, Medimmune.

I would just like to repeat the caveat again that, if that high-growth
reassortant is not a high-growth reassortant, if it\'s a low producer,
you still could find yourself in a very limited supply condition. In
other words, you won\'t be able to make the bulks fast enough.

DR. LEVANDOWSKI: Dr. Stephens, could I ‑‑

CHAIRMAN STEPHENS: Yes.

DR. LEVANDOWSKI: Could I just comment? Again, about the issue about
preparation of the seeds, those things generally go on simultaneously.
There are a lot of concurrent operations that have to be happening for
all these things to come together at the end with a formulated vaccine.
So I guess maybe you should understand that, when a new strain is
recognized as being potentially a vaccine candidate, that is sent out to
manufacturers as soon as we can.

Now the same thing with high-growth reassortants. There may be some
strains that are sent out that turn out to be not useful, and they\'re
just discarded or they have to be maintained in the freezer probably,
but it doesn\'t necessarily mean that you\'re stuck using that. It\'s
just it\'s all that preparatory work would be going on in the
background.

The point we\'re at here with this H3N2 strain is that we don\'t know
that has gone on yet. I think I need to emphasize that we normally would
have been doing quite a bit of that the last month or maybe even
earlier, but we haven\'t done any of those things in this particular
case at this point.

CHAIRMAN STEPHENS: Okay, additional comments or questions?

(No response.)

Let\'s move on to Option 3.

DR. LEVANDOWSKI: Okay. So for influenza B, here again, I think maybe the
choices are more limited. The first option, of course, is to maintain
the current vaccine strains, which are B/Hong Kong/330/01. And, again,
in favor of this, we know the manufacturers have had some experience
with these strains and have a good idea of what\'s going to happen, and
also the majority of the strains have hemagglutinin that matches up very
well with the correct vaccine strain.

We do know that most of the currently-circulating strains have a
neuraminidase that\'s different from the current vaccine strains, but I
guess I should re-emphasize what I said earlier, and others have said,
too, that we only standardize the inactivated vaccines based on their
hemagglutinin content.

I guess one thing that maybe I didn\'t emphasize really earlier; that
is, the B/Brisbane strain/32/02, is one that WHO has recommended as
being, at least for the hemagglutinin, it\'s recognized as being Hong
Kong/330/01-like. So its hemagglutinin is fine.

If there were some reason somewhere that somebody else needed to use a
different neuraminidase, that would probably be acceptable from the
point of view of the hemagglutinin. But for our considerations for
inactivated vaccines, again, I just need to emphasize that the
neuraminidase is not standardized. If it\'s present, whatever
immunologic response it causes may add to the protection.

The second option is to change the current vaccine strain. Again, that
would be hoping that we could get better coverage for the current
viruses. Against that, we don\'t really know how those strains are going
to perform.

Again, I should probably bring up about the B/Brisbane strain that I
just mentioned in a positive sense. Now I should mention it in maybe a
negative sense, that we do have some information that it does not grow
all that well. The wild-type strain is a relatively poorly growing
strain.

It probably would not perform as well as the current vaccine strains do.
That\'s in comparisons at probably the same point in work with the seed
virus that would have been done for the other strains as well. So we do
know that manufacturing delays would occur if we further reduce the
yield of influenza B component.

Then for postponing the decision, actually, again, we did not see an
advantage there because the information that\'s likely to be forthcoming
to inform recommendations may not add that much. There will be more
information on additional strains that are isolated, but how much
different that is, there\'s not something to suggest that there\'s a
different direction developing.

CHAIRMAN STEPHENS: Thank you. We\'ll open this up for discussion of the
B option and also for general discussion. Dr. Palese?

DR. PALESE: I just wanted to sort of comment or ask a question regarding
the issue that the neuraminidase may be wrong in terms of the B/Hong
Kong strain which we have currently. Can you give us an estimate in
terms of the, let\'s say, percentage protective activity which is
afforded by the neuraminidase in the vaccine which contains both
hemagglutinin and neuraminidase?

In other words, how concerned should we really be about the
neuraminidase? Can you give us some numerical value in terms of the
contribution of the neuraminidase?

DR. LEVANDOWSKI: That\'s me. I can\'t give it a numerical value. I guess
I could say that, for individuals who are immunologically naive, their
first exposure might be to such a neuraminidase, and it might contribute
in some stronger way to protection than in someone who is not
immunologically naive.

I say that because there are, as you are aware, and would want me to
think about, there are clinical studies where vaccines were given to
look at induction of antibodies, neuraminidase inhibition antibodies,
and it is clear that in situations where there is a hemagglutinin that
the individuals are already immune to, that the hemagglutinin will
predominate what the immunologic response is and that the neuraminidase
may contribute very little or there may not be much of a response to the
neuraminidase.

I think that\'s partly the issue that Nancy Cox was raising about having
antisera, ferret antisera or other kind of antisera, look at
neuraminidase issues because of some of those issues as well, I think,
of being able to measure what that response is. But I can\'t put a
numerical value on how much contribution. If you want me to say, is it
10, 50, or 90 ‑‑

DR. PALESE: Okay. So do you think it\'s more than 5 percent, less than 5
percent?

(Laughter.)

DR. LEVANDOWSKI: I\'m from the 10, 50, or 90 school. So if I have to
make any kind of answer, I guess I would say 10, but don\'t throw any
tomatoes at me, please.

CHAIRMAN STEPHENS: Dr. Myers?

DR. MYERS: Going along that same route, I guess from the data that we
have seen I don\'t really see any particular reason to change the B, but
all the decisions we\'re making relating to B have to be on incomplete
data, in that the immunologically naive, when you say that, you\'re
referring to children. We don\'t have any data on the immunologic
responsiveness to any of these antigens in children.

