UNITED STATES OF
AMERICA
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FOOD AND DRUG
ADMINISTRATION
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CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
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VACCINES AND RELATED
BIOLOGICAL
PRODUCTS ADVISORY
COMMITTEE
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94th MEETING
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THURSDAY,
FEBRUARY 20, 2003
This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation as to its accuracy.
The
Advisory Committee met at 8:30 a.m. in the Versailles Ballroom of the Holiday
Inn Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. David S. Stephens,
Chairman, presiding.
PRESENT:
DAVID S.
STEPHENS, M.D. Chairman
ROBERT
COUCH, M.D. Temporary
Voting Member
NANCY COX,
Ph.D. Temporary
Voting Member
MICHAEL
DECKER, M.D., M.P.H. Non-Voting
Industry Representative
PAMELA S.
DIAZ, M.D. Member
COLONEL
BENEDICT DINIEGA, M.D. Temporary Voting
Member
PRESENT: (cont.)
WALTER
DOWDLE, Ph.D. Temporary
Voting Member
BARBARA
LOE FISHER Temporary
Voting Member
BRUCE
GELLIN, M.D. Temporary
Voting Member
JUDITH D.
GOLDBERG, Sc.D. Member
RUTH A.
KARRON, M.D. Member
SAMUEL L.
KATZ, M.D. Member
DAVID M.
MARKOVITZ, M.D. Member
PAMELA
McINNES, D.D.S. Temporary
Voting Member
MARTIN
MYERS, M.D. Temporary
Voting Member
GARY D.
OVERTURF, M.D. Member
PETER
PALESE, Ph.D. Member
JULIE
PARSONNET, M.D. Member
WALTER
ROYAL III, M.D. Member
JODY
SACHS, D.P.M. Executive
Secretary
FDA REPRESENTATIVES:
CARL FRASCH, Ph.D.
ROLAND LEVANDOWSKI, M.D.
KAREN MIDTHUNE, M.D.
RICHARD WALKER, Ph.D.
ZHIPING YE, M.D., Ph.D.
ALSO PRESENT:
LINDA
CANAS Department
of Defense
SAMSON
LEE, Ph.D. Aventis
Pasteur
C-O-N-T-E-N-T-S
Call to Order 5
Dr.
David Stephens, Chair
Introductions 5
Administrative Matters 7
Dr. Jody
Sachs, FDA
Session 1 - OPEN SESSION
Strain Selection for Influenza Virus
Vaccine for the 2003-2004 Season 11
Introduction 11
Dr.
Roland Levandowski, FDA
U.S.
Surveillance
and
World
Surveillance and Strain Characterization
and
Molecular Characterization of
Strains 22
Dr.
Nancy Cox, CDC
Additional Surveillance
Reports 65
Linda
Canas, DOD
Vaccine Responses 80
Dr.
Roland Levandowski, FDA
Availability of Strains and
Reagents 106
Dr.
Zhiping Ye, FDA
Comments from Manufacturers 108
Dr.
Sam Lee, Aventis
Options for Strain Selection 127
Dr.
Roland Levandowski, FDA
Committee Discussion and Recommendations 170
Vote Taken 174
H1N1 174
H3N2 177
C-O-N-T-E-N-T-S
(Continued)
Section 2 - Open Session
Laboratory of Bacterial Polysaccharides 192
Overview
of Division of Bacterial,
Parasitic, and Allergenic
Products 192
Dr.
Richard Walker, FDA
Overview
of Laboratory of Bacterial
Polysaccharides 206
Dr.
Carl Frasch, FDA
Open Public Hearing 214
P-R-O-C-E-E-D-I-N-G-S
8:36
a.m.
CHAIRMAN
STEPHENS: Good morning. Welcome to the first meeting, the 2003
meeting, of the Vaccines and Related Biological Products Advisory Committee.
I
would like to start by going around the room and introducing our members and
consultants. Dr. Katz, would you like
to begin?
DR.
KATZ: I'm Samuel Katz from Duke
University.
DR.
COUCH: I'm Robert Couch, Baylor College
of Medicine in Houston.
DR.
MYERS: I'm Martin Myers from the
University of Texas in Galveston.
DR.
McINNES: I'm Pamela McInnes, National
Institutes of Health, Department of Health and Human Services.
DR.
COX: I'm Nancy Cox, CDC, Atlanta.
DR.
GELLIN: Bruce Gellin, National Vaccine
Program Office, Department of Health and Human Services.
DR.
DOWDLE: Walter Dowdle, Task Force for
Child Survival and Development, Atlanta.
DR.
PALESE: Peter Palese, Mt. Sinai School
of Medicine, New York.
DR.
MARKOVITZ: David Markovitz, the
University of Michigan Medical School.
DR.
DINIEGA: Ben Diniega, Department of
Defense, Health Affairs.
DR.
ROYAL: Hi. My name is Walter Royal, Morehouse School of Medicine, Atlanta,
Georgia.
DR.
GOLDBERG: Judith Goldberg, New York
University School of Medicine.
DR.
OVERTURF: Gary Overturf, University of
New Mexico.
DR.
KARRON: Ruth Karron, Johns Hopkins
University.
DR.
PARSONNET: Julie Parsonnet, Stanford
University.
MS.
FISHER: Barbara Loe Fisher, National
Vaccine Information Center.
DR.
DECKER: Michael Decker, Vanderbilt
University and Aventis Pasteur.
DR.
DIAZ: Pamela Diaz, Chicago Department
of Public Health.
DR.
LE: Zhiping Le, CBER, FDA.
DR.
LEVANDOWSKI: Roland Levandowski, the
Center for Biologics.
CHAIRMAN
STEPHENS: And I'm David Stephens from
Emory University in Atlanta, where it was 60 degrees yesterday and we're
expecting our first flowers.
(Laughter.)
I
want to thank everyone for coming and braving the weather.
We'll
begin with Dr. Sachs, who has some introductory comments.
DR.
SACHS: Good morning. I'm Jody Sachs, the Executive Secretary for
today's meeting of the Vaccine and Related Biological Products Advisory
Committee.
I
would like to welcome you all to the 94th Meeting of the Advisory
Committee. This morning's session will
consist of presentation and Committee discussions that are open to the public. Then in the afternoon we'll go into a Closed
Session until the meeting is adjourned, as described in The Federal Register
notice of January 21st, 2003.
I
ask that all our Committee members identify themselves each and every time they
talk, since we have a transcriber present who will need your assistance in
order to attribute all the comments to the appropriate Committee member.
I
also ask our Committee members and the public to place your cell phones on mute
since this adds a distraction that is unnecessary to the meeting.
I
would like to list the following individuals as not present today: Dr. Richard Whitley, Dr. Theodore Eickhoff,
Dr. Dixie Snider, Dr. Audrey Manley.
There
are two presenters that will not be present today, so there will be a change in
the agenda. The two people from CDC,
Dr. Alexander Klimov and Dr. Keiji Fukuda.
I
would like to read a statement for the record.
"The following announcement addresses the conflict-of-interest
issues associated with the Vaccine and Related Biological Products Advisory
Committee meeting on February 20th, 2003.
"The
Director of the Center for Biologics Evaluation and Research has appointed Dr.
Robert Couch, Dr. Nancy Cox, Dr. Walter Dowdle, Dr. Theodore Eickhoff, Dr.
Bruce Gellin, Dr. Pam McInnes, Dr. Martin Myers, Dr. Dixie Snider, Colonel
Benedict Diniega, and Ms. Barbara Fisher as temporary voting members of this
meeting.
"Based
on the agenda, it has been determined that there are no products being approved
at this meeting. The Committee
participants have been screened for their financial interests to determine if
any conflicts of interest existed. The
agency reviewed the agenda and all the relevant financial interests reported by
the meeting participants.
"The
Food and Drug Administration prepared general matters waivers for the special
government employees participating in this meeting who required a waiver under
18 USC 208.
"Because
general topics impact on so many entities, it is not prudent to recite all
potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential
conflicts of interest, but because of the general nature of the discussions
before the Committee, these potential conflicts are mitigated.
"We
would like to note for the record that Dr. Michael Decker is participating in
this meeting as a non-voting industry representative acting on behalf of
regulated industry. Dr. Decker's
appointment is not subject to 18 USC 208.
He is employed by Aventis and, thus, has a financial interest in his
employer. In addition, in the interest
of fairness, FDA is disclosing that his employer, Aventis, is the manufacturer
of the product that could be affected by today's Committee discussions.
"In
the event that the discussions involve specific products of firms not on the
agenda, and for which the FDA's participation have a financial interest, the
participants are reminded of the need to exclude themselves from the
discussions. Their recusal will be
noted for the public record.
"With
respect to all other meeting participants, we ask, in the interest of fairness,
that you state again your name and affiliation and any current or previous
financial involvement with any firm whose products you wish to comment
upon."
I
now wish to turn the meeting over to our Chair, Dr. David Stephens. Thank you.
CHAIRMAN
STEPHENS: I want to issue a welcome to
two new members of the Committee, Dr. Karron, welcome, and Dr. Royal. We appreciate very much your service.
I
also want to welcome back Ms. Fisher, who was on the Committee for four years
and is back for this meeting.
With
that, I think we will begin the program.
Our first session deals with strain selection for influenza virus
vaccine for the 2003-2004 season. Dr.
Levandowski will give our first presentation.
DR.
LEVANDOWSKI: Thank you, Dr. Stephens.
I
hope everybody can hear me. I hope this
microphone's okay.
Good
morning. Welcome to Bethesda. I'm glad to see everybody here.
Actually,
before I begin my introductory remarks for the session, I wanted to bring to
the attention of the Committee and others that yesterday and today, many of you
already know actually that the Hong Kong Department of Health and the World
Health Organization made press releases indicating that there has again been
evidence of avian influenza viruses causing human infection in Hong Kong
residents.
These
press releases indicate that the influenza A virus is of the H5N1 subtype, and
it has been isolated from a 9-year-old boy who became ill early in
February. There's also evidence of H5N1
in the lung of the boy's father, who died on Sunday.
The
source of this H5 virus isn't determined, but there has been continuing H5N1
influenza activity in waterfowl and other birds in Hong Kong during the past
year, and in particular during December, when there were a number of deaths of
waterfowl in some of the parks in Hong Kong.
Investigations
involving the family and the family's potential exposure to the H5 viruses in
this particular instance is continuing.
It is expected that there is going to be more information available in
the near future, and we expect to bring a lot more information at a later date,
but today we will need to defer those discussions with the Committee until
we've had an opportunity to really review and to verify the information.
So
I would like to make sure, I would like to encourage that since our primary
task is strain selection, that we spend most of our time dealing with those
issues, which are really going to be quite interesting, I think.
So,
as always, that is our business today, which is to make the recommendations for
the influenza vaccines to be used in the 2003 and 2004 season coming up. This is the basic question that we ask the
Committee every year, what we need to address here: That is, what strains should be recommended for inclusion in the
influenza vaccines for the 2003 and 2004 season?
This
Committee has been charged with the responsibility for making the influenza
composition recommendations on behalf of the U.S. Public Health Service, but
the recommendations also have implications for the Department of Defense, since
the same strains are used both for the civilian vaccine and also for production
of vaccines that are used by the military.
The
basis for the recommendations really comes from information that we're going to
supply this morning in these areas that are shown on the slide. Most importantly, we need to know if new
influenza viruses are evolving in nature, and there is an extensive
international network that's supported by the World Health Organization and its
collaborating laboratories to collect and analyze information on influenza
throughout the year, as we will be hearing from our colleagues from CDC and
from the Department of Defense.
In
addition, we're going to be hearing a significant amount of new data that has
only been developed within the last couple of weeks. When new variant influenza viruses are identified, the extent of
the geographic distribution of those variants helps to judge the urgency, and
changing the composition of the vaccine, often antigenic variants appear, but
sometimes these represent just dead-end branches on the evolutionary tree.
As
we have seen in the case of influenza B in Asia in the recent past, there could
be some very significant differences in antigenicity of viruses that can spread
in one geographic location, but may stay there for a number of years. Our experience was that for 10 years we
didn't see the strains in Asia spreading to the rest of the world, but that
happened last year.
Of
course, we have also seen just the opposite occurring. With significant new influenza variants,
sometimes there's very rapid spread. A
recent example of that would be the A/Sydney/5/97 virus. That virus was first isolated in Australia
during our summer months, but by winter of that same year it was very
widespread in North America. That was
after it had first appeared in August amongst passengers on cruise ships that
were touring the maritime provinces of Canada.
If
these new strains do appear to be disseminating widely, it's useful to know
whether or not antibodies are induced by the current vaccines and whether those
are likely to inhibit these recently-circulating viruses. For this, we rely on information from
serologic studies that are gathered from persons who have been immunized with
current inactivated influenza vaccines.
Finally,
if the new variants arise, disseminate, and appear to be poorly inhibited by
current vaccines, practical matters still need careful consideration. For the inactivated influenza viruses
there's an increasingly pressing question about whether enough vaccine can be
made to meet the demand that's out there.
The wild-type strains often grow very poorly, so that high-growth
influenza A viruses need to be prepared to facilitate large-scale manufacturing
of inactivated vaccines.
In
formulating an answer to the question, it is helpful to review a few facts
about the currently-approved inactivated influenza virus vaccines. We know that inactivated vaccines act
primarily to induce the production of antibodies, mainly to the
hemagglutinin. The hemagglutinin and
the neuraminidase of influenza viruses incorporated in the current inactivated
vaccines are concentrated, and they're partially purified to remove extraneous
materials that are derived from the eggs in which the vaccines were produced.
But,
as part of the production, the inactivated vaccines are only standardized for
the content of hemagglutinin, and, therefore, we place the great emphasis on
the viral hemagglutinin. However, we do
consider the neuraminidase because it, too, can add to the protective efficacy
of vaccines. Where possible, we have
tried to match those up.
Since
the use of the first inactivated vaccines in the 1940s, it has been very clear
that one of the most important predictors of vaccine protective efficacy is the
match of the vaccine viruses with the influenza viruses that are currently
causing infection.
What
we have seen also is, however, that every year there's the possibility for a
lot of antigenic diversity, some of which may be important and some of which
may not be so important.
We
will talk about antigenic drift.
Mainly, that refers to the ongoing random mutations that are occurring
in the hemagglutinin and in the neuraminidase.
But, occasionally, there is introduction of an entirely new gene for
either hemagglutinin and neuraminidase, and that's referred to as antigenic
shift.
In
this slide I'm giving a very brief overview of the timelines for preparation of
influenza vaccines. The emphasis in
this slide is on the use of the vaccine, which generally occurs in fall months. But if you look at that and work backward
through the preparation and the support, you see that there's a lot that has to
happen at certain times in order for everything to go forward.
A
number of times the surveillance information has not been ‑‑
although it's going on all the time, we get new surveillance information
always, and the influenza viruses, of course, don't always cooperate with us in
terms of this timeline. They show up
whenever they do in terms of the natural evolution.
A
new concern that we have this year in terms of this vaccine use in the fall is
that we now have only two manufacturers of inactivated vaccine supplying the
United States. Those two manufacturers
are Aventis Pasteur and Evans PowderJect.
You probably have seen press releases to know this, but Wyeth announced
at the end of the 2002 influenza vaccine production campaign that it would no
longer produce inactivated influenza virus vaccines.
Although
the current manufacturers have given us assurance of their intent to fill the
gap that's left by Wyeth's departure, we can be certain that any shock to the
system is more likely to be evident for all of us in terms of what happens.
When
there are multiple manufacturers, it's possible that if one manufacturer
experiences a temporary problem, then others can pick up the slack and help
out. That's been true often in the
past. However, if one of the two
remaining current manufacturers experiences a problem, the probability is now a
lot greater that there will be a delay or a shortage of vaccine during the
vaccine preparation period.
That's
not to say, however, that the vaccines don't need to remain current. They do, in order to maintain
effectiveness. Of course, we do, and
the manufacturers do too, anticipate change on a regular basis, but each one of
those changes represents a certain amount of risk to the vaccine supply,
particularly when we don't have all the details to support manufacturing worked
out well in advance.
So
this slide shows the most recent recommendations from both this Committee and
from the World Health Organization. The
recommendations on the left are the ones that were made by the Committee for
this current production year that we're using the vaccine from.
The
recommendation last year included one change to the trivalent vaccine, and that
was for the new influenza B strains, which are shown at the bottom of the
lefthand column. Actually, during the
past year's campaign, two different influenza B viruses meeting the
recommendation have been in use, and those actual strains in the United States
are the Hong Kong/330/01 strain and the Hong Kong/1434/02 strain.
The
recommendations on the right are those that have just been made by the World
Health Organization for 2003 production in the Northern Hemisphere. I would ask you to note that those most
recent recommendations, which were made on Friday of last week, include the
very unusual postponement of recommendation for the H3N2 strain. That postponement relates to the fact that
there was late-breaking information about influenza A H3N2 viruses. We will be presenting some of that
information this morning, along with a lot of other data.
I
think I will stop there, and if there are any questions at this point, take
them.
CHAIRMAN
STEPHENS: Questions for Dr.
Levandowski's presentation?
(No
response.)
Roland,
just can you comment further on the WHO decision not to include currently a
recommendation for an H3N2?
DR.
LEVANDOWSKI: I can try a bit, but there
are others here who may want to add to that.
I believe it really is that only in the last couple of weeks was it
well-recognized that there are some new H3N2 viruses that are becoming more
predominant or appearing at a greater frequency than they have been. I don't think I want to go into all the
detail because that's what Dr. Cox is going to present for us in her
presentation.
DR.
COUCH: Could I make just a
quickie? Couch here.
I
just want to highlight the fact that WHO is willing to be flexible on these
decisions because, while I've never participated in that to my knowledge, that
may be a precedent for WHO. You may
want to comment on that, but the flexibility has been a characteristic of this
Committee to be sure as much as possible that we hit the right target.
DR.
LEVANDOWSKI: WHO tries, at all cost, to
make its recommendations when it has its meeting in February, but they do, and
they have in the past, postponed their recommendations. It happens about once every ten years. You, Dr. Couch, have made that comment on a
regular basis about how we need to be sure we've got all the right
epidemiologic information collected.
Of
course, sometimes the influenza seasons are a little bit late developing. I think our concern is somewhat like it was
with the A/Sydney strain, which was a very markedly different antigenic virus
in 1997. It was only recognized very
late. It was recognized too late really
to make any changes for the vaccine that year.
We
think that the vaccine probably was reduced in its effectiveness by not being a
very close match with the strains that circulated that were A/Sydney, like that
following year. I think that's
reflected by WHO's decision to postpone this until some additional information
could be obtained as well.
DR.
COUCH: Just an informational
comment: For those of you who don't
worry about flu, the language that has been coined for this is the "herald
wave." So the herald wave is the
prelude to the epidemic virus the following year. So it is important to try to search for those herald waves. That is what Roland is suggesting may be
going on right now that delayed that decision.
That, of course, is important to make the right antigen decision.
CHAIRMAN
STEPHENS: Thank you, Dr. Couch.
I
think we'll move on now to Dr. Cox's presentation. Dr. Keiji Fukuda is not available, and Dr. Cox will do the next
two presentations.
DR.
COX: Thanks very much, and thanks for
the introduction, the introductory material, Roland. I do want to convey regrets from Drs. Klimov and Fukuda, who are
back in Atlanta handling a variety of activities related to the announcement by
Hong Kong of the H5 viruses.
I'm
going to present U.S. surveillance data.
I would first like to preface my remarks by saying that the season
that's ongoing now can be characterized as mild to moderate. We really haven't seen a lot of influenza
activity except with respect to influenza in young children, and there have
been a number, quite a large number, of school closings reported to us. Most of those school closings were
associated with the isolation of influenza B viruses, but influenza A viruses
have also been isolated.
Roland,
is there a pointer?
Okay,
we have data for the week ending February 8th, during which approximately 20
percent of the isolates that were tested by the WHO and NREVSS labs were
positive for influenza. I would like to
point you to the color-coded legend here.
We'll see that influenza B viruses are represented in green. You can see that the majority of the strains
so far this season that have been reported are linked to influenza B isolates,
but we also have an increasing proportion of influenza A viruses.
We
have incomplete information, of course, for recent weeks, where not all the
viruses have been subtyped. But, of the
influenza A viruses that have been subtyped, about 80 percent are H1 ‑‑
that is, they are either H1N1 or H1N2 ‑‑ and the remainder are H3N2
viruses.
I
should also note that almost half of the influenza B viruses have been reported
by the States of Texas and Missouri. So
they've had very significant outbreaks there, and that's been reflected by
school closures.
This
slide shows the percentage of the total patient visits to the influenza
sentinel physicians that are for influenza-like illness, or ILI. So during week six about 3 percent of the
total number of patient visits were for influenza-like illness. This is above the national background. These are national data, and the results for
the last three weeks are above the national background of 1.9 percent. It certainly appears that influenza activity
may be continuing to rise.
This
map shows influenza activity which was reported by the state and territorial
epidemiologists. We had a total of 13
states reporting widespread activity and 21 states and New York City reported
regional activity.
You
will see that the western part of the U.S. is reporting sporadic activity, and
that's been characteristic of all the indices that we have for influenza. The western part appears to be relatively
spared so far.
Now
we'll move on to pneumonia and influenza mortality. This is the 122 cities reporting system. You can see that for this season we haven't
actually gone above the baseline levels, the baseline or the threshold levels,
with respect to excess deaths. So we're
looking for deaths that might be above this top threshold level. These are deaths as reported to CDC by the
vital statistics offices of 122 cities.
I
would like to mention that this season, where we had a very significant peak of
excess mortality due to pneumonia and influenza, was caused by H3N2 viruses.
Now
we'll move on to influenza H1 viruses, and I should mention that in this
category we have both H1N1 and H1N2 viruses.
Reassortment had occurred between the circulating human H1N1 viruses and
the human H3N2 viruses at a point in the past, and we had quite a bit of
discussion about this event last year at our meeting. The H1 and 2 viruses have continued to circulate.
I
have really tried to distill the information that was circulated earlier into
some simplified tables. Hopefully, I
can walk you through these tables and they won't be quite as confusing to some
of you who aren't accustomed to looking at these tables as the ones that were
circulated.
So
I'll walk you through the table. We
have our reference antigens. These are
well-characterized viruses to which we have raised post-infection ferret serum. We then conduct hemagglutination inhibition
tests with these ferret sera.
We
have homologous titers for these reference antigens and their corresponding
ferret antiserum, shown in red, across the top here. What we are really looking for are differences of fourfold or
greater between the homologous titer and the titer obtained with additional
strains.
I
would like to focus your attention on column B, where we have antiserum,
antiserum to the current vaccine strain, New Caledonia/20/99. You see there's a homologous titer of 320,
and the majority of the test antigens which have been isolated in recent months
are well-inhibited by antiserum to the New Caledonia serum. This has been true of the most recent
viruses. I'll show a frequency table
later, but the vast majority of the most recent viruses are very well-inhibited
by antiserum to the vaccine strain.
We've
also seen a few viruses with reduced titers.
Particularly, we saw viruses from Chile last summer during the
circulation of influenza in the Southern Hemisphere, which were reduced in
titer with the Nanchang serum. We've
put a couple of those viruses into ferrets.
For
this particular strain that you see at the bottom, where the titers are really
quite dramatically reduced, we see that we got a low homologous titer and that
we get low titers against the currently-circulating strains. This is probably an indication that this is
a low avid strain. I'll talk more about
the sequencing results and additional results, but this virus is certainly not
typical of the majority of strains that are circulating.
We
do have a couple of strains at the bottom, the Peru/3090, which was used in the
post-vaccine serology tests that Roland will talk about later, which has a
profile somewhat similar to that of the Hawaii/15 virus. Sorry, the Peru/3064 has a profile more
similar to this virus, and the Peru/3090 is also a low reactor.
You'll
see down the far right column an indication of which neuraminidase these
viruses contain; that is, whether they have an N1 neuraminidase or N2
neuraminidase. You can see that we have
a number of viruses, a couple of viruses, from Canada. We have actually tested more which have N2
neuraminidase. We have from the United
States both N1 and N2 neuraminidase among the currently-circulating
strains. I will give frequency
information as well, but the take-home message is the vast majority of the most
recent viruses are well-inhibited by antiserum to the New Caledonia strain.
I
also should mention that there's been very little H1 activity outside of North
America. So the majority of viruses
that we have tested, and that have been reported anywhere in the world, are
actually either from Canada or from the United States.
As I mentioned before, of the most recent
viruses ‑‑ that is, viruses that were isolated between October 2002
and February ‑‑ over 95 percent are well-inhibited by antiserum to
the New Caledonia strain and only 3 percent, two of the viruses, were low
reactors during that period.
