FOOD AND DRUG ADMINISTRATION

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE MEETING

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THURSDAY,

FEBRUARY 21, 2008

The Committee convened at 8:30 a.m. in the Hilton Washington, DC North,
620 Perry Parkway, Gaithersburg, MD, John Modlin, MD, Acting Chair,
presiding.

[MEMBERS PRESENT:]{.underline}

JOHN MODLIN, MD, ACTING CHAIR

CHRISTINE WALSH, RN, EXECUTIVE SECRETARY

SETH HETHERINGTON, MD, INDUSTRY REPRESENTATIVE

VICKY DEBOLD, PHD, RN, CONSUMER REPRESENTATIVE

LISA JACKSON, MD, MPH

JACK STAPLETON, MD

JOSE ROMERO, MD

THEODORE EICKHOFF, MD

ROBERT COUCH, MD, TEMPORARY VOTING

ROBERT DAVIS, MD, MPH, TEMPORARY VOTING

FRANK DESTEFANO, MD, MPH, TEMPORARY VOTING

BRUCE GELLIN, MD, MPH, TEMPORARY VOTING

WAYNE HACHEY, DO, MPH, TEMPORARY VOTING

PAMELA MCINNES, DDS, MSC, TEMPORARY VOTING

STEVEN SELF, PHD, TEMPORARY VOTING

MELINDA WHARTON, MD, MPH, TEMPORARY VOTING

NANCY COX, PHD, NONVOTING TEMPORARY

[FDA]{.underline}

NORMAN BAYLOR, PHD

FLORENCE HOUN, MD. MPH

JOSEPH TOERNER, MD, MPH

JERRY WEIR, PHD

[CDC]{.underline}

JOSEPH BRESEE, MD,

NANCY COX, PH.D

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

TABLE OF CONTENTS

Call to Order and Opening Remarks 4

Administrative Matters 4

Topic 2: Strain Selection for Influenza Virus Vaccine

Introduction 10

U.S. Surveillance 20

World Surveillance/Strain

Characterization 36

Vaccine Effectiveness Report 90

Vaccine Responsiveness 105

Availability of Strains and Reagents 121

Comments from Manufacturers 125

Open Public Hearing 149

Manon Cox, Protein Sciences

Corporation 151

Stain Selection Options/Committee

Discussion and Recommendations 161

Vote on Influenza A (H1N1) 176

Vote on Influenza A (H3/N2) 177

Vote on Influenza B 191

Discussion: Possibility extending the

number antigens in B 192

Topic 3: Clinical Development of Influenza Vaccines for Pandemic and
Pre-Pandemic Uses

Summary of FDA/NIH/WHO December 2007

Workshop 204

Update on H5/N1 Surveillance 215

Pandemic and Pre-pandemic Influenza

Vaccine Development

Issues 226

Open Public Hearing 265

Fran Lessens 267

Paul Melman 270

Committee Discussion 273

Adjourn

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

8:33 a.m.

CHAIR MODLIN: Good morning. We have a quorum at the table, so we\'ll go
ahead and get started.

My name is John Modlin. I\'m from Darthmouth Medical School, and I\'m
serving as the Acting Chair of the Vaccines and Related Biological
Products Advisory Committee today, and I\'m going to begin the meeting
by turning things over to Ms. Christine Walsh.

EXECUTIVE SECRETARY WALSH: Good morning, everyone. 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 this meeting of the Advisory
Committee.

Today\'s session will consist of presentations that are open to the
public.

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

And I would also like to request that any media inquiries be directed to
Ms. Peper Long from the FDA Office of Public Affairs. Peper\'s over
there. Thank you, Peper.

I would now like to read into public record the conflict of interest
statement for today\'s meeting. This brief announcement is in addition
to the conflict of interest statement read at the beginning of the
meeting on February 20th, and will be part of the public record for the
Vaccines and Related Biological Products Advisory Committee meeting on
February 21, 2008.

This announcement addresses conflicts of interest for topics 2 and 3.

For Topic 2, the Committee will discuss and make recommendations on the
selection of strains to be included in the influenza virus vaccine for
the 2008/2009 flu season. This is a particular matter of general
applicability.

For Topic 3, the Committee will discuss clinical development of
influenza vaccines for pre-pandemic uses. This is a particular matter of
general applicability.

Based on the agenda and all financial interests reported by members and
consultants related to Topics 2 and 3, conflict of interest waivers have
been issued in accordance with 18 USC 208B(3) and 712 of the Food, Drug
and Cosmetic Act.

Related to Dr. John Modlin. Dr. Modlin\'s waivers include a consulting
arrangement with two firms that could be affected by the Committee\'s
discussions. The waivers allow Dr. Modlin to participate fully, and vote
on the Committee discussion.

Related to Dr. Robert Couch. Dr. Couch\'s waivers include a contract
with a firm that could be affected by the Committee\'s discussions. The
waivers allow Dr. Couch to participate fully, and vote on the Committee
discussions.

Dr. Seth Hetherington is serving as the Industry Representative acting
on behalf of all related industry, and is employed by Icagen,
Incorporated. In addition, Dr. Heatherington\'s spouse is employed by
GlaxoSmithKline. Industry Representatives are not special government
employees, and do not vote.

With regard to FDA\'s guest speaker for Topic 2, the Agency has
determined that the information provided is essential. The following
information is being made public to allow the audience to objectively
evaluate any presentation and/or comments.

Tony Colegate is the influenza technical affairs manger at Novartis
Vaccines in the United Kingdom. He is a member of several European
groups which focus on influenza vaccines and pandemic issues.

This conflict of interest statement will be available for review at the
registration table.

We would like to remind members and participates that, if the
discussions involve any other products or firms not already on the
agenda for which an FDA participant has a personal or imputed financial
interest, the participants need to exclude themselves from such
involvement, and their exclusion will be noted for the record.

FDA encourages all other participants to advise the Committee of any
financial relationship that you may have with any firms, its products,
and, if known, it\'s direct competitors.

That ends the conflict of interest statement.

Dr. Modlin, I turn the meeting back over to you.

CHAIR MODLIN: Thank you, Christine.

I\'d like to begin by asking the Members of the Committee to identify
themselves, and their home institutions. And I believe we\'ll begin with
Dr. Eickhoff.

MEMBER EICKHOFF: Ted Eickhoff, University of Colorado.

MEMBER JACKSON: Lisa Jackson, Group Health, Center for Health Studies.

MEMBER HATCHEY: Wayne Hatchey, Department of Defense.

MEMBER SELF: Steve Self, Hutchinson Cancer Research Center, University
of Washington.

DR. MCINNES: Pamala Mcinnes, National Institutes of Health.

MEMBER ROMERO: Jose Romero, University of Nebraska Medical Center.

MEMBER HETHERINGTON: Seth Hetherington, Icagen Research, Triangle Park,
North Carolina.

MEMBER DeBOLD: Vicky Debold, National Vaccine Information Center.

MEMBER COUCH: Robert Couch, Baylor College of Medicine.

MEMBER GELLIN: Bruce Gellin, Department of Health and Human Services.

MEMBER DAVIS: Bob Davis, Center for Health Research, Kaiser, Georgia.

MEMBER STAPLETON: Jack Stapleton, University of Iowa.

MEMBER DESTEFANO: Frank Destefano, RTI International.

MEMBER WHARTON: Melinda Wharton, Centers for Disease Control and
Prevention.

MEMBER COX: Nancy Cox, Centers for Disease Control and Prevention.

DR. BAYLOR: Norman Baylor, FDA, Center for Biologics, Office of
Vaccines.

DR. WEIR: Jerry Weir, Center for Biologics, Division of Viral Products.

CHAIR MODLIN: As you\'re aware, the topic of this morning\'s meeting is
the strain selection for influenza vaccines for the 2008/2009 influenza
season for the United States. We\'ll begin with Dr. Jerry Weir, from
CBER, who will be giving us an introduction to today\'s meeting.

DR. WEIR: Thank you. Good morning. I\'m Jerry Weir, from the Division of
Viral Products at CBER, and I\'m going to provide a brief introduction
to this morning\'s session of the VRBPAC.

As you know, the reason we\'re here today is to ask the VRBPAC Committee
to recommend strains that should be included for the 2008/2009 influenza
vaccines for the United States. This includes two strains of influenza
A, an H1N1, and a H3N2, as well as a B component for the vaccine.

The reason that we consider strain changes each year for influenza
vaccine relates to the efficacy of the vaccine. And essentially, the
efficacy of the vaccine is determined by vaccine potency, and the
immunogenicity that it elicits, as well as a match of the vaccine
hemagglutinate, and neuraminidase antigens with wild-type viruses.

As everyone knows, antigenic drift of HA and NA is continuous in
influenza A and B, and there was evidence of reduced vaccine
effectiveness resulting from antigenic drift noticed within two years of
the first licensed influenza vaccines in the United States.

Each year, when we go through this process of selecting the strains to
be included in next year\'s vaccines, the Committee asks itself four
questions:

The first, are new drifted or shifted influenza viruses present?

Are these new viruses spreading in people?

And do current vaccines, the ones that are currently in use, induce
antibodies against the new viruses, specifically to the HA
hemagglutinate?

And finally, last but not least, are strains suitable for vaccines
available so that manufacturers can produce vaccines for the next year?

In the next two slides, I want to spend a couple of minutes reviewing
what we did last year at this time. This is a review of the influenza
strain selection for 2007/2008, in other words, the current year. We
were here about a year ago, I think actually in the same room, to go
through this process, and select the strains, the H1N1, the H3N2, and
the B strain for this year\'s vaccine.

When we met last February, the vaccine that was in use at that time, the
2006/2007 vaccine, contained an H1N1 that was an A/New
Caledonia/2099-like strain. It was observed from the surveillance data
that there was an increasing percentage of antigenically distinguishable
H1N1 viruses present in the world. And the recommendation that the
Committee made last year at this time was to switch the H1N1 vaccine
component to an A/Solomon Islands/34/2006-like virus for inclusion in
the 2007/2008 vaccine.

For the H3N2 component, at this time last year, the vaccine in use in
2006/2007 contained an A/Wisconsin/67/2005-like strain. It was also
noted at this time last year that there was an increasing percentage of
antigenically distinguishable H3N2 viruses that were being isolated
worldwide. However, at this time there was no emergence of a well
characterized variant group, and also at this time last year, there was
no candidate virus for manufacture that was available that gave more
complete coverage of the entire spectrum of H3N2 isolates.

So the recommendation of the Committee was to retain the H3N2 component
of the vaccine, and that was an A/Wisconsin/67/2005-like virus.

And finally, for the B component of this year\'s vaccine. When we met
last year in February, the 2006/2007 strain contained a
B/Malaysia/2506/2004-like strain from the Victoria linage of B viruses.

The majority of B influenza isolates at this time last year belonged to
the B/Victoria lineage, although, as always, both lineages were present
at different parts of the world.

The recommendation last year was made to retain a B vaccine strain
similar to the B/Malaysia/2506/2004-like virus.

And so, as a result of all of the deliberations of the Committee and our
recommendations last year were for the U.S. vaccine composition to be
the same as that recommended by the World Health Organization. The
result of this was that the preparation of vaccine for the current
season was on schedule, and the supply was plentiful. However, recently
mismatches have been noticed between the strains included in this
year\'s vaccines, and strains that are currently circulating now, the
winter of 2007/2008. And this is particularly the case for the H3N2
components, and the B components of the vaccine.

I\'ll remind everyone that we now have quite a few licensed influenza
vaccine manufactures, and so the recommendations apply to an increasing
number of companies that manufacture vaccine both here, as well as the
rest of the world.

For inactivated seasonal vaccines, we have vaccines from Sanofi-Pasteur,
Novartis, GSK, ID Biomedical and, most recently, CSL.

We have one licensed influenza live attenuated influenza vaccine made by
Medimmune.

I\'ll also remind everyone that the entire process of strain selection
is fairly fixed, and somewhat rigid. This is due to the nature of the
situation of influenza.

If you look at the bottom of this slide, you\'ll see that the process of
surveillance, trying to identify new strains is a year long process.
This is ongoing all the time. However, recommendations for strains to be
included in the vaccines typically take place twice a year; (1) the time
of year now in February for the northern hemisphere season next year,
and then in the fall, in early September, usually the strain selection
for the southern hemisphere takes place. But if you notice in the
middle, preparation, seed viruses, monovalents, trivalent formulations,
all of these take quite a bit of time. And, of course, it\'s very
complex and difficult to get all three strains manufactured for
inclusion and distribution of the vaccine in time for use in the
northern hemisphere, which is shown at the very top from October through
January.

Now recently, last week, in fact, the World Health Organization convened
a group of influenza experts in Geneva to make recommendations for the
composition of influenza vaccines to be used in the northern hemisphere
winter of 2008/2009. Influenza experts from all the different WHO
Collaborating Centers met in Geneva on February 11th through 13th, and
there they analyzed the antigenic and genetic characteristics of
seasonal influenza strains circulating globally, taking into
consideration epidemiological data on influenza obtained from different
countries and regions. And at the end of their meeting, they made
recommendations for the composition of influenza vaccine for the
northern hemisphere 2008/2009 season.

This can be found on their website. But to summarize in this slide,
their recommendation was that vaccines for use in the 2008/2009
influenza season northern hemisphere winter contain the following:

An A/Brisbane/59/2007 H1N1-like virus;

An A/Brisbane/10/2007 H3N2-like virus, and;

A B/Florida/4/2006-like virus.

As you will note, all three of these are different from what is
currently in the vaccine now in use in the northern hemisphere.

They also noted that, as in previous years, national control authorities
should approve the specific vaccine viruses used in each country. And
this is why we\'re here today, because this is the role of CBER and the
VRBPAC to select the strains for use for vaccines in the United States.

Toward that end, the agenda that we\'ve set up today will be to focus on
the strains that we should recommend, and this slide shows briefly what
we will present today.

We\'ll have a review from Joe Bresee of CDC on recent influenza virus
surveillance data in the U.S., as well as some data on vaccine
effectiveness.

Nancy Cox, also from the CDC, will review world surveillance data, and
provide some information about strain characterization.

We\'ll then have a presentation from The Department of Defense by Angela
Owens and Thomas Gibson, who will talk about their data on vaccine
coverage and effectiveness, as well as some sequence analysis of
different virus isolates.

Zhiping Ye from CBER will review serological responses to current
vaccines, and Rajesh Gupta will provide an update on the availability
and timing of candidate strains and reagents.

And at the end of that, Tony Colegate, from Novartis, but who represents
PhRMA, will provide comments from manufacturers.

After that, the Committee will discuss and recommend the strains that
should be included in the vaccine. And as a preview, I\'ll provide this
slide now, but then I will come back up at the time the Committee begins
its deliberations and flash this back up. But it\'s essentially the same
question that we ask every year, and that is, what strains should be
recommended for the antigenic composition of 2008/2009 based on the
epidemiology and antigenic characteristics of the influence virus
strains circulating in the human population, the serologic responses to
circulating influenza viruses of persons immunized with the current
influenza virus vaccines, and of course, the availability of vaccine
candidate strains.

I\'ll also give you some various options to consider, and we then will
talk and make recommendations.

And that\'s all I have for the intro, and I guess unless there are
specific questions about this, we\'ll move on to Joe Bresee.

CHAIR MODLIN: I don\'t believe there will be now, but let\'s move on.
Dr. Bresee?

DR. BRESEE: Good morning, everybody.

Can I have my slides, please?

My name is Joe Bresee. I\'m from the Influenza Division here at CDC.

I hope everybody can hear me.

I\'m going to briefly, very briefly, take you through what we know about
this season as an appetizer for the meat to follow, maybe.

We\'re going to start with geographic spread. I\'m going to show you a
series of maps. These are the maps that we get from state health
departments each week. Notice that, even in November, we start counting
the season, and they start reporting in early October, the last day of
September this year, but even six weeks into the season in early
November, there was very little activity in the nation. No regional
disease yet, only three states reporting local disease, even six weeks
into the season this year. And I\'m just going to flip you through, just
to let you know how the season progressed.

Even by December, there were a handful of states with local disease,
which just means that they were identifying increased activity in one
location in a state, but nobody yet was reporting regional disease,
which would mean there is increased influenza activity in at least two
parts of the state, or regions of the state. And really wasn\'t until
the last week of the year, when we first started seeing regional
activity reported by state epidemiologists in a handful of states, and
the season actually really got going about mid-January this year, when
the first states started reporting widespread disease.

And I\'ll flip through the last four weeks, and as you see over the last
four weeks, increasing numbers of states have been reporting widespread
disease up until this last reporting week, ending last week, where there
were 44 states that reported widespread activity, 49 states reported
regional activity, just illustrating that really the same phase, or at
the same time, pretty much the whole country is reporting widespread or
regional disease in the United States. So a slow start to the season,
but over the last four or five weeks, we\'ve seen rapidly increasing
levels of disease.

The viruses we\'re seeing are represented here. And I apologize for this
small font for those unfortunate enough to be in the back. But let me
just show you what this means.

These are the viral lab data that we get reported to CDC. States around
the country will report each week the number of samples they test and
the proportion positive, and then report us any information they have on
type or subtype. And this is by week this histogram.

The bars represent the numbers of isolates that are influenza positive.
The line graph, which may be difficult to see at the back, represents
the proportion of all samples tested that are positive.

And what you see here again is that, early in the season, there was
relatively little activity. Most of it was A, and most of that was H1
early in the season. Really since mid-January, we\'ve had increasing
levels of activity in the nation, represented here by the increasing in
proportion positive, and increasing over time that the proportion of the
viruses that are H3, and I\'ll show you that in two seconds.

Right now, from September 30th, a little over 80 percent of the samples
that are the reports coming to CDC are of A viruses, 17 percent are B,
and of the viruses that are reported to have been subtyped, about 60
percent are H3, and about 40 percent are H1 viruses. And, again, this
represents a shift in recent weeks to H3 from H1.

This is represented, same curve, different box. This is the last week\'s
data that were completed yesterday.

Last week, again, we\'re getting the 80/20 A/B split, but again, this
represents the fact that, over the last few weeks, we\'ve seen
increasing numbers of H3s, 90 percent of the viruses that were reported
to be typed last week were H3 viruses, and only about 10 percent were H1
viruses.

At CDC, we monitor influenza associated mortality in two different ways.
I won\'t go through all the surveillance systems, because I suspect that
folks in here are well aware of them. I\'m happy to answer questions
about them, though.

This is our 122 cities system, which monitors the proportion of death
certificates that pneumonia or influenza listed on them by the week in
the United States. This is for each season. Our season here is on the
far right side of the screen, and what you see is that, for six weeks
running, the proportion of deaths attributable with a pneumonia and
influenza designation on the death certificates have exceeded an
epidemic threshold for six weeks running, and currently are about 8.1
percent of deaths are P and I associated deaths.

If you compare this year, both the height of the curve, the slope of the
curve and you get a hint of the area under the curve, the amount of
excess P and I mortality is not too dissimilar to these two years, three
and four years ago, in which H3N2 was the predominant strain. But it\'s
slightly higher than the last two years, which have been relatively mild
years.

The other way we look at mortality is pediatric deaths. These are a
nationally notifiable disease. All kids under 18 that die that have an
influenza positive test are meant to be reported to CDC.

Again, the far right side of this graph represents data from this
season. We\'ve had 22 pediatric deaths that have had an influenza
positive test reported to CDC so far this season. And again, I just want
you to see this compared with last year, when there were 73 such deaths
reported over the season, and the year before, when there were 46 such
deaths reported. That the slope of the curve, the height of the curve
and the look of curve really is consistent with what we\'ve seen since
we\'ve been monitoring this outcome over the last three years.

We\'re still in the middle of the season, and how this will look at the
end of the season is uncertain.

Briefly, outpatient disease, you guys have seen these curves, probably,
that have looked at our website, I hope. This is this week\'s season,
again, and just to say that the proportion of visits to sentinel
physicians that are associated with influenza-like illness is above a
seasonal baseline. The red curve we\'re looking at here is CDC data, and
it\'s above baseline in all nine regions this week, again showing
diffuse levels of illness, or levels of illness that are increased
diffusely across the nation.

We monitor hospitalizations. I won\'t go through it. Just to say that
these red curves here that no one in the back can see at this point
represent that the rates of pediatric hospitalizations are consistent
with the rates seen in previous years so far this season.

I\'ll mention briefly a word about antiviral resistance, because it\'s
been in the news lately. These are data that were produced by Dr. Sasha
Klimov and Dr. Larissa Gubareva at CDC just yesterday, and updated just
yesterday, and shows that, since September 30th, of the influenza
viruses that CDC has tested for Oseltamivir resistent, 27 of the 471, or
5.7 percent have been found to be Oseltamivir resistent. All those
resistent strains, all 27 are among H1s. And if you look at just the
H1s, you subset those out, 8.1 percent of the H1s tested so far this
year are resistent, all with the same point mutation, which is clearly
the most common mutation that confers resistance to Oseltamivir among
H1s.

Importantly, no resistance has been found, either among H3s, or among
these so far this season. The 27 cases come from all regions of the
country. The cases for which we have data, which represent about 16 of
the 27 so far, don\'t have any travel history that would be concerning,
for outside the United States, at least, and the cases don\'t have any
known Oseltamivir exposure, either personally, or in a household member
around the time of the illness.

Importantly, all the H1N1 isolates that \-- all 27 that we found that
are Oseltamivir resistent are susceptible to Zanamivir and adamantanes
so far.

And just to give you a quick update about adamantane resistance. Again,
I apologize to those in the back that can\'t see this, but so far this
year, we\'ve tested 282 influenza viruses for adamantane resistance; 99
percent of the H3/N2, I think 98.6 to be exact, are adamantane
resistent, and about seven percent of the H1s are.

Principally H1s have been tested, the lion\'s share of the viruses
tested have been H1s, just because that\'s what\'s been circulating up
until now in the U.S.

Just to compare our 8.1 percent resistance among H1s to what\'s been
seen in other countries, The global proportion of resistance is 14
percent. If you break that down, Europe\'s slightly higher, really
driven by a couple of countries, France and Norway, but the U.K has
similar proportion resistent compared with the U.S., and Canada, as you
see here, is six percent, not much different than our 8.1 percent. There
have been very few viruses tested relatively from Africa or Latin
America at this point.

Just my Public Health brain working. To investigate the Oseltamivir
resistant, we\'ve done a couple of things. We\'ve increased surveillance
in the United States, we\'ve increased the number of viruses that we\'ve
looked at, we\'ve solicited viruses from our Sentinel providers and our
state health departments, and we\'ll continue to do that throughout the
season to better monitor where this curve is going.

We\'ve also undertaken a system by which we\'re collecting fairly
detailed clinical and epidemiologic data on each resistant case, with
the intention of looking for risk factors and clinical characteristics
of these cases relative to susceptible cases.

We\'ve embarked on a fairly aggressive communications campaign, which
I\'m happy to go through later. But in short, our policy for the use of
Oseltamivir hasn\'t changed yet, principally for two reasons: (1)
because the level of resistance among As, or among flu viruses generally
is quite low, and all the resistance is among H1s at this point, which
comprise a relatively small, a minor proportion of the viruses isolated,
and probably with H3 predominating, even a less major role in the coming
weeks.

I want to mention this; Jerry had mentioned that I would, and so I will.
CDC, for the last three years, has established mechanisms to look at the
effectiveness of the vaccine each year in the United States. This year,
for the first time, we are testing methods to measure the effectiveness
of a vaccine during the year, at different time points during the year,
and we\'ve started that this year.

We\'re doing it in a population in the midwest that comprises people, or
groups, who are recommended by the ACIP to receive annual vaccination.
That\'s our study cohort. We follow these folks for medically attenuated
clinic visits, really, for influenza that\'s diagnosed or documented by
RTPCR. And their exposure history, their vaccine history, is measured or
confirmed with a validated vaccine registry.

I won\'t go through the methods or the results in any detail, only to
say that the population we\'re studying only started getting increased
flu about two and a half weeks ago, or we have about two and a half
weeks of data. In this two and a half weeks, they enrolled 616 patients
in the study; about 30 percent were flu positive, most of those were
influenza A, though we don\'t have the subtype information yet. We do
know that, in this area, H3s have predominated this year from other
data.

Preliminary results indicate that there is some protection in this
population among the influenza A viruses. And again, if that\'s H3
circulating, that\'s probably good news.

There\'s no protection against influenza B viruses yet that we\'ve seen,
though a relatively small fraction of the cases have had influenza B
viruses isolated from them.

We\'re continuing enrollment of the study to build up our sample size,
and so that we can make our numbers more precise and more reliable.

The laboratory at CDC is looking at the strains from the study so we\'ll
be able to create type and subtype specific vaccine effectiveness
estimates, and we will report these data out in the next few weeks,
probably as an MMWR.

There we go.

My last note is next Wednesday the ACIP will be voting on influenza
vaccine recommendations for the coming year. I\'ll just highlight the
fact that this year\'s discussion and the vote will be around whether or
not to expand influenza vaccine recommendations to children between six
months and 18 years of age, and so expand to five to 18 year old
children \-- five to 17 year old children, and whether that expansion
will be done this coming season, or in the seasons to come.

That\'s all I have. Thank you very much.

CHAIR MODLIN: Thank you, Joe. I think we\'ll go on with Dr. Cox\'s
presentation on global surveillance and then, hopefully, we\'ll have a
little bit of time for questions on this segment right after her
presentation.

MEMBER COX: Well, good morning, ladies and gentlemen. Because some of my
slides are visually challenging, and I\'m visually challenged myself,
I\'m going to stand over here so that I can point things out more
easily.

First, I\'m going to start out with the review of the laboratory data
for influenza A H1N1 viruses.

This is a compilation of global data that was done by the WHO
Secretariat based on reports from the National Influenza Centers in
about 93 countries \-- or actually about 120 countries around the world.

So you can see that, for H1N1, the U.S. had quite intense activity
during the early part of the year. This is the compilation from
September to January. We also have slides going through month-by-month,
but that just takes too long. And there was a lot of activity in Europe,
and Europe has experienced predominately H1N1 activity.

There was still a bit of H1N1 activity in the southern hemisphere during
this period, sort of at the end of their season, and China experienced
very little H1N1 activity compared to H3N2.

Okay. Now we start the data dense portion of the talk. And I\'ll really
try to keep this as simplified as possible.

Remember, what we are looking at here, for those of you who have been
here before, you\'re looking at the reference strains up here. These are
important strains that have been used in our lab, and often in a number
of other laboratories, Collaborating Center laboratories, and we have
made reference, ferret antisera to these viruses by infecting ferrets.

Then we have our test antigens, starting here and going down.

We have highlighted in yellow the column here for the Solomon Islands
vaccines strain that was included in this year\'s northern hemisphere
vaccine. And so what we\'re looking for is a difference in titer
relative to this homologous titer, that is the way that the Solomon
Islands virus is inhibited by ferret serum to itself. And what we\'re
looking for are numbers here, or the ability to inhibit antibody that
are actually four-fold or greater reduced in titer. So I hope that\'s
clear to most of you.

So when we see these viruses that are four-fold reduced, we have taken
those viruses and put them into ferrets to really try to see if it\'s
truly an antigenic variant, or just a low reactor of some kind.

Now, you do get ferret-to-ferret variability. Some antigens just simply
induce a better antibody response in ferrets. We don\'t understand the
nature of that, but nevertheless, we\'re looking at titers relative to
the homologous titer.

What we have seen at CDC, less dramatically than at other WHO
Collaborating Centers, is that, more recently, we\'re seeing viruses
that have four-fold and eight-fold reduced titers as compared to the
homologous titer for Solomon Islands.

We were provided with a strain called A/Brisbane/59/07 by the Australian
WHO Collaborating Center, and this antiserum to this strain seems to
cover those viruses better. We get higher titers here than antiserum to
the current vaccine strain.

We also have another virus, called South Dakota/6, which is considered
to be Brisbane/59-like, and it behaves similarly in our tests.

Now, if we just look at CDC data alone, we can see that, of the 184
viruses, H1N1 viruses that we\'ve tested that have isolation dates
between October 2007 and the current time, about 11 plus 13, or 24
percent of them have reduced titers. That wasn\'t terribly dramatic,
from our perspective, but other WHO Collaborating Centers were seeing a
bit different pattern, and have been seeing a bit different pattern for
a few months. So these are data from the WHO Collaborating Center at
Mill Hill in London. And here you\'ll see the homologous titer of 640
with the Solomon Islands vaccine strain, and you\'ll see that there are
a lot of what we would call low reactors down here at the bottom. And
these are relatively recent strains, mostly from November, December and
January.

So when they looked at antiserum, they had an antiserum against the
Brisbana/59 virus produced in Australia, and they saw much better
reactivity here than they did here. And then they produced their own
ferret antiserum, and got a similar pattern.

When the data were compiled from all four WHO Collaborating Centers, you
can see that, if you look at the low reactors that are down eight-fold
or greater, the Australia Collaborating Center was seeing a much higher
proportion than we were at CDC at the time these data were compiled.
They aren\'t the most recent data, but they are the compiled data that
were available for our meeting in mid-February.

And also, there was a much higher proportion that were low reactors to
Solomon Islands in London, as I mentioned. The other two Collaborating
Centers saw lower proportions.

Okay. So now we\'re moving on to the genetic data. The genetic data are
used as an adjunct to our antigenic data, and they\'re very important
because they really help us understand the relationships between the
viruses that we use as our vaccine strains, and as our reference
strains. And it\'s very important to note that sometimes you will see
quite striking differences in the genetic grouping of viruses, but you
do not see a difference in antigenicity. So you have to take the two
different types of data together. You have to look at the genetic data,
and you have to look at the antigenic data together to make sense of
what is actually going on.

