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UNITED STATES OF AMERICA

	FOOD AND DRUG ADMINISTRATION

	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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	VACCINES AND RELATED BIOLOGICAL PRODUCTS
	ADVISORY COMMITTEE

	MEETING

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	WEDNESDAY,
	JANUARY 30, 2002

	The Advisory Committee met at 9:00 a.m. in the Versailles I and II Rooms of the Holiday Inn Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Robert S. Daum, Chairperson, presiding.

PRESENT:
ROBERT DAUM, M.D., Chair
MICHAEL DECKER, M.D., Member (non-voting)
PAMELA DIAZ, M.D., Member
WALTER FAGGETT, M.D., Member
BARBARA LOE FISHER, Member
JUDITH GOLDBERG, Sc.D., Member
DIANE GRIFFIN, M.D., Ph.D., Member
SAMUEL KATZ, M.D., Member
KWANG SIK KIM, M.D., Member
STEVEN KOHL, M.D., Member
AUDREY MANLEY, M.D., M.P.H., Member
PETER PALESE, Ph.D. Member
GREGORY SLUSAW, PhRMA.
DIXIE SNIDER, M.D., M.P.H., Member
DAVID STEPHENS, M.D., Member
RICHARD WHITLEY, M.D., Member

ALSO PRESENT:
WILLIAM FREAS, Ph.D., Executive Secretary
NORMAN BAYLOR
DANA BRADSHAW
LINDA CANAS
ROBERT COUCH, M.D.

ALSO PRESENT:
NANCY COX, Ph.D.
BENEDICT DINIEGA, M.D.
WALTER DOWDLE, Ph.D.
BILL EGAN
THEODORE EICKHOFF, M.D.
KEIJI FAKUDA
NEIL GOLDMAN
JESSEE GOODMAN
ALEXANDER KLIMOV
ROLAND LEVANDOWSKI
KAREN MIDTHUN
MARTIN MYERS, M.D.
GREGORY POLAND, M.D.
JODY SACHS
ZHIPING YE
RICHARD YORK
KATHRYN ZOON

	I N D E X

Call to Order, Introductions, Administrative
	Matters, Dr. Robert Daum ..................	4

Presentation of Plaques to Retiring VRBPAC
	Members, Dr. Kathryn Zoon, FDA ............	8

Session 1 - Open Session
Strain Selection for Influenza Virus Vaccine for
the 2002-2003 Season

Introduction, Dr. Roland Levandowski, FDA .......  	11

U.S. Surveillance, Dr. Keiji Fukuda, CDC ........	17

World Surveillance and Strain Characterization,
	Dr. Nancy Cox, CDC ........................ 38

Molecular Characterization of Strains,
	Dr. Alexander Klimov, CDC ................. 74

Open Public Hearing ............................. 88

Additional Surveillance Reports, Ms. Linda
	Canas, DOD ................................ 89

Vaccine Responses, Dr. Roland Levandowski, FDA . 106

Availability of Strains and Reagants, Dr.
	Zhiping Ye, FDA .......................... 130

Comments from Manufacturers, Dr. Slusaw, PhRMA . 137

Options for Strain Selection, Dr. Roland
	Levandowski, FDA ......................... 146