I think it just re-emphasizes the problem that it\'s hard to ‑‑ you
know, we have this new recommendation to encourage the use of a vaccine
in that age group. This is the age group that has the majority of the B
issue activity.

CHAIRMAN STEPHENS: Okay. Additional comments? Dr. Decker?

DR. DECKER: Hopefully, this will make the Committee\'s job easier, not
harder. I think all the manufacturers would agree that, if a change in
the H3N2, particularly in the present circumstances being seriously
contemplated, that we would hope desperately that there would be no
change in the A H1N1 or the B. If you change not only the H3N2, but one
of those, you\'re really gambling with your likelihood of having
vaccine.

CHAIRMAN STEPHENS: Okay. Additional comments?

(No response.)

Let me open it up for any general discussion that we haven\'t covered.
It looks like manufacturers\' comment.

DR. ARCURI: Yes, Ed Arcuri, Medimmune.

Because of the sequential nature of the manufacturing at all
manufacturers, if they are both slow, it is just a higher level of risk
to the supply.

DR. DECKER: We are taking on more wisdom than usual with the H3N2
decision this year because of the fact that it has hit so late, and
nobody is ready for it. So to compound that would be unfortunate.

CHAIRMAN STEPHENS: Right. Thank you. Other discussion? Other points
before we move to voting on the options? Yes?

DR. OVERTURF: I would just like to echo Dr. Myers\' comments that, as we
move toward a desire to immunize larger and larger populations,
particularly children, who are immunologically naive, we have got to get
more data. I can\'t imagine that there\'s going to be great, broad-based
support to continue to immunize children if we don\'t know whether the
vaccine is likely to be protective and what the immunological
responsiveness is.

So this had been a recommendation a year ago, and I think it needs to be
in the minutes again, that this is a strong recommendation of the
Committee.

CHAIRMAN STEPHENS: It\'s very clear that that point has been made
multiple times, and I hope the regulatory agencies are hearing that
comment.

Other discussion?

(No response.)

Okay. Well, I think we will now move to considering the options and
voting on the options, unless there is objection to that.

I wanted to return to the options for the H1N1, and we have three before
us: Maintain the current vaccine, which is the A/New Caledonia/20/99;
change the current vaccine strain to a contemporary H1N1 strain, or
postpone the decision. Roland, if you agree that\'s a fair summary of
the options?

DR. LEVANDOWSKI: Yes.

CHAIRMAN STEPHENS: Okay, I\'m going to start with Dr. Katz, that end, if
he\'s willing, to give us your comments.

DR. KATZ: You want a comment just on the H1N1?

CHAIRMAN STEPHENS: Correct.

DR. KATZ: Okay, I would vote that we retain the current A/New Caledonia.

CHAIRMAN STEPHENS: Dr. Couch?

DR. COUCH: I concur.

DR. MYERS: I agree.

DR. McINNES: Concur.

DR. COX: Concur.

DR. GELLIN: Concur.

DR. DOWDLE: Concur

DR. PALESE: Yes.

DR. DECKER: I agree also.

DR. GOLDBERG: I agree.

DR. OVERTURF: Also agree.

DR. KARRON: I agree.

DR. PARSONNET: Agree.

MS. FISHER: I agree.

DR. DIAZ: Likewise, I agree.

CHAIRMAN STEPHENS: Okay, and I also agree with that option to retain the
A/New Caledonia/20/99 for the 2003/4 season.

Anything else we need on that, Jody?

Please say your name for the record, so we have an official record.

In terms of the H3N2 options, they are to maintain the current vaccine
strain, A/Panama/2007/99; to change the current vaccine strain to a
strain representing the newly-circulating viruses, or to change the
current vaccine strain to a strain representative of ‑‑ well, to change
the strain or, three, to postpone the decision.

Again, I will start on this side with Dr. Katz.

DR. GELLIN: Before you do that, do you need to clarify the date of
postponement, when it will be revisited?

CHAIRMAN STEPHENS: We discussed this briefly, but it\'s a good
opportunity to discuss that again. I think it\'s the 17th of March is
the next tentative planned session for making the final decision.

DR. SACHS: There\'s a calendar in everybody\'s folder in the back of the
lefthand section of March. It\'s on a colored purple page. You can see
when the 17th ‑‑ it\'s a Monday, and probably the 17th would be the best
date to shoot for. If there\'s anyone who can\'t make it, please, now is
a good time to state it.

DR. DECKER: Just a question: Are you talking about a Washington meeting
or a teleconference?

DR. SACHS: Telecon. If we can, we\'ll do it telecon.

DR. DECKER: Thank you.

CHAIRMAN STEPHENS: Okay, this is a potential teleconference as opposed
to ‑‑

DR. SACHS: Okay, what I would like you to do is put an \"X\" by the
17th, and if you can make it on the 14th, don\'t put an \"X,\" but just
let me know, and then pass the sheets in to me, if you would. If you
need more time, you know, let me know also.

DR. COUCH: So mark the 17th and 14th?

DR. SACHS: Yes, those are the two potential dates, the 17th and 14th.
And if you can\'t make those dates, put an \"X.\" If you can, don\'t put
the \"X\"; just pass it in as is. Thanks.

CHAIRMAN STEPHENS: Okay, with that comment, Dr. Katz, I\'ll put you on
the spot.

DR. KATZ: Thank you. As far as H3N2 is concerned, I would vote that we
retain the option, that we seek further information to see if we can
replace the current strain with a variant that would be more in line
with the antigens of the hemagglutinin and the neuraminidase of the
newer strains, but that we set a date, March 14th or 17th, at which we
would have to have enough information to make that decision, and if
it\'s a negative one, that we go ahead with the current Panama.

CHAIRMAN STEPHENS: So a clarification, Dr. Gellin?