I
had mentioned that during our summer months, the winter in the Southern
Hemisphere, there were a number of low reactors, and those viruses, many of
those viruses were actually from Chile.
Here
we have a frequency table which shows us the proportion of H1N1 and H1N2
viruses that we characterized that have been isolated between April and
September and then between October and February. You can see that about 30 percent of the viruses from the most
recent period are H1N2, the majority being H1N1.
This
reflects viruses that we have characterized at CDC. A large number of H1N2 viruses have been identified in Canada,
which have not been sent to us. The
ones that have been sent are reflected here, and they really have a vast majority
of H1N2 viruses, which is a little bit different from what we're seeing.
We
are, of course, tracking these viruses in terms of the evolution of their
hemagglutinin and their neuraminidase genes.
We've tried to simplify the tree that we had in the package and to just
focus on a few points here in this tree.
The
first point I would like to make is that the hemagglutinins of the H1N2 viruses
cluster together, and they're shown here in blue. In spite of this clustering, we do not distinguish these viruses
antigenically from the vaccine strain or from each other. So when you raise antiserum to one of these
viruses and test it against viruses in this clade, you can't detect antigenic
differences on a reliable basis.
Some
of the low-reacting strains from Chile that were isolated in the summertime are
down here, and they are not so similar to current activity in North America.
I
should also mention that we have shown here on this tree viruses that were
tested as serology antigens, the viruses that were isolated in eggs, in case we
needed to have a change in vaccine strain, and low reactors to the New
Caledonia antiserum.
I
would like to mention ‑‑ I'm not sure that it is so obvious in this
pared-down tree ‑‑ but we didn't have any real clustering of low
reactors. That is to say, we had low
reactors scattered throughout the tree, so there was no indication that we had
a growing genetic group that had reflected any antigenic changes that could be
correlated with genetic changes, and that's always what we're looking for. When we put the antigenic and the genetic
data together, we are looking for a correlation in molecular changes with the
differences that we see with our post-infection ferret serum.
At
the request of a number of different people and groups, we have been spending a
bit more time on the neuraminidase. We
had been sequencing neuraminidase for a number of years, but we've also been
looking at the antigenic properties of neuraminidase. Sometimes this is a bit confusing. I hope not to confuse you today.
I
think the H1N1 data are pretty clear.
We have ferret antisera which I should mention are not ideal because
they're made against the virus itself; they're not made against a reassortant
which has been a relevant hemagglutinin.
So these results are the best that are available anywhere in the world,
but in some senses they're not ideal because ideally you would make a
reassortant that has an irrelevant hemagglutinin, so you could be sure that
you're not looking at any stearic hindrance that might occur by antibody to the
hemagglutinin binding and inhibiting the neuraminidase.
What
we see here with these H1N1 viruses, which are recently isolated, is that we
really can't tell much difference in their neuraminidase. So the N1 neuraminidase are quite stable.
When
we expand our table and begin to look at H1N2 viruses, we see a slightly
different pattern. We can distinguish
N2s. For example, we have antiserum to
this Hawaii/10 H1N2 and we can see differences down here with some of these currently-circulating
strains. Unfortunately, we don't know
the full significance of this difference that we are seeing because, as I
mentioned, these antisera are not the ideal ones, but there is some indication
that there are differences in the N2 neuraminidase.
The
evolutionary relationships among the N1 genes are pretty straightforward. There hasn't been very much variation in the
N1 neuraminidase genes since 1999, when the vaccine strain was chosen. So we really have fairly homogenous viruses
and neuraminidase genes, and I don't think there's anything really very
remarkable about the sequence data for the neuraminidase genes.
So,
in summary, for the influenza H1N1 and H1N2 viruses, these H1 viruses have been
reported primarily from the Americas, and I would like to particularly point
out Canada, Chile, and the United States.
Greater than 95 percent of the most recent H1 viruses have
hemagglutinins that are antigenically- and genetically-similar to that of the
current vaccine strain, A/New Caledonia/20/99, and the neuraminidase of the
current H1N1 viruses are similar to the vaccine strain.
The
neuraminidase of the H1N2 viruses are similar to those of currently-circulating
H3N2 viruses, and I'll show you some genetic data when I get to the H3N2
neuraminidase.
So
now I'll be talking about the influenza A H3N2 viruses. Of course, this is the vaccine
component. This category of viruses is
represented by the vaccine component that WHO deferred.
So
I need folks to really pay attention to this simplified table. Once again, we have post-infection ferret
serum to a number of reference strains, which are shown here, our antigens
here. We have post-infection ferret
serum to the old Sydney vaccine strain, to the Moscow WHO-recommended strain,
and to the Panama vaccine strain itself.
In
addition, we have reference ferret antisera for a couple of more recent
viruses, one of which was isolated in Hong Kong, one from New York, then the
ferret serum against this reference strain A/Fujian/411/2002, which I'll be
talking about quite a bit. So I'll be
mentioning the Fujian/411 virus.
I'm
sorry, there's a mistake here. This
actually should be Fujian. It was a
mistake in the editing.
What
I would like to mention is that, until about January 31st, the majority of the
viruses that we were analyzing looked like the viruses at the top of this
table. On January 31st, we had a number
of new viruses that we had just received from Asia in a test, and we had
antiserum to the Fujian virus that we could test for the first time.
The
Fujian strain was actually not well-inhibited to antiserum to Moscow and
Sydney, and it is not reflected as much in this particular test, but we have
done a number of additional HI tests.
Typically, the Fujian virus is reduced in titer by about fourfold.
So,
as of about the end of January, we're seeing that viruses were really pretty
well-inhibited by antiserum to the Panama vaccine strain. Then we started seeing an increasing
proportion of viruses which were poorly, relatively poorly, inhibited by
antiserum to the vaccine strain.
I've
shown a number of these viruses in green here, and I will be mentioning them
later because all of the viruses shown in green here have two amino acid
changes that we have been watching very carefully. They have changes at amino acids 155 and 156. These amino acids are located in antigenic
site B of the hemagglutinin.
So,
just to emphasize a couple of points, we have viruses that are low reactors and
have these signature sequence changes from the United States, from Japan, from
Korea, and from China. So we have a
number of isolates from the United States.
It started out that we had isolates from the West Coast and from Hawaii,
and now we've got isolates from other parts of the U.S. as well.
This
is a frequency table for the antigenic analysis that we've done. You'll see that we've so far characterized,
antigenically characterized, a total of 110 influenza A H3N2 viruses that were
isolated between October 2002 and the present time, and approximately 33
percent ‑‑ sorry, 30 percent ‑‑ of these viruses are
reduced in titer by fourfold or greater with the Panama antiserum as compared
to the homologous titer.
If
we look back at the previous period ‑‑ that is, April 2002 to
September 2002 ‑‑ about 11 percent of the viruses were low
reactors. We haven't done this, but if
we were to split this time period out even more finely, we would see an
increasing proportion in the most recent months, but the numbers are relatively
small compared to those shown here.
Now
we'll move on to the evolutionary tree for the hemagglutinin genes of the H3N2
viruses. Please note that the sequence
for the Panama vaccine strain is located here on the evolutionary tree. I neglected to mention before that, when you
see amino acids and numbers, when you see letters and numbers like this, this
means that an amino acid at this particular position in the hemagglutinin has
changed, in this case from malinin to valine.
We look at both the number and the types of changes that are occurring
along the evolutionary pathway of these strains.
What
I would like to mention is that the viruses that I mentioned that have both the
155 and 156 changes are shown here at the top of the dendrogram in red. They are clustering together, and you'll see
that we have a number of viruses from China, from Korea, from the U.S.,
Washington, Georgia, Tennessee, Massachusetts, and so on, all of which have
this particular change.
Please
also notice that there is a tendency, but not an absolute finding, that viruses
that have both of these changes are low reactors. So we do occasionally see viruses that are in this genetic group
that are well-inhibited by antiserum to the Panama strain, but, generally
speaking, these viruses are poor reactors with antiserum to the Panama strain.
I
would also like to mention that this group has really developed out of a group
that was identified about two years ago as it emerged in China. We noticed that there were viruses with a
number of conserved amino acid differences from the previous strains that were
conserved among this group.
So
we were watching this so-called China group quite carefully. It wasn't until at the end of January when
we saw that there was really much more consistency in viruses that were within
this genetic group overall, but then had this additional change, but we were
seeing that they were low reactors.
We
still do have viruses that are located in this part of the dendrogram that are
without these changes here, but there really are a striking number of changes
between this part of the dendrogram, a striking number of amino acid changes
between this part of the dendrogram and this part of the dendrogram. Of course, because of the fact that H3N2
viruses cause more significant mortality than viruses H1 or B viruses, we
always watch these changes particularly carefully.
I
have simplified the neuraminidase inhibition test that we have for N2. I've really focused on the H3N2 viruses
here. We haven't tested a lot of
strains, but these are the results that we have that demonstrate that H3N2
viruses, these two viruses can't be distinguished from our reference here.
These
viruses are inhibited well by all of our reference sera that we tried. Again, I would like to provide the caveat
that these ferret sera are not ideal sera for this type of testing, but this is
the best that is available worldwide.
So
now we look at the N2 dendrogram. So
this dendrogram shows the relationships among the N2 neuraminidase genes, and
you can see that there are two different groups here. What I would like to mention is that the viruses that we are
seeing with the 155/156 change are also clustering in terms of their
neuraminidase. This is a simplified
tree that doesn't have many of the recent strains on it, but we actually have
sequenced them and they're clustering together in this portion of the tree.
So,
in summary, I should mention that H3N2 viruses haven't circulated terribly
widely in North America. However, they
have caused significant recent outbreaks in Japan, Korea, and China. An increasingly proportion of the most
recent H3N2 isolates are not well-inhibited by post-infection and
post-immunization antiserum, and Roland will be presenting the
post-immunization results.
H3N2
viruses with amino acid changes at both 155 and 156 in site B tend to be poorly
inhibited by antibodies to the vaccine virus, and low-reacting viruses with
these changes have been detected in Asia, Europe, and the Americas.
I
should also probably mention that our colleagues in the UK have similar
findings in that at the WHO Collaborating Center in London they found that the
most recent viruses that they had received from Europe are really quite poorly
inhibited by antiserum to the Panama virus.
Okay,
so now we will be talking about influenza B viruses, which are also complex but
perhaps not so troubling as the H3N2s.
We have here a simplified HI table for influenza B viruses. Please recall that we have two very distinct
lineages of influenza B viruses circulating in the world. This has been true now since 1989, and we
have been tracking these two separate lineages.
Our
vaccine virus represents this lineage here on the right where we have the
Shandong/7, Hong Kong/330, and Brisbane/32 strains. The previous vaccine strain was Sichuan/379, and we really don't
see very many Sichuan/379 strains circulating worldwide. In the most recent tests we do have a few
viruses. We have here two from China
and from Texas that belong to this older lineage that's almost been displaced
in North America by viruses from this lineage.
I
will show you a little bit more about the evolutionary relationships between
these viruses, but suffice it to say that antigenically these viruses are very
easily distinguishable. There is not a
great deal of cross-reactivity when you look using post-infection ferret
sera. So they are very easy to
distinguish.
Because
these viruses represent a really minor part of the influenza B viruses that are
circulating, we'll concentrate most of our time discussing viruses on the
right. What I would like you to note is
that Shandong/7 and Hong Kong/330 and Brisbane/32 are all actually Hong
Kong/330-like viruses.
So
if you look at these viruses, there really are not any more than twofold
differences. When you look at these
viruses themselves across the row, and it doesn't matter how many antisera we
put in there, you probably noticed this from your tables, but you can't
distinguish these three viruses using any of the post-infection ferret sera
that we have developed. So these are
really antigenically indistinguishable from each other.
But
when you test the antisera to these viruses with currently-circulating strains,
you do see some differences. This is
something that we noted starting last year in about April or May, round about
that time, as more and more influenza Bs came in to be tested.
And
we noticed that there were a number of these viruses that are circulating that
weren't as well-inhibited by the antiserum to these reference strains,
Shandong/7 and Hong Kong/330, even though these viruses couldn't be
distinguished among themselves. We
noticed that the Brisbane/32 antiserum really inhibited most
currently-circulating strains well.
I
need to call your attention to this column on the right. I don't know if you recall or not, but we
had noted that many of the influenza B viruses that were circulating late last
season were actually reassortants between the two different lineages, and it
becomes a little bit confusing, but I hope that we can clarify any questions
that you may have about the HA-NA combination of the viruses that are
circulating.
The
bottom line is that the majority of the circulating strains have Victoria
lineage hemagglutinins and Sichuan lineage neuraminidase. Our current vaccine strain has a
Victoria/Victoria combination. It's
even getting me confused.
So
if we look at the frequency table for the antigenic characterization of the
viruses that have been isolated most recently, that is, October 2002 until the
present time, we see that we do have a number of viruses which are low to the
ferret serum made against the Hong Kong/330 reference strain. However, those viruses were all
well-inhibited by antiserum to the Brisbane reference strain. We have been calling these Brisbane-like
viruses, but please remember we couldn't antigenically distinguish the Brisbane
virus from the Hong Kong/330 virus. So
it is a bit of hairsplitting that's going on here.
We
saw only a small proportion of viruses, about 6 percent of viruses, that were
Sichuan-like, and that's down just a bit, you know, probably not significantly
from the 8 percent that we saw during the Southern Hemisphere influenza season.
So
I just wanted to give you some of the overall topography of how the
hemagglutinin genes of viruses from the Sichuan or Yamagata lineage and the
Victoria lineage are related. So the
hemagglutinins are really quite distinct antigenically and genetically. They are really quite distant when we're
talking about genetic distances.
But
we'll first focus on the viruses that are on the Sichuan or Yamagata
lineage. There are two subclades. We won't need to spend a lot of time on
this, but there are two subclades.
We're seeing that the most recent viruses are peppered through both of
these subclades. But, remember, this is
a very, very small proportion of viruses that have circulated recently.
This
Victoria lineage dendrogram really represents the majority of what we're
seeing. One of the things that I would
like to emphasize is that we're seeing actually very little genetic differences
among the currently-circulating influenza B hemagglutinins. So whether we're looking at viruses from
Texas or Argentina or Thailand, there really are not great differences and
sometimes no coding difference, only silent mutations, among these strains.
So
the Victoria lineage hemagglutinins are really remarkably stable when we
compare them to the other virus groups that we have been looking at, but I
should mention that our vaccine strain is on this lineage, on this clade here,
and the majority of viruses are here.
We can't distinguish those two subclades antigenically, however. I should mention also that low reactors are
peppered through, and those are all the viruses that are well-inhibited by the
Brisbane antiserum.
In
order to really keep up fully with what is circulating, we do a lot of
restriction analysis of the hemagglutinin and neuraminidase genes of influenza
B viruses, just as we do for the H1N1 and H1N2 viruses, because we really want
to have a full picture of what's circulating.
So
we're able to separate the Sichuan-like viruses, the viruses that are
Sichuan-like antigenically, into two genetic groups, and they are reflected
here. Then we have the Hong Kong/330
lineage and what we call Oman or the Shandong lineage. So those are just those two subgroups that I
showed you on the dendrogram that I just got done showing you.
We
have also been doing neuraminidase inhibition tests on the influenza B viruses,
and the bottom line here is that we can distinguish the neuraminidase of the
viruses that have the Victoria lineage neuraminidase basis from those that have
the Sichuan lineage neuraminidase. That
is shown quite clearly here with the blocking in color.
So
these are viruses that are in the Sichuan, that have neuraminidase in the
Sichuan lineage, ferret antiserum against viruses with Sichuan lineage
neuraminidase, and vice versa. So we
can distinguish the neuraminidase of these two lineages.
Here
is how the neuraminidase genes of these two lineages are related to each
other. So these are the Victoria
lineage neuraminidase. These are
Sichuan lineage neuraminidase, and there are a number of conserved amino acid
changes in these two groups.
So,
in summary, I would like to say that influenza B viruses are predominating in
the U.S. and much of Europe. Influenza
B viruses on the Victoria lineage have predominated worldwide, and viruses on
the Sichuan lineage have continued to be isolated, but relatively infrequently.
The
most recent influenza B viruses have neuraminidase that are most closely
related antigenically and genetically to that of the Sichuan reference virus,
and influenza B viruses have remained quite stable since last September, when
we had the WHO vaccine consultation and recommendations for the Southern
Hemisphere, which Roland already mentioned to you. At that time the WHO recommended a Hong Kong/330-like virus.
Okay,
I think I'll close there and entertain any questions.
CHAIRMAN
STEPHENS: Thank you very much, Dr. Cox.
Questions? Dr. Couch?
DR.
COUCH: I have more questions. Nancy, would you explain to me why the
A/Johannesburg H1N1 is on our chart? Is
there some background of that one that's worth knowing? A/Johannesburg was at 96?
DR.
COX: No, those viruses have been
displaced, as far as we can tell, completely by the Beijing ‑‑
sorry, by the New Caledonia viruses.
So, in other words, the H1N1s had diverged. There were two very distinct lineages, one of which was
circulating in China and the other in the rest of the world. The Johannesburg virus was an old vaccine
strain, and it represents a group of viruses that has not been detected for
probably a year and a half or two years.
DR.
COUCH: So it's just being carried as a
reference strain? It's quite different
from New Caledonia?
DR.
COX: It's just carried as a reference
strain. That's right. We extracted it from a larger table.
DR.
COUCH: I see. Well, it stood out, so I wondered why we needed to know that.
DR.
COX: Yes, sorry. It went quietly by the wayside.
DR.
PALESE: Peter Palese.
Basically,
I think a major issue today will be in terms of the choice of H3N2 virus. There it really depends on knowing what has
happened over the last recent past.
One
of your first slides actually shows a number of strains which have been
obtained from the collaborating laboratories.
If you look at the Y axis, there are about 500 isolates. A large percentage of those are unsubtyped,
or at least that's what I understood, if there was a yellow part of that
column.
So
you mentioned that a large percentage is B now, and maybe you can show it. I think it was the second slide you had.
So
the creation really is, since we don't know what these unsubtyped viruses are,
and you called them A viruses, how difficult would it be to find out what kind
of H3N2 viruses these are, and would that be helping? These are quite a lot of viruses ‑‑
DR.
COX: Right.
DR.
PALESE: -- which are unsubtyped.
DR.
COX: Yes, that's true. The viruses come in to us from state health
laboratories and a number of other hospital laboratories, and so on. The percentage of viruses that are subtyped
depends on the capacity of those local labs to subtype.
I
would just like to make mention of the fact that CDC has been providing funding
to the state health departments and other collaborating labs to increase the
percentage of viruses that are subtyped.
Now what we have been doing at CDC is to actively call the states that
have H3N2 viruses reported, and we have solicited viruses from them.
DR.
PALESE: So this is exactly the ‑‑
DR.
COX: So when I left, yes, when I left
yesterday, I had a log-in sheet stack, a stack of log-in sheets this thick
(indicating) of viruses that had come into CDC since last Monday or Tuesday. So we have received a large number of
viruses from the U.S. and also some from abroad that have not even been
inoculated yet. So we will have data as
quickly as possible, and there will be additional data forthcoming.
So
I hope that answers your question.
DR.
PALESE: Yes, because if you look at the
tip which is red, we are supposed to make a decision on H3N2 viruses of very
few isolates, which is the H3 and which are the H3N2 viruses, but there is
still a large percentage out there over the last several weeks, which are
yellow, and I think they should have given some more information probably.
DR.
COX: I think, as I said, that we will
have some additional information. I
would like to emphasize that we also pay a lot of attention to viruses that
come from other parts of the world. These
are just from the U.S., of course.
In
addition to the viruses from the U.S., we want to put those viruses in context
with the larger global picture of what's going around. So what we're trying to do is place these
viruses in the context of the viruses that have been obtained from Korea,
Japan, and China, where there have been more significant ‑‑ I won't
say ‑‑ probably more significant outbreaks of H3N2. Then we're trying to, of course, analyze as
many from the U.S. as we possibly can.
It's
a very good point, and we are doing the utmost to try to assist the states, so
that they can subtype efficiently. So
the kinds of support that we're providing includes support for personnel to
actually do the lab work.
CHAIRMAN
STEPHENS: Dr. Dowdle?
DR.
DOWDLE: Nancy, I wonder if you have
information on the newer strains. Many
of them are not inhibited very well with the reference strains. But, on the other hand, how many of these
actually have low homologous reactions as well, or have you had a chance to
look at them?
DR.
COX: We don't know. We have three more viruses in ferrets. We'll have the testing done next Monday,
either Sunday or Monday.
What
I can say is that the Fujian virus had a very nice homologous titer. It had a homologous titer of 1280, and
that's reflected nicely in the package of information that you got, which is
more complete than what I showed in my slide.
But
I think the fact is that we had a very nice homologous titer, and that when we
looked down at the titers against the Fujian antiserum for those viruses that
had the 155 and 156 changes, we saw that there were, generally speaking, quite
good titers. There were other viruses
that we knew did not have those changes that were low.
I
think the thing that perhaps really was a red flag to me as well was the fact
that, if you look at the Fujian homologous titer and then look at the ability
of that antiserum to inhibit the older viruses, you see that the ability just
has fallen away and there are very low titers to those old viruses, indicating
that we may well, indeed, have a new antigenic variant.
But,
as you mentioned, we have to confirm that by using viruses, additional
post-infection ferret sera to well-characterize viruses, so that we can really
get a complete picture and we will be doing retrospective testing of the
viruses that we sequence, so that we can really get a very, very good handle on
what's going on with respect to the antigenicity of these newer strains.
DR.
DOWDLE: And those data would be
available when?
DR.
COX: We are going to have data
available next Tuesday for sure, probably Monday afternoon, definitely ‑‑
not probably ‑‑ Monday afternoon definitely, because we have a WHO
conference call on Tuesday morning at 6:30 a.m.
CHAIRMAN
STEPHENS: Ms. Fisher and then Dr.
Myers.
MS.
FISHER: Dr. Cox, I have two sort of
generic questions. This handout that we
were given, there's a statement that says, "Since September 29, WHO and
NREVSS laboratories have tested a total of 33,901 specimens for influenza viruses
and 1,195, or 3.5 percent, were positive."
Doesn't
that seem like an awfully low percentage there that were positive for influenza
virus? I assume that means that these
individuals were sick with other things that looked like the flu.
I
guess my question is, in your statistics, when people report flu, how do you
know that is actually reflecting flu and not something else?
DR.
COX: Right. There's not a really short answer to this question, but, first of
all, I would like to mention that what we had circulated, what had been
circulated to the Committee previously, was a week older data than what I
talked about today.
What
I talked about today is the figures for week six, which is the figures for the
week ending February 8th. During that
week, which is actually during the influenza season, 20 percent of the
respiratory specimens tested were positive for flu. This is what we will expect during the influenza season. The numbers that are in that report reflect
all of the respiratory specimens that have been collected since October, when
influenza viruses were not circulating.
Now
these respiratory specimens are collected from people with respiratory illness,
and there are many other pathogens that cause respiratory illness. So we don't report on those pathogens
because this Committee is really focused on influenza.
MS.
FISHER: The second question is, why do
you think there was such a predominance of influenza B virus in children that
caused the schools to be closed?
DR.
COX: I'm speculating a bit, but
probably not sticking my neck out very far.
The influenza B viruses that are circulating this year are different
from, quite distinctly different from, the influenza B viruses that had
circulated in the United States for the previous ten years.
What
we knew is that a cohort of young children had absolutely no antibody to these
newly-circulating strains, and we had a very susceptible population. I think that was part of our discussion and
consideration last year, when we choose the Hong Kong/330-like vaccine strain
for inclusion this year. So we were on
the mark in terms of updating the vaccine to include a Victoria lineage virus
because that's what actually happened in the U.S.
MS.
FISHER: Thank you.
CHAIRMAN
STEPHENS: Dr. Myers?
DR.
MYERS: Nancy, I know we're
concentrating on H3N2, but in your table on the H1 there were two recent
isolates that were very different, A/Texas/02 and A/Michigan/208. I just wondered if you would comment on
those because those were both recent isolates.
DR.
COX: Texas? Oh, they must be on another table. They're not on this table.
DR.
MYERS: Line 15 and 17.
DR.
COX: Oh, sorry. So you're saying that Texas/02 is
different? It's actually very
well-inhibited by the New Caledonia serum.
DR.
MYERS: I see.
DR.
COX: So it's not as well-inhibited by
the previous vaccine, serum to the previous vaccine strain.
DR.
