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                   94th MEETING


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                 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.




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













LINDA CANAS                           Department of Defense

SAMSON LEE, Ph.D.                     Aventis Pasteur



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


  World Surveillance and Strain Characterization


  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



                                         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.


            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.


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


            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?


            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.


            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?


            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.


            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.)