DR. GELLIN: I was hovering on the dates. Michael, representing one of
the manufacturers, do you have a drop-dead date after which there is a
problem moving forward, recognizing that it is picking a new strain and
there are going to be potential process development issues, but if the
decision is to go with Panama, what\'s the drop-dead date from a
manufacturing perspective?

DR. DECKER: No, there\'s no drop-dead date at all. There\'s just
diminishing likelihoods of success.

What you\'ve got right now is you\'ve got, because of the strange
circumstances this year, you\'ve got a window of where you\'re not
hurting yourself any worse, because we couldn\'t get started today
anyway. So you\'ve got some time, because there\'s nothing to start on.
Nobody\'s made anything to start on. So you\'re not causing any further
harm to an already-awkward situation by postponing your decision until
mid-March.

After that, I can\'t tell you, because if in mid-March there are
reassortants available, but no decision is made, then you\'re losing
real time.

CHAIRMAN STEPHENS: The option really on the table right now is to
postpone, and we\'re still debating what date we would potentially have
a reassembly to evaluate that question.

Dr. Katz, my assumption is that you would like to postpone this decision
until ‑‑

DR. KATZ: Yes.

CHAIRMAN STEPHENS: Great. Dr. Couch?

DR. PALESE: Can I just ask ‑‑

CHAIRMAN STEPHENS: I\'m sorry, go ahead.

DR. PALESE: I mean, is the date sort of in stone, the 14th and the 17th?
Would it help to be like two weeks earlier or 10 days earlier?

CHAIRMAN STEPHENS: I think, though we\'re not in stone, those appear to
be dates that were reasonable from a variety of different calendars.
We\'re just trying to get an assessment of what dates in the next
several weeks might be available for this particular ‑‑ if we decide to
postpone, and we haven\'t done that yet.

But go ahead, Nancy.

DR. COX: Perhaps I can clarify things just a bit further as well. While
we were in Geneva, we had extensive discussions about postponing the
recommendation for the H3N2 component because this is not something that
is done lightly or something that we often do. In fact, there\'s quite
the opposite pressure.

What we did was draw out a timeline and work out when the vaccine, the
wild-type, egg-grown viruses would be received in the WHO collaborating
labs, when we thought we would have ferret serum, when we thought we
would have the first possibility of testing a high-growth reassortant,
and so on and so forth.

We came up with the date of March the 14th as being a good date by which
we would be able to go ahead and have that additional experience and
make recommendations.

This timetable that we drew up was actually taken to the vaccine
manufacturers who are represented at the meeting of the International
Pharmaceutical Manufacturers Association, IFPMA, and there was general
agreement and goodwill on the part of those people who were represented
at that meeting that those dates would be okay, not ideal, but certainly
everyone would work as hard as they could to do their best to make it
come together. If they hadn\'t come together, then there would always be
the fallback position of the Panama strain.

I can answer any additional questions.

CHAIRMAN STEPHENS: Okay. Any further discussion upon this issue? Because
I think we\'re still voting really on the question of postponing. The
actual dates have not been established.

Dr. Couch?

DR. COUCH: I guess I sound a little bit like a broken record at this
meeting, but postpone, and my reason for that is much the same: that
this is the most important decision we make. All of them are important,
but H3N2, these vaccines are designed primarily to prevent
hospitalization and death, and this is the No. 1 culprit in that regard.
So we have to work a little harder to make the right decision.

I started to say a minute ago a little perspective, if I may, on this.
The reason we have the luxury of talking about a fallback here, because
if it was clear that Panama was unacceptable, well, we wouldn\'t even
have had this discussion about dates, and that has occurred in the past.

So that I think the view to take, and I take here, is that, as we know
the data now, Panama is not unacceptable. What we\'re talking about is
seeing if there is a better, more appropriate antigen to replace it
with, and somebody might not like the language I\'ve used before, but,
as I saw the data here, that\'s the only thing I came here with a
question on: Do we need to finetune the H3N2?

I think that still is not an inappropriate way to phrase the question
because, as we know the data now, we\'re not talking about a major
antigenic change. But, on the other hand, it is important to finetune
this antigen. That\'s the reason I think we want to postpone this
decision, to try to be as close as we can to being sure we get it right.

CHAIRMAN STEPHENS: Thank you very much. Dr. Myers?

DR. MYERS: I\'d postpone.

CHAIRMAN STEPHENS: Dr. McInnes?

DR. McINNES: McInnes. I would postpone the decision.

CHAIRMAN STEPHENS: Dr. Cox?

DR. COX: I vote for postponing the decision.

CHAIRMAN STEPHENS: Dr. Gellin?

DR. GELLIN: Bruce Gellin. I\'d postpone as well.

CHAIRMAN STEPHENS: Dr. Dowdle?

DR. DOWDLE: Walter Dowdle, and I also would vote to postpone. However,
the concern I would have, it seems to me that there are two issues. One
is getting enough information as you can get to make a decision, let\'s
say, on the 17th that you go forward with it.

Then there\'s another window there in which the manufacturers are
looking at these strains to make sure that they will, indeed, meet their
criteria for growth, and so on and so forth, so that they will make good
vaccine strains.

So is there a way to look at this another way and say, okay, what\'s the
drop-dead date, working backwards, not working forwards, but working
backwards? So that you know that you have to have vaccine at a certain
period of time in October. What\'s the drop-dead date to actually meet
your goals, your vaccine production goals?

Then that would be a window, perhaps as a second decision, if the new
antigen hasn\'t worked out well enough by that time, then you must go to
another fallback date to Panama.

I\'m just raising this as a question, as something we might want to
think about at the next go-round. I don\'t know that we need to have an
answer now.

CHAIRMAN STEPHENS: Any comment on that point before we go on?

DR. DECKER: Yes, and Sam and my colleague from Medimmune, jump in,
please, if you\'ve got corrections to this. But I believe a relatively
correct answer would be, if the companies aren\'t handed the high-growth
reassortants by the end of March, you\'re going to have delays. If they
don\'t grow the way they\'re supposed to grow, you\'re going to have
delays.