MYERS: Right. Nancy, thank you.
DR.
COX: Okay.
CHAIRMAN
STEPHENS: David? Dr. Markovitz?
DR.
MARKOVITZ: Yes. Nancy, I was curious, just so I make sure I
understand this completely, it seems that the H3N2 vaccine is the one that is
going to be the difficult choice, but yet there's been this reassortment with
the neuraminidase with H1 viruses. So
how much attention will we have to be paying to the neuraminidase component
vis-a-vis its protection for the H1N1 or H1N2 when we're trying to pick a
vaccine? I hope that's clear.
DR.
COX: I think that's a good
question. I think that Roland may want
to say something about this as well.
What
we have tried to do is provide the Committee with as much information as
possible about the match and the differences that we're seeing, but I would
like to remind the Committee that the neuraminidase component of the vaccine is
not standardized. So at this point in
the United States a certain amount of hemagglutinin is required to be in the
vaccine, and neuraminidase is there, but it's not standardized in terms of the
quantity that's actually contained, because of the fact that we have considered
antibody against the hemagglutinin to be the primary determinant of protection.
So
what I would say is that it's always prudent to have a good match with the
neuraminidase, but certainly we need to focus the most on the hemagglutinin.
Roland,
did you want to make an additional comment or clarify what I said?
DR.
LEVANDOWSKI: No, I think you stated it
very well.
DR.
COUCH: Well, I want to be sure we don't
lose the question that Dr. Markovitz brought up because it is one that has been
on this table many years, and I almost feel like to continue the plea ‑‑
I've inherited Ed Kilbourne's mantle, which is, of course, not the case.
But
neuraminidase is an important antigen.
Nobody questions the fact, as Dr. Cox has said, that the paramount
antigen is the hemagglutinin, and CDC is to be congratulated, maybe partly as a
result of the urging of this Committee to start including more neuraminidase
data, the relationship, the changes that are going on, in their data that they
present to this Committee because it is an important antigen.
They
have responded in that regard. It
doesn't approach the amount of data we get on the hemagglutinin, but the closer
you get to it over a period of time, the better off we will be, I think.
One
of these days, hopefully, it will be pointing toward that being a component of
the decision of the strain, so that we be sure that the neuraminidase behaves
properly. But the major problem Dr. Cox
pointed out is that right now there is no antigenic requirement for the vaccine
antigens themselves, for incorporating into the vaccine, and that's a whole
different topic, as to if there would be one, what should it be and what kind
of confidence should you have about how it should be made.
But
it's an evolving subject that we certainly don't want to lose and this
Committee should keep hearing about every year, and the kinds of questions that
Dr. Markovitz has raised should continue to be raised.
DR.
COX: I might be able to clarify things
just a bit more. The neuraminidase of
the N1 viruses are very homogeneous. So
that just kind of puts the N1 to rest, I think, unless the Committee feels
differently.
The
N2 viruses ‑‑ sorry, the neuraminidase of the H3N2 variants are in
that little cluster that I pointed out.
We don't have a lot of data on the antigenic relationship of viruses in
that group versus viruses in other groups.
So I think that, because we just got the Fujian ferret antiserum very
recently, and haven't really done a lot of testing, I think that it would be
difficult for us to base our decision very much on the N2 neuraminidase.
We
are relying, of course, on the N2 component of the H3N2 virus to provide the
neuraminidase that would be actually the component for all of the N2s, whether
the H1N2s or H3N2s, if you see what I mean.
DR.
COUCH: Again, could I just make an
additional phrase? I guess if I state ‑‑
maybe Nancy and Roland will agree with me that where we stand right now with
neuraminidase data is being reassured that there's not some major difference in
that neuraminidase that we should have taken into account with a decision.
CHAIRMAN
STEPHENS: Well, that raises ‑‑
DR.
COUCH: Using it positively for making a
decision.
CHAIRMAN
STEPHENS: The question I had regarding
the neuraminidase story has to do with the B strain, and where we're using a
vaccine strain with Victoria/Victoria, yet the neuraminidase is different. Can you comment or, Roland, can you comment
on that difference and its potential meaning?
DR.
COX: Roland, you're going to be presenting
the post-immunization data. I don't
know if you want to comment or not.
DR.
LEVANDOWSKI: Well, I think the comment
would be very similar to what Nancy Cox said related to the H1N1/H1N2. Here again, I think we do have a concern
about the neuraminidase. It is an
antigen that may lend some protection.
We
don't standardize the vaccine for that, however, and we don't really know to
what level the protection is. We don't
have sufficient data, I think, from clinical studies to understand how much of
an impact that has.
The
studies that we do have in the past looking at efficacy and effectiveness for
the most part would have been matching up both the hemagglutinin and the
neuraminidase. I think it's something
that, obviously, we do need to have consideration about, and there is a lot of
work that's going on to look at what the benefit of both manufacturing vaccines
where the neuraminidase is emphasized and also on ways to be able to
standardize both of the components in a way that would not interfere with
production of the vaccine altogether.
Just
to re-emphasize, all the studies that I am aware of, if you have both
hemagglutinin and neuraminidase, it is the hemagglutinin that is predominantly
responsible for the protective immunity, and antibody to the hemagglutinin
alone is protective. That may be true
for neuraminidase also, but I think there is some reassurance in knowing, in
emphasizing the hemagglutinin, and we are not ignoring a very important feature
of the virus and an immunity to it.
CHAIRMAN
STEPHENS: Thank you.
Additional
comments? Dr. Katz?
DR.
KATZ: I would like to go back to Mrs.
Fisher's comment, because as I look through the agenda, this Committee is
obviously focused, appropriately, on the selection of strains or the vaccine. But what doesn't get discussed here is who
is going to receive the vaccine.
When
you talk about why you're seeing school absenteeism, and we're seeing enormous
numbers of children in our clinic with B influenza virus infection because we
don't immunize children ordinarily, and there is an increasing interest at
least on the part of the various advisory committees of including young
children, particularly infants, in the first two years of life as recipients of
influenza virus vaccines.
So
you might see a major shift in the epidemiology if we protect the younger
children, both among them and among the parents and day care teachers and
others to whom they are exposed during the course of their illnesses.
CHAIRMAN
STEPHENS: Dr. Dowdle?
DR.
DOWDLE: Thank you.
Nancy,
on this discussion of neuraminidase, though, I think you pointed out, quite
rightly, that you really need sera that were produced with viruses with
irrelevant hemagglutinins. What are the
plans? Do you have plans to do that?
DR.
COX: Yes, that's a great question. We have produced some of those antisera, and
we haven't in the last perhaps two years, but we had previously. We did run a comparison and we didn't see
differences when we expected to. I
think based on the results that we have for this year, we would probably see
them if we had the reassortants for the currently-relevant viruses.
We
are really considering a number of different approaches to this problem. It can be, as you know very well, difficult
to get out of the mix the reassortant that you want. So we are going to be using reverse genetics to produce the
reassortants. We also have some very
embryonic plans underway to express the neuraminidase as in vacuo viruses or
other expression systems, and to then hyperimmunize rabbits or other animals to
produce the sera.
So
we are definitely thinking along those lines.
It is just difficult to get everything done.
CHAIRMAN
STEPHENS: Dr. Diaz?
DR.
DIAZ: I just wanted to comment that I,
likewise, with Dr. Stephens, was more curious about the neuraminidase in the B
strains and the changes that we're beginning to see. Although we do tend to focus on the hemagglutinin, I think we do
have an opportunity, and we should really work towards, increasing our
surveillance of comparisons not only of vaccine failures and also of disease
occurrence, but also looking at the differences in disease severity, if there
are any, in individuals who have similar B hemagglutinins but different
neuraminidase, the Victoria versus the Sichuan.
I
think it would be important to know if there is, likewise, a difference in
severity that might be yet another reason to think harder about the
neuraminidase components of the vaccine.
DR.
COX: I think those are very good
questions, and they are relevant to H1N2 as well as H1N1 viruses. We have actually tried to devote a
significant amount of time to looking at viruses, influenza viruses, whatever
the subtype might be, that were isolated from severe or fatal cases of
influenza.
To
date, we really have found for those viruses that we have examined that the
viruses simply reflect what is going around, and that we've not been able, in
spite of a lot of effort and looking, to pinpoint any consistent differences
between viruses that cause severe infection and complications in those that
don't.
CHAIRMAN
STEPHENS: Bruce?
DR.
GELLIN: Nancy, can you comment a little
on your response to Dr. Palese's question?
It got back to the surveillance and the state laboratory network of
doing the strain detection. I got the
impression it wasn't as robust a system as I thought it might be, and a sense
of what the volume is and how reliable the states are and whether or not you
routinely confirm everything that comes in or you just take their reports?
DR.
COX: The reports of the numbers that
you see, for example, in the first few pages, that is based on data that is
supplied to us by the states. We only
confirm the results for a small subset of viruses because we couldn't possibly
characterize all the strains that are detected in the United States.
So,
of course, we take the words of the states.
We train them from time to time and provide reagents for them to do this
kind of analysis.
But
it is very clear that the states need more assistance even than we have been
able to provide, and that, especially with respect to pandemic planning and
detection of novel subtypes of influenza, they have a way to go. So this is something that we have been
emphasizing in our efforts to improve surveillance in the United States. We have some goals, but we're, clearly, not
there yet.
DR.
GELLIN: So that implies that
particularly the novel strain, they may be likely to miss something?
DR.
COX: Well, when you look at the numbers
and you see that they are subtyping 70 to 75 ‑‑ or not subtyping 70
to 75 percent of the strains as they go through the season, yes, it could
certainly be possible that they would miss something. I think most of the time that's
not so much of a concern, but if there are new problems emerging, we really
want to do everything that we can to make it possible for them to subtype as
many viruses as possible.
That's
been one of our goals in terms of improving surveillance. As I said before, that's been very much on
the table in our discussions with the states.
CHAIRMAN
STEPHENS: I think we're going to take
our 15-minute break now. I really
appreciate Dr. Cox filling in and thank the panel for the active discussion
this morning.
So
be back in 15 minutes. Thank you.
(Whereupon,
the foregoing matter went off the record at 10:09 a.m. and went back on the
record at 10:31 a.m.)
CHAIRMAN
STEPHENS: Let's go ahead and get
started.
Our
next presentation is by Linda Canas from DOD.
MS.
CANAS: Good morning. The Department of Defense recognizes the
potential for severe disruption of mission and training programs if influenza
illness becomes epidemic within the troops and, in fact, has led the effort for
vaccines in the early days of the influenza vaccine.
The
Air Force in 1976 developed a surveillance program, partly for public health of
the troops, and recognizing that we need this influenza vaccine and we don't
manufacture it. So if we help provide
information that we may have gathered from our own surveillance programs, it
would help those of you decide what should go into it.
This
program has been very successful. In
1997, under the Global Emerging Infection System, this became tri-service, and
it's now handled in that regard.
There's
actually two parts to this program. The
first is population-based surveillance.
This is conducted in San Diego from the Naval Health Research Center,
and they have all of the recruit centers from each of the services. They know the population. They establish a certain number of samples
that should be collected weekly, so they can get a baseline of what's going on
healthwise in those individuals and will be able to tell if there are
outbreaks.
The
second part of the program is etiology-based, and that takes place in San
Antonio in my laboratory. We're out
there; we kind of look for anything that might be there. We don't really care what the population
is. We fondly say, "We're trolling
for bugs."
And
how this works, basically, it is funded by DOD GEIS. They give us program guidance, and in San Antonio we have the
clinical laboratory; we have the epidemiologists, and together with the rest of
the GEIS members in the spring at our annual meeting we decide on who the
sentinel sites will be.
The
epidemiologists make sure they have all the information to know what they're
supposed to do, and the laboratory provides all of the supplies that they need
and instructions on getting the specimens to us.
Now
I need to explain that one of the reasons this program is successful is the
laboratory does not exist for influenza surveillance. We are actually a clinical reference laboratory for all of the
DOD services, and we are based in San Antonio.
We have FedEx contracts that bring in diagnostic samples daily to our
laboratory. So it is very easy for each
of these sites to put throat swabs into the boxes that are coming to us with
PSAs, hepatitis studies, whatever other clinical diagnostic tests they are.
We
handle these as clinical samples in our laboratories. So we are getting samples from other places besides our sentinel
sites, but these are the ones we are especially tracking. We don't disregard any other data. Any flu specimen is fair game for us, but we
especially target our sentinel sites.
When
they get into our laboratory, we set them up the day they arrive, handle them
as clinical samples, according to traditional laboratory methods. We will report back to the laboratory,
submitting laboratory, anything that we isolate, but we are particularly
interested on influenza.
When
we get influenza, besides that information going back to the provider, we also
give it to our epidemiologists, who then send out an e‑mail to the Public
Health Officer at the base, so they have real-time information on what's going
on in their facility. That gives them
knowledge, public health knowledge, of what they're doing.
It
also means they can go to their commander and talk about how well the influenza
vaccination program is going. All
active-duty military are required to be vaccinated for influenza annually.
When
we work up our samples in the laboratory, we do hemagglutination inhibition
subtyping in our lab, and anything from overseas and anything interesting that
we see, we send on to CDC. We also have
our molecular department that does some other sequencing work, and then I get
to come here today and talk to you.
Now
this year we've added another level, and that's ESSENCE. That's the Electronic Surveillance System
for the Early Notification of Community-Based Epidemics, kind of one of those
intuitive acronyms like VRBPAC.
ESSENCE,
in two sentences, to explain a big program, when a military member or his
dependent visits a provider, they are diagnosed according at this point to
seven syndromic groups, one of which is respiratory illness. That is entered into a computer and is fed
to a secure website. This is tracked
across the various MTFs in the country.
Baselines
have been established for each of these syndromic groups. If something should spike, it should be
picked up. Ideally, real-time at this point
in time it's about a two- to four-day lag, as I understand it.
We
actually saw this happen last week in Ohio.
Wright Patterson Air Force Base suddenly peaked respiratory illness
there, not one of our sentinel sites.
They were contacted and asked to send us samples for
characterization. We just got those
into our lab just before I left. So we
will see what we get.
As
it stands now, our sentinel sites, how we choose those, we look for training
sites. These are people that are being
sent from many different areas. They
are going to one place. They may be
bringing their own virus with them.
Sometimes they are very stressed, depending on what they are training
for. We want to know real-time what is
going on public health-wise, and it is also a good opportunity to possibly pick
up a new virus.
We
use those bases on each of the coasts, again, people coming into and leaving
the country, maybe bringing in viruses.
Often those are bases that have missions overseas also. Then all of our overseas bases are sentinel
sites.
Now
in the past few years, under GEIS, we have been able to partner with the Army
and the Air Force to get more remote laboratories. These are laboratories that are doing outbreak investigations in
foreign countries, and they have been able to add protocols to surveil for
influenza-like illness in the local populations.
This
is an added benefit, but it is also an added challenge because, of course, we
are not doing diagnostic studies and we don't have FedEx arrangements with them. So it is much more problematic getting the
specimens to us.
We
did, two weeks ago, get 190 samples in from South America. About a fourth of those were collected
within the last two months. So we're
making some real progress in that.
You
have listed in your handout the various sites.
We do try to cover as much of the area of our responsibility as we can.
In
looking at this year, now this data is based on week collected, and that's
significant because, of course, we're getting them from all over the
world. While most are coming to us
within two to four days, as you see, we have some unfinished specimens clear
back here at the beginning of the seasons.
That's what we got in from Peru just recently.
So
most of them are finished. We've had a
very busy year. It started out from the very beginning, and we've been getting
influenza most of our season.
Most
years we talk about a flu season as being an A season or a B season, an A
trailing to B. In our program, which of
course is global, you can see that in virtually every week since we began
surveiling this year, we've had A and B somewhere in the world.
We
break this down into regions. Dr. Cox
alluded to the H3N2 over in Asia, and we saw that very early. It came up and it has continued and is
increasing. You never know if it's
increasing in numbers or if our participants are just increasing, but we're
getting more and more specimens each week.
So it's certainly not trailing off.
In
the United States we started out early with the B in Texas. Of course, we're in Texas, and we have
several bases in Texas. But Texas has
been one of the hardest hits.
It
has characterized very nicely with the B/Hong Kong in our studies. We don't put our efforts into subtyping into
those isolates in the United States because they are characterized also at
other places, and we have so many coming in from Asia.
We
try to do the first few that come in from any location, and then if it
continues, as it still is in Texas, we go back periodically and pick it up, just
to see if we see any changes there. But
our efforts are spent in those from overseas.
In
Europe and the Middle East ‑‑ now this graph looks fairly dramatic,
but you can see the numbers aren't real big here. But this is changing. We
just started getting samples in recently.
Last week we got in 30 samples from UK and Germany, and it looks like
about a third of those are positive, most of them for B at this point in
time. They just started coming in. But we do have the B/Hong Kong and the A
that we haven't been able to subtype too much.
We do have one now as an H3N2.
If
we look at this about how our season developed, these are areas that we've
actually gotten isolates from this year.
It started out in October again in Asia with the H3N2 and then from
South America.
This
is an interesting point and probably another strength of the program. We have this one A/H3N2 hanging out in New
Jersey, which we sent off to CDC because it was so unusual. In fact, it was so unusual I called and
asked for a travel history and found out the patient had been in China two days
earlier. So this is probably a China
isolate rather than a U.S. isolate. We
started, then, picking it up in Texas, which continued.
Most
of our early work was in Asia, and almost all of it has been H3N2 continuing,
and in the United States we started seeing the H1N1. We've had two H3N2s in the continental United States. Everything else has been the H1N1.
That
continued through until actually the present.
I don't have any February data on this map because it's still being
compiled.
Because
ours is a clinical program and we're getting many different isolates, and
because I know this question comes up, we like to include what else we
get. Of course, it's a virology lab, so
we're only looking for respiratory viruses.
Many providers will send viral and bacterial. So with strep throat, Bordatella pertussis, we're not getting any
of those in this kind of a study.
Now
I need to comment on adenovirus, which of course is nearly 50 percent of the
pie here. That's strictly a military
phenomenon. The recruit centers have a
real problem with adeno. Generally, at
this point it's adeno Type 4. It is a
problem in that population, but it's not spilling out into the general
population.
So
if we take that out, and I've taken it out entirely, there is, in fact,
adenovirus background in the population as a flu-like illness, mostly what we
get after ‑‑ of course, we're looking for influenza. Our case definition is fever greater than
100.5, cough or sore throat, and radiographic evidence of pneumonia or a
provider feeling there's influenza-like illness. So we do mainly get influenza.
But
the parainfluenzas, of course, it's like flu, mainly in the fall or the spring,
we'll pick that up. Enterovirus RSV, if
this were a hospital-based program or a pediatric population, RSV would be a
huge part of this pie, but it's not.
We're not looking for it. It
doesn't transport well. So unless
someone specifically asks for special tests, we don't even look for it.
It
is interesting because one of the problems with flu, of course, and you all
know this, is flu-like illness describes virtually everything. We saw this last year when we had these
reports of going out to test for flu, and if it is not flu, maybe it's
anthrax. Well, that is a little
far-fetched.
Our
sequence studies this year were really quite interesting. This represents all of the sequences from
Asia that were performed in our lab last year.
These are '02.
This
is the A/Panama H3N2 vaccine strain, and from Asia the H3N2 viruses from our
laboratory this year. So there has been
a change, and I think Dr. Cox went over those changes very nicely, of what they
have been, some amino acid changes in that virus.
Our
program this year has been really quite exceptional. I heard that it was a moderate year.
Success
breeds success. So our participants
know that they're going to get results back if they send us specimens. So we've already done almost 2,000 specimens
in our lab alone for this year since October.
We've
had many isolates, most of them coming initially from Asia, and Asia has had
the H3N2 with only a few H1N1s, contrasted in the opposite with the continental
United States being almost exclusively H1N1, with the Hong Kong everywhere,
often in the same place.
It
is not at all unusual; we test everything that comes in for A and B. We have actually had one isolate that has
had both. We have tested every way we
can, and it has both in it. There has
been, we are showing the hemagglutinin variation in those specimens out of
Japan and Korea that we have tested.
Would
there be any questions?
CHAIRMAN
STEPHENS: Thank you very much, Ms.
Canas.
Questions? We'll start at the end down there, Dr. Katz
and then Dr. Myers.
DR.
KATZ: This is an influenza virus
meeting, but you show 49 percent of your respiratory isolates were adeno
4. Until a few years ago, the military
had an excellent vaccine for adeno 4 and adeno 7.
Can
you tell us whether there's any prospect of a new vaccine?
MS. CANAS: I will refer that to Dr. Diniega.
DR.
DINIEGA: That's a very good
question. As you well know, the
manufacturer for adenovirus vaccine types 4 and 7 ceased production in the
mid-nineties, and we ran out of any vaccine in about 1998. Since then, last fall, in September we let
another contract with a new manufacturer.
It is estimated that it is going to take four to five years to get to
vaccine production and licensure.
DR.
KATZ: With the intention of reinstating
the previous vaccine program?
DR.
DINIEGA: In fact, the previous vaccine
program, it was being used by two services.
All the services will be using it the next go-round in all recruit
centers.
CHAIRMAN
STEPHENS: Dr. Myers?
DR.
MYERS: When you look at your
dependents, does that change the distribution of Bs? Are a lot of those Bs coming out of Texas in dependents?
MS.
CANAS: I don't know that we've looked
at that specifically, but glancing through it ‑‑ I mean, I can't
give you statistics, but out of Texas, yes, they have mainly been dependents.
CHAIRMAN
STEPHENS: Dr. Palese?
DR.
PALESE: I just wanted to know how many
of your isolates ‑‑ the H3N2, we have Fujian-like. Of all the isolates, it looked to me like it
was 40 percent on that one slide you had in terms of the 2002-2003 isolates, is
that correct?
In
other words, the question is: Can you
guide us? Can you help us in terms of
making a decision whether there should be a change and whether that should be
an H3N2 Fujian-like virus for the next year?
MS.
CANAS: We do kind of a first cut in our
laboratory. We use the rabbit antisera,
which does not merely give us the breakdown.
So we're only looking, as far as H3 goes, from Panama and Sydney, I
think. Then we send them on to CDC,
where they put them in a ferret antisera.
So I can't answer the Fujian question.
DR.
PALESE: But you said you had sequences.
MS.
CANAS: We have sequences that show
there has been this change, and I believe that's probably consistent with the
Fujian.
DR.
PALESE: Have you sent all your isolates
on to CDC?
MS.
CANAS: Yes.
DR.
PALESE: So they have all your samples?
MS.
CANAS: As of last week.
DR.
PALESE: But they haven't analyzed them,
is that correct?
CHAIRMAN
STEPHENS: Dr. Cox?
DR.
COX: Yes, perhaps I can help out with
that. We communicate very frequently
with Linda and folks in her group. They
have provided some very, very useful information to us.
For
example, you might have noticed on some of my slides that we are sharing not
only viruses, but sequences, and so on.
So in my sequence slides I had B as B/Brooks Air Force Base. That indicates the sequence that was shared
with us by Linda's group. So we're
compiling that data together. Yes,
indeed, viruses obtained through military surveillance in Japan and Korea have
those changes, the 155/156 changes.
Did
you say we just had another shipment? I
mean, we're working on ‑‑ we've had a number of shipments from
Linda, and we're working on some additional strains.
MS.
CANAS: Yes, last week was the last one
we have sent so far.
DR.
COX: Right.
MS.
CANAS: We try to get those out as
quickly as possible, for obvious reasons.
CHAIRMAN
STEPHENS: Thank you. Thank you very much.
We'll
move on now to a return appearance from Dr. Levandowski.
DR.
LEVANDOWSKI: Okay. Sorry, but these are going to be
overheads. I hope they are going to
project well enough that you can see them.
There aren't too many people all the way at the back of the room, but I
will try to describe what is up here.
What
I'm going to attempt to do is to really summarize the information we got from a
number of different centers. We haven't
distributed all of the raw data from the centers because that seems to be a
little bit overwhelming sometimes. What
I am going to try to do is distill this down into some manner that might make
some sense about what's going on with current vaccines.
This
first overhead that I've got here shows the serum panels that we have available
to us for serologic studies. You can
see that there are four separate sets of serum panels from both adults and
elderly from different continents. We
have them from Australia, from Europe, from Asia, and also from North
America. That's represented by
countries, Australia, Japan, the United States, and several countries in
Europe.
The
vaccines used for the immunization are shown here, and I mainly would want to
call your attention to the differences in the B components of these
vaccines. There have been three
different strains actually used for a B/Hong Kong/330/01-like strain, including
actually the B/Hong Kong/330, the strain itself. That's not represented in these serologies. The surrogate strains are B/Shandong/7/97
and B/Hong Kong/1434/02.