Now, you just need to really focus on the colors here. You don\'t need
to strain your eyes and try to read these names, but the most recent
strains are shown in pink and purple. So we have our vaccine strain down
here, Solomon Islands/3/2006 in a grouping that we called 2A. This group
two has now split out into three groups, 2A, in which the Solomon
Islands virus resides, 2B, in which the South Dakota and Brisbane
viruses reside, and which compromises the majority of the currently
circulating viruses, and 2C. And we do have a few egg isolates up here.

Now the Oseltamivir resistant viruses are all in group 2B. I have
designated, using these little triangles, those viruses that are
amantadine and rimantadine resistant, and they are in group 2C. So the
viruses, as Dr. Bresee said, that are resistant to Oseltamivir, are
sensitive to Zanamivir, another neuraminidase inhibitor, and to the
adamantanes, as well.

So I hope this gives you a bit of a reference. Once again, here\'s the
vaccine strain, here is the WHO recommended strain,
Brisbane/59/2007-like. South Dakota is another potential Brisbane-like
strain, and then there\'s another group up here.

Okay. Here is an evolutionary tree for the neuraminidase genes. Now
remember that the neuraminidase gene is the gene that most often carries
resistance to the neuraminidase inhibitors, as would make sense.

And the viruses that are resistant to Oseltamivir are down here, and all
of their neuraminidases cluster together, while their HAs form three
separate groups.

So here\'s another Oseltamivir resistant virus down here. And Japan,
most of the European viruses cluster here. You can see one from Norway,
and one from France. And the Japanese viruses, actually, are in a little
bit separate group. I think they\'re falling out somewhere up here.

Now, if we just look at the neuraminidase sequences, we can see there is
a lot of diversity here. But the neuraminidase genes have fallen
predominately into the group 2B situation, whereas we don\'t see the
neuraminidase of current viruses falling into the group where the
vaccine strain is.

Now just \-- I know that Zhiping will be covering the serologic
responses, but I thought that it would be nice to put up CDC data for
the pediatric serologies that we\'ve done. All of these children are
between the ages of six months and 34 months, and these children
haven\'t been immunized before. This group is one that\'s been
recommended for immunization and, of course, they\'re being immunized in
greater numbers. So we really want to know how they respond to vaccine.

We\'re still looking at responses after the first dose compared to after
the second dose. And then, because these children haven\'t been exposed
to a wide variety of influenza strains before, obviously, they have
responses that are really very clear cut. And so what we were able to
see, and this was reflected in the data for adults and the elderly, but
what we were able to see very clearly is that children who had two doses
of the Solomon Islands vaccine mounted a very robust response with the
post-geometric mean titer of 202 after the second dose.

When we tested the same serum against the Brisbane, South Dakota and
Cambodia strains, we saw much reduced titers of between 15 and 26. Those
are geometric mean titers.

The same pattern is shown for this separate set of serum that was
provided to us by FDA. Here we don\'t have the titers post the first
dose, but we do have a nice robust antibody response after the second
dose, and a clear diminution of titer to the Brisbane, South Dakota, and
Cambodia strains.

So in summary, H1N1 viruses predominated in most countries worldwide,
and caused outbreaks in some. Many of the viruses were closely related
to Solomon Islands/3/2006. There were a few that were New
Caledonia-like, which was the previous vaccine strain. But there really
was very clearly an increasing proportion of viruses that were
antigenically distinct from the A/Solomon Islands vaccine strain, and
more closely to A/Brisbane/59/2007.

The majority of the HA sequences were in clade 2B, and of course
Brisbane is in clade 2B.

Now there was, as Joe mentioned, an increasing proportion of clade 2B
neuraminidases with this particular mutation, that\'s been well
characterized for a number of years as being a mutation that confers
resistance to Oseltamivir.

Importantly, Oseltamivir-sensitive and Oseltamivir-resistant viruses are
antigenically similar to each other, so we don\'t have to consider this
in our vaccine strain selection.

So the WHO recommendations, based on data from the four Collaborating
Centers, and many national influenza centers, were to change the H1N1
component of the vaccine for the northern hemisphere, and update it to
an A/Brisbane59/2007 (H1N1)-like virus.

We\'ll move right along now to H3N2 viruses. This is a cumulative map of
the H3N2 activity globally from September to January, September 2007 to
January 2008. You can see that we\'ve had widespread outbreaks in the
United States. Compared to the rest of the world, the United States has
really had more H3N2 activity than any other country.

During this period of time, there was some residual activity in the
southern hemisphere as their season wound down. And China is actually
having H3N2 activity, but their season doesn\'t seem to be, or hasn\'t
seemed to be quite as intense as ours.

Okay. Now if we look at the data. This is the test that\'s been done
with guinea pig red blood cells, and we do see some differences when we
do our H3 test with guinea pig red blood cells versus turkey red blood
cells, which is the standard red blood cells used.

Here you can see the homologous titer for the current vaccine strain.
Wisconsin/67/2005, the homologous titer\'s quite high here, 2560. And
you can see down here a number of the viruses with lower reactions,
really quite markedly reduced from 2560 down to 160, and 320, and so on.

Here in the second column we have Brisbana/10/2007. The homologous titer
is 640. And we can that this antiserum covers the currently circulating
viruses very well. We have a number of other viruses over here. In
particular, I would like to point out the Uruguay/716/2007 virus, which
is Brisbane/10-like.

Now last year at this time, and I think this is very important, the two
groups of viruses that we were looking at most closely were the
Nepal/921 and Henan/147 viruses. Now these were in two slightly
different genetic groups. We were concerned about them, but then, in
fact, they didn\'t take off, and Brisbane-like viruses popped up after
our decision had been made in February last year.

So in terms of our frequency data, we have tested a total of 90 H3N2
viruses. That number will be going up rapidly as we are receiving an
enormous number of packages from state health departments and others. Of
those 90 viruses, about 82 percent are Brisbane/10-like, just a few
viruses were well covered by antiserum to the Wisconsin virus, and then
we have a few viruses that are lower to Brisbane. And that always
happens. That\'s not unusual.

Here I\'ve included an HI table from the laboratory in Melbourne for
completeness, because I wanted to make sure that you realized that, when
we make vaccine strain recommendations, we\'re really relying on data
from around a world. In Melbourne, they get quite a few viruses from
Asia, Singapore, Thailand, the Philippines, and so on.

Here is their 640 homologous titer with the Wisconsin/67 virus. And you
can see that coverage here, these titers are relatively low, in the 40s.
Many of these in the 40s, and some even less than 40, which is their
cutoff.

In contrast, we have the homologous titer of 640 for the Brisbane/10
virus, and we have better coverage, much better coverage, relative to
the Wisconsin, of the currently circulating viruses. Although there are,
as I mentioned before, some low reactors.

If we look at all of the data collected as of mid-February by the four
WHO Collaborating Centers, and this was compiled, as I said, by the WHO
Secretariat, the majority really could be characterized as
Brisbane-like, but there were low reactors, and in some WHO
Collaborating Centers, there were more low reactors than others. And we
don\'t really know the meaning of this. I think that we\'re going to be
doing a variety of tests in conjunction with the other Collaborating
Centers looking at different red blood cells, and a whole variety of
different ways to test these viruses to understand what\'s actually
going on.

Now, over recent years, we\'ve been engaged with a group that is at
Cambridge University headed by Derek Smith. And Derek, we provide all of
our data to Derek, and he does what is called antigenic cartography,
which is basically to say he uses some number crunching programs that
take our HI tables, and reduce them to a visual display that\'s actually
much easier to understand than the reams and reams of paper, and
hundreds and hundreds of numbers that we have to look at. It\'s not to
say that we don\'t get exactly the same gestalt that he gets, that he
presents by looking at all these tables every week, but this is a nice
way to display what\'s going on.

So you\'ll remember we had a large epidemic caused by the Sydney/97
virus, the Wyoming/303 vaccine strain is shown here, and you can see
that there are some viruses clustering around there in the light,
uncolored circles.

Here\'s the New York/5504, and here\'s Wisconsin virus here. And we\'ve
got a lot of scatter of the current viruses out here when they\'re
plotted in this way. And here\'s the Brisbane/7 virus. So these viruses
are closer to the Brisbane/7, but you do see these outliers. And we\'re
trying to, as I mentioned, trying to figure out what\'s going on.

I just have one more slide. These are relatively few data points, but
again, the most recent viruses were closer to the Brisbane/10 than to
the Wisconsin virus.

Okay. I think that my slides may be \-- okay. If we now move on to the
sequence data, you\'ll see right along here that you have a lot of
viruses that are in what we are calling the Brisbane/10 group, or
Brisbane/10 lineage. I\'d like to point out that the viruses that we\'re
really concentrating on as potential emergent viruses last year are down
here at the bottom of the dendrogram, and we have seen only one virus in
recent time that could be put in that group, and that was a virus
isolated in September from Massachusetts.

There is, as you can see, quite a bit of genetic variability, as pointed
out by these amino acid changes, that are key in terms of distinguishing
these different nodes on the dendrogram.

What I would like to point out is that the Brisbane/10 virus is here.
It\'s actually a February 2007 isolate that wasn\'t on our radar screen
last year during vaccine strain selection. But clearly, there are some
changes that have occurred that are common to all of these viruses, and
then there are some individual differences among these strains.

I should point out that all of the viruses that have the hatch marks
after them or the pound signs after them are egg isolates. And in
contrast to what we\'ve seen for H1N1 viruses, we find H3N2 viruses very
difficult to propagate in eggs. And so we have to go first into kidney
cells, which an acceptable substrate, and then pass on into eggs.

So we have the Uruguay egg isolate here, and it\'s considered to be
Brisbane/10-like.

I\'ll move on to the neuraminidase genes. We see exactly the same
pattern for neuraminidase genes. There are a number of changes that
occurred, and are all present in viruses within the Brisbane/10 lineage.
Here are the Brisbane/10 isolates, a whole variety of high growth
reassortants, as well as the Brisbane/10 egg isolate.

I want to note that, again, the neuraminidases of the older groups, the
Nepal lineage groups are down here, and I forgot to mention, here there
is one group that we\'re keeping a very close eye on, and we\'re calling
that the British Columbia lineage, because it does have a number of
changes in antibody combining sites that we\'re looking at. But these
viruses really haven\'t taken off. But nevertheless, we do have an
antiserum prepared to viruses in this group, and we\'re trying to obtain
an egg isolate for this group for the future, and we will watch this
very carefully.

Now once again, I\'m going to show the antibody responses of children
who were vaccinated with the Wisconsin vaccine strain. And once again,
we see that we don\'t get a really dramatic rise after the first dose of
vaccine, but after the second dose of vaccine, we have a post-vaccine
geometric mean titer of 76 for the vaccine strain itself, as compared
with less than 50 percent of that, or 35 to the Brisbane/10 strain, and
only 15 to the Uruguay strain. And that is true. There is at least a 50
percent reduction in post-vaccine geometric mean titers for the more
recently circulating strains.

This year, we decided we really needed to move forward and do
microneutralization tests on as many of the sera as we possibly could.
And here I have a table that was done using serum from two adult
populations, one from Japan, and one from the U.S.A. If you we look at
the panel for the U.S., we see that we had a nice \-- there was actually
quite a bit of antibody prior to vaccination with the GMT of 123. But
there was a very nice robust response post-vaccination, that titer went
up to 854.

In contrast, when we looked at the Brisbane/10 egg isolate, we saw about
\-- well, less than a third of the post-vaccine geometric mean titer
that was obtained with the vaccine strain. So there were reductions.

Interestingly, when we looked at some of the high growth reassortants,
we could see in particular that the Brisbane/X171 reacted a little bit
differently than the Brisbane/171A. And there was a higher titer, and it
looked a bit more like the Wisconsin virus.

We\'re continuing to look at changes in the viruses themselves for all
the high growth reassortants, and really analyze which of these high
growth reassortants are most acceptable for vaccine production.

So the WHO recommendations were to update the strain to
A/Brisbane/10/2007/H3N2-like virus.

Influenza B viruses circulated in China and Hong Kong, and not very much
in Europe, circulated in the U.S., and I think this a bit overstates.
This, as I said, was put together by the WHO Secretariat, and I think it
a bit overstates the extent of influenza B activity that we\'ve had,
although there have been some localized outbreaks.

You\'ll remember that influenza B viruses are divided into two separate
lineages, both by their antigenic reactivities, and by their genetic
patterns. And one of our major problems is that these two lineages of
influenza B viruses have been co-circulating in the world for a number
of years, and sometimes they alternate, sometimes we have several years
in a row where we don\'t see, for example, B/Victoria viruses. We had
almost a whole decade where B/Victoria viruses circulated only in Asia.
But right now we do have both groups circulating globally.

The majority of the viruses that have been examined this year are in the
Yamagata lineage, which is outlined here by the yellow color, but we do
see a few viruses that are of the B/Victoria lineage outlined here in B
in green, and you\'ll remember our previous vaccine recommendation was
A/Malaysia/2004-like, and we see a bit of antigenic drift there,
although our Ohio serum seems to cover a bit better, and they\'re
considered like each other.

Now if we concentrate on the Yamagata lineage viruses, the predominate
lineage globally, we can see that we have this Florida/4/2006 strain
that we\'ve had in the lab for a while, and we\'ve actually sent it to
all the other WHO Collaborating Centers and the vaccine manufacturers.
And these two strains here, Florida/4 and Brisbane/3, just to confuse
everyone even more, we have another Brisbane strain, were used in
vaccine manufacture for the southern hemisphere.

So if you\'ll recall, the southern hemisphere recommendations differed
from our northern hemisphere recommendations by two strains, and these
are the two strains that were used in vaccine manufacture.

So if we look at the CDC data, we tested a total of 97 influenza B
viruses. The majority were Florida/4-like. We did have some that were in
the Victoria lineage, and they were mainly Ohio-like.

This may be difficult for you to see, but I did want to include a table
from one of the other WHO Collaborating Centers, and unfortunately, I
just was able to cut and paste, and couldn\'t improve the projectability
of this particular slide. But here you can see we have the Florida/4
antiserum, and it is covering these strains that are in the Yamagata
lineage very well. So I think that\'s the main message there.

So if we look at the compilation of data, we can see that the majority
of the viruses in all of the four WHO Collaborating Centers were in the
Yamagata lineage. Actually, Japan had very few influenza B viruses to
look at. And so 84 percent overall were Yamagata lineage viruses, and 16
percent were Victoria.

So here we go with the evolutionary relationships among the HAs of
Yamagata lineage viruses, and we have a bit of a complex picture here.
We have two groups of viruses. The Florida/4 is here. Many of the more
recent viruses are here, but we can\'t detect antigenic differences
between these two groups. And it\'s not too surprising, there aren\'t
that many changes between them.

And just to be complete, although I don\'t think it has much bearing
here, we have an evolutionary tree for the B/Victoria lineage HAs. And
the most recent viruses are showing up down here. Here is the Malaysia
vaccine strain, and I don\'t really think there\'s a lot more to say
about that.

Okay. Now for the neuraminidase genes. All of the influenza B viruses
that are circulating, whether they are of Victoria lineage or Yamagata
lineage HA, contain Yamagata lineage neuraminidases. But there\'s been a
great deal of diversity that\'s occurred, and you can still separate
them out. So if you have a Victoria virus, in spite of the fact that its
neuraminidase originally came from a Yamagata lineage precursor, you can
tell where it should go on the tree unless there\'s been reassortant.
And we haven\'t seen reassortment among the viruses that we\'ve been
looking at.

Here, for your reference, is the B/Brisbane strain, and here is the
B/Florida/4 strain. So these are the two Florida/4-like strains that
were used for vaccine production in the southern hemisphere.

Again, the pediatric serologic data are really quite clear. When you
immunize children, young children, with the B/Malaysia strain, which is
on the Victoria lineage, you get a nice robust response post the second
dose, and you have post-vaccine geometric mean titers of 55 and 58 for
the two Victoria lineage viruses. But for viruses in the Yamagata
lineage, you do not see that robust response, and you only have post
second dose vaccine geometric mean titers of nine,10 and six here for
some of the circulating strains.

The same is true for the serum panel provided to us by FDA.

And we\'ve noted this in children. It\'s not true in adults, however,
but we\'ve noted this in children before that you get very clear
delineation between the antibody responses to the two different lineages
of influenza B viruses, whereas, in adults who have been exposed to both
lineages of viruses, you do see a bump in titer to viruses on the other
lineage.

So, summary of influenza B. Influenza B outbreaks were reported in
several countries. Viruses of both the lineages were reported in many
countries, but Yamagata lineage viruses predominated.

For the Vic lineage minority group, most were related to Malaysia or the
Ohio. However, most of the recent B/Yamagata lineage viruses were
antigenically similar to B/Florida/4, and the northern hemisphere
vaccine stimulated HA antibodies that were similar in titer. And I guess
I won\'t go through this point because, actually, Zhiping will be
covering that later.

So WHO recommended that the vaccine be updated to include a
B/Florida/4/2006-like virus.

Okay. So I will stop there. And if there are any questions, I will be
happy to answer them.

CHAIR MODLIN: Yes. Great. Thank you, Nancy.

Let me ask if there are questions for either Dr. Cox or Dr. Bresee
regarding their presentations. And we\'ll start with Members of the
Committee. Melinda?

MEMBER WHARTON: Nancy, that was terrific.

Has there been any discussion at WHO about potentially having a
quadrivalent pediatric vaccine that included both the lineages? I know
this is something that this Committee worries about every year, and
trying to figure out how one keeps the conversation in sync, given the
global nature of influenza vaccine production.

MEMBER COX: There really has not been extensive discussion at WHO. As
you recall, on a couple of occasions, WHO recommended either a
B/Victoria lineage or a B/Yamagata lineage virus, depending on the
epidemiology of the country. So national authorities could really
choose. But I think that WHO\'s focus is really on making
recommendations that are generally applicable, and it would be left to
national authorities to decide if they wanted to included two B strains.

On one occasion in the past, the Netherlands actually did include two B
strains in their vaccine, and they looked at responses to both lineages
of B viruses, and found good responses. But that\'s the only situation I
know where a national authority has decided to go ahead and include two
B strains.

CHAIR MODLIN: Dr. Couch?

MEMBER COUCH: Nancy, a couple of technical questions, just to help my
understanding, because I\'m not a gene jockey. But I was beginning to
assume that the genetic data is complementary, as you\'ve said, to the
ferret immuno relationship data. And how tight is that relationship, is
my question? In other words, are all 2B strains react the same with
ferret sera, and 2C strains react differently, or how do they relate to
each other in that respect?

MEMBER COX: No, unfortunately, and many people have suggested that we
just go to sequencing to do vaccine strain selection, and frankly, it
would save us a lot of work. But the problem is that sometimes you have
two genetically quite distinct groups, but they react similarly.

Alternatively, you can have one single amino acid change, and the rest
of the gene is the same, and that can cause quite a distinct antibody
change, change in antibody reaction.

So there is generally concordance, but sometimes, when you think you
should be able to detect antigenic difference, you do not, and sometimes
when you wouldn\'t expect one, you do see it.

So, but we\'re looking for reassortment, we\'re looking for low
reactors, and do they cluster together. And what we\'re seeing now is
that the low reactors tend to be sprinkled through the evolutionary
tree, and they\'re not clustering together, indicating that there may be
an issue of avidity, or glycosylation, or other issues that\'s actually
impacting the reactivity that we see.

MEMBER COUCH: You prompt me to go ahead with my question, then, is that,
how do we use that for our selection strains? How do we use the genetic
data, then, to make our strain selections?

MEMBER COX: Okay. The genetic data are actually extremely useful. First
of all, the genetic data can tell us very, very quickly whether we have
resistant viruses, so that\'s a public health issue, not a vaccine
strain selection issue, but it can tell us if certain amino acid changes
are having an impact on the antigenicity. And what we\'re often looking
for is a pattern of what we call signature changes that absolutely
confer a difference in antigenic pattern. So many times in the past
we\'ve been able to say, these are the signature changes, and this is
the antigenic pattern that we expect to see when any virus has those
particular signature changes.

Now what it looks like to me is that there is quite a bit of sputtering
around that\'s going on, both with the H3s, and with the H1s. The
differences with Bs are not so dramatic, and have a lot more to do with
glycosylation right at the tip of the molecule. But it looks to me like
we\'re in one of these periods where the virus hasn\'t quite decided, if
you want to put it that way, where the virus is looking for the next
path forward. Now that puts us in a very difficult position, because
we\'ve had B/Brisbane-like strains circulating, but there is no clear
emerging new variant, there\'s just \-- if I could go back to that, I
won\'t, but if you look at the evolutionary tree, you\'ll see that
there\'s quite a bit of amino acid variation within that Brisbane/10
group, but you can\'t say, boom, that\'s the one that\'s going to go.

MEMBER COUCH: Okay.

CHAIR MODLIN: And Nancy, presumably you sequence the entire HA or
neuraminidase gene, I would guess?

MEMBER COX: Correct.

CHAIR MODLIN: And so that there\'s going to be parts of that gene that
don\'t code for antibody binding sites, and some that do.

Would it help if you were to shorten that to a degree with the
sequencing, would it in any way \-- I was getting at Bob\'s question, is
it more likely to predict \--

MEMBER COUCH: You don\'t do the whole sequence.

MEMBER COX: We actually do.

MEMBER COUCH: I didn\'t know that.

MEMBER COX: And I don\'t know if we can go to my supplementary slides.
One of the useful things that we can do is to actually plot where the
changes are on the three dimensional structure, and we know a lot about
antibody combining sites, and receptor binding sites, and so on.

We need to go back. Okay.

So what we\'ve been concentrating a lot on is is to look at where the
changes are occurring between the cell grown isolate, and an egg grown
isolate. And then where the changes occur when you make the high grow
reassortants, and really trying to understand what\'s going on around
the receptor binding site, or the H3 viruses. Because we believe there
are changes in the receptor binding site, perhaps subtle changes in the
shape of the receptor binding site.

So the most interesting thing is to actually plot on the three
dimensional structure, and this is just a monomer of the trimer shown
here with a space filling model. And you see that, right at the receptor
binding pocket, you have a change, and this is a known egg adapted
change. And every single H3 virus that we managed to get out of eggs, or
kidney cells, and then eggs, after putting in hundreds \-- literally
hundreds of clinical isolates, has one or more changes around the
receptor binding pocket that enable it to grow.

And then what we have done is looked at the different Brisbane hydro 3
assortants, and plotted the changes there. And I won\'t go through this
in detail unless we need to.

And then we\'ve looked at the \-- you know, from the top of the
molecule, we\'ve seen that a number of the hydro 3 assortants actually
have a deletion right here at the top of the molecule. You\'re looking
down at the top, the head of the trimer. And then here\'s the receptor
binding pocket, and we have changes there.

Anyway, so it\'s really quite informative to see precisely where those
changes are, because your antibody combining sites are not contiguous,
they\'re conformational.

Does that help at all, or is that more confusing?

CHAIR MODLIN: Very much so.

Jack?

MEMBER STAPLETON: So would it be \-- I mean I think what you\'re saying,
for Bob, perhaps, to clarify for Bob, is that, in addition to those
sites, you can have mutations elsewhere: the change of confirmation, the
antibody binding sites, or the receptor. And at this point, no clear
patterns emerge in any of those sites.

MEMBER COX: That\'s right.

CHAIR MODLIN: Other questions? Ted Eickhoff?

MEMBER EICKHOFF: Nancy, could you comment a little bit further on the
Microneut tests? You\'ve avoided doing a direct comparison of Microneut
and HI. But do they track generally in parallel? Is there a Microneut
titer level that you can equate in any way with protection, in the way
we use one to 40 as a general cutoff for HI as protection, even though
it\'s far from absolute?

MEMBER COX: Yes. We\'re actually doing a lot of that work in Jackie
Katz\' lab at CDC. She has been working very hard over the years to do
correlations between Microneut and HI, both for H5 and for H3. And, of
course, for H5 you really can\'t detect antibody in the serum of
infected individuals using a standard hemagglutination and a vision
test. You have to use, of course, red blood cells and there are a lot of
complications.

And there\'s been an international study and an ongoing study to try to
standardize the microneutralization assay because so many different labs
use totally different techniques. And so there\'s an ongoing effort to
standardize Microneut and to really look at a correlation.

Now for H5 what you see is about a twofold higher titer for H5 viruses
than you do using the HI tests. So Microneuts are about twofold higher.
They\'re always more sensitive for detecting antibody.

And I don\'t think we really are able right now to say that a 1 to 40 in
HI is equivalent to a 1 to 160 or a 1 to 80 for the H3s. But that work
is ongoing.

CHAIR MODLIN: Further questions?

Let me just ask if there are any members \-- yes, Bruce Gellin?

MEMBER GELLIN: We struggle with this every year and, in fact, the
collection of presentations really helps to put it together. Jerry in
his, he commented about where we were a year ago and talked about at
this point in time things have not emerged. Joe told us about
surveillance, at least in the United States and things are just picking
up. So you\'re somewhat hamstrung by the relatively limited disease
activity and the corresponding surveillance that goes with it.

I was just trying to add up what the total number of subtyped isolates
are in the WHO Collaborating Centers. It\'s in the hundreds, maybe, if
you look at each one. Are we looking at about the same number of
isolates now as we are typically? And then it\'s also a question of what
the disease activity was in other countries. I just don\'t know whether
or not this is \-- we\'re in the place where we always are or if maybe
we\'re behind the curve because the season started relatively slowly.

MEMBER COX: That\'s for that question, Bruce.

I think for the United States we\'re a little bit behind the curve
because our season did start slowly. We certainly have more H1N1 viruses
to look at than we\'ve had for a long time because H1N1 activity has
been relatively sporadic over the past few years. Well, there were
certain countries that were effected, but globally we didn\'t have that
many H1N1 isolates.

So I think we\'re behind the curve with respect to H3/N2s. We would have
had more H3/N2s to look at at this time last year. But, you know, each
year is different and the total number is probably about the same.

And, of course, one of the difficulties is that there is a lag time
between the time the patient becomes ill and the time that we actually
do the characterization. And, you know, all of the various steps and how
do we speed that up? We keep trying. We send out the message get the
isolates to us or the clinical materials to us ASAP.

And we\'ve had an overwhelmingly positive response from the U.S. labs
this year to the point that we have boxes and boxes and stacks and
stacks of things to do. But they just arrived last week.

MEMBER GELLIN: A corollary question is, you know this reminds me a lot
of watching a Polaroid \-- if they still make those \-- develop. Where,
you know at some point you can actually see what it\'s going to turn
into. And I guess the question then is if you had more time, what\'s the
best date to be looking at? I mean, do you need to buy another month?
And I know that you can\'t answer this specifically and it varies every
year, but it\'s a question of sort of when might you have more
confidence of what that picture\'s going to look at as you get closer to
the coming season?

MEMBER COX: Well it\'s, you know, it\'s this tension between wanting to
have as much data as you possibly could and you probably would have a
better picture by the end of March, or certainly by the end of April
you\'d have a much better picture. But we really can\'t wait until then
to start vaccine manufacture. So it\'s this tension between the need to
produce vaccine on a given schedule and the need to make a decision so
that that can happen.

So in an ideal world, I suppose two more months would be wonderful. But
we don\'t have that time.

MEMBER GELLIN: I\'ll bring this up again when Tony comes about the other
side, the manufacturing end of this.

So, thank you.

CHAIR MODLIN: All right. Dr. Self?

MEMBER SELF: Well, I\'m struggling with trying to integrate the space
and the time components. The data presented here are pretty large grain,
you know countries, big chunks of time.

But it strikes me that last year certainly viruses were moving a lot
faster than the sort of granularity that you\'re describing here. And
there\'s a lot of variation it seems from Australia to the U.K. to the
CDC and they\'re chucked in time. Do you have anything that tries to
separate space and time and gives a little finer grain look at those two
components? Because that\'s the place where I have the most problems?

MEMBER COX: I would be up here for hours, and I could be. But we can
look at genetic variation by month, anagenetic variation by month; we
can look at all of these things by country and so on and so forth. But
you get lost in the data if you have only a few hours to look at it.

So the bottom line is I think that, you know, I\'m always open to
different ways of presenting the data but I have to give this Committee
an overview. And I think that that\'s part of the frustration of it. I
mean, we have reams and reams and reams of data, and a lot more sequence
data but it just won\'t show up on a slide and it won\'t make sense. So
we really try to focus on what we think will help the Committee
understand.

And I\'m not sure exactly what kind of granularity would really help at
this point.

MEMBER SELF: Well, it\'s not a question I can answer because I haven\'t
worked with the data. I would suggest that the more genetic data is
probably not what we need, but to see some time trends in the
antigenicity data by country might be useful, and I think that might be
done fairly simply that wouldn\'t take hours and hours to do.

MEMBER COX: Sure.

MEMBER SELF: But it\'s a question that we can\'t answer here. Maybe
it\'s not so much a question that I\'m posing, but a plea for a little
better statistical summary in terms of space and time with these data.

MEMBER COX: Okay. I can tell you that for example in the southern
hemisphere they were seeing low reactors to Solomon Islands last when we
made the recommendations for the southern hemisphere last October. So
they had H1N1 viruses, they were already seeing low reactors. We
weren\'t.

There\'s variation from ferret serum to ferret serum that also has to be
taken into consideration. And some of the centers have a lot more
difficulty obtaining ferrets than we do, so they don\'t put so many
viruses into ferrets, and they\'re much more limited where we can really
do a lot more ferret work.

So what I would say is that there are definitely time trends that I can
describe that we knew even last year at this time that there were low
reactors to Wisconsin. We didn\'t have a good alternative. Brisbane/10
emerged in February and the viruses have generally speaking been well
covered by the Brisbane serum.

What I think is more important than sort of kinds of time trends that
you\'re talking about is to look at where the low reactors actually fall
on the tree. So you want to know, okay, if there\'s an increasing
proportion of low reactors, where are they, can we correlate that
reactivity pattern with something very concrete like the sequence? And
if we can, then that really tells us something about an emerging new
group. However, in my slides the low reactors are scattered throughout
the tree and that tells us that there\'s really not a temporal or
geographic trend emerging within the low reactors.

