UNITED STATED OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

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101^st^ MEETING

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WEDNESDAY,

FEBRUARY 16, 2005

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The Advisory Committee met at 8:30 a.m. in the Versailles Room of the
Holiday Inn Select, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Gary
Overturf, Chair, presiding.

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 to its accuracy.

[PRESENT]{.underline}:

GARY D. OVERTURF, M.D., Chair

ROBERT COUCH, M.D., Temporary Voting Member

NANCY COX, Ph.D., Consultant

WALTER DOWDLE, Ph.D., Temporary Voting Member

[PRESENT (Continued)]{.underline}:

THEODORE EICKHOFF, M.D., Temporary Voting Member

MONICA M. FARLEY, M.D., Member

RUTH A. KARRON, M.D., Member

PHILIP S. LaRUSSA, M.D., Member

DAVID MARKOVITZ, M.D., Member

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

ARNOLD MONTO, M.D., Temporary Voting Member

STEPHEN PHILLIPS, D.O., M.P.H., Temporary Voting

Member

CINDY LYN PROVINCE, R.N., M.S.N., M.A., Consumer

Representative

BENJAMIN SCHWARTZ, M.D. (CPT)

STEVEN SELF, Ph.D., Member

WALTER ROYAL III, M.D., Member

MELINDA WHARTON, M.D., M.P.H., Temporary Voting Member

BONNIE M. WORD, M.D., Member

CHRISTINE WALSH, R.N., Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

KAREN MIDTHUN, M.D.

NORMAN W. BAYLOR, Ph.D.

[FDA REPRESENTATIVES (Continued)]{.underline}:

ROLAND A. LEVANDOWSKI, M.D.

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

[ALSO PRESENT]{.underline}:

LINDA C. CANAS

KEIJI FUKUDA, M.D., M.P.H.

ALBERT THOMAS

[C O N T E N T S]{.underline}

[PAGE]{.underline}

Conflict of Interest Statement 5

Presentation of Dr. Roland Levandowski 10

U.S. Surveillance Data, Dr. Keiji Fukuda 29

World Surveillance and Strain Characterization,

Dr. Nancy Cox 53

Update on Response to H5, Dr. Pamela McInnes 93

Report of Department of Defense, Linda Canas 102

Vaccine Responses, Dr. Roland Levandowski 137

Availability of Strain and Reagents, Dr.

Zhiping Ye 166

Comments from Manufacturers, Albert Thomas 172

Options for Strain Selection, Dr. Roland

Levandowski 201

Committee Discussion and Recommendations 216

[P R O C E E D I N G S]{.underline}

(8:34 a.m.)

CHAIRPERSON OVERTURF: I\'d like to call the meeting to order and turn it
over first to Christine Walsh.

MS. WALSH: Good morning. I\'m Christine Walsh, the Executive Secretary
for today\'s meeting of the Vaccines and Related Biological Products
Advisory Committee.

I would like to welcome all of you to the 101st meeting of this Advisory
Committee. Today\'s session will consist of presentations that are open
to the public. Tomorrow\'s meeting will consist of both open and closed
sessions.

I would like to request that everyone please check your cell phones and
pagers to make sure they are either in the off or silent mode.

I would like now to read into the public record the conflict of interest
statement for today\'s meeting.

The following announcement is made part of the public record to preclude
even the appearance of a conflict of interest at this meeting. Pursuant
to the authority granted under the committee charter, the Director,
Center for Biologics Evaluation and Research, has appointed for the
discussions on February 16th the following participants as temporary
voting members:

Dr. Robert Couch

Walter Dowdle

Theodore Eickhoff

Pamela McInnes

Arnold Monto

Stephen Phillips

Benjamin Schwartz

Melinda Wharton

For the discussions on February 17th, the following participants have
been appointed as temporary voting members:

Drs. Pamela McInnes

Stephen Phillips

Benjamin Schwartz

Melinda Wharton

Based on the agenda for February 16th, it has been determined that the
topic being discussed by the committee on the strain selection for
influenza virus for the 2005-2006 season is a general matters issue. The
committee will not be providing advice on specific firms or products on
this day.

To determine if any conflicts of interest exist, the agency reviewed the
agenda and all relevant financial interests reported by the meeting
participants. The Food and Drug Administration prepared general matters
waivers for participants who require 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 discussion before the committee,
these potential conflicts are mitigated.

We would like to note for the record that the agency is in the process
of selecting a nonvoting industry representative for this committee. On
February 17th, the committee will hear updates on FDA\'s critical path
initiative and will hear a presentation on the Laboratory of Biophysics
and the Laboratory of Pediatrics and Respiratory Viral Diseases.

Meeting participants were not screened for potential conflicts of
interest for these updates and overviews.

We would like to note for the record that Dr. Nancy Cox is serving as a
consultant for this meeting, any speaker making a presentation. She is
Chief, Influenza Branch, Center for Disease Control and Prevention in
Atlanta, Georgia.

With regards to FDA\'s invited guest speakers, the agency has determined
that the services of these speakers are essential. The following
interests are being made public to allow meeting participants to
objectively evaluate any presentation and/or comments made by the
speakers.

Ms. Linda Canas is Chief of Diagnostic Virology, Epidemiological
Surveillance Division, U.S. Air Force, San Antonio, Texas.

Dr. Keiji Fukuda is Chief, Epidemiology Section, Influenza Branch,
Center for Disease Control and Prevention, Atlanta, Georgia.

In addition, Mr. Albert Thomas is an industry speaker making a
presentation. He has financial interests associated with his employer
and regulated firms. He was not screened for these conflicts of
interest.

Members and consultants are aware of the need to exclude themselves from
the discussions involving specific products or firms for which they have
not been screened for conflict of interest. Their exclusion will be
noted for public record.

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

That ends the reading of the conflict of interest statement. Dr.
Overturf, I turn the meeting over to you.

CHAIRPERSON OVERTURF: The entire first day will be contributed to the
issue of strain selection for influenza virus for the forthcoming
season, 2005 through 2006, and the first speaker is Dr. Roland
Levandowski.

DR. LEVANDOWSKI: Thank you, Dr. Overturf.

Good morning, everybody. Welcome to Bethesda. Actually I see there\'s
lots of room left at the front. So those of you who are sitting at the
back are welcome to come up a little closer and the slides will be a
little bit better, I think, for you.

I have been reminded by a friend that this is the Year of the Rooster,
and if I can get this up here, this is the rooster family, and they\'re
all smiling because they know it\'s time to get started making influenza
vaccine again this year. So I don\'t really know who to attribute this
picture to. It was sent to me by a friend who found it on the Internet,
and if you like it, you may be able to find it, too. I couldn\'t, but I
got the picture from the friend.

DR. COUCH: I thought you were going to say it\'s our new susceptible
population image.

DR. LEVANDOWSKI: Well, it could be. This is the red jungle fowl here.

All right. Let me get down to business though. Okay.

As Dr. Overturf said, the reason that we\'re here today is for the
committee to make recommendations for selection of the influenza virus
strains, the A(H1N1) and A(H3N2) and B viruses that should be used for
the influenza vaccines to be prepared for the 2005-2006 influenza season
in the United States.

Why do we change the strains in the influenza vaccines? We do that
because it\'s really important for vaccine efficacy. We know that
vaccine efficacy relates to a couple of things, one of which is the
potency of the influenza vaccines, but from a lot of experience, it has
become very clear that the match of hemagglutinin and neuraminidase of
the vaccine strains to the wild-type circulating viruses is important
for vaccine efficacy.

And the first evidence of that for reduced vaccine efficacy was apparent
two years after the first vaccines were licensed for use in 1945. Within
two years, it became clear that antigenic draft in influenza viruses
could reduce the vaccine effectiveness.

The questions that the committee needs to consider answering in order to
make the recommendations are listed here and we\'ll be presenting
information that covers all of these areas during the course of this
meeting.

The first and most important questions is from [Surveillance and
Epidemiology]{.underline}: are there new influenza viruses that are
circulating that have hemagglutinins and neuraminidases that appear to
be different from the current vaccine?

And if the answer to that question is yes, we also want to know: are
these new viruses spreading in people? Are they in wide geographic
locations or are they just from one location?

Occasionally we see viruses that look extremely different, but it turns
out that they\'re one off, and they don\'t seem to spread anywhere. So
this question two, if it\'s answered yes, are those viruses spreading,
we also want to know whether current vaccines can induce antibodies that
will recognize those new viruses.

And if the answer to that is no, then we want to know further are there
vaccine strain candidates available that would be suitable for large
scale manufacturing of inactivated and live attenuated influenza
vaccines.

I\'d just like to go through a review of what the committee considered
last year and what the questions and the sort of resolution to the
questions was. First of all, for the current vaccine that we have now
last year, the question was were there new strains of Influenza A(H1N1)
circulating, and at that time you might remember we also had some
reassortant viruses that were H1N2. Last year there really weren\'t
strains that were antigenically different from the current vaccine
strain. All of them were very much similar to what was in the vaccine.

The same question for the H3N2. Last year the answer to that question
was yes. There were A Fujian-like viruses that we had known about since
February of 2003. As you might recall, the first season that those were
identified it was not possible to make a change in the vaccine, but
those strains continued to circulate widely around the world in people.

And by 2004, although early on those were more or less in the minority
or fairly quickly they became the majority and by 2004, those were the
main strains that were circulating in the world.

For Influenza B, the question was asked: are there new strains present?
And the answer was yes, and in 2004, the majority of the viruses were
similar to a strain called B/Shanghai/361/2002, which is from the
so-called B/Yamagata/1688 hemagglutinin lineage.

That lineage was not the one that was being used in the vaccine that was
current last year. In a minority of the strains that were found during
the epidemiologic studies were similar to the strain that was in the
vaccine for last year, which was B/Hong Kong/330/2001, which belongs to
the HA lineage that we represent with the strain B/Victoria/287.

In answer to the question were these new viruses spreading, the answer,
of course, is definitely yes. The Fujian-like viruses had become
widespread around the world and were predominant everywhere, and these
B/Shanghai-like strains at the time we were holding this meeting in
February were predominant not only in North America and the United
States, but also in Asia and Europe.

Were the new viruses that were identified and spreading, were those
inhibited by the current vaccines? And this question, as it sometimes
is, was not a very definite no or yes. It was a little bit difficult to
interpret, but it seemed like man of the A/Fujian-like viruses were not
well inhibited by the current vaccines, although some of them were.

For the B/Shanghai-like strains, of course, we\'ve known for a long time
that these two divergent hemagglutinin lineages are not that well
inhibited one by the other, and as time has gone on and antigenic drift
has occurred in these strains, that has become truer.

Generally we also know that for the B/Yamagata-like strains and the
B/Victoria-like strains, that very young children and people who
haven\'t been immunologically primed, exposure to one of these does not
seem to immediately give antibodies that cross-react with the other HA
lineage.

So were there strains that were suitable for manufacturing? And the
answer was yes. Of course, we all know that for inactivated vaccines and
for live attenuated vaccines manufacturing depends on having egg adapted
strains, either the wild-type or reassortant, and in the case of the
live vaccine, of course, it has to be a reassortant for the attenuation
phenotype.

But there were A/Fujian-like strains that were available, and there was
a high growth reassortant that was being used in manufacturing for the
Southern Hemisphere already, the A/Wyoming/3/2003 X 147 reassortant.

For the B strain, there were a number of wild-type isolates that seemed
to be suitable for manufacturing, including B/Jilin/20/2003 and
B/Jiangsu/10/2003, in addition to the B/Shanghai/361 strain itself.

So based on that, the strains that were selected for this year include
A/New Caledonia/20/99-like strain, which in this case really is A/New
Caledonia/20/99.

For the B/Shanghai/361/2002-like recommendation that was made, there
were all three of these strains, B/Shanghai, B/Jilin, and B/Jiangsu.

And for the A/Fujian/411/2002-like recommendation that was made and the
A/Wyoming/3/2003 strain was chosen or is the one that has become widely
used for vaccine preparation.

Now, the implications of the strain selection were that preparation of
the vaccines was on schedule throughout the year. All of the strains
seemed to be typical and easy to adapt for manufacturing purposes, and
going into the summer, the supply of vaccine was expected to match the
demand predicted by previous years\' experiences.

But what happened was that we ended up with a vaccine shortage at the
end of the summer, and just to try to put that into a little
perspective, from January until August, manufacturing had been
progressing on schedule even including these two new strains that were
recommended for use in vaccines, and it was anticipated there were going
to be about 100 million doses of vaccine from all of the manufacturers
combined for this year.

In August of 2004, Chiron notified regulatory authorities about a
sterility issue and indicated that investigation to identify the cause
and the implementation of corrections was underway, and at that time
Chiron made a public announcement indicating that there would be a
possible delay in distribution and possibly a reduction in the amount of
vaccine that would be available.

You also probably all know that in early October of 2004, the MHRA, the
U.K. regulatory authority, announced that they were suspending Chiron\'s
license to manufacture inactivated influenza vaccine for three months,
and that was based on the issues that have previously been identified
and were in investigation and correction by Chiron.

Subsequently, over the next few weeks and certainly by November of 2004,
it became clear after consultation between FDA and MHRA that the vaccine
that Chiron had planned to make was not going to be available for us in
the United States.

In response to that, there were a number of things that happened within
the Public Health Service, and I\'ll just very briefly indicate some of
those. At FDA there was a lot of work done to evaluate manufacturers who
were not licensed in the United States to identify whether their
vaccines could be used under IND.

There was consultation with manufacturers to discuss regulatory
mechanisms going forward from this time for getting approval of new
products in the United States. That includes accelerated approval, fast
track and priority reviews to facilitate those new licenses, and all of
these things actually have been continuing.

CDC had a number of roles to play, and I\'m not indicating everything
here, but certainly there are some very prominent roles in the public
health response to what was happening with loss of some of the vaccine
that was anticipated.

CDC immediately reviewed and communicated the use recommendations that
would be appropriate for this reduced amount of vaccine that was
anticipated. It worked very diligently in terms of coordinating
distribution of the existing vaccine supplies and were very closely
linked and working with manufacturers and FDA in terms of acquisition
and use of vaccines under IND in the United States.

National Institutes of Health also as part of the Public Health Service
responded to this and were able to provide support for a number of
clinical studies that might be done for vaccines under IND-made
commitments to help manufacturers and their interests in doing clinical
studies that would be useful for IND and possibly later on for vaccine
license approvals.

And of course, they\'ve been giving continuing support for development
of new vaccines. This is something that was ongoing already at NIH, but
have continued to try to facilitate development of new vaccines, tissue
culture vaccines, recombinant DNA, and also adjuvanted influenza
vaccines.

And the Public Health Service and HHS generally underwent a global
consultation with other partners, including national regulatory
authorities, but certainly also with manufacturers to try to find where
there might be additional vaccine supplies and to acquire those for use
here.

Currently there still is vaccine that\'s available, and I guess the most
recent recommendations that I have seen on use of vaccine for late
season use are on the CDC Website, and I would anticipate that those are
continuing to be updated. So anyone who is interested in them should
certainly check \-- interested in vaccine supply and maybe how to obtain
additional vaccine \-- should continue to check the CDC Website and see
what the latest information is.

There still, as of the time I was putting these slides together, was
inactivated and live attenuated vaccine available for use, and I think
we would all like to make sure that the vaccine that has been produced
is used effectively.

And finally, there are also IND vaccines that are available during this
year from both GSK and Berna Biotech.

Now, switching gears a little bit and thinking about where we are and
where we\'re going from here for this year. We\'re in February so there
are a lot of things that are happening. So there are a lot of things
that are happening. Obviously I\'ve put this together as a kind of a
pyramid, and the most visible part of the influenza vaccine, of course,
is the vaccine use that occurs in the fall months and into the winter,
but you\'ll see that there\'s a lot of activities that have to go on
before that can happen, including preparation of the vaccine shown in
blue here and all of those bars, and all of the support activities that
are required for the manufacturers to know what strains that they\'re
going to be using, acquire the reagents and the materials that they need
to permit them to go ahead with manufacturing.

So we\'re here in February. I don\'t have a pointer. I don\'t know if I
can get the arrow to show up here on the \-- I don\'t see one, but
we\'re here in February, and we\'re right at the point of
recommendations being made both by this committee and by other national
health authorities.

Obviously surveillance continues throughout the year. Development of
seed viruses and reagents and reference materials, that goes on
throughout the year as things become apparent and become available, and
it\'s based on all of those underlying activities that the preparation
of the vaccine can start.

Now, I showed this slide last year, but I wanted to show it again to
talk about what happens when there are new viruses that are added to the
vaccine. It\'s quite a challenge for manufacturers to get everything
together in the relatively short period of time that they have, and even
a simple strain change, we\'re talking about work that requires many,
many weeks, somewhere in the order of between 12 and 20 weeks in order
to accomplish all of the tasks that need to be done.

In order to have any change in the vaccine, of course, there have to be
reference viruses that are obtained. Those come from surveillance, and
it is not always easy to get those. As you might recall, it was
difficult to isolate some of the H3 viruses in eggs, and as you\'re
going to hear, CDC has been putting in a lot of effort into making sure
that egg isolates, appropriate egg isolates, are available for
manufacturing. I think Nancy Cox will talk about that a little bit
later.

Once those reference viruses have been acquired, then that\'s not the
end of the job because each of the manufacturers has to take the
reference virus and develop a working seed virus from that. This is not
something that is done in a day. It takes several weeks\' worth of work
to identify the strain that seems to be appropriate for the
manufacturing process and also to make sure that all of the quality
control issues that need to be handled and addressed for those new
viruses have been done.

Thank you.

So once that\'s accomplished there still need to be reference reagents
that are produced for the reference virus as well, and that can be a
rate limiting step. Once the virus has been identified or it\'s in our
hands, then we can start to work on getting those reagents made, but it
takes a period of about three months actually, well, six weeks to three
months to have everything prepared because it requires both an antigen
and an antibody that\'s made in sheep, which is a biological system
that\'s not always readily controllable.

Generally though manufacturers are already for the strains that aren\'t
changed can start working and keep working on preparation of materials
for vaccine, and when it\'s time, they can start manufacturing the third
strain so that they can formulate the trivalent vaccine, fill it, and
then distribute that vaccine hopefully in time for use in the fall.

There will be a presentation later by our industry representative who
will go into more detail about this, but I wanted to mention it also
that it\'s a fairly complex set of activities that need to be undertaken
for implementation of any strain change, and it is a kind of a stressful
situation for all parties that are involved to first make sure that
their reference virus is present, make sure that the reagents get
produced and make sure that the manufacturing can go forward.

I\'ll end up here with some bits of information from WHO recommendations
during the past year. These are the recommendations that WHO made for
the Southern Hemisphere, and you can see that the strains that were
selected for the Southern Hemisphere, which were based on information
much like what we\'ll be discussing here this morning, it was to keep
the A/New Caledonia/20/99 strain as the vaccine virus and it actually
was to include now a B/Shanghai/361/2002-like virus for the first time
in the Southern Hemisphere, but it was a continuation of what had
already happened with recommendations in the Northern Hemisphere in
February last year.

However, there was a recommendation for a change in the A/Wyoming strain
to an A/Wellington/1/2004-like virus, and that was based on the fact
that the H3N2 viruses were undergoing antigenic drift.

And finally, these were the recommendations that have been published on
the WHO Website for this coming year, and you\'ll see that although the
H1N1 and the B strain are the same as what they were for the Southern
Hemisphere, the WHO recommendation for the H3N2 virus is for another
different strain, the California/7/2004-like virus. And we\'ll be
presenting information that will probably make that understandable.

So the question for the committee that we would like to have addressed,
the specific question that we\'re asking the committee this morning is
what strains should be recommended for the antigen at composition of
2005-2006 influenza virus vaccine, and this recommendation should be
based on the epidemiology and antigenic characteristics of the
circulating influenza viruses.

On serologic responses, people have been immunized with current vaccines
and the availability of candidate strains, and I guess I can stop there
and see if there are any questions or comments.

CHAIRPERSON OVERTURF: Other questions or comments for Dr. Levandowski?
Dr. Couch.

DR. COUCH: Haven\'t the WHO recommendations for the Northern Hemisphere
for 2005-2006 already been made? Haven\'t they all? They were on the
Website at any rate.

DR. LEVANDOWSKI: That\'s right. That\'s what I showed.

DR. COUCH: But you didn\'t include them. Won\'t you tell us what those
are?

DR. LEVANDOWSKI: Right there. Isn\'t that it? Do I have it mislabeled?

DR. COUCH: No, that\'s fine.

CHAIRPERSON OVERTURF: Dr. Markovitz.

DR. MARKOVITZ: Yeah, thank you.

I wanted to ask. You showed something about the Berna Biotech vaccine in
IND, and we\'re going to hear about the GSK tomorrow, but what is the
Berna Biotech vaccine?

DR. LEVANDOWSKI: It\'s an inactivated influenza vaccine.

DR. COUCH: Aren\'t there other candidates for the IND or there was or
what\'s the status of other manufacturing candidates for interest in our
country? I guess that\'s the question.

DR. LEVANDOWSKI: Okay. Well, of course, I\'m not going to talk about any
INDs that are, you know, confidential information, but there is a lot of
interest; there has been ongoing interest. There was interest even
before this from a number of manufacturers to bring their products to
the U.S. market, and those are all things that were in the works and are
continuing.

So I guess what I can say generally is that there are a number of
manufacturers that are interested who are pursuing avenues toward
getting approval for their products in the United States, and they\'re
multiple. It\'s not just one or two. It\'s multiple.

CHAIRPERSON OVERTURF: Any other questions?

(No response.)

CHAIRPERSON OVERTURF: We\'ll go on then. Dr. Fukuda is going to give us
the U.S. surveillance data.

DR. FUKUDA: Good morning. I see that I\'m allotted more time than I
really need. I\'m only going to spend a few minutes talking about
surveillance in the United States, and then Dr. Cox will be covering
some of the events going on in Asia related to H5N1.

So normally I just talk about the activity that\'s going on in the
United States, but I thought I\'d take a minute or two and go over some
of the changes affecting how we\'re doing surveillance in the U.S.
because they really have been quite substantial over the past year or
two, and I think it\'s changes that the committee should know about.

So over in the left-hand column you can see how we\'ve done surveillance
in the United States for several years, and for quite a long time we\'ve
monitored viral activity through the WHO nerve laboratory system in the
U.S., which is largely a group of Public Health laboratories, plus
university laboratories. We\'ve monitored influenza-like illness visits
to a group of sentinel physicians scattered throughout the United
States.

We\'ve monitored mortality from influenza using two different systems.
The 122 cities systems collects data from vital registrars\' offices in
122 cities, and then the NCHS data set is the large data set reflecting
all deaths in the United States which are analyzed a couple of years
afterwards.

And then we typically get state activity assessments from the state
epidemiologists every week, and so this is basically the information
that you\'ve seen for year in and year out.

Now, there are a couple of things which are really driving changes in
surveillance. One of them is that since really the mid-1990s we\'ve been
trying to strengthen surveillance as much as possible, recognizing that
there are a number of limitations.

A second thing is that there has been a great deal of concern about
pandemic influenza, and I think this concern continues to rise, and so
that\'s another driving factor for enhancing surveillance in the U.S.

And then the third thing is that there has been directives from the
Director\'s Office at CDC really to strengthen surveillance so that the
data comes in a little bit more quickly and so that it\'s more broadly
representative of the country geographically.

So based on that, there have been a number of things done to enhance the
systems on the left, and I\'ll go over one example, which is the
sentinel provider system. There have been a number of new systems which
have been added.

We are now monitoring pediatric influenza related hospitalizations
through two different networks, the NVSN and the EIP Programs, and this
largely comes out of last year\'s experience where we had so many
pediatric deaths and so many severe illnesses reported in that age
group.

And then also as part of that, we have begun \-- we worked with CSTE,
the Council of State and Territorial Epidemiologists, to institute
national pediatric death reporting for death related to influenza.

So these are new systems, and then because of concern of H4N1 and the
initial cases that were reported back in 2003, we have been, in essence,
at a state of heightened alert in the United States where state health
department and hospitals have been on the lookout for H5N1 cases among
travelers returning from Asia. So these are new systems which have been
added over the past year or two.

Then in addition, there are a large number of systems, and I\'m just
giving two examples here which are under evaluation. Biosense is a large
conglomeration of data sets which are collected from groups such as the
Veterans Administration, DOD, pharmaceutical industry, and so on. These
are being evaluated for the potential value when conducting influenza
surveillance.