In
Australia, the vaccine that was being used there at the time these studies were
performed was their previous vaccine.
They now also are using a B/Shandong/7/97 strain in their vaccine, but
these sera were collected last summer, before that was available. So it's the previous year's vaccine strain,
which was, if you remember the term that Nancy used about a
B/Sichuan/379/99. I am going to try to
be consistent with these names to try to help make a little bit of sense out of
all that.
All
of these vaccines, no matter where they were, include the New Caledonia/20/99
H1N1 and the Panama/2007/99 H3N2. The
laboratories that participated in testing these sera include the WHO Influenza
Center in Melbourne, Australia; the National Institute of Biological
Standardization and Control in London; the Centers for Disease Control and
Prevention in Atlanta; the National Institute for Infectious Diseases in Tokyo,
and our lab at the Center for Biologics in Bethesda. These labs all share these sera, and they represent about 200
pairs of serum from different people.
They
have been used to ‑‑ the sera actually are very valuable, and the
quantity is not infinite. These have
been used to support both Northern and Southern Hemisphere influenza vaccine
recommendations. Generally, it means
testing somewhere between 10 to 20 new antigens by each of the laboratories, to
the extent that that's possible to do for each of these cycles of
recommendations.
So,
wherever possible, the potential vaccine candidate strains have been used for
testing, and that really means some emphasis on egg isolates, but there's also
an emphasis placed on strains that appear to be different by their antigenic
characterization using the monospecific ferret sera. Of course, when there are that number of antigens, logistics, and
everything else, it is not always possible for every laboratory to test every
strain, but there is an attempt to share at least some of the different
influenza viruses so that there can be some comparison made between the results
at different laboratories and get a measure of confirmation.
Can
we get the next overhead? This overhead
shows the H1N1 antigens that were used for serological testing. As I mentioned, not every one of these
antigens was used in all laboratories.
That's, again, because the amount of serum that's available needs to be
conserved somewhat, and more emphasis was placed on testing the H3N2 and the B
strains this year. So there are
relatively few antigens that we were testing at this point for the current set
of recommendations.
As
Nancy Cox has already mentioned, most of the H1 strains were actually H1N1, and
they are very similar to the vaccine strains.
So that we tested fewer antigens that would fall into the sort of
typical category and more antigens that fall into the less common category.
Among
those recent isolates ‑‑ this may not be entirely reflected in the
information that we have presented to this point ‑‑ there are some
differences between the laboratories working with these strains, but I have
tried to indicate strains that have been identified as being H1N2 strains with
an exclamation point and strains that have been at least in some of the
laboratories low reactors in the ferret antiserum testing shown here.
So
if we can go to the next overhead? What
I am going to try to do is give you some examples of the serologic results, and
then at the end I will try to summarize kind of overall findings, if I can do
that.
This
overhead shows results that were obtained with a panel of sera from adults in
Australia, and the testing was done with the same sera at either CDC or the
Center for Biologics. This table and
the other ones that I'm going to show that are like it will include data on
geometric mean titer pre- and post-immunization, the percent of the individuals
who had titers greater than 32 or 40 between the pre- and post-immunization and
the percent of individuals who had fourfold rises. I'm really going to concentrate mainly, however, on the geometric
mean titers and comparisons of those.
The
strain, the vaccine strain, for these studies, of course, was the IVR‑116
reassortant New Caledonia virus, and that was also used for testing the
antigens in these particular serologies.
Generally, I think we could say that the vaccine used was immunogenic
and it produced a reasonably good, homologous antibody response.
You
will notice that there is variability in the actual absolute titers from
laboratory to laboratory and also between the different subtypes. That relates somewhat to some differences,
technical differences, in performing the hemagglutination inhibition antibody
test, but I think you will also see that we often have, in spite of that, have
fairly good correlation between the results, as shown in this particular
instance.
Although
the more typical strains here are represented by A/Massachusetts/5/02, there
were some strains that were less well-inhibited in testing done at CDC. For example, the Canada/649/02, this was an
H1N2 strain, and the Peru/3090/02, which is a low-reactor strain.
You
can see that in this instance the Canada strain seemed to be reasonably
well-inhibited by post-immunization after sera, but the Peru low reactor was
not. We didn't see that in testing at
the Center for Biologics, but, again, as I mentioned, we sometimes see some
differences between the laboratories.
If
I can get the next overhead, this next overhead is going to show results from
serum that were obtained from elderly individuals in Europe. Testing was done at the WHO Influenza Center
in Melbourne and at the National Institute of Biological Standardization and
Control.
Here
again, in this instance, in testing in Australia, the A/Massachusetts strain
looks pretty similar to the vaccine strain, but there's a quite substantially
reduced response to both the Canada H1N2 and the Peru/3090 low-reactor strain. That's reflected for the Canada H1N2 strain
in testing done at NIBSC.
This
strain, Dakar, is one that was more typical, but, again, there was some
reduction that was seen in testing in that laboratory. That's actually the only laboratory that did
testing with that strain. So we don't
have a way to confirm that. So I will
cover in a more general sense summary information from serologies for H1N1 in a
few minutes.
The
next overhead, I'll move on to H3N2 influenza viruses, and you see there were a
lot more strains that were tested here.
These include a number of strains that are more representative of the
current vaccine strain, the A/Panama/2007/99 strain, and it also includes
viruses that were circulating in both the Northern and the Southern Hemispheres
during the last year.
I've
tried to indicate, and I'm not sure I've been entirely successful because I'm a
little bit confused about which of these strains have a single amino acid
substitution at position 155 in the antigenic B site and which have two. I believe this is probably incorrect. Nancy will have to help me out. The Shiga/41, is that 1 or 2?
DR.
COX: One.
DR.
LEVANDOWSKI: One? That's one, okay. So maybe I'm okay.
But
there are some strains that have only a single amino acid substitution in that
general site, and then there are a number of strains that represent the H3N2
viruses that have both of those amino acid substitutions that Nancy Cox was
telling us about, and I have indicated those with two exclamation points.
So
next overhead, please. This one shows
the results, again, from a panel of sera from adults in the United States
testing at the Centers for Disease Control and also at the National Institute
of Biological Standardization and Control.
There
are a number of antigens that were used here.
A/Panama is the vaccine strain, and it was also used for serologic
testing at CDC.
I
think this asterisk is wrong at NIBSC.
I believe that they were using the wild-type strain for their
testing. I'm not sure that that's
really critical.
The
A/New Jersey/4/02 strain is one of those that had the single amino acid
substitution, and these others, Korea ‑‑ let's see, Guam I think
also is a single amino acid substitution, but Korea, Beijing/301, and
Fujian/411 are all strains that had the double amino acid substitution.
I
think what you can see here is that, as compared to Panama, these double
substitution and some of the single substitution strains are showing reductions
in inhibition by current vaccines, as seen both at CDC and at NIBSC. Although the reduction here isn't quite as
marked, there still is something different as compared to the vaccine
strain. This Paris/207 strain is,
again, another one of those more typical Panama-like strains.
So
next overhead, please. This overhead
shows results from elderly in Australia, testing done at the Center for
Biologics and WHO, Melbourne, and some of the same strains here.
We're
not showing much of a difference between the single amino acid substituted
strains and the Panama strain, and A/England, again, is another recent, I think
it's a recent Panama-like strain. I'm
not entirely sure that I'm correct on that, but I believe that it is.
Other
recent typical strains like Hong Kong/1550 have been quite good antibody
responses as compared to the vaccine strain, but, again, looking at these
strains as tested at WHO Melbourne for those strains that had the single or
double substitution, I guess Osaka/70 and Korea/770 are the double
substitution, amino acid substitution; Shiga is the single.
You
can see here that they are also picking up reductions in antibody titers for
those strains. So I'll cover that again
more in summary form toward the end.
So
now the next overhead will show the antigens, the B strains that were used for
serologic testing. You will recall that
there are two hemagglutinin and antigenic lineages that are circulating. The older vaccine for us was the
B/Sichuan/379/99-like, and strains that fall into that category are indicated
by exclamation points. For the
serologic testing we're currently using a typical strain. The Shanghai/361 was chosen.
The
rest of these strains would fall into the category of being B/Hong
Kong/330/01-like, and there were a number of those that were picked up again
from fairly diverse geographic locations for testing.
All
of these serologies that I am going to show you will have been done with
ether-extracted antigen.
The
next overhead, this one will show some studies for sero collected from adults
in Australia and testing at CDC and the Center for Biologics.
In
this particular instance, the vaccine strain was the Victoria/504/2000. I think you can see that reflected ‑‑
I only put this up as a reminder of what we were seeing last year. You can see reflected that, using that as
the vaccine, you get very good responses to the Sichuan/379/99-like strains,
when it is tested, but you get very low results to the B/Hong Kong/330/01-like
strains. This is something we have been
seeing for quite some time. So this is
just sort of a reminder and not real critical information.
So
in the next overhead, looking at another serum panel from the United States in
the elderly, and again looking at different laboratories with these sera and a
battery of antigens, the top three here actually represent the going vaccine
strains. The particular vaccine strain
used for these studies was Hong Kong/1434/02, which is underlined, but there
were some other more recent strains that were tested.
Actually,
it appears from these studies that, for the most part, the responses against
the more recent strains, including B/Brisbane/32/02, are reasonably
well-maintained against the hemagglutinin.
I think that fits with what Nancy was saying about not being able to
distinguish those strains so much.
Plus, here the results are a little bit different from ferret serology
in that individuals had been exposed on multiple occasions either to vaccine or
to wild-type viruses.
So
these individuals also have pretty good responses to the other lineage of HA
lineage, partly because of their ‑‑ well, because of their previous
responses or their previous experiences with influenza B viruses. This, too, we had seen before with some
other clinical studies. So that is not
really news.
Let's
see, we can move on to the next overhead.
So I'm going to try now to summarize a little bit about what was found
at all the different laboratories contributing, to the best of my ability.
These
tables that I'm going to show you are going to try to give you a frequency
where new test antigens were 50 percent or greater reduced in geometric mean
titers compared to the vaccine strain.
We used 50 percent as a somewhat arbitrary measure, but it is quite a
substantial difference, and a twofold difference on a geometric mean titer is a
pretty reasonably big difference in this kind of study.
What
I have also tried to do here is to emphasize, as best I can, where there are
multiple labs tests, but sometimes that's not possible. So I've also included some representative
viruses that were tested maybe only in one or two of the laboratories.
So
all of the viruses here again are New Caledonia-like, and the A/Massachusetts
strain is the one that represents the 95-plus majority of all the H1N1 strains
that have been isolated, and I think you can see that really there is very
little, if any, difference between the results that were found for that
particular strain and the current vaccine strain.
For
the Canada H1N2 strain, however, the majority of the serological tests were
reduced. More than half of the tests
done by the different laboratories were reduced. On average, this reduction, looking at all the information from
the laboratories, looking here, it was more than 60 percent reduction, which, again,
is quite substantial. But it was a
fairly wide range between approximately 40 and 80 percent reduction in the
individual tests done by the laboratories.
For
the other H1N2 strain, this Yokohama/22, the one laboratory that was testing it
found it to be very similar to the vaccine strain. I put that up there just to give you some idea that there may be
differences also between these H1N2 strains and how they perform and the human
serologies.
Results
for this low-reactor Peru was done in multiple labs. Again, there was some variability, but a fair number, almost half
of the tests done, showed more than a 50 percent reduction in the post-vaccine
geometric mean titer. But, again, there
was a fairly large range, and overall you would say that, if you just would be
willing to take this at face value, it's kind of a moderate difference.
For
the A/Yamaguchi/12/02 strain, that was tested by a single laboratory. Again, it showed substantial reductions in
that laboratory, possibly consistent with it being one of these low reactors,
which may not be typical of the majority of the strains.
So
on the next overhead, trying to summarize the results with the H3N2 viruses,
and the more recent strains shown in this table with the single amino acid
substitution at position 155, the New Jersey and the Guam strains appear to be
relatively well-inhibited by the current antisera as compared to the vaccine
itself. The Hong Kong strain is one of
the more typical Panama-like strains, and it also seems to be well-inhibited.
Amongst
these strains at the bottom, which have this double ‑‑ or that have
the amino acid substitution at both positions 155 and 156, they appear to be
much less well-inhibited. Here, again,
the majority of these results from all the laboratories that were testing ‑‑
and, again, we sometimes have only one lab that tested ‑‑ but it
seems to be consistent across those strains and also pretty much across the
laboratories that the current vaccines don't seem to cross-react all that well
with significant or substantial reductions in antibody responses to those newer
antigens.
So
I will move on. So the overall picture
for the H3N2 viruses is really different from what we are seeing with the H1N1
viruses, and I guess these results would suggest, where there is this clade
developing for the amino acid substitutions at position 155 and 156, we might
expect to see a lack of inhibition with the current vaccines.
So
this final overhead shows some summary results for influenza B strains. Again, the B/Shanghai/361 strain belongs to
the Sichuan/379/99 HA lineage, but all the other strains that are shown here
are part of the current vaccine lineage.
They're Hong Kong/330/01-like.
Interestingly
enough, all things considered, most of these viruses appear to be pretty
similarly inhibited by antisera from the current vaccines. I'm not showing that the current
Sichuan/379/99 vaccines do not go back the other direction. There's not a cross in the back direction. The Sichuan/379/99 strains do not produce an
antibody response that cross-reacts well with Hong Kong/330-like strains. I think I have already mentioned enough
about that. So we can take the overhead
off.
In
summary, I would say that the vaccines used for these clinical studies appear
to be immunogenic in the populations that were tested. As usual, the serologic studies are
consistent with antigenic drift that's occurring. I would say that the results are most suggestive of antigenic
drift for the H3N2 virus strains, particularly for those strains in the cluster
that had the substitutions at position 155 and 156.
I
think I can stop there and take any questions, if there are any.
CHAIRMAN
STEPHENS: Thank you very much.
Dr.
Decker?
DR.
DECKER: I have two questions. The first, the simplest one, could you just
refresh what Nancy might have said earlier?
When is the WHO having their next meeting to consider H3N2 selection?
DR.
LEVANDOWSKI: Right. The WHO has indicated that it is going to
reconvene on February 26th to make their determination of what direction they
Are going to be going in terms of the H3N2.
DR.
DECKER: Thanks. And the second ‑‑
DR.
COX: Maybe I just need to clarify that
a bit. I think that there's going to be
a couple of points at which a number of the WHO consultants touch base. The final recommendation from WHO will occur
on March 14th. I think it is going to
be published on March 14th.
DR.
LEVANDOWSKI: I think that's the
publication date, but ‑‑
DR.
COX: Right.
DR.
LEVANDOWSKI: -- I think the press
release also mentioned doing something on February 26th.
DR.
COX: We'll have a conference call and
we'll be touching bases about additional data that are available from all of
the WHO collaborating labs on Tuesday, February 26th, I guess it is.
But
the recommendation won't be issued at that time. The manufacturers and others will have an update at that time, but
the recommendation won't be necessarily finalized at that time.
DR.
DECKER: The timing of our meeting today
was moved a month back from last year's in order to ensure that we had
available WHO's recommendations when we made ours. With that in mind, what date are you suggesting this Committee
could make a recommendation on H3N2, if it elected not to make one today?
DR.
MIDTHUNE: Karen Midthune, FDA.
We
have been working with our Exec. Sec., Jody Sachs, to find out what date we
could have the poll, Dr. Decker, and I know that Jody's been working on
that. I'm not sure exactly whether
we've nailed down a date.
CHAIRMAN
STEPHENS: I think we're going to come
to this later.
DR.
SACHS: I think this is a little
premature. I mean, there are two
possibilities, March 14th and March 17th, which after the vote we could query
the members and the consultants to see which is best for them, but I didn't
know the public disclosure wasn't going to be until March 14th. So it makes more sense to me maybe March
17th, but, again, this is premature to our vote and our discussion.
DR.
DECKER: That's good enough. I was just trying to get a sense, are we
talking February, are we talking March, are we talking April?
DR.
SACHS: Okay, but we're going to do what
we can for you today, okay?
DR.
DECKER: My second question, Roland, is
more directly on your presentation.
When I look at the minutes from last year's meeting for the flu section,
I note that Item 5 in my summary says, "The Committee requested in the
strongest possible terms that future antibody response data include a pediatric
cohort in addition to the present adult and elderly cohorts."
So,
in follow up to Sam's earlier question, I would like to ask, what steps have
been taken to implement that request of the Committee?
DR.
LEVANDOWSKI: I think it requires
resources in order to get those things to happen. The Committee ‑‑ and thank you for reminding us. We have been reminded about this every year
for probably the past ten years, and we agree strongly that it's something that
we need to undertake.
It
is not a lack of enthusiasm for doing that, I would say. It is difficulty in making sure that our
resources are used for the things that have the highest priority, and I would
have to say that that has not really gotten the priority that I think it
deserves, and that I am sure that you think it deserves, in terms of being able
to do those things.
We
need to have someone out there who can give us some support in terms of
identifying sites where some of the studies might be going on. If we can tag onto some of those other
studies in a way that doesn't interfere with them, that would be one route that
we could anticipate taking.
We
haven't been able to find those kinds of studies going on, however, on a
regular basis, and that is a difficulty for us.
DR.
DECKER: Has Stefen Gravenstein been
unable or unwilling to incorporate pediatric populations into his routine
annual testing that you rely on?
DR.
LEVANDOWSKI: Well, I guess we haven't
really approached it that aggressively with that group. They, of course, have been doing studies for
someone else for a different purpose.
The funding for that, I guess if that other source could contribute to
that some more and would make those sera available, we would certainly like to
have them.
DR.
DECKER: That resource, we'd probably
love to talk about that.
DR.
LEVANDOWSKI: Stefen Gravenstein, I
guess he's mainly involved with geriatric medicine as his background, but I
don't see any reason that it wouldn't be possible at his university to be able
to identify and immunize the population and acquire that, and we would
certainly like to have that, if it were available. I have to say I have not really aggressively pursued that with
that group.
CHAIRMAN
STEPHENS: This was a conversation at
the break, a fairly extensive one.
Nancy,
any comments on the pediatrics?
DR.
COX: We are very keen to get our hands
on pediatric sera. So it's really a
matter of having some kind of a collection of specimens, and we'll be very
happy to test them, as we did in the past, when they were available. We feel that it is a high priority.
DR.
LEVANDOWSKI: Well, could I just make
one more comment about our role in this?
We had at one time at the Center for Biologics a contract for
immunizations that included a pediatric population, and it was a very unusual
pediatric population and very informative.
It
was unusual in that it was very young children. It was children who were in the range of six months to about
three years old. The information that
came from that source was, we thought, extremely valuable because it was very
much ‑‑ because this population is immunologically naive, it was
very much cleaner information and gave a different kind of instruction for
these deliberations.
But,
again, that contract was ended because of funding issues that have impacted FDA
and other government agencies generally over time for what our resources should
go for.
CHAIRMAN
STEPHENS: Dr. Markovitz?
DR.
MARKOVITZ: Yes, I was wondering, just
to go back to the basics of these things, all the data you present are
hemagglutinin inhibition. I'm wondering
what the current view is on how well that actually correlates with protection,
and do you do some neutralization assays also?
DR.
LEVANDOWSKI: Well, the correlation with
protection is what's published. There
are a number of studies that were done in years past. Those studies haven't been repeated on a very regular basis, but
there is some information along those lines also. I think I'm going to ask Dr. Couch to comment on this because his
group is involved in doing some of those studies to try to correlate antibody
responses to protection.
But
years past, the classic information is probably 30 years old or longer, and was
with a few strains, not very well-generalized but with a few strains, that
suggested that this antibody titer of 1 to 32 or 1 to 40 might be correlated
with protection.
You're
asking about neutralizing antibody.
There are also some studies that were not part of those same studies
that suggest that a detectable neutralizing antibody titer might be correlated
with protection.
We
have studies also where there has been an attempt to correlate the neutralizing
antibody with the HI. You can show that
there is some general correlation between the two, although it's not perfect,
but that hasn't been altogether correlated to protection.
We're
not generally using neutralization antibody testing because it's a much more ‑‑
when we're trying to test 15 to 20 new antigens, it's a very daunting task to
begin with just to do hemagglutination inhibition, much less to try to do all
of that with all these strains with neutralization. We're not actually doing that in our laboratory. Some of the laboratories may be and others
may want to comment.
DR.
COUCH: I guess I don't really have much
to add to that except that the correlate to the anti-hemagglutinin and antibody
in serum is, I think it's well-established.
It's decades old. Its first
demonstration is back in the forties, and it's been, if not annually, almost
annually, demonstrated in studies. So I
don't think there's any question about the correlate.
Actual
cause-and-effect data comes a little bit from animals, but if you start
reasoning ‑‑ and I won't do that now ‑‑ about what we
know about the physiology, the accumulation, the challenge, and things like
that, all of it falls together being sera anti-hemagglutinin and antibodies as
the paramount protective mechanism for influenza. I don't think there's a whole lot of difference of opinion among
individuals about that.
As
Roland said, we have been continuously involved in studies, and each time we do
a study, I mean just off the top of my head, how many times have we found that
correlate in individual studies? Twenty
or 25 at least, I would say, and it's not just us; it's everybody. So that's well-established.
But
neutralization you asked about. We are
probably one of the few groups that's routinely done neutralization tests in
addition to hemagglutination inhibition tests, and it was also a correlate that
follows the same pattern that the hemagglutinin does, depending a little bit on
how you do the test, and I won't get into that.
You
can measure pure hemagglutinin and anti-hemagglutinin in antibody. We do it because we find it to be a somewhat
more sensitive test in general, and we find it to give us an additional test,
and it gives us more detailed data about what's going on in a particular
population.
With
regard to the neutralization test, the European group is currently involved in
considering the possibility of instituting neutralization tests into their
programs of surveillance and decisionmaking, and they have had at least one
meeting, and there is another one scheduled, to try to move forward to
consideration of neutralization and whether there is value there that should
lead to incorporating those tests into the types of discussions that we are
having here. But at the moment it's
just under consideration.
CHAIRMAN
STEPHENS: Dr. Cox?
DR.
COX: I'll just comment very
briefly. I think I can really
corroborate what Bob has said. We find
that the neutralization tests are more sensitive than hemagglutination
inhibition for detecting antibody. So
you get higher titers when you look for neutralization antibody, neutralizing
antibody.
Where
we have looked for differences between strains, we would think that the
neutralizing antibody test might be more sensitive, but we haven't in the past
found them to be so. Nevertheless,
we're going to examine the current H3N2 viruses in neutralizing antibody
tests. I'm not sure exactly when we'll
have those data available, but I believe it's sometime next week.
DR.
COUCH: One of the problems is that
there are different ways to do neutralization tests, and you can do them to
make them very sensitive and then you worry a little bit about specificity. You can increase the specificity, and then
you worry a little bit about sensitivity.
It relates to your substrates, your dose, how you picked your
antigen. There are a whole lot of
variables that go into that to begin to be as well-standardized as the HI test.
CHAIRMAN
STEPHENS: Okay, I think we'll move on
to our next presentation on
availability of strains and reagents by Dr. Ye of the FDA.
DR.
LE: I'm going to present the status of
candidate vaccine strains and their related potency reagents. Current trivalent inactivity in lines of
vaccine strains contain the antigen of two type A strains which are subtype
H1N1 and the subtype H3N2, and one type of B strain.
A/New
Caledonia/20/99 is a current H1N1 vaccine strain. IVR‑116 is a reassortant between New Caledonia/20/99 and
A/Puerto Rico/834. This reassortant has
a moderate to high yield in eggs. At
this time we do not have a new candidate strain for H1N1 influenza A.
A/Panama/2007/99,
which is a Moscow/10/99-like virus, is a current H3N2 influenza A strain. Resvir‑17 is a reassortant between
A/Panama/2007/99 and the A/Puerto Rico/8/34, which has high yield in eggs.
Again,
at this time we do not have a new candidate strain for H3N2 influenza A. However, A/Fujian/411/02-like strains, we
just substitute HA amino acid 155 and 156 were isolated in the middle of
February and are being distributed to collaborating labs this week for
development of high-growth reassortants.
Moving
on to influenza B strains, the current vaccine strains for B as a virus are
B/Hong Kong/330/01-like. There are
three strains currently in use, including B/Hong Kong/330/01 itself, B/Hong
Kong/1434/02, and a B/Shandong/07/97.
All three strains had moderated growth in eggs.