Committee Discussion and Recommendations ....... 178

Open Public Hearing ............................ 203

Adjournment .................................... 203

	P R O C E E D I N G S
	9:09 a.m.
		DR. DAUM:  Good morning.  We call the meeting to order and the first post-Nancy Cherry iteration of our Committee and having said that we are grateful to Bill Freas for being here and stepping into tall shoes.
		I think we'll begin today with asking Committee Members and guests and consultants to introduce themselves to us and then we'll proceed into our business.
		David, would you start off, please?
		DR. STEPHENS:   Yes, David Stephens, Emory University, Atlanta.
		DR. KIM:  Kwang Sik Kim, Johns Hopkins.
		DR. KOHL:  Steve Kohl, Argonne Health Science University.
		DR. SNIDER:  Dixie Snider, CDC.
		DR. GRIFFIN:  Diane Griffin, Johns Hopkins.
		DR. DIAZ:  Pamela Diaz, Chicago Department of Public Health.
		DR. MANLEY:  Audrey Manley, Spellman College, former Public Health Service.
		DR. PALESE:  Peter Palese, Mt. Sinai School of Medicine in New York.
		DR. WHITLEY:  Rich Whitley, University of Alabama, Birmingham.
		DR. FAGGETT:  Walt Faggett, D.C. Department of Health, Howard University.
		DR. GOLDBERG:  Judy Goldberg, NYU.
		DR. DAUM:  And now our guests and consultant contingent.
		Ted?
		DR. EICKHOFF:  Ted Eickhoff, University of Colorado.
		DR. DOWDLE:  Walter Dowdle, Task Force for Child Survival and Development, Atlanta.
		DR. COUCH:  Robert Couch, Baylor College of Medicine, Houston.
		DR. POLAND:  Greg Poland, Mayo Clinic, Rochester.
		DR. MYERS:  Martin Myers, National Vaccine Program Office.
		DR. DECKER:  Michael Decker, Vanderbilt University and Independence Pasteur.
		DR. DINIEGA:  Ben Diniega, Department of Defense, Health Affairs.
		DR. COX:  Nancy Cox, CDC.
		DR. LEVANDOWSKI:  Roland Levandowski, Center for Biologics, Evaluation and Research.
		DR. DAUM:  Thank you.  Ms. Fisher has arrived.  Do you want to introduce yourself, please?
		MS. FISHER:  Barbara Loe Fisher, National Vaccine Information Center.
		DR. DAUM:  And I'm Robert Daum from the University of Chicago.  And we'll turn the floor over to Bill now for conflict of interest statement.
		DR. FREAS:  I would like to read into the public record the conflict of interest statement for this meeting.
		The following announcement addresses the conflict of interest issues associated with this meeting of the Vaccines and Related Products Advisory Committee Meeting on January 30, 2002.  Based on the agenda made available, it has been determined that the Committee discussions for the influenza virus vaccine formulation present no potential conflict of interest.  The Director of the Center for Biologics Evaluation and Research has appointed Drs. Robert Couch, Walter Dawdle, Theodore Eickhoff, Martin Myers and Gregory Poland as temporary voting members for the discussion on the selection of the strains to be included in the influenza virus vaccine for the 2002-2003 season.
		In the event that the discussions involve specific products or firms not on the agenda for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted in the public record.
		With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
		Dr. Daum, I turn it over to you.
		DR. DAUM:  Thank you very much, Bill.  One of the more remarkable aspects of this Committee is it ability to renew and refresh itself and the ability of FDA and other government agencies to find such a talented group of people who are willing to drop everything six times a year and come to Washington to discuss these issues.  And with that, of course, comes a rotating nature and we have friends and colleagues who we've gotten used to having dinner with and debating issues with that take their leave from Committee service.  So it's a bittersweet time and we're going to call on Dr. Kathy Zoon to mark the rotation of some of the Committee Members who have been serving faithfully these years.  And we welcome, of course, some of our new Members as well.
		Dr. Zoon.
		DR. ZOON:  Thank you, Bob.  I guess it is one of those bittersweet moments and there's an enormous amount of hesitation I have because some of the folks who are leaving today have made so many contributions that having them not be part of the Committee right now is going to be a very sad thing for this Committee.  On the other hand, we have as Bob says, new people coming.
		I would like to ask Bill Egan to join me up here because we would like to have some special recognition for the advisors who are rotating off the Committee.
		I would just, in saying that, these Advisory Committees for us are so valuable.  They provide us advice in a public forum that allows us to collect information and recommendations for many, many important public health decisions.  In particular, this Committee which is faced with many difficult issues over certainly the past 3 years on important topics related to vaccine safety, vaccine approvals.  This has been something that has challenged all of us in the Public Health Service, more broadly, as well as in the pharmaceutical industry and the communities together and ultimately, I believe, that the advice we've gotten from this Committee over the years has always been balanced, reflected many points of view and we really try to collect that information in a way to help us give the best advice to medical care workers and consumers.
		So in saying this today, we want to reach out and give special thanks.  I would like to ask Dixie Snider, Steve Kohl and Kwang Sik Kim to please come to the podium and Bill, would you like to say a few words?  Karen can't be with us right now this morning, but I'd like to ask Dr. Egan to just maybe say a few words reflecting on his own experience over the past few years.
		Thank you.
		DR. EGAN:  I'd just like to echo Kathy's remarks and say that the sage advice and knowledge that's been imparted to us by this Committee has been extraordinarily important in helping us to reach all of the decisions, many, many difficult decisions that we've had to do.  There have been some very tough issues over the past year dealing with vaccine preservatives, additives, materials in them, licensing and new products.  It's always been hard and having this group here and their combined knowledge and wisdom has been just extraordinarily helpful and it's hard to imagine how things could have been done without this group.
		We and the Office and certainly CBER are truly grateful for everything that everybody here has done.
		DR. ZOON:  Thank you, Bill.  I now would like to provide these three gentlemen plaques, but first I'd like to read a letter to all of them that was signed by Linda Sudam.  Linda Sudam is the Senior Associate Commissioner for Communication and Constituent Relations and has responsibility for the bigger FDA Advisory Committees and overseeing them.  And she says to the Members, "I would like to express my deepest appreciation for your efforts and guidance during the term as Member of the Vaccines and Related Biological Products Advisory Committee.  The success of this Committee's work reinforces our conviction that responsible regulation of consumer products depends greatly on the participation and advice of the entire health community.  In recognition of your distinguished service to the FDA, I am pleased to present you with this enclosed certificate."
		So I want to just say first, Dixie, I will miss you here, but I know we're going to keep on talking because that's that FDA and CDC does, so thank you very much for your service.
		(Applause.)
		(Photos taken.)
		DR. ZOON:  Next we have Steve Kohl.  Steve, congratulations and thank you so much.
		(Applause.)
		(Photos taken.)
		DR. ZOON:  Dr. Kim, thank you so much for everything.  We really appreciate it.
		(Applause.)
		(Photos taken.)
		DR. DAUM:  Thank you, Dr. Zoon.  We'll now move on to the formal business at hand and begin our strain selection process for the influenza virus vaccine for next year, although some might argue that the season hasn't yet happened this year.  But we'll hear more about that as the day goes on.
		And we will begin, of course, by calling on Dr. Levandowski who will give an introduction to the topic.
		Roland, thank you.
		DR. LEVANDOWSKI:  Thanks, Dr. Daum.  I'd like to welcome everybody here this morning and I think you know why we're here, but I'm going to give a little brief introduction into what we plan to do.  As you probably know, we're here today to start the process of selecting the influenza virus strains that are going to be included in vaccines prepared for the 2002-2003 season in the United States.  Could I have the next slide, please?
		The basic question to be answered by the Committee is shown on this slide.  This is a little bit abbreviated from what's actually been handed out and I'll put that one up later, but really, what we want to know is what strains should be recommended for inclusion in inactivated vaccines for next year.
		Next slide, please?
		In formulating an answer to that question, I think it's helpful to review some facts about the currently approved influenza virus vaccines and this is true from the beginning, probably, for inactivated vaccines.  The inactivated influenza vaccines, of course, act primarily by inducing production of antibodies and the hemagglutinins and the neuraminidases of the incorporated influenza viruses in the current vaccines are concentrated and they're partially purified to remove extraneous materials that are derived from the eggs in which the vaccines are produced.  Although the antibodies to both hemagglutinins and neuraminidases are protective, the influenza vaccines that we use currently are standardized, really only for the content of the hemagglutinin and therefore we place the greatest emphasis on the viral hemagglutinin, but I would point out that the neuraminidase receives consideration and it too may have some protective effect in terms of how the vaccines function.
		Since the use of the first inactivated vaccines in the 1940s, it's been very clear that one of the most important predictors of vaccine efficacy is the match between the vaccine virus and the ones that are currently causing infection.  What's also been made clear with yearly epidemics and pandemics that have occurred infrequently is that influenza viruses have very great scope for antigenic diversification.  The on-going random mutations of the hemagglutinin and neuraminidase we call antigenic drift and exchange of entire genes can occur with other influenza viruses and we call that antigenic shift.  And both of those participate in the continuous evolution of the viruses.
		Can I get the next slide, please?
		It might also be helpful to consider answers to these questions.  Most importantly, it's necessary to know if the new influenza viruses that are out there, really are new and there's an extensive global network that exists to collect and analyze information throughout the year and we're going to hear shortly from our colleagues from both CDC and Department of Defense in terms of the surveillance and what viruses are being found.
		When new viruses are identified, the extent of geographic distribution helps to judge the urgency that we might have in trying to change the composition of the vaccine and we've often seen in the past that there are antigenic variants that occur, but sometimes these just represent dead ends and go no further than one off.
		As you've also seen in the past, however, there can be some very rapid spread of influenza viruses and that, I think, is of more concern, of increasing concern in modern times when it's possible for people to jet from one side of the globe to the other.
		If those strains have, or can disseminate widely, it's useful to know whether or not the current vaccines are likely to provide some form of protection against those and if it appears that the current vaccines could be suboptimal, then it's still necessary in a practical sense to consider whether we've got any suitable vaccine strains that would permit large-scale manufacturing within the constraints of time that exist in terms of making a new vaccine every year.
		So the agenda of presentations that will follow will try to supply information to answer each of those questions.
		If we can get the next slide?  This slide shows the recommendations that have been made during the past year and on the left are the recommendations that were made for the United States and the Northern Hemisphere by the Public Health Service and World Health Organizations, respectively.  And on the right are the most recent recommendations from the World Health Organization for the Southern Hemisphere.  And you'll note that currently the recommendations for vaccines in both hemispheres are identical.  This isn't always so.  In fact, it's more typical for us to see that there are differences between the Northern and Southern Hemisphere vaccine recommendations and that's really related again to the continuing antigenic changes that are occurring in influenza viruses.  But what I could say, part of the reason that the recommendations, the most recent recommendations made for the Southern Hemisphere in September-October of 2001, those changes reflect the fact that there have been little in the way of changes, relatively little in the way of changes that have been identified in the new influenza viruses and that's really a very unusual sort of pause in the world of influenza.
		So since the recommendations are based on information, the choice of the strains that was made in September really followed from what was available then and without giving away what's going to be presented by others, I think we're going to hear this morning that the system of making recommendations is sound, as long as the recommendations can really be well-informed by sufficient epidemiologic laboratory and manufacturing data.  And I'll stop there because that's really all I have to say at this point.
		DR. DAUM:  Thank you very much for being succinct.  Are there any comments or questions based on what we've heard so far or would we like to hear a little more first?
		Thank you very much, Roland.  We'll move on now to Dr. Fakuda.  There he is.  Good morning, Dr. Fakuda.
		DR. FAKUDA:  Good morning.
		DR. DAUM:  Dr. Fakuda will talk to us about the U.S. surveillance.
		DR. FAKUDA:  Good morning, everybody.  What I'm going to do with this talk this morning is show a couple of slides to put the season in context and really in anticipation of questions related to how does this season compare to previous seasons.
		May I have the next slide?  For those of you who have studied influenza, I think you all realize what a plastic -- or how the presentations can be very plastic and vary from season to season.  And in this slide here, there are two things that I wanted to point out.  When you look down at those circles at the bottom, these are the proportion of viruses which have been isolated each season over the past 11 years, the first season being 1991 through 1992 and the last season being the current one.  The red color are influenza A(H3N2) viruses.  The green color are influenza A(H1N1) viruses.  And the blue color are influenza B viruses.  You can see that from season to season that there can be substantial differences between the influenza viruses which are isolated each year in terms of the proportions.
		Now when you look at that sinusoidal curve up above, that represents the influenza mortality related to pneumonia in influenza-related mortality that we see each year in the country as monitored by the 122 cities surveillance system.  And again, you can see that in terms of overall mortality, in terms of mortality that it varies, it can vary substantially between years.
		And in general, you can see that in influenza A(H3N2) years, we tend to see fairly severe mortality, but this is not always true and you can see that in other years in which influenza A(H3N2) viruses are common that mortality is lower.  So it's not such a simple correlation.  But again, you can see that the severity of seasons vary substantially and the mix of viruses can vary substantially from season to season.
		Now in this slide here what I wanted to depict was that the onset in the timing and peaking of influenza seasons can also vary tremendously depending on what season we're talking about.  Now these curves here represent the proportions of specimens that are testing positive for influenza viruses by each week and generally these represent when the season is peaking and you can see that in this first curve here, this blue curve which represents the 1999-2000 season, that we have a relatively sharp upswing and a fairly early peaking in influenza viruses being isolated, so that in the 1999-2000 season, the season really peaks somewhere towards the end of the year and the beginning of the following year.
		By contrast, you see this red line over here, this red graph which represents the 1987-1988 season and you can see that the up slope of the viruses being isolated is somewhat flatter.  And you can see that the time of the peaking of the season is really quite different and this is about Week -- I don't know, between 14 and 16.
		And when you look over the data for the past several years, there can be a separation of about 18 weeks between seasons in terms of when we see peaking.  So that's quite large variability.  And so this black line right here represents the current season and as I will show I think that we haven't yet peaked, so we don't really know when the peaking of the seasons is going to occur.
		Now this is the last of the background slides, but here what we did, we went back over the past 25 seasons and tried to identify in which month each of those seasons peaked, again to give you a sense of how seasons progress in the country and you can see that over the past 25 years, the most common month in which the season peaked was in February, but again, there were four seasons which peaked in December and there were a couple of seasons which really peaked pretty far out there and so again, the variability and the timing of the influenza season can be quite wide.
		Next slide, please.  Okay, so let's go -- this is the current season now.  This is what we're seeing right now.  And this graph here represents the viruses which are being isolated in the United States for this current season.  The yellow bars represent influenza A viruses which have not been subtyped.  The red bars represent influenza A(H3N2) viruses and then again the green bar represents B viruses and blue represents A(H1N1).  And so when you look at this, it's very clear that this is an influenza A season so far in the United States.  And of those influenza A viruses which have been subtyped, by far the majority are influenza A(H3N2) viruses.
		Now this black line here represents the weekly percentages of respiratory specimens that are being tested and that are positive for influenza viruses and you can see that on each week the percentage of respiratory specimens being tested has increased in terms of being positive for influenza viruses.  At our last point, this represents about 13.9 percent of specimens being tested are positive for influenza and to put that in perspective, again, when you look over the past several seasons, seasons usually peak out at about 24 to 33 percent of respiratory specimens being positive for influenza viruses.  And so although again we don't know when the season is going to peak this year, these data suggest that we haven't yet seen the peaking of this season and so we don't know when that's going to occur again.
		Next slide, please.  So just to run some of the numbers by you, so far we've had about almost 26,000 specimens tested.  Of these, about 5 percent or 1,299 have been positive for influenza and of those positives, 98 percent of them have been influenza A viruses; 2 percent have been B viruses.  And again of those that have been subtyped or 37 percent of those viruses have been subtyped and of those which have been subtyped 98 percent are A(H3N2) viruses and 2 percent have been influenza A(H1N1) viruses.  So again, an influenza A season with A(H3N2) viruses predominating.
		Now by contrast, when we look at clinical activity in the country and these represent two sentinel physicians for influenza-like illness and currently this represents about 650 physicians spread throughout the country that are reporting fairly regularly.  We can see that the percentage of visits of influenza-like illness has really just been going up pretty slowly.  And I think this captures pretty well the general perception that it's been a fairly low and slow season so far.
		Now if you look at the national baseline for influenza-like illness visits, it's about here, about 1.9 percent is a rough national average for influenza-like visits.  And again, when you look at earlier seasons you will see that this graph will peak out somewhere between 4 and 5 percent to about 7 percent when we're at the peak of a typical season.  So again, this suggests that the activity is fairly low, but it is increasing and again suggests that it has not yet peaked out.
		Now this map of the United States represents reports from each of the State and territorial epidemiologists and this represents the most recent reporting week, the week ending January 19th.  The red States are those States which are reporting widespread influenza activity.  The blue States are those representing regional activity.  And then the green States are reporting sporadic activity and the yellow States are reporting no activity.
		So again, you can see that the activity is somewhat scattered around the country and again if anything we would typically see more States reporting either regional or widespread activity if we were toward the peak of the season.
		And then finally, this is a graph of the same data, just graphed out in terms of bars here and you can see that the aggregate number of States reporting either regional or widespread activity has been increasing, but again, it remains fairly moderate.
		And this is the last graph and this represents mortality associated with pneumonia and influenza.  And again, this is data reported through the 122 cities surveillance system.  I think all of you remember that last year it was a pretty mild season in terms of mortality, especially, and so far this year it also remains relatively mild in terms of mortality.  We haven't seen any real increase over the so-called threshold level.  So I think I will stop there and see if there are any questions.
		DR. DAUM:  We'll take a few minutes for Committee questions and opinion.
		Dixie?
		DR. SNIDER:  Could you tell us -- I think some people may not be aware about the change in the coding and how that might influence the pneumonia and influenza deaths, mortality surveillance and whether you've got that worked out so that you think we're getting, are able to show data that are comparable now?
		DR. FAKUDA:  All right, you're talking about the ICD 9 to 10 coding?
		DR. SNIDER:  Right.
		DR. FAKUDA:  I think in terms of the graph which I just showed, that takes that into account because the reporting case definition for that sidesteps that issue of ICD9 going to ICD10 and uses the case definition which specifies what a PNI death is and doesn't rely on PNI coding.  But the coding issue is a rather profound issue for people monitoring diseases.  Over the past decade, WHO has been working to revise ICD9 coding to ICD10 coding.  And in terms of reporting for respiratory diseases and particularly pneumonia and influenza-like diseases, the change from ICD9 to ICD10 codes has been quite profound and those changes, if they had been implemented as first written down would have decreased measured deaths by about two thirds in the country, looking at NCHS data sets.
		What happened subsequently was that after that profound change was detected, there was a working group of WHO with input with a lot of other people and they went back and looked at the coding algorithm and made some modifications so that the affect on respiratory deaths or measurements of respiratory deaths will be less profound, but I think the current estimates are that when deaths recorded by ICD10 begin to come out, that there will be about a 33 percent or one third decrease in measured deaths and those deaths which aren't being measured and categorized as respiratory deaths then go out into a number of other categories such as strokes or other particularly chronic diseases.
		But at least in terms of the data here, it takes those into account and the reason why we made the reporting case definition change was because of all of those changes going on.
		DR. DAUM:  Dr. Diaz?
		DR. DIAZ:  I just wondered if you could comment, I'm always perplexed when I look at the WHO and NRVs reporting, the percentage of unknowns under the As or Bs as the case may be, and wondering if those unknowns represent isolates that have yet to be subtyped or if they're isolates that will never be subtyped and what the situation is in terms of the time frame for those.  I'm always worried about not having that information and if the tie up is at the local level, State laboratory level or what the situation is.
		DR. FAKUDA:  Well, Nancy can probably talk in more detail to this, but it represents a mixture of both viruses which have yet to be subtyped.  We don't have the data.  That curve is a little bit behind and it's always being updated and then some of those will be subtyped, but others will not be subtyped by the end of the season.
		Nancy, I don't know if you want to add anything.
		DR. COX:  I think that this is an issue that we've been talking with the States about for some time and it really is a resource issue, generally speaking.  At the State and local level there is a paucity of resources for some of the lab work that needs to happen.  And particularly, within the context of influenza pandemic preparedness we'd like to try to encourage and help the States to increase their capacity to subtype.
		DR. DAUM:  Dr. Couch?
		DR. COUCH:  I'd just like to add one comment to that though, you do specify it's influenza A or B so that that data is always known.  It's B unknown or A unknown and then it's like doing a representative group.  It takes so much time and effort, as Nancy says.  And that representative group says that 95 percent of H3N2, why, almost certainly if you were doing all of them you'd find the same thing.  So there's a high degree of confidence that we know what the unknowns are and I think people operate in their thinking that way.
		But I had just some informational questions if I might, Keiji.  I think it's asking you to confirm whether in looking at the weekly surveillance of what you see is true and that is there is a reporting lag here and that what you're reporting is what you have in hand for each week because as you move the week, the other weeks begin to pick up and just in trying to go through these it looks like the data that you published the front line is lagging about three weeks behind, not only in terms of specimens reported, but in terms of the typing of the specimens as well.
		DR. FAKUDA:  Yes, I think that the lag for the different systems vary somewhat, but for the virologic system, clearly, you know it -- information comes up and so when you look at that curve, for example, the most recent week will have a lower bar typically and then as we get a week or two out from there as more data comes in --
		DR. COUCH:  And I assume this is just the reporting from the peripheral laboratories?
		DR. FAKUDA:  Yes.
		DR. COUCH:  And it's a fact of life.  Now that was my other question  Is that also true for physician visits?
		DR. FAKUDA:  No.  The data for the physician visits is, you know, it comes through and you go back and if we see something which looks strange like there are a very high percentage of visits being reported, then we will go back to confirm with the State or go back to confirm with the physician.  So there's always a little bit of error checking in that system also, but I think the lag is less than it is for --
		DR. COUCH:  For the specimens in the virus.
		DR. FAKUDA:  Right, and I think the data change.
		DR. COUCH:  The reason for that question is that in the Houston surveillance which most everybody knows was a number of years ago in which in one place you're right on top of it from a weekly basis.  That was an extremely high correlation between the physician visits for febrile respiratory disease and the specimens acquired and the number of positives, so that if you're lagging with the specimens your physician visit may be the most current data set and your epidemic is peaking now.
		Now the other question I had was, was 1987-1988, do you happen to know what the virus was and the question of influenza A versus B and Walter may comment because we -- there's been the impression that influenza B was spread out -- tends to spread out over a longer period and may be the lagging virus and the March peak as opposed to the January peak which is more typical for an influenza A and of course, you're putting them all together there with the February as the mean peak.  The difference was in A and B was the question.
		DR. FAKUDA:  Clearly, there are seasons in which when you see a bimodal peak B frequently is the latter peak.  As to 1987-1988 specifically, I'll defer to Walter or Nancy or someone with a few more years.
		DR. DAUM:  Dr. Dowdle, do you want to comment on this issue?  Okay, then could you be second in line, Dr. Goldberg was ahead of you.
		DR. FAKUDA:  I can find that out, but I don't know.
		DR. DOWDLE:  I mean I agree with what Bob has been saying.  That has generally been the case.
		DR. DAUM:  Dr. Goldberg, please.
		DR. GOLDBERG:  Just to go back to the unknown subtypes.  You made a comment that you're assuming that what is typed is representative and I guess one question I would have to follow that up a little bit longer, can you really subtype them all or are there really unknown subtypes and can you do some study at least on some of these samples to ensure that we do have something representative?
		Is there some way to check that assumption because you really, if you look at this as the number of samples peaks, you're testing less and less relative to the number of specimens of samples that exist, so that's my question.  What's your assurance that it's representative?  Are we able to test that in some way?
		DR. COX:  I think that it's a fairly good assumption that it is representative because as we move through the seasons, the State and local labs are able to do more subtyping and generally speaking the proportions remain similar.  However, there's a caveat.  And there can be a pocket of H1 activity within the country.  It's not generally true, but there can be and so therefore we like to make sure that all areas are actually subtyping.  So if you have one particular area that wasn't doing subtyping at all, you might get into trouble with that assumption.