And then we also will be talking with the Council of State and
Territorial Epidemiologists later this year about whether influenza
laboratory confirmed illnesses should be a national reportable disease,
which would probably profoundly affect how we do surveillance. It would
probably be the biggest change of all if we go in that direction.

So this is the effect of some of those changes. You can see on this
slide here that this represents the numbers of sentinel physicians in
the country and then the number of visits that are made to those
physicians for influenza-like illness.

So back in 19 96, which is the column over on the left, you can see that
we probably had somewhere between 50 and 100 sentinel physicians
reporting these data, and then if you go up to 2004, we have over 1,000
physicians reporting on a regular basis, and so this represents an
increase of less than a million patient visits to about five to nine
million patient visits per year.

Now, these physicians are scattered in the United States and these dots
represent where they\'re located, and you can see that, in general,
they\'re distributed in the way that the population of the U.S. is
distributed, and typically when we\'ve analyzed these data, we\'ve shown
you curves like this, which shows you the percentage, the cumulative
percentage of visits for influenza-like illness on a week-by-week basis,
and you can see in different years that percentage increases as we go
into the influenza season, then comes down.

What we\'re trying to do, we\'re testing a couple of other ways of
analyzing these data, however. This map here represents the application
of the so-called outbreak detection algorithms to each physician, and
so, in essence, each physician is treated as a sentinel for detecting
outbreaks or increases in activity.

And so using certain statistical methods, what we do is look for an
increase in visits for influenza-like illness for each of the
physicians, and you come up with maps like this, this sort of speckled
map where the red represents increases and the black do not.

I think right now what we\'re mostly struggling with is whether this
kind of analysis adds anything substantial to what we already have, but
anyway, so that work goes on.

So let me go into the current season now. So you can see, and this
updates the report to the committee. I think the committee has
surveillance data up through week four, and this goes into week five. So
these numbers will be a little bit different from what you have.

So basically you can see that this year it has been a mixed Influenza A
and B season, but predominantly A. To this point there have been about
65,000 specimens tested by the laboratory system and about 11 percent of
those have been positive for influenza.

And of those which have been positive, about 85 percent of the isolates
have been Influenza A and about 15 percent have been Influenza B.

Now, of the Influenza A viruses, about a third have been subtyped, and
you can see of those that have been subtyped almost all of them have
been Influenza A(H3N2) viruses, with a few H1N1 viruses or a few H1
viruses.

And so Dr. Cox will be going much further into these data in a few
minutes, and so this graph here represents the same data shown somewhat
differently, and so these stacked bars represent Influenza A viruses and
B viruses, and the numbers that have been identified as we\'ve gone into
the influenza season.

Now, one of the important things to see here is this black line. This
represents the percentage of specimens which are positive for influenza,
and in many ways it\'s often the earliest indicator of how the season is
going.

So right now you can see that approximately 23 or 24 percent of
specimens coming into the system are positive for influenza viruses.

Now, if you look in the past of the past several seasons, you will see
that this percentage typically peaks somewhere between a quarter and a
third of specimens testing positive for influenza viruses when we reach
the peak of the season. So right now this curve looks like we\'ve
reached the peak, but this was probably somewhat of an artifact, or
we\'re not sure if it\'s an artifact right now. It may represent a bit
of a reporting lag.

So based on this curve right here, it still looks like that we\'re going
up in the season and we haven\'t quite peaked yet.

Now, this slide here represents the visits for influenza-like illnesses
to sentinel providers, which I showed you a few minutes ago. The red
line represents the pattern for this year, and the green line represents
the pattern that we saw last year when we had that early season.

Now, these are curves which you wouldn\'t have seen last year. So these
are laboratory confirmed hospitalizations, and these are
hospitalizations coming into the NVSN system, and so these represent
hospitalizations of children zero to four years of age, and you can see
the blue line represents last year when we were hearing about so many
reports, and the red line represents what we\'re seeing this year.

Now, these are similar data coming into the EIP system. I won\'t go into
the details. The NVSN system and the EIP systems identify
hospitalizations in somewhat different ways, and so the absolute rates
are somewhat different, but what they show, in essence, is fairly
comparable.

And I want to point out one thing though. The blue lines here, again,
represent what we saw last year. The solid blue line represents
hospitalizations that we saw in children zero to four years of age, and
then the dotted or the broken line, blue line, represents the
hospitalizations that we saw in children five to 17 years of age.

And so you can see that there was a quite large difference in rates of
hospitalizations depending on age.

Again, the red line represents the hospitalizations that we\'re
detecting this year. So, again, you can see there\'s a substantial
difference between the experience this year and last year.

This curve here is the familiar pneumonia and influenza mortality curve
which comes out of the 122 cities system, and so far this year we have
not detected an increase in excess mortality.

I was looking at this slide this morning. So I\'m struck that we have
red states and blue states, and there are more red states than blue
states.

(Laughter.)

DR. FUKUDA: But all things change. So anyway, these are activity levels
represented by the state and territorial epidemiologists. The red, in
essence, report reveals or indicates the highest level of activity in a
state, and then the blue levels represent a somewhat lower level of
activity.

So this is the last slide here. I think that what we can say is that in
comparison with last year, this season has been relatively moderate. It
has been dominated by Influenza A(H3N2) viruses. I didn\'t go over these
data, but so far there have been six reported pediatric deaths
associated with laboratory confirmed influenza. This is in contrast to
153 laboratory confirmed deaths reported last year for the entire year.

But then, again, this season clearly has started later than last year.
We are in a period of ongoing activity. We cannot say that activity has
peaked in the country yet, and so we still don\'t know what the full
impact and what the full numbers will be.

So I\'ll stop there.

CHAIRPERSON OVERTURF: Just one question. You had that slide that looked
like four curves or four seasons with pediatric hospitalization rates.

DR. FUKUDA: Yes.

CHAIRPERSON OVERTURF: What is the quality of the data for the two prior
seasons?

Obviously we really didn\'t have a surveillance system that was looking
at pediatric hospitalizations that I know of prior to last season; is
that correct?

DR. FUKUDA: Well, this system, the NVSN system, has been in place since
2000, and so this actually represents now five years\' worth of data.

I would say that the quality of these data are excellent. You know, this
is a system which was set up by the National Immunization Program in
Rochester and in Tennessee, Rochester, New York, and then in the
Vanderbilt area, and then more recently they\'ve added a third site.

And in essence, it\'s an active system where all children coming in
meeting a certain case definition are then tested for influenza and
other viral respiratory illnesses, and so it\'s a pretty labor intensive
system, but the data themselves are quite excellent.

CHAIRPERSON OVERTURF: Other questions? Dr. Couch.

DR. COUCH: I wanted you to go ahead if you would, Keiji, and contrast
those two systems a little bit because they don\'t exactly say the same
thing.

DR. FUKUDA: Sure. I think one way to look at the NVSN system is that
it\'s close to an ideal way of trying to look at what children are
getting sick with and to identify rates of hospitalizations associated
with various pathogens.

By contrast, the major limitation I would say of the NVSN system is that
it\'s restricted to a small number of sites and it\'s expensive. The EIP
system is a program intended to look at a wide variety of issues, and so
the ABC system looking at bacterial infections comes out of that system.
FoodNet comes out of that system, and this is a population-based
surveillance system in 11 sites in the U.S. right now.

And so what this system does is take existing data. It takes how
physicians handle children or other people coming into hospitals and
looks at the virus detections and so on as they\'re currently done, and
then takes that information and makes it available and makes it
available in a way which is population based.

And so I think the strength of this system here is that it\'s a much
larger system, and like NVSN, it represents population based data, and
it reflects practice as it\'s actually done right now.

So it\'s probably comparatively less labor intensive, but I think the
sensitivity of this system \-- there will be an article coming out on
this \-- is less than the NVSN, yeah. So in a certain sense they are
pretty complementary. They try to do different things, but in fact, you
can see that the overall picture of the data is pretty similar. The
absolute numbers are different, but I think that you both get a good
sense of the rates going on, and certainly I think that these systems
are going to be very helpful for looking at differences in seasons,
particularly in children right now, you know, and this has been a major
question. You know, how much does it vary in children and what is the
impact?

CHAIRPERSON OVERTURF: Mr. Phillips.

COL PHILLIPS: Keiji, it was mentioned last week at ACIP, but I can\'t
recall. Can you comment on the percentage or the numbers of children six
to 24 months that received immunization this year compared to last year?

DR. FUKUDA: Yes. I think that actually Melinda or Ben may remember
better, but I think that when we first started out, you know, the rates
in that age group were very low, I think, less than five percent, and
then within a year it went up to about 45 percent somewhere; is that
right, Melinda? I\'m not quite sure.

DR. WHARTON: I think the most recent data for six to 23 month olds from
the BRFS for this year was 57 percent.

DR. FUKUDA: Oh, 57? Okay. Sorry.

So it has really been an astounding increase in that age group.

CHAIRPERSON OVERTURF: Yes, Ted.

DR. EICKHOFF: Keiji, two things. In the very first bar graph you showed
about the sentinel physician providers I missed something. A straight
line had turned straight down. What was that straight line? Is that the
number of sentinel physicians?

DR. FUKUDA: This is the number of patient visits. So if you take the
sort of cumulative number, and I think that the downward turn just
reflects that we\'re still going on through the season. So I think that
at the end of the season that line will be going up.

So I think that the downward line is just an artifact of where we are in
the season.

DR. EICKHOFF: Okay. Thank you.

The second part of the question related to the state epidemiologist
reporting. Now, I know there are definitions that go with each of these
categories of reporting, like regional and widespread and so forth and
so on, but yet I can\'t escape the feeling that there may, in fact, be a
great deal of observer variability in these reports.

So you have any sense of how variable these may be within a specific
definition, such as regional?

DR. FUKUDA: I think there\'s probably a substantial amount of
variability. I mean, clearly, how each state decides to report their
activity varies. I mean some states look more at their laboratory data.
Other states look at perhaps what they\'re hearing about
hospitalizations and so on, and in a sense it represents a gestalt from
that state.

Nonetheless, I think it\'s funny, but I think that it actually pretty
well represents what we see in the other parts of the system where, when
we look at increases in visits to sentinel physicians, for example, in
the northeast or in the southwest, and it correlates pretty good.

And what it does, you know, we really are not at a point yet with the
other systems where we can break the data down to a state-by-state level
and feel that they\'re robust enough that we can report on a
state-by-state level. I think we\'re getting to a state where we\'re
feeling pretty good that in a lot of the regions the data from the other
systems are pretty good for those regions.

But as we get into smaller and smaller cuts at the data, you know, it
becomes a little bit more \-- the confidence intervals become a little
bit too wide. So this really represents our way of trying to get at what
are the states themselves feeling like they\'re seeing and how, you
know, are they responding to that and reacting?

DR. FUKUDA: There\'s another question. Yes.

DR. DOWDLE: First I\'d like to congratulate CDC for continued expansion
of the surveillance system. It\'s quite gratifying to see that, and I\'m
also really interested in your discussions, upcoming discussions in
making influenza a national notifiable disease, which brings up the
question: in your discussion with the states, what do you see is going
to be the major challenges to get this done?

I mean, this has been discussed before, but there are many challenges to
doing that. So have there been any changes? Is there different
attitudes? And what do you think are the real challenges this time?

DR. FUKUDA: Walt, I think it represents a couple of things that are
changing out there. One is that, in fact, it turns out that there are
more states in which laboratory confirmed influenza already is a
reportable disease within the state than we really, I think, suspected.

I mean, when you look at it, it\'s probably around 20 states or so. So
that\'s one difference than some years ago.

A second issue is that I think that influenza has gotten so much
attention over the past couple of years that on the political agenda in
a lot of states there is now a recognition that they really want to keep
on track of what\'s going on with influenza in their states much more,
and that\'s probably a big change over, say, five or ten years ago.

And then the third thing is that, you know, the State and Territorial
Epidemiologists really pull together with CDC when there\'s kind of a
crunch going on, and I think that there has been a big push over the
past few years with the vaccine supply disruptions, the push from the
Director\'s Office at CDC really to strengthen surveillance in a way
that data is coming in a little bit more quickly. It\'s a little bit
more specific, and perhaps eventually can be used really to respond to
emergencies a little bit more quickly.

And so based on that, this idea of moving to notifiable diseases really
came out from the states. It\'s something, I think, that we would have
hesitated to approach because of all of the practical and feasibility
issues, but basically a couple of the states came to us and said, \"You
know, we really think it\'s time that influenza surveillance begin to be
treated like other diseases in the U.S. and that we begin to look for
confirmed cases and try to track those, and so I think moving into that
direction is really the biggest hurdle is going to be to get all of the
states which aren\'t doing that right now to agree that it should be a
notifiable disease.

I think if that is done then I think all of the other issues are
relatively simple to deal with, and I think for the states it\'s really
just a feasibility issue. You know, they\'re dealing with bioterrorism
activities and so on, and there are so many things going on that
everyone is trying to respond to, but that\'s the real hurdle.

CHAIRPERSON OVERTURF: Dr. Monto.

DR. MONTO: Coming from a state where we\'ve been discussing making
influenza notifiable disease and in a situation where there is concern
that there would be significant under reporting or different reporting
from different states using different criteria, is there discussion
about standard methods that would be used in different states to get
away from the situation which we have right now where the state
epidemiologists basically makes a seat-of-the-pants decision about the
level of influenza activity?

DR. FUKUDA: Well, Arnold, I think that if we do move to a situation
where laboratory confirmed influenza becomes a reportable disease
throughout the country, then the first issue is going to be laboratory
confirmed what, and it will probably focus on something like
hospitalizations because it\'s relatively restricted in numbers.

So we haven\'t entered into the discussions with the states about the
nitty-gritty of how this might be done because I think first there has
to be discussion about whether the other states think that this is how
they want to go.

But I suspect that if we get past those discussions, it will focus on
how do we start off relatively narrow and then do we expand out later
on?

CHAIRPERSON OVERTURF: Dr. Farley.

DR. FARLEY: Well, this is in many ways a follow-up to that question in
that the issue of testing, the type of testing, rapid testing versus
virologic testing, and its sensitivity/specificity issues, but also the
word is that some insurance companies cover the test and some don\'t,
and I guess if they\'re hospitalized things may be much different in
terms of coverage for testing, but where do the policy makers fit in
that equation of it we\'re going to a laboratory diagnosed surveillance
system that\'s reportable, will there be recommendations on whom to test
and whether it should be covered?

DR. FUKUDA: Yes, Monica, that\'s a big issue. If you look at everyone
who is tested for influenza right now, it\'s clear that a majority of
them are now being tested using the rapid detection kits, and we all
know that the sensitivity and the specificity of those kits is not at a
level where any individual test result, particularly in the off season
or when you have odd results is, you know, so solid, but you know, it\'s
also the increased usage of that kind of testing which has made the
whole discussion about moving to laboratory confirmed influenza
possible.

You know, without that kind of testing we wouldn\'t be having this
discussion with the states, and I think that some of the things that
we\'ll have to come to grips with and which I believe will probably
change over the next several years is that there are undoubtedly going
to be regional differences, individual physician differences in terms of
how often and how they\'re willing to use those tests, and that will
change.

And so I think that all of those will be somewhat problematic.
Nonetheless, I think that they\'re all addressable issues, and I think
that when we look at the data coming in as a large lump of data, it will
be pretty analyzable. I mean, that\'s what I suspect.

CHAIRPERSON OVERTURF: Other questions?

(No response.)

CHAIRPERSON OVERTURF: If not, Dr. Cox, are you ready to present now?

Okay. Dr. Cox will present.

DR. COX: Okay. Good morning, everyone. I\'m very pleased to be here
presenting the virologic data once again and shifting from a domestic
perspective to a global perspective.

I thought I\'d spend just a few minutes at the beginning of my
presentation talking about the H5N1 situation in Asia, and then we will
be able to focus exclusively on the task at hand, which is vaccine
strain selection for this coming year.

This slide actually shows the countries that have reported H5N1
outbreaks in poultry since December 2003. The countries shown in light
purple are the two countries, Japan and South Korea, that have their
outbreaks under control and the H5N1 virus as far as we know has been
eliminated from their borders.

The countries shown in purple have outbreaks in poultry, but no human
cases have been report, and the three countries shown in red have
outbreaks in birds and at least one case in humans. The countries in
cases with humans are Cambodia, which has reported a case recently;
Thailand, which has reported 17 cases of which 12 have resulted in
death; Vietnam, which has had a lot of activity recently and a lot of
publicity recently. There are 37 H5N1 laboratory confirmed cases with 29
deaths, for a total of officially reported cases of 55 and 42 deaths.

Now, of course, the case fatality rates are very high. We know that case
ascertainment is not perfect. It\'s far from perfect, in fact, and so
this probably represents an over estimate of the case fatality rate.
Nevertheless, it\'s a very sobering picture.

We\'ve noted that there\'s a high case fatality rate regardless of age,
although the illnesses, the detected cases have tended to be in children
and young adults.

The clinical symptoms are similar to the earlier cases in 1997, and
lymphopenia is a prominent feature.

Diarrhea has been reported as being a prominent feature in some of the
recent cases.

There was a second wave of infections that began in August of 2004, sort
of tailed off a bit, and then increased again during late January and
February.

And then, of course, I\'m sure many of you have heard in the press and
perhaps have even read the paper in the [New England
Journal]{.underline} about the Thai family cluster, where because of
particular circumstances it was possible to document probable
human-to-human transmission from a child to her mother and to her aunt.

Now, we have been looking very carefully at the antigenic properties of
these viruses, and I probably showed you this slide before, but this
slide shows that the viruses have actually drafted antigenically quite
dramatically from 2003, where we had the Hong Kong/213/2003 virus, which
had been used in the \-- the wild-type virus had been used in Rob
Webster\'s lab to produce a vaccine reference strain, and we had hoped
that it would be appropriate to use for pilot lots for the situation
that was developing in Asia.

Unfortunately, you can see that the ferret antisera against the Hong
Kong/213 virus has a very nice homologous titer. However, that antiserum
covers the Vietnam/2004 and Thailand/2004 viruses very poorly.

Likewise, we were able to see distinct differences between the Hong
Kong/97 (H5N1) viruses here. We see the homologous antiserum titer, and
this antiserum covers the 2004 viruses very poorly.

These viruses themselves do induce a good antibody response in ferrets
that have been infected intranasally, but by using these sera we can
also see distinct differences between 2003 and the 1997 H5 viruses.

So it became very clear that new vaccine candidates needed to be
developed for the ongoing situation. Candidates have been developed and
perhaps Pamela or someone else from NIH will give an update on the
current pilot production situation for candidates that have been
developed with these two particular strains if there are questions.

I\'d just like to give a very brief summary of the highlights of points
I\'d like to get across to the committee. Obviously avian influenza
viruses including all of these subtypes, but particularly the H5N1
viruses, can pose a major risk to global public health. Early detection
of human to human transmission of novel influenza viruses is essential.
It\'s difficult in Asia, but surveillance has been ramped up, and if
there are questions about what the U.S. has done to help improve
surveillance in Asia, I would be happy to field those questions.

The 2003 through 2005 Asian viruses are heterogeneous both in their
antigenic properties and in their resistance to influenza antivirals.
They are also heterogeneous with respect to pathogenicity, and the
current strains are more lethal in mammals by the current measurements
we have than the 1997 strains, and I\'m talking about animal models
here.

There is ongoing vaccine development, ongoing antiviral stockpiling, and
pandemic preparedness activities at many levels within our own country,
within other countries, and within WHO.

Surveillance in animals, including birds, swine, and other susceptible
hosts, such as felines is critical, and a research agenda needs to focus
on enhancing our understanding of the genesis of pandemic influenza
viruses.

We have a unique opportunity to view how new pandemic strains may or may
not develop, and there is now a very broad global recognition of a need
for better communication between human and veterinary health
authorities, and we are all working very diligently on improving
communications.

So now I will be shifting gears and talking about the current influenza
season, which is as Keiji has just shown you increasing and really
getting going.

I\'d like to provide a bit of an overview by way of introduction to the
global situation. Now, we have compiled information from all of the four
WHO collaborating centers, which are located in London, Atlanta,
Melbourne, and Tokyo.

And we have also included information from the European influenza
surveillance scheme, which is a very comprehensive influenza
surveillance system in Europe, and have also included the very good data
from our Canadian counterparts who report on a weekly basis their
analysis of influenza viruses that have been isolated in Canada.

Generally speaking, between October 2004 and January of 2005 through the
current time, influenza activity has been reported in Africa, the
Americas, Asia, Europe, and Oceania. In general, influenza activity has
been relatively low compared to the same period last year globally as
well as nationally.

The influenza season began in October in North America where viruses
were first detected, and it has increased quite gradually in countries
in the Northern Hemisphere, including countries in Europe and Asia.

As you can see here, Influenza H3N2 viruses have predominated worldwide
and were responsible for the majority of outbreaks. Influenza B viruses
from both the Yamagata and Victoria lineages have continued to circulate
globally and have been responsible for a few outbreaks.

Influenza A(H1N1) viruses have been detected less frequently and have
been reported to be responsible for only one outbreak so far.

I would like to note that of the Influenza B viruses, those on the
Yamagata lineage, which is represented in our current vaccine, have
predominated. If you add up the 303 and the 74 and look at the
proportion of B Victoria viruses on a global basis, it\'s about 20
percent in the United States. You can see clearly here it\'s also
roughly 20 percent, in the same ballpark at least.

We have relatively few viruses from Central-South America because they
haven\'t had much Influenza B activity, and you can see that in Africa
and Oceania B Yamagata lineage viruses really did heavily predominate.

So now we\'ll move on to Influenza A(H1N1) viruses. Now, I would
encourage anyone who really wants to see these numbers to move forward
because I know it\'s very difficult to see the HI tables on the screen.
You do have copies, but they\'re not color copies. So it\'s sometimes a
bit harder to see.

I mentioned that we had relatively few H1 isolates, but we do have some
relatively recent strains, some December strains from Florida
represented here as test antigens.

We also have quite a number of Asian isolates. There was a fairly large
outbreak of H1N1 in Thailand. We received quite a few of the viruses.
They were isolated mainly in September and October, and we also have
some viruses from Hong Kong down here at the bottom.

We do, of course, distill the information that we receive and try to
present representative data to you. We couldn\'t possibly present all of
the HI tables to you.

I gave you a bit of an orientation, well, when we looked at the H5N1
antigenic table, but I\'ll remind you that what we\'re looking for is a
fourfold or greater difference between the homologous titer with the
vaccine virus, in this case a New Caledonia/20/99, which is in our
current vaccine. We have a homologous titer of 640 here with the New
Caledonia antiserum, and we\'re looking for differences, fourfold or
greater differences with the current viruses.

Now, you can see very clearly from our own CDC data \-- and this was
confirmed by data from the other four collaborating centers \-- that the
New Caledonia antiserum covers the current viruses very well.

this is reflected in a frequency table. We have only in our
collaborating center had a total of 14 viruses, H1N1 viruses. They were
all H1N1. We detected no H1N2 viruses at CDC, and 100 percent of them
were New Caledonia-like.

And if we look back at the previous period from April to September when
influenza viruses were circulating in the Southern Hemisphere, we picked
up only one virus that was low to the New Caledonia antiserum.

Now, I\'m going to go on and remind you that we sequence the
hemagglutinin genes of geographically and antigenically representative
strains. So we tended to sequence the majority of H1N1 viruses that came
into our laboratory simply because we had so few and we were trying to
track exactly what was happening.

Our New Caledonia vaccine strain is located down here at the bottom of
this evolutionary tree for the hemagglutinin genes, and it may be just a
little bit difficult to see, but we\'ve color coded the dates of
isolation because we were very interested sine we have two distinct
clades or sublineages of (H1) HA genes. We wanted to see which of these
two clades had the most recent viruses, and it\'s this clade at the
bottom which has the most recent viruses.

Now, Roland mentioned that we had focused much more of our efforts on
obtaining egg isolates, and we have shown in all of our evolutionary
trees the viruses for which we have egg isolates. So you can see for
H1N1s where really there hasn\'t been very much change. We were prepared
in terms of having egg isolates ready should there be a surprise.

Now we\'re looking at the neuraminidase genes. As I mentioned, we have
only detected H1N1 viruses over the past few months, no H1N2s, and you
have a similar sort of pattern generally speaking with two different
sublineages or subclades, but there haven\'t been that many amino acid
changes associated with the ongoing evolution of the neuraminidase
genes.