So even if they\'re handed to us, there may still be delays if they
don\'t perform. But if you don\'t hand them by the end of March, then
you\'re guaranteed delays in availability.

CHAIRMAN STEPHENS: Okay, let\'s proceed. I think still the message on
the table or the motion, if you will, on the table is to postpone this
decision right now.

Dr. Palese?

DR. PALESE: Yes, Peter Palese. I also vote for postponing and just ask
that as much information about the actual subtype or the specific
subtype of the H3 will be generated over the next two or three weeks, so
that we can make an informed decision.

CHAIRMAN STEPHENS: Dr. Markovitz?

DR. MARKOVITZ: David Markovitz. I would also postpone the decision.

DR. DINIEGA: Ben Diniega. Postpone.

DR. ROYAL: Walter Royal. I vote to postpone.

DR. GOLDBERG: Judy Goldberg. Postpone.

DR. OVERTURF: Gary Overturf. Postpone.

DR. KARRON: Ruth Karron. Postpone.

DR. PARSONNET: Julie Parsonnet. Postpone.

MS. FISHER: Barbara Loe Fisher. Postpone.

DR. DIAZ: Pam Diaz. Postpone.

CHAIRMAN STEPHENS: And I concur that I would postpone as well.

Okay, proceeding to the B component, we might start on this side of the
room this time with Dr. Diaz and her comments about the options for B.
Let me just review those again.

Retain the current vaccine strains B/Hong Kong/330/01 or B/Hong
Kong/1434/02; change the current vaccine strain to another influenza B
strain with a neuraminidase from the Sichuan lineage, or postpone the
decision, are the three options being presented.

DR. DIAZ: I would vote that we retain the current strain. If we were
talking about a change in the hemagglutinin and we weren\'t talking
about a change in the other strain, H3N2, I might be voting differently,
but balancing all of those together, I would retain the strain, the
current strain.

CHAIRMAN STEPHENS: Ms. Fisher?

MS. FISHER: I\'m uncomfortable with the fact that there\'s been
increased influenza B activity, particularly in the U.S., and that the
recent influenza B viruses have NAs most closely related antigenically
and genetically to that of B/Sichuan rather than the Victoria lineage.
So I\'m going to abstain on this vote.

CHAIRMAN STEPHENS: Dr. Parsonnet?

DR. PARSONNET: Yes, I\'ll vote to retain it, although ‑‑ no, I\'ll just
say I\'ll vote to retain it.

DR. KARRON: I\'ll vote to retain. I base that in part on the fact that
we are postponing the decision about the H3N2 virus and recognizing the
manufacturing issues inherent in that.

CHAIRMAN STEPHENS: That was Dr. Karron.

DR. OVERTURF: Overturf. I would vote to retain it.

DR. GOLDBERG: Goldberg. I would vote to retain it, based on the fact
that we are postponing another strain and that we have to recognize all
we can do is deal with possible strain change.

DR. ROYAL: Walter Royal. I vote to retain, based on the fact that the
information we have so far demonstrates that we have seen a lot of B
activity, and it\'s unlikely that any new information is going to change
what we know about the strain characteristics that we\'ve seen so far.

DR. DINIEGA: Ben Diniega. Retain.

DR. MARKOVITZ: David Markovitz. I would like to retain this strain also.

DR. PALESE: Peter Palese. Retain.

DR. DOWDLE: Walter Dowdle. Retain.

DR. GELLIN: Bruce Gellin. Retain and hope that we can also have a better
sense of the role that neuraminidase plays in efficacy.

DR. COX: Nancy Cox. Retain.

DR. McINNES: Pamela McInnes. Retain the current B vaccine strain.

DR. MYERS: Myers. Retain.

DR. COUCH: Couch. Retain.

DR. KATZ: Katz. Retain with the caveat that Pam McInnes and Tony Fauci
get some of that money to study neuraminidase.

(Laughter.)

CHAIRMAN STEPHENS: And I agree that you should retain the current B
strain as a B component, and agree also with Dr. Katz that we should get
more money.

I also think that there\'s another message here. There was a comment
that Dr. Gellin raised earlier about our capacity and production for
influenza vaccine, which I think is a very important issue, and another
message that I hope this Committee will concur with, that we need to
look carefully at some of those issues.

And I know that HHS and others are looking at it, but I think it is
important from a capacity perspective that we deal with what could be
the major threat, or one of the major emerging ‑‑ or not emerging, but
certainly present biological threats that we have. I would hope that
there would be greater emphasis on manufacturing capacity and some way
of stimulating that particular process.

So any other comments that we would like to leave with the group before
we move on to ‑‑ Dr. Sachs has a comment.

DR. SACHS: Yes. I just want to go to back to the calendar. Could you
look on the 18th, March 18th, and if you can\'t make that date, could
you put an \"X.\" If you can, leave it blank.

So we\'re looking at the 14th ‑‑

CHAIRMAN STEPHENS: 14th, 17th, and 18th for \"Xs,\" is that right?

Dr. Katz?

DR. KATZ: My question really was at Jody. I\'m assuming that, given
those dates, you\'re going to be able to e‑mail us material in advance
on which we can make our decision.

DR. SACHS: Well, we will be able to e‑mail whatever material we get in.
It\'s going to be up to the last minute because we will not have WHO\'s
recommendations until the 14th. So we really want to get that material
to you, but this would be by telecon, so e‑mail would be the fastest way
to get it to you. That\'s why I was looking at the 17th or 18th.

You know, earlier is best, but we may not have new data for you earlier.
That\'s the trouble, and Roland can comment on what data he can get in a
timely manner. I don\'t know what data you will have in.