		Insofar as we know, there are not unsubtypeable viruses.  That is to say they are H3 and H1 viruses that are circulating.  In a pandemic situation, of course, you can't make that assumption and occasionally we do have exceptions to the general rule that they are human H1 and H3.  That is to say we have a swine H1 infection of a human and we can pick out those viruses.
		DR. DAUM:  Dr. Dowdle then Dr. Eickhoff.
		DR. DOWDLE:  I would just like to ask a question here about the ICD coding.  As you have explained it, Keiji, that is rather profound changes that we're talking about here and it's a fairly major adjustment.  So are there plans to validate that adjustment?  What -- how will you deal with this in the future?  I know Ted, this must be something that goes way back in the past, but this has been certainly a major measurement of activity over the years and validation would seem to be quite important here.
		DR. FAKUDA:  NCHS in the past year, year and a half did a validation study of it and they took the current testing algorithm and applied it and they're the ones who came up with the estimate that the decrease in measured deaths would be somewhere in the 30 percent range.  And so that has been done by them on a fairly large data set already.
		DR. DOWDLE:  Over several seasons.
		DR. FAKUDA:  I don't remember how many seasons they chose.  I don't think it was too many.  It may have been a couple of seasons.  But yes, it's something that has worried me a lot because this is such an important marker of activity for us and I don't think the people when they were originally making the algorithm changes realize what an immense impact this would have on the measurement of respiratory deaths and that certainly could have a big ripple effect in terms of the perception of respiratory diseases.  But what it will probably do will decrease PNI deaths from I think the current sixth position down to the seventh position as the leading cause of death, simply because of that algorithm change.
		DR. DAUM:  Thank you.  Dr. Eickhoff and then Dr. Poland.
		DR. EICKHOFF:  Keiji, am I correct in assuming that the physician office visit data is reported directly from physician office to CDC and does not go through the State Health Departments?
		DR. FAKUDA:  It's --
		DR. DAUM:  Can you repeat the question?  I'm not sure -- Ted, you need to speak right into the microphone for us.  I'm not sure everybody heard.
		DR. EICKHOFF:  The question was whether physician office visit data goes through State Health Departments or is reported directly to CDC?
		DR. FAKUDA:  Ted, it's kind of a hybrid situation.  Just to put the hybrid in context, as you know, much of surveillance which is done in the country has data go from primary reporters to the Health Department and then from the Health Department to CDC.  But also, many of the surveillance systems don't need to get their data out on a weekly basis in the way we do.  So what we did was come upon a compromise in which the Sentinel Physicians report data.  It goes to a server which both CDC accesses and then the States can access simultaneously and so we both get the data.
		If CDC in going through and looking at the data picks up anything unusual, we get back to the States not directly with the physicians and then ask is there anything going on in the State or can they check with the physicians about any unusual reporting issues.
		DR. EICKHOFF:  But that should still be the most current indicator of what's actually happening, isn't it?
		DR. FAKUDA:  Yes.
		DR. DAUM:  Thank you. Dr. Poland and then Dr. Diaz.
		DR. POLAND:  With the numerator and denominator kind of changing based on this coding by the same relative amount, will the epidemic threshold change?
		DR. FAKUDA:  No, again, these data -- there are two main systems for reporting deaths from influenza in the country.  The system which I'm pointing out here, using here is from the 122 cities, 122 cities which report vital statistics data on a weekly basis to CDC.  And so this represents about one third of all deaths in the United States.  So we asked those vital registrars offices to represent a PNI death and we define it in a certain way so it doesn't rely upon ICD coding.  But you know, a couple years after season you'll see those total number of deaths from influenza and those are estimated from a complete national data set obtained from the National Center for Health Statistics and that does rely upon ICD coding.
		To make it a little more complicated, there are a couple of cities in a couple of large vital registrars' offices in the country which do track only by ICD coding, New York, for example.  New York represents about 11 percent of all deaths in the system and so there are sort of complexities built in trying to get these estimates, but in general, this system is a little bit different than how we report data, the final data set a few years later.
		DR. DAUM:  Thank you.  Dr. Diaz, please.
		DR. DIAZ:  Just a couple of quick comments.  In terms of the prior comment that I made regarding the unknown subtypes, I was looking at that more from the standpoint of I certainly agree that in general as Dr. Cox pointed out, if each locale is doing some subtyping, most definitely or most likely what has been subtyped would be representative of what's going on in general in those areas and represent fairly generally the unknowns.  However, when you look at a surveillance system from the standpoint of trying to find unknown rare events like a shift or some unusual subtype that's emerging in an area, having those unknowns typed in a timely fashion would be -- go more towards an early warning system for those kinds and that's what I was really referring to in terms of the unknowns perplexing me or bothering me at times.
		Secondly, in terms of the Sentinel Physicians Network, having actually overseen the development of that in Chicago this season, we're just beginning our first season of direct reporting from Sentinel Physicians Network.  I can comment that the system that's set up in terms of direct reporting to CDC is, as you point, very important because you have to report weekly and yet on a local level we're able to access that in real time and fashion and those two elements are critical, I think, in terms of sharing information and having information that's pertinent on a local level and pertinent on a national level be available in both at the same time.
		DR. FAKUDA:  Just to add one thing to your first comment, I think that in terms of viruses which represent a shift which may be found in the U.S. at least, and even though a large number of viruses aren't subtyped, I think that if those viruses which are testing low with current reagents are identified, even if they're not subtyped generally they get slagged and I think that Sasha will frequently hear about them very quickly.  So there is some sort of extra safety measure in that.
		DR. DAUM:  As a novice to the subject, I must say I've often wondered when people who do surveillance like this and are really expert in influenza, which I'm not, would expect to see or take into account the deployment of the vaccine program in terms of influencing the surveillance that we see.  And we put out -- there's a lot of doses out there each year, X number of million and I just wonder in terms of thinking of this every day like you all do, when do you expect to see some impact on surveillance based on the program that we're here to help perpetuate?
		DR. FAKUDA:  Right.  I think that there are really two possible analyses for that, one which really hasn't been done and the other which has been done a number of times.  I think the analysis which has been done over and over again is the comparison between vaccinated and unvaccinated people for a variety of outcomes, but particularly death and hospitalizations and illnesses.  And again, I think any number of studies like that over a number of decades again show the effect of vaccinating people in terms of decreasing those adverse outcomes.
		The second analysis and what you're really getting at is can we look at mortality or hospitalizations in the country over all and say that current vaccination efforts have decreased things by so and so percent.  I think that -- I don't think that that analysis really has been done.  Certainly, it's been somewhat looked at by some people, including ourselves, but I think that analysis is yet to really be done.
		DR. DAUM:  Okay, I think we exhausted our input.  Thank you very much for sharing those data with us.  We'll call on Dr. Cox, if she's ready to talk about world surveillance and strain characterizations.
		DR. COX:  Well, good morning.  And it's really nice to see everyone here again.  There are many familiar faces, as we go through this process of selecting vaccine strains.
		Today, we have just lovely weather and I can remember a number of times when the weather hasn't been nearly this good for this particular meeting, so we can just bask in the sunshine when we go out for lunch.
		Now I'm going to be presenting the antigenic data which is comprised of both hemagglutinin inhibition and neuraminidase inhibition testing.  And I'm also going to be summarizing the global influenza activity and I'll summarize it very briefly, to put the U.S. within a more global context.
		So we'll be looking first of all for variants as Roland said.  Do we see viruses which are antigenically different from the vaccine strain?  And we'll pick those out using the hemagglutination inhibition tests primarily.  And then we'll be looking for spread of those particular variants in conjunction with human disease.  And finally, we'll be looking at whether the antibody response to the current vaccine covers those variants and whether there are reagent viruses suitable for vaccine production.
		You probably have noticed in the past that we choose, often choose to go through the virus group that appears to be the clearest cut first and that's no exception today.  So we'll start with the influenza H1N1 viruses.  And as you'll recall we had sporadic activity -- I don't know if that can be focused any better or not.
		(Pause.)
		If you look on page 11, you'll have the correct data.  What you'll see is that there actually was a reasonable amount of influenza H1N1 activity in North America and in Europe last winter.  And that also -- that H1N1 activity also occurred in the Southern Hemisphere with outbreak level activity in Australia and New Zealand and also in Asia during the summer and fall months.
		During the current season, there really has been only sporadic influenza activity associated with H1N1 viruses in the U.S., in Canada, and in Europe.  There also has been H1N1 activity that's been rather sporadic reported in Asia and in South Africa, Northern Africa and the Mediterranean.
		Now I'd like to spend just a moment orienting those of you who may be new to this to the hemagglutination inhibition tables that I'll be showing.
		On page 12 you'll see our first HI table for H1N1 viruses.  Now I'd like to remind you that there are two antigenic and genetic groups that we have been tracking among H1N1 viruses that have circulated globally over the past few years.  The first group is represented here by Johannesburg/82/96. That was a vaccine strain that was used previously.  And at one time this virus represented H1N1 viruses that were circulating globally.
		At the same time that viruses like Johannesburg were circulating globally, there was a small group of H1N1 viruses evolving in Asia, particularly in China which had a very specific -- which were already evolving and were different genetically when a deletion occurred in antigenic site A.  At that point these viruses became clearly distinguishable on an antigenic level from the Johannesburg/82/96-like strains.  And these viruses have been circulating globally, that is to say, both groups have been circulating over the past few years.  However, we found over the past year or so that the Johannesburg/96-like viruses have not been detected.  So we're really going to concentrate on viruses within the Beijing/262 New Caledonia group.
		Now what we've seen over the last year is that H1N1 viruses have really been very stable both antigenically and genetically, generally speaking.  However, we have isolated one particular variant which is very clearly shown in this particular slide by antigens 4 and 5 represented by these two antigens and I'll call this the Hawaii/15/2001 group.  You can see that these viruses, while related to New Caledonia, are antigenically distinct.
		I would like to say that there's a single amino acid difference that appears to be responsible for this change, for this antigenic difference and that we have just seen a handful of viruses popping up over the past two years.  You'll notice that the Hong Kong/1252 strain was isolated in the Year 2000 and that these viruses just pop up occasionally, but they don't appear to be really spreading or increasing in numbers over time.
		So now let's look down at the bottom part of the table and we see that we have viruses primarily from China and isolated primarily actually from -- mainly from South China and isolated during August, then September, through the summer and into the fall months when activity in South China is really peaking.  And these viruses look very similar to New Caledonia, that is to say, their titers are within twofold of the homologous New Caledonia ferret antisera titer with New Caledonia itself.  We're looking for viruses that have a fourfold or greater difference in consecutive tests. There's a certain amount of variability that's inherent in the hemagglutination inhibition test and a twofold difference in titers is not considered to be significant.  A fourfold difference is considered to be significant if it can be validated in separate tests, if it's a consistent result.
		Now we do see viruses from Hubei, which have a fourfold increase in titer.  We've gone on to take those viruses, sequence them and also to put a representative one in the human serology tests and we found that that strain was indeed well covered by antibody to the current vaccine.
		Next slide, please.
		Now we have viruses from slightly more recent activity.  We have two strains that were isolated in the U.S., one from Wisconsin, one from Washington in October.  That was the first H1N1 virus we received and then the Wisconsin virus is more recent from December.
		We also have some viruses that were isolated in Australia and New Zealand during September and October, followed by some Asian strains from Hong Kong, the Philippines and Bangkok.  Again, we see that there's a remarkable amount of homogeneity among strains.  There are occasional strains including the Brisbane strain here and the Bangkok/255 strain here which do have a fourfold reduction in titer, but as I'll show you in a minute, viruses like this are relatively rare.
		Next slide, please.
		So now we're looking at a frequency table which summarizes the antigenic analysis that we carried out at CDC on H1N1 viruses and we have the viruses divided up by region across the top and by time going in this direction.  And of course, we want to designate, we want to determine what proportion of the strains that we're analyzing are low to the vaccine strain.
		As you can see, we did have some Johannesburg-like strains circulating last winter.  Those were, according to the human serologic testing that was done, those were also well-covered by the vaccine.
		We did have a proportion, small proportion of viruses which were not as well inhibited by antibody to the vaccine strain.
		During our summer months when influenza viruses were circulating the Southern Hemisphere, we also had a fairly small proportion of viruses.  Now during the period from October to January, we have not had very many H1N1 viruses to characterize.  And only one of those has had a lower titer to the New Caledonia Ferret Serum.
		So I think in summary, we've had relatively little H1N1 activity during the past few months.  The viruses have been remarkably stable, both genetically and antigenically.  I should mention, however, that we do have some additional viruses from China which we've not yet had a chance to analyze.  They arrived very late at CDC.
		Okay, I think we'll move on to the H3N2 viruses.
		Now we have the right table up here.  Last winter we had relatively little H3N2 activity in the U.S., Canada and Europe.  There was a bit more in the Southern Hemisphere, particularly certain countries and South America had a significant amount of H3N2 activity.  The viruses were Panama-like.
		Right now I'd like to point out that in the United States, we're having reasonable amount of, an increasing amount of H3N2 activity and the same thing is occurring in Europe.  If you look at the European reports, you can see that as of the end of Week 3, they are starting to see that their epidemic is really picking up.
		Next slide, please.
		Now I'd like to just spend a moment on this HI test for H3N2 viruses and point out a couple of what I think are fairly important observations and sort of notes of caution.
		H3N2 viruses, as we all known, are associated with more severe seasons.  That is to say we see more hospitalizations and deaths associated with H3N2 viruses.
		H3N2 viruses have also been more antigenically variant during the past two decades than H1N1 strains.  And that had been true up until about 1997 when the Sydney/97 variant emerged and spread very rapidly worldwide and in that particular year, in the 1997-1998 season, we did not have a good match between the circulating strain and the vaccine strain.  The circulating strain was predominantly Sydney.  The vaccine strain was Nanching.
		But since Sydney emerged, we have had relative antigenic stability among H3N2 viruses.  And so based on what happened in the past, we are really waiting for the next H3N2 variant because this is really uncharacteristic behavior for H3N2.  So this was a major epidemic strain.  We moved on to recommending a Moscow/10-like virus to be in the vaccine and Panama is actually the strain that's included in the current vaccine and has been in the vaccine for I believe three years.  Yes.  Two years, two years.
		So the viruses have been really quite stable, but we have seen a few viruses which are -- which vary a bit antigenically and one of them is the Fujian/140 which we can distinguish using the Moscow/10 antiserum.  The Chile virus was selected because it as an egg isolate and was representative of strains circulating in the Southern Hemisphere during this past summer.
		The Darwin virus was detected as a variant by the WHO lab in Melbourne.  However, sequencing has shown us that this virus has some unusual changes that haven't been seen in any other strains anywhere else in the world.  And we don't really think that this is a significant antigenic variant, but we've been including it in the tests simply because it's very clear that we can distinguish this virus from our reference strains and because we were looking to see whether an antiserum to this particular virus would help us in grouping the currently circulating strains.
		So we're going to concentrate mainly on this column here, because this our vaccine strain and our primary reference strain.  The homologous titer is 640 and as we look down we're looking for viruses that have fourfold lower titer and we've identified one strain down here, A/S. Australia/102/2001 that was isolated in October of this past year.
		We have a number of strains from the U.S. that were isolated in October, November and December which appear to be very well inhibited.  And a number of strains from Hong Kong as well.
		Next slide, please.
		Now we're moving on to more recent data.  You'll notice that we even have some strains that were isolated during January included on this table, as well as some that were isolated earlier.  The most recent strains are from the United States from November, December and January.  And again, the U.S. strains are actually very well inhibited by the Panama Ferret Antiserum.
		We have down here at the bottom of the table a strain from  Bangkok which has fourfold lower titer as compared to the homologous.
		Next, please.
		Again, we have a number of strains from the U.S., the H3s started rolling into CDC right after Christmas, so we've had an opportunity to look at a number of strains from the U.S.
		I'd like to draw your attention down here to the bottom of the table and have you note that there are three strains from Singapore that were isolated during the summer and fall time and these three strains all have a reduction fourfold as compared, a fourfold reduction as compared to the Panama homologous titer.  And those are strains that are under continuing analysis.
		Now I didn't really emphasize -- this is a table which is not in your handout.  It was -- we actually did the test on Monday and so it couldn't be included in the package that was sent to you.  And the reason that I wanted to show this table primarily is that we have among the viruses tested a group of viruses represented by antigens 24 through 30 from recent activity in Northern China.  And we have had quite a bit of contact with our colleagues in China over the past two months.  They've indicated that there has been outbreak to epidemic level activity going on in Northern China and that they were detecting some antigenic variation among these recent strains.
		We received very late a package from China and have tried to really focus on the H3N2 and Influenza B viruses as much as we could to prepare for our meeting today.  You'll note that there's really only one of the recent strains from China which has a reduced titer in this particular test, but our analysis is on-going and we are looking very carefully at sequence data to see if we can correlate changes in any of these strains with antigenic differences.  So we're looking at the Singapore strains and at these strains from China.
		So now if we summarize the virus characterization that's occurred over the past year and a bit, we can see that Panama-like viruses were circulating in Asia.  There weren't very many U.S. or North American viruses that were analyzed.  But overall, of the viruses that we looked at, a small proportion had a reduced titer as compared to the homologous titer against the Panama strain.
		Likewise, for the Southern Hemisphere activity we saw a relatively small proportion of viruses that were reduced in titer, but we did have some from Central and South America and we have had -- I updated this table based on the HI table that I had just shown you and there were some viruses that were low from Asia and then, of course, the single virus from China and the Singapore viruses as well.
		So what you can see is it's a relatively small proportion but we are really very interested in the viruses that are coming out of Asia, that are low and are very concerned about making sure that we can pick up any corresponding sequence changes and as we look forward to what might happen next year.
		Now we had a request from the Committee last year, I believe it was, in particular Ed Kilbourn was very interested in seeing some neuraminidase inhibition analysis because the N2 neuraminidases, as you will see later on in the data presented by Dr. Klimov, are evolving in several different lineages and we wanted to make sure that antibody generated to the N2 in the Panama strain would inhibit neuraminidases of recently circulating strains.  And in order to do these tests properly, you need to make reassortants and put into your reassortant an irrelevant hemagglutinin so that when you're doing the testing, you don't have steric hindrance that is caused by antibodies binding to the neuraminidase.  For each of these reassortants to which we make hyperimmune rabbit serum, we have an irrelevant hemagglutinin in these three cases, contributed by an equine virus.
		What you can see if you concentrate on the data down here in this row is that the currently circulating strains are all -- all have neuraminidases that are well inhibited by antibody to the Panama neuraminidase and why this is important will become clear when Dr. Klimov presents his talk, but we've chosen viruses which are representative of the different genetic groups for neuraminidase.  So we feel pretty comfortable that the neuraminidase of the Panama is able to induce antibody that's cross reactive.
		So now we're going to move on to the third group of viruses which has really provided the greatest challenge for us this year.  And I think you'll find quite a few interesting points of discussion in this group of viruses.  Now if you have been with us fora while, you'll remember that we've been tracking two separate lineages of Influenza B viruses, the so-called Panama lineage or Yamagata lineage and the so-called Victoria lineage.  Now the Victoria lineage have been circulating worldwide and in the early 1990s for reasons that we don't understand, was really displaced in much of the world by viruses on the B/Yamagata lineage or the current vaccine strain on that lineage is actually the Sichuan/379/99 lineage.
		The Victoria viruses continue to circulate in Asia where they've evolved and activity was -- has been detected in China, Thailand and Japan over a number of years that was caused by the Victoria strains while the Yamagata or Sichuan viruses have been circulating worldwide.
		So if we look at what was occurring last year at about the same time we were having outbreak level activity in the Northern Hemisphere, in Europe, North America and certain parts of Asia associated with Influenza B/Sichuan-like viruses, but in Asia, we had also Victoria lineage viruses that we now are calling B/Hong Kong/22-like.  That is one of the most recent reference strains and is fairly representative of the Victoria-like strains that are circulating at this time in various parts of the world.
		During the summer months there was outbreak level activity associated with Influenza B virus isolations in Australia, New Zealand and Central and South America and then if we move on to the current influenza season in the Northern Hemisphere, we see that we've just had pretty much sporadic activity up until now.
		Next, please.
		Now I'm going to show you only two influenza B tables.  The first one is a table which shows the antigenic relationships between viruses that are genetically and antigenically related to the current vaccine strain which is, once again, Sichuan/379/99-like.  Different manufacturers have used, globally at least, three different Influenza B strains that are antigenically equivalent to the Sichuan/379 reference strain.
		What we are seeing is that we have a number of viruses which have a significant reduction in titer compared to the homologous Sichuan/379 vaccine strain.  We've seen some viruses from the U.S. that have such a reduction, viruses from Europe and China and indeed from the Middle East.  So we are seeing a number of strains that are not as well covered by our reference antiserum as we would like.  I don't think I need to point out too many additional items.  I would like to point out the fact that the antiserum to the Shizuoka/15/2001 strain does appear to cover most strains very well.
		Now we're moving on to viruses that are related to the B/Victoria/87 strain, so these are all Victoria lineage viruses.  In particular, I'd like you to note two reference strains, the Shangdong/797 and B/Beijing/243/97 strains.  Both of these have been used in either an experimental vaccine or in commercially prepared vaccine, actually the Shangdong has been used by manufacturers to produce the vaccine that was administered in some countries in Asia and the B/Beijing/243 strain was used to make an experimental vaccine in Europe and we have -- I have some human serology that I'd like to show you that we've done with human sera that were prepared in that particular trial.
		Now I'd like to point out that the B/Hong Kong/2001 can be distinguished from these two viruses, the Shangdong/7 and Beijing/243 by using Ferret Antiserum.  And we've seen that a number of viruses that are currently circulating are less well-inhibited by this Ferret Antiserum.  Here we have our reference strain Hong Kong/22.  This was one of the first strains that was sequenced and characterized extensively in our lab and to which we developed a Ferret Serum.
		We also -- and that is actually an NDC case cell isolate.  We also have two egg isolates, the Hawaii/10/2001 and the Hong Kong/330/2001 strains that have been sent out to vaccine manufacturers for further testing.
		Now right here we have two recent strains from Canada which are in this Victoria Beijing/243 lineage and you can see that they are well inhibited by antiserum Hawaii/10 and Hong Kong/330 antiserum.
		We have a group of viruses from Hong Kong, of course and South China.  They've been seeing these viruses over the years.  These Philippines strains were actually isolated fairly recently and are similar to viruses which were causing school outbreaks in the Philippines that were widely reported in the press about the same time that the Anthrax problems were occurring in the United States.
		We also have a number of viruses from India that are in the same lineage.  This is the first time that we detected viruses from India that are related to Victoria.  The surveillance in India has not been very extensive in recent years and these viruses actually came to us as part of a live attenuated influenza vaccine trial in Asia.
		We also have viruses from Oman that came to us through the military and you can see that these are also Victoria viruses.  The one thing to note is that there are -- a number of these viruses aren't well inhibited by the Shangdong and Beijing/243 serum, but there are also a number of them that aren't as well inhibited as we would like to see by the Hawaii/10 serum.  The Hong Kong/330 serum seems to be a bit more broadly cross reactive, but there are strains which are clearly fourfold, eightfold and more downed compared to the homologous.
		We'd like to show a map because I think this helps people visualize very clearly where the Victoria-like viruses have been identified up to the present.  We actually just got a call yesterday from the WHO collaborating center in London, and they wanted to report to us before our meeting today that they had identified four out of seven strains sent from Italy that were related to the B/Victoria reference strain.  We haven't seen the HI results yet or the sequencing results, but I'm sure they'll be forthcoming within the next week or so.