CHAIR MODLIN: Bob?

MEMBER COUCH: To keep this discussion going.

CHAIR MODLIN: Well, I want to keep us on time, but if it\'s an important
question, then yes.

MEMBER COUCH: Well, no, I don\'t know if it\'s an important question.
Just a comment for Dr. Self \-- for both. That I\'ve been on this
Committee, been doing this for a long time. And you always try to reduce
the decisions to a scientific basis as possible. And it reminded me of
one time in the past we had a statistician on the Committee who wanted
it reduced to numbers. And there\'s too much art and too much to be
considered in this to make it that simplified.

And so we always end up with a best guess. And we ought to appreciate
that that\'s what we are doing, but still try to make that a
scientifically a best guess as possible. And always try to keep
learning, despite the fact that I\'ve done this a long time.

Now what I did to try and teach myself something I\'ll pass along to
you. I went back to last year\'s data that we had here and asked myself
why did you miss, you see. Because why did we not pick \-- we talked
about Nepal, remember. And that was based on the serologic data that we
had last year. And we were concerned about H3. There were a lot of us on
the Committee that were concerned about sticking with Wisconsin for a
subsequent year.

And so I went back and looked at that data again. And what I came out of
that one with was a feeling was that the virus was there and in what we
looked at last year, and it was Canada. It was a Canada isolate. Well,
you know, we\'ve had isolates from Thailand here and so forth. So what
do we do with a single isolate?

Well the missing data the last year was the outbreak data in Canada to
go with those isolates, and we did not have that. And I thought that
would straighten it out for me if we had outbreaks with a new virus in
Canada, then that would point us in a direction, you know, to move away
from Wisconsin.

And the WHO data which was sent to us that time says there were
outbreaks in Canada. And, you see, we didn\'t have that data here. And
if we\'re missing something now \-- we\'re not missing, but if we don\'t
have an adequate amount of information now, I would make the plea for it
being epidemiologic data.

We\'ve got a lot of virologic data. Just huge amounts, as you see. For a
while we dealt without pediatric data, which everybody thought was
crucial. Now we\'re getting that routinely again.

I think we\'re not getting the detailed epidemiologic data we want. And
even the WHO summaries just say quickly it occurred in this country,
that country and that \-- that doesn\'t help you. I mean, we got a
isolate in Thailand. So what? We got an isolate in Nepal. If Nepal
didn\'t have any outbreaks and there was no spread and there was no
problem with the virus.

So my plea would be for more and better epidemiologic data to feed into
these decisions each year. And that\'s the best I could do for why we
missed last year, and might have actually been able to move forward with
that correction. On the other hand now, you also have to remember as was
pointed out by Jerry, where it was too late. Things are already in the
pipeline. Industry had already committed to Wisconsin and the reagents
and all that sort of thing. So there\'s so many things that hamstring
you here with even what you would like to do. But we would have
pinpointed that out, I think.

CHAIR MODLIN: Bob, those are all good points. I don\'t want to prolong
this, but I want to do point out that many, many, many countries don\'t
have the public health infrastructures to provide the data on a timely
basis like we would like to have it, which is often a problem as well.
So we\'re hearing about this much after the effect.

MEMBER COUCH: Yes. The alternative to that, as best I can tell, now
we\'re all aware the alternative of that would be that you get a whole
set of isolates from one location, even if they really don\'t know what
went on epidemiologically. That\'s the surrogate, hopefully, for an
epidemiologic outbreak in those countries that don\'t know that sort of
thing.

CHAIR MODLIN: Thank you.

I think we do need to move on. Nancy, thank you very much both to you
and Joe for a very detailed and, obviously, informative presentation.

Our next speakers will be Drs. Angela Owens and Thomas Gibbons, who will
be talking about giving us a vaccine effectiveness report.

DR. OWENS: Hello. I\'m Angela Owens, and these are my colleagues, Dr.
Tom Gibbons and Dr. Chris Myers. I\'d also like to point out there are
other people who are involved in this presentation, and that\'s Jason
Garner and Mr. Anthony Hocksworth.

We\'re going to describe the data from the DoD Global Laboratory Based
Influenza Surveillance Program.

And just a little history for you all who do not know about the seasonal
influenza and DoD. There are two main lab-based components to monitor
seasonal influenza in DoD. The Sentinel site surveillance takes place at
DoD military sites worldwide. There are also sites in countries where
collaboration efforts take place with DoD overseas research labs such as
Thailand, Nepal, AFRIMS is one of them, and it\'s Armed Forces Research
Institute for Medical Sciences, among others.

A second component is the population-based component, and that takes
place at mainly at the DoD recruit training sites and also Navy ships
and the Board of Health surveillance. And both maps actually show the
different sites. The map to the left shows the eight recruit training
sites and the map to the right to the right shows the Sentinel sites.

As far as the background for our collection methods, we request the
sites to collect specimens from patients meeting the influenza-like
illness case definition and within 72 hours of onset of illness.

Along with this we request questionnaires to be completed. And here\'s
an example of one. It includes the patient\'s history: travel history,
vaccination history, symptom history.

Although we collect vaccine data from the DoD, our beneficiaries, the
dependents the children, don\'t always have a good vaccination status.
So this is a good secondary option.

Once we receive the specimens they go through RTPCR for universal A and
influenza B and we do viral culture on all of our specimens and they
culture for a panel of respiratory viruses.

All influenza isolates are subtyped and sequenced, and the sequence
information is shared with CDC.

This is this season\'s data up to 19 February. As you can see, the last
bar is not a representation of that week because the week was just last
week. We\'re still getting specimens in this week as I speak. So that\'s
bar going to exceed. You can see there\'s a definite peak.

In the beginning of the season we\'ve seen a lot of H1s and toward the
end of the season, right now we\'re seeing H3s. About 23 percent of our
specimens are positive for influenza at this time. And this graph only
shows positive viral results.

As far as vaccine effectiveness, we can describe that in our recruit
populations. We describe vaccine coverage in our Sentinel sites. You can
see the period of review is this season, although for the recruits
because of their sessioning, it takes place in August \-- August to now.

The populations vary. In the recruits it will be population-based
surveillance, and that will include the vaccine effectiveness. And for
the active duty members and DoD beneficiaries it would be the coverage.

Our outcome in lab confirmed influenza, and we identify those patients
covered by the vaccine if they were vaccinated greater than 14 days
prior to the clinic visit.

So by eliminating those non-DoD beneficiaries we have 2,570 specimens,
of which 21.9 percent were positive for flu, 36 percent had an
identified vaccination status. Again, the reason why the low percentage
is because our population includes DoD beneficiaries which is hard to
track the vaccination status.

Seventy-seven percent were identified as covered by the vaccine, also
known as potentially vaccine breakthrough. And although we have a list
of breakdown of vaccine type, just know we\'re dealing with military
bases. These populations don\'t necessarily have an option to choose
which type of vaccine they receive. It\'s what the base has, other than
the recommendations.

This particular graph was those vaccinated patients who had influenza by
the week that it was collected. The majority were influenza A, and of
those each one was identified.

So for the population based data surveillance this would be the vaccine
effecting this data. 205 had live confirmed influenza cases. Now that\'s
of all the season of all of the recruits. Twenty-nine percent were
identified as A/H1, 36 percent were identified as H3 and we still have
pending types for 35 percent because they were the recent weeks
collected.

As you can see this graph identifies those vaccinated and those
unvaccinated.

Here\'s the calculation that NHRC, which is the Naval Health Research
Center, used to identify vaccine effectiveness. They only considered
periods when all trainees on the base were vaccinated. All the trainees
get vaccinated upon the sessioning. And at any given time they consider
about 25 percent of the population not vaccinated because of the 14 days
that it takes.

For the previous years they\'ve had estimates anywhere between 86 and 94
percent of vaccine effectiveness. And this year they have 85 percent
vaccine effectiveness based on the 102 lab confirmed cases that were
included in the analysis. Most of those were actually H1, and then you
see also the H3s or the Brisbane strain virus.

So based on NHRC\'s population-based survey elements among the recruits
the overall vaccine effectiveness remained strong among basic trainees,
but when compared to the previous four years it\'s on the low end,
because it\'s 85 percent. It\'s reduced effectiveness against influenza
A/H1 subtype. Now as far as the sequencing goes, that\'s where Dr.
Gibbons and Dr. Myers will describe a little more information about the
sequences of these since this only describes the subtypes.

MAJOR GIBBONS: I\'ll ask Andy to continue to drive, and I\'ll just give
what\'s a quick snapshot of the HA1 hemagglutinin and phylogenetic
analysis.

First of our influenza B field isolates and our lead molecular biologist
Jason Garner prepared these slides for us. For the B isolates they
include all of the specimens identified as influenza B. For the H3 and
H1 he attempted to give a representation using both genetic and
geographic data. In other words, to fit it on a single slide he would
keep the same picture but maybe omit some sequences instead of showing
the exact same sequence over and over. But you can extrapolate back on
the data that Andy\'s presented.

These specimen are from July 2007 up to present, but present being the
last couple of weeks. You\'ll notice that spike obviously wasn\'t able
to get sequencing data completed and forwarded to the CDC.

Seventy-eight percent of the isolates were collected in Nepal, Thailand
and the Philippines. And four of six of the isolates collected within
the U.S. are of the Yamagata lineage and 29 of the 50 isolates belongs
to the B/Victoria lineage. And all of the isolates that are in the
B/Victoria lineage are extremely similar. So overall we are seeing close
to a half and half of both the Yamagata and Victoria lineage.

Let me stress that this is only sequence data. This is all submitted to
the CDC and they, based on looking at that data, will request clinical
isolates for further testing.

Now with regard to the H1N1 field of isolates, as I mentioned earlier,
this is not all of the isolates. What he did here to get it all on one
slide and kind of fit in our time constraints is kind of give a
geographic representation and maybe omit some sequences that would only
be redundant in the tree here.

Only 5 of the 51 isolates represented here were characterized as
clade 1. The bulk of the isolates are characterized as clade 2. And if
you go to the first green box there, so everything above is glade 2 of
H1N1.

DR. MYERS: So this is our sequence data from NHRC and in contrast to the
variation that they see at AFIOH. You know, we\'re predominately seeing
one strain in the clade 2B section of the tree.

Most of our sequences \-- this is all the sequence data we have, but we
haven\'t sequenced every single H1 sample that we\'ve gotten in. You can
see the majority of these are from a couple of different outbreaks at
Fort Lewis and Fort Leonard Wood. So the majority of what we\'re seeing,
and again the vaccine effectiveness data on the H1N1 was about 54
percent are the single strain that we see going around.

MAJOR GIBBONS: With regard to H3/N2, 85 percent are the Brisbane. In
other words they have these key amino acid changes indicative of the
A/Brisbane. So we are continuing to find predominately Brisbane. Now of
those isolates we are seeing some additional changes, and they\'re
located at the very top of the tree there. And we do have some
hemagglutinin inhibition data from the CDC, and those have basically
shown that these are characterized as A/Brisbane-like.

DR. MYERS: And in contrast to the H1s, we do see a lot of variation in
the H3s that we\'re collecting from the recruit training sites across
the country. Again, those are shown here. All Brisbane-like in nature,
but a lot of variation within them from different sites. And just to
reiterate it again, all this sequence data is sent to the CDC. They do
make requests for specific samples and do the HAI data and provide that
back to us.

DR. OWENS: So we take knowledge, of course, of the Global Emerging
Infection Surveillance and Response Systems, which is GEIS, the Centers
for Health Promotion and Preventive Medicine and the Air Force Clinical
Information branch, of course, CDC, Marshall Regional Medical Center and
all of our Sentinel sites and recruit training sites that take part in
this program.

Thank you.

CHAIR MODLIN: Thank you.

Are there any questions? Dr. Couch?

MEMBER COUCH: Do you have any serologic data on the recruits with regard
to particularly the HI antibody responses and a cross reaction with your
isolates?

DR. MYERS: We\'ve sent those to the CDC recently. We haven\'t gotten
that back yet. I\'m sure they\'re working on it.

MEMBER COUCH: But they were collected? We just don\'t know the results
of the vaccine responses?

DR. MYERS: Right.

CHAIR MODLIN: Dr. Davis?

MAJOR GIBBONS: I believe there is some preliminary. I know some of the
AFIOHs have been sent to the CDC. And I think there has been some
hemagglutinin inhibition data on our H1s. Is that incorrect? Since it\'s
not our data, we didn\'t want to present it.

MEMBER COX: Right. Sure. If I understood Dr. Couch\'s question, he was
actually asking if serum pre and post vaccination serum had been drawn
from the recruits and if those sera had been tested against some of
these recent strains?

DR. MYERS: Actually, no. That happens in rare cases. We did that once
last year, but we haven\'t done it this year.

MEMBER COUCH: Well, you alerted us to the fact that that vaccine may not
have been very good for H1.

CHAIR MODLIN: Bob?

MEMBER DAVIS: I\'d like to go back to the vaccine effectiveness
calculations. Do you mind? I was having trouble understanding the setup
of the study. Is this a cohort study, a case control study? Could you
walk us through how the calculations of vaccine effectiveness were done?

DR. MYERS: Right. So, again, we have the denominator data because we
know everyone that\'s at the recruit training site at any given time. We
have FRI data. We have people on the ground at each one of these sites
that count every FRI case. They only collect a certain number of
samples. And so that\'s where we get our influenza numbers from and our
FRI numbers from.

The assumptions are, you know again this starts once everyone at the
base has been vaccinated, so a couple of weeks after vaccination has
started. We assume, you know, that for 14 days they are unvaccinated and
that gives us the percentage of the population that\'s unvaccinated and
from that we make the calculations.

MEMBER DAVIS: If everybody\'s vaccinated, though, is it really fair to
assume that the unvaccinated are exposed? Because there\'s a lot of herd
immunity going around.

DR. MYERS: Sure.

MEMBER DAVIS: Do you just accept that and \--

DR. MYERS: Right. And we can do the calculations with different ways
with different assumptions. And I have some of that if you want to see
it with the 7 day vaccination or a longer time period, and things of
that nature.

MEMBER DAVIS: Yes.

CHAIR MODLIN: Okay. Let\'s move on to the next presentation. Thank you
all very much.

The next speaker will be Dr. Zhiping Ye from the FDA who will be leading
us into this next issue that Dr. Davis was just getting at, which is
vaccine responsiveness.

DR. YE: Okay. Nancy Cox in her presentation the antigenic
characteristics of the circulating virus has been analyzed by using
ferret and the sera to the vaccine strain as well as to the
representative recent isolates.

In this presentation I will focus on the antigenic characteristics of
the newly isolated viruses to the human sera which immunized with
current vaccine.

So unlike the data presented by Dr. Nancy Cox, the human sera only has
the serum against the vaccine and does not have the serum against the
newly isolated viruses. So what we\'re going to see is that we see the
difference of the antigen against the serum to the vaccine strain and
how the difference between the vaccine strain as well as the newly
isolated viruses.

Okay. There are four serum panels from adults and the elderly. The four
serum panels, one has come from Australia. Another one from E.U., Japan
as well as from U.S.

The serum panel from Australia was the individual who immunized the
vaccine against H1N1 for New Caledonia, this is old one, and Wisconsin
for 83/N2 and the B/Malaysia. Then the rest of the serum panel contains
who immunized with Solomon Islands, the current vaccine, Wisconsin as
well as Malaysia. Only the difference is that the serum from Japan
instead of use Wisconsin, they used the Wisconsin-like strain, which is
a Hiroshima/52/2006.

And in addition there is the one serum panel from pediatric, that\'s
nicely or a dimension \-- another serum panel was collected by CDC.

And each serum panel contains around 24 to 32 individuals. So you start
off with seeing the individual to the serum, but here we seeing is a
group of the serum reaction to the vaccine strain \-- to the serum
against the vaccine strain.

And then the antigen for serology study was chosen on based on a few
criteria. First of all, they said the vaccine strain we have to use this
one as the control. And the representative current \-- the strain was
chosen by a few criteria. One is, of course, the reason doing this one
is to choose the suitable vaccine for suitable candidate of a full
vaccine. And we were basically focused on the isolates from eggs. And
also we have to cover the geographic difference and some of Japan and
Europe as well as from U.S. And also we have some italic font as we
present the isolate from cells.

And the color coded Brisbane/59 is the strain crossed to different
centers. I have to mention that the five centers doing the serology
studies, so the percentage is the combination of all the studies.

So this is, Brisbane is everybody uses as antigen for serology studies.
And the rest of them it depend upon the availability of the different
centers.

Here I cannot present every one of them. I only choose the one of the
representative strain. Since I do the presentation, I choose the sera
panel from CBER.

Okay. So here I present three different sera panels. As I mentioned, the
sera panel from Australia does not contain the current vaccine for H1N1,
so we didn\'t use this one for H1N1. Only choose the three panels
contains the vaccine strain to Solomon Islands.

Okay. Nancy already mentioned this, but I want to go through a little
bit. So each panel we have 24 individuals. Okay. Then since the panel
contains pre and post-immunization so we can compare the pre and the
post. So here is the antigen we used in serology studies. And here is
the vaccine strain. And here is the representative strains.

And here we can see this column which shows the percentage of rates of
four-fold increase because we have a pre and a post-immunization. And
here it shows \-- this column shows the GMT, pre GMT titers to the
vaccine strain and to the isolated viruses.

And skip the third one because I will focus on this one later. And also
we have the percentage of the individual contains 1 to 40 HI titers
antibodies.

And here you can see here the pre-immunization, the percentage of 40
percent of the individual.

Now let\'s focus on the post-vaccination GMT titers. I think Nancy
already mentioned that. I just wanted to focus on the adult/elderly and
later on mention on the children.

So here we can see that GMT titer like strains for this \-- this is
panel is 724. And then here we focus on the difference of the isolated
virus, the GMT to the representative viruses versus to the vaccine
strain. So I don\'t think you can read that from the back of the
audience. But here for the vaccine strain it\'s 724 GMT titer where the
newly isolated it\'s between 160, 20, 13 and 44 GMT titers. And so they
can see there\'s the reduction of the antibody against the vaccine
strain is very, very low. We use arbitrary titer to see how the 50
percent reduction compare to the vaccine strain. So here we can see the
\-- of the newly isolated virus has significant reduction of GMT titer
compared to the vaccine strain.

The same picture for the Japan sera panel.

I have to mention that to increase the sensitivity of the study, the
sera panel from EU, U.S. as well as from Australia has to be preselected
to choose the \-- strain. So the absolute data here, the number here
does not mean much, but the comparison of the antibody to the vaccine
strain and compared with the new isolated virus is meaningful, it\'s
here.

So you can see the GMT titer for Japan is relatively low, 109 virus to
the EU 700 or the U.S. about a 1,000.

So bottom line from this study is that the newly isolated viruses, the
GMT titer to the new isolated viruses compared to the vaccine strain is
very, very low.

Here it shows the elderly population. I\'m not going to go through that
again to show the same picture as those from adults.

Okay. Here Nancy already mentioned on the HI antibody response to the
vaccine strain from children. Here she shows the first two rows was from
the study from CDC, the last one from U.S. I\'m not going to go through
that again since it show the same picture that the newly isolated
viruses, GMT titer is very low compared with vaccine strain. And overall
of reduction, like 74 percent reduction compared to the vaccine strain.

So the conclusion from this study for H1N1 is that they have significant
reduction to the vaccine strain.

Here is a summary to give you whole picture. Since we have five centers,
this serology study, one from CBER, CDC, U.K., Australia and Japan. So
here is to show the whole picture how many strains and what\'s the
outcome of the study from different centers.

Here at the CBER we used Lisbon, we used the South Dakota and Cambodia
as our antigen for the serology studies. And the same as the CDC. NESC
choose the Brisbane, Egypt, Hiroshima and the Netherlands.

So what we can see here is the frequency of these sera panel have a
reduction of 50 percent reduction. So as we can see here, the three
panels, three out of three has 50 percent reduction. So here this last
column shows the actual percentage of reduction. Here you can see 87
percent of reduction of the newly isolated viruses compared to vaccine
strain. So indicated as the antibody against the vaccine strain does not
cover well for this Brisbane/59. Same as the rest of them. Only one
exception is Netherlands/345, and it\'s no reduction. I think the one
reason is that this may not be representative of the whole picture. But
this virus is isolated from cells. But none of the viruses from Norway
also isolated from cells, but they have significant reduction, which is
97 reduction compared to vaccine strain, where the Netherlands have 25.

So put the whole picture together, 45 out of 50 cell panels shows 50
percent reduction. And overall average of the reduction is 79 percent if
you put a whole picture together and compare it to the vaccine strain.

So bottom line from this study shows that newly isolated virus does not
cover well by vaccine strain.

And here this shows the reduction from elderly and for children, and I
mentioned this at 74 percent of reduction. And for the elderly it\'s a
67 reduction. And 44 out of 50 sera panel shows a 50 percent reduction.

Okay. Here we go move on to H3/N2. Again, the vaccine strain, as I
mentioned, that everybody use Wisconsin itself but Japan use Hiroshima
as the alternative vaccine strain.

And the representative current strain as follows: Is the Brisbane/10
itself and the Henan and Jinshui/147, Taiwan and the Texas and the other
one was isolated from cell isolates. I think Nancy may not mention this.
This H3/N2 egg isolated is very limited. And the Uruguay one is
everybody used for this antigen for their serology studies.

And here show, this representative study was choose from the U.K. And
again there are three sera panels. And here is the GMT titer to the
vaccine strain, which is Wisconsin is the 563, then the new isolated
virus include Brisbane/10 it\'s 93 versus the vaccine strain GMT total
vaccine strain 563. And the rest of the viruses had similar picture that
have more than 50 percent reaction. And the same thing from Australia as
well as U.S. So this is the picture from adults from U.K. study. And
next one it shows the elderly. Again, I\'m not going go through the
details. You cannot see this one anyway. And it shows the same picture
that the newly isolated viruses include the Brisbane/10 and the Uruguay
has more than 50 percent reduction compare those to the vaccine strain.

And here is the pediatric population and shows the HI antibody response
to H3/N2. And, again, Nancy already mentioned that, so the conclusion
for this one is that you get the viruses not only in from adult, but
it\'s in the children has a very significant reduction to the vaccine
strain itself. So the percentage of reduction for children is around 80
percent reduction compared to this vaccine strain.

And here just a summary table from different centers. And the bottom
line is the 55 out of 61 had 50 percent of reduction. And the average of
reduction is 75 percent compared to the vaccine strain. To that is again
that the GMT reduction is very significant.

Now here just shows the elderly and the 55 out of 61 had a 50 percent
reduction. And the average of the percentage of reductions is 71. So,
again, the picture\'s very clear. It\'s different.

Here we move on B. The current vaccine strain is B/Malaysia, and the
representative current strain that basically we chose two that\'s
Victoria-like because it\'s controlled for the serology studies, and we
choose Hiroshima and Pennsylvania/5/2007. And the rest of them are the
Yamagata lineage. So the one color coded is B/Florida/4, and that
antigen has been used for all the centers.

Okay. As Nancy mentioned, B a little bit it\'s not clear cut like H1 and
H3 and also different from different sera panels. But here I choose two,
one from U.S. and one from EU.

As you can see here the post the GMT titer to vaccine strain is 222. And
as you can see here the Victoria-like strain B/Pennsylvania/5 pretty
close have 252. So very close to the vaccine strain. However, B/Florida
has 240 GMT titer and Delaware had 101, and Sendai had 247 and
Bangladesh had 104 GMT titer to the sera immunized B/Malaysia. And
however, the EU panel shows a little bit different result that the GMT
titer to the Malaysia is 202 and the similar Victoria-like strain,
Pennsylvania 202, whereas for the \-- representative strain it\'s 92, to
the Florida/4 30, to Delaware and 28 to Sendai and 43 to Bangladesh.

And here shows the elderly. So I think this is a similar picture as
those from adults. And I\'m not going to go through this one again, but
it shows a similar picture as those from adults.

And here is the pediatric. The pediatric, unlike the adults and elderly,
give you pretty good clear picture. And here I just mention again from
U.S. we have for the GMT titer to the Malaysia the 22, but then for the
rest of the Yamagata lineage and less than 50 percent.

So overall summary for the pediatric study that the reduction to the GMT
titer over newly isolated viruses is 83 percent compared to the vaccine
strain. So it\'s very significant difference.

And here again to show the whole picture across the different centers.
And this only showed the reduction to the Malaysia itself. I didn\'t
include the reduction to the Yamagata lineage. So here it shows that 40
out of 60 panels it showed 50 percent reduction. And the average
reduction is 52 percent for the adults and 39 out 50 sera panel has 50
percent reduction in elderly. And the average of 50 percent reduction
\-- average of the reduction is 58 percent in whole picture.

Okay. Here is the summary. The study with human sera collected after
immunization with the current vaccine strain shows that for H1N1
representative recent viruses was less well inhibited by HA antibodies
to the current vaccine strain, which is Solomon Islands.

And for H3/N2 the representative recent viruses was less well inhibited
by HI antibody to the vaccine strain.

For the B strain it depend upon the lineage. For the Victoria lineage it
represents the recent viruses was less well inhibited by the HA antibody
to the vaccine strain, which is a Malaysia/2506/2004, which is the
Victoria-like. However, for the Yamagata lineage the representative
recent viruses generally were less well inhibited by the antibody
against the current vaccines.

Thank you.

CHAIR MODLIN: Thank you, Dr. Ye.

Are there any compelling questions for Dr. Ye? None at all. If not, I\'m
going to suggest that we take our break now. And let\'s try to be back
at 11:00 sharp and we will continue on with Dr. Gupta\'s presentation.

(Whereupon, at 10:48 a.m. a recess until 11:03 a.m.)

CHAIR MODLIN: Our next speaker will be from the FDA, Dr. Rajesh Gupta,
who will be speaking on the availability of strains and reagents, a
very, very important topic and one that\'s critical for us in our
discussions later on today. So could I please ask everyone to be seated?

In order to select strains, we have to know if there are strains
available that will grow in eggs. That\'s what Dr. Gupta\'s going to be
leading us through that discussion.

DR. GUPTA: Good morning. My name is Rajesh Gupta. I\'m in the Division
of Product Quality in the Office of Vaccines. And we are responsible for
providing potency reagents for the seasonal flu vaccines. And as you
know, the potency reagents are critical for the formulation of vaccines.
So I will give you some update on the availability of reagents for this
season.

So for influenza A (H1N1), as all you know, that the current vaccine
strain is the A/Solomon Islands and reagents for this strain are
available from our lab, from the NIBSC in the U.K. and the IGA in
Australia. These are the agencies including the NIID from Japan. We do
the calibration and collaborate on the calibration of the reagents so
that the quality of the vaccines in a global setting can be I think
consistent.

And as you know also that for this year the WHO has recommended the
A/Brisbane/59 strain, 59-like viruses. And the possible candidates which
I think reassortments are being made or are available are A/Brisbane/59,
IVR-148 and then the A/South Dakota and the reassortments are in
preparation for that strain.

We have estimated that if this strain is selected today, we are
estimating that we can have the potency reagents available by late May
of this year.

For the H3/N2 strain, the current strain is A/Wisconsin and the like
reagents are available from three agencies. And, again, as the WHO
recommended strain for H3 is the A/Brisbane/10-like viruses. And the
possible candidates are the A/Brisbane, then the IVR-147 and then the
reassortments. Probably we will have some discussion on these
reassortants this afternoon.

And then the A/Uruguay strain, the assortments are in preparation.

The potency reagents for these strains are available from TGA, as most
of you know that. This strain is being used as a vaccine strain for the
southern hemisphere. So they already have the potency reagents
available. And based on our estimates the CBER will have the potency
reagents available by the end of the May this year.

For the influenza B strain the current strain is B/Malaysia and the
potency reagents are available for this strain. And the WHO recommended
strain is the B/Florida-like viruses. And the possible candidates can be
B/Florida and the B/Brisbane.

And again, this is one of the strains which is in the southern
hemisphere vaccines and reagents are available from TGA, which are for
B/Brisbane. And we have already started working on these reagents as our
best guess based on the southern hemisphere information. So these
reagents may be available from CBER if this strain is selected by the
end of next month.

I think that\'s all about the three strains.

CHAIR MODLIN: Thank you, Dr. Gupta.

Are there any questions?

Dr. Gupta, we can assume that these are all strains if you say that
they\'re available or expect to be available, that they do grow well in
eggs?

DR. GUPTA: I know that there will be portions there. I do not want to go
into the details of the \-- like the deletion reassortment for the H3
and some growth issues. So probably that can be taken during discussion.

CHAIR MODLIN: Is there anyone else that would like to go into detail?
Okay. Well, we probably will need to address those issues.

Thank you, Dr. Gupta.

Are there any further questions? If not, we\'ll go onto the next item on
the agenda, which will be comments from the manufacturers. And I
understand that Tony Colegate will be representing the manufacturers.

MR. COLEGATE: Good morning. Thank you for the opportunity to give the
industry perspective in this work. I think it\'s going to be a very,
very difficult year for us.

This presentation last year was given by Al Thomas, and basically have
updated his presentation because I thought it was very good. And I\'ll
give you insight into the time pressures and the benchmarks that we have
to follow through to get the vaccine out on time. And then kind of
update where industry thinks we are as far as producing vaccine for this
year.

So what do we need? Well, the critical factors to produce the millions
of doses that we need to produce for the U.S. market. I guess probably
the most essential one is the gross potential of the seed virus. And
what is often forgotten is that the quality of trivalent vaccine that
can be produced is limited by the least productive one available strain.
So the more information we\'ve got about the strains and how they grow,
we can best plan our production. This year we\'re in a very good
position.

The timing of the strain selection is also important. Because we have a
limited production time due to the necessity of distributing and
administering vaccine prior to the influenza season. And new working
seeds require at least four weeks from receipt of seed candidate for
development to use in large scale manufacturing.