B/Brisbane/32/02
is a strain with B/Hong Kong/330/01-like HA, but B/Sichuan/379/99-like HA in
eggs. Brisbane appears to be low to
moderated growth in eggs.
Now
let's focus our attention on the potency reagents. Antisera and antigen for the current influenza A vaccine strain,
A/New Caledonia/20/99 and A/Panama/2007/99, are available from CBER from
manufacturing. However, if another influenza
A strain should be chosen, new reagents will be needed, but they will be
available in May at the earliest.
For
the current B vaccine strain, both antisera and antigens for B/Hong
Kong/330/01, B/Hong Kong/1434/02 and B/Sichuan/07/97 are available from
CBER. However, if a new strain is
chosen, specific reagents will be available in May at the earliest.
Thank
you.
CHAIRMAN
STEPHENS: Okay, questions for Dr. Ye?
(No
response.)
Okay,
moving to comments from Aventis, one of the manufacturers, Dr. Sam Lee from
Aventis.
DR.
LEE: Thank you, Dr. Stephens. I want to thank you also for the opportunity
to share our manufacturing perspective on influenza vaccine strain selection,
and I want to thank the members of the Committee for taking time to review all
the data and facing a very difficult challenge today.
Certainly
you have to review a lot of data from the strain surveillance, but also you
need to decide whether the need to change a strain outweighs the risk of making
that change. So, certainly protecting
the public's health against influenza means not only selecting a vaccine strain
that antigenically protects against circulating influenza viruses, but also
allows us to produce enough vaccine to protect the public. In the U.S. it's up to 70 to 80 million
doses needed each year.
The
manufacturers have developed processes that are quite robust, and we have
successfully produced sufficient quantities of vaccines for the U.S. market in
most years. But I do want to remind
you, for the recent experience in 2000, when we had a strain, A/Panama, that
was expected to be high-yielding, but when put into full production, turned out
to be low-yielding.
So
over the next several months manufacturers did respond to that and made
improvements. However, it did cause a
delay in vaccine distribution over the next two months.
What
I plan to share with you today are the key factors involved with manufacturing
influenza vaccines and how your decisions can help assure a sufficient and
reliable supply.
Of
course, the primary objective of this Committee today is to select the vaccine
strains that will protect against the circulating strains, and you have
reviewed and seen the data for hemagglutinin inhibition and also
cross-reactivity and similarity for the different strains.
I
have also described to you that there's a secondary objective that may or may
not be as apparent, and that is to select strains that propagate well enough in
eggs to allow manufacturers to produce vaccines needed for the U.S. market. Certainly the best way to ensure this
predictability of supply is not to recommend any changes, but, of course, it is
not always possible because we must protect the public against the circulating
strains.
A
second best way is to minimize the number of strain changes. Each new strain can yield anywhere from 50
to 120 percent of the average strain.
So one low-yielding strain could mean as much as 20 million doses fewer
for the market. Two low-yielding
strains would certainly make even less available.
So while manufacturers have been fairly
successful at supplying the market with sufficient quantities of influenza
vaccine, each change does infuse more risk.
If
a change is necessary, there are two factors that are important to
consider. First is that the strain
propagates well in eggs, and a second is that the new strains need to be
identified as early as possible. The
reason for this will become more apparent in my next response.
But,
simply put, early strain selection allows manufacturers more time to understand
the growth characteristics of the new strain and to make adjustments, if
needed. So there is a real balance
between optimizing vaccine strains and making your selection early enough to
have the vaccine available.
Certainly
there are many factors involved in manufacturing a vaccine, but I want to
review some of the critical components.
First of all, the vaccine is manufactured in eggs, and so we must ensure
that there is a reliable supply of eggs.
Several hundred thousand eggs are used daily, and traditionally we have
been able to have a sufficient quantity and quality of the eggs and a reliable
supply, but we do have to monitor any diseases such as avian disease that could
threaten the flocks, and we also have to look at weather for delivery. I'm glad to say that the recent snowstorms
and all have not impacted our manufacturing at all and we did not lose any
production days.
The
second critical component is the seed virus.
Certainly the availability of the high-growth reassortants in a timely
fashion is critical and also that the yield in general is predictable, but it
is really not fully understood until we have reference reagents available.
So
that leads to the last critical component, which is the availability of the
potency test reagents. These are
specific to each strain, as you know, and are required prior to formulating the
vaccine.
My
final slide is to show you a timeline for manufacturing that encompasses the
time we order chicks for producing the eggs all the way through distribution of
the vaccine. In order to ensure that we
have a reliable supply, we order chicks as early as a year in advance. We'll order then starting in January of the
previous year and then move them into the houses for the laying of the eggs in
October and November.
The
other component is the seed viruses, and we'll receive candidate seed viruses
in the fall and in the early months of the year. Along with CBER and other laboratories, we will prepare the
high-growth reassortants, and we also have internal passaging that we can
perform in order to improve our yields.
So,
typically, those seeds are produced and continual yield improvements are made
throughout the spring, and we will begin production as early as January each
year.
I
do want to point out that, by starting in January, manufacturers take a risk
because they are producing before the strains are actually selected, but we do
this in discussion and collaboration with CBER and other laboratories and other
agencies.
Typically,
we do produce the first strain starting in January. We'll look at the second strain starting in February at some
point and move into a third strain as it is selected.
However,
this year the timing of the strain selection is a little different in that we
are making it probably in the middle of when we would typically be starting the
second and third strains.
So
the last piece is the preparation of the test reagents during this time
period. Really, this piece cannot start
until the strains are selected. I know
CBER does begin work in preparing the purified HA antisera and also preparing
the reference antigen, but until that is available in May and into June, we
cannot begin formulating the vaccine.
The
main consideration here is that the vaccine is typically distributed September
and October and into November. Because
of this limited time window for distribution, all product must be formulated,
filled, and tested in a very short time period, roughly about 17 weeks.
So
any delay in strain selection or availability of test reagents does delay the
beginning of this point, and all this work must be compressed in a shorter time
period.
At
this point that basically summarizes what I wanted to say today. I wanted to kind of give you an
understanding of the decisions and the timeliness that's needed, and I am open
at this point for any questions.
CHAIRMAN
STEPHENS: Thank you very much, Dr. Lee.
Open
for questions, comments. Dr. Katz?
DR.
KATZ: What progress has been made in
getting out of eggs and into a cell culture system?
DR.
LEE: I'm not familiar with all the
research that has been done with that.
I know that it has been looked at for several years, and I believe there
was a cell line that was licensed in Europe to perform this.
My
understanding at this point is that the yield in cell culture is still
extremely low, and that production capacity would not be there to supply the
entire vaccine supply.
DR.
KATZ: Thank you.
DR.
COUCH: I know, just by hearsay, that
Aventis in Europe was pursuing a cell culture vaccine as a possible
product. Is that still being pursued by
the company, do you know?
DR.
LEE: My understanding is that we are
still looking at it, but at this point it is probably still too early to say
when it would be available.
CHAIRMAN
STEPHENS: Other questions, comments,
for Dr. Lee?
(No
response.)
Any
other manufacturers who would like to make any comments? Evans, I guess, or maybe Medimmune? Anyone else want to make comments on these
issues? Okay.
DR.
ROYAL: Walter Royal.
Given
that there's always the risk that your vaccine may not work, what sort of
in-house R&D takes place to try to reduce that risk, and what sort of
information might be passed onto some of the agencies that are doing the
various antibody and neutralization testing?
DR.
LEE: I'm not sure I fully understand
your question. Could you repeat that?
DR.
ROYAL: Well, what I am wondering is
whether what's done is that the information that's given to you regarding the
candidate viruses, presumably, there's, as you said, a risk that your vaccine
may not work.
DR.
LEE: Uh-hum.
DR.
ROYAL: So I would assume that there are
some in-house steps that are taken to reduce that risk, or are there?
DR.
LEE: Okay, I assume you're talking
about new candidate strains ‑‑
DR.
ROYAL: Yes.
DR.
LEE: -- for any new strains that may be
selected?
DR.
ROYAL: Or even once you get to the
vaccine formulation step. There's
always a chance that your vaccine will be ineffective, but are there steps that
you take to reduce that risk?
DR.
LEE: I guess I'm trying to
understand. It seems like there's two
different issues. One is effectiveness
in terms of protection and the immune response?
DR.
ROYAL: Yes.
DR.
LEE: Okay. At that point I guess I can't speak too much about that, but in
terms of productivity, we are in constant discussion with Roland's lab to let
them know what our responses are from various candidate strains that we have
been given and working with. Then once a strain selection is made, we do continue
to crop, passage the seed viruses in eggs, and to try to improve the
yields. New seeds are made available
and sent to Dr. Levandowski's for approval for use in production.
CHAIRMAN
STEPHENS: Dr. Decker and then Dr.
Levandowski.
DR.
DECKER: Yes, Dr. Royal, let me help
answer your question. You caught Sam
offguard because he's just focused on manufacturing.
The
simple answer is nobody can do anything to address that. Everyone has to take it on faith that the
strains selected, if grown properly and inoculated, will produce the relevant
antibodies and they will not only work against that strain, but they will,
hopefully, work against whatever circulates.
All
that has to be taken on faith, because by the time you produce it, there's no
time left to do any testing. Were there
any time to do testing, there would be no time left to manufacture anything.
So
from the manufacturer's point of view, their obligation is to produce whatever
this Committee tells them to produce.
Whether or not it works has to be based on the faith that the data
collected by CDC and FDA and presented to this Committee will be relevant and
accurate.
CHAIRMAN
STEPHENS: Dr. Levandowski?
DR.
LEVANDOWSKI: Yes, I just wanted to add
a little bit to that also. Our
Committee is charged with making the recommendation, and in itself, that's why
we emphasize, I think, the practical information, to try to avoid a situation
where a recommendation is made that can't be implemented.
We
do need to take a look at the practical side of things here and make sure that
strains that we're recommending are strains that have some likelihood of the
manufacturers being able to develop things.
Probably,
we don't emphasize it, but there's a lot of work that goes on behind the scenes
in advance of this meeting to look at new strains, and when they are available,
they are sent to the manufacturers at the earliest time point.
We're
in a little bit different situation here today. As you have already heard, these new H2N3 strains have not even
been distributed to all of the laboratories that would be involved in preparing
the reference material, the reassortants, and so on, that the manufacturers
need to support them to be able to do what we ask them to do.
And
then just further to the clinical side of things, we don't really ever know how
immunogenic any particular strain is going to be before a vaccine is
manufactured, and there really isn't time to do the kind of clinical trials you
would anticipate for any other kind of vaccine. Influenza virus vaccine is different from every other one in that
it is changed almost every year and it's a new experience with each one.
I
think we can say from experience that there is variation in the inherit
immunogenicity of individual viruses.
Sometimes it's higher and sometimes it's lower. We're always hoping that it's going to be
higher, but there may be instances where a strain is chosen that does turn out
to have lower immunogenicity.
I
think, fortunately, it seems to be that in most instances where it has been
examined, when there is a good match between the vaccine strain and the
circulating strains, then efficacy is usually shown. Of course, the vaccine itself, the efficacy of the vaccine is not
a hundred percent. It's probably 79 to
90 percent in adults, and it's quoted as being 30 to 50 percent in the
elderly. We're really talking about
preventing illnesses, predominantly trying to prevent the serious consequences
of influenza infection.
But
your questions are very good ones, and we're struggling with that issue about
what the implications will be when we make a change. We're very concerned about both the practical manufacturing and
also the clinical implications.
CHAIRMAN
STEPHENS: Ms. Fisher?
MS.
FISHER: Well, I think that Dr. Royal's
question is extremely important, but is there a systematic surveillance after
we use a flu vaccine in any given year to measure how many of those who are
getting the flu have been vaccinated? I
mean, what is the followup? How big is
the population you're following up, or is there any followup?
DR.
LEE: Yes, I was going to say probably
the CDC does most of that surveillance.
Dr.
Cox, do you want to respond?
DR.
COX: There is no systematic followup to
see, to document whether the general population who receives flu vaccine
actually is infected by flu virus because it's an impossible task. I mean we have 80 million doses or 70
million doses given, and it would be impossible to follow up.
Where
vaccine efficacy studies have been done in the past, vaccine efficacy has been
found when there's a good match between the circulating strain and strains in
the vaccine. The only ongoing
surveillance for vaccine effectiveness that I know of was done, I think, for
about five years, up to last year.
What
investigators were doing was to look at the Medicare population, the elderly
population, and look at vaccinated and unvaccinated individuals who are 65 and
older and see if there were reductions in respiratory hospitalizations and
death among the vaccinated compared to the unvaccinated. And effectiveness, vaccine effectiveness,
was definitely shown.
There
you are using a very high bar because there are a lot of other respiratory
infections that are going around at the same time as influenza, but,
nevertheless, effectiveness was demonstrated in this high-risk elderly
population.
MS.
FISHER: I just think that, from a
public confidence standpoint, I think that there needs to be some thought
given, particularly as we move to recommend flu vaccine for infants and
virtually everyone in this society, that there be some mechanism for measuring
and also in consideration that many things can look the flu, that we somehow
try to measure how many people get the flu who have already been vaccinated. I mean I think that is sort of elementary as
we move into this universal use of flu vaccine.
CHAIRMAN
STEPHENS: Thank you. Dr. Decker?
DR.
DECKER: Well, just a quick response or
followup to what Dr. Cox said: Although
there are not routinely systematic, ongoing studies of the type that you're
wishing for, in fact, there are so many efficacy and effectiveness trials done
with flu by various research groups and universities every year that, despite
the fact there's no single, ongoing systematic study, the literature for almost
every year is that efficacy or effectiveness data, because this is such a rich
area of research.
I
mean I know the hospital immunology literature, I can guarantee you that every
year there will be a half a dozen studies submitted in the literature in the
hospitals about how effective the vaccine was in their health care workers, and
so on.
So,
despite the absence of an ongoing, systematic, centralized study, there is
actually an area of very rich data.
CHAIRMAN
STEPHENS: Okay, a couple of questions.
DR.
GELLIN: I want to go back to a
manufacturing question. You highlight
the risk that the manufacturers take by getting out in front of the
recommendations. You have also, since
this is your graph, you could put the arrows wherever you wanted, and it looks
like you put two arrows ahead of where we are currently.
Historically,
have you, your company or other companies, missed on that guess?
DR.
LEE: Well, I can speak for
Aventis. Perhaps the other
manufacturers would like to comment.
The
strains that are selected for early manufacturing are done under
discussion. We certainly make the
decision ourselves to go ahead at risk, but in terms of the strain selection,
that is made under discussion.
In
the past we have not missed, to date.
So we've been fairly fortunate that the available data was there for us
to make that decision.
This
year we have not gone into production for the second strain because there's
been a big uncertainty about the second and third strains. So while I do have the arrow for the second
strain there starting in February, this year is an exception to that, and it's
pretty apparent why we made that decision.
CHAIRMAN
STEPHENS: Dr. Katz?
DR.
KATZ: My question may be for Dr. Lee
but also for Dr. Decker or whoever else can answer it. We heard that from four companies we have
gone down to two in the United States.
I don't know; is Evans a United States company? Do they manufacturer? I thought they were English. Aventis is French, but they make it at
Connaught in Swiftwater, Pennsylvania.
I
guess my question was, who makes vaccine for the rest of the world? Who uses vaccine other than the United
States? Western Europe I assume does. Who are the other companies involved?
DR.
LEE: There are actually quite a few
companies around the world that are involved.
To name a few: GlaxoSmithKline
is a large player. There's also Chiron,
Sorbet Dufar. Up in Canada there's
Biochem Pharm, I believe, and certainly Evans Vaccine and PowderJect are
involved with that.
So
it is not an exhaustive list of other suppliers, but ‑‑
DR.
KATZ: No, but several of the companies
that you mentioned do distribute other products in the United States or they
don't do flu.
DR.
LEE: That's correct.
DR.
KATZ: GlaxoSmithKline has a large
market for a lot of different things, but they haven't chosen to do flu. I guess the question is, how important is it
that we have an augmented source? If
H5N1 came along next year, who could make enough vaccine to protect us?
CHAIRMAN
STEPHENS: It doesn't sound like there
are any direct takers for that.
(Laughter.)
DR.
COUCH: That's going to be left on edge.
(Laughter.)
CHAIRMAN
STEPHENS: Dr. Decker, and then we have
got to move to Dr. Levandowski and the options.
DR.
DECKER: Well, I will just give you a
very general response, Sam. That is,
availability of flu vaccine in this market is determined by market forces,
frankly. You have had two companies
leave it because they can't make enough money to pay for the buildings that
they need to make the stuff.
As
flu prices have risen in the last couple of years, driven by the companies that
want to stay in the business and who raised prices so they could, then we have
seen foreign-based companies devote more efforts to bringing flu vaccine
here. For example, Evans is sending a
much larger proportion of its production to the U.S. now that U.S. prices are
approaching European prices. Those are
the types of market forces that one presumes the other companies will
eventually respond to.
DR.
KATZ: Thank you.
CHAIRMAN
STEPHENS: Okay, Dr. Gellin.
DR.
GELLIN: Let me comment from the HHS
perspective, and I didn't bring with me the budget, the '04 budget, that was
released a few weeks ago. But what was
highlighted in there was a piece on pandemic flu, and it was really recognizing
some of the issues that Sam has alluded to on the need to have a greater
manufacturing base to be able to produce a sufficient supply of flu vaccine in
such an event.
So
I think the details of that are being worked out, but at the highest levels
that I get to see in the Department there is sufficient interest in making sure
that that capacity is there.
I'll
also highlight, if you look at the language, it focused on the domestic
capability because of the recognition that, in the event of a pandemic, it is
probably where the vaccine is produced is going to be the most important in the
country that receives it. So, again,
these are details that are now being discussed, but they put that out there to
emphasize the Department's interest in making sure that we're thinking forward
about this.
CHAIRMAN
STEPHENS: Thank you very much.
Dr.
Levandowski, I think it would be appropriate for at least our thinking at lunch
to introduce the options for the vaccines.
DR.
LEVANDOWSKI: All right, I've got
overheads.
CHAIRMAN
STEPHENS: Being prepared for PowerPoint
failures is good.
DR.
LEVANDOWSKI: Am I permitted to complain
a little bit? I couldn't get my
Microsoft Word document to go into PowerPoint directly, so we tried a different
route.
Okay,
while we're waiting, let me just summarize some information. I'm going to try to go through some options
for recommendations for the next year's influenza vaccine. I would like to start, and I'll just
summarize. I'm actually going to steal
the summary that Nancy Cox gave you earlier.
So if you have that, you could just read along with me.
But
for H1N1 viruses or H1 viruses, including both the H1N1 and the H1N2, since
last winter, H1N1 and H1N2 viruses have been reported primarily in the
Americas, which means Canada, Chile, and the United States. That means more than 95 percent of the
recent H1 viruses have HAs that are antigenically and genetically similar to
those of the current vaccine strain, the A/New Caledonia/20/99.
The
neuraminidase of the current H1N1 viruses are similar antigenically and
genetically to the N1 of A/New Caledonia/20/99, and the neuraminidase of the
current H1N2 are similar to those of the currently-circulating H3N2 viruses,
meaning predominantly, I think, the strains that are more like A/Panama.
So
in terms of what our options might be for next year, first of all, there's
always the opportunity to maintain the current vaccine strain, which is A/New
Caledonia/20/99. In favor of that,
manufacturing is very well worked out and the yield is very predictable now,
after several years of using this strain.
Also,
more than 95 percent of the viruses that have been analyzed this year are A/New
Caledonia/20/99-like by their antigenic characterization of both the HA and the
NA. Against that, however, there are
some, a small percentage, less than 5 percent of the viruses analyzed this year
are low reactors.
If
I could get the next overhead? The
second option would be to change that strain which came from what we first had
in 1999 to a more contemporary H1N1 strain.
In favor of that, some of the viruses analyzed this year have been low
reactors. But, against that, the low
reactors do seem to be scattered throughout the genetic dendrogram, which
doesn't suggest any particular common mutation occurring.
There
is no broadly representative strain that has been identified, so that none of
the manufacturing issues that would need to be addressed have even been
investigated at this point. Then there
is always the possibility that we were discussing earlier, that a new strain
might not provide any superior coverage to the current vaccine strain.
So
there is always the possibility to postpone, but in this case we don't see that
there is any advantage to postponing a recommendation, mainly because there is
not going to be any real significant new data that will be appearing in the
near future.
So
moving on to the H3N2 viruses, again, the first option ‑‑ let me
just first go through a review of a summary.
Sorry.
The
H3N2 viruses have been causing, as has been mentioned, recent outbreaks in
Asia, and in particular in Japan, Korea, and China. An increasing proportion of the recent H3N2 isolates have not
been well-inhibited by post-infection or by post-immunization data.
The
H3N2 viruses that have the amino acid changes at positions 155 and 156, which
is in antigenic site B on the hemagglutinin, tend to be poorly inhibited by
antibodies to the vaccine virus. These
low-reacting viruses with these changes at 155 and 156 have been detected not
only in Asia, but also in Europe and also in the Americas.
So
the first option for the H3N2 would be, again, to maintain the current vaccine
strain, which is A/Panama/2007/99. In
favor of that, again, the manufacturing is very well worked out. Although the yield might have been low for
this strain at one time in its early days, it has become a very good, reliably
high-yielding strain for manufacturing.
Many of the viruses that have been isolated this year actually are still
A/Panama/2007/99-like by their antigenic characterization of the hemagglutinin.
Against
maintaining the current vaccine strain, there is this increasing proportion of
recent H3N2 influenza A viruses that are not well-inhibited, and many of those
viruses seem to be in the clade that has the amino acid substitutions at
positions 155 and 156.
This
strain, as mentioned in the summary, has been ‑‑ the new H3N2
variant has been identified in Europe ‑‑ I guess there are strains
from Norway and UK ‑‑ in Asia, China, Japan, and Korea, and also in
North America and the United States.
What
we do know is that sometimes new strains may spread very rapidly in susceptible
populations. We also know that H3N2
influenza virus has often caused significant morbidity and mortality, and they
are most often associated with those epidemics where there is a large amount of
excess mortality.
So
the second option would be to change the current vaccine strain to something
that's more representative of these newly-circulating viruses. In favor of that, these are all just the
things that were again on the previous slide, but the new variant does appear
to be spreading geographically and causing disease. When new strains appear, they may spread very rapidly.
A
more recent strain might provide a closer match for the hemagglutinin and the
neuraminidase of the contemporary strains.
Again, the H3N2 viruses are often responsible for significant morbidity
and mortality in all age groups.
Against
changing would be that information about the newest strains is not yet
completely analyzed, and we are at a fairly late date. There aren't any new strains that have been
distributed for evaluation for manufacturing issues, although that is
happening.
New
strains may cause difficulties in manufacturing, as has been pointed out, until
all the process parameters can be optimized, and we don't minimize that
possibility.
A
new strain, again, may ultimately not provide superior coverage compared to the
current vaccine strain. We won't know
that until we see results from the vaccine.
So
the next overhead. A third option here
would be, again, to postpone the decision.
In favor of that, postponing that decision today would provide time to
further analyze these newly-collected strains and gather information that would
be relevant to manufacturing and would also tend to keep the process parallel
in the United States and elsewhere in the rest of the world.
A
more recent strain might provide the closer match with the hemagglutinin and
neuraminidase of the contemporary strains.
So if it turns out that these strains, once they have been completely
analyzed ‑‑ and we don't know whether they will be suitable or not,
but when they're completely analyzed, we may be in a better position to
understand what that likelihood would be.
The
H3N2 viruses, they are a cause of morbidity and mortality, and I'll keep saying
that. But there may be a fallback
position to consider also as part of the postponement, which is that, if we're
not able to do something about these new strains as they're circulating, a
possibility would be to maintain the Panama current vaccine strain as a
necessary resort.
And
then against that, again, we don't know what's going to happen with
manufacturing. By postponing, the
manufacturing issues are still not resolved and they are not likely to be
easily resolved, and those activities are very time-critical.
We
do know that if there are manufacturing delays, that that will reduce the
amount of vaccine that is in use for a lot of different reasons. One is because of the manufacturing itself,
but also the social implications of when people expect to receive the vaccine
and be immunized.
Okay,
so moving on to influenza B viruses, in summary, again, the influenza B viruses
have been predominating in the United States and in much of Europe during this
current season. The influenza B viruses
that have been predominant worldwide really are in the current vaccine, our
current vaccine lineage, the B/Hong Kong/330/01 lineage, although there are a
few of the older lineage which are still persisting.