		We have a question mark about whether or not these viruses have been identified in Russia, simply because we haven't had a chance to analyze them, but they were reported to us by our colleagues in Moscow.
		So you can see that the B/Victoria viruses have been identified in a number of countries and that the geographic distribution has clearly increased over the past six to nine months.  In particular, we have isolated -- we have identified the B/Vic-like viruses in Hawaii and in Canada.  There have been three isolates from Canada that have been identified as being related to the Vic reference strain and one Sichuan-like virus.
		We had activity in Hawaii during the summer and early autumn, Influenza B activity and a number of those viruses were B/Victoria-like.
		So if we can summarize a fairly complex picture, we can see that we first picked up the Hong Kong/22/2002-like strains  during the period from October to March.  They were picked up in Hong Kong, of course, and those viruses are actually distinguishable by sequencing and Dr. Klimov will talk about the signature amino acid changes that are associated with those currently circulating B/Vic-like viruses.
		We still had some viruses that we were characterizing as B/Beijing/184 which is the pre-B/Vic vaccine strain as well as B/Sichuan-like strains which were in the majority.  And we had a number, but a relatively small proportion that were reduced in titer to the B/Sichuan reference strain.
		As we looked at the viruses that were being isolated during the Southern Hemisphere's influenza season, we continued to get viruses from Asia that were in this group, but we also had the viruses from Hong Kong that were in this group.
		We had a number of B/Sichuan strains that were low and that have continued and actually, I think, this summary table doesn't quite reflect the extent to which we see viruses that are reduced in titer to the Sichuan vaccine strain because we haven't reported out all of the testing that we've done because we're trying to do confirmatory testing to make sure that these strains are low in successive tests.
		Now I mentioned that I would be touching on some serologic information.  If you turn to page 56 now, I'll only be going over one serology table and you recall that I mentioned that the B/Beijing/243/97 strain was used in an experimental vaccine in Europe and the sera were actually tested at CDC and in Europe.
		What I have here on this table, remember the Beijing/243 is in the vaccine and we have three recent Victoria-like strains shown in black below the vaccine strain and then two strains that are representative of Sichuan-like viruses shown in blue.  So if you look at the post-vaccine geometric mean titers, induced by the Beijing/243 vaccine strain to these recently circulating strains, you'll see there's pretty good coverage.
		However, we can see that there's a reduced titer to one of the two Sichuan-like strains, the B/Anhui/2001 strain and we don't really know what that means.  Actually, the Vic/504 had a reduced titer.  There's a 50 percent or greater reduction in post-vaccine geometric mean titer to both of the B/Sichuan-like strains.
		Now we had done some studies earlier and we found with more limited testing that the antibody induced by the Beijing/243 vaccine strain did seem to cover earlier strains that were related to Sichuan, so the earlier iterations of viruses on the Sichuan lineage were fairly well covered by antibody to the Beijing/243, but admittedly we had more limited data.  We really were only testing against one or two strains as opposed to six here.
		Okay, with that, I think I'll close and entertain any questions.
		DR. DAUM:  Thank you very much, Dr. Cox.  We'd like to welcome Dr. Katz to our proceedings and we'd like to ask people that unlike the airlines where they want devices turned off at 10 minutes prior to take off and landing, we'd like devices turned off the whole time during the meeting.  And please, beepers, cell phones are really disruptive to the proceedings here.  If you could turn them off or place them on vibrate or something like that so they don't disturb us.  I'd be grateful.
		Dr. Couch, why don't you start the discussion, please?
		DR. COUCH:  I had two, Nancy.  I think you answered one of them and that just to be sure though that the B/Victoria is not just a sporadic isolate that has shown up in the Northern Hemisphere and in North Africa and the Middle East.  It's actually been a cause of outbreaks and even in the Northern Hemisphere, it's been a significant number of isolates, is that correct, in Canada and even here?
		DR. DAUM:  We are going to need the question repeated.  We had events while you were asking.
		DR. COUCH:  The question was just trying to get at whether -- well, for those of you who haven't been on the Committee regularly, we've been looking at B/Victoria in Asia for a number of years now and I guess kind of hoping it would go away.  And ignoring it with the considerations for the vaccine decision for B in this country.  And it doesn't seem to be going away.  But in fact, it seems to be invading our territory and the data you mailed and we had, it suggested that, but I think you verified that indeed, it does, it has been the cause of outbreaks in the Middle East and these are not just sporadic isolates, but you have a number of isolates from the Northern Hemisphere of the B/Victoria lineage?
		DR. COX:  Yes.  The isolates in Canada were really associated with sporadic, activity sporadic cases.  The number of viruses that we received from Hawaii last summer would indicate that there was significant activity going on.  The Philippines school outbreaks were caused by both B/Victoria and Sichuan lineage viruses, so it's hard to tell which were -- I mean they were both responsible.
		DR. COUCH:  Were the isolates in Canada from more than one location?
		DR. COX:  Yes.
		DR. COUCH:  Just a second question.  I wasn't here last year, but we're glad to see neuraminidase coming of age, but I should know and I don't, I know that Ed and the group have used rabbit sera for differentiating among the neuraminidases and these would represent immunization antisera.
		DR. COX:  Yes.
		DR. COUCH:  It reminds me a little bit of the chicken for inter-immunization sera for hemagglutinins which were not so good for differentiating among the viruses whereas the ferret sera have proven to be very sensitive in that regard.  But the state of science is to use the rabbit sera, I guess is my question.
		DR. COX:  That's true and we also have --
		DR. COUCH:  So we may not be able to be quite as sensitive for those differences as we think of with the hemagglutinin in the ferret sera.
		DR. COX:  Right, but we did do very similar set of assays using ferret sera.  Now those ferret sera were produced by infecting ferrets with the homologous virus so we didn't have an irrelevant hemagglutinin.  When we use the ferret sera, the same ferret sera that we use for the HI tests and NI tests, we see exactly the same picture.  We can't differentiate among the neuraminidases of the viruses that are on these different neuraminidase lineages.  And they're well inhibited.
		DR. COUCH:  Rabbit sera tells you the same thing?
		DR. COX:  Yes, the ferret sera and the rabbit sera give us exactly the same picture.
		DR. DAUM:  Dr. Couch, could we get you to talk right into the microphone.
		DR. COUCH:  I was just confirming that the rabbit sera are as good as the ferret sera is what you were saying and confirming what Ed's already said, the neuraminidase doesn't change as rapidly as the hemagglutinin.
		DR. DAUM:  Thank you very much.  Dr. Kim?
		DR. KIM:  I assume that the viruses that you have used at least from this country are derived from nonvacinees, is that information available or is my assumption correct?
		DR. COX:  The majority of the viruses that we receive are from people who have not been vaccinated, but we do also receive occasionally, and it varies from year to year, but we receive a certain number of viruses from vacinees, but the majority are from individuals who have not been vaccinated.
		DR. DAUM:  Dr. Stephens and then Dr. Katz.
		DR. STEPHENS:  For those of us who are not as familiar with influenza as many at the table, the issue of A/Sydney in 1997, I guess, was that -- were there lessons learned by that rapid spread?  Was it predictable?  Can you just comment on, in retrospect, were there any lessons that we could learn from the emergence of A/Sydney as an H3N2 virus in terms of predicting for the vaccine.
		DR. COX:  Yes, I think that the lesson that we learned was that sometimes we're going to -- and this isn't a very helpful lesson, but sometimes there will be viruses which will emerge and spread very rapidly and we're not really sure why.  But there will be times when the vaccine does not match the circulating strain as closely as we would like.
		DR. STEPHENS:  So there weren't clues at that time?
		DR. COX:  No.  Those viruses were detected, first detected as being important in August and September and so the vaccine had already been produced.  So they were emerging in the Southern Hemisphere at a time when it was really too late to do anything about changing strains in our vaccine.  So there will be occasions.  We have been using the surveillance in Asia that goes on through the WHO global network to try to pick up new variants and we've been very successful in picking up the Beijing/353, Beijing/32, 92 and so on, and updating the vaccine almost in anticipation of what would be circulating in North America and Europe.  But in that particular case, the virus emerged and spread very rapidly and was really recognized as being important at a time when it was just simply too late and that will happen on occasion.
		Now we did see that in spite of the fact that there wasn't such a good match vaccine effectiveness against hospitalization could still be measured among vaccinated individuals compared to unvaccinated individuals.
		DR. STEPHENS:  My second question relates to the complex B story that you've presented.  It sounds like we have emergence of the Victoria lineage, but you really didn't have a solution or I didn't see a solution.  The Beijing/243 strain didn't appear to be better.  Can you clarify that, at least for me?
		DR. COX:  I think the Bs are very problematic and I don't think there is a really clear solution.  We probably are going to have to grapple with a whole variety of possibilities.  I think once all of this serologic data are presented and the sequence data are presented, we can really talk about those issues.  But we also need to get some feedback from the manufacturers about how some of the B strains that have been distributed to them are growing.  So I think hopefully some of that will emerge and become clear.
		DR. DAUM:  Thank you.  I'm a little confused.  Drs. Katz and Griffin, did you both want to speak?  That's what -- I think you hand was up behind Dr. Katz and so I didn't see it.  I apologize.  Dr. Griffin first.
		DR. GRIFFIN:  I just wanted to further clarify the B story as well since I think that's going to be our problem child with this round.  And one of the questions is it's clearly emerged in Asia and it's clearly spreading.  I don't think there's any doubt about that, but what I didn't get is the idea of the proportions of even if you looked in the Philippines or in Southeast Asia of the two different B strains, both of which appear to be there and causing outbreaks, or is that not correct?  It looks like from the chart, at least, that they're both there, they're both causing problems, but is one more abundant than the other?
		DR. COX:  It changes over time and so if you look at reports from Hong Kong there will be months where B/Vic-like viruses predominate and other months where the Sichuan lineage strains predominate.  So it's not really clear.  What we need to remember though is that because B/Victoria-like viruses have not circulated in the U.S., well, in North America, South America and Europe for a decade, we have a whole cohort of young children who are totally susceptible.
		DR. GRIFFIN:  Right.
		DR. COX:  And that's not true in Asia because they've had the two co-circulating for a long period of time.
		DR. GRIFFIN:  Right, so the idea that introduction of this, successful introduction of this virus may cause us problems.
		DR. DAUM:  Now Dr. Katz, please.
		DR. KATZ:  My question is somewhat tangential, Nancy.  There have been several stories in the newspaper recently about influenza-like illness with many children with encephalitis in Japan.  I didn't see any isolates from Japan in any of your charts.  Can you confirm that or have you received any information from WHO or is that just a newspaper story?
		DR. COX:  No, that is a problem, an issue that the Japanese have been grappling with for a number of years.  I don't know what the situation really is this year.  I don't know if you're referring to recent press reports, but Japanese colleagues have been publishing information over the past couple of years and I think that pediatricians in this country are interested in why we haven't been seeing a similar picture in the United States when the viruses circulating in Japan and the U.S. are very similar.
		DR. KATZ:  These are confirmed as truly influenza illnesses?
		DR. COX:  Influenza has been isolated from a number of these patients and maybe Keiji will want to comment further about it.  He's been in touch with our Japanese colleagues.  It's not always clear that there's a causal relationship between the influenza and the encephalitis.  I think there are a lot of questions to be explored, but there are some very interesting observations.
		DR. KATZ:  Thank you.
		DR. DAUM:  Do you wish to comment?
		DR. FAKUDA:  Just to add a couple of things to what Nancy said.  You know, in Japan in the last couple of years, they've identified probably a couple hundred cases per year at least and these are actually typically encephalopathy cases, not encephalitis cases and they've been quite severe, a substantial proportion of these young children die and then the vast majority of them who live have some chronic sequelae, some substantial chronic sequelae.  And in the majority of the children, influenza viruses have been isolated, but typically from respiratory specimens.  There have been a small handful of cases in which using PCR virus has been or antigen has been identified in the CSF, but I think that's much more controversial.  And when you look at the picture epidemiologically, there appears to be some seasonal pattern in which the increase in these cases occurs in the winter time and it appears closely superimposed on the influenza virus isolations.  There is a case control study which has been either started or is being designed.  I don't know where it is right now because I think some of the questions are whether this is really associated with influenza.  Is this potentially associated with some medications or other factors associated with influenza or associated with winter time illnesses?  I think those things are not clear right now.  But there is a great deal of interest in this.
		DR. COUCH:  One interesting feature of that, I think the case control study is supposed to be under way right now to try and clarify that, is that the onset is almost identical with the respiratory disease as opposed to something like Roya Syndrome.  Maybe the case control study will identify the relationship between virus and something else.
		DR. DAUM:  Thank you very much.  I have Dr. Eickhoff, Ms. Fisher and Dr. Myers.
		DR. EICKHOFF:  A question again on Influenza B.
		Nancy, are you aware of any precedent for this kind of behavior among Influenza B viruses or even Influenza A viruses for that matter in which a lineage of B virus that was once prevalent sort of goes into eclipse and falls almost totally off the radar scope, but never totally off the radar scope and then a decade later appears to be going, undergoing a resurgence and coming back to haunt you?
		DR. COX:  I think that probably I don't know of any other case where we can say decisively that that has occurred with Influenza B.  Part of it has to do with the fact that Influenza B, we haven't been looking at Influenza B for so many decades, but it's very clear that the circulation of Influenza B viruses is more complex than it is for each of the subtypes of Influenza A, but what we have observed with the H1N1 viruses was the separate evolution of a lineage of H1N1 strains that could not be distinguished antigenically from what was in Asia that could not be distinguished antigenically from viruses that were circulating in the rest of the world.  Then an amino acid deletion occurred.  We could distinguish the two groups and the Chinese virus, we could distinguish the two groups antigenically and genetically at that point and then the Chinese groups, so-called Chinese group actually spread globally and have sort of supplanted the Johannesburg-like strains.  So I think that given the epidemiology of influenza and the B/Vic-like strains or B/Vic lineage strains do pose a real challenge to us because we do have a lot of people, especially children who are fully susceptible.
		DR. DAUM:  Thank you very much.  Ms. Fisher, please.
		MS. FISHER:  This returns to the question of the reports of the encephalopathy in children in Japan that appears to be flu-related.  Are children in Japan routinely vaccinated with the flu vaccine, given a flu vaccine and those children, had they received flu vaccine?
		DR. COX:  Flu vaccine is not now recommended for pediatric use, so those children, generally speaking, were not vaccinated.  I don't know -- there might have been one or two cases where they were vaccinated, but generally children in Japan now are not vaccinated.
		There was a time in the past, however, when Japanese children were vaccinated, when the recommendations were, in Japan, were to focus on vaccinating school children to help limit the spread of influenza in the community, but their recommendations have undergone an evolution so now they recommend flu vaccine for high risk groups and elderly, pretty much as we do.
		DR. DAUM:  Thank you.  Dr. Myers and then Dr. Couch and then we're going to move on to hear from Dr. Klimov.
		DR. MYERS:  Nancy, within the B/Victoria isolates, there looks like there's another lineage.  Are these new isolates related more like the Oman, India, Philippine isolates or are they more like the B/Victoria, the ones that you're recovering now?
		DR. COX:  I think that Dr. Klimov will be talking about the genetic characterization of these viruses and it's very clear that the antigenic picture that we're seeing is a bit complicated by some of the sequence changes that we see among them, in particular, we're seeing the presence or absence of a glycosylation site at a particular point and that seems to have some effect on how they appear antigenically, but genetically, they're pretty homogeneous as you'll see.  Antigenically, they're a little more heterogeneous and it's not easy to peg them.
		DR. DAUM:  Thank you.  Dr. Couch?
		DR. COUCH:  Just a quickie, the serology that Nancy showed us showed that in these adult and elderly sera there were responses reasonable for one antigen and not for the other annually, but we had no children sera results here, but Roland and Nancy can confirm if my memory is correct, that children sometime in the past when we started the concern about the Victoria vaccinated with whatever the Yamagata lineage was at that time, their post-vaccination sera had extremely poor -- my recollection is almost negligible coverage against the B/Victoria virus, so in children it just exaggerates this uniqueness of the B/Victoria.
		DR. DAUM:  Thank you, Dr. Couch.  I think we'll move on now and ask Dr. Klimov to share his comments with us and look at some of the molecular characterization of some of these strains.
		DR. KLIMOV:  Good morning.  You know, the genetic data which we are collecting quite a lot in the influenza branch of CDC from our point of view are providing some additional information to the antigenic representation of the viruses and I will on in the same order like Nancy did, starting with H1 through H3 and we'll finish with Influenza B viruses.
		So the first slide shows the evolution for the HA1 part of the hemagglutinin of recent Influenza A H1N1 viruses and I should mention that this slide represents viruses isolated June and after June of 2001.  So this the most recent Influenza H1N1 viruses.
		A current vaccine strain is indicated here on the top.  It's New Caledonia/20/99 and just to remind you that previous vaccine strain was Beijing/262/95 just to give you some idea about sort of genetic differences between the previous vaccine strain and the new current vaccine strain.
		Also, I should mention that these vertical distances do not have any meaning, only horizontal differences can indicate relative genetic relationship between strains.  For example, genetically this strain would be different from let's say this strain by somebody of this distance plus this distance.  Distance from this line through this line.
		Anyway, vertical distances are not essential, just horizontal lines should be taken into account.
		You can see that if you look at the scale, you can see that there is no dramatic genetic involvement among recent influenza H1N1 viruses.  They are different, very little from each other.  They do form two genetic subgroupings and you can see that the viruses from U.S. are presented here, there are some Hawaiian viruses in the bottom part of the three.  And you can see some so-called signature amino acid differences which characterize those groups.  But I should stress that there is no antigenic differences between those two genetic subgroupings.
		Also, I should mention that rather few viruses which are low antigenically to the current vaccine strains.  They are spread quite evenly among those two genetic groups and we see some particular groupings which would characterize low reactors.
		Nancy already mentioned that we had previously viruses belonging to another genetic lineage of Influenza AH1N1 viruses which is so-called Johannesburg/82/96 lineage or sometimes we call it A/Berne lineage.  And this year we didn't see -- this season we didn't see viruses from this genetic group from Influenza AH1N1 strains.
		This table shows the number of amino acid differences between consensus sequence, sort of typical sequence of currently circulating viruses and egg grown viruses which we have available right now.  And those tables are useful in sort of two senses.  First of all, they show us to what extent circulating viruses, including, for example, vaccine strain are different from the consensus.  Our experience shows that, generally speaking, the closer the vaccine strain is to the consensus sequence, the better the vaccine is to make it -- to say it in plain words.  So you can see that New Caledonia vaccines -- I'm sorry, I tried to highlight but I did a mess.  It's still pretty close, just three amino acids difference from the consensus.  So it's pretty close to the consensus of current influenza viruses circulating worldwide.  There are some viruses which have 4, 5, 6, 7 amino acid differences and we studied those viruses in human serology tests or just in HI tests.  And they behaved lower, I mean they weren't caught very well by the current vaccine strain, but all those strains have unique amino acid changes which could explain why they are antigenically rather different from the vaccine strain, but as Nancy mentioned to you, you do see very few viruses which are low to New Caledonia vaccine strains.
		Now I'm going to move on.  In neuraminidase N1 genes evolutionary tree and again, New Caledonia is here.  This tree includes not only viruses from June 2001 through now, but more older ones as well, just because we do not have too many neuraminidase sequences right now and in particular, you can see one of the strains which is currently 1/2001 in the Johannesburg or Berne genetic lineage, but this is the end of last influenza season, so the Berne-like or Johannesburg-like virus was isolated at the end of the previous influenza season.  So during this influenza season, as we mentioned, we do not see viruses from the Berne or Johannesburg/82/96 lineage.  So the majority of viruses form a pretty homogeneous genetic group and you can see that once again the majority of them are still cloned genetically to New Caledonia in the neuraminidase gene sequences.  There is another group of sort of genetic subgrouping of the neuraminidase genes, but importantly as you saw from Nancy's talk and you saw from the H1 tree, you do not see dramatic differences in antigenic properties of the viruses against the current influenza of vaccine strain New Caledonia.
		The next table shows, demonstrates a number of differences for the neuraminidase gene from the consensus and you can see that New Caledonia is pretty close to the consensus sequence of the neuraminidase genes and as I mentioned it's a good sign for the vaccine.  It's still matches pretty well the majority of separating viruses.
		Next slide please.
		Now we will go into H3 hemagglutinin gene evolution and to some extent the picture here is a little bit more complicated than it was for Influenza AH1N1 viruses.  In red you can see the current vaccine strain A/Panama/2000/799.  That means actual vaccine strain.  Moscow/10/99 WHO recommended strain is over here, and you can see that there are two genetic, major genetic subgroupings of the recent Influenza AH3 hemagglutinins.  With these sort of arrows, I tried to indicate some of the low reactors, as Nancy mentioned, we did see still quite a few of low reactors.  And they are spread more or less similarly on both genetic groups.  But Nancy mentioned that we had one more H3 test, the day after we actually sent the package.  And yesterday morning, some more sequencing data became available and those data relates to the viruses from China which we have received recently which Nancy mentioned.  And I allowed myself to actually add several branches or several more strains in here to indicate that new viruses, H3 viruses from China which we received in the last package, they tend to group in this area and they have some additional signature changes which may be indicating on sort of additional evolution of recent Influenza H3 viruses in the Asia area.
		I should add that several viruses from Singapore which Nancy mentioned are also behind this actual point, so Singapore viruses and recent Chinese viruses form a sort of separate genetic group right now and we are working right now very hard to get details about the sequences.
		This is a table which demonstrates amino acid differences between the consensus and available egg grown viruses and you can see that Panama/2000/799 so far is matching pretty well the consensus of circulating viruses.  We have some more egg isolates, some of them like, for example, Darwin/3/2000 which Nancy mentioned which was low in both HI tests and human serology tests, but this particular virus has some unique changes which can explain those low reactivities.
		Once again just to point out that unfortunately, we do not have yet data in this table about the Chinese viruses.  As I mentioned, there is some evolutionary events which are definitely happening in Asia right now and we are watching this very carefully.
		The neuraminidase gene evolutionary tree, once again, Panama, is in here and there are two genetic groupings within this recent Influenza H3N2 neuraminidases and as you can see by scale which is here, the genetically evolved recent viruses are pretty much evolved from the Panama/12/799 vaccine strains.  That's why actually we considered very important to have neuraminidase inhibition tests to be done and as you remember Nancy demonstrated this test and they are in the package.  So far we do not see obvious antigenic differences between neuraminidases, even between Panama vaccine strain and neuraminidases of currently circulating viruses.
		So I should say that the majority of those changes which we see are not in the antigenic sites of the neuraminidase model.
		This table demonstrates amino acid differences between consensus and available egg isolates.  You can see that Panama, in this particular case, is rather different from the consensus sequence, but once again, fortunately it doesn't seem to influence the antigenic properties of current influenza viruses which are still reasonably well covered by a Panama vaccine strain.
		Now Influenza B evolutionary tree for the hemagglutinin of the B/Yamagata lineage which is different from the B/Victoria/287 lineage.  The vaccine strain is Sichuan/379/99, but the recommended vaccine strain is very important and one of the real vaccine strains Victoria/544 is next to Sichuan here.  		I have to mention that the Yamagata lineage also consists of two genetic subgroupings and one of them is let's call it Sichuan subgroup and another one is -- we call it Harbin/7/94 genetic subgrouping and those of you who are involved in influenza may remember that Harbin 7/94 virus was a vaccine strain four, five or six years ago for a couple of years.  But genetically, it's sort of emerged into two genetic subgroupings.
		Now we start to see and for a number of years, actually, we did not see Harbin-like genetic lineage viruses in Americas, but this year we started to see them.  In Argentina, there was one strain.  There was on strain in Minnesota and this is also -- sort of forms the top of the study related to B/Victoria lineage.  It's sort of another interesting point to mention today that this genetic subgrouping seems to be expanding as well.	
		So far we did not see dramatic intergenic differences between Sichuan and Harbin genetic subgroupings, but it looks like recent data shows that it could be that recent B/Harbin-like viruses are becoming antigenically more diverged from the Sichuan-like.
 		Next slide.  This has quite a number of egg isolates and this is the table demonstrating the differences between the Yamanashi-like -- Yamanashi is 166 right here.  It's the same Sichuan-like lineage.  It's the same lineage.  Panama, and let's say Beijing/184, Yamanashi, Sichuan.  The same lineage.
		This yellow line divides viruses belonging to the Sichuan genetic subgrouping and Harbin genetic subgrouping.