Now following on from that we need to the potency test reagents, and
they are obviously limited to a large extent by the strain selection.
Because the antigen used in those potency test reagents is usually
supplied from the first production batches produced by the
manufacturers. So these things are linked.

These potency reagents are required to determine the potency of
monovalent components prior to formulation in the trivalent vaccine.
They\'re also required for us to know how much monovalent we\'ve used.
And this year it would appear we\'re going to be processing blind until
these reagents are made available to us, which makes life a little bit
difficult.

And these reagents have to be produced and standardized for every new
strain.

And then the final thing is the timing of the annual license ultimate
approval. We can\'t release the product onto the market until we have
that.

What I\'m going to run through quickly is the ideal model for influenza
vaccine manufacturing. I hope you can see that. It\'s not that very
clear even from here.

Basically we have a time line to work to which is the delivery of the
vaccine. It\'s becoming increasingly clear; it was always said that if
you haven\'t got the vaccine there for people to have by Thanksgiving,
they don\'t take it. I think that\'s probably being demonstrated again
this year despite a quite extensive campaign to try and get people to
get vaccinated in December/January.

So how do we achieve that? We start early, basically. We manufacture one
strain at risk. Now in hindsight I can see you\'re thinking well which
strain did they produce. Well, at the time Solomon Islands looked good.
Towards the end of January it became clear that it wasn\'t so good. But
there we are.

And then rather about this time we like to start on the second strain.
That\'s going to be challenging. And we normally have seeds and
everything prepared ready for that. And then round about the middle of
April, and the latest in May, we start the production of the third
strain. And in the meantime we\'re producing, or people are producing
reassortants for us and we\'re producing the working seeds. But this
year we\'re still in that same situation for the second strain. So
we\'re already in some delay.

And then we try to balance the strains. Because up until the point at
which we have the potency reagents, we don\'t actually know how many
doses of each of the three strains we\'ve produced up until that time.
So until we have that information, we can\'t balance the strains. And as
I said before, we\'re limited by the strain which grows the last well or
produces the fewest doses. We have to do a longer production on that
than the ones that grow well.

Once we have the reagents we can then start to formulate and to fill.
And when we have the annual license approval, then we can start to
distribute. That\'s how we would like it to be.

Where are we this year? Well production is underway as usual. We started
at risk of strains that would not be selected for 2008/2009 northern
hemisphere just to make sure that we could have sufficient vaccine in
the marketplace when it was required. And based on publicly available
surveillance information at the start of this production, manufacturers
have chosen to produce the A/H1N1/Solomon Islands. And, as I said
before, when it became not so sure that this strain would be chosen, we
changed to B/Florida/4/2006-like strains.

Now as we\'ve said before, there are two strains here available.
There\'s the B/Florida/4 and the B/Brisbane/3. And, again, I guess to
show how difficult this product is to produce, some manufacturers
favored the Brisbane/3 and others favor the Florida/4,

And you could argue well why didn\'t we start with the B in January. At
that time we were faced with this dilemma that Florida was good for some
manufacturers and Brisbane good for others. And we also had three new
B/Florida-like strains from CDC to evaluate. And until we evaluated them
to see if any of those were better than these two, because these strains
are adequate but they\'re not good. So we would really have preferred
there to be something better, but it would appear there isn\'t. And as
you know, WHO have not recommended Solomon Islands for the next season.

So it looks as if there could be three new strains for 2008/2009. And
this is unprecedented for the northern hemisphere. And in the last 20
years this has not happened before. So we have a very, very challenging
year.

So we\'re all busily evaluating new strains at the moment. You\'ve heard
about the IVR-148 Brisbane/59 reassortant from CSL \-- sorry. I\'m
talking H1N1s. I\'ve gone on to H3/N2s.

The H1N1, the Brisbane/59 there is a reassortant that has been received
by manufacturers only recently and is current under evaluation. But it
does appear to grow reasonably well and is a good candidate.

Last Monday and Tuesday of this week from New York Medical College we
received South Dakota/06/2007 and we have one, two, three, four
reassortants there to look at. But I understand they have not yet been
fully characterized and therefore, may or may not be of use to us. The
Brisbane/59 I believe has been characterized and should be an acceptable
strain.

The B strains, both B/Florida and Brisbane where we use production for
the southern hemisphere and other viruses were received from CDC or
NIBSC, CDC through NIBSC by most companies. And these viruses don\'t
appear to offer any yield advantage over B/Florida or B/Brisbane. But I
think the plea from the manufacturers is can you please give us the
option to use either/or as they are both like-strains. That will cause a
problem in reagents, of course, but we can sort that out, hopefully.

So as far as the H3/N2 is concerned, IVR-147, A/Brisbane/10 was used for
the souther hemisphere. And the one good thing that shown us, I guess,
is that it is not suitable for production for the northern hemisphere.
It does not grow well and we have no possibility of producing sufficient
doses if we use that strain.

New York Medical College have been trying also to produce a Brisbane/10
reassortant and out of four or five that they produced, only one grows
reasonably well. That\'s 171B. But it has a deletion A193 and is under
evaluation at the moment. Additional serological studies have been
taking place at CDC. So we don\'t know whether we can use that or not.

Better news, I guess, is that since the Uruguay/716 egg isolate became
available, that was received by the three reassortant laboratories that
produce reassortants for us, CSL, NIBSC and New York Medical College,
and they have all been working on this particular strain to try to
produce reassortants for us. And New York Medical College is due to ship
the beginning of next week. Is that 25 or 26 of February? And CSL and
NIBSC should be available the week beginning the 3rd of March.

So we have things in the pipeline, but we\'re not in the situation where
we would like to be at this time of year with two strains, with working
seeds ready to go and reagents in late stages of preparation. So, as I
said before, it\'s going to be a difficult year.

So this year, more than any other I guess, we will need public/private
cooperation. And what we need is a timely Committee selection of the
appropriate antigens. And we ask you here to consider not only the
antigenic match, but the ability of the strains you select to enable us
to produce sufficient vaccine for the marketplace. We need seed viruses,
especially the high growth reassortants.

Normally we have more opportunity to evaluate the growth characteristics
of potential strain candidates. This year we\'re right against the wire
and it\'s going to be very difficult. And we need the potency test
reagents. And we need all three of these by early June.

I was encouraged to hear that we could get them by the end of May. I
just wonder if that\'s a little bit optimistic. If manufacturers don\'t
know which strain to produce, they won\'t produce the antigen. And if
you\'ve got the sheets here that\'s good. But if you haven\'t got the
antigen, you can\'t produce the reagents and then there\'s the
standardization question which always seems to take longer than anyone
anticipates. And then following on from that we need a timely approval
of annual license supplement.

If you\'ll bear with me, I have a colleague in Liverpool who likes
putting information together and producing tables. And so he looked at
the northern hemisphere strain changes since 1989. And the ones he read
are where the strain changed. And you can see if you look right at the
bottom that never before has an H1N1 not run two years running. So we
thought we were on pretty safe ground with starting with that, but
we\'ve been caught out this year.

If you look at the H3/N2s, you can see that that changes far more
frequently. And the B strains.

When we have the question about the quadrivalent vaccine, I thought not
this year. But I think it does bring home the problems that we have and
that would potentially give us producing a quadrivalent vaccine. Years
like this would be \-- I don\'t know if Bob Couch has had further
thoughts about his suggestion last year that we do the B strains
year-on-year; one year Yamagata lineage and the next year Victoria. And
that would also help us with the bank of strain right at the beginning.
It would give us something to go at. And it\'s a thought. Anyway, I was
quite taken with the idea last year and I wish we\'d done it.

So this is just a summary, but you can see that if you go down to the
bottom, zero strain changes in the single years happened four times and
all the manufacturers are happy you do that. A single strain change nine
times, which again we\'re happy with. Two strain changes happened six
times, but three strain changes in a single year hasn\'t happened to
date.

And I will end with that.

CHAIR MODLIN: Thank you, Mr. Colegate.

Let me ask if there are questions for the manufacturers from Members of
the Committee and our guests. Bob?

MEMBER COUCH: Well, just one comment for Tony. And I think the
manufacturers know that this Committee has always given serious
consideration to the availability of vaccine. And we don\'t make vaccine
available. You make vaccine available. So that always, quite frequently,
enters into our decisions on what to recommend, as well. Not just the
selection of strain now.

I thought, when I looked at what had been done to the southern
hemisphere, we weren\'t doing what you\'re saying we\'re doing to you,
and you\'ve suggested that maybe the B strain for the southern
hemisphere, maybe that one\'s already relatively in place. But you\'re
looking at two new changes, and, as you\'ve said, that does occur, but
that\'s not quite as unusual.

And I had thought that the A/Brisbane, you had that one for the southern
hemisphere. But you\'ve indicated that was a poor grower, so you\'ve got
to go back to the drawing board to make the H3N2 strain for that
recommendation. And that you\'d only have an H1N1 strain.

I don\'t want to accept it\'s quite as bleak as you say, but for the
northern hemisphere, very clearly as you said, is three new strains.

I want to ask you a question. I don\'t know whether you\'ll want to
answer it or not but, see, WHO now has given you those three strains.
And influenza vaccine and manufacturing is very international now;
distribution, manufacturing, what have you. What if we selected a
different strain from the WHO recommendation, what would be your
reaction to that?

MR. COLEGATE: It would depend on whether there is a reassortant
available, how it kind of affects our production schedule, really. I
think, because the U.S. market is so big, it can go into low, as it
were, really, as far as manufacturers are concerned. Because all of the
major manufacturers are now looking to this market to use.

MEMBER COUCH: You want the market, so you\'d try to meet it. But then
you\'d be, perhaps, making two vaccines; one for the U.S. and one for
Europe, for example?

MR. COLEGATE: Well, certainly we\'ve done it in the past in Liverpool.

MEMBER COUCH: And that would reduce doses, correct?

MR. COLEGATE: Not if you plan it properly. Again, it depends on how well
the strain yields. If you choose something that yields better than is
being produced for Europe, then in that same time frame, you produce
more doses. I mean, it\'s down to well, how well the virus grows, and
how many doses you get out of every batch that you put into production.

I mean, the southern hemisphere really has been a dress rehearsal for us
\-- well, it should be a dress rehearsal for us every year, and usually
it puts us in good stead to start. But this year our star performer,
Solomon Islands, is sick. And we found that the IVR-147 reassortant
didn\'t grow well enough, so we need it more, and the B strain, neither
of those grew particularly well. But we have found that we could live
with those particular two, the Florida or the Brisbane. So at least
we\'ve got something to use.

I mean, what we are doing as an industry group, just for information, is
that we are currently talking to WHO Collaborating Center in Australia
with a view to have an egg crate with them, as well as with CDC, so that
we can, hopefully, pick up egg isolates in the southern hemisphere. And
maybe if that had been in place this year, we may have been in a little
better position. I don\'t know. But we\'re trying the whole time to make
this situation better where we can.

CHAIR MODLIN: Bruce?

MEMBER GELLIN: Tony, building on your last comment, if you had a wand,
and could wave it and improve the system so that things got to you
faster, or there were more choices, what would the system look like? How
would it look different than the one we currently have?

MR. COLEGATE: Dare I say? The biggest problem we have, and it is
improving, is coordination within WHO, basically, to make sure. I mean,
we now have three industry-funded facilities, institutes, that are
producing reassortants for us. So we\'ve got CSL, who have been
producing them for years. We\'ve got Doris Brooker at New York Medical
College, and last year, we set up NIBSC, we funded them to start
producing again.

They can\'t produce egg reassortants for us if they don\'t get the egg
isolates to do it. But we, as industry, can\'t decide which egg isolates
they should be looking at. They need some kind of WHO prioritization and
timely supply of those. I don\'t know if Nancy wants to comment on that.

It is a wish list, really. Because I know the difficulties. It\'s easy
to say, this is what we want, but I appreciate it\'s not easy to do.

MEMBER COX: Sure. I\'ll just make a couple of comments.

I think that there was a lot of discussion at the IFPMA Roundtable and
within the WHO Collaborating Centers and other reference labs, as well,
about how to really improve the communication within the system, and
also with manufacturers. Because, for example, although I was aware that
the IVR-147 strain was not growing well at first, I certainly was not
aware, until very recently, that it would be unacceptable. So my
assumption was that it was being used for southern hemisphere
production, therefore it must be okayn and there were reagentsn and so
on. So that kind of feedback needs to come to us.

One of the things that we\'ve experienced over the years is a plea for
more egg isolates to be sent. And then we send a lot, and then we get
told \"That\'s too many to look at.\" So we\'re trying to find that
balance so that the viruses that we send are those that are most likely
to be useful to you.

And I want to emphasize that, for the H3N2 viruses, I believe the
statistics are something like this: we put 488 original clinical
specimens into eggs, or into kidney cells and eggs, and got something
like three or four or five egg isolates. So it\'s very, very difficult
to \-- it takes a huge amount of effort to derive one. Then, when you
have an isolate, you find it always has changes for adaptation to eggs
for the H3. So it\'s not always true for the other subtypes. But right
now, it\'s true for the H3s.

So then you need to be sure that it\'s suitable, it\'s in the right
genetic and antigenic group.

So we\'ve all been really, really struggling with this renewed effort to
provide timely information, and viruses that are truly going to be
useful, not just flood the industry with viruses that might never come
to fruition. And I think there\'s a balance there that we\'re getting
closer to. But I agree, there\'s room for improvement.

MR. COLEGATE: Yes. I mean, that was, I guess, the main reason for
setting, or trying to set up an egg grate with WHO. Now, we\'re open to
trying to get more H3N2 egg isolates available. And maybe that will pay
off.

CHAIR MODLIN: Bruce?

MEMBER GELLIN: Yes. Let me ask a couple more things.

Your animated graphic was really quite helpful. The boxes have looked
the same for a long period of time, as far as their dimensions, but the
manufacturing capacity has expanded significantly recently. And so I
guess the question is, we\'re all faced with the same calendar, and we
can\'t lengthen it. So that\'s the biggest problem.

So within that, can those boxes, can they get fatter? And I guess I\'m
not quite sure if we\'re going to have excess vaccine this year, and the
growth curve of the amount of vaccine that\'s produced for the U.S.
market has been tremendous. The question then is, how is that being
accommodated by potentially shortening the time when each of those boxes
is running?

MR. COLEGATE: Well, I mean those boxes, I think, have been getting
fatter in recent years to accommodate the increased market requirement.
But you still have all these time points that you have to follow, and
you\'ve got to balance the strains. And the fatter the box, the bigger
chance you\'ve got of going dangerously wrong by producing twice as much
of the fast growing strain before you\'ve got potency reagents to tell
you what it\'s yielding.

It is a very, very exacting \-- well, it\'s not exacting, in some
respects, it\'s kind of bucket science as far as flu production is
concerned, because it\'s an old product. But it does take a lot of
management to try and get everything lined up, and the vaccine out on
time.

CHAIR MODLIN: Other questions?

If not, I\'d like to thank Mr. Colegate. Thanks very much for an
eye-opening presentation.

At this point in time, we will move on to the open public hearing for
this session, and I\'ll turn things over to Christine.

EXECUTIVE SECRETARY WALSH: Thank you, Dr. Modlin.

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

CHAIR MODLIN: Yes. Both the Food and Drug Administration and the public
believe in a transient process for information gathering and decision
making. To ensure such transparency at the open public hearing session
of the Advisory Committee, FDA believes that it is important to
understand the context of an individual\'s presentation. For this
reason, the FDA encourages you, the open public hearing speaker, at the
beginning of your written or your oral statement, to advise the
Committee of any financial relationship that you may 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 for your travel, lodging, or other expenses in
connection with your attendance at the meeting.

Likewise, FDA encourages you, at the beginning of your statement, to
advise the Committee if you do not have any 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.

EXECUTIVE SECRETARY WALSH: I have received one request from Ms. Manon
Cox, representing Protein Sciences Corporation.

Ms. Cox?

MS. MANON COX: Okay, Thank you. I am Manon Cox, I\'m Chief Operating
Officer at Protein Sciences, so I\'m employed by the company.

And the reason for this public statement is that I would like to update
the Committee and the public here of the fact that Protein Sciences is
planning to submit a BLA application for a novel recombinant
hemagglutinin vaccine within the next couple of months, and we hope to
be able to have some vaccine in the market later this year.

We also expect to come to the Committee with more detailed information
on our clinical studies. But I just wanted to give you a brief update on
our plans in the next few minutes.

First of all, for those of you are not familiar with FluBlok, it is a
recombinant hemagglutinin protein-based vaccine, so it only contains
hemagglutinin, and instead of the licensed vaccines, it contains 45
microgram, as determined by the ID of the hemagglutinin, versus the 15
percent that is present in the licensed vaccine. These recombinant
antigens are produced using the baculovirus system in insect cells, and
the manufacture does not involve inactivation, thus, of an influenza
virus.

The recombinant protein is highly purified, and does not contain egg
protein, and as a result, we expect this vaccine to be providing
beneficial benefits for people that are egg allergic.

We also, in using this technology, it\'s not necessary to select or to
adapt an influenza virus to growing in eggs, because you basically use a
virus that is very well suited to grow in insect cells, and you use a
kind of pluck and play mechanism to produce your antigen of interest.

The cloning expression and manufacture of FluBlok can be accomplished in
a relatively short period of time, less than two months. So, for
example, we only received the latest H1N1 isolate from CDC yesterday,
and we expect to be able to go in production within two or three months
with that antigen.

FluBlok provides an alternative to the currently available licensed
vaccines. And in principle, one of the major advantages is that you
don\'t need so many embryonated eggs. And another advantage would be
that biocontainment, since a baculovirus is not really harmful for
people. It\'s less of an issue than using live influenza viruses.

So we are planning to use four clinical studies to support our BLA.
Well, we are looking for approval for those in 18 years and older using
the accelerated approval mechanism, and what I want to do today is I
want to share very briefly results of two of those studies which have
been fully completed.

The first one is PSC01, which was an efficacy study in healthy adults,
where we had 451 subjects, which were randomized to receive either
placebo or one of two doses, a low dose and a high dose. I want to speak
briefly about an efficacy study that we performed in adults older than
65. This included 868 subjects that were randomized one to one to either
receive FluZone or FluBlok. And then there\'s two very large studies
ongoing, of which we will use interim day 28 safety and immunogenicity
data to support the accelerated filing. And in principle, those reports
are in production, but I don\'t want to share the results here today
yet, since our investigators in the field are still blinded, and this
study is ongoing, since it\'s a formal efficacy study.

The first study is PSC04. It\'s a field efficacy study in healthy adults
where we have enrolled 4,650 subjects in 25 centers across the United
States, and they were randomized to receive either placebo or FluBlok.
And then the other study is a study called PSC06, which is a
non-inferiority immunogenicity and efficacy study in 600 healthy adults
of the age group 50 and 64. And here we compare FluBlok with FluZone,
again.

So very briefly, study results from PSC01 was that the commercial dose,
where we used four times 45 microgram, protected 100 percent against
cell culture confirmed influenza. We also observed a little over 50
percent reduction in CDC-ILI, and what we observed was the lower dose,
which contains the same amount of the licensed vaccine, but only 45
microgram of the H3 component, since that causes most of the illnesses
and hospitalizations in elderly subjects.

We saw that this vaccine component had an efficacy of a little over 70
percent, and resulted in a 30 percent reduction of CDC-ILI versus
placebo.

We further noted that there was a significant dose response effect
between having more antigen present for the B and the H1 antigen, and
that led us to conclude that it would be useful to develop a vaccine
that would be based on three times 45 microgram.

What we saw was that the vaccine was highly immunogenic. We had
protective levels of antigens for at least six months, and particularly
the H3 component showed very high and sustained immunogenicity, with GMT
levels of over 500 at the month six.

Very importantly, we isolated ten H3 isolates. This study was conducted
in the 2004/2005 season. And as you may recall in that season, the
vaccine component of the vaccine which was A/Wyoming did not really
match very well with the circulating virus, which was a California-like
virus.

Part of these results were published by John Trainer et al in *JAMA
Journal,* for those who want to take a closer look at that.

And then, also very briefly, PSC03, this was a study that was conducted
last year. And what I\'m showing here \-- what I\'ve tried to do is to
look at the criteria that were described in the May guidance document of
2007. There\'s two criteria that you need to meet for non-inferiority.
And the criteria in this age group is that the lower bound of the two
sided confidence interval for the percent of subjects achieving sera
conversion should meet or exceed 40 percent.

And these slides, the picture is a little smaller than I had imagined,
but maybe I\'d like you to focus on the yeses in this slide, because
what you can see is that, in principle, FluBlok meets this criteria in
all cases.

I do want to point out that FluZone does miss this endpoint in one
instance.

What is even more interesting is that, if you look into a subset of 280
\-- approximately 280 individuals that are over 75, that this difference
even becomes more pronounced. So having more antigen appears to be of
greater benefit to people that are older.

Now in PSC03, we were faced with a problem because, during that year at
VRBPAC meeting, it was decided that the vaccine should contain a B/Ohio
component, and because the manufacturers couldn\'t make B/Ohio, CBER
decided to produce B/Malaysia reagents for the SRID assay, which we also
used for the release of our product. And as a result, it\'s really very
difficult to compare the immune response that you obtain against a
B/Ohio component and a B/Malaysia component, because FluBlok contained
B/Ohio, and FluZone contained B/Malaysia.

So I would like you to focus in this slide on the GMTs, and the GMT
ratio that relates to the New Caledonia, the H1, and the A/Wisconsin.
And again, for GMT, the criteria is that the upper bound of the two
sided, it\'s 95 confidence interval, and the ratio to GMTs does not
exceed one and a half. And it turns out that this criteria is met for
FluBlok for both antigens.

As I mentioned, study PSC04 and 06, we have done an interim analysis.
The reports are being produced. We do meet all the endpoints. We plan to
submit this BLA filing within the next couple of weeks, and we hope to
be back later this year to present those data in greater detail to this
Committee.

Thank you.

CHAIR MODLIN: Thank you, Ms. Cox.

One question? Bob?

MEMBER COUCH: Yes. Manon, I want to be sure whether I understood or
misunderstood. I thought one of your slides suggested that, in your
healthy adult one, you were giving two does of FluBlok. It didn\'t say
how many doses in the other blocks.

MS. MANON COX: We only give one dose.

MEMBER COUCH: One dose to a healthy adult?

MS. MANON COX: Right. It\'s one dose, but in the healthy adult study, we
had a low dose and a high dose that we were comparing.

MEMBER COUCH: I see. That\'s what you meant by two dosages, if you\'ll
permit me, rather than doses?

MS. MANON COX: Yes. Two different doses.

Thank you.

CHAIR MODLIN: Thank you.

At this point, I\'ll have Dr. Weir return to the podium to set up the
rest of the discussion for the session.

DR. WEIR: Thank you. So I guess we\'re at the stage of our meeting to
where we deliberate which strains should be recommended for inclusion in
the vaccine for the United States for the upcoming season.

In this slide, I\'ve sort of framed the overall discussion that will
take place. In other words, what strains should be recommended for the
antigen and composition of the 2008/2009 influenza vaccine based on the
epidemiology and antigenic characteristics of influenza virus strains
circulating in human population, the serologic responses to circulating
influenza viruses of persons immunized with current influenza virus
vaccines, and finally, of course, the availability of suitable vaccine
candidate strains.

The final slide, which we will leave up, Dr. Modlin can decide how he
would like to do this, but generally we go through them one strain at a
time.

What I have put on this slide is the listing for what is in the current
vaccine, that\'s the top sub bullet in each one. For example, H1N1, we
have a current vaccine strain, A/Solomon Islands/3/2006-like virus.
I\'ve listed the WHO recommended virus strain in the case of the H1, an
A/Brisbane/59/2007-like virus. And, of course, left open the possibility
for your consideration of other strains that should be included.

So I\'ll leave this up, and turn it over to Dr. Modlin.

CHAIR MODLIN: Thank you. Some of these are going to be easier than
others.

Why don\'t we go ahead and take them in order, as we\'ve done in the
past. Dr. Couch and Dr. Eickhoff, you are the experts on the Committee.
I think we\'re going to rely heavily on you. But why don\'t we go ahead
and open up the discussion, and we\'ll focus on the H1N1 strain to start
with.

Ted?

MEMBER EICKHOFF: A question for Nancy. In your discussion this morning,
I thought I detected a hint that maybe we should seriously consider a
strain in the 2C clade, rather than 2B. That may be a misread on my
part. On the other hand, the 2C strains that were in your big reference
table didn\'t really look that all different from the several 2B strains
there.

So what do you see as the future of the 2C clade? Is it spreading within
\-- is there epidemiologic data to support consideration of such a move?

MEMBER COX: We can\'t distinguish the two antigenically. So there really
isn\'t a reason to suggest at the moment that, until more change occurs,
that that would be advantageous. So while there are a number of strains
in the 2C group, the 2B group is predominating. And I think that, since
we can\'t tell them apart, it\'s kind of a moot point.

CHAIR MODLIN: Bob, maybe you could help us out with, starting off with
what you\'re thinking about with the H1N1 strain?

MEMBER COUCH: The H1N1? No, I was a little surprised that the changes
that we\'ve been looking at appeared. Because I would have thought
industry, if you hadn\'t shown me any of this data we received, I would
have said A/Solomon Islands was probably a pretty good guess, if you had
to do one up front, but it turned out not to be quite as good as I would
have thought it might be.

I accept the variation, and we had a major outbreak in this country this
year that, if we can change the H1, we need to, and the suggestion to
WHO, I will go along with. I have no problems with that one.

CHAIR MODLIN: Ted?

MEMBER EICKHOFF: I will certainly second that motion.

Well, nothing further at this point. I\'m sensitive to the comments that
we heard from Tony Colegate. If we can accomplish a timely selection of
candidate strains, if we can do it today, so much the better.

That\'s all I have to say.

CHAIR MODLIN: Okay. Dr. Jackson, you can help us out here, too, as well.
As an influenza person, how do you \--

MEMBER JACKSON: I\'m not in the same league.

CHAIR MODLIN: Yes, Jack?

MEMBER STAPLETON: Well I think, if you look at, particularly ay the CDC
ferret data, that there is certainly no other candidate that looks
superior. So I don\'t see that there\'s a lot of argument against this
WHO strain.

CHAIR MODLIN: Is there anyone on the Committee who feels that we should
not accept the WHO recommendation for H1N1? Yes, Seth?

MEMBER HETHERINGTON: I just wanted to raise a question here. You know,
there are two key points I think from the industry presentation. One is
that \-- and this is globally. I don\'t want to necessarily focus on
H1N1. But what I\'m trying to get at is, where is our greatest risk in
each of these three strain considerations, and where can we minimize the
risk that, at the end of the day, we\'re not going to have enough doses
of a suitable vaccine for distribution. We may end up in a position
where we\'re looking at some sort of a compromise of efficacy versus
numbers of doses and coverage.

The two things that I think that really struck out were that it\'s
unprecedented to do a three strain change, and anytime you get a new
process and a new series of challenges, you\'re just increasing your
risk. And the risk that we might fall down at any single step, when you
multiply them all together, the total risk becomes quite large.

And the second is that there\'s a difference between two of the slides
we saw, and that has to do with delivery of the vaccine. Not delivery in
the sense of, it\'s on the shelves, but in terms of usage.

Initially we saw a slide where the distribution of the administration of
vaccine goes through December. And what Tony Colegate mentioned was
that, really, there\'s not much usage after Thanksgiving. And I\'m not
sure how much of a restriction at that end of things there really is,
but clearly, there\'s a hard stop in terms of when you\'re going to be
able to effectively use a vaccine, and where that is I think adds
another dimension to the level of risk. It just makes your window of
opportunity even shorter.

So I guess what I\'m trying to get at is, as we go through each of these
three strains, is there a way that we can identify what\'s a much have
change, and what\'s a, well, we may need to give a little bit here,
because otherwise the risk is going to be great. And the risk may be
difficult to quantify, but perhaps either Dr. Couch, Dr. Eickhoff can
give us a little bit of history lesson here on how we might best balance
that.

CHAIR MODLIN: Let me ask \-- I\'ll push back just a bit, but first of
all, what do you think \-- what is your best assessment of which of
these strains we must have, and which would be the one that we could
least do without?

MEMBER HETHERINGTON: Well, I\'m not sure I can give that kind of a
recommendation at this point prior to the discussion. I think that one
of the key issues I wrestle with is I saw some of the data on the
antibody responses is trying to decide what\'s a suitable antibody
response? What\'s the correlate of efficacy for a vaccine?

We saw information on reduction in titer from some baseline, which is a
response of a vaccine to its homologous strain. But it\'s unclear to me
where the HA greater than 40 titer comes into play. Are we trying to get
everybody above a titer, or are we trying to get the least decrease from
baseline? And I don\'t know which is the best correlate, because they
are very different answers.

The reduction from the baseline was quite dramatic for some of these
strains. But if you looked at the proportion of subjects greater than 40
for their HA titer, it wasn\'t that bad. It was more like 80 percent.

So I\'m wrestling with trying to assess what\'s the correlate of
protection, because that may influence how we decide what ends up being
something we can deal with.

CHAIR MODLIN: I would just point out, one of the things we haven\'t
discussed in any detail, but obviously it\'s a major factor, and that is
making some \-- you can\'t guess as to when next year\'s influenza
season will occur. We have had data presented to us in the past about
the timing of peak influenza activity during different years, and it\'s
my understanding it\'s more likely to peak January or February than it
is in December. But of course, we can\'t predict that will be the case.

I will tell you that, up at Dartmouth, we have been pretty good about
following a recommendation to continue vaccination well into January.
And I think there\'s more and more attention to the fact that we may
have an opportunity, at least in most seasons, to extend the vaccination
season beyond what we\'ve done in the past. And so I think that is yet
another factor that needs to be taken into consideration, recognizing
that you\'re still rolling your dice.