I forgot to mention for this previous slide that, of course, we are
unable to distinguish antigenically the viruses in this sublineage
versus this sublineage. So there are no antigenically detectable
differences with post infection antisera between these two groups.

I\'m going to skip the serologic responses. There are a number of tables
in the CDC package. We did a lot of post vaccination human serology this
year. We actually had two panels of serum from children, one panel from
children zero to 23 months of age and another panel from children five
to eight years of age.

And so if you have specific questions about those tables of serologic
results, I\'ll be happy to answer them, but Roland will be doing a
summary talk in which he compiles all of the serologic data accumulated
by all of the collaborators to the WHO Global Influenza Program.

So our H1N1 summary is as follows. Relatively few H1 viruses have been
detected worldwide. The majority of the H1 viruses were closely related
antigenically to the New Caledonia vaccine strain, and no significant
variance of H1N1 viruses were detected during recent months.

No H1N2 viruses were detected, and that is true with respect both to the
U.S. strains and the strains analyzed globally.

N1 neuraminidase genes of recent H1 viruses were similar to those of
viruses isolated prior to October 2002. So you can see the H1 situation
is fairly straightforward.

Okay. We\'ll move on to H3N2. H3N2 viruses always cause us a lot of
headaches. They are responsible for more severe influenza seasons,
generally speaking, including a higher numbers of hospitalizations and
deaths.

I\'ll walk you through this table which includes our reference panel up
here. Here\'s our Wyoming vaccine strain right here with a homologous
titer of 640.

Here is the Wellington virus here, Wellington/1/2004, which was
recommended as a vaccine strain for the Southern Hemisphere. It has a
homologous titer of 320, and then we have some relatively new variants
which will be mentioned later on. We have the North Dakota/1/2004 virus.

And I would like you to note that the Wellington, North Dakota,
California, and Singapore/37 viruses are all egg isolates, and
therefore, I\'m concentrating on data generated with viruses and
antisera to these viruses that are potential vaccine strains.

Now, at the beginning of this season we were seeing that the majority of
the viruses were similar to the Kentucky and New York/57 strains, and
they were really quite well inhibited by antiserum to Wyoming. If you
see a twofold difference, it\'s not considered significant because
that\'s within the error of the test, but as the season progressed, we
began seeing more viruses with titers of 80 and even a few viruses with
titers of 40 against to Wyoming serum.

Once we got the California egg isolate and product a post infection
ferret antiserum to it, what we found in this test and which has been
borne out in our laboratory in other tests as well as in the other
collaborating centers is that the antiserum to the California egg
isolate covers recent strains better. It has a lower homologous titer,
and there are not reductions or there are no more than twofold
reductions compared to the homologous.

The same is true to a great extent with the North Dakota strain,
although the California strain did seem to cover viruses slightly
better, and we found out that the North Dakota egg isolate did not grow
particularly well.

So I\'ll show only one more table, and I\'d like to mention that this
particular hemagglutinin inhibition test was done using getting pig red
blood cells. The H3 viruses, the current ones grow relatively poorly,
and sometimes it\'s necessary to use guinea pig red blood cells to
detect high enough titers to do HI tests, and we do all of our screening
for H3N2s using guinea pig red blood cells.

And if we have a virus with a low titer, it\'s too low to test with the
turkey red blood cells, which were the red blood cells used for the
previous HI test. Then we use guinea pig red blood cells to do the HI
test.

Now, turkey cells are the standard cells used in all of the WHO
collaborating centers.

What we have found, and it has been very, very interesting, indeed, that
with guinea pig red blood cells, we often see that there\'s greater
differentiation between strains, and so if you look at the Wellington
homologous titer, it\'s 640 here, and it\'s dropped even lower against a
couple of current strains, Victoria/500 from the Southern Hemisphere and
the California/7/2004 from our recent season.

It doesn\'t matter whether you use guinea pig red blood cells or turkey
red blood cells. The antiserum to the California strain covers recent
isolates and even those that are difficult to quantitate using turkey
red blood cells very well. In contrast, you see a homologous titer of
640, and a number of titers of 80 here with recent strains. And that\'s
true no matter which continent you\'re looking at.

So in summary, I\'d like to try to explain this frequency table which is
a little bit more complex than the frequency tables that we normally
have simply because we didn\'t have the ferret antiserum to the
California egg isolate until January 5th.

Since that time, since the time we\'ve been using that, we\'ve been able
to characterize 30 percent of the total 261 H3N2 strains that we\'ve
looked at from global sources as California-like, but we also had prior
to the introduction of the California ferret antiserum been
characterizing a number of strains that we haven\'t had a chance to go
back and test retrospectively that were low to the Fujian.

Our guess is that until you do the studies you don\'t know for sure. Our
guess is that these will look California-like when we eventually are
able to test them retrospectively.

Last season, which isn\'t shown here, we had a bumper crop of H3N2
viruses, and we had well over 1,000 strains that were analyzed during
the period preceding this, which was our influenza season last year, and
the majority of those viruses were Fujian-like, as you will recall.

Okay. Now, you see the evolutionary tree for the H3 hemagglutinin genes.
Our vaccine strain, Wyoming/3/2003, is right down here shown in red.
Once again, the blue strains are our egg isolates. The Wellington
strain, which was recommended for use in the Southern Hemisphere is
here. You can see that we\'ve moved up the tree from Wyoming for the
Southern Hemisphere vaccine recommendation.

The one change that does not appear, the one amino acid change that does
not appear in the Wellington strain that appears in the majority of the
currently circulating strains is this change at amino acid 145 that
you\'ll note. It\'s a K to N change, and it has in the past proved to be
significant in terms of antigenic variation.

Our California reference virus is shown right up here. It is designated
as a low reactor. Some of the other egg isolates that have been sent out
to other collaborating centers and to vaccine manufacturers include New
York/55/2004 shown here and New York/40/2004 and Wisconsin/19/2004, and
these are all quite representative of the currently circulating strains.

The Singapore/37 strain, which was shown on the previous HI table, is
right here.

When we look at the pattern of evolution for the N2 neuraminidase genes,
we see that the neuraminidase genes are clustering in a fairly tight
group. Of course, for those of you who aren\'t so accustomed to looking
at the evolutionary trees, it\'s really not \-- the distance between
viruses is measured like this, not like this. These are spaced out.

So the vertical distance is not the important distance, and so these are
clustering fairly tightly.

Here is the Wellington strain. Here is the North Dakota strain, and here
is the California/7/2004 strain. New York 55 is right here, and of
course, its neuraminidase is right on the backbone and very close to the
consensus sequence for neuraminidase genes.

So in summary, Influenza H3N2 viruses have circulated in many countries,
in the Americas, Asia, Europe and Oceania. In HI tests, H3N2 viruses
were antigenically heterogeneous. Viruses isolated early in the season
were often more closely related or most closely related to Fujian/411
and Wyoming/303 viruses, our two reference strains.

But an increasing proportion of recent isolates were antigenically
distinguishable from these vaccine reference strains, and as I have
shown you, were most closely related to the California/704 reference
virus, both antigenically and genetically.

And sequence analysis of N2 neuraminidase genes of recent H3N2 viruses
indicates that neuraminidases of recent viruses are genetically
distinguishable from the Wyoming virus with these changes, but were very
similar to the neuraminidases of Wellington and California.

Okay. Well, now I\'ll move on to Influenza B viruses. As Roland
mentioned, there are two distinct genetic and antigenic groups of
influenza viruses circulating globally. As I mentioned before, the
Yamagata lineage viruses which are represented here in yellow have
predominated both in the U.S. and worldwide. The Victoria lineage
viruses are shown here represented in green. They are still circulating.
The viruses that you see here are from Asia, but we had a number of
viruses on the Victoria lineage from Florida as well \-- from Hawaii as
well.

We can see here from this table that the Shanghai/361 reference vaccine
virus antiserum covers the current Yamagata lineage viruses quite well.
That\'s true also in this test for the Jilin/20, a little bit less true
for the Jiangsu, but there\'s the very high homologous titer here, and
you\'ll note that there\'s a recent virus from Florida. We also did have
some B activity in Florida earlier, and we had an egg isolate, which we
were able to put into ferrets, and that particular egg isolate covers
the current strains very well.

With the B Victoria lineage viruses, you\'ll remember that the previous
vaccine strain was Hong Kong/330-like. Hong Kong/330 was used by some
manufacturers. Hong Kong/1434 was used by others, and we\'re seeing that
there\'s drift away from the previous vaccine strain. We\'ve worked
very, very hard to get a vaccine strain that would be suitable on the
Victoria lineage, and what we found rather disappointingly is that as
soon as we put the B Victoria lineage viruses into eggs, as soon as we
isolate them in eggs, they lose the glycosylation site, and they tend to
produce ferret antisera which don\'t uniformly cover the currently
circulating B Victoria lineage viruses.

So we put a lot of effort into this, and have been relatively
disappointed with the results. Nevertheless we\'re continuing to pursue
this.

This is an updated summary of the Influenza B isolates characterized by
CDC. Remember the previous table I showed as a compilation from all the
WHO collaborating centers. As I mentioned, we\'re seeing quite a number
of the B Hong Kong low, the viruses that are fourfold or greater reduced
in titer compared to the homologous Hong Kong virus.

But the Victoria lineage viruses are a minority compared to the Yamagata
lineage Shanghai-like strain, and the majority of the Shanghai lineage
viruses that have been isolated recently are well covered by antiserum
to the current vaccine strain.

Okay. I\'ll be showing evolutionary trees separately for the Yamagata
lineage and the Victoria lineage. This is an advantage because you can
actually see the strains better on the tree, but it\'s a disadvantage
because you can\'t see the rather distant relationship between the
Victoria and the Yamagata lineage viruses because they\'re not both on
the same tree.

But I think for the purposes of our discussion today, it\'s best to do
the presentation this way.

Here we have our Shanghai/361 reference virus. You can see that there
are a number of amino acid changes that have occurred, but that we
don\'t see a consistency in terms of viruses which are low reactors.

Again, shown in blue we have egg isolates designated. We have a large
number of egg isolates, and I think I\'ll move on to the B Victoria
lineage, HA genes.

Our previous recommended vaccine reference strain was Hong
Kong/330/2001. You can see that the viruses have moved on. Here are some
of the Hawaii strains, the egg isolates that have lost the glycosylation
site and haven\'t produced good antiserum in terms of covering the
currently circulating strains.

Again, I\'d like to emphasize that the minority of viruses are on that
lineage.

Now, if we look at the evolutionary relationships among the Influenza B
neuraminidase genes, you can see that there are two distinct subgroups
here, but the majority of viruses have neuraminidases in this group
here, which indicate that they are reassortants between the two
lineages.

So anyway, the neuraminidase genes are being tracked, and we can see
that there are some differences, but we have representative strains from
both lineages.

So in summary, Influenza B viruses continue to circulate in many
countries. The majority of analyzed Influenza B viruses belong to the
Yamagata lineage and are closely related antigenically to the B
Shanghai/361 reference vaccine strain.

Most B Victoria/287 lineage viruses that we analyzed were reassortants
bearing Hong Kong-like HAs and the Szechwan or Yamagata lineage
neuraminidase genes. B Victoria lineage viruses were antigenically
distinguishable from the previous vaccine strain from this lineage that
was used a few years ago.

And then I just put up the summary table one more time in case there are
any questions about the circulation of the different groups of influenza
viruses that have caused problems around the world.

Okay. I think I\'ll stop there and entertain questions.

CHAIRPERSON OVERTURF: Are there questions? Dr. Monto.

DR. MONTO: Given the diversity between the Yamagata and Victoria lineage
occurring in Asia at the WHO meeting last week was there any concern
expressed in making a global recommendation for continuing with the
Yamagata lineage?

DR. COX: We discussed that at length, and I think that what you can see
here is that at least for the Asian viruses that we\'ve had, there is
approximately a 50-50 split. However, Japan is just experiencing the
beginning of its influenza season, and it\'s predominantly B, and all of
the viruses that they had obtained so far were B Yamagata lineage
viruses.

So you know, our most current information was that B Yamagata was
continuing to predominate in Asia even though the numbers we have are
relatively small here for Asia and indicated about a 50-50 split.

DR. MONTO: Do we know anything from China? Because they\'ve diverged
from the recommendation, as we all know, in the past.

DR. COX: China has, as you probably know from press reports, had to
close down their Institute of Virology due to a SARS incident, and that
led to delay in analyzing and shipping influenza strains from the
National Influenza Center in the Institute of Virology in Beijing to the
WHO collaborating centers.

So we have not yet received a recent shipment with viruses from December
and January.

CHAIRPERSON OVERTURF: Dr. Markovitz.

DR. MARKOVITZ: Yes, I wanted to ask a couple of questions. One, this is
just for my information. With the two different strains of Influenza B,
in the past when there has been serious illness in kids with Influenza B
and deaths, is one strain more likely than the other, you know, one
lineage, I should say, Victoria versus Yamagata more likely to cause
serious illness?

And then the second question I had is if you could just tell us a little
bit more about efforts to develop vaccines for avian flu. I know it\'s a
long story, but if you could summarize a little bit about what different
institutions are doing about that.

DR. COX: Okay. With respect to the first question about whether more
serious illnesses are caused by Victoria or B Yamagata lineage viruses,
we really don\'t have enough data to say definitively, but based on my
knowledge of the characterization of viruses from children who have died
or had serious illnesses, I would say that both lineages are capable of
causing serious illness in children.

I would like to offer the opportunity to Pamela McInnes to really talk
more about the vaccine development issues. I think I mentioned that
vaccine reference viruses had been produced in three different
laboratories around the world, one in the U.K. and two in the U.S., and
a couple of those reference viruses have been given to manufacturers for
production of pilot lots and so on, and Pamela has much more recent
information than I have. So perhaps she could make a few comments.

CHAIRPERSON OVERTURF: Dr. McInnes, do you want to do that?

DR. McINNES: Do you want me to do that now or you want to finish any
questions for Nancy? Whatever your preference.

CHAIRPERSON OVERTURF: Are there any further questions for Dr. Cox? Yes,
Ben.

DR. SCHWARTZ: I just have a question about interpreting some of the HI
data, and specifically with respect to the Type B. You\'ve emphasized in
your presentation that what one should look for is a fourfold difference
between the various strains with a particular antisera, but you don\'t
really emphasize at all the absolute height of the titers.

If you look at the B data and you look at the Shanghai 361 and compare
it with the Florida/7, and both of them seem to be very good across the
whole Yamagata lineage, but the Florida/7 titers are higher compared
with the Shanghai, and I was wondering if that has any meaning
whatsoever and whether that has any predictive value in terms of which
may be a better vaccine strain.

DR. COX: We haven\'t noted that titer \-- there is some ferret to ferret
variation in terms of the height of titer, and sometimes when we get a
very low titer with the particular ferret, we\'ll inoculate the same
strain and we\'ll get a higher homologous titer. So there is
ferret-to-ferret variation.

We have not noted a correspondence of the homologous titers that we
obtain with ferret serum, and a corresponding either enhancement or
diminution of titers in humans using those strains for vaccines, but
it\'s a good question, and we have \-- there are some factors about the
hemagglutinin which we don\'t understand which makes some strains
inherently more immunogenic than others.

We have been discussing and thinking about ways to get a better handle
on what those factors may be and how to predict which strains might be
the best vaccine strains. So far we don\'t have a handle on that, and
we\'ve often been very, very limited in terms of the number of egg
isolates that we had available. I think we\'ve put after we faced the
Fujian situation where we didn\'t have an egg isolate. We\'ve put an
enormous amount of effort and had partnership with industry in this
effort to obtain more egg isolates. So we really may have more options
in the future, and it may be more important to really have a handle on
predictors for immunogenicity in humans.

CHAIRPERSON OVERTURF: Dr. Eickhoff.

DR. EICKHOFF: Nancy, a question about the H3N2 data. If I\'m reading the
dendrograms correctly, and I may be stumbling on them, is the drift
represented by the recent A/California-like isolates in the same
direction as that started by the A/Wellington strain, or does it go off
in a wholly different direction?

DR. COX: You are correct. The A/California virus has simply moved on
from the Wellington strain. So it\'s just an advance. It\'s just
Wellington progeny with a few more changes.

DR. EICKHOFF: And I also get the impression that the shift, the degree
of drift, rather, is much less dramatic in this instance, in the
A/California strains than the drift of the A/Fujian strain was from its
predecessor. Is that correct?

DR. COX: That is correct.

DR. EICKHOFF: Up to a point.

DR. COX: Up to a point. I mean, you really have to look at the gestalt,
and I think that when Roland begins discussing the human post vaccine
serology, you\'ll see why I was greatly surprised by the human post
vaccine serology.

It seemed to differentiate current strains even better than our ferret
sera did, and that is the first time in my memory that that has been the
case. So I was, shall we say, unpleasantly surprised by results for the
H3 post vaccine human serologic testing that was done, and we\'ll get
onto that later.

DR. EICKHOFF: Can I ask a further question then?

DR. COX: Certainly.

DR. EICKHOFF: And maybe this is a question that Keiji can answer also or
can\'t answer also, as the case may be. Do you have any sense,
considering that the A/California strains now at least in some parts of
the country seem to predominate? Is this strain behaving any more
aggressively epidemiologically and can we, therefore, anticipate that
our season this year may go on further than it already has? Is that a
fair inference to draw or not?

DR. COX: I think it is very difficult to say. I think we could have in
areas of the country that were not so heavily affected by influenza last
year, we could have continuing H3 and B activity. It\'s really difficult
to predict how the strains are going to behave in the population. I
think we just have to wait and see. We can\'t predict.

CHAIRPERSON OVERTURF: Yes.

DR. KARRON: Two questions actually about the H5 presentation. One was
that you mentioned heterogeneity and antiviral susceptibility, and I
assume that means a susceptibility to amantadine and rimantadine, and
these are all susceptible to the neuraminidase inhibitors, or is that
not the case?

DR. COX: You\'re right. I didn\'t go into a lot of detail. Not all of
the H5N1 viruses that we received last year were resistant to the
adamantanes, but all of those that were isolated from humans were
resistant to adamantanes. So there were some in birds that were
sensitive to adamantanes. We have tested all of the H5N1 viruses that
we\'ve received, and in laboratory tests, the viruses are sensitive to
the neuraminidase inhibitors or we use oseltamavir. We don\'t use
zanamivir.

And animal experiments done by Rob Webster and others have indicated
that [in vivo]{.underline} in animal models the viruses are also
sensitive.

DR. KARRON: And then my second question was actually about I noticed
that you had said with the ferrets when you \-- obviously there\'s
tremendous drift of the H5s, but they all, in fact, make antibodies to
all of the viruses. I was wondering if you had any data from the
survivors of H5 human infections about the quality of their HI responses
to these H5 viruses.

DR. COX: A very good question. It has been extremely difficult getting
serum from survivors. Oftentimes individuals are reluctant to give blood
for a variety of reasons, and then it\'s often difficult to get the
serum sent to us. We do have some serum in very limited quantities and
have requested additional amounts and we\'re looking at the ability of
serum from survivors to inhibit in neutralization tests a variety of
viruses.

So we should have a better handle on that, and of course, one of the
ideas for the pilot lot testing in humans is to look at the ability of
the antibody induced by the pilot lot vaccines to inhibit a variety of
the antigenic variance of H5.

CHAIRPERSON OVERTURF: Dr. Couch.

DR. COUCH: I want to pursue Arnold\'s comment a little bit, and I guess
I really have a comment rather than a question for you, Nancy, and I was
not here last year, but I\'m sort of back in the same mode I was two
years ago with the Influenza B strains.

And you look at these epidemiologically. Well, I think mostly people
know they were dominant in Asia for a number of years before they began
to show up in the rest of the world, and then they\'ve been jockeying
with each other for dominance would be the way I would describe what\'s
gone on in the last few years.

And our approach to handling that dominance is to guess which one is
going to be dominant in a coming year, and it has been amazingly
successful that the Victoria derivative was guessed the right year and
then went back to Shanghai. But I think it emphasized that we\'re
guessing is the point I wanted to make.

And we\'ve looked at the serologic data in the past that looks very much
like the same data we have this year, and that is that adults and
elderly individuals have a reasonable degree of cross-reactivity to
vaccine responses to either one. You get the Yamagata derivative and you
have a reasonable cross-reactivity to the Victoria and vice versa.

It\'s children where the differences are really distinctive. If they got
the Victoria vaccine, they have very little immune response that you
would say would be protective against the Yamagata derivative and vice
versa, and if you wanted to look at some of that data, what\'s going to
happen with some of our guessing, some of you remember an old term that
Paul Gleason brought in a few years ago of herald wave. We\'re looking
at a herald wave, you see, of the Victoria derivative, and here we\'re
guessing that that\'s not going to be true. It\'s going to be the
Shanghai.

I think I asked Walter the last time I did this if he could remember,
but the two separate Bs have been used in the vaccine in the past. I
meant to go back and check when that was done, and you see, I tried this
a couple of years ago and it didn\'t fly. I\'m going to try it again.

You see, based on what we know about these immunologically, if you took
that 15 micrograms, and let\'s assume that at least for the time being
is fairly rigid, and you split it between those two and you look at the
responses in the elderly, adults and the elderly, that they would be
pretty good to either one if you\'ve split it, you know, based on what
we know about the cross-reactivity of the 15 micrograms of each.

That might not give you as much response as you\'d like in those
children, but it would insure that you\'ve got protection against both
of these strains, which will be present, we would say, and hopefully
when we only pick one we\'re guessing the dominance, but that would be
of less concern.

Now, I know that has not been pursued, and you need immunologic data to
go along with that kind of thing, but if we continue to see these two
jockeying, I think we need to think about ways to approach that other
than immunologically with vaccines rather than just guessing which one
is going to be dominant.

So I didn\'t have a question. I meant it as a comment, unless you want
to add to that.

DR. COX: I think that you have hit the nail on the head. As long as we
have these two quite distinct lineages of Influenza B circulating
worldwide, we are making an educated forecast for which virus is likely
to predominate, and we could be wrong.

I think that in an ideal world, we would have a tetravalent vaccine, but
we\'re not in an ideal world and we know that that would reduce the
number of doses of vaccine in an environment where we already are
concerned about vaccine supply. We know that young children respond
relatively poorly to the influence of the B component of the vaccine. We
have to think about the manufacturing issues involved and the
standardization issues, the whole complex of issues that these changes
bring up.

And I think we are in a dilemma, and we should talk about these things,
but we should also recognize that there are many practical issues that
would go along with the departure from the way we\'ve been doing this.

Roland may wish to add something or others may wish to.

CHAIRPERSON OVERTURF: I\'m going to give Dr. Couch the last say for this
segment and then we\'ll take a break for 15 minutes, come back, and we
can discuss that.

DR. COUCH: Manufacturers certainly would not like to hear adding a
different antigen, but part of my point, Nancy, was that we have had a
tetravalent vaccine. So we have the precedent of it being available and
it having been circulated, and that tetravalent was with the B strains.

CHAIRPERSON OVERTURF: So I would propose we take a 15 minute break and
be back at 10:45.

Thank you.

(Whereupon, the foregoing matter went off the record at 10:31 a.m. and
went back on the record at 10:55 a.m.)

CHAIRPERSON OVERTURF: Dr. LaRussa.

One more comment about the B issue, and then we\'ll turn to Dr. McInnes.

DR. LaRUSSA: So a number of us pediatricians were talking on the side
during the break, and before I make this comment, I want to emphasize
that I\'m not proposing we do this for this coming year, but just to
plant this seed for the future.

If, in fact, it could be shown that if you put the two B lineages in the
same vial and you could get good immunologic responses in children, one
way around doing this dance we do every year about which B lineage
we\'re going to pick is to make a separate pediatric vaccine, which
you\'ll already do. You\'d know that you\'d have a stable demand for it
every year. You\'d make your eight million doses. It would be there
because we do very well with immunizing kids, and you could get around
this whole issue because one of these years we\'re going to do the wrong
dance and pick the wrong strain.

So what I would propose is that we think about the kinds of serologic
studies you would need to do to show that you could put two B lineages
in the same vial and get a good response in kids, and then think about a
separate pediatric vaccine for the six to 24 age group.

CHAIRPERSON OVERTURF: Dr. McInnes.

DR. COUCH: It\'s testable.

CHAIRPERSON OVERTURF: Yes, you can stay there.

DR. McINNES: Thank you very much.