DR. LEVANDOWSKI: Do you want me to respond to that? There will be
additional information. Mostly it\'s going to be coming, I think, from
colleagues at CDC, and there will be exchange of information going on
throughout this period of time. So I believe that we should be able to
provide some information in advance of the meeting. I don\'t know what
day that would be, but some period of time, to give you at least a
chance to see it.

I\'m encouraged, if you\'re asking for e‑mails, we would certainly ‑‑ as
much as possible, we would like to exchange that information
electronically just to cut down on the amount of paper that we\'re
handling.

DR. KATZ: Well, the 14th is a Friday, and the 17th is a Monday. So that
if we\'re postponing until the 17th or the 18th, it would be nice if we
could, if there are data and information, that we got it by Friday.

CHAIRMAN STEPHENS: Now I would certainly ‑‑

DR. SACHS: That\'s reasonable.

CHAIRMAN STEPHENS: Dr. Levandowski?

DR. LEVANDOWSKI: Could I just make one more comment? This is the first
year ever that the Committee has gotten materials sent out to it from us
related to the recommendations more than one day before the meeting, and
you realize that it\'s still being collected even as you\'re coming
here. As Nancy Cox showed with her handout, there\'s new information
that\'s coming along all the time.

But I actually am proud of us for having gotten something out at least a
week in advance, which is ‑‑ what is that, a 700 percent increase in our
capability?

(Laughter.)

DR. KATZ: Well done.

DR. COUCH: Over the years there\'s also been a 700 percent increase in
the quantity of data you give us, too, not just the time.

CHAIRMAN STEPHENS: I think the other message that the Committee
certainly seems in agreement with is the pediatric data. Again,
hopefully, the regulatory agencies have gotten that particular message.
It was sent last year, and we\'ll send it again this year as well.

Okay, any further discussion or comments?

(No response.)

We will move to our Session 2, which deals with the Laboratory of
Bacterial Polysaccharides.

This is an open session. So you\'re welcome to stay.

Our first presentation will be that of Dr. Richard Walker of FDA who
will give an overview of the Division of Bacterial, Parasitic, and
Allergenic Products.

DR. WALKER: Good afternoon. This afternoon I would like to just give you
a brief overview of the Division of Bacterial, Parasitic, and Allergenic
Products.

The basic mission to assure safe and effective products, radiological
control of bacterial, parasitic, and allergenic agents affecting human
health. The people that are tasked with doing this mission are involved
not only in laboratory research, but also in review, product review, and
post-licensure they\'re also involved in inspection, ensuring
compliance, lot release testing, protocol review, and label/promotional
activity review.

In addition to the things I just mentioned, they are also involved with
numerous outside agencies like NIH and WHO, as far as consultations in
various technical areas.

The point I would like to make with this slide and the slide that will
follow that is that our association with the product is a
cradle-to-grave type of operation. We begin way back at the pre-IND
stage with meetings with the sponsor, and then through submission of the
IND, we review the original submission. Then we\'re involved in
providing technical advice, and so forth.

And the thing is not to focus on all these various activities that we
have under these different stages of product development, but just be
aware that there\'s a lot of activities that are involved all the way
through and continues to be exercised through post-licensures. That\'s
what I want to drive home.

The other point I would like to drive home is that there\'s a wide
variety of products that come under this category for us. We have
respiratory pathogens, quite a few of those; sexually-transmitted
pathogens; pathogens such as Lyme\'s disease and malaria, and so forth.
Special pathogens have become an increasing emphasis: anthrax, botulinum
toxin, tularensis, and plague.

Also, we are involved with various diarrhea-causing pathogens and other
pathogens such as Helicobacter, and so forth, that are also attacking
mucosal sites.

The other area that we deal with is allergenic products and skin test
antigens.

So that we have to have expertise in quite a variety of different
specialties. To do that, we\'re organized into eight laboratories, as
shown on this slide. There\'s the immediate office of the Director,
which is where I am, and this slide is extremely up-to-date because, as
of this coming Monday, I\'ll have a Deputy Director for a change, Dr.
Madeline Blake. Also in this office we have a regulatory staff, an
administrative staff, and our job is to help all these other people do
their job.

As you can see, we have a Laboratory of Respiratory and Special
Pathogens, under Dr. Burns; the Laboratory of Bacterial Toxins, under
Dr. Vann; the Laboratory of Microbacterial Diseases and Cellular
Immunology, under Dr. Morris; the Laboratory of Methods Development and
Quality Control, under Dr. Mead; the Laboratory of Immunobiochemistry
that deals with the allergenics products, under Dr. Slater; the
Laboratory of Biophysics, under Dr. Pastor; the Laboratory of Enterics
and Sexually-Transmitted Diseases, under Dr. Kopecko, and last, but not
least, the Laboratory that we\'re considering this afternoon, the
Laboratory of Bacterial Polysaccharides, under Dr. Frasch.

I would like to just run through these very quick, just to give you a
brief flavor of some of the activities that they\'re involved in.

The Laboratory of Methods Development and Quality Control is involved in
developing and standardizing quality control methods for various
bacterial vaccines; also, in evaluating and applying serological testing
to clinical trials; coordinating our quality assurance activities within
the Division.

The Laboratory of Bacterial Polysaccharides will be gone into in much
more detail in just a few minutes by Dr. Frasch. So I will just skip
over that one.

The Laboratory of Biophysics applies various high-end technologies to
evaluating and characterizing bacterial, parasitic, and allergenic
products. They not only characterize biopolymers, and so forth, but they
also have instrumentation, like NMR support to provide new ways of
looking at the products.

The Laboratory of Bacterial Toxins deals with botulinum toxin,
tetanus/diphtheria, and our anthrax toxin. They are interested in such
things as how toxins work, how various products or factors, such as
iron, may affect the production of these toxins. Also, there\'s a
glycobiology group in there that\'s involved in the mechanism of
capsular polysaccharide biosynthesis.