Most
of the recent influenza B viruses that are in the Hong Kong/330/01 lineage,
however, have neuraminidase that are more closely related to the neuraminidase
of that other hemagglutinin in lineage influenza B virus. But what we have seen is that that has
remained fairly stable in terms of the overall antigenic composition of the
strains as they have been appearing over the last several months.
So
moving on to this, again, options here:
The first option, of course, is to retain the current vaccine
strains. Again, we know manufacturing;
it's well-defined; it's very predictable.
Most of the viruses that have been isolated this year have hemagglutinin
that by antigenic characterization is very similar to the B/Hong Kong/330/01
vaccine strains. But against that would
be the concept that most of the currently-circulating strains have their
neuraminidase from B/Sichuan/379/99.
A
second option for influenza B would be to change to another strain, and, of
course, we would do that because of the vaccines might provide better coverage
for those current influenza B viruses, but, again, we don't really know
anything, we don't know very much about what the difficulties in manufacturing
might be.
I
guess what I could say, or just to repeat what we know from limited
experiences, that the B/Brisbane strain, for example, is a moderate- to
low-growing strain, which would make it less yielding for manufacturers than
the current strains. Of course, also,
manufacturing delays, again, would reduce vaccine availability and use.
And,
again, a third opportunity or possibility would be to postpone the decision,
but, again, there doesn't seem to be any advantage. Although there will be some additional data, because I guess
there are still lots of influenza B viruses coming in; it's not clear that that
will help to inform whatever the decisionmaking is.
So
I would stop there and see if there any questions before I sit down.
CHAIRMAN
STEPHENS: Thank you very much. We're going to continue this discussion
after lunch, but I want to have the opportunity at this point to have Roland
respond to any questions.
Dr.
Gellin?
DR.
GELLIN: Roland, is there ever, or how
often are there, differences in the strains that are selected for the U.S.
versus the ones that WHO selects, and what implications does that have on
confusion and everything else?
DR.
LEVANDOWSKI: Well, all the strain names
are confusing. So any differences in
the names is confusing, even within the United States.
In
terms of being consistent with the recommendations, the WHO recommendations are
worded in such a way and actually say that national authorities should make
their own choices for what the strain should be, but they recommend the strain
that is "like." And generally
it's possible to meet those recommendations, even using some slightly different
individuals strains; they still fit the overall recommendation, but there could
be different strains that are used. As
we have in the United States for influenza B right now, there are two different
influenza B viruses that are being used.
CHAIRMAN
STEPHENS: Julie?
DR.
PARSONNET: I guess I just have a very
naive question that sort of relates a little bit to the previous question,
which is, you know, if we could put infinite numbers of viral strains in each
vaccine, we would probably try to do it.
We would probably put the number in that we thought were really going to
be circulating or guess. If we could
put five or six in, we might try to do it.
So
the other way to do that is to allow manufacturing companies to make some
differences in the ones that they produce.
So you might have different companies but be different, maybe one virus,
different vaccines.
The
advantage of that might be that you would have herd immunity and a wider
variety of vaccines in the population, and also that you might have a vaccine
that's already prepared that you could use if you guessed wrong on the third
virus, for instance.
So
I guess this is a naive question because I'm sure companies think about this,
and people think about this all the time, but what are the possibilities, since
there are at least two, and actually FluMist, a third company that produces flu
vaccines in the United States, to allow those companies to make a decision
where there are areas of uncertainty and so that we can have actually broader
coverage possible?
DR.
LEVANDOWSKI: I think we try to build
flexibility into the system. As I was
mentioning, it is already possible for manufacturers to use different strains
that would fit the "like."
For inactivated vaccines, the real issue, as we have discussed, is
predominantly the hemagglutinin, although we're concerned about the
neuraminidase.
There
could be instances ‑‑ you mentioned FluMist ‑‑ there
could be instances for a vaccine like that, where it would make sense for a
completely different strain to be used that would be pertinent to their own
manufacturing issues that need to be worked out.
The
issues are different there. It would be
an attenuated vaccine. They're more
worried about maintaining attenuation and matching up as best possible the
hemagglutinin and neuraminidase, but there would probably be, there probably
will be, we would expect and anticipate that flexibility is necessary for
overall manufacturing. We're trying to
show that now.
I
thought you were going to ask, why not a quadravalent or a pentavalent vaccine
or something like that?
DR.
PARSONNET: I've heard before that
wouldn't be possible. So can we do the
equivalent by having two different trivalent vaccines?
DR.
LEVANDOWSKI: Okay, well, the
manufacturers themselves may want to address that concept of having different
strains possibly, because if you are the manufacturer who has the strain that
nobody wants, where does that leave them for the following year, if they can't
sell their product?
I
think we're trying to make sure that, as best we can, all of us, that there's
plenty of vaccine to go around and that manufacturers all have an even chance
at being able to have their product used, and that it's a good one.
CHAIRMAN
STEPHENS: We have had the discussion
about multi- or additional components.
Could you just comment on that?
I'll put you on the spot.
DR.
LEVANDOWSKI: All right, I had to open
my big mouth.
There
are a couple of issues. One of them is
very practical. There's only a certain
number of egg days available or tissue culture days. Whatever you want to look at in terms of manufacturing, there's
only a certain amount of time for production.
Whatever
gets used for ‑‑ if you have three components and you're going to
make 90 million doses, okay, you need 30 million of each. If you want four components and you can make
90 million, then you are going to reduce the amount, the total number of doses
that you can produce within that period of time.
The
issues about the yield of these different strains also is an important one
within that context. The
poorest-yielding strain is going to be the one that pretty much determines or
it drives how much vaccine the manufacturers will ultimately be able to
produce.
I
don't know if anybody wants to comment on that from a manufacturing point of
view before I go on, but I could say some more things.
DR.
DECKER: Well, you said it well. Let me just correct one thing. If Aventis,
for example, wants to have 50 million doses on the market, to pick a round
number, that means we've got to make a minimum of 150 million doses, 50 of each
strain. If you want four strains,
that's 200 million. We can still only
make 150. So you just very
arithmetically cut the availability.
On
top of that low-yielding issue is a roll of a dice with every strain. As you said, whatever is the lowest yield
for that caps your production.
With
respect to whether companies would want to offer different strains, I rather
doubt it, not only for the reason you mentioned, but with current technology ‑‑
and this isn't likely to change anytime soon ‑‑ you've got one roll
of the dice to make vaccine for the year.
You have to start right now. In
fact, we started a month ago, just gambling that we've made the right choice.
So
by the time you know what's the right strain, you can't do anything about
it. Today, and over the next couple of
weeks, people are going to make the best possible choice. Once this group has articulated the best
choice, why would any company want to go with what's not the best choice?
DR.
PARSONNET: My comment would be that it
may be that we will come out and say, well, we're not sure what the best choice
is. With the A3 and 2, I think there's
a question about what the best ‑‑ we may have a question at the end
of what the best strain is.
That's
the issue for me. It's not the other
two. You know, no company would want to
do differently.
But
when there's a question about the third strain, for instance, and we are not
sure which one to put in, the question is, should we be encouraging people to
do both, so that in either case, if there is an incredible outbreak of one, or
the one that we didn't expect, or the one we didn't predict, there's another
source of vaccine to cover that?
DR.
DECKER: There is one more answer to
that, which is the big risk for production is not a couple of weeks' delay to
get better data. The big risk is making
the decision to make a new strain.
The
delay plays into that a little bit because if it turns up, it's harder to grow
it; you've lost a few weeks of your time.
But,
generally speaking, you're far better off, if you have to, to wait a few weeks,
make the best decision and go with it, even if it involves a change, than to
make a change now that perhaps you don't need a much higher risk.
So,
again, for that reason, companies aren't likely to do what you say, unless
their choice is, let's just keep making what we made before.
CHAIRMAN
STEPHENS: Okay, I would like to have
one last question from Dr. Karron, and then we're going to break for lunch and
resume the discussion at 1:15.
DR.
KARRON: I guess just a comment about
the issue of different companies manufacturing different vaccines: One is that manufacturers can probably
comment better on this distribution than I can, but my understanding is that in
this country Aventis still makes the majority of the vaccine. It's certainly not an even distribution
between Aventis and Evans.
Then
also just to mention that, in fact, for children under four there is one
manufacturer of influenza vaccine, and that is Aventis. So there would not be a distribution.
CHAIRMAN
STEPHENS: Okay, we'll continue this
discussion at 1:15. Thank you very much
for all the presenters and the comments from the panel.
(Whereupon,
the foregoing matter went off the record for lunch at 12:17 p.m. and went back
on the record at 1:19 p.m.)
A F T E R N O O N S E S S I O N
1:19
p.m.
CHAIRMAN
STEPHENS: Okay, let's go ahead and get
started.
If
I could ask Dr. Levandowski come to the podium with the options, we'll continue
that discussion.
We
have a session on open public hearing, if anyone would like to make a statement
from the public.
(No
response.)
Okay,
seeing no one, Dr. Jody Sachs has a statement to make.
DR.
SACHS: Well, as part of the FDA
Advisory Committee meeting procedure, we are required to hold an open public
hearing for those members of the public who are not on the agenda and would
like to make a statement concerning the matters pending before the Committee.
I
have not received any requests at this time.
If there is anyone in the room that would like to address the Committee,
please come forward to the mike and this is the opportunity.
(No
response.)
I
would like to close the open public hearing at this time because I don't see
anybody who is approaching the mike. So
I'm going to turn the meeting back over to Dr. Stephens. Thank you.
CHAIRMAN
STEPHENS: Okay, Roland, I think we cut
you off a little bit, but this is the heart of the matter, in a sense, and it
may be helpful to review these options very briefly and ask for further
discussion on the options.
DR.
LEVANDOWSKI: Okay. Well, I'm not quite sure how brief I should
be, and I don't think I probably need to belabor all of the pros and cons
again, but just to maybe indicate the highlights of what the options are that
were laid out here.
Okay,
so the first, starting with the H1N1, of course, the first option is always to
keep the vaccine strain the same. Here
we have a strain that we have had in the vaccine for several years, so it is
getting a little bit old, but still it represents the majority of the viruses
that are circulating.
Certainly
the manufacturers have had enough time to really get to know it well. A concern might be the small number of
viruses that have been low reactors in some of the serologic tests, but we also
know that those low reactors are not clustered in any particular genetic
branch, so that they probably represent independent kind of mutations and maybe
not the development of a specific clade that's going somewhere on its own.
The
other main option here for H1N1 would be to change the strain, and the main
reason to do that would be to try to have better coverage for some of those
strains that look like they're low reactors, but, again, we just don't really
need ‑‑ those low-reactors by themselves are not forming any kind
of group. They really are not
representative of the mainstream of activity which we have seen mostly in the
United States during this year in terms of the H1N1 strains.
Although
the Committee could consider postponing the decision, we really don't think we
would see an advantage from the point of view of what information could be made
available to do any better than what we're presenting today.
CHAIRMAN
STEPHENS: Comments or questions on the
H1N1/H1N2 options?
(No
response.)
Okay,
go ahead.
DR.
LEVANDOWSKI: Okay. So the H3N2 is a little complex, as pointed
out. You probably noticed I had a lot
more pages to go through on that one than on either H1N1 or the B.
Here
again, one choice would be to maintain the current vaccine strain, the
A/Panama/2007/99. Here again, in favor
of that, we really know quite a lot about this strain. It has been in the vaccine for several
years. Most of the viruses that have
been identified up until about two weeks ago look very much like
A/Panama/2007/99 by their antigenic characterization for the hemagglutinin.
But
not in favor of maintaining the current vaccine strain, there are a number of
issues, most of them relating to the fact that there appears to be a new clade
of H3N2 developing that has some very specific signature, amino acid changes in
one of the important antigenic sites of the hemagglutinin.
Not
only does that strain appear to be coherent in the sense of its evolutionary
background, it seemed to have spread quite a bit. We're seeing most of the strains, I guess, from Asia, but there
are also isolates from Europe and a couple of countries and also in the United
States.
As
I have belabored before, we do know that new strains can spread very
rapidly. We have had that experience
with an H3N2 strain in the past. Once
it got seeded, it really got going. We
are maybe early in seeing this, but, you know, we don't know for sure.
The
H3N2 viruses also tend to be those that cause or that tend to be associated
with more morbidity and mortality than the other strains. So one of the other options, or the main
option, or one of the main options here, the second main option is to change
the current strain to a different strain that would be more representative, and
really all the pros here are basically like the cons for not changing the
strain.
So
I don't think I will spend a lot of time going through them, except to say that
these new variants have appeared and that they seem to be spreading widely, or
they have spread somewhat widely already, and that we would normally take that
seriously in terms of the consequences, if it did become seeded and cause
widespread infection.
Against
making a change, however, we don't really have a lot of information about the
newest strains because they haven't been available to work on. In this sense, I don't mean the
epidemiologic work. I mean strains that
could be used for manufacturing.
I
guess predominantly we have not had the opportunity to get those strains
distributed, evaluate them, make sure they have got the correct antigenic
characteristics and genetic characteristics, and then be able to optimize the
manufacturing process.
We
do know that, as we have heard, if manufacturing is not smooth, then delays and
shortages are likely to occur. We
ultimately don't really know whether we would get better immunogenicity out of
a new strain.
So
the third option here ‑‑ I guess this one is probably still as
strong as the other two ‑‑ is postponing the decision in order to
get some more information to make a better ‑‑ or to have more
information to inform the decision in terms of these strains that are just
being distributed right now.
Again,
the concerns always are the tradeoff between being able to manufacture the
vaccine or to have some vaccine of some sort that may still provide some level
of protection, even if it's reduced because there's not a good match between
the vaccine and the circulating strains.
So,
as mentioned here, a fallback position might be considered as maintaining the
Panama strain, if it turns that we're not able to provide a practical response
to what we're seeing in terms of the surveillance and epidemiology.
I
guess I can probably stop there and don't need to go through those.
CHAIRMAN
STEPHENS: Questions? Dr. Dowdle?
Dr. Couch?
DR.
COUCH: It is just a reassurance
question because I had carried A/Fujian/411 as one of the possibilities,
looking through these, but it wasn't on the amino acid sequence list. Did you say it's also that 155/156 set of
strains?
DR.
COX: Yes.
DR.
COUCH: It is?
DR.
COX: It definitely has those strains.
CHAIRMAN
STEPHENS: Dr. Dowdle?
DR.
DOWDLE: Thank you.
Roland,
just a little clarification on how you see a fallback position of A/Panama
actually working. I mean, what you're
saying, that a certain amount of time could be allowed to look for a high-yield
strain, let's say the new H3N2 strain.
But at some point then you would have to make a decision of go/no-go and
fall back to Panama. Is this what
you're referring to?
DR.
LEVANDOWSKI: I think that is a very
important, practical consideration, yes.
The manufacturers, if it is a low-growing strain, the manufacturers will
be unable to really respond anyway, even if they get the strain. In order to produce a high-growth
reassortant, that in itself takes several weeks, probably in the range of six
to eight weeks by classical methods, if that's what we're doing.
Manufacturers,
once they have that strain in hand, require about a month to develop their seed
viruses. So we will be talking about
manufacturing with such a strain probably two to two-and-a-half months from now
at the earliest, if everything went smoothly from here on.
So
there are some of those sort of considerations in terms of the timelines that
would have to be there. Even if a
recommendation were made to implement such a change, now or later on, if those
things don't work out, and they might not be completely worked out in the next
week or two, then we would have to have some sort of an idea as to what
direction we ought to take. Should we
keep going and I guess risk very low vaccine supply or should we try to
maximize what the coverage for the vaccine would be?
DR.
DOWDLE: May I? I would think the last thing we would want
to do is get caught in a very low vaccine supply situation, as we have had
before. At the same time we always have
the competing goal of wanting the best possible strains in the vaccine.
But
I have a pretty good feel for what happens, what needs to happen, in order to
incorporate a new strain, but it is still not clear to me exactly when the
drop-dead date is, I mean when the decision has to be made. That's still quite nebulous. Are we talking about a month? Are we talking about two months?
DR.
LEVANDOWSKI: By precedent, we have gone
into mid-March in finalizing recommendations in the past. When we have done that, we have usually had
quite a lot of information that has been developed subsequent to our January
meeting and even subsequent to the WHO meeting in February.
So,
in some sense, although this isn't what we would like, in some sense we are in
a similar situation to what we have had in past years, when we had planned on
having a meeting in January and a meeting in March. That was not necessarily what we would desire.
We
would hope that we could make sure that all these recommendations are completed
by this time, but I think we are still in a situation, except for being
somewhat later, several weeks later than we would normally have been with
getting some work done on developing a new vaccine strain, I don't think that
the timelines have bent that much. I
think that if we maintain that kind of timeline, we would still be consistent
with what has gone on in the past, although we would like to be better.
CHAIRMAN
STEPHENS: I believe, Dr. Myers, did you
have a question?
DR.
MYERS: No, it's been answered.
CHAIRMAN
STEPHENS: Okay. Dr. Diaz?
DR.
DIAZ: Just a real quick question: In following along the theme of that
fallback possibility, if in fact something would happen and a recommendation
would be made to make a change, and yet it couldn't be and the fallback was the
Panama strain, if the H1N1 and B strains remain the same, we would be at that
point facing using the exact same vaccine that we used for this current
year. And I am wondering if the manufacturers
keep or have on hand vaccine from the current year that doesn't get used that
is viable for use in a subsequent year, if in fact that were the case.
DR.
LEVANDOWSKI: If you're asking ‑‑
I'm addressing this one? Okay. The manufacturers may want to address this
also, but generally the manufacturers produce as much as they think, or close
to as much as they think they are going to need for any given campaign. It's not really to their advantage to have
monovalent bulk vaccines carried over, but that does happen sometimes, but
we're usually talking about a very limited, small amount of vaccine that might
be available for subsequent years. It
usually would only be carried over from the end of one season to the beginning
of the next one.
DR.
DIAZ: It could provide a jumpstart in
that kind of a situation potentially?
DR.
LEVANDOWSKI: I don't ‑‑
what do you consider a jumpstart? It's
a very limited amount. It would maybe
be one, or at the most two, monovalent bulk vaccines from a manufacturer. So we're not talking about an amount of
vaccine that would really help them out in any way.
DR.
DIAZ: That would be very useful, right.
CHAIRMAN
STEPHENS: Dr. Decker, you have a
question, but you may want to comment on this issue as well.
DR.
DECKER: No, I don't have a
question. I was going to give a
response to Dr. Dowdle's question, and I'm not sure if we have segued from
questions to discussion or not.
CHAIRMAN
STEPHENS: Well, I think we're going
through a discussion of the issues as he's presenting the options.
DR.
DECKER: Then let me go ahead. Dr. Dowdle was asking about how much time do
we really have. My belief is that a
delay for a couple of weeks that was talked about earlier would be
inconsequential as long as the Committee makes a decision on two of the strains
today because, particularly in the face of no manufacturing strain identified,
let alone reassortants generated, even if we picked an A strain today, it
wouldn't make any difference for at least a couple of weeks and maybe more.
In
all likelihood, if it would help improve the decisionmaking, a delay towards
even the end of March would be valuable to improve the decisionmaking and would
not interfere with the timelines, if we were going to make a change.
Beyond
that, you're really eating the timeline.
I emphasize again that the gamble is making the change, because once you
do that, it will be some time. When we
had a problem in the year 2000, it took several months to know that things
weren't working well.
We
heard earlier today that the reagents will not be available until May. It is not until the reagents became
available in May of 2000 that anyone knew that the strains were not growing
adequately. You inoculate the eggs; you
harvest the product, but you can't titer it until the reagents become
available. When you titer it and
discover there's only half as much there as you thought, you suddenly realize
that you've got a real problem.
So
that's where the gamble is, and the delay of this Committee's decisionmaking
for two weeks or three weeks or four weeks, if it will improve the chances that
we can actually produce vaccine after that decision is made, is
worthwhile. The question is, and this
kicks right back to FDA and CDC, and the data they think they might have, will
we improve the decisionmaking by that?
The
other question that was raised is, can we make any advantage for next year of
this year's production? As Roland
indicated, the answer to that basically is no.
DR.
ARCURI: Yes, my name is Ed Arcuri. I'm Senior Vice President of Manufacturing
Vaccines for Medimmune.
The
only comment that I wanted to make is the discussion of A/Panamized backup
strategy which is reasonable to look at, but one has to realize what we're
talking about is proceeding in parallel with going after a new strain that will
put us probably in all likelihood in a situation where the manufacturers would
have to take on more risk to manufacture A/Panama in case the second strain
does not work out. So there's that
piece of this that has to be put into the puzzle also.
As
has been pointed out, the manufacturers have already taken on A level risk,
manufacturing bulks in preparation for the season.
CHAIRMAN
STEPHENS: Thank you.
DR.
DECKER: If I can just add to that, and
correct me if I'm wrong about this, but the way you phrase it implied that the
two would be made simultaneously, but that's basically not what happens. I think what would happen is that there
would be the attempt ‑‑ perhaps some production of Panama might go
on while waiting for manufacturing strains of the new choice. Once those become available, the focus would
be on using the eggs to try to make, and only once you've realized that it's
failed would you then abandon that and go back to making Panama.
DR.
ARCURI: Yes, but the problem could be
that could be way too late for a backup strategy of Panama to really work.
DR.
DECKER: That's right. You chew up a lot of time.
CHAIRMAN
STEPHENS: Dr. Gellin?
DR.
GELLIN: Related to that, is there a way
to quantify by week what that risk is, if you go down one of these parallel
tracks and then have to reverse it later on?
DR.
DECKER: Not really, because what you
don't know is how hard it will be to get the new guy to grow and how much time
it will be judged reasonable to invest in that. Maybe you can make an arbitrary
decision right now. You can say,
all right, we'll give it until June 17th; on that date we give up, but that's
not sensible.
All
I can do is point to historical experience, which is that sometimes it can take
as long as a couple of months, 10 weeks, to figure out how to make something
grow. Right now we've got Panama that
we could make beaucoup tomorrow, but if it doesn't cover, that wasn't the best choice.
DR.
GELLIN: I guess you answered my
question. If you could make beaucoup of
it tomorrow, what does it cost you to make that? And then if in a month you find there's a decision not to go that
route, what does that cost?
DR.
DECKER: Well, that's a different
question than you asked a minute ago.
DR.
GELLIN: Yes. The real cost, and the opportunity cost isn't entirely clear,
either, because you're going to do these somewhat sequentially because you have
to wait for the strain to come around anyhow, the seed to come around to grow.
DR.
DECKER: I can't tell you dollar cost,
but I don't even know if that's a critical thing because it's resource
consumption that's the critical thing:
the A's, the time on the manufacturing line, and so on.
DR.
GELLIN: So to do parallel tracks, there
are not enough eggs?
DR.
DECKER: Well, you don't do parallel
tracks. Yes, one manufacturing line,
and you've got a bunch of eggs coming every day and you make something. Whatever you make today ‑‑
DR.
GELLIN: But if you made a bunch of
Panama, you would use up all the eggs?
DR.
DECKER: Well, right now we're making
something else. So we have to stop
making that something else to make the Panama.
We're making the H1N1 strain.
CHAIRMAN
STEPHENS: Okay, Dr. Katz, then Dr.
Myers, then Dr. Dowdle, then Dr. Couch I think.
DR.
KATZ: I agree we need to rely on Nancy
Cox for this or Bob Couch because Cagey isn't here, but it seems to me one of
the reassurances, which will probably fail this year if we don't have it, that
even though we anticipate flu in November-December, it has always come later in
the United States. It has been
December, January, February. So that
there is a margin at least of error as far as, okay, we don't get vaccine out
as expected in October; we get it out in November/December instead. There is at least that margin. Michael doesn't like that one.
DR.
DECKER: Nobody buys it. You not only throw away 10 million ‑‑
DR.
KATZ: They buy it if there's an
epidemic occurring.
DR.
COUCH: Granted, it hasn't occurred
often, but it has occurred. We had ‑‑
I can't remember the year; if I stop, I may ‑‑ the major outbreak
period for H3N2 was November. Now that
is an exception, but almost as a rule the H1N1s and the Bs will start early in
December, sometimes in late November, and you've already heard we had outbreaks
of B in Texas, I think ‑‑ I got called; I should remember the date,
but I think it was mid- or late November.
It was before Thanksgiving. So,
yes, you just can't predict flu that clearly, Sam.
CHAIRMAN
STEPHENS: Dr. Myers?
DR.
MYERS: It seems to me that what we
really care about is what's in that yellow bar and how small the red piece is
in Dr. Cox's graph. Monday afternoon ‑‑
it seems to me there are a couple of scenarios we could paint, is that many of
those will move from yellow and will be 155/156 deleted. I think we would all think at that point
that this is a pretty easy decision because we don't think this is a
herald. If we're suddenly seeing in
geographically-diverse areas a new strain that was predominated, I think we
would say we should go to a new strain.