		You can see that both Johannesburg/5 and Victoria/544 existing vaccine strains are pretty close to the consensus, but the consensus sequence is becoming more complicated when you look at the -- when you summarize actually Sichuan lineage and Harbin lineage.  The Harbin lineage has, of course, more amino acids differences from the consensus.  As I mentioned so far we didn't see dramatic antigenic differences between those two groups in spite of the fact that quite a number of amino acids changes.  But as I mentioned it could be that during the evolvement of this season we may see more viruses from this genetic subgrouping relating very well to the vaccine strain.
		This is hemagglutinin of the B/Victoria lineage and here is actually a clear cut -- just for reference, this is a Sichuan current vaccine strain and you can see that it's different genetically.  And you can see that there is clear cut in genetic groupings between previous B/Victoria-like viruses presented, for example, by Shangdong/7/97 strain here and recent viruses from Hong Kong, Hawaii and some other areas, from Japan for example.  And Nancy mentioned that there are at least three so-called signature amino acid differences which clearly distinguish this genetic group of new B/Victoria viruses from the old ones.
		Next table shows the number of amino acid differences between previous B/Victoria lineage -- and you can see that there are several strains of grown viruses which are almost identical to the consensus sequence.  The only point I have to make is that the only difference which isn't in position 197 or in the position 199, either of them are creating a potential glycosylation site in the HA molecule of the B/Victoria like viruses and that's why in some cases all egg grown viruses we have so far and some MBCA grown viruses can behave different from the viruses which do not have these potential antigenic site.  It's related to the question which was raised earlier today.
		And a couple of words about the -- okay, this is a table, sort of frequency table but for the genetic data, not for the antigenic data and we do so-called PCR restriction analysis for rapid differentiation between different genetic lineages.  We don't need to sequence all the viruses.  We may use some specific restriction enzymes which would differentiate between Sichuan subgroup, Harbin subgroup and B/Victoria subgroup for example.
		And you can see that if we didn't see many B/Victoria-like viruses from October to March of 2001, you started to see much more of them from during the summer time and in particular, there were 28 viruses which are mentioned here under the USA column, but actually all of them are from Hawaii.  Just to repeat that we found quite a number of Victoria-like viruses in Hawaii, some belong with Sichuan-like viruses in the same region.
		Also, it looks like there is a tendency in increasing of the percentage of B/Harbin/794 genetic subgroupings among recent viruses.  So-so far, starting from October through January, we have approximately 50 percent of viruses tested worldwide, belonging to the B/Victoria lineage and presented mostly, almost exclusively actually, by B/Hong Kong/22/2001.  Still, there is about some subgroups belonging to the Sichuan/379 and there is some increasing -- not extremely dramatic but there is some tendency in the B/Harbin/794 genetic subgroup.
		Just a couple of words about the neuraminidases evolutionary tree for the B viruses, and in this case we have both B/Victoria-like viruses in here and interestingly recent B/Victoria/487-like viruses form separate genetic group of the neuraminidase gene as well and here are the signature, I mean as it changes for each different shape, new B/Victoria neuraminidase from the previously circulating B/Victoria neuraminidase.  So we have genetic changes not only in the HA but also in the neuraminidase.  It's very difficult to say right now to what extent this could influence the intergenic part of this, of the intergenic neuraminidase.
		The Sichuan or Yamagata lineage, Sichuan vaccine strain is over here.  Both of the neuraminidases also consist of two subgroups and one of them is Sichuan and another one is Harbin/794 and agents are in parallel in this sense for B viruses and you can see that recent viruses which are here and here belong to both Sichuan genetic subgroup and B/Harbin/794 genetic subgroup.
		Okay, the amino acid difference table shows -- again, this yellow line divides the Sichuan genetic subgrouping from the Harbin genetic subgrouping and you can see that the Sichuan/379 vaccine strain matches consensus during the sequence pretty well and actually the B/Shizuoka/15 virus which was mentioned also pretty close to the consensus in the sense of the neuraminidase.
		Thank you very much and I will answer your questions.
		DR. DAUM:  Thank you, Dr. Klimov.  Committee questions or comments?
		Dr. Couch?
		DR. COUCH:  I have one.  Help me with the consensus sequence data which is based on 27 viruses isolated.
		DR. DAUM:  Dr. Couch --
		DR. COUCH:  The variety of viruses, the consensus data based on 27 viruses, it's going to depend on some extent on the 27 viruses and to what extent is the B/Victoria represented in those 27?
		DR. KLIMOV:  No, no.  This is consensus.  Are you talking about the HA?
		DR. COUCH:  Well, I was actually looking at the neuraminidase at the time, but I guess the question would be for both.
		DR. KLIMOV:  Neuraminidase, so the neuraminidases consensus as well as HA consensus is done for just Yamagata lineage, not for B/Victoria because we did for HA, we did several consensus for the HA.  We didn't do this for the neuraminidase because we have just very few sequences.
		DR. DAUM:  Okay.  No other Committee input.  Thank you very much, Dr. Klimov and that concludes this initial cluster of presentations.
		What I'd like to do now is move to the Open Public Hearing which I inadvertently bypassed before.  Is there anyone that wishes to address the Committee from the audience?
		There being no one scheduled and no one rushing forward to the microphone I will conclude the open public hearing at this point and put the Committee briefly into recess for a break.  We will break for 10 minutes and resume at 11:35.
		(Off the record.)
		DR. DAUM:  Could we take our seats and come to order?  I'd like to get everybody settled in so we can continue, please.
		Ms. Canas, are you ready?  We'd like next to call on Ms. Linda Canas from the Department of Defense who always has, in my view, an additional interesting perspective on this flu surveillance business and I hope she will follow in step today.
		MS. CANAS:  Good morning.  The Department of Defense has been following influenza for many years, especially in the Air Force as part of the health protection of the forces that are stationed around the world.  And since we are around the world it has worked very well to do surveillance for influenza and it has been so successful that in 1997 when the Presidential Decision Directive was instituted for the Global Emerging Infections System that this program became tri-service.
		There are two parts to this.  The Navy, at the Naval Health Research Center in San Diego conducts population health surveillance where they track health viruses and diseases in the recruit population for all the services.  The Air Force at Brooks Air Force Base and my laboratory in San Antonio, we're out in bases around the world doing etiology-based surveillance.  We like to say we're just trolling for bugs.  Whatever is there, we're looking for it.  We have a case definition consistent for influenza.  That's what we're interested in, but we want to know what's going on and that's what I'm going to talk about today  It does cover all of the services, but it's what we have collected in San Antonio.
		And since there are new Members on the Board and certainly new people in the audience, I want to do a quick run through of just how this program works since it is a little bit unique.  Every year we have a meeting, usually in the summer with the epidemiologists and laboratory people from all the services get together and we talk about what we've done and where we can go.  We want to look at the sites that we have, what's going on in the world, are there areas where deployments are taking place, should we have new surveillance sites.  And this input is forwarded then to the Surgeon General, the Air Force Surgeon General particularly, and he sends out a letter every year mandating that all of the active duty individuals in the Air Force will be vaccinated.  Each of the services has this policy.  They are required to vaccinate the active duty individuals.  And in this message for the Air Force they also name the Sentinel Sites.  And these Sentinel Sites then are supplied with any collection materials that they need for the collection of specimens and the public health officers at each site run this program to make sure they're collected and then they're sent to us at Brooks.  Now this is a full service reference laboratory.  We have specimens coming to us for all the areas of laboratory testing from all over the world which makes this whole program possible.  It also makes it cost effective because these are coming in the same FedEx boxes with other samples so they can come to us in a timely basis.  This is a surveillance program, but we also treat it as a clinical program and we try and turn these samples around as quickly as possible so they can have some idea of what's going on in their facility.
		We put our results back into the computer where they get patient results, they can treat them.  It also goes to the epidemiologists where they will contact the public health officer at a base to tell them they have influenza on site so they can take any interactive measures that may be necessary.
		And then of course we get to make all kinds of reports and send up recommendations every year which will lead to changes in the program.  We also do our own subtyping analysis on site of selected samples and we send others on to CDC where they do their own analysis and then I can come here today and tell you what we have.  So this is an overall view of how the program works.
		Next slide.
		This is what our map looks like today.  These are the Sentinel Sites.  Now we do get samples from other areas because we certainly have bases from other areas, but these are our named Sentinel Sites where they're asked to send so many samples each week from symptomatic patients.  We choose these sites based on location.  If they're on the coast we've got people that are traveling in an out of the country where they may be bringing their own viruses.  We have training sites where people may be crowding together from different places and then we've also been able to add with making this tri-service, the Army and the Navy have research labs in various areas of the world doing research on various Malaria, Dengue, other diseases and we've been able to institute protocols consistent with influenza.  And these have been very successful.  This is especially true in Thailand with surveillance in Nepal and it's been very extensive in South America.
		We have just established a site in Uganda.  This has been established.  They made me go over there and set this up.
		(Laughter.)
		We haven't gotten any samples yet, but the infrastructure is in place and it's being set up.  We've been able to hook onto an existing health protocol over there in Kaloisso, Uganda.
		HIV and Malaria rule the diseases in this country and they're so overwhelming, but by their own statistics, acute respiratory illness is the third most common reason for individuals coming to the clinic there in Kaloisso.  And they have no idea what really is the underlying cause.  So we hope to provide them with their own information of what's going on as well as give us samples from an area that is undersurveilled right now and on this trip I was able to make some more contacts and perhaps they can encourage me to go back and set up some more sites.
		If we look at what we've done so far this year, as has already been presented, it's been very light.  I've had a busy year.  It wasn't too bad for me to have to go along with nothing, but as far as I'm concerned flu hit last week.  The season has begun and we're in it full swing.  Our samples generally are about two days away from collection when we get them.  This is not true, of course, from South America and Thailand.  They can be up to 5 months, but the collection dates are represented here.  And this is the actual isolates that we've had and you can see that we've had a dramatic input.  Everything has been -- excuse me, Influenza A, so far.
		And if we look at by week the number of samples that have come in compared with the percentage of isolation, you can see it pretty much follows along with what's been on the CDC charts and this is real time so in the later months, excuse me, the later weeks, these are still works in progress.  They've just come into the lab.  On Monday, we have been working up 20 to 30 samples a day, consistently and on Monday we had 84 samples and 32 of those were positive.  They tended to be from the same sites, but we are starting to see it traveling.  And if we look at this over time because this a global picture, just numbers doesn't really tell me what it looks like.  It did start out very slow in October.  About the only thing we had was in Alaska and we got seven and those tended to be later in the month and they were, the ones we got to type were the H3N2.  November, Alaska was there.  We pretty much every day had some coming from them and a high percentage of those they sent us were positive, with just sporadic flus around.  We did get some samples in from South America and the only Bs we've had this season came in.  Now they were collected in November, but we only got them a couple of weeks ago, so we haven't been able to look at them any closer than what they are.
		December started getting a lot busier with -- excuse me, Alaska not quite as heavy, but picking up dramatically in Hawaii and that has continued.  And of course, there's a lot of where the sites are that we have and the emphasis the public health gives and the Navy in Hawaii has been very aggressive in tracking this and I don't always know where they come from.  I believe some of them are from ships, but from the island, all over the island they're responsible for getting them to us.  So we've been seeing quite a bit of activity there.
		And in January, as of last week, we're seeing dramatic increases in Texas, in San Antonio, actually, we're picking up quite a few more flus and I failed to mention in December the only H1 that we've seen all season was picked up in Korea.  We did get some more Koreas this week, so we'll be looking at them to see if that H1 continues or they too now have the H3.
		Next.
		And always it comes up, if it's not flu, what is it?  We can probably answer that a lot of them may have been collected too late to actually detect a viable virus.  Perhaps it's really a bacteria.  We're not going to detect any of the chlamydia pneumoniaes or the strep pneumoniaes, the more common cold viruses.  RSV is certainly a big player in most hospital populations, but for us, we're not looking so much at the pediatric patients and this is also not a virus that transports well.  So it's not one that we pick up in our culture system.
		But we do pick up a fair number of adenoviruses and I've had a note on all of these that these numbers have been adjusted to exclude adenovirus because this is a very important player in the military recruit population.  It dominates in that area and our numbers are very skewed if I have them.  So I've pulled those out since it is a unique military issue.  But we do still get adenoviruses as background viruses in the population.  It is seen quite often and a fair number of pari-influenzas and interoviruses, we're still picking up some coccaci Bs and a few others that aren't typed any further and so roughly around 25 to 30 percent of our overall viruses tend to be the flus with some more thrown in, but probably because of the case definition, we do tend to get flu the most.
		And this is our own analysis of sequence analysis of adendogram of the ones that have been looked at so far and you can see it's very similar to what you've seen already.  We've only done H3N2s and they've all been very tight.  We have not seen in these that we've done here any of the substitutions that have been reported.  These are all that we have so far.
		This is our program so far this year.  I do think it's going to change a lot in the coming years or excuse me, the coming weeks.  Are there any questions?
		DR. DAUM:  Ms. Fisher, then Dr. Katz.
		DR. KATZ:  I understand your exclusion from the original data of adenovirus.  Does your lab do the typing of adenovirus so you can tell us if these are 4 and 7 or what serotypes they are?
		MS. CANAS:  We try and keep up with it a little bit.  Mainly that's done in San Diego and it is, it's actually 4 right now with some 7s in there.  It's still staying very tight with the historic 4s and 7s.  We would like to do more of this.  In fact, there is some talk of picking up a site in Venezuela of military populations and looking specifically to see if they might have an adenovirus in their, recruit population also.  We haven't been able to find anyone else who actually looks in their recruits for this particular virus.
		DR. DAUM:  We are nothing if we're not flexible.
		Ms. Fisher and then Dr. Dowdle.
		MS. FISHER:  I just want to be clear.  You say it's 17.3 percent of all samples of suspected flu cases were positive for any respiratory virus.
		MS. CANAS:  That was also then including parainfluenza, interoviruses, I'm not looking at that particular chart right now.
		MS. FISHER:  It's only 17 percent were positive for any virus?
		MS. CANAS:  Right now, yes.  It's been very low up to this point.
		MS. FISHER:  Well, then when you are categorizing flu cases and you're not actually looking at whether or not they're positive, doesn't that seem like there's an awful lot of suspected flu cases that are not actually caused by the flu?
		MS. CANAS:  Oh yes, that's what I was trying to say.  Many of them may be bacteria.  They may have been collected too late for us to actually detect them.
		MS. FISHER:  But what does that say in terms of vaccination though?  In other words, the total number of suspected flu cases in this country, potentially only 17 percent are actually due to the flu?
		MS. CANAS:  But this is at a part of the season where we don't really have flu circulating yet.  We're just now getting into the season when we'll actually see flu.  It will go up dramatically.
		DR. DAUM:  Dr. Dowdle and then Dr. Goldberg.
		DR. DOWDLE:  I just had a question about demographics, if I may.  Now on your Sentinel Sites, is this some attempt here to standardize this or do you have some sites you have military personnel, some sites you have mixture of both military and dependent personnel or how do you do this, how do you work this out?
		MS. CANAS:  Anyone who comes to a military treatment facility that presents with a case definition would be eligible whether they're dependent or military.  We make no distinction.  We do keep track of that data.  The obvious question here is can we follow vaccination status.  That's an attempt we're always trying to make, that data is, especially in the Air Force, is input into a computer system where we do try to track it.  We actually are trying to set up a trial in Misawa, Japan where we have a population we can study, but they haven't had flu this year yet so we haven't been able to do anything.  But we don't make any requirements --
		DR. DOWDLE:  But is it fair to say that in each of these Sentinel Sites that you do have a military population that's under surveillance?
		MS. CANAS:  Yes.
		DR. DOWDLE:  But they may be recruits as opposed to seasoned personnel?
		MS. CANAS:  The recruits are at the recruit centers, so in this data only Wilfred Hall or Lacklan would be represented, just because historically they've sent to us and we've kind of handled their clinical isolates, but they also sent isolates to San Diego for recruit studies.
		DR. DAUM:  Dr. Goldberg and then Dr. Diaz.
		DR. GOLDBERG:  Just one clarification.  The military are all vaccinated you say, so therefore, if I'm following correctly, I would assume that you should see less flu.
		MS. CANAS:  Yes.
		DR. GOLDBERG:  If the vaccine is against the strains that are there.
		MS. CANAS:  Right, and that's one of the things we would like to try and find out.  We do track whether they're active duty, but we cannot tell whether they're retired or active duty.  So it's hard to tell when they were vaccinated.
		DR. GOLDBERG:  So you really don't know --
		MS. CANAS:  It's a work in progress.  That's something that we want to know as much as anyone.  It is a population where we should be able to study that.
		DR. GOLDBERG:  That's the confusion in the presentation because you would expect it to be low if they truly were vaccinated.
		MS. CANAS:  This is very heavy.  I try and watch it each day on the children and the dependents so we don't know any of their vaccination status.
		DR. GOLDBERG:  Are they required to be vaccinated, the children?
		MS. CANAS:  No.
		DR. GOLDBERG:  So it's just the recruits themselves.  Okay, thanks.
		DR. DAUM:  I must add that those data would be incredibly valuable.
		MS. CANAS:  Yes.
		DR. DAUM:  Dr. Diaz.
		DR. DIAZ:  Actually, just in follow-up to the same kinds of discussion, I was -- when you were describing surveillance system I was wondering if the surveillance system is integrated into the DMSS, the Defense Medical Surveillance System because all that data should be in those interrelationship data bases.
		MS. CANAS:  Right, making sure it's up to date.  There are efforts to match that and to try and --
		DR. DIAZ:  So this doesn't automatically dump into that system then?
		MS. CANAS:  No.
		DR. DIAZ:  What are your triggers for doing, trying to do isolate recovery from cases?  Is it voluntary or is there a certain threshold from the Sentinel Sites that you look for before you start swabbing?
		MS. CANAS:  Basically, it's October 1st when they're asked to start sending samples.  And this is part of the military culture, especially in the Air Force.  It's been part of what's been done for a long time.  When we first hit the problems with the vaccine a couple years ago there was considerable interest on what it was going to mean.  There's a history in the military of what happens when influenza hits.  So probably more than in any other single population, this is  very important, so it is something that's mandated, that it be followed and there's an interest on every level.  I get calls from people who say I'm not a Sentinel Site, but I want to be part of this.  Okay.  But these are the ones -- we try and get a representative geographical population and it is for the health of our people too.  So if they're going to be deployed, we want to know what's going on with them, if it's flu or if it's something that can be treated, if we can get amantadine in there or not.  This is of interest to the DOD.
		DR. DAUM:  Dr. Manley?
		DR. MANLEY:  Yes, would you clarify again what you said about the vaccination status of the recruits on the information that you get?  And if they are vaccinated, is there a particular time in the annual cycle at which the Air Force would be vaccinating?
		MS. CANAS:  It's my understanding they're vaccinated soon after they arrive at the recruit centers.  I believe that's all year round, but I'm not sure in the summer about that.  Someone might be able to clarify that.
		DR. DINIEGA:  This is Ben Diniega from Health Affairs.  We do have a policy for year round vaccination of recruits on entry to the installation.
		DR. DAUM:  Now sir, do you wish to ask a question of the speaker?  Tell us who you are.
		DR. FREAS:  For the transcriber, sir, will you come to this microphone here?
		DR. DAUM:  Could you begin by telling us who you are and --
		MR. BRADSHAW:  Yes.  My name is Dana Bradshaw.  I'm currently with DOD Global Emerging Infections Surveillance and Response System here located at Walter Reed Army Institute of Research.  I was formerly Chief of Preventive Medicine in the Air Force, Surgeon General's Office, so was involved with a lot of this stuff.  I was just going to try and help clarify some of the questions that were asked.
		We do kind of a hybrid kind of surveillance in terms of influenza surveillance and respiratory disease surveillance.  There's a program at the Naval Health Research Center which she mentioned which is population-based surveillance where they have a denominator, clear denominator at all the recruit centers.  They have them with the Army, the Navy and the Air Force and they collect respiratory disease surveillance information on those recruit populations, so they specifically look at recruit populations.  They have a web site.  If you're interested in this, the questions, for instance, earlier about adenovirus 4 and 7, they have that information on their website.
		The Sentinel Sites that we use for influenza surveillance, we pick the sites looking, trying to look at portals of entry, places where historically we've seen influenza start and spread, etcetera.  And so those are the sites that you saw.  Most of these bases do have dependents with them.  The policy in the military and the Air Force is to vaccinate all of our active duty, but we have -- we follow ACIP recommendations on dependents.  So as you can imagine, we have variable uptake in our populations just as the rest of the U.S. and the world does in terms of uptake of influenza vaccination.   But the Air Force has a policy and we do do immunization tracking.  We've done this for our population's active duty since 1998 and since 2000 for all of our dependents.  So we can get influenza vaccination information and Linda was mentioning that we are looking at doing some efficacy studies, trying to look at vaccines, diagnosis of influenza and correlate with some of our laboratory data, so hopefully maybe that helps clarify.
		DR. DAUM:  It does.  Thank you very kindly for those comments.
		Are there other questions for Ms. Canas?  Thank you very much for an insightful presentation.
		We'll move on to Dr. Levandowski and he will put before us a plethora of vaccine responses.
		DR. LEVANDOWSKI:  Well, I sometimes feel plethoric.
		Okay, my task is to give some information about the vaccine studies that have been done in anticipation of this meeting.  And I have to tell you that looking at the tables, my eyes start to cross.  I'm sure yours do too.  So what I'm going to try to do here is to summarize all of that data into some form that is more readily digestible.  I don't know whether I'll succeed, but I'm going to try.
		What I'd like to say is background information is the data that we're presenting and actually you have tables from both the Center for Biologics and from CDC in the handouts that you received.  I'm not going to follow those directly, but the information I'm going to present comes from that.  There is an on-going international collaborative effort to look at immune responses or the antibody responses for current vaccines and that's largely possible because of the commitment that there is from the World Health Organization and its influenza centers and this overhead that's up here now shows the different serum panels that were provided for doing the testing that we're looking at today.  These have come from adults and elderly from Australia, Europe, Japan and the United States.  The vaccines that have been used for immunizing the people in these studies are shown and I really would just call your attention to just a couple of items here.  The Influenza B strains that have been used, as has been mentioned, there have been several different ones.  Really, there are three different strains that are currently in use around the world and they're considered to be equivalent and B/Sichuan/37/99-like.  The three strains that have been used are B/Johannesburg/5/99 which are -- Australia and Japan and I'm not really clear.  They might also be using B/Guangdong/120/2000 in Australia now.
		And the B/Guangdong/120/2000 strain has been used predominantly in Europe and for the studies that was the vaccine strain, but they have also been using B/Johannesburg/5/99 as their vaccine strain.  And the strain that's been used predominantly in the United States is B/Victoria/504/2000, but we also have B/Guangdong/120/2000 containing vaccines in the United States.  So these are the components that were in the vaccines that were used in the clinical trials I'll be talking about, but just to make -- I'm trying to make it clear that there's a mix of vaccines being used around the world for, at least for Influenza B.
		So the laboratories that are participating here include WHO Influenza Center in Melbourne, Australia, the National Institute for Biological Standardization and Control in London, CDC in Atlanta.  More recently, the National Institute for Infectious Diseases in Tokyo is involved in these studies and we at the Center for Biologics have been involved also.  And the five labs are sharing the sets of sera that shown and this represents about 200 individuals who have been immunized for the studies and I should say that there still is testing that's going on.  You have been used to seeing, I think, in previous years information from Europe and from Australia, but we have not had access to that yet.  So what I'm showing is current to Monday of this week and on the next overhead these are the H1N1 antigens that have been used for serological testing for the studies that you'll be looking at.  Not every one of these antigens was used in all the laboratories, so that a wide variety of new antigens could be examined, but there's a core of antigens that can be tested in each of the laboratories and that gives us an opportunity to compare what the results are between labs and we do know that there are technical differences between the laboratories and you'll see that reflected in some differences in the level, the absolute titers for specific serum panels and for the same strain.
		These studies were performed, that I'm going to show were performed actually in two different go's. Some were done as part of the preparation for the Southern Hemisphere, WHO Southern Hemisphere recommendations in September last year and some of these were done during the last few weeks.  The antigens that are shown here for H1N1 are representative of the different strains that are circulating and all of these are in the A/New Caledonia/2099 group.  None of these represent the BAYERN or Johannesburg strain that Sasha and Nancy were talking about.