This is a summary update. A year ago at the vaccine strain selection
meeting, Dr. Lambert made a presentation on H5, and the initial
responses of different agencies within the Department of Health and
Human Services, and this is an update for you.

It is personally been one of the most gratifying experiences in
government because I think the flu machine within government has always
worked very, very well, but this has been really a marvelous experience
of people really working extremely well together, as well as with
manufacturers and other government contractors, working very hard.

Nobody should underestimate how seriously the department is taking the
threat of pandemic influenza. It is the subject of a great percentage of
our lives and of our time, and I will just summarize. I\'m not going to
provide lots of details.

The reference virus, you heard Dr. Cox talk about the reference virus
for the H5. The particular reference virus that is being used to provide
the pilot lots of vaccine that I will be talking about was produced
under a government contract, and it utilized reverse genetics technology
to make this reference virus, and it turned out to be a real test of the
select agent rule.

And so the dry run of, in fact, going through the process of generating
the data and the pathogenicity data on these genetically engineered
viruses did go through the select agent rules and, in fact, the data
were very compelling, and it resulted in the exemption from select agent
rule.

And we still though were subject to the U.S. Department of Agriculture
permitting process to move this virus. So the reason I am sharing these
pieces with you is that many of the pieces that will be in play during
pandemic response have, in fact, been tested in this past year and
hopefully will facilitate the path for future journeys.

Pilot lot contracts were awarded to the two licensed and inactivated
vaccine manufacturers in the United States, licensed in the United
States, and that was Aventis Pasteur, and I\'m not sure if I should be
calling it Sanofi now, but when I say \"Aventis,\" I hope I\'m calling
it the right name, and Chiron.

So the contracts were awarded around May of 2000, May through June 2004.
The reference viruses were produced, characterized, exempted from select
agent and moved to both manufacturers, and both manufacturers have been
underway with pilot lot production of an H5N1 inactivated vaccine
candidate.

The quantities of doses that have been procured for the pilot lot scale
is less than 10,000 doses from each of the manufacturers, and they\'re
in two different dose concentration formulations.

Aventis has completed its bulk manufacture, as well as its formulation
and filing and finish and testing, and the IND. We have filed the IND
for the clinical evaluation of this candidate.

Their clinical development plan has been designed and laid out and will
be implemented through the NIAID vaccine and treatment evaluation unit
contracts. We have proposed two different programs, one for the Aventis
candidate, one for the Chiron candidate because they\'ll be available at
different times, as well as we want to insure access to the appropriate
number of individuals in each of the target population groups.

The clinical trial scenario will begin with a trial for safety and
immunogenicity in healthy adults, and with those data in hand, we\'ll
move to evaluation in the elderly and in younger children.

Coupled with this for the pilot lot scale of production, the department
awarded a contract for the commercial scale production of an H5N1
vaccine and the intent of this was to test the commercial production
capacity and the ability to respond, as well as handling of these
candidates in the facilities. This is a much larger scale.

This has been completed. The vaccine bulk has been made. The
formulation, finishing and vialing will be dependent on the data that
come out of the clinical evaluation program of the investigational pilot
lots.

In addition, the department has awarded a contract to secure egg supply
year around to enhance our capacity to respond to produce pandemic
vaccines. Couple a deliverable under this egg securing contract is, in
fact, pilot lots of investigational candidate vaccines for pandemic
preparedness, and so over a period of years, several of those will be
made and will be evaluated, all of which is designed to build on our
knowledge of safety and immunogenicity, the human response to these
novel antigens.

That\'s really a summary of where we are on the response to H5.

CHAIRPERSON OVERTURF: Dr. Markovitz.

DR. MARKOVITZ: Yes, thanks.

I had a couple of questions. One is how did people get around the issue
that these tend to kill eggs, chicken eggs?

And then second of all, how are the vaccines that you\'re talking about
\-- are they going to be able to deal with this heterogeneity issue that
Nancy Cox was alluding to or is that going to mean that we\'re going to
have to be, you know, similar to what we do with the other strains, sort
of constantly revising them?

DR. McINNES: Sir, the issue around being able to get a meaningful yield
by growth in eggs is dealt with by engineering the virus, the wild type
virus so that, in fact, you\'re going from the tiger down to the
pussycat that can, in fact, be grown in egg, moved to the manufacturers
and dealt with under usual biocontainment levels. So that, in fact,
happened very successfully and yield was quite good.

We would anticipate that the early clinical studies will, in fact, be
generating sera in response to this particular reference virus candidate
that can be the subject of investigation in terms of what sort of
protection one might derive to strains that have some change in them or
some drift in them.

DR. MARKOVITZ: Can you tell me more about how it was mutated without
violating proprietary matters?

DR. McINNES: There is, in fact, a publication on this, which I\'d be
happy to share with you.

DR. MARKOVITZ: Yes, that would be good.

CHAIRPERSON OVERTURF: Dr. Eickhoff.

DR. EICKHOFF: Pamela, I know regarding the reverse genetics technique
great concerns have been expressed in the past about intellectual
property rights. Have those been resolved or is that being addressed?

DR. McINNES: It has been, I think, addressed extensively, and I think
there are paths to resolution for this. In the investigational framework
and experimental framework it\'s not an issue. The issue comes around
the commercial area. So, yes, this is the subject of a lot of
discussion, and I think there are solutions on the table to deal with
it.

CHAIRPERSON OVERTURF: Dr. Karron.

DR. KARRON: Are there differences in this Sanofi and the Chiron products
or are they essentially the same product?

DR. McINNES: Our goal was to go as close as possible to their currently
licensed methodology and formulations because we felt that that would
assist in a licensure process in an emergency situation. So you
wouldn\'t be dealing with trying to deliver huge amounts of vaccine
under IND.

So given that they produced them in a pilot facility, it\'s not
identical, but the hope was that the process would be as close as
possible and the formulation would be as close as possible to their
license formulation.

CHAIRPERSON OVERTURF: Were there any other questions or comments anybody
else wanted to make? Yes, Dr. Royal.

DR. ROYAL: Thank you.

One would expect that since this is a genetically engineered virus that
one could introduce a series of mutations and establish panels that one
could use to screen different strains. Is that sort of approach being
considered?

DR. McINNES: I don\'t quite understand the question.

DR. ROYAL: Well, since you said that this is a genetically engineered
virus, so one would expect that one could introduce mutations in the
hemagglutinin and other regions that could be used to generate reference
sera to anticipate, so to speak, strains that might arise instead of
waiting for various strains to appear on the horizon and sera to be
generated at that time.

Is that sort of approach being considered?

DR. McINNES: Along with this program, there is a large effort and CDC is
involved in it as well, which is a genomic spaced program to actually
characterize a whole series of viruses in the intent that you might
select particular cannons for the particular tributes to manufacture
vaccines.

The reverse genetics approach that I\'m talking about here is
specifically for generation of a relevant reference virus which is
taking the two relevant genes and inserting them into a backbone, a
worker virus backbone to facilitate the yield.

So, yeah, there is a lot of discussion about how one might generate
hypothetical candidates, whether you would utilize genomics
technologies, whether you would engineer technologies, whether you would
use wild-type, classical reassortant methodologies. It is a great deal
of discussion around what might be the appropriate candidates to try.

CHAIRPERSON OVERTURF: I think if there\'s no further questions we should
probably proceed on the agenda with the report from the Department of
Defense. Linda Canas.

MS. CANAS: Hello. Good afternoon or morning.

In 1942, the precursor organization to what is now the Armed Force
Epidemiological Board began a series of clinical studies using
concentrated inactivated Influenza A and B virus vaccine. In 1943, the
next year, there was an Influenza A outbreak. In the control group,
those people who had not been vaccinated, there was a three to six
percent increase in illness compared to those who had received this
trial vaccine.

The incidence of hospitalization was seven percent in unvaccinated
individuals and two percent in vaccinated individuals. As Dr.
Levandowski indicated, in 1945, the military licensed this vaccine, but
in 1947, it was quite ineffective against the circulating virus, and
thus we proved that the changing nature of the influenza virus compels
us to match the vaccine each year with the virus that we expect to
circulate.

In 1976, the Air Force began a surveillance program that was fondly
called Project Gargle, which was based with a series of sentinel sites
around the world where we had people stationed, and this was also public
health, wanting to know what\'s going on with our active duty members
and their families.

And in the process, we were in areas of the world where influenza was
emerging and causing disease so that we could share that information
with those organizations that would make the vaccine decision.

It is a mandatory vaccination for active duty military.

In the mid-\'90s, there was a presidential decision directive
establishing the global emerging infection system, GEIS, and their
mandate is to be a force against microbial emergence of pathogens and to
assure the biosecurity of the United States, and we had influenza
already, a program that was well established. So it only made sense to
expand this and make it a tri-service program.

So in 1997, it did become tri-service with Air Force, Army and Navy
participation, and the influenza part of this program. In the GEIS
Program there\'s two wings. I\'m going to be talking today about the
part that we do in San Antonio, etiology based, where we have sentinel
sites, and whatever they send into our lab in San Antonio we work up for
viral pathogens and report anything we find.

The other wing is Naval Health Research Center in San Diego, California,
and their sentinel sites are all of the recruit centers of each of the
services. They know the demographics. They have an established
population. They keep track of the febrile respiratory illness going on
in that population, and based on those demographic numbers, a certain
number of samples are collected and submitted weekly to this lab in San
Diego. So they can establish rates and know trends and tell when
something is getting out of hand.

Now, I always think it\'s important that the board understand how this
program work. We have a variety of layers of cooperation which make it
work, make it effective, and also give us opportunities that we can
respond to.

As I\'ve indicated, DOD GEIS oversees the program, and laboratorians and
epidemiologists from all of the services work together. Each year we do
have an annual meeting. Last year it was in late May in San Diego, and
27 individuals from each of the services, again, laboratorians and
epidemiologists, representatives of the central hub of GEIS.

We had people from Bangkok lab and the Cairo lab there, and also a
representative from CDC, and the purpose is to analyze the program from
the year before, much as we\'re doing here today, see what we expect to
come about, where our opportunities will be, how we can cooperate and
work together.

We choose the sentinel sites. The epidemiologists make sure that they
have all the information they need to run this program. They put
together a PowerPoint presentation that goes out to the Public Health
officers of each of these sites that they can use to develop educational
programs for their providers so that they understand what the program is
about, what it\'s trying to accomplish and what their role is.

We\'re very aware that we\'re adding to their daily work load. So to try
and involve them and make them benefit from it as much as possible helps
everyone.

During the season, a weekly report is put out on the Web. Anyone who has
access to a dot-mil Website can access this report, and this year,
actually very recently, it is now being posted on the Epi-X Website.

Over in the laboratory we make sure that the sites all have the
collection materials, they have all the information on what we expect
from them, how they should collect the samples and preserve them, and of
course, this is all best case scenario.

I need to emphasize that this is a full service virology lab working
within a full service reference lab. This is not a stand-alone program,
and that helps us because we have the infrastructure of a lab. We have
FedEx contracts set up for deliveries from around the world. It\'s very
easy and timely to collect two or three samples that meet a case
definition, get the in a FedEx box going out the next day, and arrive in
our laboratory in a timely manner.

We do operate this as a clinical program, and for the most part
everything is set up the day it arrives in our lab.

When we do get flu isolated, we use conventional methods where tissue
culture. We want the isolate. We\'re not interested in just knowing if
flu is there. We want the isolate. So we do use a variety of different
tissue cultures, and once we have those, then we become more modern and
have various molecular tests that we can go on to characterize as virus.

And, again, I said it was a clinical program. So when we have it
isolated, it goes back to the submitting site as a patient report. The
epidemiologist notify the Public Health officer what\'s going on at
their base for two reasons. First, we\'re giving back to them
information that they have provided for us, again, trying to involve
them in the program, but also so they can go into the Air Force
reportable event surveillance system, AFRESS. Culture confirmed
influenza is a reportable event, and this gives them all of the
information they need to go in and update those records.

Meanwhile back in the laboratory, after we\'ve identified as Flu A or B,
we do go in and subtype selected samples, and some of those go on to be
molecularly sequenced, and all of this information is then shared with
CDC, and then I get to come here and tell you about it.

This is our map for this year. The red stars indicate those sentinel
sites that are new this year. The blue ones have been around for a
while. The green sites are representative from Army in Thailand and the
Navy in Lima, Peru, where they\'ve had longstanding research labs, and
we\'ve been able to hook on with their protocols. They have IRBs, and do
surveillance in the local populations. This has proved to be very
helpful.

There\'s other labs, Kenya, Cairo, and Jakarta, that are also supported
by GEIS, but I do not have their information here today.

Reporting from the Air Force, we can say that 80 percent of the active
duty Air Force have been vaccinated as of the 14th of February. When the
vaccine shortage issue was first announced, the decision was made that
the priority status in the active duty military forces would be the same
as what had been suggested by CDC with the addition that people who were
deployed or deploying would also be in that priority group.

Eventually the recruits got FluMist, and they are all being vaccinated
now and FluMist is available for other active duty members. There is now
vaccine for all of the active duty members of either the injectable or
the FluMist.

We had a great many questions in the beginning about FluMist. It is an
inactivated virus. Were we going to pick this up in the laboratory?

So we had the sequence information for what the seed strain, the
A/Wyoming would look like. We did not look for this in every virus we
got, but in those that were referred to us as being particularly of
concern, we did look at those, and we have not found any that match
that.

This slide was submitted by NHRC in San Diego. As I said, they are
responsible for surveillance of the recruits. In the military there\'s a
particular problem with adenovirus in the recruit centers.

So NHRC is to adeno what our laboratory is to influenza, but this year
right around the time when they were just getting to vaccinating the
recruits, they have isolated a total of nine Influenza A viruses. One of
those was in a person who had been vaccinated for more than two weeks.
All of these have been subtyped as H3N2.

Now, every season has its own personality. I\'m preaching to the choir
here, and this graph kind of shows dramatically the last two seasons.

One of the things we do in this program that we\'re particularly trying
to get out that we are a resource for outbreak investigation, both
laboratory support and epidemiology support, and this was dramatically
exemplified this past summer when we received word from the lab in
Thailand that there was evidence of an influenza-like illness in Napal.

So two of the researchers stationed from Thailand that were working in
Katmandu traveled to southeastern Napal to a refugee camp. There were
actually three. When I made this slide I thought there were two camps,
but there were three camps, and between July 1st and July 3rd of this
past summer, they collected a total of 64 samples from hospitalized
patients.

They only went to the hospitals because of the political situation in
Napal. It was not considered safe to be traveling through the
countryside.

Within two weeks, we had those 64 samples in our lab in San Antonio and
had isolated 42 Influenza A viruses. All 42 were subtyped to be H3N2,
and I want to say here I don\'t have HI data, nice pretty charts like
Nancy Cox does, because we do not have animal studies. We don\'t have
ferrets. We use the WHO reagents, which basically just gives us a
breakdown of whether it\'s H1 or H3. So more extensive studies we send
off to CDC and also then we do some molecular work.

And that\'s what we did here. Twenty-seven samples of the 42 that were
positive were randomly selected to see if we could look at a molecular
basis for this outbreak, and we studied the hemagglutinin gene, and in
the majority of those 27 isolates, there was a four amino acid
substitution from the A/Fujian virus. All four of those were either
within or near an antibody binding site.

And here we have the signature, K 145N substitution that Dr. Cox
mentioned earlier as one of the samples that had drifted, and we do feel
that this shows there had been a significant drift away from the
A/Fujian viruses.

This is a graph of our season so far. Judging from the way samples are
coming in, we have not peaked. It is an A season predominantly. We had
received just under 1,300 samples as of the 9th of February.
Thirty-seven percent of those were positive for any respiratory virus.
Twenty-six percent were positive for Influenza A.

We have subtyped so far about 40 percent of those, and they have all
been H3N2, and a portion of those then have had nucleotide sequencing
and all of those have shown the four amino acid substitution that I
mentioned earlier.

Overall three percent of our viruses were B, and it was a mix. It was a
50-50 mix between B/Yamagata lineage and the B/Victoria, but there was a
very definite difference in the season. We got samples in from Hawaii
late summer, early fall, and they were split with the Hong Kong and the
Shanghai. That made us nervous about what we were going to face this
year.

All of our other Hong Kong isolates have come from Peru. One of those
was isolated in December, but all of the others had been from the past
summer, June, July and August. Everything we\'ve seen so far \-- now,
we\'re not talking bit numbers here, 38 total \-- have been Shanghai.

Just this past week we already started getting more B viruses. So we
haven\'t had a chance to subtype those yet, but so far everything late
in the season has been B/Shanghai.

If we looked at a breakdown of our basis, of our sentinel sites compared
to CDC regions, our season started much as everyone else\'s did with the
early results coming in from upstate New York. We\'re still getting some
samples from them, but it has moved much more down coast into New
Jersey. All of those As that we have subtyped have been H3N2, and I
think there\'s only one B that we\'ve had in this region prior to last
week. It was the B/Shanghai.

We\'ve started getting a lot from Alabama and Mississippi, and of
course, we just have specific bases. So it\'s very dependent on what
they send us from those, but we had a sudden surge of A from these bases
and a few Bs that came late.

This is probably the region that has the greatest number of sites, and
it does include Lackland Air Force Base with the Air Force recruits.
Now, the Air Force recruits are in the sentinel site for NHRC, but ours
is a clinical lab, and it\'s Air Force, and we\'re in the same city, and
we just handle their samples for clinical purposes, and because it is
recruits, we\'ve had a great deal of the adenovirus early in the season.

And, in fact, the big mystery right now is where is adeno at this point.
We\'re just not seeing it. We\'re getting a lot of samples, and we are
getting flu. Certainly there\'s a lot of flu in the area, both A and B
at this point.

There\'s only one site in Illinois, but they\'re very enthusiastic, and
I was concerned last week when we got three Bs from them because I hope
they\'re not getting another wave.

Colorado has the Air Force Academy. We\'ve always been very concerned
about those. They are not in barracks, as the recruits are, but it is a
training center, and for public health purposes, we\'re very interested
in detecting early outbreaks, and of course, knowing what they have
that\'s circulating there.

Overseas our early isolates came and still continue to come from
Lakenheath Air Force Base in the U.K. They seem to have more flu than
the surrounding area. So it\'s probably enthusiastic Public Health
officers making sure that they are doing a good job of surveillance.

Most of what they have is A. It has been very boring I\'m told to do
their work because they look exactly alike. They are H3N2, again, with
the four amino acid substitutions.

They are beginning to pick up a little more B, and the ones here, again,
are B/Shanghai.

Italy and Germany are just coming up. We\'ve got quite a few from there,
and I should mention in Germany, in addition to our Air Force base
there, there\'s the Army Landstuhl regional Army medical center. They
have a very good virology lab of their own.

And the same is true with Tripler in Hawaii, Tripler Army Medical
Center. They isolate the viruses there and then send us the positives.
So we\'re only working up the positives from them.

Of particular interest are those areas that are deployed, and there are
many challenges to getting samples out of the deployed areas. Influenza
surveillance is not their primary objective, and even if they\'re
concerned about it, they don\'t have supplies. They have limited storage
space. They don\'t have any dry ice, but they are concerned.

This represents a site in Iraq. I reported last year on a site from
Kyrgyzstan. We haven\'t gotten anything from this year, and we\'re told
they\'re not seeing any respiratory illness, which of course is the good
news.

We have 13 isolates here. Eight of the people had been vaccinated before
they arrived in country. The other five were vaccinated when they got in
country. We don\'t have any information on where they got the illness,
if it was from the surrounding community, other individuals. I don\'t
have any denominator status.

We don\'t understand that this is a particularly big problem, but these
are the only ones we have received, and it has worked well. This is
where you just do what you can do: collect the samples and ship them
however you can. They do come FedEx, but they don\'t have dry ice. So
we\'ve given them gel packs to use, and we\'re getting very good
isolation.

So we go for best case and settle for whatever we can get from some of
these more esoteric sites, and of course, the deployed areas we continue
to monitor for any of the respiratory pathogens.

I mentioned that in Hawaii we get from Tripler where they isolate their
own. We are just beginning to see samples from Asia. They are a primary
concern. They\'re very interested. We get a lot of queries about what\'s
going on. Many of them are very aware of their location in regards to
the H5.

But they just now started coming in. We did have reports a couple of
weeks ago of an outbreak in Hokkaido, but it was an exercise. It wasn\'t
an established base of any kind. They had no samples or no collection
supplies. We tried to get things to them, but of course, there are
limitations, and of course that illness had run its course by the time
we got them there.

There was even an effort made to contact the local hospital where the
patients had been sent to see if we could get isolates from them, but
there was a language problem. So hopefully we\'ll start seeing more from
them.

South America sends us a shipment of between 150 and 200 samples every
few months. In fact, we just got a box in this past week, and they\'re
very good. We get a very good percentage of isolation in what they send
us.

We have seen a lot of flu A, more flu B from them than we have seen from
some of the other sites, as I mentioned, most of it being the B/Victoria
lineage.

This slide represents kind of \-- there\'s always an interest. If it\'s
not flu, what is it? So we put together this slide, actually added on
the last year. So it\'s a fix full seasonal year review. It kind of
represents seven different seasons on this slide.

But our case definition is specific for influenza. We have been
stressing this year to make sure fever is in the case definition of the
samples that are selected. So we look for flu and we get flu.

We do have a variety of other things circulating at the same time, and
we have picked up several of the enteroviruses and parainfluenza
viruses.

I think there are two unique things to our population that I need to
point out, the first being adenovirus. Because of the recruits and what
we pick up with NHRC and ours with Lackland, we do have a higher
percentage than you would see in the normal civilian population, and
just the reverse is true for RSV.

RSV is a very big problem this time of year for babies and
immunocompromised, and they don\'t make up very much of our population.
And even if it is there, the RSV virus is very fragile and is better
detected on site with a rapid test. It doesn\'t survive travel very
well. So a program like ours, we get one or two a year at most.

But this is one of our big concerns, and it is certainly a goal of the
program because we\'re back to the same thing. If it\'s not flu, what is
it?

And SARS really brought this to the forefront. When we really needed to
know a sample was coming, and we didn\'t get any samples from SARS, it
was just the intellectual discussion in the labs that were getting them,
it\'s difficult to actually identify. So if you\'re in a SARS endemic
area and you have a symptomatic patient and you get a negative, how do
you know that it\'s not SARS? You\'d much rather know what you do have.

We\'re working very hard to get tests. There are tests, but they\'re not
easy and they\'re not cheap to do in the laboratory for things like
chlamydia pneumoniae, mycoplasma, Legionella, pertussis, and of course
SARS and the other coronaviruses and things yet to be determined.

We do like to think of ourselves as being in position to handle these
kinds of outbreaks. It\'s a challenge because most of our work certainly
with flu, we do large numbers and we emphasize safety all the time, and
the laboratory technicians are very aware of safety issues, but I will
tell you last February we got a sample in from our lab in Thailand, and
the report sheet said, \"From soldier sick after culling chickens in
avian-endemic area,\" and that got everybody\'s attention.

Well, it\'s nice to have that information because we immediately took
that sample into the BL-3 laboratory, and always in the laboratory it\'s
the ones you don\'t know that you have to be concerned with. So it was a
real eye opener to all of us that, oh, yeah, this is true. This can
really happen.

We never know what\'s coming into our lab. We get so caught up in the
Flu A and B that sometimes we have to step back and make sure that our
procedures are going to be there to cover things that are more
pathogenic.

If we summarize our season this year, it has certainly been
predominantly A. All of what we have seen has been H3N2, and all of
those have had this four amino acid substitution indicating to us a
drift away from the A/Fujian last year and even the A/Wellington from
South America.

The B, while it\'s in our population evenly split between the two, it
suggests to us since the latter ones are Shanghai that that is the way
it\'s continuing to go, and we have nothing to add to the H1 story. We
know it\'s out there, but we haven\'t isolated even a single one.

Thank you.

CHAIRPERSON OVERTURF: Are there cases for Linda Canas? Yes, Dr. Farley.

DR. FARLEY: On the current slide that you have up, I\'m just noticing
that it seems in 2003 that things changed a bit in the distribution or
the prevalence. Did anything change in the methodology. The influenza
isolation rates seem to have gone up, and the adeno went down a bit from
the previous years.

MS. CANAS: The adeno is difficult to understand because a lot of times
they just quit sending us so many samples. If you look at the \'99-2000,
everything we got was adeno. The number of samples went from 2,000-some
to over 6,000 because they were giving us so many. So adeno went up.