The Laboratory of Respiratory and Special Pathogens, special pathogens
refers to bioterrorism-type agents or the study of Bordatella pertussis,
anthrax, and also Yersinia, and they try to characterize virulence
factors and study mechanisms of actions in some of these factors and the
regulation of gene expression, important in these factors, and develop
animal models to study the importance of these factors in pathogenesis.

The Laboratory of Microbacterial Diseases and Cellular Immunology is
evaluating the protective effects of innate and adaptive immune response
for intracellular bacteria. They\'re assessing DNA vaccination
strategies for tuberculosis, as well as looking at other proteins that
might be important in tuberculosis. This group is also working with
Francisella tularensis, another important intracellular pathogen.

The Laboratory of Enterics and Sexually-Transmitted Diseases is involved
in looking at a variety of enteric pathogens and studying the invasive
mechanism, the Shigella Campylobacter and others; the regulation of
bacteria virulence genes.

Also, it\'s very important, a new area that they have started is ‑‑ I\'m
just trying to understand better gene immunization, and strategies to
manipulate that.

Also, they have been using the attenuated typhoid vaccine, PY21A, as a
vector for pathogen antigens such as the PA of anthrax, and previously
they have done Shigella sonnei,and now they\'re working on Shigella
dysenteria.

It\'s a good thing I showed this one after lunch, I guess. The
Laboratory of Immunobiochemistry is involved in allergen structure and
function, as well as understanding the immunomodulation of allergic
responses.

I just put in this last slide just to emphasize that the biggest change
in the Division over the last year or two has really been the emphasis
on bioterrorism. As you have been able to see in these slides I have
just run through, a number of the laboratories are involved in work
involving anthrax, tularensis, or one of the other bioterrorism agents.
We\'re trying to understand regulation of these agents and virulence
factors, and so forth, that are associated with these pathogens.

Just a couple of administrative things I would like to run through, just
because it is germane, particularly to the review of the Laboratory of
Bacterial Polysaccharides, is the promotion plan. Just so you understand
the wording that we use, we have independent and non-independent career
tracks. Like there are technicians; there are people who work under the
direction of a senior scientist, but then other people come in as sort
of an apprenticeship, and there\'s a staff fellow. Then you move up to a
senior staff fellow during a seven-year period, and then, based on the
productivity of that person, it is decided as to whether they should be
promoted to a senior investigator. That is where a lot of our key
scientists fall into.

I will say just a little bit about funding because funding is a little
bit different perhaps for us than certain other organizations. Salary
and overhead are part of the FDA base, but we are actually given at the
Division level our funds for expendables and equipment.

In general, we have broken it down into two categories here: the general
FDA appropriation ‑‑ this is everybody who is not working with
counterterrorism agents ‑‑ and counterterrorism funds. This past year we
have had both kinds of fund.

So we have Division operating funds that we take out of this, as well as
we identify special needs, if there is some unusual expense coming up
for somebody in the Division in the next year, and then the rest of the
money is distributed on a per-capita basis. That takes care of things
like pipettes, reagents, and so forth.

Some people do get extramural funds, like from the National Vaccine
Program Office, Office of Women\'s Health, and so forth. Those go
directly to whoever is working on that.

Then these are some year-end funds that we can use for a variety of
things, particularly special pieces of equipment that we have identified
but not been able to purchase up to that point.

So that\'s, very quickly, finance in our Division.

The final two things I would like to leave you with is what I call the
challenges and realities facing our researcher reviewers. Now some of
the things that we are faced with are the same things that other people,
particularly in the government, are faced with, like funding levels are
uncertain year to year and dependent upon the appropriation process. Of
course, we\'re still waiting on that.

There are bureaucratic hurdles that are part of any large organization.
That doesn\'t mean that we don\'t have very good people working with us
and they are trying to support us, but personnel and purchasing and
other types of things can sometimes be very cumbersome in our type of
organization.

The biggest thing, and the thing that is unique to the FDA, is that the
timing of our workload for our researcher reviewers is determined by the
sponsor, and not by CBER. When something comes in, the clock starts
running and we have to deal with that.

So that is something that you need to keep in mind when you are looking
at the work that our researcher reviewers accomplish, because what they
have accomplished, they have accomplished even in view of the fact that
they spend sometimes maybe 50 percent of their time in review-type
activities.

Finally, the thing that I left the Site Visit Committee with is to
review our individuals, review our program, and comment on our future
directions. I guess that is what we will be talking about a little bit
later.

So that is really all I have to say at this time. If you want me to, I
will just turn it over to Carl Frasch.

CHAIRMAN STEPHENS: Comments for Dr. Walker?

(No response.)

Could you just elaborate a little bit more? I know you showed us a chart
of the pathway for career development. Could you go back to that and
just help those of us in academic medicine kind of ‑‑

DR. WALKER: Also, just to put it in the academic terms, like somebody at
a GS‑15 level would be appropriate to be a full professor. That is one
way to think of that.

Or somebody coming out of a post-doc and a few years past that would be
what we call our senior staff fellow positions. These lead people, they
would be getting paid at roughly what we call a GS‑11/GS‑12 range. Then,
as they go forward, now we are talking moving from like assistant to
associate professor, we\'re moving up, and like I said, what you think
of a GS‑15 is like a full professor.

We have one other category that a few of our scientists fall into. These
are people in the Senior Biomedical Research Service. These are people
who have really become a leader in whatever field they are in, and they
are really outstanding people. So this would be a very senior person in
the academic field.

The other track we have is that some people are just like very senior
technicians that have a reasonable amount of responsibility and some
degree of independence. These people may work up to, let\'s say, a GS‑12
level.

There are other people that can be doctoral or not doctoral, as they
show here, that can even go higher. We have some doctorate-level people
who elect not to be an independent senior investigator and have their
own program and post-docs and things, but they would prefer to work
under the mentorship of another senior scientist. So that\'s a track
that kind of a person could fall into.