		On the next overhead these are some typical results.  If you push that up towards the top, there's an opportunity for people to see it -- it will be a little bit hard from the back.  But these are sera from adults in the United States and this table and the others like it that I'm going to show will include data that has the geometric mean titer, the percent that are greater than 32 or 40 and the percent of 4 fold rises.
		What I've attempted to do is to underline what represents the vaccine strain and also I think the organization for all of these is that results from the CDC will be at the top and from the Center for Biologics at the bottom.
		So the vaccine strain here was the IVR-116 reassortant virus for A/New Caledonia/2099 and it was also used as the test antigen in these serologic results.  Generally what I can say is that the vaccine used was immunogenic and it produced good, homologous antibody responses.  Although the New Caledonia-like strains were mostly well inhibited by the antisera in response to this vaccine antigen, there were some strains that were less well inhibited and in testing done at the CDC, for example, you can see that the geometric mean post-immunization titer for the Auckland/65/2001 strain was 50 percent of what the result was for the vaccine strain.  And I believe that Auckland/65/2001 is one of those strains that was pointed out as being one of the low reactors.
		Similarly, in testing that was done at the Center for Biologics, the results for the -- I guess it's the Hawaii/15 strain here was more than 50 percent reduced compared to the vaccine strain.
		Next overhead, this overhead shows the results that were obtained from sera that were from elderly in Australia.  And again, the vaccine that was used seemed to elicit pretty reasonable responses to the vaccine antigen and in general, the inhibition of the other H1N1 viruses was very similar to the vaccine strain.  In testing that was done at CDC, I think you can see there's some minor reductions here to the Bangkok/255/2001 strain and the Hawaii/15/2001 strain, but not to the extent of being 50 percent or a 2 fold difference.  And in testing done at the Center for Biologics, there was also again a minor sort of reduction for the Hawaii/15/2001 strain.
		Other serum panels that were tested gave somewhat similar results and I'll try to cover that in a summary form in some later tables.  So now moving on on the next overhead what I'll be showing you are some results for the H3N2 viruses or I guess I'll be showing you the H3N2 viruses that were used for the testing.  Again, these are strains that are representative of many of the strains that have been circulating over the past year in both the Northern and the Southern Hemisphere.  And on the next overhead I'll show results for one of the serum panels.
		This table is for adults who were immunized in Europe and what it shows, generally, is that the current vaccine strain, the A/Panama/2007/99 was reasonably immunogenic in terms of the response to the vaccine strain and again, this particular vaccine strain was a reassortant virus, the rest are 17  reassortant.  However, in this table, I think you'll see that there are geometric mean titers that are reduced for some of the other strains that were tested.  Neither the A/Chile/6416/2001 strain or the A/Singapore/15/2001 strain seem to be well inhibited in the tests that were done at CDC and for both of those, the geometric mean titers were reduced by more than 50 percent and similarly data from testing done at Center for Biologics shows 50 percent or greater reductions for both the Darwin/3/2000 strain and again for the Chile/6416 strain.  So for other strains, I guess I could say generally the antibody responses seem to be pretty much similar to those for the vaccine and the next overhead will show some results for some elderly in the United States.
		These data, I think, again demonstrate that the current vaccine produces antibodies that cross react reasonably well with many of the new H3N2 viruses such as the Argentina/37/59 strain and also the Alaska/14 strain.
		In tests that were done at the Center for Biologics, there was more than 50 percent reduction in the responses for the Philippines/78890 strain, but that was not seen in testing at CDC.  And again, I'm going to cover other serologic results in more of a summary form a little bit later.
		So moving on now, this overhead shows a list of the Influenza B viruses that were used for serological testing and you'll recall that there are two hemagglutinin lineages that are present in circulating viruses.  The antigens that were chosen here represent, I think, as best we could both of those lineages as they're circulating and those at the top here are related to the current vaccine strains and they're all in the B/Sichuan/379/99 lineage, generally, or maybe I should qualify that some and say this B/Johannesburg/69 strain here is in that sort of -- can I call it a splinter group?  I'm not sure it's a lineage, but there's a divergence, antigenic divergence developing and it's more like the B/Harbin/794 strain.  And then at the bottom I'm showing the B/Victoria lineage or as it's sometimes being called, the B/Beijing/243/97-like strains.
		Unless I say otherwise, all of this serologic testing that I'm going to present here was done with B antigens that had been ether extracted for use in the serology.
		In the next overhead there should be results from a panel of adults in the United States again and I think this gives a pretty reasonable overview of recent isolates from a number of locations around the world and in general, the antibody responses seem to be pretty good to the vaccine strain and also to most of the newer strains that are circulating.  However, there were some reductions in geometric mean titers for some of the antigens that were tested and in particular I'll just call your attention at the CDC testing with the Johannesburg/69/2001 strain was more than 50 percent reduced compared to the vaccine strain.  And in testing that was done -- or as I mentioned, that particular strain is in that Harbin/794 lineage.
		In testing that was done at the Center for Biologics, there were reductions of 50 percent or more for a couple of strains, both the B/Hong Kong/332/2001 which is not in the same lineage, HA lineage as the current vaccine and also for the B/Hong Kong/692 AND B/Sichuan/317 viruses.
		Now I will point that that result does not seem to be typical of results from either the Center for Biologics or from CDC, but it is one of the variations in the antibody responses that we sometimes note.
		In the next overhead, these are some results that were obtained from a panel of sera from elderly in Australia again and what they demonstrate are again reductions, predominantly reductions in antibody responses to the B/Victoria/287 lineage strains represented here by B/Hong Kong/330/2001 and B/Hawaii/10/2001 and what you can see is what we have come to expect with current vaccines of the B/Yamagata lineage in terms of producing antibody responses for the other lineage and I will not have any data from any pediatric populations, but what I could say is that in earlier years when the B/Victoria strains were not circulating so widely, but were still present, what we had found was that adults and elderly tended to have, although reduced titers, somewhat higher.  So I think we're starting to see for adults and elderly over the last couple of years, in fact, continually decreasing responses in the face of the current vaccine strain.
		So now moving on to sort of a summary, in this table and the following tables, what I'm going to be showing are how we've tried to handle these data which are complex and coming from different laboratories in the past few years and what we'll have here is a table that shows the frequency with which we found new test antigens that gave a 50 percent or greater reduction compared to the current vaccine strain.
		We picked 50 percent arbitrarily, but it represents a 2 fold reduction in geometric mean titer and that's fairly marked in terms of GMTs.  The data that are included in the table are as much as we can for antigens that have been tested in more than one laboratory and I should note that we haven't really had access to  information outside the United States at this point, partly because the WHO meeting for strain recommendations will occur next week and others are getting ready for that.
		In this table for H1N1 viruses, all these viruses again are New Caledonia-like and if you just more or less look at the line for the total results, generally there are really two instances in which multiple tests detected differences compared to the vaccine strain and that would be for the A/Hawaii/15/2001 strain and also for the Auckland/65/2001 strain.
		The majority of the tests performed resulted in a 50 percent or greater reduction in titers as compared to the vaccine for both of those.  For the Hawaii strain on average, the reduction was about 60 percent with a range from 31 to 82, depending on which of the serum panels were picked.  And for the Auckland/65 strain, that difference was somewhat less than 50 percent, just less than 50 percent and it ranged from no change to 93 percent reduction.  So there was quite a broad range there.
		However, I'd say overall, the data don't indicate that there is a generalized substantial lack of inhibition of the current strains by the current vaccines.  So the next overhead should show summary data for the H3N2 viruses.
		And what you'll see here, I think is that many of the more recent strains were very well inhibited by sera from persons who were immunized with the current vaccines, but here again, there are also some strains that appear to be somewhat less well inhibited in comparison to the vaccine.
		And those that are less well inhibited include the A/Chile/6416 strain, the Philippines/78890 strain, the Singapore/15/2001 strain, and possibly the South Australia/102 strain.
		Although there was reduced inhibition for the Chile/6416 strain in the majority of the tests, on average for all these tests there was only, there was somewhat less than a 50 percent reduction, and again the range for the difference here was wide, from nothing to about 75 percent.
		For the A/Philippines strain, the reductions were only seen in one laboratory and so you have to factor that into thinking about this particular one and on average for all these tests it was really very moderate and there was a very, again a very wide range of responses that were seen in the tests that were done.
		I think here with the Singapore/15 strain, I believe, both the Singapore/15 and the Australia/102, South Australia/102 strains again represent those that were low responders.  Is that correct?  I think I got that right.  And so I would suggest again factoring that in and sort of considerations about what these responses are showing.  But for the Singapore strain, in particular, it was consistent in all the tests that were done, it was really a very narrow type range of reductions here, so there may be something more to that particular strain.
		The overall picture though, I'd say is somewhat similar to what we're seeing for the H1N1 viruses and that the results don't suggest a generalized lack of inhibition of currently circulating strains.  And also, similar to the results for the H1N1 viruses, the results for the mean percent reductions shown in the last column are somewhat variable with some tests where there really is no reduction at all.
		Okay, so moving on to Influenza B, this overhead should show the summary data for Influenza B viruses and just again as a reminder, the B/Hawaii/10/2001 and the B/Hong Kong -- where's B/Hong Kong, B/Hawaii/10 and B/Hong Kong/330/2001 are strains that are in the B/Beijing/243/97 or B/Victoria/287 lineage, hemagglutinin lineage.  All the rest are in the B/Yamagata lineage and the B/Johannesburg/69 is in that B/Yamagata lineage, but it's representative of the divergent, the strains that are diverging more like the B/Harbin/799/794 strain.  		Although most of the strains that are in this B/Yamagata group seem to be very well inhibited by the current vaccines, the only notable exception to that is the B/Johannesburg/6901 strain where about half of the tests done indicated a reduction and on average that reduction was just shy of 50 percent with a somewhat broad range, but again, there were reductions seen in -- some reductions seen in each of the tests that were done.
		I think it's no surprise that the recent B/Beijing or the recent B/Victoria/287-like strains were poorly inhibited and I don't think I need to really dwell on that since that information is very consistent with what we've been seeing in the past couple of years.
		So you can take the overhead off and I'd say in summary the vaccines that were used for the clinical studies appeared to be very immunogenic in the populations that they were tested in and for all three of the vaccine component strains, we can see some evidence of antigenic drift.  The results, I think, are the most obvious for the Influenza B strain, where only the strains that are in the same HA lineage are well inhibited by sera from the current vaccine studies and any even there there's some evidence that antigenic drift is continuing.  And so I'll stop there and take any questions, if there are any, that I can answer.
		DR. DAUM:  Thank you very much.  Are there questions?
Ms. Fisher, then Dr. Poland.
		MS. FISHER:  Dr. Levandowski, every year when new flu vaccine candidates are tested for efficacy, do those tests usually involve about 200 individuals?  I think you mentioned that was true for this year.  Is there any reactivity data gathered and are children or pregnant women included?
		DR. LEVANDOWSKI:  These aren't for efficacy.  They're really looking for immunogenecity and the real purpose behind is to have some -- we're trying to emphasize a comparison between the current vaccine strain and the newly circulating strain, but the number of 200.  There are no pediatric patients that are being immunized at this point.  And we're not including pregnant women and I don't know whether in all of these serologies that are done in other places and I don't know the answer to the question about whether reactogenecity data are being collected from those 200 people.  It's not the specific reason for the study.
		MS. FISHER:  Right.
		DR. LEVANDOWSKI:  It might be done elsewhere, but in the United States I don't believe we're doing that.
		MS. FISHER:  But these immunogenicity studies are the only ones conducted, correct, every year on the new flu vaccine candidates, or am I wrong on that?
		DR. LEVANDOWSKI:  Well, it might not be the only ones, but these are the ones that we have access to the antisera.  We get these antisera specifically for this purpose that I mentioned, to try to get information to compare responses about the current vaccines with the newly circulating strains.
		MS. FISHER:  Right, but I think it's really important for the public to understand, is there more testing done on the flu vaccines other than this immunogenicity testing?
		DR. LEVANDOWSKI:  If you're asking is the Public Health Service doing some specific testing --
		MS. FISHER:  No, is there any other testing besides this testing done on new flu vaccine candidates?  Is anyone aware of any other testing?
		DR. LEVANDOWSKI:  Okay, well, specifically related to the influenza vaccine candidate strains, I think the answer is probably not.
		MS. FISHER:  Okay, that's all.
		DR. LEVANDOWSKI:  But are there studies being done to look at current vaccines, in a number of ways I think the answer is yes, but I don't know that I can give you a categorical response to that.
		MS. FISHER:  Thank you.
		DR. DAUM:  Dr. Poland, please.
		DR. POLAND:  Just a point of information, Roland.  Are the laboratory protocols that CDC and CBER are using identical?  Because it appears almost systematically that CBER's results are in some cases significantly lower than CDCs.
		DR. LEVANDOWSKI:  Right.  I understand that and we do, although we follow very much the same procedure, there are some technical differences that we know about and that we have perpetuated purposely, I think.  One difference is that serologic studies that are done in CDC are done using Turkey red blood cells which tend to be less different in their response to hemagglutination inhibition than chick cells.  Chickens, individual chickens tend to be either good or poor responders in terms of hemagglutination and at the Center for Biologics, we have continued to use chick cells.  It's pooled chick cells, but I believe that may have something to do with the technical differences.  And then possibly another area that could result in differences that we see in any of the serologic testing is what you exactly call the end point because telling exactly where hemagglutination has been inhibited is sometimes a little bit tricky and there can be interferences within the sera with the red cells themselves.  The serum can have nonspecific glutinins that we try to remove with neuraminidase, but we see those kind of things and then just being able to decipher exactly what you're going to say is the end point, there may be some difference there.
		DR. POLAND:  In terms of looking at the data and trying to make a decision is do we really understand what the statistical significance is of these findings and which one do you believe, sort of.  I know that overall we're looking at kind of the preponderance of evidence to make a decision, but in the specific case of the HAI titers --
 		DR. LEVANDOWSKI:  Right, well, there's a logistical issue here too in trying to get the information for recent strains and how many serologies you can do and that's the reason we have multiple laboratories involved in this that we don't -- we think that if more laboratories are saying the same thing, maybe not the absolute titers are the same, but the same direction seems to be true, that that is confirmatory and I think that's what we've been trying to do all these years with multiple labs being involved as to -- I don't think we can do statistics in a real sense because of the small numbers that we're looking at here generally, but I think we can get a pretty good idea about the trend and get confirmation from multiple views of the same data.
		DR. DAUM:  Before I call on Dr. Kohl and then Dr. Couch and then Dr. Goldberg, I wanted to just follow up on this particular point.  I was also struck by the discrepancy sometimes between the two labs and then at the end, I believe you showed some summary data, where results done in each laboratory were sort of added up and then summed, so that we get a sense of how many low responders there were, how many high responders there were.  And if two labs differ in their results markedly, so that one was low and one was high for a given virus, were they then summed into that total and if so, is that statistical double dipping or do I not understand statistics very well?
		DR. LEVANDOWSKI:  Well, I'm not going to answer the statistical question, but the answer to the first part is yes, we're not making any differentiation between whether we had high antibody titers or lower ones.  We're looking there mostly at a ratio between the pre and the post -- not the pre and the post -- we're looking at a ratio between the vaccine strain and the new influenza viruses that are circulating and we're hoping that whatever technical differences there are, affect everything equally, proportionally between the vaccine strain and the other strains.  What I would say as another way of trying to control for that, when these serologies are done, when you see one of those serum panels, everything would have been done on the same day with the same red cells, the same reader doing the -- reading the end points and so on.  So as much as possible, there's a control over that part where we're trying to get the comparison between the vaccine strain and the newly circulating strains.
		DR. COUCH:  Could I get my comment in now?  It relates to that.  I just wanted to say that if you had a third lab, you would get a third set of data.  That's the reproducibility of the HI between laboratories and between tests to some extent as well.
		DR. DAUM:  Okay, Dr. Goldberg wants to speak to this very point.
		GOLDBERG:  Could I ask a question of clarification about your design really?  Are you testing sera from the same 24 individuals in both labs?
		DR. LEVANDOWSKI:  Yes.
		DR. GOLDBERG:  In which case what you really need to be doing is thinking about comparing the results individual for individual in the labs and then looking at what you have because the real issue is some individuals were low in one lab, high in another, and that would speak to the assay variability.  It may be that low is low, but the range is different and it's a systematic lab bias which would have to do with what you talked about about the kind of -- the way the assay is done.
		So I think you need to relook at how you present the data and pair up the data so that you're looking at individual by individual and then summing up differences or whatever the appropriate measure is.  I'd be happy to discuss it with you outside.
		DR. DAUM:  Thank you, Dr. Goldberg.  Now we'll go to Dr. Kohl.  You've been patient.
		DR. KOHL:  Roland, thank you again for your usual lovely annual report.  I get to take my plaque home today because it's four years of serving on the Committee, but I have the same frustrating question that I've asked for four years which has previously been reflected, I think, by Bob Couch's question and by Barbara Loe Fisher, where are the children?  We're thinking about using a new antigen this year, I guess, with the B/Vic and I'd love to see some data on children.
		What can we do to help whoever needs to be helped so we can get some children data because those are a critical group to be considered?
		DR. LEVANDOWSKI:  Pardon me, well, I guess we can't disagree with what you're suggesting and it is something that we would like to see done and again, it's I believe predominantly a resource issue.  The pediatric population, of course, is a protected one and we want it to stay that way, but in terms of being able to do studies, there needs to be some way to access an appropriate population which requires both time, investigators and money, all three of the key issues for doing anything successfully.
		DR. KOHL:  It's an unprotected population, unfortunately, not a protected one in terms of the influenza virus and there's more and more data showing that children have quite a high burden of disease.  We need to do something about this.
		Bob, I don't know if there's something, a sense of the Committee that can carry this forward a little bit, because it really has been a major frustration over these years on my part and I think other members of the Committee.
		DR. DAUM:  Well, I think that making comments like you make put it into the record.  There are many people here who pour over every word that you and everyone else says and I think that it comes up this afternoon when the Committee is deliberating and casting their votes as an issue again that we'd be heard.  We have said it before.  You've spoken about it before and so have others and I think it's a crucial issue.  And FDA, audience, industry people, please hear us.
		Dr. Cox, you had your hand up.
		DR. COX:  Yes.  I just wanted to say that unfortunately this year, as Roland mentioned, we don't have access to data that has been generated or is being generated in London, in Tokyo and in Melbourne and it really helps when you have more than two sets of serologic data.  So when you have five sets you do begin to see patterns and it falls out a little bit more clearly.
		DR. DAUM:  Thank you.  Okay, I think Levandowski, you're off the hot seat.  Thank you very much for your input.
		Dr. Ye is here.  There he is.
		DR. YE:  And I'm going to present the status of candidate vaccine strains and the related potency reagents.
		Next slide, please.  Inactivate  trivalent influenza vaccine contains the antigen of two type A strains which are H1N1 and H3N2 and one type of B strain.
		The current vaccine for Influenza A, H1N1 strain is A/New Caledonia/20/99, reassortant between New Caledonia and PR8 is VIR-116 which has lower to higher growth curve characteristics in eggs.
		At this point we do not have a new candidate for H1N1 virus.
		Next slide, please.
		The current vaccine for Influenza A, H3N2 is Panama/2007/99 which is A/Moscow/10/99-like viruses.
		Resvir-17 a reassortant between Panama/2007/99 and PR-8 which has moderate to high growth characteristics.  Again, at this point we do not have a new candidate for this strain.
		Next slide, please.
		Now we will move on to Influenza B strains.  The current vaccine strain for B Influenza viruses is B/Sichuan/379/99-like viruses which belong to Yamagata/1688 lineage.  There are three current vaccine candidates.  One is B/Johannesburg/599 which has lower growth characteristics in eggs.  The second one is B/Victoria/504/2000 which has moderate growth characteristics in eggs.  The last one is B/Guangdong/120/2000 which has moderately growth characteristics.  		Next slide, please.
		The candidate strain for B Influenza viruses are shown on this slide.  There are two lineages for Influenza B viruses.  One is B/Yamagata/1688-like virus.  There are two possible candidates for B.  One is B/Shizuoka/15/2001 which gives a lower to moderate growth characteristic in eggs.  B/Sichuan/117/2001 which has moderate growth characteristic in eggs.  The second lineage represented by B/Beijing/243/97 and this also belongs to B/Victoria as mentioned earlier.
		There are three candidates to be considered.  One is B/Hong Kong/330/2001 which has lower growth characteristics in eggs.  B/Hawaii/22/2001 also has a lower growth characteristic in eggs.  B/Shangdong/797 which has moderately growth characteristics previously used for vaccines in Asia in 1999 and the year 2000.
		Now we are moving to the potency reagents.  The antisera and antigen for H1N1 New Caledonia/2099 and 83 N2B Panama/2007/99 are available now from CBER. If new strains are choosing new reagents, need to be made and will be made available at the earliest.
		Next slide.
		In reagents currently available for B Influenza viruses as follows, the antisera and antigen for B/Victoria/504/2000 now available from CBER for manufacturer usage.  Antisera for B/Guandong/120/2000 available from CBER, but antigen for this virus can be required from NIBSC.  NIBSC also produced both antigen and antibody for B/Johannesburg/599.
		Now we will move on to single lineage which is represented by B/Beijing/243/97 which is also Victoria-like lineage.  The antiserum and antigen for B/Guangdong/797 are also available now in CBER for manufacture usage.  Next slide, please.
		The candidate strain for B viruses, if the new strains are choosing and again reagents needed to be made from CBER and will be available May at the earliest.
		Thank you.
		DR. DAUM:  Thank you very much, Dr. Ye.  Are there Committee questions or input? Dr. Decker.
		DR. DECKER:  Is there a handout available that has those information -- those data?
		DR. YE:  Pardon?
		DR. DECKER:  Is there a handout available that has those data?  The Committee would be interested in having them.
		DR. YE:  Not now but I think we can make it after meeting.
		DR. DECKER:  So after we decide, we can get the data.
		(Laughter.)
		DR. YE:  I think we can get this from Web site.
		DR. DAUM:  I think what Dr. Decker is hinting at is that it would be nice to have them for this afternoon's discussion.  If there's any way this could be accomplished during lunch, we'd be grateful. Dr. Griffin, then Dr. Levandowski.
		DR. GRIFFIN:  Could you just remind which of the strains in the current vaccine, we've had production problems over the last couple of years which has been due to slow growth.  Is that due to the B, the current B strain or which of the three strains in the current vaccine?
		DR. YE:  B strains is always the problem because compared B to A, B always grows lower, never can see the HI titer higher than 1,000 compared to A. And the second thing is to B, we do not have the reassortant available for like A to generate a high growth viruses.
		DR. GRIFFIN:  And from what you know about the strains, if we went to the Victoria-like strain, there's no reason to think those would be better than the current strains that we're dealing with in the Yamagata lineage?
		DR. YE:  If I understand your question, we have one, it's a Shangdong/797 which previous to use of vaccine, commercially has been used in Asia.  So we had quite an experience for that strain.
		Another one is Beijing/243/97 and as mentioned by Nancy as being experimentally started in Europe.  So I think we have the information for that strain, but compared to Guangdong --
		DR. GRIFFIN:  The Victoria/504 is what's currently in the vaccine?
		DR. YE:  I would defer to Roland.
        		DR. LEVANDOWSKI:  Yes.  In the United States, both B/Victoria/504/2000 and B/Guangdong/120/2000 have been used in vaccines that are currently in use here in the United States.
		DR. GRIFFIN:  Right, and their growth characteristics you would say in general are sort of comparable to what we're looking at for the B/SHANDONG?
		DR. YE:  It is the best that we have right now.
		DR. GRIFFIN:  Okay.
		DR. DAUM:  Dr. Levandowski, did you want to make any other comments?  You had your hand up.
		DR. LEVANDOWSKI:  I'll just follow up on that last bit, the Shangdong/797 strain was a reasonably good growing strain when it was used for commercial purposes a few years ago.  And as Zhiping has mentioned most of the B strains, they usually are the great limiting step I think for most manufacturers because we don't have high growth -- the capability currently of making high growth reassortants although that's something that's on the table and there are other ways to get to that.
		DR. DAUM:  Thank you.  Oh, one more.  Dr. Eickhoff and then --
		DR. EICKHOFF:  A question for Dr. Levandowski.  Was the B/Shangdong strain used by U.S. manufacturers and have they had experience with it?
		DR. LEVANDOWSKI:  Yes, the answer is at least one U.S. manufacturer has had experience, but that strain was distributed widely to many manufacturers, for examination and feedback from them suggested that that strain would be a reasonable grower as Influenza B viruses go.
		DR. EICKHOFF:  Thank you.
		DR. DAUM:  Okay, at this moment we have adjourned our morning session.  Thank you, Dr. Ye, and we will now go to lunch.  I think we can safely take a one hour break.  It will be quarter of one in the Eastern Time Zone now and we'll reassemble promptly at quarter to 2.
		(Whereupon, at 12:48 p.m., the meeting was recessed, to reconvene at 1:45 p.m.)