So they quit sending us so many. So adeno, it\'s hard to tell what that
means because we weren\'t looking at them.

And the other one was Influenza A and what?

DR. FARLEY: Well, the Influenza A isolation rates, they now represent 25
percent in 2003 and 2004.

MS. CANAS: Flu has its own. A lot of times it\'s the people who are
taking the samples. I think in the last two years, I don\'t have
definitive data on this, but I think we put out information on these
rapid flu tests about their sensitivity and their specificity, and they
should culture the negatives. I think they send us all of their
positives, too. I know some places do because I\'ve talked to them.
\"Oh, but we want you to see what our virus looks like.\"

So I think the last two years that\'s been a big part of it, but we\'ve
also stressed a lot more the case definition. I reported last year that
we did a records review at one of the sites that was overwhelming us,
and of those patients that had fever in the diagnosis, 40 percent were
positive for a virus. Of those that did not have fever in the diagnosis,
eight percent were positive. So that was strong indication to us that
this was a way.

This program keeps getting bigger and bigger, and our resources don\'t,
so to try and target those that truly are ill with influenza or
respiratory virus. So those two things, I think, have.

DR. COUCH: Just a quickie. You partly answered that, I think. Your case
definition for sampling is just acute respiratory illness in the reports
for health care?

MS. CANAS: Yes, they do visit, and it is ‑-

DR. COUCH: No fever criteria or syndrome criteria?

MS. CANAS: Fever of 100.5 or greater.

DR. COUCH: They must have fever?

MS. CANAS: Well, that\'s what we tell them, and we give them sheets and
they fill them out, and you say fever and they say 98.7.

DR. COUCH: Otherwise your percent of rhinovirus, of enteroviruses and no
rhinoviruses would be very \--

MS. CANAS: Well, we don\'t have the right conditions for rhinovirus. So
I suspect a lot of our negatives are rhinovirus. Our temperatures are
around 36. You need to be 34 to 35 to isolate the rhinovirus.

DR. COUCH: But you are asking for fever.

MS. CANAS: But you\'re asking for fever, and that\'s what we\'re
stressing with the FluMist also, when people are reporting after getting
FluMist that they\'re sick. As long as they have the fever and submit
it, then we can ascertain whether it is disease or not. Those that
don\'t, the FluMist people feel bad afterwards, but they don\'t have
fever.

CHAIRPERSON OVERTURF: Dr. Monto.

DR. MONTO: Two questions. First of all, could you update me as to the
situation with adenovirus vaccine in the military? I know there was no
vaccine for a while. Are you vaccinating now for adenovirus, number one?

And, number two, are you able to get anything about seasonality in other
parts of the world from your data? This has become a major issue in
trying to identify impact.

MS. CANAS: Right. I\'ll answer the second one first and then refer to
Colonel Phillips for the adenovirus.

I one time made a comment about when South American first started
sending samples, that, oh, good, we could get theirs in our off season
when they had flu season because they\'re Southern Hemisphere. That just
made sense to me.

And the reply back was, \"How do you know that? We\'re trying to figure
it out.\"

And, in fact, we get flu from them all year, and they say it\'s because
they have so many different sites and their topography in the country
where they have some around the coast, some in the mountains, and it
varies more with that, and I can only comment. The rest of them tend to
follow the same seasons that we see.

Colonel Phillips.

COL. PHILLIPS: Regarding adenovirus, and you had commented on the
epidemiology on the slide there, 1999 was the last year that we had
adenovirus vaccine and were able to give it, and have seen steadily
cases since then.

We are aggressively pursuing the pursuit of the new adenovirus. Our
researchers are working real closely with the folks from Bar
Laboratories that has the contract for that.

Phase 3 clinical trials have begun and are underway currently, and
we\'re anticipating FDA licensure of a vaccine by 2007.

CHAIRPERSON OVERTURF: Yes, Dr. Dowdle.

DR. DOWDLE: Thank you.

One of the real advantages, I think, of this system, global system, in
terms of influenza surveillance, of course, is sampling sites throughout
the world, and it\'s a real opportunity for sort of timely sampling in
the sense of you know what\'s going on.

The question I would have is how does the timeliness relate to, for
example, other shipments that Nancy would get in from other parts of the
world and other WHO centers. Does this system lend itself to completing
or being ahead of some of those or would it be lagging behind, depending
on how the shipments are arranged?

MS. CANAS: Well, I can only comment on our system, and those that come
in from South America and Thailand do have a lag, sometimes as much as
five months, but the others are coming in a day or two after collection,
and then within a couple of weeks, we try to get anything off to CDC,
but I don\'t have any idea.

DR. COX: I can comment just a bit further on what Linda said and can
concur with what she said. In some cases, we do get viruses through the
military surveillance sites on a very timely basis, and it\'s really
excellent.

She mentioned but didn\'t emphasize probably quite as much as I would
like to emphasize that there\'s a lot of sequence work going on, which
feeds directly into the sequence information that we have and,
therefore, that goes into the WHO system.

In other cases, we get viruses, for example, from Thailand, directly
from their National Influenza Center, in a more timely manner than we do
from the military. So it varies depending on site and a variety of
circumstances.

What we have found generally is that GEIS is a tremendous value added to
the WHO global influenza program, and that we would very much like to
see it continue, the GEIS activities to continue.

Along the same lines, we\'ve had the opportunity this past year through
efforts of the department to work in closer partnership with some of the
military labs and will be providing some financial support for NAMRU-2
and NAMRU-3, to enhance the already existing influenza surveillance
infrastructures that are in place there in the hopes of both expanding
influenza surveillance into more rural areas in Indonesia and some other
countries, and also having more timely shipments of viruses to our WHO
Collaborating Center.

So I think there\'s very close interaction and real value added is the
bottom line.

CHAIRPERSON OVERTURF: Any other comments?

One thing I didn\'t hear was whether there\'s any enhancement of this or
has been an attempt to enhance the system recently to look for H5, H7,
H9 strains, particularly from those areas where they used to come in the
past.

What I heard was that you rapidly grow the viruses that you tend to
characterize their hemagglutinins. Are there additional epidemiologic
data in those sites where these viruses are likely to emerge that are
collected that in any way changes your operation at that point?

MS. CANAS: Well, this is what we struggle with. As long as we can keep
geography in that mix there, we feel pretty safe that those things that
are coming in from endemic areas we can handle in the BL-3 laboratory.

We work again with CDC to know what\'s going on in the world. Other than
that it\'s just trying to keep up with what\'s going on and be prepared.

CHAIRPERSON OVERTURF: Are there other questions or comments? Yes,
audience.

DR. GAYDOS: My name is Joel Gaydos. I work with Linda and the other
people on the GEIS program.

In response to some of the questions that have come up over the last few
minutes starting with Dr. Dowdle, one of the reasons that we meet once a
year is to make sure that the programs are complementary, and there are
a couple of things that I think are important in addition to what has
been brought up.

We have people who are permanently stationed at places like Cairo and in
Lima, and we do a lot of bulk processing. But if something is happening,
we can speed up the processing. If something happens at the CDC and they
think that we should be getting more specimens from Napal or from Peru,
then we get the word from them, and then we go out and collect the
specimens.

We also have the opportunity because of having military people stationed
there to get into some areas where other people aren\'t and where
specimens would not be easily obtained, like some of the places you have
heard about in Napal.

So I think the program has worked very, very well with the CDC. As Linda
pointed out, specimens come to her laboratory. She works very closely
with Atlanta and also with the Navy group in San Diego.

Not all of our specimens come in that way. Our lab in Cairo for a number
of reasons works directly with the CDC. Our lab in Jakarta for a number
of reasons works directly with the CDC or with the laboratory in
Australia.

So I think it is, in fact, a surveillance system in that we are
regularly collecting specimens. We\'re working together.

We also respond to situations, and we do have the epidemiologic
capability to immediately jump on something if it\'s picked up in the
laboratory.

CHAIRPERSON OVERTURF: Thank you.

Are there any other questions or comments?

(No response.)

CHAIRPERSON OVERTURF: We have 15 minutes extra for lunch, and the
proceedings of the meeting will begin, again, at one o\'clock sharp.

So thank you very much.

(Whereupon, at 11:46 a.m., the meeting was recessed for lunch, to
reconvene at 1:00 p.m., the same day.)

[AFTERNOON SESSION]{.underline}

(1:08 p.m.)

CHAIRPERSON OVERTURF: I\'d like to call the meeting to order please.

Good afternoon. We now open our open hearing, and I\'ll ask Christine
whether there\'s any members in the audience or otherwise who would like
to address the committee.

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

Dr. Overturf, would you please read the open public hearing statement?

CHAIRPERSON OVERTURF: Both the Food and Drug Administration and the
public believe in a transparent process for information gathering and
decision making. To insure such transparency at the open public hearing
session of the Advisory Committee meeting, FDA believes that it is
important to understand the context of an individual\'s presentation.

For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement to advise the committee
of any financial relationships that you have with any company or any
group that is likely to be impacted by the topic of this meeting.

For example, the financial information may include the company\'s or
group\'s payment of your travel, lodging, or other expenses in
connection with your attendance at this meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the committee if you do not have any such financial
relationships.

If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.

MS. WALSH: I have not received any requests at this time. Is there
anyone in the room who would like to address the committee?

(No response.)

MS. WALSH: I see no response. Dr. Overturf, I turn the meeting back to
you.

CHAIRPERSON OVERTURF: So we will proceed with the agenda and talk about
vaccine responses. Dr. Roland Levandowski.

(Pause in proceedings.)

DR. LEVANDOWSKI: Okay. While we\'re working out the technical end of
things here, maybe I\'ll just give a little bit of background
information about the serologic information that I\'m going to be
discussing.

The serological data that I\'m going to be presenting actually will be
coming from a number of different centers, and I\'m going to try to
summarize that information as best I can. I think you all are aware that
we share serum panels between several different laboratories and test
these same serum panels, each within those laboratories.

The whole point of doing this serological exercise really is to try to
see whether the responses to current vaccines confirm what we have found
already with the antigenic and genetic characterizations that have been
presented this morning already by Nancy Cox.

And whereas you saw for the tables with the ferret sera where there were
a few very well characterized ferret sera used to test an enormous
number of different antigens, for the serologies we\'re really kind of
reversing that procedure. We\'re looking at a relatively few antigens
that have been selected to be representative of the current circulating
strains that seem to be different to us, and we\'re using a much larger
panel of sera.

Now, the sera that we use, those different serum panels that we have
available to us are not all identical. They\'re not all collected the
same way. I think that\'s something that everybody should be aware of
also.

Some of these serum panels, you\'ll see the number of sera on each one
of them. Some of these serum panels have been prescreened to select out
people who respond well to the vaccine, and that\'s actually okay.
That\'s good because if there\'s not a response of any sort, then we
won\'t be able to perform what our primary purpose for this whole
exercise is, which is to try to compare the responses between the
different antigens.

We\'re not really trying to say that any of the vaccines used are
immunogenic. We\'re not trying to say anything about the vaccine itself.
Really we\'re focusing on trying to compare what kind of antibody
response we see for the vaccine strain as compared to the test antigen.

And so what I\'m going to be emphasizing as I have on some previous
occasions are the geometric mean titers, the post immunization geometric
mean titers. The tables that I\'m going to show you are going to be in
the traditional sense. They\'re going to have percent fourfold
increases. They\'re going to have percent of people who are above an
arbitrary cutoff point like one to 32 or one to 40, but I\'m really
going to be focusing on the geometric mean titers and how that relates
the test antigen to the vaccine strain.

You\'re going to see also as I show you these results that there are
going to be differences in the absolute titers between labs, and again,
that\'s not something I want you to focus on. What I really want you to
see are the differences that are shown between the labs.

And what I can tell you generally when we look at this, although there
are differences in the absolute values from each lab, when you do a rank
order of the way the different antigens fall out, the test antigens,
they come out to be not exactly the same but pretty close to the same in
terms of which is recognized as the highest response and second and
third and fourth, and so on.

So these are the serum panels that have been provided shown on this
slide and the next one, and you\'ll see here that the vaccine strains
used in all of the centers were pretty similar. I just point out some
slight differences.

All of the centers using A/New Caledonia and A/Wyoming as the H1N1 and
H3N2 strains, but there are differences in the B strain. The vaccine
used for preparation of these sera from Australia contain the older
B/Victoria-like vaccine antigen, B/Brisbane/32, but the other centers
have used more recent B/Yamagata-like vaccine strains, B/Jiangsu/10/2003
or B/Shanghai/361 and that should be 2002.

We also have a couple of panels of sera from children. Nancy Cox
mentioned that they had tested two. There\'s only one that I\'ll be
discussing, one panel from the CDC that I\'ll be discussing with the
following information.

We had even a third panel of sera from children, and I\'ll be presenting
some information from those. So these are not exactly the same two
panels that Nancy mentioned, but they are two panels of sera from
children that we have to look at.

So jumping right into it, these are the different antigens that are used
for the H1 serologies, and all of them are H1N1 viruses. As Nancy
mentioned, there really haven\'t been any H1N2 viruses circulating, but
we have a good representation of strains from around the world, from
Asia, from North America, from Europe, from Oceania.

And in terms of responses, I\'ll be showing you some tables that are not
all the tables that were available or all of the data, but some that are
just representative of results that came out from the different centers.

So here is a table of results for three different serum panels from the
United States, from Australia and Japan. These are sera that were done
in the lab here at Center for Biologics, and these are the numbers of
serum pairs that we had from each of these sites. The antigens that were
tested are shown here, and in blue on every one of the slides I\'ll have
the vaccine antigen, and in red I\'ll point out the ones where there\'s
a 50 percent or greater reduction in the post immunization titers as
compared to the vaccine strain.

So from this you see that we tested not only New Caledonia, the vaccine
strain, but also A/Florida/4/2004, A/Bangkok/1544/2004, and
A/Okinawa/42/2004.

And for the most part the post immunization responses of people who were
immunized with A/New Caledonia were very similar for the other strains
that were tested. The one exception here is that in this particular
serum panel with A/Florida, there was a more than 50 percent reduction
against the A/Florida strain as compared to the vaccine.

So those were adults, and now elderly, from the tests that were done at
National Institute for Biological Standard and Control, or NIBSC.
They\'re ordered somewhat differently here and different numbers and so
on, but again, A/New Caledonia was the vaccine strain.
A/Netherlands/128/2004, A/New Caledonia/9/2004, and A/Okinawa/42/2004
were the test antigens.

And by saying that, I\'d also point out that we didn\'t test all of the
same antigens in every lab, but there is overlap between antigens that
were tested in the different labs. They\'re not all exactly the same. So
we have a somewhat broadening of the numbers that are tested and some
similar or some identical strains that are tested in the different labs
to give us some idea of where we\'re standing in terms of the overall
results in comparison between labs.

But here, again, you see in the post immunization geometric mean titers
for the most part the new strains were well inhibited by antisera that
were raised against the vaccine strain. In this case, the one exception,
it was for this A/Okinawa/42/2004 H1N1.

So those were adults and elderly. For the pediatric population, the two
different groups of children were children who were six to 23 months of
age. I don\'t know exactly what the mean age is, but they were all less
than two years old, and another group of children who had a mean age of
21 months with a range of eight to 38 months.

And, again, the antigens that were tested are shown here. For the
somewhat older children, we did not really see much of a difference
between the vaccine strain and the test antigens, although it\'s a
little bit low for this Florida strain, which is similar to what I
showed on the first slide that didn\'t quite reach this 50 percent
reduction

And here these younger children for these two antigens, A/Florida/4/2004
and A/Netherlands/128/2004, there were more than 50 percent reductions,
and I\'m just going to go right on to a table where we\'ve tried to
summarize all of these results looking at the percents that were greater
or the reductions in geometric titer that were more than 50 percent.

Why are we emphasizing this? This is a way to try to get some idea of
how severe or how the magnitude of the difference. It\'s a somewhat
arbitrary way to do things, but it does give us a way to try to handle
the data which are somewhat disparate between the different labs and for
the different antigens.

And if you look at this, there are a number of different antigens that
were tested. Many of them were tested in more than one lab, and I\'m not
including some of the information for strains that were just tested in
one lab, although I have a little bit here.

But what you see generally is that for all of these H1N1 strains, for
the most part on average there was not really a 50 percent reduction
either by the total numbers or by the mean averaging the percent
reduction for all of the studies all together. Actually they\'re quite
low.

So the difference here wasn\'t very much, and you can see from the range
also that for the most part, very few of these antigens when they were
tested were there 50 percent or more reductions.

So now moving on to the H3 strains, A/Wyoming, of course, was the
vaccine strain, and there were a whole range of representative current
viruses. All of these, I think, can be categorized as California/7/2004,
although I\'m not entirely sure about the Singapore strain. That might
not be truly considered California/7-like, but it\'s a more recent
strain than Wyoming, and if anything, it would be somewhat like
Wellington or out farther than Wellington on the genetic dendrogram.

But, again, we have a range of viruses that were tested, and here I\'m
showing some data from the CDC lab for adults, from the United States,
Europe, and Australia. The antigens that I\'m showing here, Wyoming is
the vaccine strain, and here there were A/California/7/2004,
A/Singapore/36/2004, and A/Tennessee/6/2004. Those strains were tested.

And I would call your attention to the fact that for every one of these
serum panels and with all three of those California-like antigens, the
reductions in post immunization geometric mean titer are really quite
obvious. They\'re very large reductions. It\'s much more than 50 percent
in each one of these cases.

And as you\'ll see on the next slide, that holds true for the elderly
here as well. These are sera that were run at NIBSC for several serum
panels. They tested California/7/2004, Singapore/37/2004, Oslo/807/2004,
and Shantou/1219/2004. And here, again, you see it stands out very much
that there\'s a big difference between the post immunization responses
for the vaccine strain and for these newer California-like antigens, and
it\'s a lot more than a 50 percent reduction.

And, finally, for the H3, here are some data for the pediatric
population again, and again, just not to belabor this too much you see
that even in these young children or particularly in these young
children, you see that there\'s a big difference between the post
immunization titers for the California-like strains and the Wyoming
vaccine strain.

For a summary of all of this, in this table I just call your attention
to the totals over here. You\'ll see that almost every one of the
serologic tests that was done show that there was a 50 percent or
greater reduction in geometric mean titer as they were tested, and the
magnitude of this difference was really quite amazing and substantial.
All of these are much, much more than 50 percent, and in many instances
the percent reduction \-- none of the tests were under 50 percent and
most of them were almost 100 percent.

So now moving on to Influenza B, this is a little bit more complex. As I
mentioned in the vaccine, the Australian vaccine has B/Brisbane/32 as
the vaccine strain. The vaccine that we\'re interested in here in the
United States would have contained B/Jiangsu/10/2003. So I\'m really not
going to be focusing on results that came from the vaccine that was used
in Australia in this case.

There were both Victoria-like Influenza B viruses that were tested here.
I\'ve listed them as Hong Kong/330-like. That was the last vaccine
strain that we used here in the United States.

And there are also a group of viruses that are more like Yamagata/1688
or our current vaccine is Shanghai/361-like. So there\'s a range of
different antigens to look at here.

And, again, this table from data from the CDC in adults for a number of
the different serum panels. In this particular instance B/Jilin/20,
which is equivalent to B/Jiangsu/10, was used as the test antigen, but
that\'s equivalent to the vaccine.

And I guess I should point out that in this case the antigen was ether
treated. Not all of the labs do this, but many of the labs do ether
treat the antigen before doing the serologic testing.

There are a number of antigens that were new viruses that were included
in the test, including B/Colorado/4/2004, B/Florida/2004, and
B/Fujian/2004, and again, all of those are in the same HA lineage as the
vaccine, and you can see all of these in each of these instances were
very well inhibited by the current vaccine.

The only thing that was not in this particular test was
B/Hawaii/13/2004, which is representative of the other HA lineage
that\'s not in the vaccine right now, and there were more than 50
percent reductions here, and this is very consistent with what we have
been seeing in the past in the same situation. This is really not new.
It\'s what we have identified in previous years when we\'ve been
comparing the responses of vaccine containing one HA lineages to viruses
in the other HA lineage.

These are data from the Australian center, an elderly population, and
here they were testing \-- that should be B/Jiangsu/10. Sorry \-- but
they were using B/Jiangsu/10 as the equivalent of the vaccine strain,
and then tested B/Brisbane/4/2004, B/Victoria/501/2004, and
B/Hawaii/13/2004.

And here the results are not quite as clear-cut as in the previous
slide. Here in this instance, compared to the vaccine response, we would
say that the response for all of these test antigens, including the one
that\'s not from the same HA lineage, the B/Hawaii/13, looked pretty
similar.

But in this other panel from Europe, one of the strains that\'s in the
same HA lineage as B/Jiangsu actually gave responses that seemed to be
low in this particular center\'s tests, as did the Hawaii which we would
have expected because it\'s in the other HA lineage.

And then the last in this particular panel of sera here. Again, there
was not really a difference seen even between the Hawaii strain which
was in the other HA lineage and the vaccine strain.

So these are results from children, these two different groups, and here
it\'s a little bit more difficult to interpret because the vaccine
responses to the vaccines themselves were on the low side. The sera
tested at CDC using B/Colorado/4, B/Florida/7, B/Fujian/430, Hawaii/13,
and the other similar strain to Hawaii, Phitsanulok \-- I think I\'m
getting that right or close \-- even though these results are low, it
looks like for all of the strains that are equivalent to the vaccine
there\'s a similar response, whereas it was a lower response for the
non-vaccine antigens.

For these children, these slightly older children, however, although we
had some response to the vaccine, we really weren\'t able to detect
response to any of the antigens, including those that are similar to
what\'s in the vaccine.

So trying to put this into a summary slide, looking at the 50 percent
reduction between the different sera, I\'d say overall it still sort of
holds up that the strains that are in the HA lineage, not currently in
the vaccine, Hawaii/13 and Phitsanulok/2053, that there are some
reductions, but you know, they\'re not really high magnitude all the
time. It\'s not really consistent between all the centers and all of the
tests that there\'s a 50 percent or greater reduction, and in only about
half of them, if I\'ve done the math there right \-- and I might have
made a mistake, but it looks okay as I do it quickly in my head \--
although it did reach like 50 percent for mean, there was a huge range
here for the results.

For the viruses that are in the same HA lineage as the vaccine strain,
here again there\'s some data that suggests that there may be some
reductions for some of these viruses like Brisbane/4, and on the other
hand, other data suggest that for new, more recently circulating strains
similar to the B/Shanghai/361 that there\'s not so much reduction.

But, again, you see there\'s a wide range here in the results for these
different serum panels, and the highest percent reduction actually would
come from the children. So if I excluded those, you would see for adults
and elderly that it looks like even less a difference between those more
recently circulating strains that are like the vaccine strain,
B/Shanghai/361.

So in summary, I guess what I would say overall is the studies were done
with sera that were collected after immunization from a number of
centers with a number of different vaccine products, and at this point
it looks like the representative H1N1 viruses are very well inhibited by
the current vaccine.

On the other hand, it looks very clear that the A/California/7/2004-like
viruses are poorly inhibited compared to the current vaccine.

For the B strains, the B/Shanghai/361/2002-like viruses seem to be
reasonably well inhibited, but those that are in the other HA lineage as
represented by B/Hong Kong/330 are less well inhibited than the vaccine
strains.

And I will stop there and see if there are any questions.

CHAIRPERSON OVERTURF: Are there questions for Dr. Levandowski? Dr.
McInnes.

DR. McINNES: Roland, the infant data one presumes that some of these
children are receiving their first dose of flu vaccine and some are
maybe second, maybe, I guess, second. So what was the timing around the
sera collection post dose, and for those who are receiving it for the
first time, was this collected post two-dose?

DR. LEVANDOWSKI: Okay. I should have made that clear. Both of those
serum panels were from children who had received two doses of vaccine.
It was post the second dose of vaccine. I don\'t have information. I
can\'t tell you at this point whether any of those children had been
immunized previously or infected.

Some of the older children in the second serum panel more than likely
were either immunized or infected. The younger children though you\'d
have to ‑- since these were studies done some time in the summer to
early fall, late summer to early fall, this would have been happening in
between flu seasons, but I can\'t really totally tell you how all of
their exposure history fits in because I don\'t have those data.

And I think, you know, still these are really very young children, and
it gives you an idea of what you would expect in a population of very
young children.

CHAIRPERSON OVERTURF: Yes, Dr. Karron.