Jose?

MEMBER ROMERO: Well, let me echo that. I mean, as a practicing
pediatrician in NID, we are immunizing well into January, and even into
the epidemic today.

The other issue is that we are educating our pediatricians to start
earlier and earlier, to the point that we\'re telling them that we want
to start during those school physicals that are going on during August.
So, you know, whether it\'ll happen or not - I see John raising his
eyebrow - but that\'s the issue is that I think the windows are going to
shift, and they\'re going to shift because pediatricians are really
getting the idea that this is important, family practitioners, and that
we are vaccinating well into the influenza season.

CHAIR MODLIN: Melinda?

MEMBER WHARTON: Yes. I wanted to just make a comment about this issue of
extending the influenza season. With support from HHS, CDC has, for the
last couple of years, sponsored national influenza vaccination week,
following Thanksgiving, with the specific intention of trying to focus
on extending the influenza vaccination season. And we\'ve only done this
for two years now. This is not anything that had been done previously,
and we do have some evidence, albeit still preliminary that, in fact,
that there has been some increase in later season vaccination in the
last couple of years.

So I just want to support what my colleagues around the table have
presented.

I don\'t think we should give up on extending the influenza vaccination
season. And just as we\'ve seen this year, where it was well into 2008
before the influenza disease season really took off, I think we do have
more time, and both in the clinical and public health realm, we can do
better with extending vaccination later to make sure that some of this
later season production can be used.

CHAIR MODLIN: Dr. Couch?

MEMBER COUCH: No. I just want to thank Seth for that question. That\'s
an excellent question, because we get caught up in the practical aspects
of this, not just in the scientific, as you said. And I understand and
appreciate what\'s being said, that extending the vaccine season is,
indeed, worthwhile almost certainly for a lot of individuals. But I want
to emphasize that this vaccine really still needs to be available the
1st of September. And when we\'ve had it in the past, on occasion, the
middle of August, that\'s a whole lot better off for delivering. And so
we\'d like not to compromise on that anymore than possible.

Even though we advise recommending late, I still advise everybody to get
your vaccination before Thanksgiving. And that guarantees almost always,
actually there\'s one exception. We had a November H3N2 massive
outbreak. But that\'s only one exception in a couple of decades. Then
you\'ll be all right.

Otherwise, you\'re running the risk. And this year, it was H1N1, with a
risk of not having that vaccine delivered until after the epidemic was
already here.

And so that\'s important for us not to compromise that part of the
vaccination need for a strain selection which is desirable, perhaps not
essential. And if you would have told me I\'m reducing the dose so that
we can\'t start vaccination until the middle of October, only half as
much like we\'ve had to live with, Solomon Islands is fine with me. That
would have been a relatively easy decision for me.

CHAIR MODLIN: Any additional discussion?

If not, I\'m going to call a vote. For those of you who have been to
past VRBPAC meetings, we have changed the way in which we vote. Rather
than going around and asking for each individual voting member\'s vote
one-by-one, the procedure has been changed in that we\'ll be voting all
at one time. And we will ask you to raise your hand, either as an
affirmative or a negative vote.

We don\'t have a specific question, but the issue is, in essence, to
accept the WHO recommendation for replacing the current vaccine H1N1
strain with the A/Brisbane/59-like virus, if I understand it correctly.

So I\'m going to ask that those in favor of accepting this
recommendation raise their hand. For H1. This is just H1. We\'re doing
this one at a time.

EXECUTIVE SECRETARY WALSH: And please keep your hand raised until Dr.
Modlin calls your name.

CHAIR MODLIN: Okay. Dr. Cox is not voting.

Dr, Wharton, Dr. Destefano, Dr. Jackson, Dr. Davis, Dr. Gellin, Dr.
Couch, Dr. Modlin, Dr. Debold, Dr. Romero, Dr. McInnes, Dr. Self, Dr.
Hachey, Dr. Jackson, and Dr. Eickhoff all vote, yes.

Those voting, no? Those abstaining?

EXECUTIVE SECRETARY WALSH: Just for the record, I think you said Dr.
Jackson \--

MEMBER STAPLETON: You called me Dr. Jackson, I believe.

EXECUTIVE SECRETARY WALSH: Instead of Dr. Stapleton. So it was Dr.
Stapleton.

CHAIR MODLIN: My apologies. It\'s not been the first time, it will not
be the last time, either.

Dr. Eickhoff?

MEMBER EICKHOFF: Just a point of clarification. The slide reads
A/Brisbane blah, blah, blah dash like virus. This gives the
manufacturers, I presume, a little bit of latitude in selecting the best
like \--

CHAIR MODLIN: That\'s certainly my understanding. Jerry, is that the
case?

DR. WEIR: That\'s always the case for us, yes.

CHAIR MODLIN: Thank you.

Let\'s move on to the H3N2 strain. And again, I think we\'ll open up the
discussion as we have in the past. The recommendation is to replace the
current H3N2 isolate with the A/Brisbane/10-like virus.

Dr. Couch, you want to start us off again?

MEMBER COUCH: Not much discussion, again. We wanted to change the
Wisconsin last year to something else, we just didn\'t get the chance.
So there\'s no question about changing it this year. The concern is that
we\'ve got it right again this year, but I think with the data we\'ve
got in front of us, we don\'t have much choice. We have to accept the
recommendation for A/Brisbane.

H3N2, I will say the same thing I think I\'ve said two or three times,
is the major decision each year.

CHAIR MODLIN: Jack?

MEMBER STAPLETON: Yes. I have a question about, is the Uruguay/716
isolate considered to be Brisbane/10-like?

CHAIR MODLIN: Jerry or Nancy?

MEMBER COX: Yes, it is.

CHAIR MODLIN: Seth?

MEMBER HETHERINGTON: Yes, just a comment. I mean again, getting back to
risk, from Tony Colegate\'s presentation, this seems to be the strain
that could be the limiting factor. And remember, the total number of
doses is dependent upon your weakest of growing strains, and it sounds
like there will be some shipment of some reassortants, if I got it
right, sometime in late February for the Uruguay strain. So that\'s
still a big question mark, but it sounds like it is a potential solution
to a problem. The IVR-147 Brisbane strain was declared as being not
viable. And I think we just need to understand that this may be where
the biggest risk resides for vaccine production in this year. And I hope
Dr. Couch and Dr. Eickhoff have a comment on that, or anybody else with
\--

MEMBER COUCH: Well, we can comment on that, but I think we all take it
as A/Brisbane-like. And the chart, as Nancy says, Uruguay is a
Brisbane-like. And Dr. Gupta gave us the alternatives that are being
sought. And Dr. Colegate did with around three sites in the world trying
to get those reassortants to go. So it doesn\'t have to be A/Brisbane.
A/Brisbane-like is the decision.

CHAIR MODLIN: Further discussion? So we\'ll call the vote on this.

Those in favor of accepting a WHO recommendation, would you raise your
hands?

Those voting yes are Dr. Wharton, Dr. Destefano, Dr. Stapleton, Dr.
Davis, Dr. Gellin, Dr. Couch, Dr. Modlin, Dr. Debold, Dr. Romero, Dr.
McInnes, Dr. Self, Dr. Hachey, Dr. Jackson, and Dr. Eickhoff.

Easier than I thought it was going to be so far.

Let\'s move on to the B strain. The recommendation is to replace the B
strain with an alternative B/Florida-like isolate. The data here were a
little more murky.

MEMBER COUCH: I\'ve got a comment.

CHAIR MODLIN: Bob?

MEMBER COUCH: I had a comment for B that I carried with me that I want
to make. I\'m going to go ahead and make it.

I went back a little bit like, maybe like Tony did, and a couple of
others, that what\'s going on with the Bs. And I went back to 2000
trying to see if we can get any patterns out of that.

We got selected correctly out of the eight years they\'ve both been
circulating that I read. We selected correctly four of the eight. We
missed four of the eight. We might as well flipped a coin, to see, for
selecting the Bs, if we couldn\'t do any better than that. I think
that\'s still somewhat where we are with these things still circulating
around the world, both of them, which one is going to be dominate. And
if we talk about guessing, this is the one that we do the most guessing
on currently.

And so I go back to what \-- I was about to say what Tony introduced
earlier. You look at some of those responses in adults and elderly, you
see, and either one, they do very well against the other strain. And in
the absence of attacking it head on, which we discussed to some extent
last year, I made up my mind that I\'m going to come into the meeting,
if I keep coming to the meeting, every year with the decision that I
want to change the B to the one we didn\'t use the previous year.

And that, at least, will improve the circumstance for the elderly and
the adults. And if those children, at least the older children, got
their vaccinations as they should have the previous year with Malaysia,
they\'ll get the right one this year, and then they\'ll be in better
shape, as well.

And in the absence of being able to guess better than that, I think
that\'s the decision we have to make. Well this time, based on
circulation, it says, pick a Yamagata, and we picked Malaysia, based on
a circulation. And we had a Yamagata, so I think it\'s an inexact
science.

CHAIR MODLIN: Your point\'s well taken, and I wonder if that shouldn\'t
take us back to Melinda\'s original question about whether or not you
can, in some respects, obviate this as an issue by including both
lineages in the vaccine. Obviously, this is not something we\'re going
to impose upon the manufacturers this year, and it\'s likely that the
only way in which that would happen, if we thought it was a good idea to
happen, is to signal our intent to do that at some time in the future.
Maybe next year, maybe two years from now. I don\'t know what that time
interval would be. But that might be something that would be worth
discussing, and I think probably should.

But I also don\'t want to get off on that right now. Obviously, we\'ve
got another task here. But maybe, if we have time, maybe we can come
back to it.

Is there further discussion about the B strains? Again, Ted, do you have
a strong opinion?

MEMBER EICKHOFF: No. I had a thought similar to the thoughts that Dr.
Couch had, mainly, maybe we should select the non-dominant strain for
this past year in anticipation of the fact that it may be the dominant
strain next year. But you\'re right, it is a guessing game.

I think Nancy pointed out that this strain, the Yamagata strain, could
be dominant for the next five years. We just don\'t know.

CHAIR MODLIN: Bruce?

MEMBER GELLIN: Well, let me put a slightly different proposal on the
table, as well. I think that it\'s not necessarily that we\'re imposing
on the manufacturers, but I think we\'re going to provide a roadmap, and
maybe an opportunity. And so what if we were to think about priorities?

That we think that for sure they should make X, but if they have the
wherewithal, they should consider a second strain, which would then get
to a tetravalent.

Without getting into naming names, a lot of companies use the number of
valencies in their vaccines to say that they have a better vaccine than
the next guy. So I guess I would like to think that that\'s something
that we want to at least start to put down some markers for, and not to
compromise, but to then have this prioritization there that everybody
should make this one, but if others want to get into it. Now that would,
obviously, get into a whole complexity of not everybody having the same
vaccine, which is a larger discussion. But then it might help to move
the field.

CHAIR MODLIN: Further discussion on B, at least on this particular
point? If not, I will call for a vote. And the question again is, do we
accept the WHO recommendation for the B strain? Those in favor of
accepting the recommendation, if they\'d raise their hands?

Those in favor, Christine, or Dr. Wharton, Dr. Destefano, Dr. Stapleton,
Dr. Davis, Dr. Gellin, Dr. Couch, Dr. Modlin, Dr. Debold, Dr. Romero,
Dr. McInnes, Dr. Self, Dr. Hachey, Dr. Jackson, and Dr. Eickhoff. Thank
you.

We got through that a whole lot faster than I had anticipated,
particularly given the difficulty.

I think, in the interest of time, I I think it probably would be
worthwhile having a little bit further discussion about the possibility
of extending the number antigens, particularly the B antigens. And I\'d
be very interested in actually having the manufacturer\'s perspective on
that. I don\'t know if Mr. Colegate, or anyone else representing any of
the manufacturers would like to speak to that topic. And you\'re welcome
to do so using the microphone right there, if you\'d like to do it.

Anyone else?

MR. COLEGATE: I think the presentation last year at this meeting, or the
one following on the implications of tetravalent vaccine, apart from the
obvious time constraints, and you can see with the situation we\'re in
this year, we just could not do it.

With three strain changes, we are at risk now of falling down on two of
those strains, because two of them are totally unknown to us. I guess
the Brisbane/10 is not totally unknown, we know that IVR-147 will not
work for us, so therefore, we have to look for an alternative. But there
are three possibilities there ready and waiting for us. Well four, I
guess, if IVR-171B is not completely out of the picture. And I\'d like
you to remember that. If it does come good with the additional
serological studies, if we could use that, maybe that could help us to
get to a flying start, if there\'s some uncertainty over the Uruguay.

I think we ended up last year with saying really what is needed now is
we need some help with the regulatory pathway. Because a tetravalent
vaccine would need all kind of regulatory, and I thought somebody from
the Committee was going to come back to industry and tell us what we
needed to do to actually get this tetravalent vaccine off the ground,
because we obviously will need some kind of guidance on clinical
studies.

We discussed, do we put seven and a half micrograms of Yamagata and
Victoria in, or do we put a full 15 in, and we really need some kind of
discussion, and some program to work this forward. But I think we do
need some help and some guidance, and then I\'m sure we can \-- if it\'s
in the public good, we\'ll do it.

CHAIR MODLIN: This sounds like naivetè on my part, and probably is, but
I would think, if there were two B antigens, the likelihood of having to
change the B antigens on an annual basis might decrease, would they not?
Bob, you\'re the B expert.

MEMBER COUCH: Well, actually, I wanted to ask that question, maybe much
the same question, a little bit different way. I want to remove it from
this year, Tony. Because this came up about, let me guess, six or eight
years ago. And I can remember that the industry \-- because the proposal
was, which is actually, if we had to make a change right now, that would
still be number one on my list is to give seven and a half of each one,
so your total is still 15. We brought that up for discussion, and the
industry representative said, well one of them we did last year, and
we\'ve got the reagents, and we\'re only using half of it, so we only
have to make half as mach of a new one. That will delay us, but not
significantly. Would you share that kind of view?

MR. COLEGATE: I think so. I mean, we need as much warning as possible. I
mean, it just needs to be planned. I guess we can do all of these
things, if it\'s planned in, and I guess, if it means we have to
increase our capacity, then we increase our capacity.

MEMBER COUCH: But you only make half as much of the one you made the
previous year.

MR. COLEGATE: Yes. If it\'s seven and a half micrograms, have we got any
clinical data to show that that is \--

MEMBER COUCH: Yes, that\'s the problem. FDA wants was a clincial \--

MR. COLEGATE: Yes.

CHAIR MODLIN: Any other discussion?

Melinda, did you have a comment?

MEMBER WHARTON: Yes. You know, this issue has come up every year that
I\'ve been at this meeting, for however many years that\'s been, and
just from having gone through the annual agony of trying to flip the
coin, or get out the crystal ball regarding what strain is going to \--
of the two co-circulating lineages of type B, which one will
predominate, and seeing, once again, that the issue really has to do
with children. It seems to me that, if there is a public health case to
be made for improving influenza B protection of children, and there are
people around this table who know those data better than I do, and then
the next question is what is the scientific base that needs to be
brought forward in terms of clinical trials to tell us what the vaccine
should look like.

And then, what do the manufacturers need to actually make that happen.

And, you know, where this Committee sits vis-à-vis other advisory
committees, I\'m not completely sure, but I would really like to have a
pathway forward by which we could get there so we\'re not having the
same conversation every year.

CHAIR MODLIN: That\'s a great point. Norm, obviously we\'re not going to
settle this now, but do you have any thoughts? Would this be something
that would be a proper role for this Committee to take up in another
forum, another time?

DR. BAYLOR: I think it would be very useful. I mean, I echo what Melinda
said. You know, we bring this issue up every year, and it sort of drops.
And maybe it\'s now time for us to say, let\'s just tackle this issue.
Let\'s have the discussion. We can put together a VRBPAC and discuss and
supplement this Committee with other experts, and discuss what kind of
data would we all recommend to, say, form a quadrivalent vaccine
containing two B strains, what kind of safety and effectiveness data we
would require. I think we can have that discussion in this type of
forum.

CHAIR MODLIN: Yes?

MR. COHEN: Hilal Cohen, Novartis.

Going back to last year, we raised a point that we have to mentioned
again, which is that we\'ll need a legislative fix, as well as just the
pure science. The current legislation covers for reimbursement, and for
insurance, a trivalent vaccine. And while I certainly personally like
the idea of the fourvalent with two Bs, we\'ll need that other fix, as
well.

So I second the idea with Dr. Baylor. It does pay to put together
everything at one time and view it as a whole. Because even if we had a
recommendation today for a second B, I\'m not so sure that manufacturers
would be able to deliver, be willing to deliver.

CHAIR MODLIN: And one option would be to consider to having a
quadrivalent vaccine only for children. We do have other pediatric
formulations for the vaccine, and I recognize that that introduces all
kinds of other complexities, as well. I\'m not sure we want to get into
that discussion, but at least that\'s yet another thought there.

MR. COHEN: That would be basically a new vaccine that we would have to
bring forth to the agency for licensure. That\'s certainly doable, but
it is a new product completely, and would require an extensive safety
database. So again, I would like the idea to do something like that, but
I think it would require industry working with CBER to define the needs.
And then we can move forward.

CHAIR MODLIN: Any further discussion? Yes, Pam?

MEMBER McINNES: I just want to second what Melinda said. I mean, I\'ve
also been coming here for a long time, and I think the Committee, these
are not frivolous decisions that are made. And there is always this
dynamic of, oh, don\'t change the decision, because we might not be able
to deliver.

There\'s risk on both sides. There\'s risk of not having sufficient
antigen, and there\'s risk of us really not having the right strain.

So this is not a risk-free business, and I think we need \-- one of
these years, we\'re going to have a B year. And I\'m personally quite
concerned about that. And this is, in fact, maybe a year we should have
two Bs in the vaccine. And for a whole host of reasons now, we can\'t
appear to even sort of move in that direction. But if we don\'t step
into the water, we\'re never going to solve this, because there will
always be the push back.

So I just, absent having the proof of a decision that, yes, this is the
year you need two, and you\'d better pretend this is the year you need
two, what is it going to take to move this discussion forward?

CHAIR MODLIN: Jack?

MEMBER STAPLETON: I have a kind of an historical epidemiology question
for Drs. Eickhoff and Couch, and that is, since I\'ve been paying
attention, since I\'m not a flu person, there has been this mix between
Yamagata and Victoria lineages, and for the last, at least eight to ten
years. Is there, historically, a time when one has emerged where
there\'s been a single B lineage?

CHAIR MODLIN: Nancy, you may be able to address that, as well.

MEMBER COX: Yes. When the B Yamagata lineage emerged, of course, it had
been circulating in Asia - it was detected first by the name in Asia -
we saw, for a couple of years, and it was more prominent in Europe,
co-circulation of the previously circulating B/Victoria strains with the
Yamagata. In the United States, there was a pretty clear transition, a
pretty sharp transition to B/Yamagata-like viruses.

Then for the next ten years, B/Yamagata circulated very little, if at
all, in Europe and North America, South America, but remained in
circulation in Asia. And first it was really only in China, and then we
would see it in China and Japan. And after ten years of its absence, as
far as our surveillance was able to detect it, we had a resurgence of
the B/Victoria viruses. And we anticipated that, I think, through our
surveillance. I would have to go back and look and see for sure. And I
think we did move to B/Victoria lineage vaccine.

Since then, it\'s been a mixed bag. And it\'s been very difficult to
determine what to do.

I agree very much. We do see that going on right now in Hong Kong,
approximately 50 percent of the viruses are Victoria, and 50 percent are
Yamagata, whereas, in Mainland China, there\'s a different picture. The
rest of China, there\'s a different picture.

So it is a very difficult forecast to make, and there\'s not, one year
it\'s Yamagata, the next year it\'s Victoria, which would make it very
easy for us. But also, just in line with what others have said, it\'s
really the young children where you see this dichotomy of antibody
responses, where basically it\'s all or nothing. In the adults, you see
a much more \-- because the adults have been exposed to both lineages,
you do see that bump in titer to the opposite lineage.

So I think the public health focus really is on young children where we
would not expect them to be proactive. And we do see childhood deaths
associated with influenza B viruses.

MEMBER STAPLETON: I mean, I just want to comment that, given that
epidemiology that we\'ve observed, and I don\'t see how we can avoid,
like others have talked about moving towards a tetravalent.

CHAIR MODLIN: Bruce.

MEMBER GELLIN: So Tony Colegate, as usual, told us very many important
things. He started by giving us this cautionary note about the
tetravalent. But then he came back to the microphone and said, if it\'s
in the public good, we\'ll do it. And we can do all these things if we
can plan. And then sort of put out this regulatory challenge.

So my question is really to Norman or the FDA is that, if a manufacturer
wanted to come in this year, and to produce, for some segment of the
population, a tetravalent vaccine, do you think that \-- I guess the big
question is, would it require a phase three trial which would take it
off the map for bringing it into the next year, but do you think that
there\'s enough time to be able to perform the kind of studies that
might be needed to bring such a product forward?

DR. BAYLOR: To bring a product forward, say if someone said it today,
and to bring that product forward in the fall? That would be cutting it
close. That would be very difficult to do. But there\'s another
complication here, and it\'s not insurmountable, but influenza, as we
all know, influenza vaccine is very unique. It\'s really the odd vaccine
out, because it follows into all the manufacturers, the public health;
we follow in step. So this one is very close. And to have a manufacturer
\-- this has come up a lot this year about quadrivalent vaccines. To
have one manufacturer out of step from the others, so we have one
manufacturer who wants to make a quadrivalent, and the others do not. I
mean, that is somewhat difficult.

I mean, it can be done. But as far as the way our influenza system has
gone all these years, I mean it\'s a partnership, and we try to keep
everything in step with all the manufacturers, with all the government
recommendations. So that would be a challenge.

From a regulatory point of view, we could do it. But how would this be
implemented as far as public health policy, that\'s another question.

MEMBER GELLIN: Yes. I didn\'t say it was simple, but I guess you want to
have a core vaccine, and then in some way you may want to add to it. I
mean, it\'s not the only product that different manufacturers have
different numbers of valences.

DR. BAYLOR: No, but it\'s really the only product where we sit here and
make a recommendation on what will go into that vaccine. If you wanted
to make a hib vaccine, and you put a different conjugant in it, that\'s
up to you.

MEMBER GELLIN: Another, not a different. So they have to meet these
three, and then they may have, you know, FluPlus, or whatever they want
to call it, but they now have something that has an additional
component.

I\'ll stop.

DR. BAYLOR: It\'s doable from a regulatory point of view. We could do
it.

CHAIR MODLIN: Bob?

MEMBER COUCH: I would like to urge, I\'d certainly support a discussion,
serious discussion, of how to move forward on these issues. But I would
personally not like it to be restricted to Influenza B. Because I think
some of us have had the view for quite some time now that we\'ve got one
vaccine for all you say, as though that\'s all you got to have, and
reduce the dose for reactions in young children, and you\'re fine.
We\'ve been at the point for quite some time that we need vaccines
tailored a little bit better for different individuals. We\'ve got the
elderly, my view, and it won\'t surprise many people, the vaccine dosage
is not high enough. Now it\'s fine for perfectly healthy young adults,
and the military has got the beautiful data on that for a long time, and
we\'ve addressed questions that are unique for children here on
influenza B, and that also applies to children on H1 and H3 to an
extent, as well.

So you see, we\'ve got these different considerations, and some of us
are now worried about how do you immunize immuno-compromised
individuals? See, there\'s another group, that that\'s a part of the
discussion of how to make \-- well, I know Dr. Baylor said a minute ago
that we\'ve got one system. But look how many cephalosporins we\'ve got?
Now that won\'t mean that we want that many different versions of
influenza vaccine, but that sort of circumstance would not be unique for
our country, if they\'re picked and they\'re tailored for the right
populations.

CHAIR MODLIN: If flu vaccines made as much money as cephalosporins did,
then we would have no problem.

Yes, Lisa?

MEMBER JACKSON: Well, Bob, along those lines, I\'d just say I was a bit
surprised by the sort of suggestion that we might consider reducing the
dose of B to include more strains because to me, if anything, maybe you
would want to have more B than we currently do. I mean, especially in
young children where the serologic response, if that\'s meaningful, is
obviously not what we\'d like to see, and really necessitates two doses,
which still, a very substantial proportion of children do not receive.

I think the other thing we\'ll run into as we go down this road is the
realization that there\'s quite a dearth of information on how well the
B component works. I wondered if you would agree with that.

It seems like in young children, especially of the relatively small
number of studies that have done a good job evaluating efficacy in
general, the B circulation hasn\'t been extensive enough in those years
to allow a reliable calculation of effectiveness, specifically against
those strains.

MEMBER COUCH: Again, maybe I sound like an industrialist here, but the
regulatory requirements are of major importance, and you remind me of
that one because of how strict we want efficacy to be proven for these
various things. Because that\'s difficult and time consuming for
influenza, and when a company asked me about this, I said, don\'t ever
plan for one year. You\'ll almost certainly won\'t make it. That\'s the
unpredictability, and you\'re talking about investments that go in large
numbers over three years to prove \-- I don\'t mean to be sounding like
I\'m picking on FDA \-- to prove a surrogate that was established
decades ago. Now how many times do we need to prove it?

But, you know, I want supported data. I\'m not arguing against that, but
how rigorous should that data be to prove that same surrogate that
we\'ve had for decades?

CHAIR MODLIN: Norm?

DR. BAYLOR: And at some point, Bob, I\'d like to have that discussion.
Because I don\'t disagree with you, but I think we need to have that
discussion.

CHAIR MODLIN: It sounds like we\'ve got a topic for another meeting.

DR. BAYLOR: And if we want vaccines to be tailored for the population,
we just have got to have some discussion about, what is the minimum
requirement, as opposed to what is the desired data.

CHAIR MODLIN: Okay. We\'ll let that be the last word.

We\'ve gone from being behind to being considerably ahead of time. I\'m
going to suggest that we start up at 1:30 rather than 2:00, if that\'s
okay with everyone. So we\'ll start the afternoon session at 1:30.

(Whereupon, at 12:34 p.m. the meeting was adjourned, to reconvene this
same day at 1:36 p.m.)

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

1:36 p.m.

CHAIR MODLIN: I would like to welcome everyone back to the afternoon
session of the VRBPAC Committee meeting for February 21st.

We\'ll be moving on to the next topic, a very interesting critically
important one, and that is the development of the influenza vaccines for
both the pre-pandemic and for pandemic uses. And I understand that Dr.
Golding from the FDA is going to, first of all, provide a summary of a
government workshop on pandemic preparedness, influenza preparedness
that was conducted this past December.

Dr. Golding?

DR. GOLDING: So we are moving from a game to looking for the crystal
ball when we are starting as the world to be prepared for the unknown,
which is a potential of pandemic influenza.

So it become apparently in the past couple of years that we cannot just
sit and wait to see what happen, but rather there is a very big push
both by the World Health Organization, the U.S. Government and really
globally to try and prepare for the event of the avian influenza
starting to move from one person to another. And in order to best be
prepared there is a need to prepare some vaccine and there is real
mandate to prepare stockpiles of vaccines trying to at least partially
protect and curtail pandemic in the case that it started. But as we were
starting as an agency to decide how to address it from a regulatory
point of view, we realized that there are a lot of scientific gaps that
need to be answered. And that was the reason for organizing a workshop
that took place back in December. It was co-organized by scientists at
the FDA, NIH and the World Health Organization and it took place in
Bethesda. And I just want to take a couple of slides to summarize what
was the nature of the workshop and what was the general recommendation.

I do want to make it very clear that none of the slides will present any
formal FDA viewpoints or standpoint. This is just reflecting what came
out of that particular workshop.

So, as we all know, the common situation, which is still good in that
very limited human-to-human transition of avian influenza have been
reported or confirmed. We\'ll hear more about it from Nancy, but the
current situation is not conducive to traditional vaccine clinical
trial. Therefore, evaluation of pandemic influenza vaccine is relying on
immunological measures that currently have evolved from the seasonal
influenza vaccines that we\'re all very familiar with.

And as you know, the principle correlate of influenza vaccines efficacy
at the moment is the hemagglutination and inhibition antibody titer as
the real doubt, and we saw many slides with type of data today.

But the big questions are, of course: Is it appropriate to extrapolate
what we know from seasonal influenza vaccination to pandemic influenza
vaccines when most of the population are lacking in preexisting
immunity?

Is it also possible that due to the higher pathogenicity of the H5/N1
what will be protective against seasonal vaccine may not be fully
protected against these viruses?

Most specifically, is an HI titer of any antibody measurement
appropriate to predict clinical benefit from new types of influenza
vaccines such as live attenuated vaccines, plasma DNA vaccine,
virus-like particles and vector vaccines, all of which are currently
under development by many different manufacturers and sponsors?

And we know already even from the seasonal vaccines that the
live-attenuated vaccine using the HI titer was not always a good
predictor of protection.

And, of course, the big goal is therefore how do we establish the
protective level associated with newly defined immunological endpoints
and accurately quantify the responses following vaccination, which is
what we will eventually need to license such vaccines.

So the goals of the public workshop were, first, to identify the gaps in
our knowledge and abilities in addressing the unique challenges
encountered in the development evaluation of vaccine intended to protect
against pandemic influenza and then to facilitate implementation of
global research agenda to improve efficacy assessment of pandemic
influenza vaccines.

There were four sessions. The first session was chaired by Dr. Robert
Couch, who is with us today. And this session included descriptions of
humoral and cell-mediated responses to influenza with an emphases on
immune mechanisms that contribute to protection against influenza
infection or disease.

Of course, I cannot cover all the talks that were discussed. But this is
sort of trying to just summarize this particular session in that
probably both antibody responses contribute to protection against
seasonal influenza. May an analysis of human challenge studies support
the conclusion that HI antibody titer of 1 in 40 is associated with at
least 50 percent reduction in the risk of contracting influenza
infection or influenza disease. That was published by Dijon in 2003.