	A F T E R N O O N    S E S S I O N
	1:56 P.M.
		DR. DAUM:  Okay, could we come to some degree of order, please?
		(Pause.)
		Everybody sort of finish their conversations and have a seat.
		Dr. Slusaw at hand, here he is.  Get ready, Dr. Slusaw.  	
		With the departure of Nancy I don't have the little bell that I didn't realize it was she that furnished.  The bell is gone, but we still need to get moving quickly because it's an airplane day and we're going to call on Dr. Slusaw, please, to give the comments from manufacturers.
		DR. SLUSAW:  Thank you.  It's my pleasure to address the Committee once again this year on behalf of the manufacturers and just give a little bit of insight and share some of our concerns on the practical aspects of manufacturing flu vaccine.
		The Committee is once again faced with the challenge of recommending strains for the 2002-2003 vaccine formula and I see this as kind of a dual challenge.  One is, of course, you're trying to find the best antigenic match for the circulating viruses, but of particular concern to us is that you also make a timely selection and you choose strains that are practical for vaccine manufacturing.
		I think it's safe to say that the manufacturers feel fairly comfortable that we know how to make the current strains and turn them into vaccines, but each time we adjust the vaccine composition or fine tune the formula, we're introducing some uncertainty and some risk into the process that we may have difficulty growing the viruses or purifying the viruses to make the final vaccine.
		Just to give an overview of the process and the components that have to fall into place each year in order to successfully produce vaccine, the first slide lists the key ingredients that are required.  Of course, the most important raw material is the supply of embryonated eggs that are used each year to grow the virus.  Second, the activity that we're doing today is looking for candidate strains and seed viruses and in particular, not just any seed virus, but where possible, it's extremely important that we have high growth reassortant viruses available for production.
		Those ingredients allow us to start manufacturing the monovalent components for the vaccine, but we can't test or measure the quantity that we've produced or we can't formulate the trivalent vaccine until we have the potency test reagents and homologous reagents that are created specifically for each new vaccine component.
		I'd like to give a brief overview of the process and just hit some of the highlights that are perhaps most critical to us today.  This time line demonstrates from start, from obtaining a vaccine manufacturing seed through distribution of final container the process of making flu vaccine.  And for the new strains we're considering today we're right here somewhere where we're talking about potential new strains in some cases, potential A strains, even the H3 which we don't have candidates in hand yet.  And of course, it takes about 6 to 8 weeks to prepare a high growth reassortant of an A strain and then another month or so to prepare working seed and begin using that to make the vaccine components.  So just to caution that anything new we're talking about considering as a candidate strain today that the manufacturers do not have in hand and have not had a chance to work with, we're perhaps 3 to 4 months away from being able to produce the vaccine components with a new strain.
		The B strain, since we're currently not using high growth reassortants has a somewhat shorter time line and isn't as critical in that regard.
		Next slide, please.
		And briefly, an overview of the annual manufacturing cycle, the entire process of manufacturing actually begins about a year in advance when the egg suppliers order their birds in order to be able to supply the embryonated chicken eggs that we use each year.  And that typically happens in January for use the following year that they'll order those birds.
		This time of year we're somewhere in here where we're receiving some candidate strains and also hope today to definitely at least get the recommendation for the first strain in the vaccine formula.  And the model of annual production has worked out fairly well for us, recently, as to have the first strain in January and then following with the second strain about a month later and the third strain about a month after that.
		I think in summary, we could do worse than following last year's scheduled strain selection as a model.  I think it went rather well, at least from a manufacturing standpoint for most of the manufacturers in that the data was analyzed and considered thoughtfully at this meeting and then with the kind of pragmatic outlook, the strain selection proceeded rather quickly and we had received the third strain selection by March, which actually made for a fairly smooth and efficient manufacturing cycle.
		Any questions from the Committee or any comments?
		DR. DAUM:  We do have some.  Dr. Faggett, please?
		DR. FAGGETT:  Yes, thank you for that very clear presentation.  You mentioned from this point it would take 4 or 7 months to have vaccine ready for use?  What was the time line from now to having it on line?
		DR. SLUSAW:  Actually, if you could go back one slide?  If we're talking about the A strains in particular, again, adding on the time line of the high growth reassortant, it's about from the identification of the initial wild type candidate strain to having a final container, it's about a 6 month period.
		DR. FAGGETT:  Six month, okay.  Thank you.
		DR. SLUSAW:  Of some interest, perhaps, in that is the actual manufacturing time of the vaccine components is less than 2 weeks and all the rest of the time is various testing and release process for the intermediates and vaccine components.
		DR. DAUM:  Dr. Kohl and then Dr. Eickhoff.
		DR. KOHL:  How big a problem would a quadravalent vaccine be in terms of time and also if there are any other licensure problems, if you have to do four strains?
		DR. SLUSAW:  Well, I think it's safe to say that it would reduce the total quantity of doses that would be available this year and/or delay the timing of the availability of the doses.  Just simply having to produce more antigen.  I think most of the manufacturers are currently running, essentially, at full capacity insofar as the number of eggs they're producing or consuming per day to use in their manufacturing process.  So producing additional vaccine components would mean less doses or more time.
		DR. KOHL:  But I'm asking you to try to quantify that.  How much more time, for instance?
		DR. SLUSAW:  For a fourth component I would say that that would add or reduce the total doses by about a third or add that one third on additional manufacturing time.
		DR. DAUM:  Dr. Eickhoff and then Dr. Couch.
		DR. EICKHOFF:  We may be in the position this year of having the most slowly growing problematic strain being the last one to be selected.  Does this introduce another element of delay?
		DR. SLUSAW:  Well, that's actually about the worse combination of events that can happen and kind of reflective of the events that occurred several years ago where the supply was a little later than expected.  But really, the critical factor in the timing of the availability of the vaccine is the characteristics of that third strain and when the third strain is announced exceptionally late or if it's a particularly slow grower, the results are very serious and reduce the number of doses that are available.
		DR. DAUM:  Dr. Couch.
		DR. COUCH:  To follow up on Steve's question, when you're talking about a quadravalent vaccine, you were talking about the time delay.  That was the assumption that all components would be 15 micrograms because you were talking about the total vaccine produced, isn't that correct at that level?
		So if you split one of them to 7.5 and 7.5, then there would be some delay there, but not to the level that you had suggested.  Is that correct?
		DR. SLUSAW:  Right, as far as the total quantity there would be less impact because of that, but handling a fourth vaccine component --
		DR. COUCH:  Fourth vaccine --
		DR. SLUSAW:  Our systems are generally set up to handle three would be a bit of a change that's difficult to make on the fly in a short period.
		DR. COUCH:  And you're manufacturing time line in which you say start the third strain, that's actually start the production line, correct?
		DR. SLUSAW:  Right.
		DR. COUCH:  Everything has got to be right for the production line?
		DR. SLUSAW:  That's right.
		DR. DAUM:  Can I ask a question about how the process occurs by which industry or people who manufacture flu vaccines help you prepare for these comments and how you take what you hear here back to industry?  Can you give us some sense of how that back and forth works?
		DR. SLUSAW:  Representatives of the manufacturers and the FDA and CDC meet in December of each year where we essentially do a post-mortem and analysis of the previous year's manufacturing cycle and distribution, testing, release, all the aspects of vaccine production and that's a fairly open forum where we raise a lot of the issues, where we had difficulties that we'd like to correct the following year and if we also have any suggestions for streamlining or improving some of the systems, we generally identify them at that time.  It's also an early update for us on surveillance information and also sharing some feedback on growth characteristics of any candidate strains that have been distributed up to that time.
		So that's the forum where a lot of the background information is discussed before this meting.
		DR. DAUM:  But companies that make the vaccine are aware that through you, I guess, they have representation today and input into this process?
		DR. SLUSAW:  That's right, and again, I mentioned the December meeting, but we also have additional telephone and e-mail contacts where we share concerns that we would like to emphasize and bring up at this meeting.
		DR. DAUM:  Thank you.
		MR. YORK:  This is Richard York from Wyeth Laboratories and I'd just like to reaffirm what Greg has just told you.  He's actually sent the slides out to us ahead of time to review and it's pretty much an industry situation, the time lines that he described is the same for us.  I'd just also like to emphasize that if you throw a fourth strain in and it takes -- sometimes it takes 6 months before we can play with that to get the yield up if it's a low yielder and that would certainly delay our time line and that's part of what happened with A/Panama a few years ago.  That was a very poor grower to begin with and now we all love it.  It's a great growing strain because we've had time to work with it.
		DR. DAUM:  Thank you very much.  I think we'll move on now to hear the options for strain selection from Dr. Levandowski and then we will begin Committee discussion and recommendations.
		DR. LEVANDOWSKI:  Okay, thank you.  I'll try to be to the point and brief. I'll start out with a little bit of review.  You can take that down.  I'll start out with a little bit of review about each of the strains and then go over what I think we see as reasonable options here.
		First of all, I'm going to go in the order that the presentations were previously with H1N1, H3N2 and then B viruses.  		So just to summarize, I think what we heard this morning, so far there have been relatively few influenza A/H1N1 viruses isolated in North America and Europe.  However, there's some recent isolates from China that CDC has, but hasn't had a chance to really analyze fully at this point.
		What we know from what's been done the HAs of most of the strains are antigenically are very similar to the current vaccine strain which is A/New Caledonia/2099 and H1N1 viruses generally seem to be well inhibited by the antisera from people who have been immunized with the current vaccines that contain A/New Caledonia/2099.
		The high growth reassortant of A/New Caledonia/2099 is already available, obviously.  It grows well and the manufacturing for that has been very well worked out.  So the first option that we would have, I think, if you want to put the first overhead up, please, would be to maintain the current vaccine strain as A/New Caledonia/2099.  And in favor of that, the manufacturing is worked out.  The yield is very predictable.  Most of the viruses this year are A/New Caledonia-like by antigenic characterization.  On the negative side for that, however, there have been relatively few recent strains for analysis and so that leaves a little bit of a blank in terms of where things are really headed.  And some of the recent H1N1 isolates have not yet been completely analyzed.  So a second option would be on the next overhead would be to change the current vaccine strain to a strain that is more representative of currently -- the few currently circulating viruses that are out there and a reason to do this in favor of that would be that a more recent strain might provide a closer match with the hemagglutinins and the neuraminidases of contemporary strains although I think we heard that in that respect it doesn't seem like there's too much that's changing from the strains that have been analyzed.
		I guess that would be that a new strain might not provide any superior immunogenicity or efficacy compared to the current vaccine strain.  And furthermore, we heard that there aren't any new strains suitable for manufacturing that have been identified, therefore any manufacturing issues that there could be haven't been investigated.  And then a third option for the H1N1 and I'm going to repeat this so this will be the sort of order I go through things, the third option would be to defer the decision to accumulate more data and in favor of this, I'd say that possibly there could be some additional analysis of contemporary strains that might identify some change that would lead to suggesting a change in the vaccine, but I guess that is there's really very little new information that appears to be forthcoming, not only because there's -- although there's some work to do in the laboratory, there just aren't really many strains out there.  So you can take that off.  I don't need a slide yet.
		So moving to the influenza A/H3N2 viruses, again to summarize, predominantly there have been influenza A/H3N2 viruses isolated during the recent past and there have been quite a number of them.  The HAs, most of the strains that have been investigated seem to be similar to the A/Moscow/1099-like viruses and that includes the current vaccine strain A/Panama/2007/99.  However, at this point, it looks like the influenza season, not only in the United States, but in other parts of the Northern Hemisphere, is really still just developing and we don't really know what is likely to turn up at a later point.
		Furthermore, Nancy Cox mentioned that analysis of some new H3N2 viruses from outbreaks in China are just in progress and we've seen in the past a lot of the N3N2 strains that are really different have come from China to begin with.
		The A/Panama-like H3N2 viruses tested to date are generally well inhibited by antisera from people who have been immunized, but as I pointed out earlier in the serologic data, there are some exceptions to that, mostly in terms of those viruses that have been identified as low reactors with ferret sera.  And finally, the current high growth reassortant of A/Panama/2007/99 grows well and the manufacturing is very well worked out.
		So the options for the H3N2, the first option again would be to maintain the current vaccine strain which is A/Panama/2007/99.  And in favor of that again, the manufacturing has worked out and the yield is very predictable.  And also, most of the viruses this year are Panama/2007/99-like by their antigenic characterization.
		Against that would be the analysis of some newer strains really hasn't been completed and just to reiterate what's been stated before, the H3N2 viruses often are responsible for the most significant morbidity and mortality.  This is not to say that the other influenza viruses don't cause that, but H3N2 in many occasions in the past seem to have been associated with some significant morbidity and mortality.
		So the next option would be to change the current vaccine strain to one that's more representative of the other strains that are out there.  And the reason to do that would be that the more recent strain might provide a closer match for the hemagglutinins and neuraminidases and again, a reason to do it would be because the H3N2 viruses often are responsible for significant morbidity and mortality, but against that option of changing at this point at least would be that the analysis of the newest strains really isn't completed and a new strain might -- we don't actually know, there might be other strains that pop up, a new strain may not provide superior immunogenicity or efficacy compared to the current vaccine strain.  And finally at this point there aren't any new strains that have been identified as being suitable for manufacturing, so that manufacturing issues have not really been investigated.
		So now that brings me to the third option here and again, it's to defer the decision to accumulate more data and in favor of that, this would provide some additional time to complete analysis of the strains that have been recently received from Asia.  A more recent strain might provide a closer match with the HA and NA of the contemporary strains and again, just to reiterate the H3N2 viruses are viewed as being responsible for morbidity and mortality.
		On the negative side, however, again, we don't know whether a new strain would provide anything superior in terms of immunogenicity and efficacy, compared to the current vaccine strain and again, we don't really, at this point have anything identified that seems to be suitable for manufacturing.  And in manufacturing, the practical issues have not been addressed.  So you can take that overhead off.
		And now I'll move to influenza B viruses which I think is a lot more complex.  What seems to be happening is that there's antigenic drift continuing and influenza B viruses in both of the two known HA lineages continue to circulate.  Some of the strains that are in the vaccine HA lineage are antigenically distinguishable from the current vaccine strains and all of those vaccine strains are similar to the B/Sichuan/379/99-like strain.
		There's evidence that some influenza B viruses in the vaccine HA lineage are less well inhibited by antisera from people who have been immunized with current vaccines.
		The viruses that are in the B/Victoria/287HA lineage also seem to be undergoing antigenic drift and strains in that lineage have been only recently, really, within the last couple of weeks, identified in a number of regions where they had not previously been found.  So there's evidence for recent spread of those strains where they had been mainly in Asia over the last several years.
		Strains in the B/Victoria lineage seem to be poorly inhibited by antisera from people who are immunized with current vaccines and as I pointed out earlier today, again, we've been seen developing not only for children, but for adults who are immunologically prime.  We've been seeing much reduced responses to the current B/Victoria-like strains.
		The current vaccine strains, the Johannesburg/5, the Victoria/504/2000, and Guandong/120/2000 all seem to be pretty well worked out in terms of their manufacturing status and vaccines with all three of those strains, actually, are being manufactured, have been manufactured this year.
		A B/Victoria/287-like strain, actually two of them have been used in producing experimental vaccines, both the B/Beijing/243/97 and the Shangdong/797 have been used for experimental vaccines in Europe.  And furthermore, the B/Shangdong/797 strain is one that has been used for producing commercial vaccines for parts of Asia a couple of years ago, so that there is some information on manufacture there as well.
		And finally, there are strains in both of these influenza B lineages that have been distributed to manufacturers and there is some development that's on-going.  It's not complete, but there's development of information as to how these strains might perform in terms of manufacturing.  So I'll just go on to the options now.
		Next overhead.  One option would be, of course, to just retain the current vaccine strains which for the United States are really predominantly B/Victoria/504/2000 and B/GUONGDONG/120/2000.  And in favor of that, of course, the manufacturing is well defined and it's predictable, but against that is that there have been new variant strains that have been identified in the vaccine HA lineage and in addition to that, B/Victoria-like strains, B/Beijing/243/97 HA lineage strains are appearing in increasing numbers and in new regions.  And some of the influenza B strains, particularly those in the B/Beijing/243/97 HA lineage are not really well inhibited by post-infection or by post-immunization antisera.
		So this brings me to the second option and of course this one is to change the current vaccine strain to some other influenza B strain.  In favor of that, of course, our hope would be that the vaccines would provide broader coverage for the current influenza B viruses and also in favor of that, I think from a practical point of view, several candidate strains have been identified and they're being examined for their suitability in terms of manufacturing.  But against that, again, we don't know whether a new strain is going to be any more useful than the current strain in terms  of its immunogenicity and efficacy, although we might expect that for the B/Victoria lineage and it's always possible that a new influenza B strain, and in particular, could cause some difficulties in manufacturing.
		And so the third option here would be again to defer the decision to accumulate some additional information and in favor of this, I think it would provide some additional time to look into the antigenic properties of influenza B isolates of both lineages that are out there.  It would provide some, more time to evaluate the candidate vaccine strains and see how they're likely to perform and it would also -- a more recent strain might again I think we would hope that that would be true would provide a better match for the hemagglutinin and neuraminidase.  Against, this option, again, a new strain might not be any superior.  I think that's all I have to say there and I'll stop and see if there are any questions or comments.
		DR. DAUM:  I'm sure we have some.  Dr. Katz, first and then Dr. Dowdle.
		DR. KATZ:  The one contraindication you didn't list in your three options was the price of deferring, as far as time is concerned.  As we listen to the schedule of how vaccine is prepared, with the new strain, the necessity to be able to replicate to high enough titer to produce enough vaccine, it seems to me that the threat lies in again having a delay in availability if you hold the manufacturer to waiting until you have additional information.
		Can you comment on that at all, Roland?
		DR. LEVANDOWSKI:  I think that's the tradeoff.  I think we're always concerned.  As I mentioned at the very outset, the understanding about how inactivated influenza vaccines work, it's based on antibodies to hemagglutinin and the match of the hemagglutinin to the vaccine has a lot to determining how well the vaccines are going to perform.  I think that's been seen since the very first influenza vaccines have been used.  So it's always a tradeoff, I think between making sure that there's the best match we can get for the vaccine and understanding that it's a huge stress on manufacturers to try to put together more and more vaccine every year and have uncertainties about what's going to be coming to them.  Obviously, we have a lot of faith in their capabilities and I think they have shown time again what resourcefulness they have in manufacturing to overcome some of these obstacles, but obviously there is a point in time in which it becomes too late to do anything and I guess I would argue at the moment, I don't think we're at that point where it's too late to do anything.  I think the additional information that could be accumulated could help, for example, just the practical end of it, knowing which strains do not perform so well and which strains the manufacturers are not interested in pursuing any further.  That sort of feedback is helpful to us.  So I think we understand why you're asking that question and I think it's a concern that we all have to try to balance those two needs to have a good vaccine match and still permit manufacturer's to do what we're asking them to do.
		 DR. KATZ:  	Well, you know, it's February now and I'd love to hear from the gentleman who preceded you as to what he sees as the deadline beyond which it's just not possible to meet time commitments if you were to give them a new strain on March 1st, is that too late or is that still possible?
		DR. DAUM:  Dr. Slusaw and perhaps Dr. Decker want to comment on these things?
		DR. SLUSAW:  It's really two different questions whether the final decision is made March 1st or if March 1st were considering a new candidate strain isolate that has just arrived and thinking maybe we should include that in the vaccine formula.  I think the key is some time in March, preferably by mid-month to have the third strain identified and ready to use in manufacturing.
		DR. DAUM:  Thank you.  Mike, do you want to say anything?
		DR. DECKER:  Yeah, I'd like to comment because Dr. Slusaw and I approached this from different viewpoints.  He's got to make the stuff.  I approach it from the viewpoint of a public health physician.
		First thing, Sam, is there's no specific deadline in the sense that what's going to be handed over on March, a strain that grows easily and well or a strain that takes three months to labor over.  No one knows until you hand it over.  So there are risks in every element of our decision making here, trying to enhance the public health.  If we go for a quick answer and we pick the strains badly, bad for the public health.  But if we wait too long and pick well, bad for the public health.  We don't know where the cutoff for sure is.
		I can tell you this, that I know from being there that the manufacturing plant from the moment it can go, runs at full capacity basically 24/7 until production is shut down which happens when we reach the end of the production season.  We go as long as we can.  We make every bit we can.  That was -- this year, for example, and the ability to do that enabled us to put some more doses out there in the marketplace, most of which, got bought, but not all.
		If -- let me comment on the potential impact of adding a fourth dose which -- a fourth in the strain which looks attractive for some reason.  We're not sure.  Is this Victoria going to resurge and be the problem and the public is not well protected against them?  But you're adding a risk.  So if, for example, the two best B strains both look -- the two that look the best are both strains with which the manufacturers don't have familiarity, you've doubled the risk of having year before last recur.  If you hand them one strain they haven't seen before, that's one unit risk.  B is the hardest to grow.  It's the most problematic.  It's the one that's obviously going to get handed to them last.  You've already stacked the deck a little bit against timely delivery of vaccine.
		If the Committee ends up going for two B strains, what I would say is a public health doc, I would immediately turn to my friends at CDC and I would say you have to redouble your already excellent efforts from last year to make sure that the practitioner community is ready to immunize late and they don't like that and they're a little bit better, but not good enough, and the press will understand why the vaccine is showing up late again, that it's a deliberate thing.  So this is all intertwined and the public health decisions aren't easy.
		DR. DAUM:  Thank you, Michael.  Dr. Dowdle and then Dr. Kohl.
		DR. DOWDLE:  Thank you.  My question was the same as Sam's.
		DR. DAUM:  Okay.  Then Dr. Kohl.
		DR. KOHL:  Roland, can you address CBER's view on the possibility of a four component vaccine?
		DR. LEVANDOWSKI:  I'm sorry, I didn't hear all of that.
		DR. KOHL:  Can you comment on the possibility of a four component vaccine?
		DR. DAUM:  From CBER's perspective was the question.
		DR. LEVANDOWSKI:  Okay, you guys really want to put me on the spot, don't you?
		(Laughter.)
		DR. DAUM:  We sure do.
		DR. LEVANDOWSKI:  What I could say is that in the United States, there have been all sorts of valencies of vaccines at one time or another.  Through a large part of the 50s and 60s we had pentavalent vaccines and of course, in the 70s it was mostly a bivalent vaccine and it's only -- it was only when the H1N1 strain came back and persisted unexpectedly, along with the H3N2 influenza A, that we developed a trivalent vaccine.  So if you're asking is it something that could be done, I think the answer is yes.  And in more recent times, there have been quadravalent vaccines produced with 2B strains.  In Europe, in the mid-1990s, in the Netherlands there was a quadravalent vaccine that was used.  Commercially, it was the vaccine that went out which had 60 micrograms total of HA, so 15 micrograms of each component.  It was not large scale manufacturing, but from the study that was published from use of that vaccine or from the experience from that vaccine, it sounded like that there was not an increase in acute adverse reactions, meaning local pain, fever, febrile responses and so on, but it was, I believe the studies were directed mainly toward adults so it would not necessarily cover pediatric.
		In the immunogenicity part of the study, both of the B strains that were included seemed to be immunogenic.  So in terms of the performance of more valent vaccine, I think our expectation is that it would be somewhat similar and in terms of the total amount of hemagglutinin that goes in, there does seem to be some relation to at least acute adverse reactigenicity, particularly in young people, children and those who haven't been infected or immunized previously.  But that we don't exactly know where that point is.
		DR. DAUM:  Thank you.  Dr. Couch, please.
		DR. COUCH:  Did you call on me?
		DR. DAUM:  Dr. Couch.
		DR. COUCH:  I'm pursuing the same thing because Steve keeps doing the quadravalent and that was the option that you did not have up there was the four component vaccine.
		I don't know how long it's been, but as you say, there have been bivalent B components in vaccines in the past and in the past that total dose for B has been split between the two components.  That was the reason for my question.  If you had two components, but only half the quantity, what does that do to manufacturing?  Well, you know it would lengthen it a little bit, so the question is since you already have both strains that are moderate growers, one with experience here and one with experience in another country.  The two strains that you would want to consider for the bivalent B are in hand with experience now.  If you split it, 7.5 and 7.5, you don't have the 60 microgram reactigenicity risk.  That's more of a risk, I think, than it is a reality of concern as well.  That was an option I thought you ought to have up there.
		DR. DAUM:  Dr. Levandowski, do you want to respond to that before we call on Dr. Snider?
		DR. LEVANDOWSKI:  Well, I'd actually like to hear from manufacturing on that issue.
	DR. DAUM:  Okay, punt over, Dr. Slusaw, do you want to comment on that?
		DR. SLUSAW:  I'd like some of my other colleagues in the audience to chime in with their individual reactions to the question.
		Clearly, if we're including two B components, but reducing the amount of antigen, it's not as big a problem related to our capacity to produce vaccine.  Clearly, all our systems have been evolved and geared around producing a trivalent vaccine, the last decade plus and it would introduce additional testing, perhaps release delays.  Handling another vaccine component which we wouldn't normally have to include in the vaccine.  So it would introduce complications, not as much impact on capacity.
		DR. DAUM:  Dr. Levandowski.  Don't go away Dr. Snider, we've got you.  Dr. Katz and Diaz next.
		DR. LEVANDOWSKI:  So just as another reminder about history, from 1978 to 1981, the vaccines used in the United States had 7 micrograms of each hemagglutinin present.  That was changed in 1981 because there was some recognition from clinical studies that were done that antibody responses were higher against the vaccine strain and also they seemed to be substantially higher against heterologous viruses that weren't exactly the same as the vaccine strain.  That's actually how we got to 15 micrograms, HA, of each of the three components.  So those vaccines were trivalent with seven micrograms of each component.  The immunogenicity at that time, I guess, was thought to be not as optimal as it could be with -- by increasing the dose twofold.  I don't know if others have comments along those lines, or thoughts.  Maybe Dr. Dowdle.  No.
		DR. DAUM:  Let's go on to Dr. Snider and then Dr. Katz and Diaz.
		DR. SNIDER:  I just want to bring up the point which I'm sure everybody is aware of.  There's another variable that needs to be put into this discussion when we think about what are we going to include in the vaccine and how many doses are going to be available.  Another piece of this, of course, is who is the target audience for receiving this vaccine?  As many of you know, we have targeted the over-65 and those under 65 who have certain medical conditions and I'm sure many of you know we have not done a very good job, particularly with the latter group and there has been a great deal of interest in lowing the age of eligibility and the population at large to 50 and to recommending everybody 50 years of age and over, receiving influenza vaccine.
		And then recently there also have been discussions about immunizing infants and young children because of publications, I'm sure many people have seen addressing not only the morbidity issues in children, but the role they play in the epidemiology of the disease in bringing the influenza to older family members who may have medical conditions and may suffer from influenza or die from it.  So at the same time we're talking about this, we also need to keep in mind that we're talking about the potential for expanding the target population for influenza vaccine in order to achieve optimal public health outcomes and so I'm just saying that we consider all of this, we not forget about on the other end that there is a desire to vaccinate more people this coming year or more people in the near future than we have been able to reach in the past.
		DR. DAUM:  Thank you.  Dr. Katz.
		DR. KATZ:  I think Dr. Diaz and I had the same question which Roland alluded to indirectly and that is if you halve the dose of antigen in B by having two different strains, what do you anticipate as far as immunogenicity is concerned?
		DR. LEVANDOWSKI:  Okay, so let me use the analogy from 1981 again.  At that point there was both an H3N2 and an H1N1 component to the vaccine and they were both at 7.  The two didn't seem to result in increased immunogenicity for the other, I guess I would say at the end.  I think the situation with the influenza B viruses might be similar.  They're not different subtypes, but certainly antigenically they seem to be about as far apart or closer to about as far apart as the H1N1 and the H3N2 strains are.
		Maybe I'm exaggerating that a little bit, but I think that's a reasonable analogy.
		DR. DAUM:  Thank you, Dr. Diaz --
		DR. DIAZ:  That was my question too.
		DR. DAUM:  Okay, good.  Dr. Decker.
		DR. DECKER:  A question.  Maybe it will turn into a series of questions for Roland and possibly the manufacturing representatives.  If there were two B strains included this year, would one of them -- would you recommend that one of them be the strain that was included last year or would you favor changing the strain that's covering that lineage to an alternate as well as introducing one to cover the new Victoria lineage?
		DR. LEVANDOWSKI:  Well, now you're asking me to make the recommendation, I think.
		DR. DECKER:  Well, I'm trying to simplify --
		DR. LEVANDOWSKI:  I will answer it though.  I think the concern is that there are differences in the current influenza B HA lineage as well as what we're seeing as a new geographic spread of the B/Victoria lineage, so I think those are two slightly different directions, but I think the answer is that I don't know that I have enough information to answer strongly that if even the current HA lineage were the one to be in the vaccine, whether the current strains would be ideal.
		DR. DECKER:  The reason I asked because based on what I knew and absent of reassurance on the manufacturing specialists here, I would think that changing both B strains would represent an unreasonable risk to the vaccine supply for the year.  Whereas changing, adding a half strength one and retaining the one they already know how to make is a safer gamble and so I think if there's an interest by the Committee in pursuing two, we'll have to get quite precisely into what two, and the choice will alter the risk.
		DR. DAUM:  Fair enough.  Dr. Couch?
		DR. COUCH:  Just a couple more comments along that same line.  If we look at the information from Asia, most of the lineages have co-circulated for more than one year, you see, and it looks as though we're getting the Victoria here, will Sichuan disappear?  I doubt if anybody can answer that.  If they can answer that, then your question can be clearly answered.
		And the other is I would differ with Roland a little bit to take the 7 microgram analogy as to what we would do to immune responses if we had two Vs in.  We've looked at the immune response data here to B/Sichuan and it does cross react with the B/Victoria lineage viruses.  We don't have the other half of that equation.  I didn't know until today that maybe it's available in Europe, that if you give B/Victoria, do you cross react and if so, in what age group against the Sichuan, but I would at it as two B drift viruses with some relationship and something to be gained in the direction of that 15 micrograms as opposed to an isolated 7  of unique antigens.