DR. KARRON: Two questions. the first is I actually first want to commend
you on having these pediatric panels of sera. I think a couple of years
ago we were discussing how important that was, and I think it\'s very
useful to have them.

I guess my first question is now that we have two types of vaccines in
this country \-- we have an activated and we have live attenuated \--
would it be useful to have data from individuals immunized with live
attenuated vaccine to have that as a comparator, obviously not in the
children under five, but you could have school age children and adults
18 to 50. I think, particularly when these issues of antigenic drift
come up, that might be a useful comparator to have.

I\'ll let you say something, and then I have a second question.

DR. LEVANDOWSKI: I think it would be interesting, but I just would like
to point out that the whole point of this, again, is to compare. It\'s
not so much to say whether the vaccine is immunogenic or not. I don\'t
think with the strategy that we\'re using here, I don\'t think we can
really make any comment on that. So really we\'re trying to focus on
getting a comparison between the different antigens, the vaccine
antigens versus the newly circulating strains.

Having said that, I think it would be very interesting to have access to
more sera all together from different populations, and it might make
sense to explore that and see if that gives us any additional data
compared to what we get from inactivated vaccines. I don\'t see any
reason it wouldn\'t be useful information really.

DR. KARRON: And I guess the follow-up question really relates to
something that Dr. Couch was talking about earlier, but you know, I
guess my question is really we see very poor responses in very young
children to the B strain. Is that consistent with what we\'ve seen
before, data that we have before?

And if so, I mean, I\'m almost wondering whether it matters which B
strain we choose because responses are poor. You know, it\'s hard to
look at reductions when your geometric mean titer is ten.

DR. LEVANDOWSKI: Right. Well, those numbers are small, and I don\'t know
how much of that is technical artifact and how much of that is
significant in terms of what protection would be. Most people are used
to thinking about titers of one to 40 or greater being representative of
protection, but actually the data are fairly sparse in terms of
indicating that there\'s a correlation between the titer and efficacy.

We do know the higher the titer of antibodies the more likely you are to
be protected, but I don\'t think we know for sure that, you know, even
at lower titers there might not be some level of protection. So I would
hesitate to comment on what the meaning of those titers that we saw
there are.

But we have for children, we have seen titers that have been very low.
Usually it\'s for the H3 strains that we\'ve seen that in previous
years, but they vary quite widely, and when I said there may be some
technical artifact, I guess we occasionally see differences that may be
related to some aspect of the virus itself in terms of their avidity for
binding to red cells, other things that are going on in the system.

But I\'m rambling around here and not trying to answer your question
directly because I don\'t think there is a direct answer to it.

DR. KARRON: But I guess my question is that I\'d have to go back and
look at these data, but the titers to be were not uniformly low across
populations. You know, if you thought it was a technical issue, then
presumably whether you tested adults or elderly or children, you would
have uniformly lower titers.

My question is given how low the titers are to the B strain in these
very young children, is that inconsistent with what we\'ve seen before
or is that consistent with what we\'ve seen before in TIB in very young
kids?

DR. LEVANDOWSKI: Well, I did answer that part directly. I think we\'ve
seen low titers for different antigens, not necessarily for B, but we
have seen low titers for different antigens, not necessarily for B, but
we\'ve seen low titers with different antigens in very young children,
and I don\'t think we always would predict what that would be. I think
we\'ve seen differences between children and adults for, you know, the
same antigen and we also have seen if you look at a series of antigens
like H3, for example. It seems that some of them are just more
inherently immunogenic than others.

CHAIRPERSON OVERTURF: Dr. Couch.

DR. COUCH: Just for a moment, a lot of what we\'re looking at here is
very test dependent, as Roland pointed out, and the split product is
used for the B which, in order to give it the kind of sensitivity that
will permit these spread out comparisons, and what he is giving us is
really relative, not absolute, and when we\'re using the A strains,
we\'re using it there in an entirely different HI test.

But in general, Influenza B responsive is when you do one type of assay,
you see, which carries, as we know, the same kind of sensitivity.
Neutralization tests are generally speaking not quite as good as they
are to A, but that\'s all fairly relative. So it\'s difficult to compare
B responses to A responses when we\'re looking at them here because
it\'s so person and so test dependent. But he\'s going with relative
findings for strain selection, you know, this percent of GMT, and then
the same is true for the equal to or greater than 40, you know. What is
the validation of a one-to-40 with a split product versus a one-to-40
with a whole virus antigen when you\'re doing Influenza A, and certainly
a major difference is if you do B with whole versus the split product.

So it\'s all sort of a test-test nuance in that. So one of the reasons
that I think that really caught my eye that you didn\'t comment on,
Roland, was page 37 in the CDC surveillance where the pediatric
population age is five to eight, 274 children by Kathy Neuzil, and only
ten percent of them had a rise to be Hong Kong. There\'s a major
disparity in that age group, both of which has inactivated and live
recommended for.

You really would have liked to have seen the live to see how it does in
that comparison in that regard, but as we go back to Roland\'s point,
that doesn\'t influence our selection here. That\'s the kind of thing
that the ACIP would want to be looking at when they talk about relative
criteria for recommendations, but that data would have really been
interesting to add to that one.

I only had one other just minor question, and I couldn\'t pick it up
here, but in the individuals it looked like the elderly in the U.S. and
Japan didn\'t respond as well as the elderly in Australia and Europe.
That\'s got to be partly population dependent in testing. What do you
\--

DR. LEVANDOWSKI: No, no, no, no, please. I said at the very beginning
that you should be aware that some of these serum panels have been
prescreened to select out higher responders to begin with. Not all of
these serum panels have been so prescreened.

DR. COUCH: I missed that.

DR. LEVANDOWSKI: So I think you have to be very careful. There are
differences in how the sera were handled before they got to the
individual labs to be tested. So I wouldn\'t draw any conclusions from
that. I\'d try to focus on the relative responses between the antigens.

CHAIRPERSON OVERTURF: Dr. Monto.

DR. MONTO: Just a further comment about B responses in young children.
They don\'t even respond well to HI ether treated antigens post
infection because we\'ve had, when we were back doing our community
studies in Tecumseh years ago, we could show that children under five
were heavily infected when there was a B outbreak, but if you look just
in terms of rises in antibody titer, a fourfold rise in titer, it looked
like they were spared.

So there basically is a problem in just immune responses and young
children measured by HI, we don\'t know how that translates to other
things.

DR. COUCH: Just a quickie for general information. That same thing is
true for the neutralization test, and I think our test is fairly
sensitive. The same finding.

CHAIRPERSON OVERTURF: Yes, Dr. Dowdle.

DR. DOWDLE: Like Bob, when I saw that chart, the Australia sera were
looking so good that I was ready to move to Australia, but \--

(Laughter.)

DR. DOWDLE: So thank you very much for your explanation, Roland.

But this is just to say that I think that the evolution in sort of the
use of human sera to interpret the strain differences has been really
quite helpful and is moving forward quite a bit.

I wonder if there\'s further discussion on how this can be standardized
even more because particularly I think there were core viruses, but
could there be more core viruses, it might be used. In addition, the
labs could use whatever other strains that they want, but I\'m sure
those discussions must be taking place.

DR. LEVANDOWSKI: You\'re right. There are discussions going on all the
time about how to try to do this better. It\'s very difficult because of
the logistics of transport of all of these materials, and although I did
not get into that as part of the presentation, there are differences in
the antigens, too, because in order to do the testing, it\'s done with a
pool of virus that is grown usually in the laboratory where this is
being done, and so there may be some subtle differences from passage
levels in the different laboratories that have an impact on that.

But the logistic part of it is very tricky, and I\'m not emphasizing
that, but of course, these California viruses have only really been
recognized as a separate group of interests since about mid-January. So
to get these shipped around to the different labs and to be able to do
the testing on those has been, you know, a challenge, quite honestly.

But in the ideal world, if we had more time and it wasn\'t flu, then
maybe we could get it right.

CHAIRPERSON OVERTURF: Dr. Cox.

DR. COX: If I could just add a couple of more comments, we really have
put a lot of effort into improving the testing and the consistency of
choice of antigens and so on. Every year there\'s some different factor
that\'s a problem, and this year, in particular, we had a rather slow
start to the influenza season not only in North America, but also in
Europe, and this year, as in other recent years, we have had two
preparatory WHO conference calls, part of which are dedicated to talking
about what strains we should include in the human serologies and where
the serum panels are in terms of their availability for shipment and so
on.

So there is really a lot of effort that goes into this. It\'s just a
matter of, as Roland said, getting the viruses out there and then seeing
what viruses grow best and how many you can actually put in test given
the limited amount of antiserum that you actually have.

CHAIRPERSON OVERTURF: Dr. Eickhoff.

DR. EICKHOFF: Just a general comment. I think this year particularly
illustrates the importance of having human serum panels available for
study because as Nancy pointed out to me earlier in response to one of
my questions, the difference between A/Fujian strain and the
A/California strain wasn\'t really that clear in the ferret antisera
data, but in the human sera data it\'s apparent that there\'s a real
problem.

CHAIRPERSON OVERTURF: If there\'s no more comments, we can go ahead and
progress to the availability of strain reagents. Dr. Ye.

DR. YE: Thanks.

In his presentation, Dr. Levandowski described the immune response to
the current influenza virus vaccine, and I\'m going to present this
status of candidate virus vaccine that is used for production as a viral
vaccine and the potency reagent that had to be used for standardize the
antigen of vaccine product.

Influenza vaccine contains three antigens: H1N1, H3N2, and B virus.
Current vaccine for H1N1 is New Caledonia/20/99. IVR/116 is a
reassortant between New Caledonia/20/99 and A/Puerto Rico/8 or PR/8 high
growth viruses in the lab.

This reassortant grows quite well in eggs. Currently we do not have
antigenically divergent strains available for this particular subtype.

Wyoming is the current vaccine reassortant. NYMC-X-147, NYMC-X-149,
RVR-134 are the reassortants between Wyoming and PR/8. All of them grow
pretty well in eggs.

The candidate strain for H3N2 is a little bit complex. The first one is
the A/Wellington/01/2004. There are three reassortants. RESVIR-20,
IVR-139, NYMC-X-155 are the reassortants between Wellington/01/2004 and
PR/8. All of them grow reasonably well in eggs.

And as Roland mentioned, Wellington/01/2004 is a strain recommended for
the Southern Hemisphere in the 2005 season.

The next one is A/California/7/2004-like strain. Currently we do not
have high growth reassortant for this particular strain. Although
IVR-140 is a resortant between Singapore/37/04 with PR/8, this
particular reassortant does not grow very well in eggs, neither grow
well in eggs nor ideal strain represent A/California/7/2004.

However, we have at least six circulating viruses that represent
A/California/07/2004. All of them are egg isolates. One of these
strains, A/New York/355/2004, are the most among the six \-- grow
reasonably well in eggs, and this strain may be ideal strain to be used
for generating high growth reassortant between this particular strain
and PR/8, and the rest of them do not grow very well in eggs.

I\'m putting up this slide to give you the sense of the possibility we
can generate high growth virus for this particular subtype. There are at
least the six laboratories work wholeheartedly to generate high growth
reassortant for A/California/7/2004. There are three in the United
States, one from CBER, CDC, New York Medical College, and three from
overseas. They are NIBSC from New York (sic), CSL from Australia,
National Institute, Infected Disease, from Japan, and hopefully, by
mid-March we can have this high growth reassortant for A/California/704.

The reason I\'m saying that is I mentioned one strain grows reasonably
well. Then the possibility we have with high growth reassortant for this
particular strain would be likely.

The current Influenza B strain \-- current vaccine strain is
B/Shanghai/331/2004-like. There are three strains: B/Shanghai/361/04
itself, B/Jilin/20/2003 and B/Jiangsu/10/2003. All of them grow
moderately, at a moderate rate in eggs.

And currently we do not have a new antigenically divergent strain
available for this B strain.

Now we move on to the potency reagents. We have antisera and antigen for
standardization of the vaccine for both H1N1, which is New
Caledonia/20/99 and Wyoming/03/2003. If the new strain is going to be
chosen and the particular reagents needed to be prepared so that they
wouldn\'t be available before May.

We also have antisera and antigen for both HA lineages, one for
Shanghai/361/04, which is a Jiangsu/10/2003, and also we have antisera
and antigen for Yamagata lineages, which are B/Hong Kong/330/2201 and
Hong Kong/1434/2002 and B/Shandong/7/97.

Again, if the new strain are choosing the reagents, it would be
available in May in the earliest.

Thank you.

CHAIRPERSON OVERTURF: Are there questions? Yes.

DR. BUCHER: I just wanted to mention that we had submitted a high yield
B reassortant for Jiangsu, NYMC \-- I\'m from New York Medical College
\-- NYMC-BX-7. So it doesn\'t \-- in our hands it grows about twice as
well as the B/Jiangsu. So just to let people know that that\'s
available. We did submit it to the CDC. It was also sent to your lab.

CHAIRPERSON OVERTURF: Maybe you can clarify something for a
bacteriologist. What is it that you do to make the \-- is it all trial
and error or are there genetic or molecular elements known for egg
growth?

DR. BUCHER: No, it isn\'t that random. We do use, although we do take
advantage of a lot of possibilities here \-- Ed Kilbourne had the main
lab, and we\'re continuing on with his assistant as well and his
reagents, and we\'ve generated improved selection reagents.

So he developed the system for As, and that\'s what people have been
using, using an old, well adapted egg strain as the donor, which is
A/PR/8/34. So it\'s been in an egg since 1934.

For the Bs now, we \-- and that\'s how we made X-147 and X-149, which
were mentioned, and now we\'re working on the high yield A/New York/55.

For the B strains, we selected B/Lee/40, which has been in egg since
1940, and as I said, it doesn\'t give us the tremendous enhancement that
we see for the As, but the Bs generally \-- they generally are growing
better than the new isolates of the A strains, but we did see an
increase in yield.

So we know that it has the eight gene segments. Of course, we have to
have the two from the current strain, the strain that\'s circulating
currently. So we have to have the hemagglutinin and neuraminidase from
the B/Jiangsu.

We know we have the M gene from B/Lee/40, and we\'re in the process of
analyzing the rest of the genes.

CHAIRPERSON OVERTURF: Thanks.

Are there any other questions or comments?

(No response.)

CHAIRPERSON OVERTURF: Thank you.

We now have time for the comments from the manufacturers, and that\'s
going to be presented by Albert Thomas of Sanofi Pasteur.

MR. THOMAS: Good afternoon. My name is Albert Thomas. I\'m the Director
of Viral Manufacturing for Sanofi Pasteur, the vaccine maker previously
known as Aventis Pasteur.

I\'d first like to thank the committee for the opportunity to present
today, and I\'d like to begin by talking about some of the critical
factors that are involved with influenza vaccine supply and how the
strain selection process can impact each of those factors.

First of all is the growth potential of the seed virus. Obviously there
are many factors that can impact the number of doses of influenza
vaccine that can be produced, such as the overall capacity that is
available to each manufacturer, the average yield of all three of the
monovalent strains currently in that formulation, but many times it is
the yield of basically the lowest performer, the least productive
monovalent strain that will ultimately impact or determine the number of
doses that can be produced in that given season.

You may be successful in producing 40 million doses of your H1N1
monovalent component, 40 million doses of your B component, but if you
can only produce 20 million doses of your H3N2 component, you will
ultimately only be able to distribute 20 million doses of trivalent
influenza vaccine.

Probably the most critical constraint is time. Given that the timing for
influenza vaccine manufacturing is limited at the beginning by the
timing of strain selection and is then limited at the end by the
necessity to be able to manufacture, release, distribute, and administer
the vaccine prior to the onset of the influenza season, your actual time
is very limited, in which case you can actually manufacture the
monovalent components and then formulate the trivalent vaccine, fill,
package, release, and ultimately distribute.

Also, please keep in mind that the working seeds typically require about
four weeks for development and release prior to them being able to be
utilized in large scale manufacturing, and usually that four weeks is
based upon the time that we initially receive the seed candidate.

The potency test reagents are also a factor that must be taken into
account. Given that each monovalent component, the potency of that
component or the amount of hemagglutinin must first be determined prior
to formulation of the trivalent vaccine, and that\'s done via single
radial immunodiffusion, which requires a strain specific reference
antigen and antiserum.

Those two components, the potency test reagents must first be
manufactured and calibrated or standardized for each new strain prior to
the formulation. That can be anywhere from, say, an eight-week process
to about a 12-week process, depending on when the seed candidate is
first involved or first available.

The time line that I\'ve got listed here has several assumptions built
into it. I\'d like to first describe those. This is based upon assuming
that there is one strain change from one year to the current year, and
the new strain here is listed as B or is listed as the blue component.

The way this is broken down is really first the upper half here is
related to the production of the individual monovalent components. The
lower half here is involving the formulation of the bulk trivalent
vaccine, the ultimate filling, packaging, and then distribution of that
vaccine.

Again, as I mentioned before, the time constraints are we are required
or limited by the time that we need to begin distributing the vaccine,
again, typically the August to the, say, early November timing. This
past season was a bit of an exception. Obviously we\'ve been able to
extend the time, in which case we can distribute the vaccine.

This basically ends or defines when you need to begin distributing, and
again, the actual beginning of the strain selection really determines
when you can begin production.

Now, something you might notice here is is I\'ve got this arrow here
listed as essentially the timing that the strains are announced,
basically the middle of February. If you\'re not familiar with influenza
manufacturing, you may see that manufacturing is already underway.

Some manufacturers may choose to manufacture one of the strains at risk,
and that risk is the fact that that strain may not actually be included
in the vaccine the coming year. The reason why manufacturers may choose
to do that is, again, because the time here is very limited, in which
case you can actually produce those monovalent strains and be able to
distribute that vaccine in time.

So, again, here, you know, assuming a model of one strain change for the
year, assuming that manufacturers would have already had some of that
production underway, manufacturers would typically be looking to begin
production at that second strain very soon after the strain
announcement. Basically the concern with the fact that they want to
build too much of one strain without ultimately knowing the yield of all
three strains that will be in the vaccine.

So typically following the strain selection, you know, assuming a
working seat is available, manufacture of the second monovalent strain
would begin. Once a working seed would be available for the strain,
manufacture of that would also commence.

That depends now upon what is the timing or the availability of the
reassortant. This time line here would assume approximately a mid-March
availability, which again for this year may be aggressive, but at least
it\'s something to start with.

Again, approximately the four weeks necessary for each manufacturer to
produce the working seed to use in large scale production from that
reassortant, and then the beginning production of that third strain.

Now, what then happens in parallel with that is the production and
standardization of the potency reagents, again, the reference antigen
and the antiserum. Until these reagents are available, the final or true
yield to this third strain is not known. Once the reagents are
available, manufacturers now have a very good idea of what their yields
of the three strains are. So they then begin the strain balancing
process here.

Again, each of the three strains are produced independently, and
depending on what the yield is of each strain, manufacturers will
emphasize one or the other with the ultimate goal at this time to have
an equal number of doses produced of each of the three monovalent strain
components.

And, again, once the potency reagents are available, the formulation of
the trivalent vaccine can begin, which then would be followed by the
filling, packaging, and ultimate distribution of the vaccine.

Current manufacturing status, as I alluded to in the previous time line,
for some manufacturers the H1N1, New Caledonia, the 20/1999
manufacturing is underway, and again, that was initiated at risk, again,
of that strain potentially not being selected to be in the vaccine
formulation for the 2005 and 2006.

Again, the reason why manufacturers decide to produce that risk is,
again, because the manufacturing time point here is very limited. We
have a limited time. That\'s really our most critical constraint that we
have to work with, and by manufacturing at risk with some knowledge of
the surveillance data that\'s available allows us the opportunity to
produce some of that product prior to that very critical time frame.

The H3N2 and B strain, obviously we\'re awaiting the strain selection
process and are currently evaluating any new potential seed candidates
that we\'re receiving, whether they\'re the A/California type of other
type strains.

Basically, in conclusion, it\'s really cooperation. I think it\'s very
clearly necessary for the successful influenza vaccine production and
supply, and that really comes from all parties involved in the overall
process. I would say the timely selection of the appropriate antigens,
both consideration of the antigenic match, as well as the potential
growth potential for that strain; the availability of the height of the
seed viruses, especially the high growth reassortants.

Again, because time is so limited, the best yielding strain you have to
produce each day will maximize the number of doses that can actually be
distributed. And something that worked, I believe, very well last year
and I think is a good representation of the availability or the greater
availability of egg isolates is the opportunity for manufacturers to
evaluate the growth characteristics of strains that are antigenically
similar but may have very different growth characteristics and large
scale production.

Again, the example last year, evaluation and selection of the
B/Shanghai/361/2002 light strain. Manufacturers were given several
strains to pick from, and actually it was the Jiangsu strain here which
was received last but had by far the best growth potential, and that\'s
what was utilized in production.

Again, just showing the fact that antigenically similar strains can have
very different growth characteristics, especially in large-scale
production, and the availability to have additional egg isolates is a
key factor for a lot of the manufacturers to pick potentially what would
be significantly a greater yielding strain which ultimately will yield
many more doses for the marketplace.

And, again, the availability of the potency test reagents and the time
frame or the time required to produce those must be taken into account
in the overall campaign.

CHAIRPERSON OVERTURF: Thank you.

Are there questions for Mr. Thomas? Yes.

DR. SCHWARTZ: I\'d like to ask you a question about your last point
about the B/Shanghai-like strains. Two questions. One is: did all of the
manufacturers come to the same conclusion or will one strain or a
different strain grow better with one particular manufacturer\'s
processor, a different manufacturer\'s process?

Secondly, I\'m wondering if when those three different strains were
supplied to industry whether there was an indication that the Jiangsu
would be the best growing of those three strains or whether it was
something that you had to test out in your manufacturing system before
that recognition came about.

MR. THOMAS: Sure. Could I possibly defer the first question to someone
on the committee? Again, I\'m not \-- typically each manufacturer is not
involved with what the other manufacturers are selecting. I believe we
all chose that same strain, but I\'m not sure if possibly anyone from
CBER would like to talk about that. Yeah.

CHAIRPERSON OVERTURF: Roland.

DR. LEVANDOWSKI: We\'ve had two different strains based on preferences
for manufacturers in past years, and I don\'t remember what year it was,
but it was in the late 1990s we had \-- actually it was the Hong
Kong/330/2001 and the Hong Kong/1434/2001. We had different
manufacturers producing different strains, and that went even further
because in Europe the strain that was being used was the B/Shanghai/7/97
strain. So all three of those strains that Zhiping mentioned in his talk
were used by different manufacturers based on what they saw as what was
best for them.

It\'s a little bit stressful for the system to have that happening, but
it can be accommodated.

MR. THOMAS: And then answering the second part of the question, I
believe that\'s pretty much each manufacturer will probably come to that
decision independently. I mean, there is data usually given to us when
the seed candidate arrives, but eventually based on what each of our \--
whatever process each manufacturer would follow to develop and evaluate
that seed candidate, if it would be a good candidate for their process.

DR. SCHWARTZ: So that you actually tested all three of those before
selecting that particular strain?

MR. THOMAS: Oh, yes, yeah, tested them in multiple passages. Sort of
it\'s when the race begins. When you start receiving the seed candidates
you begin very aggressively looking at each of these and try to quickly
narrow the list down for those that you would continue to evaluate.

CHAIRPERSON OVERTURF: Kathleen.

MS. COELINGH: It\'s Kathleen Coelingh from Medimmune.

And just so people know, the live attenuated has the B/Jilin strain as
the B component last year, and because we use a reassortant, the early
growth of the wild-type strains is not necessarily a good indicator of
how our reassortant will grown, but at the same time, I would agree with
what Albert said. It\'s important to get these wild-type strains in
early because we make our own reassortant. So we\'re sort of on the same
time line with CDC and the FDA and Doris Bucher and so forth.

So it\'s the same. It\'s true we need to get these strains in early, but
for different reasons.

CHAIRPERSON OVERTURF: Dr. Couch, did you \-- oh, I\'m sorry. Go ahead.

DR. HJORTH: Richard Hjorth from Sanofi Pasteur.

I\'d just like to also say about yields that I don\'t believe CDC or
CBER are that focused on assays that can really pick up differences
between yields, such as the manufacturers are. I think Nancy has
mentioned that before. You don\'t focus on early assays, especially,
before the potency reagents are available.

So I think the manufacturers are probably in the best position to
evaluate the yields coming out in the allantoic fluid, not that we
necessarily run them all the way through our process, but we look at the
allantoic fluid in a more quantitative way.