In the second session we moved to avian influenza. This was chaired by
Dr. Jackie Katz from the CDC. And we tried to cover information that was
gained from people who were either exposed to H5/N5 and other avian
influenza as well as early vaccine trials. And the main data that was
shared came also from information on poultry workers. And it turns out
that immune responses to several avian influenza vaccines candidate both
an activated LAIV were presented from clinical studies performed in the
U.S. as well as in Europe.

What was I think the most important note by Jackie Katz is that in
poultry workers that were indeed exposed the titers of antibodies were
relatively low. Only in very high exposure one found 1 in 80 titer of
microneutralization. And in many cases they did not last for very long.
So you really had to capture them in the right time.

This is a very important initiative by the World Health Organization
that was presented by Dr. Fred Hayden, describe the Southeast Asian
Influenza Clinical Research Network that will facilitate international
collaborative epidemiology and immunologic studies of pandemic
influenza. And most of the centers are in Asia in about five different
countries. And, hopefully, they will be able to get access to
post-exposure samples from infected individuals and start to gain some
more insight of what type of antibodies may be correlated with level of
protection.

In session three we started to really hone down on the assays that are
used to evaluate vaccine immunogenicity. The assays that are used in
clinical trials. So it included a discussion of the limitations of the
current assay to the antibody responses to NNA and described new assays
to evaluate cell-mediated immunity in M2 specific antibody responses.
Novel assays that used pseudotyped viruses of H5/N1 as well as genomic
\-- display libraries were also described.

It was expressed quite repeatedly that the traditional H1 curves based
on chicken or turkey red blood cells are not optimal for H5/N1/HI. Horce
red blood cells seems to have more sialic acid \-- which are the
preferred receptor for H5/N1 strains. However, Horce HI needs
validation.

In the fourth session we looked at the value of various animal models,
and it was chaired by Kanta Subbarao from the MAID, which was also one
of the co-organizers. And in this session animal models for pandemic
influenza were described. Results of wild-type virus challenge in mice
and ferrets to determine the immunogenicity and efficacy of new vaccines
were also presented.

These animal models provided important information about vaccine
immunogenicity and correlates of protection including heterologous
protection. The vaccine effect included reduced viral loads in the upper
respiratory tract and the lungs, lower morbidity and less lung
pathology. However, it was felt that lethality as an end point is often
not an optimum endpoint for vaccine effect and/or dose findings.

The workshop, the two day was actually then there was a panel discussion
and a general sort of recommendations that came out of it. So I think
the sentiment was that it may be premature to extrapolate what we know
from seasonal influenza vaccination to pandemic influenza vaccine,
particularly the use of a given antibody endpoint to predict pandemic
vaccine efficacy.

Specifically, the use of HI hemagglutination in addition they say may
not be appropriate for all types of pandemic influenza vaccines.
Additional immunogenicity measurement need to be defined and the
protective levels associated with the newly defined endpoints
determined.

Moreover, novel assays should be developed to measure mucosal immunity,
cell-mediated responses and antibody responses to neuraminidase and
other targeted antigens.

Animal models, both mice and ferrets, can provide important insight
regarding correlates of protection against emerging avian strains. In
order to facilitate the standardization of assays to evaluate and
compare vaccine responsiveness there is an immediate need for standard
reference reagents, low pathogenicity of viral stock, working cell banks
and very importantly shelve SOP. I think Nancy referred to one such
working group that now has been sort of initiated by the World Health
Organization and CDC and try and validate at least the
microneutralization assay.

So in conclusion, we felt the programmatic approach to pandemic vaccine
trials was use of standardized assay should facilitate comparison of
vaccine candidates and expedite pivotal studies and licensure of
pandemic and pre-pandemic preparedness.

And that\'s it.

CHAIR MODLIN: Thank you, Dr. Golding for a very nice and concise
summary.

I\'m going to suggest that we go ahead with all three presentations and
then maybe open things up to discussion and I ask you to participate
with the full Committee discussion when we do it all at once.

So, Nancy, would you like to summarize H5/N1 surveillance?

MEMBER COX: Okay. Thanks very much.

I will try to quickly go through some of the latest epidemiology and
virologic results for H5/N1 viruses.

This is a slide that is a composite slide showing, first of all in
green, all the reported, OIE-reported outbreaks in birds. And, of
course, we know that this is an under representation of the true number
of outbreaks. Because there are many that are reported in the press.
Many that are confirmed by a reference lab that are never actually
reported to OIE. But you can see there are outbreaks throughout Europe
and the Middle East, and certainly in Bangladesh right now there are a
lot of outbreaks being reported. And they have been reported throughout
China and this part of Russia.

Also in Africa.

And then there\'s the color coding so that the most recent human cases
are in the yellow triangles. And you really can\'t see those very well
because of the color overlap. The purple shows the 87 human cases
identified in 2007 and so on.

And you can see that there\'s a lot of purple down the Nile River in
Egypt. There\'s a confirmed case here. One confirmed case in Pakistan,
and so on. But the majority of the cases that you see here in the purple
color, which is last year, are in Indonesia, in Egypt and a few cases in
China and then a few cases in Vietnam, and so on.

Maybe you can advance the slide for me. Okay. I think we\'ll skip this
slide and that slide, please. Okay.

So as of February 20th there were 362 human cases reported to WHO, 228
of those were fatal giving a case fatality ratio of about 63 percent.

Now we\'ve already had 13 cases that have been reported to WHO, and we
know that there are additional suspect cases in 2008. So it seems that
we\'re getting off to quite a rapid start to counting how many cases or
to accumulating cases of H5.

So you can see here that the case fatality ratio hasn\'t really varied
that much over time. It\'s been about 60 odd percent. But if you look
country-by-country you\'ll see some striking differences. We won\'t go
into that today.

So just for the most recent cases, we had a case in Vietnam in a 40-year
old male reported on February 15th. And then yesterday China reported a
new H5/N1 case in a 22 year old male from Hunan Province.

Next, please.

And this just shows where the case occurred. There are a lot of poultry
outbreaks now being reported in the northern part of Vietnam. They had
instigated or put in place a very aggressive poultry vaccination program
and really had human cases until last year again. And there\'s a fairly
high case fatality rate. So just from the wave that\'s been occurring in
Vietnam, 8 of the last 12 cases have died.

Now if we look at cases in Indonesia, which is another hot spot as
everyone knows, we\'re seeing cases reported in January. And there have
been a 127 cases reported in Indonesia.

Next slide, please.

This is Vietnam. My talking points were a little bit out of order. So
you can see this is the wave of infection starting in May of 2007, the
current wave and extending into 2008.

For the majority of the cases that we hear about there has been exposure
to sick and dead poultry prior to symptom onset. So that has not changed
in the last year or so.

I think I probably showed a similar slide. We\'re really trying to get a
handle on the nomenclature for the H5 viruses. If you read the
literature, it becomes extremely confusing. And the nomenclature\'s a
bit arcane, but we feel that we have a much better handle on the amount
of genetic variation that is occurring. And the new nomenclature will
allow us to go forward using a standardized format so that we will be
able to relate what\'s circulating at a given point in time with what
has circulated in the past.

So if you look at the viruses that have circulated in birds during the
past three years, you can systematically divide them up into nine
clades. There are actually ten clades if you count the 1997 era of
viruses.

This evolutionary tree was based on public domain sequences. So there\'s
a lot of sequence data in the public domain, and over 800 HA sequences
were used to draw that particular tree.

Now this is going to be harder to see. And I have tried a whole variety
of ways to display these things. And if you really want to get down to
the nitty-gritty you need to have a certain number of viruses on the
tree.

So the nomenclature is quite simple, except that for some of the clades
we are now talking about third order. So we have clade 2.1.1, 2.1.2 and
2.1.3. So it becomes quite complex. But for those of us who are looking
at the data on a weekly basis it really helps us to keep a handle on
where we are going.

Now in yellow I\'ve highlighted those viruses that have been used to
produce candidate vaccine strains. So you can see that we\'ve covered
parts of the dendrogram pretty well. Now we haven\'t seen human cases
caused by viruses in clades 8,9,6,5 and 4. But we are keeping a close
eye on those. And 7 as well. So there are a number of clades that
haven\'t actually been in humans, as far as we know.

So there is a very good correlation between the genetic information and
the antigenic information in that if you look a the clade designations,
at least to the second order, you can really divide the viruses into
groups. And there is more cross reactivity generated by the
Indonesia/5-like viruses, the clade 2.1 viruses than some of the other
clade viruses. But there are really clear distinctions in the reactivity
patterns of these viruses, thus necessitating having a variety of
different vaccine candidates so we don\'t know which, if any of these,
will take off.

This is a table that was put together trying to look at very closely at
what\'s been happening more recently. And it was a compilation of data
from a number of different tables. So you\'ll see that there are data
points missing here.

What I want to emphasize is that we do need to fill in some gaps. We
have these viruses here that are clade 2.3.2 which are not well
inhibited by anti-sera to any of our referenced viruses.

There are a couple of other things that I would like to point out.
We\'ve seen some viruses from Egypt that have reduced reactivity to the
referenced viruses. And I\'ll amplify on that when I get to my last
table in this presentation.

Another thing that I would like to point out is that we do have a virus
that\'s in clade 2.1 that is the Indonesian clade that looks like it\'s
a progenitor of the Indonesia viruses. It was isolated from a duck in
Hunan Province in 2002. There are other viruses from Hong Kong that
appear to be very similar to this duck Hunan viruses, and you can see
that the cross-reactivity with the Indonesia/5 antiserum is very good.

So I\'ll move on to the next slide. This, again, is very difficult to
see except for the colors. I hope you can see the colors in the back of
the room. But the red colors indicate the viruses that are available to
vaccine manufacturers for use in clinical trials. The blue colors
indicate viruses that are actually in progress. So we may have a reverse
genetics modified vaccine strain, but not all the safety testing has
been done.

So this is the last side, last data slide. And these are the
reassortants with completed regulatory approval. So, of course, all of
these are reversed genetics modified viruses on a PRA backbone. And we
have representatives from clade 1.2.1, 2.2, 2.3.4 and so on. And then
these are reassortants that are prepared and awaiting regulatory
approval or safety testing. And we have a number of viruses here that
will expand the antigenic diversity among the viruses that are
available.

And then in Geneva a week ago we decided that there was a need to make
some additional reassortants and it would be prudent to go ahead and
make duck/Hunan/2002-like virus and clade 2.1. That would be done at St.
Jude, and then eventually hopefully would be made available through
NIAID. And as I mentioned before, we needed to include an Egypt virus.
It appears that there\'s quite a bit of diversity. The clade 2.2 viruses
are geographically the most widespread of all of the groups of viruses.
And it appears that there is enough diversity occurring so that we\'re
probably going to put a third order designation and have 2.2.2.1 and
2.2.2.2

And then we have this virus, which is the only \-- represents the only
human case in China, that was from the north and is a 2.2. virus. We\'re
working with our Chinese colleagues to make the reverse genetics
modified version of this.

And then we didn\'t yet have a clade 2.3.2 virus, and so St. Jude is
going to use this virus to round out our collection.

So I just would like to acknowledge all the people in my group,
especially Ruben Donus who worked so hard on revising the nomenclature.
There was actually an OIE/FAI/WHO working group that came up with the
nomenclature. I guess it looks like a nomenclature that a committee came
up with.

And then, of course, I\'d like to acknowledge all of the WHO
Collaborating Centers, the WHO H5 reference laboratories, the National
Influenza centers, the Ministries of Health, the Ministries of
Agriculture around the world for making it possible for us to do these
kinds of analyses and to become better prepared should H5 turn into the
pandemic strain.

Thanks very much.

CHAIR MODLIN: Thanks, Nancy.

Let\'s go on to the next presentation, which will be by Dr. Joseph
Toerner from the FDA on pandemic and pre-pandemic influenza vaccine
development issues. And then we\'ll open the floor up for questions for
each of our presenters.

DR. TOERNER: Good afternoon. My name is Joe Toerner. I\'m a Medical
Officer in the Division of Vaccines in the Office of Vaccine Research
and Review. And the topic of my talk this afternoon is evaluation of
insulins and vaccines and pandemic and pre-pandemic indications.

And when I ran into my friend Zhiping this morning, who gave one of the
marque presentations this morning, he said to me \"Joe, you\'re giving
the hot topic presentation at today\'s meeting.\" And I hope I can live
up to that expectation.

So the overview of my talk today I\'ll be providing a summary of last
year\'s Advisory Committee presentation where we began to discuss
pandemic influenza. And then I\'m going to clarify the indications of
pandemic vaccine versus a pre-pandemic vaccine. And there are very
limited amounts of data available on immune responses. And I\'ll be
sharing those data as well. Then, again, the goal of my talk is to help
the Advisory Committee focus their discussion this afternoon. And so
we\'ll be reviewing then the discussion points.

At last year\'s Advisory Committee meeting we introduced the topic of
development pathways for pre-pandemic vaccines. And an important part of
that discussion was the determination of immune responses following the
initial immunization with a pandemic vaccine as well as the subsequent
immunizations. And as a part of that discussion the longer term follow
up of subjects to receive subsequent immunizations was encouraged. And
as a result, we\'re now seeing clinical development studies where
subjects are followed for longer amounts of time in order to gain data
on the immune response determinations to the subsequent immunizations.

And we also view today\'s discussion as an ongoing discussion of
pandemic and pre-pandemic influenza vaccine development.

As this has evolved over the past year, we found important to clarify
the definition of a pandemic indication versus a pre-pandemic
indication. And the reason why this is important is because the proposed
indicated or intended use of an influenza vaccine under development will
determine the type of clinical data needed to support the safe and
effective use of the vaccine. And this has been a source of confusion
because we\'re currently in an inter-pandemic period, and so these
vaccines are being developed. And so we, again, find it important to
clarify this nomenclature for regulatory purposes.

So the pandemic indication this is a vaccine that\'s intended to be used
to immunize persons who are at high risk of exposure to an influenza
virus strain with pandemic potential. And what do we mean by that? Well,
it\'s immunization of anybody during a pandemic. But it also covers the
immunization of laboratory workers who might be exposed to H5/N1, for
example in the course of their laboratory work.

Persons who are deployed to areas where there have been documented human
cases of an influenza virus of pandemic potential, they may desire to be
immunized.

And so pandemic indication, we\'ve outlined in our guidance document for
industry, which was filed in May of 2007, the types of data and the
clinical trials that are necessary to support that indication.

So now I\'d like to move on to the pre-pandemic indication and define
for you what we mean by that indication. And this is the vaccine
intended for the active immunization of persons against influenza virus
subtypes with pandemic potential during the inter-pandemic period. And
this is an immunization as a strategy for population-based pandemic
influenza preparedness.

And so I\'m going to come back to this indication later in my talk. And
I\'m going to shift gears back towards the pandemic indication.

And before I go on to present some immune response data, I just wanted
to reiterate the immune criteria that we feel is reasonably likely to
predict clinical benefit. And that\'s a hemagglutination inhibition
antibody titer of a four-fold increase that the lower bound of that two
sided 95 percent confidence interval should be 40 percent or greater,
and the proportion greater than or equal to a titer of 1 to 40 that the
lower bound of that 95 percent confidence interval should be greater
than 70 percent.

And we\'ve outlined for the geriatric population a bit lower criteria.

So data that are included in the approved product, Sanofi-Pasteur H5/N1
vaccine. And you\'ve heard these data presented last year. And to use
our adult immune response data 28 days after the second immunization.
And you can see here in the blue that 43 percent of subjects that
achieved a four-fold response in the HI antibody titer. And you can see
that number is beginning to approach the criteria that we\'ve outlined
in our guidance document.

And I\'m going to move on. I just wanted to pause for a moment to say
that this slide is the only slide in my presentation that contains data
that have been fully reviewed by the FDA.

So on this next slide of a representative example of other H5/N1
vaccines. And again, this is summary data that have been shared with us.
And you can see that with what might be considered a standard amount of
antigen, that we can all agree we\'re not achieving robust immune
responses. In only example we\'re beginning to achieve some of those
numbers that are outlined in our immune response criteria.

So our concern is that a standard amount of antigen might not meet our
current immune response criteria for the pandemic indication. And so
what can be done to enhance that immune response?

Well, you saw data last year that there was a dose response that was
observed with the Sanofi-Pasteur H5/N1 vaccine, but that might not be
practical because the highest amount of antigen was approved for use in
that product.

And I\'ll go through data that demonstrate that adjuvants may enhance
the immune response. And then finally I\'ll talk a bit about cross
reactivity to the different influenza virus subtypes.

Before I represent data on the enhanced immune response to an adjuvant,
I just wanted to outline in our guidance document for industry that the
added value with the adjuvant that we describe. And this is an early
development, phase 1 or phase 2 studies, where we expect the immune
response that\'s solicited by the vaccine with adjuvant is greater than
the vaccine used alone. And we define that as a difference in immune
response rates as the lower bound of the confidence limit of the
difference that excludes equality.

Alternatively, you can demonstrate the added value of the adjuvant by
showing noninferior immune responses between a dose optimized
non-adjuvanted vaccine in comparison to an adjuvanted vaccine containing
a lower amount of the antigen.

And so, again, these are summary data that have been shared with and
source data has not been submitted to us for review. But I just wanted
to use this to illustrate that in this particular instance the addition
of an adjuvant to a low amount of antigen resulted in an immune response
criteria here in blue that appear to meet or exceed our immune response
criteria outlined in our guidance document for a pandemic indication.

In a different study on the next slide, again what might be considered a
more standard amount of antigen did not elicit an appropriate immune
response, but with the addition of an adjuvant you see enhancement of
the immune response so that you begin to approach some of the numbers
that we\'ve outlined in our guidance document for the immune response
criteria.

And this is just to demonstrate that not all adjuvants are created
equal. And that why we do ask for a demonstration of the added value of
the adjuvant. In this particular study the addition of a different
adjuvant did not enhance the immune response.

And now I\'d like to shift gears a bit to talk about cross reactivity.
And again, these are summary data that were shared with us. And again, a
low amount of antigen did not elicit an immune response to a
heterologous HI antibody response.

In contrast to the addition of adjuvant, where you started to see some
immune response to a heterologous antigen. And the higher the amount of
antigen with the adjuvant, you see an even greater immune response.
Although to point out that these don\'t approach the numbers that we
outlined in our criteria, it\'s beginning to demonstrate some evidence
of cross reactivity.

Are there data from other studies that might help understand cross
reactive immune responses? In a study of a small number of subjects
there appear to be broad cross reactive immune responses among subjects
who receive an adjuvanted vaccine in comparison to subjects who receive
an unadjuvanted vaccine.

And can we glean any information from animal studies that have been
conducted? There have been two published studies using the ferret model.
And these are ferrets that had received an H5/N1 vaccine and then
subsequent to that a heterologous H5/N1 virus challenge. And small
numbers of animals in both of these studies, but one study demonstrated
the higher antigen content appeared to be ameliorate signs of clinical
illness. And in another study, the addition of an adjuvant to a low
amount of antigen in the vaccine appeared to be a survival advantage.

So these are data that are beginning to show the potential for cross
reactivity.

And so with the pandemic indication what are some of our current
regulatory challenges? And these are questions that we\'ve been asking
ourselves and that we\'re faced with. Not necessarily questions for you
to discuss in the Committee. Later on in the talk I\'ll try to focus the
discussion. But these are issues that we\'re faced with.

How will we know that the pandemic vaccine will provide protection
during a pandemic?

There\'s no correlation of immune protection that\'s known and so how
can we address of efficacy of a vaccine that has a pandemic indication?

What levels of human immune response should be achieved?

What are the roles of animal data that might help us to understand
vaccine activity?

What role do studies with seasonal influenza vaccine where the
manufacturing process is identical to pandemic vaccine, what role does
that have to infer effectiveness of the pandemic vaccines?

And, are there other options to evaluate a pandemic vaccine?

And so before I leave the pandemic indication, just some summary
considerations and things that we\'ve identified that might be the
optimal pandemic influenza vaccine:

And that\'s one immunization that would provide protection;

There would be a rapid development of an immune response;

And that immune response would be sustained for the duration of the
pandemic to offer protection for the duration of the pandemic;

There would be a demonstration of broad cross reactivity and the
evaluation would be completed in special populations;

The vaccine would have an ability to be stockpiled during the
inter-pandemic period;

And finally, the vaccine would have an acceptable profile.

And I think we might agree that these are lofty goals for an optimal
characterization and, therefore, the pre-pandemic indication is what\'s
being considered.

And now I\'d like to shift gears to discuss the pre-pandemic indication.
And again, our working definition of this indication is immunization is
a population preparedness strategy against influenza strains of pandemic
potential during the inter-pandemic period. And it\'s important to
recognize that the immunization may not provide immediate benefit or
immediate efficacy, but it\'s an immunization that would enable a robust
boosted response or a robust immune response to a future immunization
with a pandemic strain.

And again, with this indication it\'s important to recognize what types
of data that we would like to see and the clinical evaluations that
would be necessary to support that indication. And so the immune
response criteria to the initial immunization:

Should that be the same immune response that we\'ve outlined in our
guidance document for pandemic?

Would we be willing to accept a less robust immune response so long as
you can identify an adequate immune response to the subsequent
immunization?

And what should that immune response to the subsequent immunization?

Again, should it be the same criteria or more robust criteria than what
we\'ve outlined for the pandemic?

And what if the subsequent immunization is with the same subtype or
whether it\'s with a different subtype, what should those immune
response criteria be?

Again, for the pre-pandemic indications, safety is an important
consideration. So we would expect some large simple safety studies to be
conducted. But what level of serious adverse events should be ruled out?
At last year\'s presentation I had gone through a series of slides
outlining the experience in 1976 of Guillain Barrè Syndrome that was
associated with the swine flu vaccine, and it was one event per 100,000
persons vaccinated that brought that population preparedness program to
a halt. So what level of serious adverse event rate should be ruled out
for the pre-pandemic indication?

So the components necessary for this indication include the immune
response following the initial immunization, the immune responses
following subsequent immunization and an assessment of effectiveness of
the population preparednesses and an acceptable demonstration of safety.

This slide is just meant to illustrate some of the different options
that we\'ve considered in population preparedness followed by a
subsequent vaccine that might be administered during a pandemic. And so
when the initial immunization does not include an adjuvant and the
subsequent immunization does not include an adjuvant, I\'ve shown you
data that you may lack an appropriate immune response with that
approach, but perhaps there are less safety concerns because we don\'t
have a new adjuvant with potential safety concerns.

The current focus of activity in this area has been the use of an
adjuvant vaccine for the initial population preparedness and an
adjuvanted vaccine for immunization during the pandemic. Now I had shown
you data that an adjuvant can enhance the immune response. So that might
be the best approach in terms of the immune response considerations. But
the addition of a new adjuvant, what potential safety concerns might
arise? And so we view that as a disadvantage with this particular
approach.

And then are there hybrid approaches that we might consider that might
offset some of the safety concerns that we might have with a new
adjuvant? For instance, the initial population preparedness without an
adjuvant where there may be diminished concerns about safety is an
advantage, but with the adjuvant during the pandemic you\'d have the
advantage of an enhanced immune response.

And so these are some considerations that we\'ve had internally on a
design for population preparedness strategy.

So the optimal characteristics for a vaccine that has a pre-pandemic
indication for a population preparedness strategy would be a robust
immune response to the subsequent pandemic immunization. It would be a
vaccine that has a low adverse event profile. A vaccine that would be
capable of having a long duration of immune memory. And it would be a
vaccine that could be given with other vaccines including other
influenza or seasonal vaccine.

And so now I have two slides to present the topics for discussion for
the rest of the afternoon.

And topic 1: Please discuss the criteria to evaluate the immune response
with an adjuvanted vaccine.

Now the first two bullet points under that are the criteria early in
development for the added value of the adjuvant with the difference in
the immune response criteria that would exclude equality and not
inferior immune responses with the lower antigen plus adjuvant. But if
we were to lean toward licensure, would you expect a robust difference
in the immune response rate with an adjuvanted vaccine?

For instance, an adjuvanted vaccine having a geometric mean titer
twofold higher over the unadjuvanted.

Topic 2 is, please comment on the options to confirm clinical efficacy
of a vaccine for pandemic or pre-pandemic indication.

And topic 3 is, please discuss the immune response criteria for the
pre-pandemic, or again this is a population preparedness strategy, for
that indication and the relevance to the criteria that are outlined in
our current guidance document for the pandemic indication.

And so please discuss whether a lower immune response to the initial
priming, if you will, so long as subsequent immunization results are
acceptable. And then what should those subsequent immune response
characteristics be to define acceptable immune response? And should
those differ whether you administer the subsequent vaccine that contains
the same antigen or that contains the heterologous antigen?

And then topic 4: Please discuss the size of the pre-licensure safety
database for the pre-pandemic indication. And in your discussion please
comment on the population preparedness and the role of large sample size
studies to rule out a rare serious adverse event rate such as 1 in
100,000.

And that concludes my talk. I\'m just going to put this slide back to
the discussion items. And I\'ll turn it back over to Dr. Modlin.

CHAIR MODLIN: Okay. Thanks very much.

Before we launch into a discussion and the public comment, I\'d like to
ask if members of the Committee have questions for any of our three
presenters, Dr. Golding, Dr. Cox or Dr. Toerner regarding their
presentations?

MEMBER COUCH: I only have one quick question for Dr. Toerner. All of the
data you presented was H5 antibodies? You gave some FDA privileged data.
It was all H5?

DR. TOERNER: Yes, that\'s correct. It was all H5.

CHAIR MODLIN: Jose?

MEMBER ROMERO: For Dr. Cox. Could you give a little bit more detail on
the breakdown of pediatric versus adult cases of avian influenza and
then mortality rates? Are there differences in the two groups?

MEMBER COX: I think Joe will try to answer that.

I think the bottom line is that there are more cases in young adults and
children than older adults. But I don\'t really think that there are
differences in mortality overall.

The most striking differences in mortality that we\'ve seen have been in
Egypt where at the time they did the analysis they had fewer cases than
they do now. But it was very striking that the mortality in the children
was much lower than the mortality in adults. And that was because the
adults when they got sick thought, oh it\'s nothing, yadda, yadda,
yadda. But when their child became ill and they knew that they had dead
chickens, they got the child in for early treatment.

So I think the key is really whether or not the individual gets early
treatment. And so many of these cases, as we see, have been referred
from a local clinic to a local hospital, to a district clinic and so on
before they really get proper care. And they\'re so seriously ill by the
time they get to one of the treatment facilities that actually
specializes in treating cases, that there isn\'t really a hope.

CHAIR MODLIN: Joe, did you want to add to that?

Lisa?

MEMBER JACKSON: Well, a question for Dr. Toerner. There\'s discussion in
the document and your presentation about boosting, you know later
boosting and so forth. I wonder, do you all have a working definition of
what you mean by \"boosting\" or \"booster response\"?

DR. TOERNER: Well, I think that was one of the items for discussion
today to help us understand what immune response criteria should be for
that subsequent immunization.

I think what we mean by the boosted response, if you will, is the immune
response to a subsequent immunization of either the same vaccine or a
different vaccine that contains a different subtype and what immune
response would be elicited with a vaccine of a different subtype in
subjects who earlier received the population preparedness initial
immunization.

So it would be the immune response of the vaccine during a pandemic that
we would be interested in hearing your feedback on.

CHAIR MODLIN: Other questions? Dr. Davis.

MEMBER DAVIS: I was intrigued by the last point of your last slide which
called for a large simple safety studies. I\'m wondering if you could
expand upon that a little bit? Are there discussions underway in the FDA
about setting up the infrastructure for such large simple studies?

MEMBER COX: I think that the issue arose if you\'re engaging in a large
population preparedness strategy and you\'re immunizing hundreds of
thousands or millions of people with a new agent. So something
previously not licensed in the U.S. or maybe not licensed in the world,
maybe a new adjuvant in a preparedness strategy to reap benefits it may
be decades in the future or, we\'re hoping, a long time in the future.
And so to understand safety was very important.

And in terms of what kinds of monitoring. I mean, we\'re open to hearing
uses of different kinds of databases to monitor during clinical trials,
you know what you have in terms of ideas.

The usual kinds of safety monitoring that are in the clinical trials
that you\'ve seen for like Roderick\'s yesterday are very intense. And
would you recommend that or would you recommend other types of data
sources, such as maybe through claims data or other automated sources?

CHAIR MODLIN: Other questions?

Could I raise the issue of \--I\'m sure there\'s been an awful lot of
discussion about this. We haven\'t brought it up for the topic today.
And that is what truly is the goal of pandemic influenza immunization.
Obviously, we\'re never going to be able to test a vaccine well prior to
a pandemic. And so you inevitably all recognize that we\'re going to
need to rely on surrogate data to make judgments regarding the ability
to employ such a vaccine. But is the goal to prevent disease? Is the
goal to prevent hospitalization, or is the goal to prevent death? We
might look at a vaccine differently according to what those various
different goals may be for a vaccine.

Norm?

DR. BAYLOR: I\'ll start out addressing that. John, I think it\'s going
to vary. But if we think about this, if we think about a pandemic in
general, the ultimate goal is to save lives. And so looking at
protection from influenza-like illness, I mean that\'s a higher goal.
That\'s a goal that we wold expect for seasonal. But I think that at a
minimum we want to be in a position to save lives and decrease
hospitalizations as much as we can. So that\'s sort of the bottom. If we
can achieve better than that, that would be good.

Let me back up a little bit. Because I think we\'ve heard a lot and used
a lot of the term \"pre-pandemic versus pandemic.\" And if you think
about where we were in the past with swine flu, with Hong Kong flu, we
were looking at making a pandemic vaccine. In the midst of a pandemic
then we would use that vaccine. We\'ve historically used a two dose 15
micrograms of a pandemic vaccine, and that\'s what we\'ve deployed.