Does that hit what you were trying to convey?

CHAIRMAN STEPHENS: Dr. Myers?

DR. MYERS: We were talking before about, in the influenza session, about
concerns of funding for particular areas of regulatory research, which
are often not appreciated for their difficulty and their importance.
They are not as sexy as some of the other types of research.

At both prior VRBPAC meetings and at EMDAC meetings the Committees
expressed a great concern and frustration about the level of funding
support that CBER specifically receives for its regulatory research. You
sort of alluded to the uncertainties of that.

I wondered if you could specifically tell us how CBER, and then the FDA,
sets those priorities and how the Department would respond to the
advisory committees, because they have not, either the Department or the
FDA, about the concerns of the really inadequate regulatory research
funding.

DR. WALKER: Yes, because I have only been here a little over two years,
but, as I understand, back in the mid-nineties funding was much better
than it is now. Now it is making a little bit of an upswing now, but
that has been an ongoing battle.

In fact, if it hadn\'t been for the influx of counterterrorism money and
some of the outside money that I referred to that people have been able
to get, it would be very difficult to carry on the level of research,
productive research, that we have been doing.

You mentioned setting priorities. This is something that the advice of
the Site Visit Committees is taken very seriously and reviewed, and we
use that to help identify what our priorities should be. In fact, a plan
that I will commit to, and I have already discussed, is that after this
review is over, and also I wanted to wait until Dr. Blake got on board,
we are going to take a retreat for the Laboratory of Bacterial
Polysaccharides to talk about some of the research directions that that
group should be following.

We continually try to review our work, so that we make sure that we are
doing what we believe is the most important things and putting our
resources where they are needed. The problem is sometimes getting the
financial resources to do that. We are all working to make that better,
and all the way up through the CBER people are trying to improve that,
but eventually it comes from an appropriation. That is what we are
dealing with.

CHAIRMAN STEPHENS: Dr. Couch?

DR. COUCH: I had two questions that were a little bit the same as Marty.
One was, if one of these levels is your tenure level, is that the senior
investigator level, basically?

DR. WALKER: Yes, that\'s when you\'re getting ‑‑

DR. COUCH: Then they are tenured -‑

DR. WALKER: Yes, that\'s a tenured person, yes. I should have mentioned
that. That is a good point.

DR. COUCH: And not before that ‑‑

DR. WALKER: Right.

DR. COUCH: \-- and a staff scientist is not a so-called tenure-level
either?

DR. WALKER: Right.

DR. COUCH: The second was, is your budget totally available to you or to
CBER, or whatever level, to do with as you choose or is some of it
mandated for regulatory responsibilities and a proportion is available
for personal research?

DR. WALKER: Most of it that we get is available to use for the research
as we see fit. Also, we have to set aside certain money for lot release
activities.

DR. COUCH: Those decisions on the use between the regulatory ‑‑

DR. WALKER: Right.

DR. COUCH: \-- or other research are made within the Division?

DR. WALKER: Within the Division, yes.

Any other questions or clarifications?

(No response.)

CHAIRMAN STEPHENS: Thank you. Thank you very much.

We will move now to a presentation by Dr. Carl Frasch on the overview of
the Laboratory of Bacterial Polysaccharides.

Carl?

DR. FRASCH: Okay. You have heard about the Division. Now you are going
to hear about an overview of the Laboratory of Bacterial
Polysaccharides.

Unlike some of the other laboratories you may have heard about, we are
not unified around a single organism. The mission of this laboratory is
unified around the fact that most all invasive bacterial diseases in the
young pediatric population are caused by bacterial species having
polysaccharide capsules. This includes Hemophilus influenza, Neisseria
meningitides, streptococcus pneumoniae, streptococcus A galactae, also
known as Group B strep. We have vaccines, either licensed or in clinical
studies, for each and every one of these organisms.

Now our laboratory has an extensive list of vaccines for which we have
licensed and have direct responsibility for: polysaccharide vaccines; we
have a pneumococcal 23-valent vaccine by Merck that I just had to take
literally off the list.

We have a 4-valent polysaccharide vaccine by Aventis Pasteur, the VI
typhoid vaccine, the polysaccharide vaccine by Aventis Pasteur, and we
have conjugate vaccines. We have several different Hemophilus influenza
type B vaccines made by Wyeth, Aventis, Merck.

We have the relatively-new pneumococcal-7 valent conjugate vaccine. Not
only that, we have combination vaccines; for example, Merck\'s Combex
vaccine. So, therefore, we have a number of vaccines that our laboratory
is directly responsible for.

So, therefore, we have quite a bit of regulatory activities. We have
over 125 active INDs, the product license applications and supplements.
I went through 1980 when we changed numbering systems. So we have had
over 80 submissions up through the fall of last year.

We hold meetings and conference calls with manufacturers, and all those
vaccines you saw on the list, we do lot release protocol review and lot
release testing. We receive approximately 400 protocols per year for
these products. So that is one of our other responsibilities, not only
research, but a heavy regulatory load.

We also assist in training of reviewers and inspectors, and some members
of my lab actually participate in inspections in manufacturing
facilities. Of course, some of us make presentations to VRBPAC.

All right, now various members of our laboratory are well-recognized
outside of the FDA. That is important. We are temporary consultants to
the CDC, PAHO, WHO, PATH, the Gates Foundation. We help draft WHO
requirements of conjugate vaccines. In the past we have done that for
polysaccharide vaccines.

We review Red Book chapters on polysaccharide and conjugate vaccines. We
do journal reviews for multiple journals. Some of us are on the
editorial board of journals. We do grant review for the Meningitis
Research Foundation in UK. I do Military Infectious Disease or MIDRP
reviews.