CHAIRPERSON OVERTURF: Dr. Couch, you had a comment?

DR. COUCH: Yeah, I had a question that\'s along that same line, and if
you would confirm or perhaps deny the impression that many of us have
that while we know you can balance a number of eggs you put in one
strain or another, in terms of the actual yield of a single strain, is
it true that the B is most commonly your limiting antigen?

MR. THOMAS: Historically, yes, the B strain has been limiting.

DR. COUCH: And that need for a high yield that Dr. Bucher referred to
that\'s being worked on right now still carries a high priority that it
has carried for a number of years now.

CHAIRPERSON OVERTURF: Comment from the floor?

DR. SUN: This is Wellington Sun from Walter Reed.

One question I had based on your time line, it\'s very stressful, and
you said that manufacturers manufacture the first strain at risk before
the selection. So what is the impact if the selection is the wrong one,
and how often has that happened?

MR. THOMAS: Well, probably the first impact is probably a different
person standing up here next year \--

(Laughter.)

MR. THOMAS: \-- based on the selection.

The second is I would say now that\'s manufacturing time that you just
lost. So obviously you try to make the best educated decision to pick
that strain as to which one you think is the greatest probability of
being in the vaccine for the following year.

But, again, because your overall time is fixed and you\'re working
within the time constraint of strain selection to really when do I need
to stop production to meet the last available time to distribute
vaccine. That time is fixed. So you try to find any way to potentially
build up a bit of a hedge if you have a potential low yielder. Right now
the yield, say, of the new strain is unknown. So by beginning that
production, that gives you a bit of a cover factor knowing that you
could potentially build up enough doses of the other strains in time.

But, again, obviously it is a decision made at a business risk of that
product, potentially not being able to use in the vaccine.

CHAIRPERSON OVERTURF: Yes.

DR. FARLEY: If I remember correctly, the California strain is at an
earlier phase of development from the previous presentation. Can you
comment on concerns from a manufacturing standpoint about getting a
California-like strain up and ready and going in the time frame this
year?

MR. THOMAS: I think that\'s probably similar to \-- I\'ll give you the
analogy of last year ‑- the B strain. Again, we had two strain changes
last year, both the H3N2 and the B strain, and it was actually the \-- I
believe the B/Jiangsu seed candidate we did not receive, I think, until
some time in March, which means that we had very little time to pass
that, to develop a seed candidate ready for large scale production.

Now, the issue is now currently with the A/California type, assuming
that is what is selected for the vaccine. It\'s really how successful
this process is going to be and how quickly a reassortant with
reasonable growth potential can be completed, released and given to the
manufacturers in time. You know, it\'s kind of obviously that\'s a
strain that we\'re just seeing very quickly show up, and we\'re just
beginning to receive candidates for that. It\'s really how quickly can
that reassortant be put together and a working seed developed, and what
will ultimately be the yield of that.

Probably no different than in previous years in which case, you know, a
strain shows up near the middle or end of the season and it appears to
be the right match for the next year\'s vaccine and how quickly can
manufacturers put that into production.

CHAIRPERSON OVERTURF: Yes, Dr. Schwartz.

DR. SCHWARTZ: And just to follow up on that, in the previous
presentation, it was mentioned that there were six different
laboratories working on the reassortants for the A/California strains.
Is it possible to tell us are they working on different strains or is it
all the New York/55 or are there different California-like strains that
are being investigated by these laboratories?

DR. YE: They are working on all six strains. So their own preference is
to see which strain grows well in their hand. It\'s early in the
development of the candidate strain.

CHAIRPERSON OVERTURF: Dr. Cox.

DR. COX: Just as a matter of information I\'d like to mention that at
CDC we are not using the traditional or the classical reassortment
techniques, bur rather we have decided that in this particular instance
we\'re going to actually use reverse genetics to attempt to make six,
two reassortants for California and for one other California-like strain
and we\'re choosing based on the knowledge we have about those
particular viruses.

I think a number of other labs will be using the New York/55 because it
does appear to grow better. So there will be some consistency in that,
but you know, there will be a lot of effort and some diversity, I\'m
sure, as Zhiping has said in the candidates that eventually come out.

CHAIRPERSON OVERTURF: Dr. Markovitz.

DR. MARKOVITZ: Nancy, I\'m happy to hear you\'re going to use reverse
genetics, but I have a question. I thought with reverse genetics you
have to go through a cell line before you go into eggs, and then that
brings up all of the problems of certification of the cell line. Is that
incorrect?

DR. COX: That is not incorrect, but we will be using certified cells,
certified virile cells in laboratory conditions as close to GLP
condition as it\'s possible to maintain. So we\'ll be making sure we
have introduction of no TSCs and so on, and we\'re documenting
everything so that we believe that the strains that will be made at CDC
will be suitable than to go into eggs for production should the
necessity arise.

DR. MARKOVITZ: Yeah, that sounds like a very good plan. I\'m just
curious in terms of who decides that a cell line is okay? I\'m not
speaking against that in any way. I think that\'s great, but I\'m
curious. Who gives you the green light to do that?

DR. COX: These are cells that have been certified through a long process
of testing by one of the vaccine manufacturers, and they have provided
those cells to us. FDA has the dossier on these cells, and so it\'s all
very well contained and controlled.

DR. MARKOVITZ: So it\'s an FDA decision that the cell lines are okay?

DR. COUCH: But that approval is FDA, is it not?

DR. BAYLOR: This is Norman Baylor, FDA.

It\'s not an approval, but when we get information and, say, at a drug
master file and what have you, we can review the characterization of the
cell line, and then we can give that a green light. We don\'t approve,
quote, unquote, cell lines, but we can evaluate whether they\'ve been
adequately characterized to our satisfaction to make products.

DR. COUCH: Just a clarification. I think what we\'re understanding is
that you don\'t approve a cell line. You approve a vaccine.

DR. BAYLOR: Correct.

DR. COUCH: If it\'s made in a substrate of a particular type, that\'s a
part of the review process.

DR. BAYLOR: Correct.

DR. COUCH: And that\'s what would be going on with this one also. So
it\'s still an FDA review because the vaccine has to be approved if it
had that substrate in its preparation.

DR. MARKOVITZ: Right, but I\'m wondering who at FDA. I mean who finally
says, \"Yes, it\'s okay to do this\"? I\'m a little perplexed. It sounds
very good. I\'m not in any way against this. I think it\'s a great idea,
but I just want to know who finally says yes.

DR. BAYLOR: CBER\'s office. if it\'s a vaccine, CBER\'s Office of
Vaccines.

CHAIRPERSON OVERTURF: That\'s fairly nonspecific.

(Laughter.)

CHAIRPERSON OVERTURF: Robert. Yes, Dr. LaRussa.

DR. LaRUSSA: Just a clarification. Let\'s assume a worst case scenario,
that you weren\'t able to make high growth reassortments from the
A/California-like strains. Are you saying that the reassortment that\'s
available for A/Singapore 37/04 would not be appropriate and would not
work as a vaccine strain? Because that\'s the one you do have a
reassortment.

DR. COX: Roland warned me that I would need to go first on this.

I don\'t know if you recall, but when I showed on one of my H3HI tables,
what we found when we put the Singapore/37 strain into ferrets was that
the ferret serum generated did not cover the current strains quite as
well. We went back and very carefully went through the genetic data to
see if we could find a reason for why this might be true, and we found
that there were two potentially significant genetic changes right in the
same neighborhood in the HA molecule, and although this neighborhood,
this area of the HA molecule hasn\'t typically been associated with
antigenic changes or major antigenic changes in viruses, there is right
adjacent to an isoleucine to methionine change, and changes to
methionine are fairly infrequent I would say overall.

We also see loss of a potential glycosylation site, which certainly
could affect anogenicity. So these are changes relative to the majority
of the California-like viruses.

So while the Singapore strain shares the change at amino acid/145, which
we believe is critical, it also contains these two other changes which
are not part of the consensus and may cause a slightly different
antibody response in the recipient.

So we would view the Singapore/37 strain as less than idea.

DR. LaRUSSA: So that\'s a very gracious way of saying no.

(Laughter.)

CHAIRPERSON OVERTURF: Yes, Dr. Karron.

DR. KARRON: Just as a follow-up question to that, of all the other
A/California-like strains, are any of those like the Singapore or none
of the other California-like strains have those changes?

DR. COX: Correct. None of them do.

CHAIRPERSON OVERTURF: Yes, from the floor.

DR. BUCHER: I just wanted to raise the issue of our high yield
A/Wellington strain, which was NYMC-X-155, which I had understood from
the sequencing was a step ahead of the A/Wellington and I would presume
toward the A/California type.

We had discussed this at the previous meeting, and there was a mention
of that going into ferrets. So I wondered if that had been looked at any
further. That is the highest yielding reassortant I think we\'ve ever
seen. So I wonder if that could be under consideration, as is the
A/Singapore as fail safe.

DR. COX: If you can give me two minutes to look at our data again so
that I\'m sure that I give you the correct answer, maybe we could go on
to another question and then I\'ll have the answer to that.

CHAIRPERSON OVERTURF: A question from the floor?

AUDIENCE MEMBER: Assuming all reassortants grew poorly, can a wild-type
virus be used in a vaccine?

CHAIRPERSON OVERTURF: I\'m sorry. Could you repeat that? It was not
quite clear through the mic.

AUDIENCE MEMBER: Oh, yeah, that\'s regarding discussion on the H3N2
virus. So if the reassortants obtained not growing as well as the
wild-type virus or even poorer, then can the wild-type virus originally
isolated be used in the vaccines?

CHAIRPERSON OVERTURF: Yes, Roland.

DR. LEVANDOWSKI: The simple answer is yes. The wild-type virus can
always be used in the vaccine, and that\'s what we use typically for
Influenza B, and as you recall, even for Influenza A, the A/Taiwan/186
strain was a wild-type virus which was not a reassortant.

So, yes, we would make use of whatever seemed to be appropriate. If the
question is related to the California-like strains, it doesn\'t seem
very likely to me that that\'s going to be the case because the
California-like strains as Zhiping showed are generally low to moderate
growth, if any, so that it\'s unlikely that those would be suitable for
large scale manufacturing, at least not within this decade.

DR. BUCHER: Since I\'m not a manufacturer, in our hands the New York/55
is growing quite well. We\'ve been passing wild-type along with our
reassortant passes, and it\'s gaining. So it may not be so hopeless to
use that as wild-type.

DR. LEVANDOWSKI: Thanks for that comment, but I wasn\'t saying it\'s
hopeless. I\'m just saying that generally the wild-type strains do not
grow better than the reassortants. That\'s the whole point of doing the
reassorting in the first place.

CHAIRPERSON OVERTURF: Dr. Cox.

DR. COX: Yes. So now I\'m prepared to answer Doris\' question with 100
percent accuracy. We had taken your new Wellington virus, your new
Wellington reassortant, and we put it into ferrets and did the
cross-test, and most unfortunately \-- well, the antiserum that we
generated had a very, very high homologous titer, but when you look at
the relative titers to the current strains, it covers many of the
current strains no better than the Wellington wild-type antiserum did.

CHAIRPERSON OVERTURF: Dr. Schwartz.

DR. SCHWARTZ: I just have one other question for you, Nancy, and that is
that we talked this morning about some potential limitations to the
commercial use of a vaccine that\'s made using reverse genetic reference
strain, and so I\'m just wondering if you can just describe the decision
that you and your laboratory made to use reverse genetics for this
California-like strain rather than to use traditional reassorting
methodologies.

DR. COX: Well, it was really a very \-- it\'s a forward looking strategy
really. We do feel that it\'s very important for federal laboratories to
be practicing reverse genetics on a regular basis for generation of
vaccine strains, even knowing that there are some potential intellectual
property issues associated with them.

We made this decision at a time when the North Dakota virus, which was
one of our candidates, was growing extremely poorly, and we were getting
reports back that California was also not performing well.

So we decided that we would go ahead and really work toward perfecting
the system and moving viruses through making reverse genetics modified
strains as quickly as possible just in case we were unable to generate
one using classical reassortment.

It looks now like some of the additional egg isolates that have come on
line since then are much more promising. So it may not be necessary, but
nevertheless it\'s good practice in many senses of the word, and I think
we\'ll be doing this in the future as well.

DR. LEVANDOWSKI: Yes, sir.

DR. COUCH: A very minor question. I would have guessed at least two and
possibly three other sites that are also at least trying reverse
genetics. Would you agree with that?

DR. COX: I don\'t believe so. I believe NIBSC is \--

DR. COUCH: Leaving it alone?

DR. COX: Going to use classical reassortment.

DR. COUCH: How about Japan?

DR. COX: They didn\'t make any mention of using reverse genetics. At the
WHO meeting I did discuss our plans.

CHAIRPERSON OVERTURF: Any other comments, questions?

(No response.)

CHAIRPERSON OVERTURF: We are about a half an hour ahead. So I thought we
would just go ahead and take the break now, reconvene at three o\'clock,
and we\'ll try to answer the questions for the vaccine selection.

(Whereupon, the foregoing matter went off the record at 2:33 p.m. and
went back on the record at 3:01 p.m.)

CHAIRPERSON OVERTURF: Okay. I\'d like to call the meeting to order
again.

First of all, I\'m going to have \-- Roland is going to give us a
breakdown of the options for strain selection. He\'s going to answer all
questions at this point.

(Laughter.)

DR. LEVANDOWSKI: Okay. If you\'re expecting me to boil this down to one
number, I don\'t think I can do that.

Something has happened to my slides here. Where are we? Sorry for that.

Okay. So just to summarize a little bit before I go into what the
options might be here, for H1N1 Influenza A viruses, as we heard this
morning, there are relatively few Influenza A H1N1 viruses that have
been circulating around the world, and at this point in time, there is
no firm evidence that there is any H1N2 viruses that are still
circulating.

There have been isolates sporadically from a number of areas, including
Africa, the Americas, Asia, Europe, Oceania, basically everyplace, and
there has been a single outbreak that was reported in Tunisia.

The HAs of the H1 strains are antigenically all very similar to the
current vaccine strain, which is A/New Caledonia/20/99, and the H1
viruses that are currently circulating are also generally well inhibited
by antisera from people that have been immunized with vaccines that
contain A/New Caledonia/20/99.

The high growth reassortant of A/New Caledonia/20/99 is available. It
grows well. It manufactures well, and it\'s a well know entity for the
last several years. So for H1N1, of course, the first option is to
retain the A/New Caledonia strain as the vaccine strain.

And in favor of that, as I just mentioned, most of the H1 viruses are
the most recent H1 viruses, the most recently isolated H1 viruses are
A/New Caledonia-like by their antigenic characterization. The current
vaccines do appear to be well matched for the HA of the current strains,
and manufacturing is very well worked out.

Against this might be only that there have been so relatively few
strains to analyze at this point in time, and the influenza season
isn\'t exactly over yet.

For the second option, the second option would be to use a more recent
H1N1 virus for manufacturing, and this probe here is, I think, a fairly
weak one. There might be a closer match with a hemagglutinin and a
neuraminidase of contemporary strains. I think that\'s more likely in a
genetic than in an antigenic sense.

Against this option would be that a new strain, of course, we\'re never
really sure that it\'s going to provide any superior immunogenicity or
efficacy compared to current vaccine strain, and certainly nothing has
been done to investigate what might need to be done to support
manufacturing for any new virus that would be chosen.

A third option would be to defer the recommendation, and in favor of
that, that there might be or I guess there could be some hope that there
would be some other contemporary strains that might be identified that
would look closer to what we might expect for next year.

But based on what\'s happened so far, I don\'t think we have any true
expectation that there\'s going to be any new forthcoming information on
H1N1 viruses so that that would not point to a good option.

For the H3N2 viruses, the H3N2 viruses have predominated globally during
this season, and that has actually been going on for quite a long time,
the global predominance of the H3N2 viruses.

A new variant that\'s represented by the A/California/7/2004 strain has
been identified already in many areas of the world, although it has only
been recognized relatively recently. In January, I think, is when it
really became obvious and clear from analysis of the strains that were
being collected that there was this new variant that was developing.

The HA, most of the strains have been identified, not all, but most are
antigenically distinguishable from either the A/Wyoming/3/2003 or the
A/Wellington/1/2004 vaccine strains that have been currently in use.

And as you saw from the serologies, it\'s very clear that the
overwhelming majority of new H3N2 strains are poorly inhibited by
antisera from people who have been immunized with the current vaccines
that do contain A/Wyoming/3/2003.

High growth reassortants, however, for the A/California/7/2004-like
strains are not yet available, but on the plus side, there are a large
number of egg isolates that have been recovered, and they\'re being
evaluated and work is ongoing in many laboratories to prepare high
growth reassortants that could be suitable for manufacturing.

So for the H3N2, the first option, of course, is to retain
A/Wyoming/3/2003. In favor of that would be the manufacturing has been
very well worked out. Yields are predictable, and that could all be
accomplished easily.

Not in favor of that, however, is that, as mentioned, the HAs or most of
the H3N2 viruses and certainly the great majority of the viruses in the
last several weeks are antigenically distinguishable from the current
vaccine strain.

And in addition to that serologic results from the current vaccines
indicate poor responses against the more recently circulating viruses,
and we also know that H3N2 influenza viruses are often responsible for
significant morbidity and mortality, and so this choice should be made
very carefully.

The second option is to change to use a more recent H3N2 virus, and here
in favor of that, a more recent strain is likely to provide a closer
match with the contemporary strains, and the ones that would be expected
to be going forward.

The serologic results with the current vaccines do indicate, again, that
most of the current strains are not well inhibited by current vaccine,
and, again, the morbidity and mortality of H3N2 viruses is often quite
significant.

Not in favor of this, however, is the fact that we don\'t at the moment
have a high growth reassortant for an A/California-like virus in hand,
and so yield potential for this, if that would be a choice is really
there\'s no information to go on at all on this.

The third option is to defer the recommendation, and in favor of this,
the choice does need to be made carefully because of the significance of
the morbidity and the morality, and a more recent strain might be likely
to provide a closer match for the HA and the NA.

But against this is that we already have a great deal of information
from a number of sources about their current H3N2 viruses, and we don\'t
really expect that there\'s going to be anything that we acquire that\'s
going to change, significantly change or enhance our understanding of
that in the next few weeks.

And then moving on to Influenza B, as has been pointed out and as has
been continuing for some time, the Influenza B viruses and the two known
HA lineages are co-circulating. Strains that are like the vaccine HA
have continued to circulate, and they seem to be predominant everywhere,
including in the United States.

However, there are strains that are more like the non-vaccine HA
lineage, and they\'re making up approximately 20 to 30 percent of
Influenza B viruses in the United States. Influenza B viruses haven\'t
been predominant most places, but where they have been found, the
majority of the strains have been B/Shanghai-like, and as was mentioned,
in Japan so far with their influenza season, those are the only
Influenza B viruses that are being recovered. It doesn\'t mean that that
would be true in the future, but that\'s certainly true at the moment.

We didn\'t dwell on, but there does seem to be some antigenic drift in
the non-vaccine HA lineage Influenza B viruses, and for the most part,
the B/Shanghai-like viruses, B/Shanghai/361/2002 vaccine-like viruses
seem to be pretty well inhibited by antisera from people who have gotten
the current vaccine. It\'s not as clear cut for young children where
responses may be less robust, and whereas we have information that
suggests that although responses may be reduced against the non-vaccine
lineage in adults and elderly, it\'s pretty clear cut that for very
young children who haven\'t been immunologically primed and/or boosted
with both of the different HA lineages that we can expect that
immunization with one lineage is not going to produce antibodies that
cross-react with the other lineage.

At this point no other vaccine strains have really been evaluated for
potential for vaccine production, but there are some egg isolates that
are available.

So having said all of that, the options here, again, would be the first
option would be to retain the current vaccine strain, which is
B/Shanghai/361/2002-like. In favor of that, manufacturing is very well
defined. It\'s predictable now. The predominant strains continue to be
in the same HA lineage, and they have been found in many parts of the
world.

Against this would be that Influenza B viruses not in the HA lineage in
the vaccine have been increasing in frequency a little bit in some
places, and it\'s clear that they\'re not as well inhibited by either
post infection or post immunization antisera, and in particular, in
relation to the immunologically naive young children.

That brings me to the second option which would be to change to use a
more recent B virus, and in favor of that we might get a better coverage
for Influenza B viruses.

Against that, we don\'t really know that a new strain would provide
superior immunogenicity and efficacy compared to the current strain.
It\'s not clear that non-vaccine strains will increase any further
infrequency, and again, they\'re not found in all areas of the world.

And adding another Influenza B strain may causae difficulties in
manufacturing. As you heard, the B viruses are often the rate limiting
ones these days and particularly if a wild-type virus needs to be used.

So the third option, again, is to defer the recommendation. In favor of
that, there may be some additional information that comes out about what
strains might be closer matches with the hemagglutinins and
neuraminidases of the contemporary strains.

But against that, there\'s not any way really to know whether a new
strain of either HA lineage would prove to be superior either in
immunogenicity or efficacy compared to the current one overall, and it
seems at this point, although there are still strains being collected,
it\'s not clear that there will be any additional significant
information to help to inform the recommendation.

So this is the question for the committee, just to put that up there.
I\'ll leave that up there during the discussions. Again, the question
for the committee would be: what strains should be recommended for the
antigenic composition of the 2005-2006 influenza virus vaccine? And I
would ask that that recommendation be based on consideration of the
epidemiology and antigenic characteristics, serologic responses, and
availability of candidate strains.

And I\'ll stop there.

CHAIRPERSON OVERTURF: Roland, usually it\'s intuitive in your
recommendations what you\'re recommending, but I didn\'t catch it for
the H3N2 strain. Could you be a little more precise there?

DR. LEVANDOWSKI: I\'m sorry. I\'m not sure I understand the question.

(Laughter.)

CHAIRPERSON OVERTURF: Did you have a specific recommendation for the
H3N2 direction? You gave the pros and cons of three different decision
pathways.

DR. LEVANDOWSKI: Right.

CHAIRPERSON OVERTURF: Did you have a preference for one of those
pathways?

DR. LEVANDOWSKI: Oh, you\'re asking my preference.

CHAIRPERSON OVERTURF: Yes.

DR. LEVANDOWSKI: Well, I think what is very clear is that the current
H3N2 viruses are antigenically distinguishable from what\'s in the
vaccine, and furthermore, the current vaccines do not seem to produce
antibodies that cross react with those viruses very well.

There is the difficulty of being able to prepare vaccine, but as
compared to some previous years, we\'re in much better condition because
CDC has been able to get some egg isolates very quickly for a lot of
these strains, and it puts us in the position of being able to respond.

And as you heard from the manufacturers, they have some ability to wait
to get the third strain. If there\'s a change in a strain, they have
some ability to accommodate that in their manufacturing, although
obviously, it would be ideal for them not to have any down time at all.

But there is the possibility of responding with a new antigen for the
H3N2, and I would say that the data that\'s available to us points to
that direction.

CHAIRPERSON OVERTURF: Yeah, I think I just want to clarify for the
committee. I think the options actually include recommending a lineage
reference for the H3N2 strain but could still defer, if we wanted, the
final selection until we have more information about that.

DR. LEVANDOWSKI: Okay. So I really didn\'t understand the question. Yes,
if you make a recommendation for a like strain, if it would be a
California-like strain, for example, we would expect that it would be
possible for us to meet that recommendation with whatever strains that
we find that seemed to be appropriate.

And as the manufacturers indicated, we\'ve done this in the past where
the recommendation could be met by more than one strain if that\'s
necessary.

CHAIRPERSON OVERTURF: Are there additional questions or comments from
the floor? Dr. Schwartz.

DR. SCHWARTZ: The California-like seems to be the strain that\'s
emerging, but if it were to stop emerging and the strains that we saw
circulating were more like the Wyoming or the Wellington strains that
had been used in the past, I think that the data that Nancy presented
suggested that at least based on the ferret studies that the
California-like strain would probably provide good coverage.

Can you go into anymore detail on that? Does that seem like a reasonable
assumption based on the data? And are there any other data that you
could share with us that might provide an indication that a
California-like strain would still be effective against some of those
Fujian-like?

DR. LEVANDOWSKI: I think that\'s actually a question more for Nancy than
it is for me. I don\'t have the tables of data in front of me to look
at, nor do I have an immediate response to that.