What\'s new I think now is we\'re trying to say is how do we prepare for
a pandemic. So agreeing in the concept of pre-pandemic immunizing
individuals prior to a pandemic, preparing those individuals for the
inevitable pandemic. And so that\'s really where we\'re having
challenges, and I think the industry and all of us are having challenges
in these areas. Because how do you evaluate a vaccine that\'s going to
be used in a pre-pandemic or in the pre-pandemic period if you will?

The vaccine that we license, the sanity vaccine as we\'ve said and Dr.
Toerner has shown in his earlier slides, that vaccine would be used in
high risk when a declaration of pandemic has been declared or the
laboratory workers, what have you.

So the goal of the pre-pandemic vaccine is really to prepare for the
inevitable pandemic. And there are challenges with that because what
will be the next pandemic? Will this vaccine that we license as a
pre-pandemic provide any use preparing those individuals in advance of
the pandemic?

CHAIR MODLIN: Fair enough.

Other questions? Dr. McInnes?

MEMBER McINNES: So, Norm, just to follow up on that. So if you\'re
thinking in that you want some measure then of immunologic priming
whether it takes one dose or two doses or three does, however many doses
it takes to show some incremental immune response which we\'ve narrowed
to a neoantigen like H5 is surprisingly disappointing, but you know you
can see an increase in immunologic readout with the second dose compared
with the first dose. And then you want some evidence of memory recall at
some time remote from the priming event. Is that sort of conceptually
what we\'re thinking about and how we might measure what that memory
recall parameter is?

And then you want some ability to characterize safety. And I\'m using
those words carefully because I\'m not sure we can promise that it\'s
100 percent safe. But you want to be able to have a profile that you can
tell people who agreed to have this vaccine that this is the risk, this
is what you can expect?

Is that really what we\'re talking about?

DR. BAYLOR: Yes. And let just say a few words about that.

In essence, yes. I mean we\'re priming that population, and we might
prime that population with one dose. And we want to know what level of
immune response should we achieve. I mean, should we achieve an immune
response that we require, as we\'ve stated in our guidance document, 1
to 40 level? Is that necessary for that prime or is a lesser response
adequate knowing that you\'re going to give a boost, if you will, and we
use that term not in the sense of the pediatric vaccines? But you may
give those boosts six months, a year out, maybe a year and a half out.
And there are variations on that.

So it is a type of memory recall, but also part of that is cross
reactivity. Because you can prime with the heterologous or homologous, a
neoantigen, if you will.

The other part of the equation, as you\'ve mentioned, is characterized
as safety. And in particular because we\'re using new adjuvant,
nonaluminum salt adjuvant, we\'re seeing those come back I think the bar
for safety is going to be higher. So we want to make sure that we do
characterize that because we\'re actually immunizing individuals in the
absence of that real disease. And so the benefit where you have to
really define the benefit. Because benefit is really I\'m preparing you
for something that we believe will come, but if it doesn\'t.

MEMBER McINNES: Just two follow ups. I mean, I just want to be sure
we\'re open to the idea that priming may take more than one dose. And we
tend to sort of think we\'re going to put one dose in and everybody down
the line is going to come back and mount a magnificent response to it.
But they may not. So identifying the parameters around what might
constitute priming sort of seems to be important.

The other issue around the safety profile of novel adjuvant, I mean
obviously it can also be addressed in the framework of annual influenza.
It is not exclusive to the domain of characterizing in pandemic, right?
Okay.

CHAIR MODLIN: Bob?

MEMBER COUCH: Well, you asked if CBER wants us to discuss this. So let
me just address a few items here.

First of all, I\'ve not been that close to pandemic considerations and
H5. About three or four years ago I was asked to review what we knew
about past pandemic circumstances and with regard to vaccination. And
I\'ll give you the bottom line of the conclusion I came up with looking
at \'57, \'68 and \'77, which is where the data was for the three.

And that is that I cannot tell you, I could tell you what was needed to
protect against that pandemic strain, unless a lot of the seasonal data
where we have some pretty good guidelines. I simply couldn\'t do it.

So I said to myself well if I can\'t say I\'ve got to have 50 percent or
70 percent, 1 to 40 or a GMT of 150 or something like that, what would
be a reasonable criteria to say I have a useful and potentially
effective vaccine. And I came up with the same one people keep hearing
from me: I want to see an immune response. If I\'ve got a immune
response in 100 percent of the individuals who received the vaccination.
And you\'ve maybe also heard me, I believe some antibody is better than
no antibody. And that\'s the starting point I\'ve got a vaccine that may
or may not be useful.

Because I can\'t give you a number. I tried to see if I couldn\'t come
up with some numbers, and I could not do it. That\'s one.

And the second is that no matter what the numbers are, the present state
of science says that antibody must be directed in optimal quantities
against the hemagglutinin. Whether it\'s an HAI or some other assay,
that\'s a different discussion. But it must be anti-hemagglutinin.

If we want to say an anti-M2 vaccine is okay, that may be true. But that
data is yet to be developed. So at the present day where we stand, it
must be anti-HA. And if it must be anti-HA, and I don\'t know how much
of it is required to protect, I want as much of it as I can get.

Now, see, that doesn\'t help the regulatory authorities very much,
unfortunately. Because they want a criterion that they can say it has
been met. But that was the best I could do when I reviewed the science
to try to come up with that answer.

CHAIR MODLIN: Well, I think that helps out a tremendous amount. Because
I think that gives us a floor to begin our discussion. I truly do.

Are there questions.

MEMBER COUCH: I got other discussion if you want to let me go on.

CHAIR MODLIN: Go right ahead.

MEMBER COUCH: Primed boost came up a year ago, too. Because, see,
priming is an immunologic phenomenon. And if you really want to say
somebody\'s primed, you\'re looking at the lymphocytes. But that\'s
probably not practical. And if we start looking at the lymphocytes, we
then have to validate and discuss what priming consists of when we do
that, you see. So we end up with operational definitions is the phrase I
like to use for priming. And that is measuring\--we do measure a
specific immune response, see. It doesn\'t have to be HI. But a specific
immune response. And if a 100 percent of people showed that, I would say
they\'re primed. The level of priming and all that, it\'s another
discussion. But they are primed.

And since we\'re dealing with operational definitions, then boosting is
the same. We\'ve got to say that needs a new unprimed at the same time
you\'re testing the primed to show that that group up here was indeed
primed. And those, again, are operational definitions that don\'t give
you hard numbers that can be used as criteria for having met a level,
you see. But getting those levels is a problem.

I can keep going with a couple of more here if you want me to.

CHAIR MODLIN: Well, we actually have plenty of time for discussion later
on. I intended for this for questions to the presenters. But I still
think this is a useful discussion, so please go straight ahead.

MEMBER COUCH: Well, pre-pandemic there has got to be a risk benefit
consideration. I can\'t see that one any other way. And there\'s another
source of great uncertainty because look how much uncertainty we\'ve
lived with for four or five years about the risk of H5 pandemic. And it
hasn\'t materialized. It may yet materialize. It may not materialize.
You know, what was the risk, you see? How can we assess that risk? And
that\'s not very easy.

And then if we can\'t assess the risk, how hard to assess the benefit?
And so if it\'s out there on its way, it\'s a little bit easier. The
pandemic is a little easier decision than the pre-pandemic is. But I
consider that one a risk benefit discussion.

Safety. I guess, again, a little bit of the same kind of plea I did this
morning. If we want to make the safety requirement \-- we\'re talking
about licensing requirements. We want to make the safety requirement
something that is doable and reasonable. And, you see, now we live with
safety pre-licensure in appropriate numbers, but not a 100,000. That\'s
always been a post-licensure consideration. And that if that\'s still
where we end up, which is the way I would lean, I would not want to
require a \-- actually, there\'s one circumstance we may come back in
which I might want to see that, but otherwise not want to require a
100,000.

The post-licensure must be set up ahead of time ready to go and you are
monitoring that so you don\'t miss the Guillain Barrè at 1 in 100,000
rather than let a mercy occurrence determine what your post-licensure
safety was.

CHAIR MODLIN: All good points.

Are there questions, other questions? If not, I think probably this is
the optimum for public comment.

Christine?

EXECUTIVE SECRETARY 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. Modlin, will read the open public hearing statement?

CHAIR MODLIN: Yes. I\'ll do this again.

Both the Food and Drug Administration and the public believe in a
transparent process for information gathering and decision making. To
ensure 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, the FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the Committee of
any financial relationship that you may 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 the meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the Committee if you do not have 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.

EXECUTIVE SECRETARY WALSH: I have received one request to speak from
Carol DeRosa and Fran Lessens from Passport Health.

MS. LESSENS: Hi. My name is Fran Lessens. I\'m President, CEO and
founder of Passport Health.

We have no financial receipt of any kind. We\'re here on our own. I
didn\'t have to go far. I live in Baltimore. And it\'s a quarter tank of
gas.

We\'re on the front lines of providing flu, and that\'s why we\'re here
today. We wanted to hear what the strains were.

I have been in the vaccine business for 20 years and we have over 160
locations with doctors, nurse, nurse practitioners, PAs. And we give
vaccines on a daily basis. We answer Department of Defense Call Center
365 days a year. Vaccines are our passion, so we\'re here today to find
out what\'s going on.

We also want to enlighten you. I\'ve heard here today that it\'s
partnership between the government and the manufacturers. I\'d like to
add that I think it\'s a partnership with the providers out there who
are vaccinating people daily. And we\'ve been involved in many years of
giving flu vaccines through contamination, shortages. And we get the
message from the consumer. So we\'re hearing their complaints on the
front line on a daily basis.

We have responded to pandemic emergencies. Any vaccine that\'s developed
needs to be put on people in a pandemic. We have the search capacity.
And I wanted to enlighten the folks here as to our past experience. Two
days before Christmas in 2001, in two days we responded to anthrax and
we had sites from New Jersey from Florida covered with medical
personnel, doctors, nurses.

Katrina, we were in and out before FEMA ever showed up. We vaccinated
first responders for our clients, utility companies, oil rig companies.

Tsunami, we vaccinated volunteers to go over there.

And we have done clinical trials as well. The Protein Science trial we
did the 65 and over. We secured the vaccine for sites. Not the study
vaccine, but it was compared to the egg-based vaccine and we secured
that vaccine and disseminated it. That year was very rough because the
Sanofi-Pasteur product was out late.

So anytime there\'s any vaccine out late, we hear about it; frustrated,
angry patients, angry corporations.

My message here today is we\'d like you to know that we\'re here as a
resource. We\'re here to help you. We have no financial \-- if we don\'t
have vaccine, we don\'t make any money. And no one sent us here today.

Thank you very much.

CHAIR MODLIN: Thank you, Ms. Lessen.

Yes, Paul Melman.

MR. MELMAN: Paul Melman, Infectious Diseases.

I have no financial ties to any company working on pandemic. But two
questions with regards to safety. Because recently there\'s been the
licensure of two vaccines that are only going to used if there\'s an
urgent emergent situation. So based on the internal deliberations at FDA
and the negotiations with the manufacturers, as a starting point I think
it would be very useful for us in the audience as well as for the
Committee to understand for the Sanofi-Pasteur 90 micrograms H5/N1 a
month apart, what\'s the size of phase 4? How many phase 4 trials? How
big is it? Are they vaccinating first responders? Is it an attempt to
get kind of, maybe I\'ll call it prime boost, but just get additional
data? And if they go back and get them again what\'s \-- it may be about
the design, but how big is the designer phased for?

For the ACAM 2000, which we heard or at least my memory was, 1 in
100/150 recruits will get myocarditis from the vaccine. So maybe that\'s
a smaller safety study, but define that target. But how big is the ACAM
2000 phase 4? And that\'s licensed to be used when it\'s been determined
there\'s been a serious exposure.

So I think the FDA has already thought this through because they told
the two companies thou shalt do phase 4. So I\'d just like to know how
big phase 4 is for those two programs, and that might be the starting
point for the pandemic vaccines.

CHAIR MODLIN: Thanks, Paul.

DR. HOURN: For the ACAM 2000 smallpox vaccinia vaccine live they have
committed to do some extensive active surveillance and myocarditis
registry studies. And actually they\'re powered in terms of trying to
accumulate enough case events of myocarditis so that we could try to
understand more risk factors associated with development of that adverse
event.

That vaccine, because of its identified safety concern with transmission
as well as development of myocarditis was approved under restricted
distribution. So the controls for safety are quite extensive.

In terms of the Sanofi-Pasteur H5/N1 vaccine that, as you know, was
approved with a very small safety and efficacy database that was
presented before this Committee last year. And the discussion was that
the manufacturing being unchanged from the Fluzone influenza vaccine and
the difference being primarily the micrograms. I think that\'s the only
difference. And did folks feel there was sufficient data to understand
if there was going to be a risk associated with 90 micrograms versus 45
micrograms that you get of different antigens every year. And I don\'t
think we heard that there was that safety relative to its indication for
use in a high risk situation.

That vaccine is in the national stockpile and is not for distribution
commercially and is being intended to use for when there\'s a
declaration of pandemic.

CHAIR MODLIN: Thank you.

If we could, why don\'t we put the questions back up on the screen, if
we may. And I think that we\'ll ask the Committee to focus in one-by-one
on each of the questions.

We have talked about this and around this to a degree, but I think we
need to focus on it specifically.

Please discuss criteria to evaluate immune responses with an adjuvanted
vaccines. Differences in HI antibody titer that exclude equity,
noninferior immune responses with lower antigen plus adjuvant and
adjuvanted twofold higher over unadjuvanted.

So these specifically criteria to compare two different types of
vaccines?

Bob?

MEMBER DAVIS: I\'m probably just coming out on the end of a long
conversation. But I just was struck by the nonequality of those first
two bullets. They\'re very different conclusions to make about a vaccine
and they really imply different things.

And speaking as a complete naive observer to this arena, I would say
that I would prefer the first bullet than the second. But be that as it
may, it just seems like those are very different statements.

CHAIR MODLIN: I think, indeed, that\'s why they put them there.

How do others feel about this topic? Lisa?

MEMBER JACKSON: Well, I agree that the second bullet, for one thing,
lower is sort of a qualitative term. But you could have no effect of the
adjuvant and still meet that criteria potentially. so that seems not
optimal.

CHAIR MODLIN: Seth?

MEMBER HETHERINGTON: Well, more questions, actually. I guess the point
is what are you trying to accomplish with an adjuvant. And there are
many instances where adjuvants have been used in the past.

One is to get a broader range of responses among your population. So it
has not so much anything to do with titer as it is just getting a higher
percentage of people to respond. And maybe that\'s really the criteria
you ought to be using.

Another is that you know what sort of titer you need to achieve immunity
and you want to get above that. And I guess this gets back to I mean if
Dr. Couch doesn\'t know what to predict a level of antibody is, I don\'t
think any of us do. So I\'m not sure how you come to that conclusion.

The last of the three sub bullets I\'m puzzled by. It almost sounds as
if you think that antibody raised by adjuvant vaccine is somehow less
adequate than an equivalent amount of antibody generated by an
unadjuvanted vaccine. So I\'m not really sure what that third sub bullet
means.

I think you need to define what you want out of your vaccine first and
then make a decision as to how does an adjuvant play into this. Because
one thing\'s for sure, you\'re probably going to get more side effects
with an adjuvant. And the question is what do you get for that, do you
get some sort of benefit?

CHAIR MODLIN: Bob?

MEMBER COUCH: Maybe we need the second bullet clarified. Because my
assumption with the second bullet was let\'s say you have a response
with 15 micrograms, then the second bullet would be what would be
inferior if you\'re using 3.8 plus an adjuvant so much so it\'s an
antigen sparing approach to getting the same way. And then how would you
define it as inferior? And I wasn\'t aware that it looks like the FDA
defines it as plus or minus 10 percent, which is I think a little tough.
But okay.

CHAIR MODLIN: Dr. Toerner, do you want to respond to that?

DR. TOERNER: I think Dr. Couch was right, we are talking about an
antigen sparing approach with the second bullet point.

CHAIR MODLIN: Dr. Self?

MEMBER SELF: Yes. So I guess \-- I\'m having trouble. I see this
question not so much as a comparative one but evaluating a whole series
of different possible regiments, some including and other maybe not
including adjuvant. So I don\'t like any of those hypotheses that are
working underneath the three sub bullet points. And probably the
criteria that Dr. Couch described, albeit it pretty subjective, is the
best that we can do. You know, whatever the regiment is should be
subjected to that and try and ratchet that up as best you can.

CHAIR MODLIN: Perhaps I can summarize and we get the sense from whatever
is saying. I think I heard Pamala say the same thing. I certainly heard
Bob say it.

And that is is that the quantity of antibody may be less important than
evidence that there\'s been a response in the first place. I certainly
would tend to agree very much with that.

Norm?

DR. BAYLOR: Yes. Just to clarify a little bit. I mean, where we are
struggling here is looking at the added value of that adjuvant. And
there are a variety of areas where you might propose that there\'s an
added value. But just on the surface if I have a vaccine that\'s a 50
microgram vaccine and it\'s nonadjuvant and I get a 1 to 40 response.
And I add an adjuvant to that product and I get the response, then
there\'s really no added value there, although one could then ask \--
you could get into other things like well maybe there\'s a T-cell
response or something like that, but I mean the scientist was early on
that.

CHAIR MODLIN: I think what we\'re saying is it\'s not so much the
response of 1 to 40 that\'s important, but it\'s the sera conversion
rate. It\'s the number of participants in the study that actually show
an evidence of an immune response. And if by adding an adjuvant to the
vaccine you raised your sera conversion rate from 20 percent to 50
percent or 70 percent, that may be a more important measure than the
actual level of antibody that you achieve.

Am I getting that right?

DR. BAYLOR: And we understand that, John, because that\'s the other side
of it; the sera conversion rate. But, again, how do you evaluate the
value added? Again, if I put an adjuvant in there and I\'m seeing the
same sera conversion rate, or say I see a five percent increase in sera
conversion rate, is that really enough? But then you\'d have to know
something about the adjuvant and the risk that may be associated with
that adjuvant before you could make that decision if that\'s adequate.

So there are a lot of factors involved here. But just to add an adjuvant
with no added benefit, regardless of whether it\'s the titer or the sera
conversion rate, I think that we have to consider that.

CHAIR MODLIN: Ted?

MEMBER EICKHOFF: I think that the primary reason for talking about
adjuvants in this setting are the considerations of global vaccine
production capacity. As we heard here in this meeting last year, as
David Fedson writes about all the time, we\'re never going to make
enough vaccine in the event of a pandemic unless we have some antigen
sparing device, which right now is an adjuvant.

So I think the primary goal of even considering an adjuvant is the
antigen sparing effect. Indeed, I think we\'re forced to consider an
adjuvant in this setting.

If you get out of it the additional benefit of both reducing the amount
of antigen and increasing the GMT or the four-fold conversion rate; so
much the better. But even if we got the same thing or the same thing in
terms of serologic titer and with sparing of antigen in significant
quantities like 5 micrograms of antigen rather than 90, so much the
better.

CHAIR MODLIN: Ted, would you agree that, if indeed if I heard your
correctly, you would then probably consider the first bullet perhaps to
be the most important because that\'s the one that would most likely
lead to an antigen sparing strategy?

Bob?

MEMBER COUCH: Well, you asked Ted a question first, I thought.

MEMBER EICKHOFF: No. I would consider the second bullet the critical one
of those three.

MEMBER COUCH: I don\'t like to create problems with licensing, but I
answered this question one time before and I was just sitting here
thinking, I guess I\'d have to lean that direction still. That when you
put an adjuvant in there, let\'s say you do anything different but an
adjuvant is the example we\'re talking about there, TH1, there are TH2,
a mixture is probably going to get you closet; the precedent data does
not include an adjuvant. There\'s a good bit from \'57, unfortunately
it\'s not as high quality as we\'d like for the use of adjuvants because
there was quite a bit at that time. But if you start then, then I went
back in my thinking. I said well now we\'re changing the vaccine. And
when I change the vaccine what am I going to want to see? And it\'s got
to be more than just anti-HA antibody when you change that vaccine,
which one would be just anti-HA antibody. And two things would make me
happy?

Well, the gold standard is always going to be efficacy. If the efficacy
says that you\'ve done something worthwhile; whether it\'s better,
whether it\'s the same with lower dose or whatever, then that\'s the
gold standard.

Can we get at a gold standard that is less intensive than that?
Actually, what constitutes that gold standard is another question; you
know, illness, isolation, things like that. But at any rate, efficacy.

If we get anything less than that, what would I might not be happy with
for a change that did not include efficacy? And I can only answer that
in saying every immune response that I could measure I would want to
know the anti-hemagglutinin, I would want to know it\'s avidity, I would
know the anti-neuraminidase, I\'d want to know what happened to the
lymphocytes and cell-mediated immunity. And if I really got across the
board an improvement in those immune responses, then I don\'t think I\'d
require efficacy. But even that\'s not easy to do.

CHAIR MODLIN: Bruce?

MEMBER GELLIN: You know in some ways it\'s surprising that this is the
first question out of the box, and Seth can sort of hit on this, is that
we need to figure out what we want and then we need to define that
pretty clearly and then think about the different pathways to get there.

The data that\'s been generated over the year shows an adjuvant, looks
like an attractive and maybe a simpler way to get there.

Clearly the antigen sparing is what got adjuvants into the game
initially. I think to me the hidden surprise was the dual benefit of the
cross protection.

So I think it goes back to this risk benefit ratio. And the benefit
would be to have some demonstration that you\'ve provided some
immunologic response such that later on, whether you get another vaccine
or you\'re exposed to another virus, you\'ve already achieved some
immunological benefit from it.

An adjuvant is likely to be part of that, but I wouldn\'t think it\'s
necessarily a part of it. I think there\'s a definition of what you need
and then second is how you\'re going to get there.

CHAIR MODLIN: Further discussion? Yes, Norm?

DR. BAYLOR: I just wanted to make a comment.

Bob, I hear all your points. Of course, you recognize that for the
pandemic the efficacy is, you know we can\'t do that. So that\'s not a
consideration, I mean you know pre-licensure.

On your point, Bruce, I mean what do we want. In one sense the \"we\"
has to be the public health. But at the same time we know there are
manufacturers, and they\'re out in the audience and they can speak up,
that are developing all types of vaccines for pandemic. And I guess
where we\'re trying to go is we have to have some criteria to evaluate
those vaccines, not necessarily what kind of vaccine does the FDA want,
it\'s what type of criteria do the FDA need to evaluate those vaccines
that are coming forth. And that\'s where we\'re going. That\'s where
we\'re trying to go. Because we know that all of these, we\'re facing
these now. This is not something that we\'re going to face down the
road. These are real. This is now.

MEMBER JACKSON: I think also for antigen sparing, it has a great public
health implication in terms of population, inoculation during a
pandemic. But for the individual, whether your vaccine is antigen
sparing or not, is less. I mean you\'re looking for disease protection.

So I think antigen sparing is important. From a public health
perspective I think for the individual perspective, the adjuvant
contribution to a clinical benefit may be more important.

MEMBER COUCH: Norman, most of us call it the two animal rule, but I
don\'t want you to necessarily explain that. But you\'re not going to
get that efficacy in the field on H5, hopefully, before we\'ve already
used that vaccine. And I\'m not an animal model person, but an animal
model needs to mimic the human infection and disease role as much as
possible. That animal model needs to be described with that same
vaccine, even if it\'s antigen sparing, for an immune response profile
that clearly is the explanation for the immunity and the efficacy in
that animal model. And then that\'s part of the information I\'d want to
transfer to what I\'m looking for in humans to guarantee me the same
thing.

Historically that\'s been quite good. So we\'d hope that it doesn\'t
change.

CHAIR MODLIN: Dr. DeBold?

MEMBER DeBOLD: I don\'t envy the situation you\'re in because you are
clearly having to deal with a fair amount of uncertainty and to some
extent theoretical risk especially in the pre-pandemic sort of situation
here. But the risk benefit, a piece of this seems crucial from the
consumer perspective. Because with adjuvants there are some risk that
people will have some reaction, some adverse reactions to the adjuvant
itself. so if there is some way to minimize the potential for
individuals to experience adverse reactions that will be real, even
though we may be dealing with a theoretical pre-pandemic situation, I
think that would be preferable.

CHAIR MODLIN: Those are good points. And I think the intent is that
we\'ll probably discuss that even in a little bit more detail with some
of the subsequent questions.

Bruce?

MEMBER GELLIN: Some information that we haven\'t heard I don\'t think
that may have come up in the meeting that Dr. Golding briefed us about
is this very precious resource of one third of the people who actually
survived this infection. And it seems to me that there\'s a lot to be
gained from understanding what their immunology looks like right now.
And I don\'t know \-- I think this is clearly very difficult data to
get, but I can\'t think of more important data to begin to have to begin
to answer this question. Because here are people whose immune systems
should tell a lot about what it meant to be exposed to this virus.

I don\'t know, Hana, did that come up as far as the data that was there?

DR. GOLDING: I think this is clearly a very, very important point.
Because I think a lot can be learned even from the small number of
people that have been exposed and survived.

I think Nancy will probably be able to give a little bit more
information on the studies that were conducted in poultry workers that
Jackie Katz presented. And I\'m not sure if there\'s more data like that
from other hot spots of transmission, especially Indonesia.

There is clearly currently a reluctance on the part of some of these
countries to share post-exposure sera. On the other hand, the World
Health Organization, Dr. Hadden, did describe the establishment of this
Southeast Asia multi-clinical centers new infrastructure that,
hopefully, will build trust and wiling to share. And most importantly,
to introduce the right assays so these kind of questions, which I
consider also of prime importance, will be able to address. Because I
think we can learn a lot from the survivors.

In my own personal program on influenza we were able to establish a
collaborative effort with the Oxford group in Vietnam. And we are now
able to actually analyze the immune responses, all the antibody isotopes
recognizes by these individuals. And we find some very interesting \-- I
think it will really give us some very important information that
eventually can be applied to vaccine. But those are five individuals.

So this kind effort, if indeed can be expended to other survivors either
through our effort or the CDC and so forth, I think will provide
important information. And as a group we probably should try and
encourage it.

CHAIR MODLIN: Bob?

MEMBER DAVIS: Maybe I missed something. But there\'s probably a lot to
be gained from studying people who were exposed and didn\'t get sick as
well, not just survivors. There\'s probably an order of magnitude, if
not more, people who were in the vicinity and one could assume that many
of them were exposed and somehow didn\'t even get sick.

CHAIR MODLIN: Nancy, there have been a number of sera surveys of people
with high risk of exposure and it would have included a number of people
that have never developed disease as far as we can tell. Isn\'t that not
the case?

MEMBER COX: Yes. There have been a number of sera surveys that have been
conducted and more that are underway.

If we go back to the 1997 experience and look at poultry workers in Hong
Kong who were exposed to H5/N1, we found sera prevalence of about ten
percent in that group. And we were using a Microneut cutoff of 1 to 80
because we had done a lot of calibration of our assay. But we couldn\'t
tell, of course, if those individuals had been exposed or infected to
the highly pathogenic H5/N1 or some precursor. Because we only had a
single serum that was snapshot in time.

In many of the other studies that have looked at poultry workers who
either were wearing PPE or weren\'t wearing PPE and so on and so forth,
we see some real differences. In some studies there were zero people who
had antibody among the poultry workers who were involved in calling. And
in other studies there were sort of 6 to 9 individuals who were sera
positive.

So it\'s very clear that a lot of people are heavily exposed and never
become infected. And I think that while that\'s very interesting, that
probably has something to do with a genetic factor that may or may not
play in to actual pandemic and may or may not play in to an antibody
response. So I think we need to kind of tease those things out.

It is very difficult to obtain serum from the survivors of H5/N1. I
think the Southeast Asia Clinical Trials Network will have the greatest
chance of actually being able to obtain enough serum and large enough
amounts of serum, basically, to actually do some of the studies that
Hana and others are trying to do.

We find that when we do obtain serum samples for the sera surveys, we
get very small amounts of serum. And so by the time we\'ve tested
against a couple of different antigens, a clade 2.1 and 2.2 or a 2.3
we\'ve exhausted the serum that we have.

What we can say is that for the few individuals whose serum we have and
whose response to the infecting virus was quite robust, they have a very
markedly reduced titer to viruses in another clade. So it shows that for
naive individuals their response to H5/N1 is quite strain specific. So
that\'s with natural infection. And I think that if adjuvants really do
broaden the immune response, that is a very significant improvement,
even over natural infection.

CHAIR MODLIN: Other questions or comments?

Why don\'t we move on to question 2. Please comment on options to
confirm clinical efficacy of a vaccine for pandemic or pre-pandemic
indication. We\'ve certainly been talking about this the entire time. I
think that probably the problematic words are \"confirm clinical
efficacy.\" But I wonder if any have any further thoughts about this?

MEMBER COUCH: You can\'t confirm clinical efficacy on a pandemic until
after it\'s already occurred or failed. So you\'re talking before. I
guess we\'re back to \--

CHAIR MODLIN: Is there more to this question, Florence, or

DR. HOURN: The new pandemic vaccines that will have adjuvants that have
never been approved before or new technologies that we haven\'t used
before can be approved under what we call accelerated approval
regulations which allow us to use a surrogate that reasonably likely
predicts a clinical benefit. And that surrogate we will be using is the
HI immune response. But then the regulations say that the sponsors must
conduct studies to confirm the clinical benefit.

So we are now asking you how to help us try to get a better handle on
clinical efficacy. In our guidance we had suggested that if
manufacturers are pursuing a seasonal vaccine using the same
manufacturing process or the same adjuvant, that some of the seasonal
efficacy data might be able to be used to confirm the efficacy of
pandemic. And we would like your response on that. Is it useful? Is it
not useful? What are pros and cons?

DR. BAYLOR: And, John, let me follow up on that.