If,
in fact, they are mostly A/Panama-like, we're still in the same conundrum we
are now because we don't have any sort of guidance, and we'll all be still very
nervous. So it seems to me that if we
had that information, this would be a much easier decision.
CHAIRMAN
STEPHENS: Dr. Dowdle?
DR.
DOWDLE: Does Nancy want to respond to
that?
CHAIRMAN
STEPHENS: Do you want to respond?
DR.
DOWDLE: Do you want to respond, Nancy?
DR.
COX: I probably could say a couple of
things about the information that's going to be available over the next few
weeks. When we have our conference call
with WHO next Tuesday, we will be getting not only ‑‑ we will have
not only the data that we have generated, but also the data that has been
generated by the other WHO collaborating centers during the past week, since
actually it is about a week and a half since the time that we all departed for
Geneva, and between that time and next Tuesday.
So
there will be quite a bit of additional information, particularly with respect
to H3N2 viruses that are circulating in Asia and in Europe, as well as the
U.S. So we will have that information.
We
will also have some additional information derived from testing some ferret
sera that we're producing with three other of those viruses that have the
double mutations, the 155/156 changes.
So you only have the one ferret antiserum, the Fujian/411 antiserum, at
the moment, but we'll have three more that we will have generated to see how
consistent the reactivity is with post-infection ferret sera and these
currently-circulating strains.
In
addition, we should have had a bit of an opportunity to work with the two egg
isolates that the Japanese WHO collaborating center had isolated, and,
hopefully, we would be able to report on the growth properties, at least in our
hands. It doesn't translate into what
the manufacturers can do, but sometimes it gives us a little bit of an
indication.
Those
viruses are going to be distributed as soon as possible to the labs in the UK
and the U.S. and Japan that make the high-growth reassortants, and we're going
to all be working on those simultaneously.
Of course, we'll go with whatever succeeds and comes up first.
DR.
DOWDLE: That's okay. That took care of it.
DR.
COX: Okay.
DR.
DOWDLE: That's okay. Thank you.
CHAIRMAN
STEPHENS: Dr. Palese?
DR.
PALESE: Will it be an option to make a
recommendation for the H1 and the B only and wait for the H3, or is that not
what we can do in terms of the Committee?
CHAIRMAN
STEPHENS: I think the Committee can do
that. We're going to do these
independently.
DR.
PALESE: They will be independent?
CHAIRMAN
STEPHENS: Yes.
DR.
PALESE: Okay.
CHAIRMAN
STEPHENS: Yes. Is there discussion? Dr. Karron?
DR.
KARRON: Just another question from the
manufacturing perspective: Am I
understanding this right, that if we decided on two strains and deferred the
decision on a third strain, say for a month, that from a manufacturing
perspective that wouldn't make a difference, given that these are made
sequentially? Is that correct?
DR.
DECKER: Yes, based on the information I
have right now, I believe that that is correct.
CHAIRMAN
STEPHENS: Dr. Lee, you have a comment?
DR.
LEE: Yes, I was going to respond to
that as well. We introduce one strain
at a time. If we do get two strains
selected, then we shift to the second strain, and we are producing that for a
while.
I
do happen to recall that to do a third strain is not just a matter of when we
could start production but that we would be preparing seeds in preparation for
that manufacturing. So even though we
won't be starting manufacturing for another two months, we still can be
preparing the seeds for that.
DR.
KARRON: But if we were to switch
strains, let's say, for H3N2 virus, you wouldn't be able to start preparing the
seed right now anyway because we're not at that point with the new strain,
right?
DR.
LEE: Right, that's correct.
DR.
COUCH: Well, unless it happens to be
Fujian/411, which was already distributed to you, wasn't that correct?
DR.
LEE: My understanding is that that
there are no high-growth reassortants for that particular strain. So we would need it.
DR.
ARCURI: I would just like to
repeat ‑‑
CHAIRMAN
STEPHENS: Just identify yourself again
for the record.
DR.
ARCURI: Sure. Ed Arcuri, Medimmune.
I
would just like to repeat the caveat again that, if that high-growth
reassortant is not a high-growth reassortant, if it's a low producer, you still
could find yourself in a very limited supply condition. In other words, you won't be able to make
the bulks fast enough.
DR.
LEVANDOWSKI: Dr. Stephens, could
I ‑‑
CHAIRMAN
STEPHENS: Yes.
DR.
LEVANDOWSKI: Could I just comment? Again, about the issue about preparation of
the seeds, those things generally go on simultaneously. There are a lot of concurrent operations
that have to be happening for all these things to come together at the end with
a formulated vaccine. So I guess maybe
you should understand that, when a new strain is recognized as being
potentially a vaccine candidate, that is sent out to manufacturers as soon as
we can.
Now
the same thing with high-growth reassortants.
There may be some strains that are sent out that turn out to be not
useful, and they're just discarded or they have to be maintained in the freezer
probably, but it doesn't necessarily mean that you're stuck using that. It's just it's all that preparatory work
would be going on in the background.
The
point we're at here with this H3N2 strain is that we don't know that has gone
on yet. I think I need to emphasize
that we normally would have been doing quite a bit of that the last month or
maybe even earlier, but we haven't done any of those things in this particular
case at this point.
CHAIRMAN
STEPHENS: Okay, additional comments or
questions?
(No
response.)
Let's
move on to Option 3.
DR.
LEVANDOWSKI: Okay. So for influenza B, here again, I think
maybe the choices are more limited. The
first option, of course, is to maintain the current vaccine strains, which are
B/Hong Kong/330/01. And, again, in
favor of this, we know the manufacturers have had some experience with these
strains and have a good idea of what's going to happen, and also the majority of
the strains have hemagglutinin that matches up very well with the correct
vaccine strain.
We
do know that most of the currently-circulating strains have a neuraminidase
that's different from the current vaccine strains, but I guess I should
re-emphasize what I said earlier, and others have said, too, that we only
standardize the inactivated vaccines based on their hemagglutinin content.
I
guess one thing that maybe I didn't emphasize really earlier; that is, the
B/Brisbane strain/32/02, is one that WHO has recommended as being, at least for
the hemagglutinin, it's recognized as being Hong Kong/330/01-like. So its hemagglutinin is fine.
If
there were some reason somewhere that somebody else needed to use a different
neuraminidase, that would probably be acceptable from the point of view of the
hemagglutinin. But for our
considerations for inactivated vaccines, again, I just need to emphasize that
the neuraminidase is not standardized.
If it's present, whatever immunologic response it causes may add to the
protection.
The
second option is to change the current vaccine strain. Again, that would be hoping that we could
get better coverage for the current viruses.
Against that, we don't really know how those strains are going to
perform.
Again,
I should probably bring up about the B/Brisbane strain that I just mentioned in
a positive sense. Now I should mention
it in maybe a negative sense, that we do have some information that it does not
grow all that well. The wild-type
strain is a relatively poorly growing strain.
It
probably would not perform as well as the current vaccine strains do. That's in comparisons at probably the same
point in work with the seed virus that would have been done for the other
strains as well. So we do know that
manufacturing delays would occur if we further reduce the yield of influenza B
component.
Then
for postponing the decision, actually, again, we did not see an advantage there
because the information that's likely to be forthcoming to inform
recommendations may not add that much.
There will be more information on additional strains that are isolated,
but how much different that is, there's not something to suggest that there's a
different direction developing.
CHAIRMAN
STEPHENS: Thank you. We'll open this up for discussion of the B
option and also for general discussion.
Dr. Palese?
DR.
PALESE: I just wanted to sort of
comment or ask a question regarding the issue that the neuraminidase may be
wrong in terms of the B/Hong Kong strain which we have currently. Can you give us an estimate in terms of the,
let's say, percentage protective activity which is afforded by the
neuraminidase in the vaccine which contains both hemagglutinin and
neuraminidase?
In
other words, how concerned should we really be about the neuraminidase? Can you give us some numerical value in
terms of the contribution of the neuraminidase?
DR.
LEVANDOWSKI: That's me. I can't give it a numerical value. I guess I could say that, for individuals
who are immunologically naive, their first exposure might be to such a
neuraminidase, and it might contribute in some stronger way to protection than
in someone who is not immunologically naive.
I
say that because there are, as you are aware, and would want me to think about,
there are clinical studies where vaccines were given to look at induction of
antibodies, neuraminidase inhibition antibodies, and it is clear that in
situations where there is a hemagglutinin that the individuals are already
immune to, that the hemagglutinin will predominate what the immunologic
response is and that the neuraminidase may contribute very little or there may
not be much of a response to the neuraminidase.
I
think that's partly the issue that Nancy Cox was raising about having antisera,
ferret antisera or other kind of antisera, look at neuraminidase issues because
of some of those issues as well, I think, of being able to measure what that
response is. But I can't put a
numerical value on how much contribution.
If you want me to say, is it 10, 50, or 90 ‑‑
DR.
PALESE: Okay. So do you think it's more than 5 percent, less than 5 percent?
(Laughter.)
DR.
LEVANDOWSKI: I'm from the 10, 50, or 90
school. So if I have to make any kind
of answer, I guess I would say 10, but don't throw any tomatoes at me, please.
CHAIRMAN
STEPHENS: Dr. Myers?
DR.
MYERS: Going along that same route, I
guess from the data that we have seen I don't really see any particular reason
to change the B, but all the decisions we're making relating to B have to be on
incomplete data, in that the immunologically naive, when you say that, you're
referring to children. We don't have
any data on the immunologic responsiveness to any of these antigens in
children.
I
think it just re-emphasizes the problem that it's hard to ‑‑ you
know, we have this new recommendation to encourage the use of a vaccine in that
age group. This is the age group that
has the majority of the B issue activity.
CHAIRMAN
STEPHENS: Okay. Additional comments? Dr. Decker?
DR.
DECKER: Hopefully, this will make the
Committee's job easier, not harder. I
think all the manufacturers would agree that, if a change in the H3N2,
particularly in the present circumstances being seriously contemplated, that we
would hope desperately that there would be no change in the A H1N1 or the
B. If you change not only the H3N2, but
one of those, you're really gambling with your likelihood of having vaccine.
CHAIRMAN
STEPHENS: Okay. Additional comments?
(No
response.)
Let
me open it up for any general discussion that we haven't covered. It looks like manufacturers' comment.
DR.
ARCURI: Yes, Ed Arcuri, Medimmune.
Because
of the sequential nature of the manufacturing at all manufacturers, if they are
both slow, it is just a higher level of risk to the supply.
DR.
DECKER: We are taking on more wisdom
than usual with the H3N2 decision this year because of the fact that it has hit
so late, and nobody is ready for it. So
to compound that would be unfortunate.
CHAIRMAN
STEPHENS: Right. Thank you.
Other discussion? Other points
before we move to voting on the options?
Yes?
DR.
OVERTURF: I would just like to echo Dr.
Myers' comments that, as we move toward a desire to immunize larger and larger
populations, particularly children, who are immunologically naive, we have got
to get more data. I can't imagine that
there's going to be great, broad-based support to continue to immunize children
if we don't know whether the vaccine is likely to be protective and what the
immunological responsiveness is.
So
this had been a recommendation a year ago, and I think it needs to be in the
minutes again, that this is a strong recommendation of the Committee.
CHAIRMAN
STEPHENS: It's very clear that that
point has been made multiple times, and I hope the regulatory agencies are
hearing that comment.
Other
discussion?
(No
response.)
Okay. Well, I think we will now move to
considering the options and voting on the options, unless there is objection to
that.
I
wanted to return to the options for the H1N1, and we have three before us: Maintain the current vaccine, which is the
A/New Caledonia/20/99; change the current vaccine strain to a contemporary H1N1
strain, or postpone the decision.
Roland, if you agree that's a fair summary of the options?
DR.
LEVANDOWSKI: Yes.
CHAIRMAN
STEPHENS: Okay, I'm going to start with
Dr. Katz, that end, if he's willing, to give us your comments.
DR.
KATZ: You want a comment just on the
H1N1?
CHAIRMAN
STEPHENS: Correct.
DR.
KATZ: Okay, I would vote that we retain
the current A/New Caledonia.
CHAIRMAN
STEPHENS: Dr. Couch?
DR.
COUCH: I concur.
DR.
MYERS: I agree.
DR.
McINNES: Concur.
DR.
COX: Concur.
DR.
GELLIN: Concur.
DR.
DOWDLE: Concur
DR.
PALESE: Yes.
DR.
DECKER: I agree also.
DR.
GOLDBERG: I agree.
DR.
OVERTURF: Also agree.
DR.
KARRON: I agree.
DR.
PARSONNET: Agree.
MS.
FISHER: I agree.
DR.
DIAZ: Likewise, I agree.
CHAIRMAN
STEPHENS: Okay, and I also agree with
that option to retain the A/New Caledonia/20/99 for the 2003/4 season.
Anything
else we need on that, Jody?
Please
say your name for the record, so we have an official record.
In
terms of the H3N2 options, they are to maintain the current vaccine strain,
A/Panama/2007/99; to change the current vaccine strain to a strain representing
the newly-circulating viruses, or to change the current vaccine strain to a
strain representative of ‑‑ well, to change the strain or, three,
to postpone the decision.
Again,
I will start on this side with Dr. Katz.
DR.
GELLIN: Before you do that, do you need
to clarify the date of postponement, when it will be revisited?
CHAIRMAN
STEPHENS: We discussed this briefly,
but it's a good opportunity to discuss that again. I think it's the 17th of March is the next tentative planned
session for making the final decision.
DR.
SACHS: There's a calendar in
everybody's folder in the back of the lefthand section of March. It's on a colored purple page. You can see when the 17th ‑‑
it's a Monday, and probably the 17th would be the best date to shoot for. If there's anyone who can't make it, please,
now is a good time to state it.
DR.
DECKER: Just a question: Are you talking about a Washington meeting
or a teleconference?
DR.
SACHS: Telecon. If we can, we'll do it telecon.
DR.
DECKER: Thank you.
CHAIRMAN
STEPHENS: Okay, this is a potential
teleconference as opposed to ‑‑
DR.
SACHS: Okay, what I would like you to
do is put an "X" by the 17th, and if you can make it on the 14th,
don't put an "X," but just let me know, and then pass the sheets in
to me, if you would. If you need more
time, you know, let me know also.
DR.
COUCH: So mark the 17th and 14th?
DR.
SACHS: Yes, those are the two potential
dates, the 17th and 14th. And if you
can't make those dates, put an "X."
If you can, don't put the "X"; just pass it in as is. Thanks.
CHAIRMAN
STEPHENS: Okay, with that comment, Dr.
Katz, I'll put you on the spot.
DR.
KATZ: Thank you. As far as H3N2 is concerned, I would vote
that we retain the option, that we seek further information to see if we can
replace the current strain with a variant that would be more in line with the
antigens of the hemagglutinin and the neuraminidase of the newer strains, but
that we set a date, March 14th or 17th, at which we would have to have enough
information to make that decision, and if it's a negative one, that we go ahead
with the current Panama.
CHAIRMAN
STEPHENS: So a clarification, Dr.
Gellin?
DR.
GELLIN: I was hovering on the
dates. Michael, representing one of the
manufacturers, do you have a drop-dead date after which there is a problem
moving forward, recognizing that it is picking a new strain and there are going
to be potential process development issues, but if the decision is to go with
Panama, what's the drop-dead date from a manufacturing perspective?
DR.
DECKER: No, there's no drop-dead date
at all. There's just diminishing
likelihoods of success.
What
you've got right now is you've got, because of the strange circumstances this
year, you've got a window of where you're not hurting yourself any worse,
because we couldn't get started today anyway.
So you've got some time, because there's nothing to start on. Nobody's made anything to start on. So you're not causing any further harm to an
already-awkward situation by postponing your decision until mid-March.
After
that, I can't tell you, because if in mid-March there are reassortants
available, but no decision is made, then you're losing real time.
CHAIRMAN
STEPHENS: The option really on the table
right now is to postpone, and we're still debating what date we would
potentially have a reassembly to evaluate that question.
Dr.
Katz, my assumption is that you would like to postpone this decision
until ‑‑
DR.
KATZ: Yes.
CHAIRMAN
STEPHENS: Great. Dr. Couch?
DR.
PALESE: Can I just ask ‑‑
CHAIRMAN
STEPHENS: I'm sorry, go ahead.
DR.
PALESE: I mean, is the date sort of in
stone, the 14th and the 17th? Would it
help to be like two weeks earlier or 10 days earlier?
CHAIRMAN
STEPHENS: I think, though we're not in
stone, those appear to be dates that were reasonable from a variety of
different calendars. We're just trying
to get an assessment of what dates in the next several weeks might be available
for this particular ‑‑ if we decide to postpone, and we haven't
done that yet.
But
go ahead, Nancy.
DR.
COX: Perhaps I can clarify things just
a bit further as well. While we were in
Geneva, we had extensive discussions about postponing the recommendation for
the H3N2 component because this is not something that is done lightly or
something that we often do. In fact,
there's quite the opposite pressure.
What
we did was draw out a timeline and work out when the vaccine, the wild-type,
egg-grown viruses would be received in the WHO collaborating labs, when we
thought we would have ferret serum, when we thought we would have the first
possibility of testing a high-growth reassortant, and so on and so forth.
We
came up with the date of March the 14th as being a good date by which we would
be able to go ahead and have that additional experience and make
recommendations.
This
timetable that we drew up was actually taken to the vaccine manufacturers who
are represented at the meeting of the International Pharmaceutical
Manufacturers Association, IFPMA, and there was general agreement and goodwill
on the part of those people who were represented at that meeting that those
dates would be okay, not ideal, but certainly everyone would work as hard as
they could to do their best to make it come together. If they hadn't come together, then there would always be the
fallback position of the Panama strain.
I
can answer any additional questions.
CHAIRMAN
STEPHENS: Okay. Any further discussion upon this issue? Because I think we're still voting really on
the question of postponing. The actual
dates have not been established.
Dr.
Couch?
DR.
COUCH: I guess I sound a little bit
like a broken record at this meeting, but postpone, and my reason for that is
much the same: that this is the most
important decision we make. All of them
are important, but H3N2, these vaccines are designed primarily to prevent
hospitalization and death, and this is the No. 1 culprit in that regard. So we have to work a little harder to make
the right decision.
I
started to say a minute ago a little perspective, if I may, on this. The reason we have the luxury of talking
about a fallback here, because if it was clear that Panama was unacceptable,
well, we wouldn't even have had this discussion about dates, and that has
occurred in the past.
So
that I think the view to take, and I take here, is that, as we know the data
now, Panama is not unacceptable. What
we're talking about is seeing if there is a better, more appropriate antigen to
replace it with, and somebody might not like the language I've used before,
but, as I saw the data here, that's the only thing I came here with a question
on: Do we need to finetune the H3N2?
I
think that still is not an inappropriate way to phrase the question because, as
we know the data now, we're not talking about a major antigenic change. But, on the other hand, it is important to
finetune this antigen. That's the
reason I think we want to postpone this decision, to try to be as close as we
can to being sure we get it right.
CHAIRMAN
STEPHENS: Thank you very much. Dr. Myers?
DR.
MYERS: I'd postpone.
CHAIRMAN
STEPHENS: Dr. McInnes?
DR.
McINNES: McInnes. I would postpone the decision.
CHAIRMAN
STEPHENS: Dr. Cox?
DR.
COX: I vote for postponing the decision.
CHAIRMAN
STEPHENS: Dr. Gellin?
DR.
GELLIN: Bruce Gellin. I'd postpone as well.
CHAIRMAN
STEPHENS: Dr. Dowdle?
DR.
DOWDLE: Walter Dowdle, and I also would
vote to postpone. However, the concern
I would have, it seems to me that there are two issues. One is getting enough information as you can
get to make a decision, let's say, on the 17th that you go forward with it.
Then
there's another window there in which the manufacturers are looking at these
strains to make sure that they will, indeed, meet their criteria for growth,
and so on and so forth, so that they will make good vaccine strains.
So
is there a way to look at this another way and say, okay, what's the drop-dead
date, working backwards, not working forwards, but working backwards? So that you know that you have to have
vaccine at a certain period of time in October. What's the drop-dead date to actually meet your goals, your
vaccine production goals?
Then
that would be a window, perhaps as a second decision, if the new antigen hasn't
worked out well enough by that time, then you must go to another fallback date
to Panama.
I'm
just raising this as a question, as something we might want to think about at
the next go-round. I don't know that we
need to have an answer now.
CHAIRMAN
STEPHENS: Any comment on that point
before we go on?
DR.
DECKER: Yes, and Sam and my colleague
from Medimmune, jump in, please, if you've got corrections to this. But I believe a relatively correct answer
would be, if the companies aren't handed the high-growth reassortants by the
end of March, you're going to have delays.
If they don't grow the way they're supposed to grow, you're going to
have delays.
So
even if they're handed to us, there may still be delays if they don't
perform. But if you don't hand them by
the end of March, then you're guaranteed delays in availability.
CHAIRMAN
STEPHENS: Okay, let's proceed. I think still the message on the table or
the motion, if you will, on the table is to postpone this decision right now.
Dr.
Palese?
DR.
PALESE: Yes, Peter Palese. I also vote for postponing and just ask that
as much information about the actual subtype or the specific subtype of the H3
will be generated over the next two or three weeks, so that we can make an
informed decision.
CHAIRMAN
STEPHENS: Dr. Markovitz?
DR.
MARKOVITZ: David Markovitz. I would also postpone the decision.
DR.
DINIEGA: Ben Diniega. Postpone.
DR.
ROYAL: Walter Royal. I vote to postpone.
DR.
GOLDBERG: Judy Goldberg. Postpone.
DR.
OVERTURF: Gary Overturf. Postpone.
DR.
KARRON: Ruth Karron. Postpone.
DR.
PARSONNET: Julie Parsonnet. Postpone.
MS.
FISHER: Barbara Loe Fisher. Postpone.
DR.
DIAZ: Pam Diaz. Postpone.
CHAIRMAN
STEPHENS: And I concur that I would
postpone as well.
Okay,
proceeding to the B component, we might start on this side of the room this
time with Dr. Diaz and her comments about the options for B. Let me just review those again.
Retain
the current vaccine strains B/Hong Kong/330/01 or B/Hong Kong/1434/02; change
the current vaccine strain to another influenza B strain with a neuraminidase
from the Sichuan lineage, or postpone the decision, are the three options being
presented.
DR.
DIAZ: I would vote that we retain the
current strain. If we were talking
about a change in the hemagglutinin and we weren't talking about a change in
the other strain, H3N2, I might be voting differently, but balancing all of
those together, I would retain the strain, the current strain.
CHAIRMAN
STEPHENS: Ms. Fisher?
MS.
FISHER: I'm uncomfortable with the fact
that there's been increased influenza B activity, particularly in the U.S., and
that the recent influenza B viruses have NAs most closely related antigenically
and genetically to that of B/Sichuan rather than the Victoria lineage. So I'm going to abstain on this vote.
CHAIRMAN
STEPHENS: Dr. Parsonnet?
DR.
PARSONNET: Yes, I'll vote to retain it,
although ‑‑ no, I'll just say I'll vote to retain it.
DR.
KARRON: I'll vote to retain. I base that in part on the fact that we are
postponing the decision about the H3N2 virus and recognizing the manufacturing
issues inherent in that.
CHAIRMAN
STEPHENS: That was Dr. Karron.
DR.
OVERTURF: Overturf. I would vote to retain it.
DR.
GOLDBERG: Goldberg. I would vote to retain it, based on the fact
that we are postponing another strain and that we have to recognize all we can
do is deal with possible strain change.
DR.
ROYAL: Walter Royal. I vote to retain, based on the fact that the
information we have so far demonstrates that we have seen a lot of B activity,
and it's unlikely that any new information is going to change what we know
about the strain characteristics that we've seen so far.
DR.
DINIEGA: Ben Diniega. Retain.
DR.
MARKOVITZ: David Markovitz. I would like to retain this strain also.
DR.
PALESE: Peter Palese. Retain.
DR.
DOWDLE: Walter Dowdle. Retain.
DR.
GELLIN: Bruce Gellin. Retain and hope that we can also have a
better sense of the role that neuraminidase plays in efficacy.
DR.
COX: Nancy Cox. Retain.
DR.
McINNES: Pamela McInnes. Retain the current B vaccine strain.
DR.
MYERS: Myers. Retain.
DR.
COUCH: Couch. Retain.
DR.