MS. COX: I think there are a couple of points I\'d like to make. One is
that that serologic data that we have from ferrets would indicate that
California antiserum does cover a variety of viruses really quite well.

But the second point I\'d like to make is that we really haven\'t in the
past seen a situation where you have a new group of evolutionarily
successful viruses which the California viruses really do appear to be
now sort of falling off the radar screen and then going backwards to a
previous strain. It might be that something even more successful and
advanced comes along that we haven\'t seen yet, but we wouldn\'t expect
to go backward.

But if we did, we would expect reasonable coverage, yes.

CHAIRPERSON OVERTURF: Any further discussion, questions?

(No response.)

CHAIRPERSON OVERTURF: What I would entertain then, I suppose, is a
motion from somebody on the committee regarding perhaps the H1N1 strain,
and then we can proceed with further discussions about the next
discussions.

Dr. LaRussa?

DR. LaRUSSA: I make a motion that we retain the current H1N1 strain.

CHAIRPERSON OVERTURF: Okay.

DR. MONTO: Second.

CHAIRPERSON OVERTURF: We\'ll start with Dr. Wharton, and please vote yes
or no.

DR. WHARTON: Yes.

CHAIRPERSON OVERTURF: Now, the motion actually, just to restate that,
was that the current H1N1 strain would be retained.

Dr. Monto.

DR. MONTO: Yes.

DR. MARKOVITZ: Yes.

DR. ROYAL: Yes.

DR. FARLEY: Yes.

DR. McINNES: Yes.

DR. PROVINCE: Yes.

COL. PHILLIPS: Yes.

DR. COUCH: Yes.

CHAIRPERSON OVERTURF: I also vote yes.

DR. LaRUSSA: Yes.

DR. SCHWARTZ: Yes.

DR. WORD: Yes.

DR. DOWDLE: Yes.

DR. EICKHOFF: Yes.

DR. SELF: Yes.

DR. KARRON: Yes.

CHAIRPERSON OVERTURF: That was unanimous to retain the current H1N1
strain.

So I think we should proceed next to a discussion about what the
committee\'s wishes would be for the H3N2 strain or the B strain for
this year. Is there any discussion or suggestions?

DR. COUCH: I\'d just like to make a comment that I think is important
for us to keep in mind with our actions, and that is that we already
have recommendations that are very specific from the World Health
Organization. You see, we used to do this, and then they met after us.
Now they meet, and we meet after them.

And harmonizing is a strong criteria for selection. If we don\'t agree
with that, I would say that we\'re in the of having to need very strong
evidence. We\'ve got manufacturers who are already underway, and that is
what they\'re doing, and their primary manufacturing sites are in
Europe, not in this country.

If we want more vaccine in this country, harmonization, I think, has to
be a part of our consideration.

Now, having said that, I would say that, you know, all of the data
points to needing to change the H3N2, and they have selected
A/California, and we\'ve heard data all about A/California. So we vote
for A/California, for H3N2.

DR. MONTO: Second.

(Laughter.)

CHAIRPERSON OVERTURF: I would agree. I think the clarification that was
necessary was to know that all we\'re really doing is voting for a
lineage. We\'re not really the ones. Obviously the virologists have to
decide how to do that, and I think that\'s all we really are voting for
at this point.

Yes, Dr. Eickhoff.

DR. EICKHOFF: A question for the maker of the motion. Is your motion to
be construed as including A/California or an A/California-like virus?

DR. COUCH: A/California is never a specific recommendation. Any time you
say that it will always be an A/California-like virus. I think that\'s
implied. Oh, sorry.

It\'s always an A/California-like virus, never a single specific virus.

CHAIRPERSON OVERTURF: So there\'s been a motion for a change in the H3N2
virus to an A/California-like virus. I guess at this point we can start
on the other end of the room and ask Dr. Karron to vote.

DR. KARRON: Yes.

CHAIRPERSON OVERTURF: You can make any comments you wanted to when you
vote.

DR. SELF: Yes.

DR. EICKHOFF: Yes.

DR. DOWDLE: Yes.

DR. WORD: Yes.

DR. SCHWARTZ: Yes.

DR. LaRUSSA: Yes.

DR. COUCH: Yes.

CHAIRPERSON OVERTURF: That\'s right. Yes.

COL. PHILLIPS: Yes.

DR. PROVINCE: Yes.

DR. McINNES: Yes.

DR. FARLEY: Yes, and my only comment, and it\'s really a question that
we can discuss after we finish, but the idea of coordinating this with
WHO\'s decision making process and the timing of such meetings comes to
mind here. I mean, we don\'t want to just be rubber stamping another
organization, but if we\'re all doing the same thing, is there some
benefit of working together in some way more directly?

So my vote is yes.

DR. ROYAL: My vote is yes.

DR. MARKOVITZ: Yes.

DR. MONTO: Yes.

DR. WHARTON: Yes, and a comment. My compliments especially to I guess my
colleagues at CDC for having had the foresight to assure the
availability of a number of egg isolates so that we\'re in a good
position this year to move forward to development of a high yield
reassortant.

CHAIRPERSON OVERTURF: Yes, Dr. Markovitz?

DR. MARKOVITZ: Yes. I\'d also like to make the same or to second that
thought, that really I was very impressed with the preparation this
year, and I think that\'s very nice.

CHAIRPERSON OVERTURF: Well, sometimes I think we are endowed with good
luck in terms of having isolates, and I think this year that seemed to
be the problem, and I think actually deferring most of the
recommendations at this point would probably have little influence.

And having been through this process now this is the fourth year for me,
that rarely results in any major change. Two to three weeks more data
just doesn\'t usually provide us with enough information. It has on
occasion.

So the next issue the B viral strain for this year, and the suggestions
and options for the B viral strains included retaining the
B/Shanghai/361/2002-like viruses or to consider using a more recent B
virus or to, again, defer that recommendation to another point in time.

So I open it up to the committee\'s discussion as to whether or not they
would like to see more data or whether they think we should vote on the
B strain now.

CHAIRPERSON OVERTURF: Dr. LaRussa.

DR. LARUSSA: Well, it seems to me that since most of the strains are
still Shanghai and we\'re not going to get a whole lot more information
and we\'re not in any position right now to recommend putting two B
strains into the vaccine, but I think at least for now it would be wise
to recommend retaining the strain, but moving towards the future to
potentially providing a pediatric vaccine with the two Bs where it\'s
most needed.

So my recommendation would be to retain.

CHAIRPERSON OVERTURF: Any other discussion? Yes, Dr. Farley.

DR. FARLEY: Well, I guess I\'m wondering what would put us in the
position of making such a recommendation. I mean, what do we need to
come together for that recommendation to make more sense?

DR. LaRUSSA: You mean of having two strains? Well, I think the studies
need to be done that you can actually get a good immune response in
young children to two strains and that you could actually provide enough
viral antigen to actually make that response.

Once that data is available, then it becomes a logistics problem of
whether it\'s physically possible, but at least you\'ll know that if it
works immunologically that you\'re going to have a constant need for it
every year, and you\'d feel much more comfortable about doing it, and
then you could go ahead and do whatever you want for the adults.

CHAIRPERSON OVERTURF: Actually, this particular issue has been discussed
almost every year that I\'ve been on this committee, and I think there
has been always a great desire on the committee\'s part to expand the B
strains.

What is unique now is that we have a pediatric option, which we did not,
and that may be a unique way to enter the problem and begin to
accumulate the data.

Yes, Dr. Dowdle.

DR. DOWDLE: I think this issue about two circulating B strains or at
least some concern about there being two types that are essentially two
groups that seem to be around at different times and changing and
prominent and so on is not new. This has been going on for a long time,
and it seems that looking back, it seems that we\'ve been more in this
quandary than we have not had this quandary. I mean it has been more of
a usual thing.

It would be very useful if I think next meeting that we could have a
little paper on Influenza B and some of the issues over the years about
how this, number one, has been dealt with, what are the issues in the
past, and what are the advantages and disadvantages of going with two
strains?

I mean, it would be nice to have some data for a change, and I think
we\'ve been faced with a lot of opinions and a lot of memories, but my
memory could be completely wrong. It\'s just certainly what I remember
in the past, and we\'ve had this discussion, many, many times.

CHAIRPERSON OVERTURF: Dr. Farley.

DR. FARLEY: I fully agree, but I wonder what will motivate. Who will do?
Who would produce the data and who\'s motivated to produce that data? Is
that the manufacturer of the pediatric vaccine or is that FDA? You know,
I guess I\'m wondering about the process so that we won\'t be in the
same place each year without some new data.

CHAIRPERSON OVERTURF: Yes, Dr. Eickhoff.

DR. EICKHOFF: I think the process or the discussion here has gone maybe
a step beyond in what Walter commented on, namely, it\'s now at a level
where are we going to talk about a whole separate pediatric product.

That raises a host of issues, and we would need manufacturer input on
it, but a pediatric use of influenza vaccine we kind of anticipate is
going to grow almost logarithmicly for the next several years. It\'s an
issue that needs to be considered very carefully, but maybe not in this
immediate framework of strain selection.

But, again, I think manufacturers will have lots to say about that.

CHAIRPERSON OVERTURF: The assumption I had from Dr. LaRussa was that he
actually is talking about expansion of the or exploring the use of two B
strains in young children, the current population in whom routine annual
immunization is now recommended, the six to 23 month old children; is
that correct?

For this year. We still have the difficulty of deciding which of the
three options the committee would like to proceed with in terms of the
option. My personal feeling is that I don\'t see it. From the data that
Dr. Cox presented this morning, it\'s clear that the B/Shanghai lineage
was about 80 percent of the isolates in the United States so that there
seems very little reason right now to change that, although there are
these disturbing data \-- there always are \-- of isolated settings
where there is perhaps a 50-50 breakdown in certain settings.

PARTICIPANT: Dr. LaRussa made the recommendation to keep (speaking from
an unmicked location).

CHAIRPERSON OVERTURF: Did you make that recommendation?

DR. LaRUSSA: Yes.

CHAIRPERSON OVERTURF: Do you want to make it as a motion?

DR. LaRUSSA: I\'ll turn it into a motion.

CHAIRPERSON OVERTURF: Okay, fine.

DR. LaRUSSA: I make a motion that we keep Shanghai this year.

CHAIRPERSON OVERTURF: Would somebody like to second that motion?

DR. WHARTON: (Show of hand.)

CHAIRPERSON OVERTURF: Dr. Wharton. Okay.

Well, we will start with you for the first vote. So the motion on the
floor is to retain the B/Shanghai isolate for the current vaccine.

DR. WHARTON: Yes.

DR. MONTO: Yes.

DR. MARKOVITZ: Yes.

DR. ROYAL: Yes.

DR. FARLEY: Yes.

DR. McINNES: Yes.

DR. PROVINCE: Yes.

COL. PHILLIPS: Yes.

DR. COUCH: Yes.

CHAIRPERSON OVERTURF: Yes.

DR. LaRUSSA: Yes.

DR. SCHWARTZ: Yes.

DR. WORD: Yes.

DR. DOWDLE: (Speaking from an unmicked location) Yes.

DR. EICKHOFF: Yes.

DR. DOWDLE: Yes.

DR. SELF: Yes.

DR. KARRON: Yes.

CHAIRPERSON OVERTURF: This may have been done in record time this time.

(Laughter.)

CHAIRPERSON OVERTURF: Is there any further discussion or clarification?
Does anybody want to speak? Dr. Eickhoff.

DR. EICKHOFF: Now that we have voted and we\'re not slavishly following
WHO recommendation, the WHO recommendation for the Southern Hemisphere
was just a little bit different than that for the Northern Hemisphere
and the B component, and a question for Roland or Nancy, I guess: do you
have any insight into why this recommendation changed slightly?

DR. LEVANDOWSKI: Actually, maybe I misled people. The serologies were
done with an older Southern Hemisphere vaccine. The current vaccine is
recommended by WHO for Southern Hemisphere includes a
B/Shanghai/361/2002-like vaccine virus. The previous vaccine that was
used in the Southern Hemisphere had B/Brisbane/32/2002, and that\'s the
serum that was available for doing serologies because the new vaccine
for the Southern Hemisphere, according to the current recommendations is
only just now being produced and used. So it was not available at the
time the sera were collected for the studies.

So maybe I confused people with that, but the recommendation, the
current recommendation for the Southern Hemisphere is
B/Shanghai/361/2002-like.

CHAIRPERSON OVERTURF: Dr. Schwartz.

DR. SCHWARTZ: I\'d just like to briefly raise three issues. Just to get
a sense, and this is the first time I\'ve been at this committee
meeting. So I don\'t know how the committee deals with these types of
recommendations, but I think Monica mentioned the possibility of
changing the timing of this meeting to perhaps more closely coincide
with the WHO meeting or at least to have maybe better communications
between the two groups.

I was wondering if that\'s a recommendation that the committee could
make and how the committee would handle that particular idea.

It has also been discussed that we believe that a pediatric vaccine
containing the two different B lineages should be studied, and I don\'t
know if there is additional force if there\'s a vote and if that becomes
an official recommendation of the committee.

Also I don\'t know if the manufacturers have candidate vaccines that
include the B/Victoria lineage and whether there is material right now
that could be used or whether new pilot lots would have to be produced
and, therefore, there would be substantially increased time and costs
involved with doing that.

The third issue that I just wanted to very briefly mention has to do
with H5N1, and Pam earlier talked about some clinical studies that NIH
is doing of investigation of lots of H5N1 vaccine, and I think it would
be useful for this committee in some future meeting to discuss under
what circumstances it might be considered to have H5N1 as a component of
the influenza vaccine which would provide priming to those folks who
were vaccinated in case H5N1 or H5 emerged as a pandemic strain.

That\'s certainly not something to talk about now, but I think it would
be an interesting discussion to have in the future.

CHAIRPERSON OVERTURF: To me the pride \-- and somebody from the FDA can
correct me \-- I would think that if there\'s a process that we really
want to devote an entire meeting or a day to expansion of the B types,
which would include presentation of data, and then an official
recommendation and a vote, I think it would require me to \-- I don\'t
think we can do that here. I think this has come up over and over and
over and over again, and perhaps it\'s something that the FDA needs to
take into hand and perhaps plan a meeting for the VRBPAC specifically to
address that single issue some time with some inclusion of data.

I think that\'s the process that has usually been used; is that correct?

Yes, Dr. Dowdle.

DR. DOWDLE: I\'m going to change the subject. Go ahead, Nancy, please.
I\'m going to change the subject.

DR. COX: Yes. Well, I was going to change the subject as well.

(Laughter.)

DR. COX: And for those of you who haven\'t been involved in the vaccine
strain selection process as long as I have, it may seem to you as if
this meeting could be a rubber stamp and that may feel uncomfortable to
you.

We used to have the U.S. meeting first. This caused a great deal of
discomfort on the part of the rest of the world which felt that the U.S.
was preempting the vaccine. It also put the U.S. at a disadvantage
because our meeting was first. We didn\'t have access to the global
data.

We had our WHO vaccine meeting in Geneva. It finished on Friday at about
noontime on Friday, the 11th. We\'re here only a few days later really
if you take the weekend into account. We were able to bring back all of
those data, the global data, and compile them. And so some of the charts
that I showed you really had incorporated the data from the other four
WHO collaborating labs as well as data from some other national
influenza centers.

And, of course, Roland was able to include the serologic data from the
other four WHO collaborating centers in his presentation. So from the
perspective of completeness, I think it is an advantage for the
committee to actually see all of the data that\'s available globally,
and so I think I just wanted to clarify that and make sure that you
understand that there is extremely close coordination between CDC and
FDA and WHO and the NIH and WHO as well, even if you don\'t see that
specifically as a committee member.

DR. FARLEY: That\'s very helpful. Thank you.

CHAIRPERSON OVERTURF: Dr. Markovitz.

DR. MARKOVITZ: If I could just add to what Nancy said, from what I\'ve
seen \-- I think this is my fourth year on the committee \-- is that
having the meeting earlier would not be good because we seem to get like
a lot of our best data within the last few weeks right before the
meeting actually takes place. So I\'m less concerned about appearance of
rubber stamp and more concerned that we have everything together to make
the best decision.

CHAIRPERSON OVERTURF: I think the only thing I would add is that at the
time the presentation is made about what the options are, I really think
we should \-- it was in the very first presentation that I think Dr.
Levandowski made this morning, what the recommendations for the Northern
and the Southern Hemispheres were, but it probably needs to reappear at
the time just prior to the vote again because I think Dr. Couch \--

DR. COUCH: I think Nancy and Roland could confirm it. The technical
comment, as I understand it, the WHO is a global recommendation, and
then it is up to each individual country and organization who deals with
these decisions to then consider and make their own independent
decisions.

But that doesn\'t negate the comment I made earlier. It\'s important for
us to harmonize unless there\'s a strong reason not to.

CHAIRPERSON OVERTURF: Norman.

DR. BAYLOR: I just wanted to comment on the comment made about in a
sense the vaccine development, like the H5N1, incorporating that into
the current vaccine and whether this body would be the one to discuss
that and make recommendations.

I think that process starts with the manufacturers and sponsors of INDs,
and we have that discussion with FDA, and there\'s a process to have
those type of meetings. And as those discussions expand and we start
moving into clinical studies, that may be something that we would bring
back to the VRBPAC, but the process will start with a discussion between
the manufacturers, sponsors, and the FDA.

CHAIRPERSON OVERTURF: Any other discussion, questions? Dr. Markovitz.

DR. DOWDLE: If I understand your question, Ben, it really is how would
an avian flu vaccine interdigitate with this one, right? So that\'s, I
think, your question. What would be the answer to that? I\'m curious,
too.

No takers.

CHAIRPERSON OVERTURF: Dr. Levandowski.

DR. LEVANDOWSKI: Well, I think there are many precedents for going all
different directions with influenza vaccines. Historically people have
been telling me all day how we\'ve had five and six antigens in the
vaccine in very early days. In early times it would be something like
PR/8 plus another H1 and B/Lee plus another B, and some of those uses, I
guess we wouldn\'t go back to doing it exactly that way.

But we\'ve had monovalent vaccines. We\'ve had monovalent supplemental
vaccines. Most recently the one that comes to mind was in 1986, the
A/Taiwan/186 supplemental vaccine. It\'s possible to have a monovalent
vaccine. I mean we\'re used to thinking about trivalent vaccine, and
that\'s a convenient way to administer the product, but in reality
that\'s just one way to do it, and monovalent is always available for
us.

And this may be a consideration not only for an H5N1 vaccine, if it
comes to that, but it could be a consideration for priming and boosting
young children as well. If we need an additional component for a
specific population that might be an alternative way to go.

But, again, thinking about how we get the different valencies of
vaccines, before H1N1 reappeared it was an AB. It was a bivalent vaccine
and nota trivalent vaccine.

So there are ways to get there, and I don\'t think there\'s anything
that\'s so set in stone that it couldn\'t be evaluated and worked out

CHAIRPERSON OVERTURF: Dr. LaRussa.

DR. LaRUSSA: Just two quick comments. Can we work on some way to get
some updates on what\'s going on with the California light strains once
you see how the reassortments work out?

And then the second thing is I\'m not sure how we left things with the
discussion about the pediatric vaccine. Is that something you\'re going
to go get back to us about, whether we could discuss that at a future
time?

DR. MIDTHUN: Karen Midthun, FDA.

I think with regard to trying to explore bivalent B vaccines in a
pediatric population that\'s certainly an excellent suggestion. I think
what\'s needed though, and I think Dr. Baylor was alluding to this in
the context of H5N1 is that you need to have a sponsor working in
conjunction with a manufacturer who is willing to undertake such
studied, and certainly we as FDA are there to work with them as they put
these particular products into clinical trials to evaluate them.

So I think the question really is, you know, there has to be
identification of an entity who is willing to make such a product, and
then there has to be a sponsor who\'s willing to take that product into
an IND. And obviously we\'re there to work with whoever would want to do
this and think that would be very good information to be able to have
for everyone\'s consideration.

But you know, we, FDA, don\'t have the ability to make let\'s say a
candidate vaccine and then conduct a clinical trial. We\'re there to
provide oversight as this goes forward, and I think that\'s certainly
hearing the discussions that have been made here. You know, we can get
together with the rest of the other agencies and Health and Human
Services and discuss, you know, are there some ways that one could
facilitate moving into that direction.

CHAIRPERSON OVERTURF: I think it\'s a problem a little bit of agency
overlap. I think there\'s issues that a lot of who makes recommendations
about research and what needs to go forward. Obviously the NIH is
involved. NVAC and other advisory committees really have to make a
decision about whether this is a viable alternative.

I don\'t know whether this committee can do anything more than get it on
the table, and I think that\'s what we\'ve done, but I still think that
it could be carried as a topic, even as a portion of a meeting some time
in the future so that we give it a little more airing.

Dr. Dowdle, did you have a question?

DR. DOWDLE: No, no, no, no, no. The point I was going to make was
exactly the same point Nancy made about a plea not to change this
meeting in relation to the WHO meeting, and just to point out that as
Bob said, if there\'s a good reason to change, we certainly could
change. And I would add that it wouldn\'t be the first time that we went
against U.N. advice.

CHAIRPERSON OVERTURF: My experience has been the same. This is my fourth
year on this committee, is that the data that are available from all
sources seem to come together for this meeting, and usually it\'s very
close to the WHO meeting. It would seem unlikely that it would be
helpful to move it back much further. We would have even less data to
try to develop our own policies and recommendations.

DR. COUCH: I have one more comment. I need to point out to this audience
my name is not Ed Kilbourne, but we continue not to give the kind of
emphasis that many of us think we should to the neuraminidase.

You see, we\'ve gotten it from when Roland talked about selections, he
didn\'t just say the hemagglutinin. He said the hemagglutinin and the
neuraminidase, and when Dr. Cox presented her virus isolates, she gave
us the evolutionary development of the neuraminidase.

It\'s an important antibody most of us think. I\'m a strong believer. We
really want the hemagglutinin as the primary antigen, but the
neuraminidase is an important second antibody. I think that was one of
Walter\'s terms one time, and we\'ve never really come to grips with
what kind of standards or that we could adopt to include the
neuraminidase.

It does contribute and it is desirable, and we do know from some of the
tests that have been done on vaccine marketed preparations that the
quantity of neuraminidase activity varies all over the map, and
presumably some of them lack immunogenicity for the neuraminidase at
all, and others are probably pretty good.

This is not to anything other than make that as a point of record, that
I think this committee needs to continue to think and to try and make
attempts to how to address the neuraminidase in some sort of standards,
and that\'s not easy in itself, for those of you who are worried about
what would you say is your standard for the neuraminidase in each
vaccine. I have my own ideas. That\'s a different discussion.

But I don\'t think we should lose sight of that antigen as an important
one that we all recognize is a part of the vaccine immune response that
we\'d like to have and somehow get it in with not hopefully in the too
distant future some criteria for its presence and appropriateness of
immunogenicity.

CHAIRPERSON OVERTURF: Dr. Schwartz.

DR. SCHWARTZ: Let me just ask you a question about that. So we\'re
talking about a number of potential California-like strains that we\'re
developing reassortants for, and so let\'s say that there are
reassortants for five different California-like strains that go to the
manufacturers.

Some of them may produce more neuraminidase than others and some of them
may grow better in eggs than others. Are you suggesting that their
neuraminidase production be a criterion for which is the best
California-like strain that could be selected?

DR. COUCH: No. I think it\'s a manufacturing product decision, not an
antigenic seed. I think that what CDC would contribute to that and the
FDA would be that if there are neuraminidase differences among the
A/California-like strains, then they would select one that is more
characteristic and more changed perhaps than A/Wellington or an
A/Fujian, just for that hope that that gets the appropriate
neuraminidase.

So far I don\'t think there have been any examples in which that\'s been
necessary, but that would be the seed control on that. No, we\'re
talking about manufacturing control on the presence and immunogenicity.

CHAIRPERSON OVERTURF: Any further comments?

Are there any further comments from the floor or the manufacturers?

(No response.)

CHAIRPERSON OVERTURF: Christine Walsh has an announcement.

MS. WALSH: I\'d just like to ask all of the committee members to please
take your red folders with you tonight. They do contain confidential FDA
material that\'s in them, and we cannot leave them in the room
overnight.

Thank you.

CHAIRPERSON OVERTURF: The meeting is adjourned.

(Whereupon, at 3:51 p.m., the meeting in the above-entitled matter was
adjourned, to reconvene at 8:30 a.m., Thursday, February 17, 2005.)