We are on the organizing committee for major workshops, and then we
train and work with foreign laboratories in quality control and have
members from their laboratories in our laboratory in a training
situation.

So getting to the research, the Laboratory of Bacterial Polysaccharides
overall is responsible for conducting the basic and applied research on
problems related to the preparation, purity, stability, and
immunogenicity of investigational and licensed vaccines for encapsulated
bacterial pathogens. We are involved in evaluating host-parasite
interactions for the pathogenesis and protective immunity.

Okay. As I said earlier, our laboratory is not organized around a single
bacteria but around the fact that the bacteria produce capsular
polysaccharides. Now since many of the bacteria also elaborate
lipopolysaccharides, that is under our purview also.

So the organization of the Laboratory of Bacterial Polysaccharides is
the Polysaccharide Immunity Section is headed by myself. Our new
Cellular Immunology Section, looking at the immunology of the immune
response to polysaccharides, and later on conjugate vaccines, is headed
by Mustafa Akkoyunlu.

The Pathogenic Neisseria Section is headed by Dr. Margaret Bash, and the
Lipopolysaccharide Section is headed by Dr. Chao-Ming Tsai, and most of
the lot release activities are in the Polysaccharide Conjugate Vaccine
Release Section, under Dr. Chi-Jen Lee.

So what I am going to do next is I am going to go through very briefly
some of the emphasis for each of these different labs and then give,
very quickly, a couple of bullet points on recent achievements.

So, first of all, the research objectives for the Bacterial
Polysaccharide Immunity Section is we conduct research to evaluate the
ability of polysaccharide and conjugate vaccines to induce protective
immunity, and we do studies on different conjugation chemistries to
improve conjugate yields and to improve the immune response in the
native polysaccharide epitopes.

The research objectives for the Immunity Section: We focus on the
initial phase of the polysaccharide vaccine encapsular bacterial
interaction with host immunity. We seek to define the interaction of
polysaccharides with toll-like receptors on innate cells. The biological
research resulting from this effect may affect the development of
adaptive immune responses against polysaccharides.

Then we investigate the role of proliferation-inducing ligand, or APRIL,
and B lymphocyte stimulator, or BLyS, and infant and adult immune
response to bacterial polysaccharides.

I actually have a few comments I want to make on the achievements, some
brief, quick achievements of each of the labs. Let me quickly see if I
can find this. Okay, here.

For example, one of the achievements we have made in the Immunology
Section, which is, of course, we have only had that section for less
than a year, we have identified a polysaccharide interaction that
affects the activity of toll-like receptors. We don\'t know if that
interaction is directly on the receptors or whether it is through
mediators.

Let me go back to one point from the Polysaccharide Immunity Section.
One of our accomplishments is that we have developed a new, general
purpose, high-yield conjugation method with yields greater than 70
percent, and we are in the process of having this method patented. We
have applied this method to several different bacterial species, and it
works for each one of them. So that is one of our achievements in the
Bacterial Polysaccharide Section.

Now the Pathogenic Neisseria Section, they investigate the por proteins
of Neisseria gonorrhoea and Neisseria meningitides. So, therefore, that
is why we call it the Pathogenic Neisseria Section, because we
originally got started looking at the outer membrane proteins of
Neisseria meningitides, and then evolved in looking at the proteins of
Neisseria gonorrhoea.

So we look at studies of the natural epidemiology of por variation using
novel marker titer methods. We evaluate the effects of por variation on
host pathogenic interaction, including immune responses to por,
structure function restrictions on por, and transmission patterns. Then
we identify the mechanisms of a por variation through investigation of
mixed infections, diverse in clonal populations.

So a couple of the key accomplishments in the last couple of years in
the Pathogenic Neisseria Section is that, one, we showed that the
osteoto groups of the meningococcal group A polysaccharide are really
critical for the induction of protective bacteria cell antibodies.

The second achievement is that we have developed a sensitive gonococcal
genetic por typing system that we are using to investigate por-specific
immunity to gonorrhea. Again, that section is by Dr. Bash.

So the last section I am going to tell you about is the
Lipopolysaccharide Section. It conducts research to evaluate chemically
or genetically detoxified meningococcal LPS bound to protein as a
potential vaccine for group B meningococcal disease. As a number of you
realize, we really have no licensed vaccine for the group B
meningococcus. So we are looking at possibilities from a variety of
angles, including the LPS.

Then Dr. Sigh has also looked at studies on the genetics of LPS
biosynthesis in pathogenic and commensal Neisseria species,
characterizing their LPS immunochemically.

And a couple of achievements with the Lipopolysaccharide Section is to
find a new gene, LTGH, in the biosynthesis of the meningococcal
lipopolysaccharide, and he has also found that the sylation of the
terminal galactose in meningococcal LOS requires at least a
tri-saccharide moiety in the alpha chain for the sylation to occur. Of
course, in the gonococcal sylation, it is critical for the
serum-resistant strains.

So that\'s all I have to say.

CHAIRMAN STEPHENS: Thank you, Carl.

Any comments, questions, for Dr. Frasch?

(No response.)

Okay, thank you very much.

We now have an open session. Dr. Sachs?

DR. SACHS: As a part of the FDA advisory committee meeting procedure, we
are required to hold an open public hearing for those members of the
public who are not on the agenda and would like to make a statement
concerning matters pending before the Committee.

I have not received any requests at this time. If there is anyone in the
room who would like to address the Committee at this time, please come
up to the mike.

(No response.)

For the record, there is no response.

Thank you, and at this time I would like to close the open public
hearing and turn the meeting back over to Dr. Stephens. Thank you.

CHAIRMAN STEPHENS: Please, consultants, if you can, and all of you, stay
for this session; we need a quorum for this discussion.

(Whereupon, the foregoing matter in open session went off the record at
2:49 p.m. to reconvene in closed session at 2:49 p.m.)