KATZ: Katz. Retain with the caveat that Pam McInnes and Tony Fauci get some
of that money to study neuraminidase.
(Laughter.)
CHAIRMAN
STEPHENS: And I agree that you should
retain the current B strain as a B component, and agree also with Dr. Katz that
we should get more money.
I
also think that there's another message here.
There was a comment that Dr. Gellin raised earlier about our capacity
and production for influenza vaccine, which I think is a very important issue,
and another message that I hope this Committee will concur with, that we need
to look carefully at some of those issues.
And
I know that HHS and others are looking at it, but I think it is important from
a capacity perspective that we deal with what could be the major threat, or one
of the major emerging ‑‑ or not emerging, but certainly present
biological threats that we have. I
would hope that there would be greater emphasis on manufacturing capacity and
some way of stimulating that particular process.
So
any other comments that we would like to leave with the group before we move on
to ‑‑ Dr. Sachs has a comment.
DR.
SACHS: Yes. I just want to go to back to the calendar. Could you look on the 18th, March 18th, and
if you can't make that date, could you put an "X." If you can, leave it blank.
So
we're looking at the 14th ‑‑
CHAIRMAN
STEPHENS: 14th, 17th, and 18th for
"Xs," is that right?
Dr.
Katz?
DR.
KATZ: My question really was at
Jody. I'm assuming that, given those
dates, you're going to be able to e‑mail us material in advance on which
we can make our decision.
DR.
SACHS: Well, we will be able to e‑mail
whatever material we get in. It's going
to be up to the last minute because we will not have WHO's recommendations
until the 14th. So we really want to
get that material to you, but this would be by telecon, so e‑mail would
be the fastest way to get it to you.
That's why I was looking at the 17th or 18th.
You
know, earlier is best, but we may not have new data for you earlier. That's the trouble, and Roland can comment
on what data he can get in a timely manner.
I don't know what data you will have in.
DR.
LEVANDOWSKI: Do you want me to respond
to that? There will be additional
information. Mostly it's going to be
coming, I think, from colleagues at CDC, and there will be exchange of
information going on throughout this period of time. So I believe that we should be able to provide some information
in advance of the meeting. I don't know
what day that would be, but some period of time, to give you at least a chance
to see it.
I'm
encouraged, if you're asking for e‑mails, we would certainly ‑‑
as much as possible, we would like to exchange that information electronically
just to cut down on the amount of paper that we're handling.
DR.
KATZ: Well, the 14th is a Friday, and
the 17th is a Monday. So that if we're
postponing until the 17th or the 18th, it would be nice if we could, if there
are data and information, that we got it by Friday.
CHAIRMAN
STEPHENS: Now I would certainly ‑‑
DR.
SACHS: That's reasonable.
CHAIRMAN
STEPHENS: Dr. Levandowski?
DR.
LEVANDOWSKI: Could I just make one more
comment? This is the first year ever
that the Committee has gotten materials sent out to it from us related to the
recommendations more than one day before the meeting, and you realize that it's
still being collected even as you're coming here. As Nancy Cox showed with her handout, there's new information
that's coming along all the time.
But
I actually am proud of us for having gotten something out at least a week in
advance, which is ‑‑ what is that, a 700 percent increase in our
capability?
(Laughter.)
DR.
KATZ: Well done.
DR.
COUCH: Over the years there's also been
a 700 percent increase in the quantity of data you give us, too, not just the
time.
CHAIRMAN
STEPHENS: I think the other message
that the Committee certainly seems in agreement with is the pediatric
data. Again, hopefully, the regulatory
agencies have gotten that particular message.
It was sent last year, and we'll send it again this year as well.
Okay,
any further discussion or comments?
(No
response.)
We
will move to our Session 2, which deals with the Laboratory of Bacterial
Polysaccharides.
This
is an open session. So you're welcome
to stay.
Our
first presentation will be that of Dr. Richard Walker of FDA who will give an
overview of the Division of Bacterial, Parasitic, and Allergenic Products.
DR.
WALKER: Good afternoon. This afternoon I would like to just give you
a brief overview of the Division of Bacterial, Parasitic, and Allergenic
Products.
The
basic mission to assure safe and effective products, radiological control of
bacterial, parasitic, and allergenic agents affecting human health. The people that are tasked with doing this
mission are involved not only in laboratory research, but also in review,
product review, and post-licensure they're also involved in inspection,
ensuring compliance, lot release testing, protocol review, and
label/promotional activity review.
In
addition to the things I just mentioned, they are also involved with numerous
outside agencies like NIH and WHO, as far as consultations in various technical
areas.
The
point I would like to make with this slide and the slide that will follow that
is that our association with the product is a cradle-to-grave type of
operation. We begin way back at the
pre-IND stage with meetings with the sponsor, and then through submission of
the IND, we review the original submission.
Then we're involved in providing technical advice, and so forth.
And
the thing is not to focus on all these various activities that we have under
these different stages of product development, but just be aware that there's a
lot of activities that are involved all the way through and continues to be
exercised through post-licensures.
That's what I want to drive home.
The
other point I would like to drive home is that there's a wide variety of
products that come under this category for us.
We have respiratory pathogens, quite a few of those;
sexually-transmitted pathogens; pathogens such as Lyme's disease and malaria,
and so forth. Special pathogens have
become an increasing emphasis: anthrax,
botulinum toxin, tularensis, and plague.
Also,
we are involved with various diarrhea-causing pathogens and other pathogens
such as Helicobacter, and so forth, that are also attacking mucosal sites.
The
other area that we deal with is allergenic products and skin test antigens.
So
that we have to have expertise in quite a variety of different
specialties. To do that, we're
organized into eight laboratories, as shown on this slide. There's the immediate office of the
Director, which is where I am, and this slide is extremely up-to-date because,
as of this coming Monday, I'll have a Deputy Director for a change, Dr.
Madeline Blake. Also in this office we
have a regulatory staff, an administrative staff, and our job is to help all
these other people do their job.
As
you can see, we have a Laboratory of Respiratory and Special Pathogens, under
Dr. Burns; the Laboratory of Bacterial Toxins, under Dr. Vann; the Laboratory
of Microbacterial Diseases and Cellular Immunology, under Dr. Morris; the
Laboratory of Methods Development and Quality Control, under Dr. Mead; the
Laboratory of Immunobiochemistry that deals with the allergenics products,
under Dr. Slater; the Laboratory of Biophysics, under Dr. Pastor; the
Laboratory of Enterics and Sexually-Transmitted Diseases, under Dr. Kopecko,
and last, but not least, the Laboratory that we're considering this afternoon,
the Laboratory of Bacterial Polysaccharides, under Dr. Frasch.
I
would like to just run through these very quick, just to give you a brief
flavor of some of the activities that they're involved in.
The
Laboratory of Methods Development and Quality Control is involved in developing
and standardizing quality control methods for various bacterial vaccines; also,
in evaluating and applying serological testing to clinical trials; coordinating
our quality assurance activities within the Division.
The
Laboratory of Bacterial Polysaccharides will be gone into in much more detail
in just a few minutes by Dr. Frasch. So
I will just skip over that one.
The
Laboratory of Biophysics applies various high-end technologies to evaluating
and characterizing bacterial, parasitic, and allergenic products. They not only characterize biopolymers, and
so forth, but they also have instrumentation, like NMR support to provide new
ways of looking at the products.
The
Laboratory of Bacterial Toxins deals with botulinum toxin, tetanus/diphtheria,
and our anthrax toxin. They are
interested in such things as how toxins work, how various products or factors,
such as iron, may affect the production of these toxins. Also, there's a glycobiology group in there
that's involved in the mechanism of capsular polysaccharide biosynthesis.
The
Laboratory of Respiratory and Special Pathogens, special pathogens refers to
bioterrorism-type agents or the study of Bordatella pertussis, anthrax, and
also Yersinia, and they try to characterize virulence factors and study
mechanisms of actions in some of these factors and the regulation of gene
expression, important in these factors, and develop animal models to study the
importance of these factors in pathogenesis.
The
Laboratory of Microbacterial Diseases and Cellular Immunology is evaluating the
protective effects of innate and adaptive immune response for intracellular
bacteria. They're assessing DNA
vaccination strategies for tuberculosis, as well as looking at other proteins
that might be important in tuberculosis.
This group is also working with Francisella tularensis, another
important intracellular pathogen.
The
Laboratory of Enterics and Sexually-Transmitted Diseases is involved in looking
at a variety of enteric pathogens and studying the invasive mechanism, the
Shigella Campylobacter and others; the regulation of bacteria virulence genes.
Also,
it's very important, a new area that they have started is ‑‑ I'm
just trying to understand better gene immunization, and strategies to
manipulate that.
Also,
they have been using the attenuated typhoid vaccine, PY21A, as a vector for
pathogen antigens such as the PA of anthrax, and previously they have done
Shigella sonnei,and now they're working on Shigella dysenteria.
It's
a good thing I showed this one after lunch, I guess. The Laboratory of Immunobiochemistry is involved in allergen
structure and function, as well as understanding the immunomodulation of
allergic responses.
I
just put in this last slide just to emphasize that the biggest change in the
Division over the last year or two has really been the emphasis on
bioterrorism. As you have been able to
see in these slides I have just run through, a number of the laboratories are
involved in work involving anthrax, tularensis, or one of the other
bioterrorism agents. We're trying to
understand regulation of these agents and virulence factors, and so forth, that
are associated with these pathogens.
Just
a couple of administrative things I would like to run through, just because it
is germane, particularly to the review of the Laboratory of Bacterial
Polysaccharides, is the promotion plan.
Just so you understand the wording that we use, we have independent and
non-independent career tracks. Like
there are technicians; there are people who work under the direction of a
senior scientist, but then other people come in as sort of an apprenticeship,
and there's a staff fellow. Then you
move up to a senior staff fellow during a seven-year period, and then, based on
the productivity of that person, it is decided as to whether they should be
promoted to a senior investigator. That
is where a lot of our key scientists fall into.
I
will say just a little bit about funding because funding is a little bit
different perhaps for us than certain other organizations. Salary and overhead are part of the FDA
base, but we are actually given at the Division level our funds for expendables
and equipment.
In
general, we have broken it down into two categories here: the general FDA appropriation ‑‑
this is everybody who is not working with counterterrorism agents ‑‑
and counterterrorism funds. This past
year we have had both kinds of fund.
So
we have Division operating funds that we take out of this, as well as we
identify special needs, if there is some unusual expense coming up for somebody
in the Division in the next year, and then the rest of the money is distributed
on a per-capita basis. That takes care
of things like pipettes, reagents, and so forth.
Some
people do get extramural funds, like from the National Vaccine Program Office,
Office of Women's Health, and so forth.
Those go directly to whoever is working on that.
Then
these are some year-end funds that we can use for a variety of things,
particularly special pieces of equipment that we have identified but not been
able to purchase up to that point.
So
that's, very quickly, finance in our Division.
The
final two things I would like to leave you with is what I call the challenges
and realities facing our researcher reviewers.
Now some of the things that we are faced with are the same things that
other people, particularly in the government, are faced with, like funding
levels are uncertain year to year and dependent upon the appropriation
process. Of course, we're still waiting
on that.
There
are bureaucratic hurdles that are part of any large organization. That doesn't mean that we don't have very
good people working with us and they are trying to support us, but personnel
and purchasing and other types of things can sometimes be very cumbersome in
our type of organization.
The
biggest thing, and the thing that is unique to the FDA, is that the timing of
our workload for our researcher reviewers is determined by the sponsor, and not
by CBER. When something comes in, the
clock starts running and we have to deal with that.
So
that is something that you need to keep in mind when you are looking at the
work that our researcher reviewers accomplish, because what they have
accomplished, they have accomplished even in view of the fact that they spend
sometimes maybe 50 percent of their time in review-type activities.
Finally,
the thing that I left the Site Visit Committee with is to review our
individuals, review our program, and comment on our future directions. I guess that is what we will be talking
about a little bit later.
So
that is really all I have to say at this time.
If you want me to, I will just turn it over to Carl Frasch.
CHAIRMAN
STEPHENS: Comments for Dr. Walker?
(No
response.)
Could
you just elaborate a little bit more? I
know you showed us a chart of the pathway for career development. Could you go back to that and just help
those of us in academic medicine kind of ‑‑
DR.
WALKER: Also, just to put it in the
academic terms, like somebody at a GS‑15 level would be appropriate to be
a full professor. That is one way to
think of that.
Or
somebody coming out of a post-doc and a few years past that would be what we
call our senior staff fellow positions.
These lead people, they would be getting paid at roughly what we call a
GS‑11/GS‑12 range. Then, as
they go forward, now we are talking moving from like assistant to associate
professor, we're moving up, and like I said, what you think of a GS‑15 is
like a full professor.
We
have one other category that a few of our scientists fall into. These are people in the Senior Biomedical
Research Service. These are people who
have really become a leader in whatever field they are in, and they are really
outstanding people. So this would be a
very senior person in the academic field.
The
other track we have is that some people are just like very senior technicians
that have a reasonable amount of responsibility and some degree of
independence. These people may work up
to, let's say, a GS‑12 level.
There
are other people that can be doctoral or not doctoral, as they show here, that
can even go higher. We have some
doctorate-level people who elect not to be an independent senior investigator
and have their own program and post-docs and things, but they would prefer to
work under the mentorship of another senior scientist. So that's a track that kind of a person
could fall into.
Does
that hit what you were trying to convey?
CHAIRMAN
STEPHENS: Dr. Myers?
DR.
MYERS: We were talking before about, in
the influenza session, about concerns of funding for particular areas of
regulatory research, which are often not appreciated for their difficulty and
their importance. They are not as sexy
as some of the other types of research.
At
both prior VRBPAC meetings and at EMDAC meetings the Committees expressed a
great concern and frustration about the level of funding support that CBER
specifically receives for its regulatory research. You sort of alluded to the uncertainties of that.
I
wondered if you could specifically tell us how CBER, and then the FDA, sets
those priorities and how the Department would respond to the advisory
committees, because they have not, either the Department or the FDA, about the
concerns of the really inadequate regulatory research funding.
DR.
WALKER: Yes, because I have only been
here a little over two years, but, as I understand, back in the mid-nineties
funding was much better than it is now.
Now it is making a little bit of an upswing now, but that has been an
ongoing battle.
In
fact, if it hadn't been for the influx of counterterrorism money and some of
the outside money that I referred to that people have been able to get, it
would be very difficult to carry on the level of research, productive research,
that we have been doing.
You
mentioned setting priorities. This is
something that the advice of the Site Visit Committees is taken very seriously
and reviewed, and we use that to help identify what our priorities should be. In fact, a plan that I will commit to, and I
have already discussed, is that after this review is over, and also I wanted to
wait until Dr. Blake got on board, we are going to take a retreat for the
Laboratory of Bacterial Polysaccharides to talk about some of the research
directions that that group should be following.
We
continually try to review our work, so that we make sure that we are doing what
we believe is the most important things and putting our resources where they
are needed. The problem is sometimes
getting the financial resources to do that.
We are all working to make that better, and all the way up through the
CBER people are trying to improve that, but eventually it comes from an
appropriation. That is what we are
dealing with.
CHAIRMAN
STEPHENS: Dr. Couch?
DR.
COUCH: I had two questions that were a
little bit the same as Marty. One was,
if one of these levels is your tenure level, is that the senior investigator
level, basically?
DR.
WALKER: Yes, that's when you're
getting ‑‑
DR.
COUCH: Then they are tenured -‑
DR.
WALKER: Yes, that's a tenured person,
yes. I should have mentioned that. That is a good point.
DR.
COUCH: And not before that ‑‑
DR.
WALKER: Right.
DR.
COUCH: -- and a staff scientist is not
a so-called tenure-level either?
DR.
WALKER: Right.
DR.
COUCH: The second was, is your budget
totally available to you or to CBER, or whatever level, to do with as you
choose or is some of it mandated for regulatory responsibilities and a
proportion is available for personal research?
DR.
WALKER: Most of it that we get is
available to use for the research as we see fit. Also, we have to set aside certain money for lot release
activities.
DR.
COUCH: Those decisions on the use
between the regulatory ‑‑
DR.
WALKER: Right.
DR.
COUCH: -- or other research are made
within the Division?
DR.
WALKER: Within the Division, yes.
Any
other questions or clarifications?
(No
response.)
CHAIRMAN
STEPHENS: Thank you. Thank you very much.
We
will move now to a presentation by Dr. Carl Frasch on the overview of the
Laboratory of Bacterial Polysaccharides.
Carl?
DR.
FRASCH: Okay. You have heard about the Division. Now you are going to hear about an overview of the Laboratory of
Bacterial Polysaccharides.
Unlike
some of the other laboratories you may have heard about, we are not unified
around a single organism. The mission
of this laboratory is unified around the fact that most all invasive bacterial
diseases in the young pediatric population are caused by bacterial species
having polysaccharide capsules. This
includes Hemophilus influenza, Neisseria meningitides, streptococcus
pneumoniae, streptococcus A galactae, also known as Group B strep. We have vaccines, either licensed or in
clinical studies, for each and every one of these organisms.
Now
our laboratory has an extensive list of vaccines for which we have licensed and
have direct responsibility for:
polysaccharide vaccines; we have a pneumococcal 23-valent vaccine by
Merck that I just had to take literally off the list.
We
have a 4-valent polysaccharide vaccine by Aventis Pasteur, the VI typhoid
vaccine, the polysaccharide vaccine by Aventis Pasteur, and we have conjugate
vaccines. We have several different
Hemophilus influenza type B vaccines made by Wyeth, Aventis, Merck.
We
have the relatively-new pneumococcal-7 valent conjugate vaccine. Not only that, we have combination vaccines;
for example, Merck's Combex vaccine.
So, therefore, we have a number of vaccines that our laboratory is
directly responsible for.
So,
therefore, we have quite a bit of regulatory activities. We have over 125 active INDs, the product
license applications and supplements. I
went through 1980 when we changed numbering systems. So we have had over 80 submissions up through the fall of last
year.
We
hold meetings and conference calls with manufacturers, and all those vaccines
you saw on the list, we do lot release protocol review and lot release
testing. We receive approximately 400
protocols per year for these products.
So that is one of our other responsibilities, not only research, but a
heavy regulatory load.
We
also assist in training of reviewers and inspectors, and some members of my lab
actually participate in inspections in manufacturing facilities. Of course, some of us make presentations to
VRBPAC.
All
right, now various members of our laboratory are well-recognized outside of the
FDA. That is important. We are temporary consultants to the CDC,
PAHO, WHO, PATH, the Gates Foundation.
We help draft WHO requirements of conjugate vaccines. In the past we have done that for
polysaccharide vaccines.
We
review Red Book chapters on polysaccharide and conjugate vaccines. We do journal reviews for multiple
journals. Some of us are on the
editorial board of journals. We do
grant review for the Meningitis Research Foundation in UK. I do Military Infectious Disease or MIDRP
reviews.
We
are on the organizing committee for major workshops, and then we train and work
with foreign laboratories in quality control and have members from their
laboratories in our laboratory in a training situation.
So
getting to the research, the Laboratory of Bacterial Polysaccharides overall is
responsible for conducting the basic and applied research on problems related
to the preparation, purity, stability, and immunogenicity of investigational
and licensed vaccines for encapsulated bacterial pathogens. We are involved in evaluating host-parasite
interactions for the pathogenesis and protective immunity.
Okay. As I said earlier, our laboratory is not
organized around a single bacteria but around the fact that the bacteria
produce capsular polysaccharides. Now
since many of the bacteria also elaborate lipopolysaccharides, that is under
our purview also.
So
the organization of the Laboratory of Bacterial Polysaccharides is the
Polysaccharide Immunity Section is headed by myself. Our new Cellular Immunology Section, looking at the immunology of
the immune response to polysaccharides, and later on conjugate vaccines, is
headed by Mustafa Akkoyunlu.
The
Pathogenic Neisseria Section is headed by Dr. Margaret Bash, and the
Lipopolysaccharide Section is headed by Dr. Chao-Ming Tsai, and most of the lot
release activities are in the Polysaccharide Conjugate Vaccine Release Section,
under Dr. Chi-Jen Lee.
So
what I am going to do next is I am going to go through very briefly some of the
emphasis for each of these different labs and then give, very quickly, a couple
of bullet points on recent achievements.
So,
first of all, the research objectives for the Bacterial Polysaccharide Immunity
Section is we conduct research to evaluate the ability of polysaccharide and
conjugate vaccines to induce protective immunity, and we do studies on
different conjugation chemistries to improve conjugate yields and to improve
the immune response in the native polysaccharide epitopes.
The
research objectives for the Immunity Section:
We focus on the initial phase of the polysaccharide vaccine encapsular
bacterial interaction with host immunity.
We seek to define the interaction of polysaccharides with toll-like
receptors on innate cells. The
biological research resulting from this effect may affect the development of
adaptive immune responses against polysaccharides.
Then
we investigate the role of proliferation-inducing ligand, or APRIL, and B
lymphocyte stimulator, or BLyS, and infant and adult immune response to
bacterial polysaccharides.
I
actually have a few comments I want to make on the achievements, some brief,
quick achievements of each of the labs.
Let me quickly see if I can find this.
Okay, here.
For
example, one of the achievements we have made in the Immunology Section, which
is, of course, we have only had that section for less than a year, we have
identified a polysaccharide interaction that affects the activity of toll-like
receptors. We don't know if that
interaction is directly on the receptors or whether it is through mediators.
Let
me go back to one point from the Polysaccharide Immunity Section. One of our accomplishments is that we have
developed a new, general purpose, high-yield conjugation method with yields
greater than 70 percent, and we are in the process of having this method
patented. We have applied this method
to several different bacterial species, and it works for each one of them. So that is one of our achievements in the
Bacterial Polysaccharide Section.
Now
the Pathogenic Neisseria Section, they investigate the por proteins of
Neisseria gonorrhoea and Neisseria meningitides. So, therefore, that is why we call it the Pathogenic Neisseria
Section, because we originally got started looking at the outer membrane
proteins of Neisseria meningitides, and then evolved in looking at the proteins
of Neisseria gonorrhoea.
So
we look at studies of the natural epidemiology of por variation using novel
marker titer methods. We evaluate the
effects of por variation on host pathogenic interaction, including immune
responses to por, structure function restrictions on por, and transmission
patterns. Then we identify the
mechanisms of a por variation through investigation of mixed infections,
diverse in clonal populations.
So
a couple of the key accomplishments in the last couple of years in the
Pathogenic Neisseria Section is that, one, we showed that the osteoto groups of the meningococcal group A
polysaccharide are really critical for the induction of protective bacteria
cell antibodies.
The
second achievement is that we have developed a sensitive gonococcal genetic por
typing system that we are using to investigate por-specific immunity to
gonorrhea. Again, that section is by
Dr. Bash.
So
the last section I am going to tell you about is the Lipopolysaccharide
Section. It conducts research to
evaluate chemically or genetically detoxified meningococcal LPS bound to
protein as a potential vaccine for group B meningococcal disease. As a number of you realize, we really have
no licensed vaccine for the group B meningococcus. So we are looking at possibilities from a variety of angles,
including the LPS.
Then
Dr. Sigh has also looked at studies on the genetics of LPS biosynthesis in
pathogenic and commensal Neisseria species, characterizing their LPS
immunochemically.
And
a couple of achievements with the Lipopolysaccharide Section is to find a new
gene, LTGH, in the biosynthesis of the meningococcal lipopolysaccharide, and he
has also found that the sylation of the terminal galactose in meningococcal LOS
requires at least a tri-saccharide moiety in the alpha chain for the sylation
to occur. Of course, in the gonococcal
sylation, it is critical for the serum-resistant strains.
So
that's all I have to say.
CHAIRMAN
STEPHENS: Thank you, Carl.
Any
comments, questions, for Dr. Frasch?
(No
response.)
Okay,
thank you very much.
We
now have an open session. Dr. Sachs?
DR.
SACHS: As a part of the FDA advisory
committee meeting procedure, we are required to hold an open public hearing for
those members of the public who are not on the agenda and would like to make a
statement concerning matters pending before the Committee.
I
have not received any requests at this time.
If there is anyone in the room who would like to address the Committee
at this time, please come up to the mike.
(No
response.)
For
the record, there is no response.
Thank
you, and at this time I would like to close the open public hearing and turn
the meeting back over to Dr. Stephens.
Thank you.
CHAIRMAN
STEPHENS: Please, consultants, if you
can, and all of you, stay for this session; we need a quorum for this
discussion.
(Whereupon,
the foregoing matter in open session went off the record at 2:49 p.m. to reconvene
in closed session at 2:49 p.m.)