CHAIR MODLIN: Certainly, Norm.

DR. BAYLOR: I guess where we\'re trying to go is we recognized, Bob,
that really a true confirmation, we can\'t do in the absence of
pandemic. So how far do we go? I mean, are there options that would
reassure us that at least we have something out there we believe is
effective?

CHAIR MODLIN: Would it be helpful if it were possible, and I\'m not sure
that it is, but if it were possible to identify one or a small number of
laboratory measures, markers for immune response to one or more doses of
vaccine? A measurable HI titer as a measure of sera conversion. I\'m
kind of struggling right here. But is this \--

MEMBER COUCH: Well, I don\'t know if that\'ll help you, but I\'ve been
there before. And I need a clarification, Norman, as to what you are
talking about with clinical efficacy. We talk about animal models,
pandemic you don\'t get that until after the fact and so forth. If
you\'re talking about a new vaccine now, which I think is what the
thrust of your interest is and we\'re talking about adjuvant in vaccines
in here, do you want clinical efficacy before you approve that even
though your proposal is to use it in the pandemic, for example? And the
question then would be your only opportunity to do that in humans is
going to be with the seasonal vaccine.

So when you say I want to see clinical efficacy with a seasonal vaccine,
then my question will be the same one I asked earlier. With that
clinical efficacy with a seasonal vaccine using the adjuvant, must it be
superior to the nonadjuvant vaccine? That\'s the tough question. You
see, if it must be superior, I wouldn\'t advise many companies to invest
hugely in that. But, you know, they might be lucky and they may have an
exceptional adjuvant. But on the other hand, I think it can be shown to
be as good as standard vaccine.

DR. HOURN: So in a seasonal adjuvanted vaccine versus a seasonal
unadjuvanted vaccine, again to understand what is the clinical benefit
of an adjuvant, why are you adding the adjuvant, are there
subpopulations that could be explored that there could be a clinical
benefit asked of over an unadjuvanted vaccine?

MEMBER COUCH: I\'m not asking for that benefit with that question for
seasonal influenza. The benefit you expected would be with pandemic, but
if you require that you won\'t get it until after the fact.

DR. BAYLOR: Let me ask you, Bob, I mean in the past we\'ve had to do
this in the sense that we based our licensure on the seasonal in the
sense that we use the same manufacturing process and we just exchange
that strain. We identified the pandemic strain and we exchanged and
we\'d used immunogenicity and we really never truly confirmed that. I
mean, there were studies done to see how well we did. And that\'s where
we were. And are you kind of saying that\'s the best we can do? And if
it is \--

MEMBER COUCH: I don\'t mind you asking the clinical efficacy for an
adjuvanted vaccine. What my concern would be is it should be clearly
seen as superior during the seasonal pandemic. It is equivalent to the
seasonal vaccine without an adjuvant, would you accept that as having
shown clinical efficacy?

The expectation in the pandemic is that it will be better because of the
superior immune responses it presumably would show. But if you have to
show superiority for seasonal vaccine at the same dose, you could show
equivalent, say, at one-quarter of the dose maybe, something like that.
Maybe that would satisfy your requirement for clinical efficacy.

I\'ve got an industry cap on, I guess, with those questions. That\'s
kind of touch.

MEMBER SELF: I guess it seems to me that you know, part of this is that
the seasonal flu is a poor animal model for the effective adjuvant in a
pandemic vaccine.

MEMBER COUCH: That\'s been the case so far. There\'s some candidates out
there that companies are hoping will change that perception. But that\'s
where it is right now.

MEMBER SELF: Yes. But that seems to be the problem that I hear with
using seasonal vaccine, seasonal flu as the test bed specifically for an
adjuvant.

CHAIR MODLIN: I think it\'s a bad model for any vaccine, adjuvant in it
or not. It\'s new for pandemic flu simply because you\'re dealing with a
very different population. The difference between a primed and an
unprimed population is critical.

Ted?

MEMBER EICKHOFF: The only way you could do is to drop the dose, is to
alter the dose, as Bob said.

MEMBER COUCH: But there are two ways to do it. Actually, you can tell
I\'ve been here before. There are two ways. One is to drop the dose and
then show equivalent with a quarter of the antigen.

MEMBER EICKHOFF: Yes. Right.

MEMBER COUCH: Would that then be the kind of data that the FDA would
like to see?

Otherwise, you\'re talking about doing it in very young, relatively
unprimed children. And that would do it also, but that\'s not an easy
way to go either.

CHAIR MODLIN: Bob?

MEMBER DAVIS: Is it just completely off the table to do the real world
experiment of vaccinating people who appear to be at higher risk in
Thailand or Vietnam, places where the background rate of this is at
least somewhat detectable and really taking a look at what goes on in
human beings?

CHAIR MODLIN: I don\'t know if Nancy or Joe \--

MEMBER DAVIS: I mean, I\'m sort of asking you to win the lottery and the
world series and the super bowl all at once, I know.

MEMBER GELLIN: What question do you want to answer?

MEMBER DAVIS: The question, the ability to prevent invention. This is
really a clinical efficacy trial in the field.

CHAIR MODLIN: Bob wants to go live animal markets in Southeast Asia and
\--

MEMBER DAVIS: Right. So I know very little about the subject. But it
seems to me like that perhaps gives us a little bit better information
than making inferences based on seasonal flu.

MEMBER COX: Mike, I don\'t have a lot to say except that WHO has been
promised a vaccine for it\'s H5/N1 stockpile. And there has been
discussion about what needs to be need. Advice has been obtained from a
variety of experts and so on, and there are different documents on the
web. But there have been discussions in some countries that have ongoing
outbreaks in birds about immunizing poultry workers on the frontlines.
Those trials are very difficult to do. But that would be one way to
obtain immunogenicity data, safety data and so on. But it would be
extremely difficult.

CHAIR MODLIN: Pamala?

MEMBER McINNES: So if you pull all the pieces apart, you may be able to
answer discreet pieces. I\'m not sure that you can assemble them into a
coherent puzzle again.

So you could look what is the value of the adjuvant, adjuvant X, which
you could certainly look at in the seasonal influenza framework and the
variable could be dose concentration of antigen. And you could get as
full an immunologic response profile as possible looking at adjuvant
together with varying dose concentrations of HA. So that\'s one piece of
information.

If you look at the data that Joe put up about \-- I guess it was on
slide 12 which showed an H5/N1 less than 5 micrograms with no adjuvant
in less than 5 micrograms with adjuvant and you\'ve got 82 percent of
people with a four-fold rising antibody and 84 percent with greater than
titer of 1 in 40, that\'s sort of comforting kind of. I mean, that is
sort of data that we\'re used to looking at in the framework of
response.

And I presume this is post-second dose, sometime remote post-second
dose. What I don\'t know is what they looked like post-first dose or at
baseline. But if you could assume that you have neoantigen with and
without the adjuvant that you\'ve now dissected apart in the framework
of seasonal flu and you developed data that looked like this with maybe
no rise from zero to one, but certainly from one to two, you got this
increasing immune response. I mean, I would be feeling reasonably
comfortable that one is then immunologic priming of these subjects. And
you would do the safety profile on both the seasonal flu and then on
this set of pandemic studies.

I\'m not sure you can get a whole lot more than that. Because we can\'t
then move the pandemic HA with the particular adjuvant into a challenge
study, although I do know several people I could volunteer for the
challenge study. And I\'m sure we could all contribute.

I don\'t know from the workshop \-- I just don\'t know this literature
whether there is value from an animal model with challenge that could in
fact contribute to rounding out this sense of what you have about these
discreet pieces of the puzzle. But I think that\'s sort of about the
extent of how far I can get in trying to round out this package.

CHAIR MODLIN: Norm?

DR. BAYLOR: Let me throw out your comfort level as far as \-- say we
just looked at immunogenicity and looked at sera conversion rate and
ended it there. I mean, could you give me some feedback on that? Say we
just approved these vaccines based on an immune response and looking
four-fold rise and sera conversion I mean for a pandemic knowing that
there are no definitive confirmatory studies that we could do in the
absence of a pandemic.

MEMBER McINNES: I think if there was some information that at sometime
remote, a year later for example, I was able to come back, deliver maybe
a different H5 and I saw a response, I would feel pretty good about
that.

CHAIR MODLIN: I mean, Norm, from a public health standpoint I think
there\'s no question whatsoever that you\'re far better off doing that
than not doing that. I think that\'s kind of the simple.

Ted?

MEMBER EICKHOFF: Norm, are you talking about an adjuvanted vaccine?

DR. BAYLOR: Either.

MEMBER EICKHOFF: Either\> You may well be in that position eventually.

CHAIR MODLIN: Yes, Bruce?

MEMBER GELLIN: Just for the record, I want to second with Pamala. To me
that\'s something that demonstrates you\'ve had something that you might
want to call priming and then at sometime later with a new thing that
wasn\'t the same one that you get some benefit. To me those are the
parameters. Obviously, with a little more detail than that. But it seems
to me those are the kinds of parameters that we need to have.

CHAIR MODLIN: I think it\'s unlikely that you\'re going to get into a
situation where you can demonstrate an immune response and not be able
to demonstrate some degree of immunologic memory somewhere down the
line. I think that\'s a very logical sequence and important to do. But I
think the first step is more important than the second. But both are
important.

Could we put up the next slide, please?

Please discuss the immune response criteria for pre-pandemic indication
and relevance to criteria in the pandemic guidance document. That\'s
just what we\'ve been doing.

Please discuss a lower immune response result to initial immunization
prime if subsequent immunization results are acceptable.

Please accept immune response characteristics to the subsequent
immunization with the same antigen and with a heterologous antigen.

And, again, I think we\'ve already pretty much gotten into this question
in some depth already. I don\'t know if there\'s anyone \-- does anyone
else have something to say about it? Pamala?

MEMBER McINNES: I just wonder if Hana could talk to us about the animal
model? Is there some contribution that this in challenge could give us?

DR. GOLDING: So actually Kanta Subbarao and Jackie Katz presented very
beautiful data looking at the two major animal models, the mice and the
ferrets.

And there\'s no question that the mice are unique in that not all H5/N1
strains have been adopted to grow in them. And if they do, they don\'t
always lead to lethality. However, there are a lot of reagents
available. You can challenge them to some degree with both, especially
H5/N1 with both clade 1 and clades 2 so far.

And there was a lot that was learned and Dr. Subbarao was able to use
even passive immunity transferring some antibodies. So a lot could be
learned I think both in terms of direct protection, homologous and
heterologous protection.

Of course, the distribution of the glycan and the \-- are not exactly as
in human, and it will be very difficult to use them as a sort of
efficacy model, per se. But you can do a lot of preclinical proof of
concept studies. You can compare different vaccine, different adjuvant,
T-cell mediated versus antibody I think the mice can help us to learn a
lot.

The ferret is I think is the crucial issue here. Because ferrets do
seems to have a more similar distribution of the receptors, the \-- and
do seems to have a disease that is maybe similar to human. Also, you
don\'t need to do any adaption of viruses. And they have been used for
challenge experiments quite successfully.

It was felt that even with the most successful vaccine you can\'t
actually reduce the level of replication in the upper respiratory tract
in the site of inoculation. But you can, indeed, reduce the level viral
replication in the lower, in the lungs. And you can protect from
lethality and from other sign of morbidity.

Actually, it was felt that the lethality endpoint was the less robust in
terms of dose finding. There was not really a good correlation. There
were quite a few cases where the immune parameters measured in the
ferret were not predictive of the endpoint if lethality was the end
point. You could get protection very easily.

And that is a problem. Because if you not have a response, a BLA or a
licensed product and you say, okay, let\'s take the ferret as our next
model, you may be able to show protecting from lethality against
multiple strains that may or may not be translated into the human
scenarios.

So we don\'t know enough I think about the ferret model. And, of course,
you have the other confounding problems that further are so sensitive to
influenza, that almost a very percentage have currently found ferrets or
have some preexisting antibodies to seasonable influenza. Which again it
very elegantly shows that if they antibodies against some of the
seasonal influenza and now you give them an H5 or avian influenza
vaccine, you give higher titers.

So all of those become confounding in terms of really mimicking what
happened out there in the unprimed population. Nevertheless, it was felt
that in parallel to licensure, to the pivotal studies, this type, the
preferred in particular can give nice additional data about close
protection in the challenge models that you are talking about.

CHAIR MODLIN: Any further discussion on question 3? If not, let\'s go on
to question 4 which is please discuss the size of pre-licensure safety
database for pre-pandemic indication. In your discussion please comment
on population preparedness and the role of large sample size throughout
a rare serious adverse event at a rate such as 1 in 100,000.

Bob Davis, you might be able to help us out a little bit more with this.
My recollection from swine flue era was that even though the observed
rate of Guillain Barrè was 1 in 100,000 that also comes close to what
the background rate of Guillain Barrè is in the normal population.
Actually the attributable risk was something less than that, or was that
not the case which gives you further challenge in terms of determining
sample size for a adverse event this order of magnitude?

MEMBER DAVIS: This was actually a very challenging issue and one which
actually probably needs to be talked about a lot in its own venue.

I think I\'m not sure I can answer this specific question. But what I do
know is that I think there have been very specific lessons that we\'ve
learned from swine flu where the whole issue kind of got away from the
people who are in charge of the vaccine study. And it became an event in
the media. And that\'s a situation that you always want to avoid. And it
might take two or three years of planning to create an environment where
you avoid those events. And I want to compare that to the \-- issue that
came up where within 24 hours we were able to get good population based
data out there. And we were able to say this is what we know and we\'re
going to be monitoring it every day or every week, and that\'s what we
did. And we sort of gave updates every week. And even though the data
wasn\'t completely reassuring, we were at least able to say this is what
we know and it didn\'t get away from us. And it was able, I think, to
inform and reassure the general population.

And I guess to me that brings an issue that I thought was worth talking
about, which is that for these sorts of studies where you\'re ready to
actually do a pre-licensure study, you have to realize that the
infrastructure that we currently have, like the Vaccine Safety Data
Link, is an observational one. They choose to use vaccines and then we
observe the safety of those vaccines in a very large population-based
setting. This is going to be almost like an intervention where we will
actually request their participation in a very unique type of
pre-licensure study, and there\'s no guarantee that they will to
participate. I mean, they might. But no one can make the assumption that
they will in fact agree. And so the discussions that have to occur
really actually have to start occurring now. We can\'t wait until there
is a vaccine that is in the pre-licensure arena. Because it may take,
you know, 12, 24, 36 months to go through the whole issue of getting
buy-in, getting HMO buy-in. I mean this is so unique that you will
actually have to walk people through all of these issues that we\'re
grappling with right now.

There are other settings. If the VSD doesn\'t necessarily work, there\'s
the larger network of 60 to 100 million people that are being recruited
or being studied for the GBS. But that\'s one where we actually have
even less inaction with the health plans than we have with the VSDs. So
those are going to be tricky issues that are going to be necessary to
work through for a pre-licensure.

As I say, I know that this is probably far more than you wanted me to
talk about, but I\'m almost done.

So that\'s for the pre-pandemic. And for the pandemic study it\'s
actually different. I think in a pandemic study situation where you\'re
trying to keep a handle on safety and you\'re worried about things like
Guillain Barrè Syndrome, which are almost too rare study. They are too
rare to study in the VSD. I mean, that\'s why we went and created a
brand network of 60 to 100 million people.

For GBS you actually probably want to recruit a series of Sentinel
hospitals from around the country and simply do very, very rapid
turnaround case control studies as the pandemic is occurring and analyze
the data as each new case accrues and be ready to make statements about
that. Very similar to what we\'re doing with the rapid cycle studies
with the VSD. And we could talk more about that, but it\'s a little bit
out of this arena.

The one thing I do want to say is that trying to handle on this through
some sort of enhanced DEVRS mechanism, which I know is sort of something
that\'s been discussed, I think is exactly the wrong direction that we
want to go. You know, that\'s nonpopulation-based. It\'s
nonepidemiologically sound data. It\'s completely hypothesis generating
and what we\'re trying to do here is hypothesis test in a very, vary
rapid, very accurate way. And so I would actually just want to put it
out there to make the statement I don\'t think that\'s the direction we
want to go.

So I think that there are issues here having to do with the size. You
know, currently we\'re looking at ACAM 2000 where I think ACAM 2000 is
doing intense observation on 15,000 and even less intense but still
observational data on 40,000. Something around that area. And Roterex I
think is 40,000 plus or minus a bit. So, you know, I think that\'s an
accepted number. Is that correct? I\'m not sure. But that\'s the
ballpark we\'re talking about.

So that\'s probably where we probably would need to go from some sort of
pre-pandemic study. For the pandemic study it\'s a completely different
issue. And that one needs to be sort of discussed from the ground up.

CHAIR MODLIN: It looks like to me that Norm is asking for an appropriate
size for the safety database for pre-licensure study. And I don\'t think
that you\'re going to be asking manufacturers to enroll hundreds of
thousands of people pre-licensure. So the question is what is the
adequate size?

We don\'t know much, and it\'s actually a very difficult thing to say.
Because we don\'t know anything about even phase 1 and phase 2 studies
with respect to risk for various adjuvants. And I think those probably
have to inform this question, would be my guess.

Frank?

MEMBER DESTAFANO: Well, yes. I think I agree with \-- and as you were
implying, that pre-licensure is going to be hard to do a phase 3 trial
with a 100,000 people or something like that. But maybe it could be down
staged, you know, with a requirement with a large phase 4 study to
vaccinate in stages a large group in which you build in some backbone to
get some fairly intensive surveillance.

This is a preparedness model, after all. And the model we have for that
would have been the small pox program. There was sort of a registry of
vaccinated and it was built in with theirs and other reportees so that
you did have your numerators and denominators. And it proved to be
successful in identifying the cardiomyopathy and those kinds of things.

So I think maybe a phased approach. I don\'t know if it\'s possible to
do some provisional licensure given completion of a large well conducted
phase 4 study.

And I think, you know, for something as rare as Guillain Barrè Syndrome,
1 per 100,000 for swine flu is the attributable risk. But I think for
rare events like that; I don\'t know Guillain Barrè Syndrome maybe is an
a priori hypothesis, but I don\'t think we know that for these vaccines.
And we don\'t know anything else.

I think there\'s, with enhanced reporting could be a suitable backbone
again for signal detection, which is primarily what you\'re going to be
doing right now with these vaccines that we really don\'t know what kind
of rare adverse events they may have.

CHAIR MODLIN: Dr. Self?

MEMBER SELF: It was said earlier that this is all about a risk benefit
calculation, and I think that\'s exactly right. And what we\'re not
talking about is the benefit and what the odds are of a pandemic over
\-- or some reasonable horizon. And I think that\'s the way the
structure. And to specify that is going to be required to make any sort
of rational decision about what level of risk you need to bound and
therefore how big a study you need pre-licensure to define the risk side
of that equation.

CHAIR MODLIN: In other words to predict the likelihood of an H5
pandemic?

MEMBER SELF: Well, that\'s what we\'re talking about. That\'s when this
would have some benefit, right?

CHAIR MODLIN: Yes. Ted?

MEMBER EICKHOFF: I\'m not sure where our conversation earlier about
using adjuvant in seasonal vaccines came out. But it seems to me the
issue is relevant to the struggle we seem to be having with this
particular question.

Because if the FDA and the manufacturers, we could encourage them to do
some trials of the several adjuvants that are out there and seem to be
at least somewhat effective in the seasonal vaccine context, that would
at least begin to give us a handle on the adjuvant safety issue even
though it wouldn\'t be anywhere near 100,000. Nice if you could 100
people.

CHAIR MODLIN: Bruce?

MEMBER GELLIN: So before I start over, I\'ll look over the GSK corner so
you can start thinking of who you want to bring to the microphone.

But I think that the question here is that we have \-- this is
obviously, we\'re worried about a pandemic which is a global problem. We
have global companies, and they\'re operating in other places than North
America. So thanks technology there\'s a press release today from GSK
from Europe that talks about their candidate adjuvant Prepandrix
vaccines reaches important EU milestones, regulatory milestones.

So I\'d actually like to hear some of the experience that the companies
had with the EU with the EMA or I believe that\'s the right one, to say
how has your experience there, how can that inform our discussions here.
Because this is about your Prepandrix, which is as it says here is the
first candidate Prepandrix influenza vaccine to receive a positive
opinion, in capital letters, from the CHMP.

So clearly you\'ve been down this line. I would think of a similar set
of questions both in terms of what you need to demonstrate to say that
the pre-pandemic vaccine is providing some kind of benefit, what you\'re
proposing for safety studies. So I\'d be curious to know what those
conversations are like that lead to a press release today. And for the
record, it says \"Not for distribution to the U.S. media.\"

CHAIR MODLIN: You\'re certainly welcome to respond. Barbara?

MS. HOWEL: Barbara Howel from GSK.

Actually, Bruce, we don\'t have anyone from the global headquarters here
today, so I can\'t really speak to the discussions with the EMA.

We did see the press release as well while we\'re sitting in the
audience, however.

CHAIR MODLIN: Okay. Bob?

MEMBER COUCH: I\'ve not been involved in any of those discussions as
priority groups. But you could consider, at least as you sit around and
think about it, that there is a risk if H5, take that as an example,
that\'s one that came up with a discussion that I was involved in \-- if
there is a risk of H5 and we say it\'s still a risk, the risk of being
able to adequately handle the pandemic rests with the first responders.
So that if we say, okay, we\'re not pre-pandemic vaccinating that
population, we\'re pre-pandemic considering vaccination for those
individuals, health care professionals you know emergency and so forth,
who would be required to care for the pandemic when it occurred.

If any of you were around in \'68, I wasn\'t, doing something else, you
know it was a disaster.

CHAIR MODLIN: Any other comments or questions?

Dr. DeBold did you want to expand upon your earlier comments now that
we\'re talking about safety?

MEMBER DeBOLD: I guess I just have a general question about the
adjuvants that are being discussed. Because I\'ve heard the term being
tossed around a couple of times \"novel adjuvants.\" Are there new
things that in the works that we don\'t know about? And if so, I think I
would agree with what I believe you said earlier about trying to test
the adjuvant by itself before combining it with a vaccine. And maybe
that\'s what happens anyway, because otherwise it seems to me you\'re
putting two unknowns together and you\'re not going to be able to tease
out necessarily the effect due to the adjuvant versus the vaccine.

CHAIR MODLIN: Norm? Actually, just for clarification, it was not exactly
what I was suggesting. But obviously I think what we\'ve already heard
from Ted, which is that with these adjuvants the opportunity to study
them in the setting of seasonal influenza would give us an immense
amount of information.

Norm, did you want to \--

DR. BAYLOR: I\'d like to kind of follow up with Ted and also the rest of
the Committee as far as do you see the development and sort of, I guess,
the development of the adjuvant in seasonal vaccine? So if we\'re going
to use that sort of as a model, do you see applying that? I mean,
what\'s your opinion on applying that to the pandemic? I mean we\'re
talking about a different hemagglutinin. And so what\'s the comfort
level there of applying that, and even the idea of developing the
seasonal adjuvanted product and the need for that seasonal adjuvanted
product?

CHAIR MODLIN: Ted?

MEMBER EICKHOFF: My comfort level would be pretty good. Because I could
see a significant use for an adjuvanted seasonal vaccine if it broaden
cross protection. In other words, we might be able to think seriously
about not changing strains quite as often as we have to do now. We might
be able to tease out immune response, a better immune response out of
some people at least who don\'t respond well in the immunocompromised
category. I don\'t think an adjuvant is suddenly going to make people
respond magically, immunocompromised people respond magically. But there
may be subgroups of immunocompromised patients who will do better with
an adjuvanted vaccine.

And there may be a couple more examples. I just can\'t think of them
right now.

CHAIR MODLIN: And also, obviously, we\'re talking about completely
different risk benefit ratios. so I think that if you have a fair amount
of data that gives some level of confidence with seasonal influenza, I
think once you migrate into the very different risk benefit ratio for a
pandemic or even a pre-pandemic vaccine, I think the ability to accept
previous data regarding an adjuvant is pretty high. At least in my
opinion. I would suspect that the others would agree.

Does that get at your question, Norm?

Any further discussion? Yes, sir.

MR. KENNEY: I\'m Rick Kenny from GSK.

We wanted to respond a little bit more to your question. You caught us a
little bit off guard.

We clearly \-- the AMEA file is handled by a second group. A full
discussion of that would require other folks to come to the microphone.

But the database that was used for the approval of that vaccine for the
pre-pandemic setting was just in excess of 7,000 adults and elderly
subjects. We\'re not yet into the pediatric trials in any major way. So
that\'s kind of denominator of where we are.

I think one of the biggest lessons that was learned that may be
appropriate for this context from that series of studies was that
adjuvants enhance the cross protection potential. That if you look at
the heterologous protection, that may be the crux of what should be the
benefit for a pre-pandemic vaccine. In fact, the mathematical models
that have been proposed over the last year to show the possible benefit
of a vaccine have really required somewhere around a 30 percent
heterologous protection to stop a pandemic.

So what we are trying to move towards proving is the potential for that
cross protection using some sort of a readout, some sort of a surrogate.

Does that help.

DR. HOURN: Can you just clarify in terms of the favorable decision? Is
it for a use in the inter-pandemic period as we were describing
pre-pandemic vaccine or you mean that to be used during a declared
emergency?

MR. KENNY: Well, there\'s actually two files that were submitted. One is
for a pandemic use \-- a pandemic vaccine. Europe defines the whole
pandemic/pre-pandemic terms a little bit differently.

But both the pre-pandemic vaccine and the pandemic vaccine were
recommended for approval.

Whether or not it\'s actually used by a country in the pre-pandemic
setting, I believe is a country-specific decision. But this allows it.
And for a lot of countries, it allows the purchase of that vaccine.

MEMBER COUCH: But when you say \"pre-pandemic,\" you\'re talking about
for example now. Start next week if everything was ready for the
population recommendations?

MR. KENNY: Their definition \-- right. Their definition hinges on making
vaccine that\'s using a strain that\'s available in the pre-pandemic
period. So making vaccine now, yes, that can be stockpiled or used for
first responders, or what have you.

CHAIR MODLIN: Did you want to follow up on that?

MEMBER GELLIN: Right. Just a couple of other things.

We had this discussion about some kind of priming and then something to
follow up later. That wasn\'t part of the discussion in this regulatory
pathway in Europe, is that right, about some evidence of a demonstrated
boost later on?

MR. KENNY: To my knowledge, the prime boost data was not part of that
package.

MEMBER GELLIN: Okay. Thanks.

MR. KENNY: But if I may, in a pre-pandemic period, again if you can show
that there is a possibility of a heterologous boost, to me that seems
like a very strong argument in favor of allowing a pre-pandemic
indication, allowing the possibility of protecting the population;
that\'s the benefit.

MEMBER GELLIN: No, nobody would disagree. I was just wondering what bar
you were trying to jump over in Europe and if that was one of the preset
bars about cross protection \--

MR. KENNY: No.

MEMBER GELLIN: As well as this question about coming in at some point
later to demonstrate a subsequent immune boost.

MR. KENNY: And I think that the difference is in the definition of
pre-pandemic vaccine. They\'re seeing it as a vaccine that can be made
with today\'s strains versus the mock pandemic vaccine that has to be
made in the future with future strain.

CHAIR MODLIN: Bob?

MEMBER DAVIS: Just a remark that makes me want to qualify a little bit.
And that is that, and seasonal vaccines is what I know and I doubt if
the H5 is much different, you get heterologous protection because you
have measurable heterologous cross reacting antibody. That\'s our
surrogate for that. And that\'s a consequence of the magnitude of the
homotypically antibody because that determines the extent to which is
cross reacts with related drift variance. And I think that must be true
for H5 also, but I don\'t know that. In which case the value of the
adjuvant is not producing the cross reacting antibody, if the value of
the adjuvant is increasing the antibody response homotypically and that
increases the cross reactions.

CHAIR MODLIN: Lisa?

MEMBER JACKSON: Well, Bob, I\'m sure you know this literature better
than I, but doesn\'t the recent follow up study the VTU did to the
Sanofi-Pasteur vaccine sort of imply that that may not necessarily be
the case? Because it seemed like the boost response or the response to
the post-one year administered antigen was not necessarily a factor of
what dose was given at day zero and the antibody response at that. So it
seemed to raise the possibility that whatever is going on
immunologically may not be well identified by the 29 day post HI
response necessarily.

MEMBER COUCH: You\'re talking about John Trainer\'s H5 data?

MEMBER JACKSON: Well, the Kingswell paper. So they did a follow on that?

MEMBER COUCH: I don\'t know the H5 data that well.

MEMBER JACKSON: Yes. Yes.

MEMBER COUCH: But the two things that you do with a new antigen that in
addition to the magnitude, as you give repeated doses, you actually
broaden that response which can be shown to be specifically reactive
antibody. So that\'s another function that might have been counted for
something like that.

CHAIR MODLIN: Further discussion?

Norm, do you and Florence want to have the final word?

DR. BAYLOR: I guess I\'ll say something.

I think this discussion that we\'ve had this afternoon demonstrates the
complexity of this issue, in particular the complexity that the
regulators have. I mean because we have to have criteria to evaluate
these vaccines. And we will continue to come back as we gather more
information, as we see more data as we try to develop a pathway to
license these vaccines. But we will be coming back and updating you and
asking for more advice.

I think this was a good discussion, but I think the questions are still
complex and the answers are not that cut and dry, as you can see.

CHAIR MODLIN: Norm, they obviously are.

We want to thank you I think for probably educating all of us and kind
of raising our awareness with respect to the degree of complexity here.
I think there\'s a general awareness of this, but it\'s helpful I think
for the members of the Committee to be able to get our arms around it.

I would like to thank the members of the Committee for a terrific
actually two day meeting. And thank you for your participation. And I
look forward to working with you at the next meeting.

We\'re adjourned.

(Whereupon, at 4:09 p.m. the meeting was adjourned.)