		Now the problem with 7 , if you should do something like that is that the cleanest separation of that would probably be in the young children.  Where they would get one they won't get the other antibodies.  But if you've got both of them, you got a little bit of something maybe for both of them.  You can tell where I'm leading it's fairly obviously.
		DR. DAUM:  Dr. Dowdle and Dr. Myers have their hands up before.  Dr. Palese was ahead of you.  So we're going to do Dr. Palese, Dr. Dowdle, Dr. Myers and then I'm going to ask people to really and try to bring this to a close so we can start polling the Committee and seeing what people sort of think.  Dr. Palese, please?
		DR. PALESE:  I just wonder whether we get sort of carried away in terms of the re-emergence of the B/Victoria, because if you look at the handout of the CDC on page 44, there is in the time period of October of 2001 until January 2002, there are very few isolates, really, from which we try to make a conclusion.  And particularly we are sort of disturbed by the 25 isolates from Asia which make up 66 percent of the A/Victoria-like viruses.  So I think there's a sort of a very, very small number and also I would like to note from what geographic distributions do those 25 isolates come from?  If they all come from the same city, then I think we might be very much misled here, particularly if you talk about small numbers.  All the four isolates we have from the United States are all from the current vaccine strains.
		So I just wonder whether we are -- are those all the data we have?  Twenty-five isolates from Asia and we're getting all worried?  How sure are we that this is really a representative sampling?
		DR. DAUM:  Maybe that question goes to CDC folks first?
		DR. COX:  Right.  Peter, I think that what you're looking at here is the viruses that we've tested at CDC, but you have to remember that there are additional viruses that have been testified by the other WHO Centers.  And we did have a call yesterday morning from Alan Hay in London and he called specifically to tell us that four out of seven Italian viruses that they had received were B/Victoria-like, and furthermore, three out of four of the viruses that they received from Genoa were Victoria-like.  We --
		DR. PALESE:  It is still a very small number.
		DR. COX:  It is small numbers, but when we've seen -- you have to take this within the context of not having seen Victoria-like viruses at all for the past 10 years in North America and Europe and South America and so on.  And that when we have seen this pattern where viruses were confined to distinct geographic areas, once they move out they tend to move quickly.  We've seen that before with the Yamagata, B/Yamagata strain which emerged from Asia and subsequently supplanted the Victoria-like viruses.  We saw it with a sublineage of B viruses represented by the B/Beijing/184-like strains and then we saw it again with the Beijing/262-like strains.  So it's a pattern that we have seen before for other groups of viruses, either A viruses or B viruses and it's a red flag to us, certainly.
		DR. DAUM:  Thank you.  Dr. Dowdle now.  You've been patient.
		DR. DOWDLE:  Well, two issues and basically two questions is that I think adding an additional B strain on the surface sounds like a very good idea, but I think that we -- the question is can we make assumptions here and by splitting the dosage in two different strains would we have to undergo a certain, at least a limited field trial in order to see what serologic responses may occur and indeed if there was a difference and whether that would add to the additional time period.
		The second question is that I think one of the options that were listed here was a broader B strain and it wasn't clear to me that which B strain might give broader coverage, is there a candidate strain that's available?  Or is that one which you're waiting for that might show up and would take additional time for surveillance?
		DR. DAUM:  Dr. Levandowski do you want to comment?
		DR. LEVANDOWSKI:  Well, I don't think I can answer all the surveillance end of it, so Nancy Cox may want to answer also, but I think or the sense that maybe I would convey comes from looking at the data from the study in which a B/Victoria-like strain was used to immunize people who had been previously primed with a B/Yamagata-like strain and there, the antibody responses were recently good, were they not?  There's a -- I'm blocking on the word.  It's the original sin concept, where the antigens of first contact are also increased with contact with another strain if it's similar enough or even in the right ballpark.  So I think what we saw with those studies was that the B/Victoria-like strain induced antibodies, as long as there was immunologic priming.  Without immunologic priming, however, there was not antibodies produced against that second lineage.  So I guess the question would become similar to what was being raised about populations in which population would you be aiming to protect that way, if you knew the population was immunologically primed and had some reasonable expectation that you'd get antibody responses that were protective to both lineages and that might be one direction.  If, on the other hand, you think that there will be no response say someone who is immunologically not primed, then you have to weigh what the risks and benefits are for which strain is going to win the contest the following year.
		I would maybe follow up on something that Nancy said about the B/Yamagata strains.  I believe the year that that was chosen for the vaccine here, there were none of those strains identified in North America.  I believe they were only from Japan at the time.  In fact, I think -- and I don't think there were very many.  I wasn't here, so I may be completely wrong, but my sense from what was happening at the time was was that was not a strain that was present in the United States and then the next year, the next influenza Bs and those were the only strains.  We did not see the B/Victoria-like strains at all here, although in Europe, it was 50-50 for a couple of years.  They had about half B/Victoria and half B/Yamagata-like strains, so those I don't think that we know how to predict whether that -- which of those scenarios might be likely to play out.
		DR. DAUM:  Thank you very much.  Dr. Myers, you're on my list here.
		DR. MYERS:  Well, I guess considering the third option of waiting.  Keiji showed that only 21 of 1278 isolates were B and looking at the graph that Nancy showed, this is very few of the isolates around the world are B strain, so I guess the question would be if we waited until March to make a decision, would we actually gain any sufficiently more information to have a more informed -- be able to make a more informed decision or will we be basically working with what we have now and maybe a couple more strains?
		Does it really matter if we wait for the amount of data we'll have?
		DR. LEVANDOWSKI:  I'll take a stab at that.  The influenza season is very early.  I think we're still in the early phases of it as I think Keiji was trying to point out.  I don't think we've seen the end of the year and we have had experiences in the past where the year starts out with one type of influenza virus and ends up with a second one and I can remember several years where it's been combined influenza A and B.  I believe there was a relatively significant amount of influenza B activity last year, so maybe that wouldn't be true this year, but I don't actually know.  So the fact that we're hearing about strains from Italy and this is information in just the last couple of days, I don't know exactly when the strains were isolated, but the fact that we're hearing about B/Victoria-like strains in a part of Europe where it hasn't been reported is a little bit-- I don't know how much activity there's going to be and whether that will give guidance in terms of epidemiology.
		DR. DAUM:  Okay, thank you.  I'd like to, unless there are issues which haven't been touched on, haven't been thought about, haven't been raised, what I'd like to do is begin the process of asking each Committee Member, consultant and guest to reflect on each of the three viral components or if you wish, four viral components, but reflect on each of the serologies that were involved and addressing sort of the way Roland has set things up with what is your opinion about what should be done about next year's vaccine composition, with the choices being to keep, to change or to defer.  And once we get that process going we'll appreciate hearing from everybody on it and we'll call on everybody to speak to it.
		So Dr. Kohl, did you have one last burning thing to say?
		DR. KOHL:  One last burning thing.  I strongly want to reiterate what I believe most of my colleagues agree with, my colleagues on the Committee, that we desperately need pediatric immunogenicity data, especially as we move to new vaccine strains and potentially new doses of vaccine.
		DR. DAUM:  I think that this is something that everybody at the table seems to be in favor of doing and I think the message is very clear and I think that it should be clearly part of our record today that this group is strongly supporting the notion that Dr. Kohl is advancing.
		Okay, so let's go.  Dr. Manley, this is truly the last comment.
		DR. MANLEY:  Well, it's a question really.  Do we need to hear from FDA about that statement and if there's anything other than making the statement that this Committee should do to assure that there will be some action on this item?
		DR. DAUM:  That's a fair question.  We'll ask Dr. Levandowski or Dr. Midthun or whoever from the Agency wants to comment, whether something else should be done or whether you've heard us.
		DR. MIDTHUN:  I think we've heard you and it's very important here that you feel so strongly about that and we will take it under advisement.
		DR. DAUM:  There you have it.  I think that was actually well put.
		So Dr. Stephens, you're up there.  I can see you.  Would you begin our discussion please and we'll hear from each person and we really want you to address each component of the vaccine and we're recording your opinions.
		DR. STEPHENS:  From this end of the table, things appear reasonably clear, moderately clear and murky regarding the three components of the vaccine.
		(Laughter.)
		I think that the data from my perspective suggests that for the H1N1 component, the A/New Caledonia/120/99 strain is I would think that that will be the strain for the vaccine.  I think that for the H3N2 component that it's moderately clear.  I'm a little concerned about some of the Chinese strain information that we are still waiting on, that the A/Panama/2007/99 strain appears to be the component.
		I'm really unclear about the B component.  My sense of the discussion is that covering both the Victoria strains and the Yamagata lineage strain would be appropriate and I think a strong consideration should be made in that arena, based again upon the information presented today.
		I will say that overall, I think we may be a bit premature in making some of these recommendations in the sense that the influenza season, I think it's already been emphasized, is early.  There is an upcoming WHO meeting where additional data from additional laboratories will be available.  Other world-wide data will be available.  More information, for example, about the Chinese strains, so I think additional information in the next few weeks would really help crystalize some of our thought process, especially about the B strains and I think that's a summary, at least from this end.
		DR. DAUM:  I need, we need a little more from you.  Sorry.  I'd like you to sort to say with respect to H1N1 that you would keep the present component?
		DR. STEPHENS:  Yes.
		DR. DAUM:  And H3N2?
		DR. STEPHENS:  Keep.
		DR. DAUM:  And B?
		DR. STEPHENS:  Defer.
		DR. DAUM:  Thank you very kindly.  We now have what we need.
		Dr. Kim?  Perhaps your swan song.
		DR. KIM:  Steve, I think he elaborated on the issues that I think, that I concur.  I guess in addition to that, again, I think it's as we discussed, again including the manufacturing logistical issues and providing broad coverage and then lastly, we talked about perhaps having a consideration for different target populations such as immunologically naive for the antibodies that perhaps also may change the composition or target vaccines.
		But based on the information that is available or presented today, I again, I agree the H1N1 will stay with the same and H3N2 more likely stay with the same, although I think additional data will be useful from China strains and B's concern, I think if there is such a thing, defer, because there are too many questions on the table that we are not clear at this juncture how to reach all those issues, resolved at this time.
		DR. DAUM:  Thank you very much, Kwang Sik.  Dr. Kohl?
		DR. KOHL:  I basically concur with my colleagues which would be to roll now on the current H1N1, go ahead with that; to probably point toward continuing using the current H3N2, but to wait for the analysis of the Chinese strains in case there are any big surprises and to defer B, but expect that we'll need two different Bs and a quadravalent vaccine.
		DR. DAUM:  Steve, could you just run through that bottom line one more time for us?  H1N1 keep or defer?
		DR. KOHL:  Keep H1N1.
		DR. DAUM:  H3N2?
		DR. KOHL:  Probably keep H3N2, but wait for the Chinese, the recent Chinese isolates to be defined better by Nancy and her group.
		DR. DAUM:  But that's defer?
		DR. KOHL:  Yes, that's defer.  And to defer the Bs, but expect to have two Bs.
		DR. DAUM:  We got it.  Thank you very much.  Dr. Snider?
		DR. SNIDER:  I'll try, Bill, to get this in your categories clearly.
		DR. DAUM:  Well, please don't feel constrained.  You can make comments on any issues you like, but we do need those three things for Bill's sake and we'll read out the tally at the end.
		DR. SNIDER:  Well, I think we had a good discussion around a lot of these issues.  I won't belabor the point.  And I think I agree with my colleagues who have spoken before me, basically, but today I would retain A/New Caledonia/2099, the H1N1.  I see no reason to change that and there are not that many strains around and not likely to be any additional information to make us want to change H1N1.
		I agree that H3N2 is likely to wind up in the column of retain, but since we have a little time for your purposes, put it in the defer box, Bill.
		DR. FREAS:  Thank you.
		DR. SNIDER:  Because I would like to see the additional data at the WHO meeting.  So thats that one.  With the B, I think we all are struggling quite a bit.  I definitely put it in the defer box, put it in the defer box.  But I mean it seems to me that it's highly likely that we are not going to retain at least in my view, that we are going to have to change and the question is going to be what do we change to and it would be nice to have as much information as we can.  We'll have to take it up to that point, Sam, where we guess is the optimal point, make the best decision, have the most information, but not be too late to get the manufacturers in business to produce the optimal amount of vaccine and that can't be much after the beginning of March.  So we don't have much time, but  we can get much more information and make a decision about B.
		DR. DAUM:  Thank you, sir.  Dr. Griffin?
		DR. GRIFFIN:  Well, I think for H1N1, that's quite straight forward, we should retain the New Caledonia strain.
		I disagree a little bit about the H3N2 in that I think we should agree now to retain the Panama strain as well.  There are several problems with suggesting deferral of that strain, a choice of that strain.  Admittedly, it will be interesting to get more information from these new isolates from China, but we have to recognize we have no candidate strains for vaccine manufacturers.  We don't have any reagents for changing that strain.  We would then be talking about deferring two of the strains to very late in the manufacturing process and I think that since we have so little information that there is any need to change the H3N2 strain that I think we should decide today that that should be retained.  Obviously, if some huge epidemic occurs next week, you know, we would have -- we would still revisit that, I guess.  But I would think that retain.
		For the B strains, I think that there's personally good evidence that we should have a Victoria lineage strain in next year's vaccine and I think that -- I do agree that we'll probably have more information that points in that direction presumably, although possibly it would become dramatically different if we waited, even another few weeks.  And so I certainly wouldn't disagree with deferring that decision.  I think the big decision is whether we also need to have a new also Yamagata lineage strain.  I'm not as convinced of that.  What I am convinced of is that we do need to include this new -- the new Victoria lineage strain and the Shangdong looks like that that's a reasonable virus that manufacturers already have experience with and so therefore we would be able to produce a timely vaccine.
		And the need for changing then and/or adding a new Yamagata lineage strain I think is a lot less clear.  Whether that will be clear with more data, I'm not sure.  What I think will become clear with more data is whether there's the sort of accelerating appearance of Victoria strains.  And two of these strains are from Hawaii, isn't that right?  It's not just Europe, of the Victoria lineage strains?  Were they from Hawaii?
		DR. COX:  There were a number of isolates from Hawaii during the summer and early autumn.
		DR. GRIFFIN:  Right, so it's not that it's not already in the United States.  It's going to be here.  I mean we can feel confident of that.  So therefore I think personally we should make the decision that that's going to need to be included and to defer the decision whether we should also have this three or four component decision is the one that I personally would hope that we could go with just a three component vaccine.
		DR. DAUM:  So Dr. Griffin your bottom line today is to -- is what on the B?
		DR. GRIFFIN:  Defer.
		DR. DAUM:  Thank you.  Dr. Katz, would you mind waiting for just a moment.  I want to put Dr. Couch up next because air planes are starting to call.
		DR. COUCH:  Later flight out of Houston has been canceled.  So I appreciate that and I'm not changing, differing a whole lot from here, but New Caledonia is an obvious.  That one we retain.  The H1N1.  That's the easy one.  It's the other two that are not so easy.
		Take them in the order that we had them up here.  I would defer H3N2.  And my reason for deferring H3N2 is that's the one, our biggest concern for hospitalizations, mortality.  We've had Panama out there now.  We've got it again this year.  It's ripe for the change ,you see, and we might have had nothing and if we're getting it, it's just now emerging out of Northern China and the tracings are just beginning and so that one is so important and because we may be emerging into a need and an obvious change, why that one I would defer for those reasons alone.
		The next one, I would have either a deferral or a vote for half and half.  I cannot -- we must have B/Victoria, I think, and so the question is do we have B/Victoria only and take a risk that Sichuan was not needed at all?  Well, if we defer, then the information may emerge there when everything comes in that well, that Sichuan is gone, you know.  It's now B/Victoria and that decision could be made.  So that would be my deferral.  But I would be perfectly comfortable today with taking that 15 micrograms and splitting it half and half between Sichuan and a B/Victoria derivative.
		So if the majority vote continues to go for deferral, I think that would be the question, does B/Sichuan -- it's not B/Victoria has emerged.  The question is did B/Sichuan disappear.
		DR. DAUM:  Thank you very much, Dr. Couch.  Go safely.
		Dr. Katz, now we'll come back.
		DR. KATZ:  I don't think I have anything new to add.  I would retain A/New Caledonia as H1N1.  I would agree very much with Dr. Couch on if we're going to defer, let's defer both H3N2 and B.  I don't know again from the comments of the manufacturer how long we can wait when you give the roosters their Viagara and what the schedule is to produce eggs that don't age out too rapidly.  But if we can, I would defer both H3N2 and B and I would retain H1N1.
		DR. DAUM:  Thank you very much.  Dr. Diaz, looks like she stepped away from the desk, so maybe we'll go on with Ms. Fisher and we'll come back to Dr. Diaz if she does.
		MS. FISHER:  I will abstain and defer to the expert judgment of the other Members of the Committee and the FDA staff as to which strains should be included in next year's flu vaccine.  However, in general, I do think there needs to be more data on immunogenicity and safety of new flu vaccine candidates in children and pregnant women, if the flu vaccine is going to be recommended for them.
		DR. DAUM:  So I need to press you a little bit because I didn't quite understand.  You said I'm going to abstain and defer.
		MS. FISHER:  I'm going to defer to the judgment to the rest of the Members of the Committee and the FDA staff to making the selection of the new --
		DR. DAUM:  So we're going to record you as abstaining?
		MS. FISHER:  That's correct.
		DR. DAUM:  Okay.  I understand.  Thank you very much.
		Dr. Manley?
		DR. MANLEY:  Thank you.  I concur in general with my colleagues, not all, but some, who have spoken already.  I think that A/New Caledonia is very clear that we should stay with that and will vote to defer on the H3N2 and defer on the influenza B.  And I'm not clear as to how we should go on that, but right now I think we should wait if we have the time and I'm getting the general impression that we have probably until about mid-March to get new information to make the decision on both of these.
		DR. DAUM:  March 6th might not be called mid by some.
		DR. MANLEY:  March 6th.
		DR. DAUM:  I think that's what we're getting is a follow-up.  Is that correct, Dr. Levandowski?
		DR. FREAS:  All Committee Members should have a little orange sheet saying that March 6th we're scheduling a teleconference to follow up by phone on the results of this meeting.
		DR. MANLEY:  I see.
		DR. DAUM:  Defer comes back like a boomerang.
		Dr. Griffin?
		DR. GRIFFIN:  I guess I want a clarification because -- and so the manufacturing time line was to have one that they could start in January, okay, they've got one day to do that.  So in January we'll probably make one decision at least.  Another one that needs to start in February and the third one to start in March in order to be able to produce a vaccine on time and so is there a mechanism by which a decision could be -- some kind of a decision could be made in February on one of these deferrals or is everything going to -- when we say defer, everything waits until March 6 is my question.
		DR. DAUM:  We'll ask the Agency for clarification, but that's my understanding.
		DR. LEVANDOWSKI:  Well, I guess the basic answer is yes, that everything in the sense of looking like something on the outside is happening would be deferred until March, but the fact is that information would be collected and any pieces that would be useful to the manufacturers would certainly be sent on to them, including any strains that seem to be helpful to them, any reassortants that might be in the process of being made.  We don't actually know -- because I haven't been in touch with anybody to know if there are some other reassortants that are available at this point.  We might hear something like that from WHO next week.  I mean any information that comes along and any useful tools for the manufacturers would be sent to them immediately.  We would not be waiting to start to share information and materials for the next meeting.
		DR. DAUM:  But basically, we will reflect next on this issue March 6th.  Isn't that correct, not before?
		DR. MANLEY:  Yes, but that is the basis of my deferral.  Thank you.
		DR. DAUM:  Dr. Palese?
		DR. PALESE:  Yes.  I am concerned that if we defer that there will not be enough time to really get enough vaccine doses and this is important for me that one will get the benefit of vaccine to as many people as possible.  So therefore I would retain the H1N1 clearly at this point, also the H3N2 and with the information we have today, if the question is today what decision should we make, I would also go for retaining the B component because I'm not convinced of the data that the Victoria has reared its head at this point.  So clearly, one can always change his mind, but if I'm asked today, to me the evidence is weighing towards retaining all three components, to allow enough vaccine doses to go out.
		DR. DAUM:  Well, I think it's fair to say we are asking you today.
		DR. PALESE:  Then I would retain, retain, retain.
		Can I make just one other point?
		DR. DAUM:  Please.
		DR. PALESE:  And that has to do with the statistical analysis in terms of percent of all deaths due to pneumonia and influenza.  I can't believe that suddenly we have, in effect, two different numbers from what we had over the last 10 or 20 years and then there's a new sort of tweaking of the data and then it's only 30 percent of.  Why don't we know how many people die of pneumonia and influenza?  I mean this is somewhat disturbing.  I can't believe that we can't get sort of really straight numbers.  And also, that someone tries to help us to compare earlier data with the new data if theres really a compelling reason to do this.  So I feel very uncomfortable with numbers changing by 100 percent suddenly because the statistical parameter gets changed.
		DR. DAUM:  Thank you, Dr. Palese.  Dr. Diaz, you were out when it was your turn.  Would you now like to step up?
		DR. DIAZ:  Thank you, I will.  I had to answer a page.  I wasn't in the restroom.
		DR. DAUM:  We didn't ask.
		(Laughter.)
		DR. DIAZ:  Well, knowing how the Oscars go these days, I thought I would clarify.  In regards to the strains that we have to pick today, I would agree with most of the colleagues that I've heard speak which is the H1N1 is fairly clear in my mind that we stay with the current strain.
		The H3N2, I was prepared to consider deferring more out of the concern of the severity of that particular strain and wanting to get the data from China as has been brought up and yet Dr. Griffin reminded me in her comments that we don't really have much on the horizon in terms of alternate strains available from a manufacturing standpoint.  With that in mind and knowing that at least for that particular strain we probably have the most data at this point, I would vote to continue this coming year with the same H3N2 component.
		The B strain, in particular though, I would likewise defer.  I agree.  I'm not sure deferring another month will give us a tremendous amount more data and yet it's the  paucity of data completely that worries me about that B strain.  And so I would probably defer and I agree that we probably will end up with a picking a B/Victoria-like strain for that component ultimately.  I would have to have more discussion or be convinced about how effect a quadravalent vaccine would be and yet would defer those kinds of discussion for more data.
		DR. DAUM:  Thank you, Pam.  Rich, Dr. Whitley?
		DR. WHITLEY:  Yes, I'll preface my vote by saying that from a public health perspective I think the worse thing in the world would be to have the vaccine appear in the public domain late, especially after the events of the last six months in this country and the concern about bioterrorism.  If that happened, it would be horrible.
		So I do think decisions needs to be made as quickly and as appropriately as possible, based upon the soundest medical information that's available.  So my vote for H1N1 is to keep it.  My vote for H3N2 is keep it.  I see no alternative strain that's immediately available and I don't see a change in the epidemiology which would alter that position and for B, I would defer two weeks, three weeks, but you can't defer past March 1, if the industry is going to be able to produce these vaccines and make them available to the public by the fall.  And I would just point out one other opportunity that CBER and its colleague at the NIH, namely, the Division of Microbiology Infectious Diseases has and it goes back to looking at the behavior of these vaccines in children, there is the opportunity to collaborate with vaccine treatment and evaluation units and that should be capitalized on as an inter-agency collaboration for children.
		DR. DAUM:  Thank you very much.  Dr. Faggett?
		DR. FAGGETT:  Thank you.  Again, I go on record as applauding increased involvement in children as well.  In coming out of the DC experience immunizing of school kids, I am really concerned about the urgency of the matter and I vote to keep New Caledonia/2099, H1N1.  For the H3N2, based on that sense of urgency as well as unavailability of a new candidate strain, I think we should keep H3N2.  Again, we still have the opportunity in our March 6 meeting, if something comes up at that point, we could possibly comment again, but I think at this point we should keep H3N2 and for the influenza B candidate, I would defer at this time.
		DR. DAUM:  Thank you very much.  Dr. Goldberg.
		DR. GOLDBERG:  I would retain the New Caledonia for the H1N1 for all the reasons that my colleagues have given.  I would retain the H3N2 since I don't really see any viable alternatives in the short run.  And for the B, I think we have to defer it, but I don't know how much more we're really going to have.  I mean my gut from the data that we're seeing today is that we do need to consider the Victoria strain very seriously and then we're into the quadravalent issue which I think we'll have to discuss at length, pending, hopefully the new data will clarify this.
		DR. DAUM:  Thank you very much.  Dr. Eickhoff?
		DR. EICKHOFF:  I came down just about where Dr. Griffin came down.  H1N1 retain, H3N2 retain, B defer.  Now having said that I'd like to make just a few comments about the B issue.  One, I am not one of those in favor of a quadravalent vaccine.  I think we sacrifice immunogenicity to the point of being on the marginal side if we do that, unless we go to 15 mics each and then we affect timely delivery of vaccine and we affect the total number of doses that are likely to be made.
		Two, I think we will be moving to a B/Victoria strain rather than one of the current strains.
		Three, the consequences of making a wrong decision with an influenza B candidate are really nowhere near as grave with influenza B as they are with influenza A, particularly H3N2.  Influenza B is not a huge cause of mortality in the elderly, not a huge cause of morbidity in adults.  I think the target population to use Dixie's argument earlier, the target population for whom B is in the vaccine in the first place is really high risk children.  That's the group we're most trying to protect with the influence of B component.
		I think that's all.
		DR. DAUM:  Thank you.  Dr. Dowdle?
		DR. DOWDLE:  Well, we seem to be on a trend here.  I would vote to retain H1 and retain the current H3.  I would support deferring on the B, however, I would like to join Ted in urging caution about considering a quadravalent vaccine.  I think we have to be very careful about doing that and if that's being considered, then I think the pros and cons have to be very carefully laid out in the scientific data supporting that decision, because it is precedent setting.  It's been done before, but it certainly is precedent setting from the last two years of vaccine decisions.  So it's not something that should be made lightly.
		DR. DAUM:  Thank you. Dr. Poland had to leave, so Dr. Myers, I think you're our last person up there with a vote.
		DR. MYERS:  For the H1N1, I would retain the New Caledonia, the H3N2, the A/Panama, but I concur with comments of several people made that we ought to watch that very closely.
		DR. DAUM:  Marty, can you speak into the mike?
		DR. MYERS:  I'm sorry, we can always reevaluate later, but I think you need a vote today, so I would vote to retain the H3N2 as the A/Panama.
		On the B, I think the data that we've seen today, particularly what Nancy showed us suggests that we need to include a B/Victoria strain, but I think the -- I mean we need to include a B/Victoria strain and I guess the point I'd make on deferral would be I think the only decision that I would recommend that we defer on is whether we need to consider a fourth strain or not.  But I would go with the B/Victoria now.
		DR. DAUM:  So is your B issue a --
		DR. MYERS:  A B/Victoria strain.
		DR. DAUM:  B/Victoria now.
		DR. DAUM:  Okay, good.  So there are three things left to do.  One of them --
		DR. FREAS:  Could we get the industry opinion and your opinion before we change the topic?
		DR. DAUM:  I wasn't going to change the topic, but we certainly have industry representatives' opinion.
		Dr. Decker?
		DR. DECKER:  Had I a vote it would have been keep, keep, defer.  Not even having a vote, I still offer the comment that I'm delighted to see that the vote has ended up being 11 to 5 if I counted right on the H3N2 keeping because every deferral is a risk, every change is a risk and there's only a certain number of risks that we ought to take in a year if we can help it.
		I would think that if we were changing H3N2 that that would then constrain our options with respect to B.  And I think it's much more clearly important to retain options on B.  But we're deferring on B is the question of which strains, how many strains and if we have two strains, how many of those strains will be new strains which is more than enough to defer to create headaches for production.
		So I think it's doing the right thing to defer and is the right thing to defer only that one.
		DR. DAUM:  Bringing things on home, what we will have now is I will vote and Bill will announce the results of the vote.  Then Bill Egan will make a comment from FDA's perspective orienting us toward a March discussion, then we will have an open public hearing and then we will adjourn.
		So with that last four items in mind, I vote to keep the H1N1.  I think there's unanimity on the Committee on that issue.  H3N2, I would love to hear more data in March, however, I'm very persuaded by Dr. Griffin and the many others who made the point that the candidates aren't there and the need to give as close signal today as we can is there.  So I vote to keep H3N2 the way it is, but I sure would like to hear more data in March if there is some.  And the B issue, I think is a heavy one and I think it's very clear from the discussion and the learned points of view that were exchanged today that the B/Victoria needs to be part of this, but whether to have two B components or just go with one is the difficult question and I'm hoping that we're not compromising industry by waiting until March and I'm hoping that Roland and Nancy and their colleagues will have some light to shed on this topic by March.  So I'm going to defer on the B issue.
		I also would like to encourage Department of Defense presenters and others, CDC, perhaps NIH, BTEUs, although I hadn't thought carefully about them in that role, to gain more information for us about how these vaccines are performing.  I feel like a bit of a broken record saying this over and over again, but this is an enormous vaccine program.  It's one the public has learned to have confidence in and trust and I would like to know more about what's working and what's not working each year that we make these changes and put these vaccines out there.
		And so I would like to see money, real money spent on monitoring the field performance of the vaccines each year.  By tailoring some of this surveillance data that we collect so carefully and linking it up to the immunization status of the patients from whom the isolates came and trying to learn what's going on in terms of field performance from them.
		So just a strong advocacy from my point of view and hopefully many others of the Committee as well.
		DR. BAUM:  With that, Bill, perhaps you can announce the results of the vote?
		DR. FREAS:  Okay, my unofficial tally is for the H1N1, 17 voted to keep it and there was one abstention.  The industry rep favored the majority vote.
		For the H3N2, there were 12 votes to keep the current strain.  There were 5 to defer with one abstention and the industry went with the majority vote.
		For the B, there were 16 votes to defer, 1 vote to keep, industry went with the majority and there was one abstention.
		DR. DAUM:  You are quick.
		DR. FREAS:  I hope Im right.
		DR. MYERS:  There was one vote for B/Victoria.
		DR. FREAS:  That is absolutely correct.  There were 16 to defer, 1 to keep.
		DR. GRIFFIN:  It's was a change now.
		DR. FREAS:  Could somebody clarify that for me?
		DR. GRIFFIN:  It's a change of strain.  It's a different strain than we're currently using.
		DR. DAUM:  Okay, Dr. Egan, let's call on you to keep things going.
		DR. EGAN:  Yes, I just wanted to make one quick comment about the B strains and the possibility of having two and the dose that might be used.  I think our default position is that if there are going to be two B strains, then they're going to be at 15 micrograms each unless there is data, compelling evidence that 7.5 will work, that is, that they are -- that those two B antigens are cross protective.  So I just wanted to raise -- to put forth this point to help prime some of the discussions that will be coming up next month or in March.
		DR. DAUM:  Thank you very much, Bill.  My guess is that there wouldn't be anybody that wanted to change their deferral decision now based on that, but I think that it will influence how we think about what goes on next time.  If I'm incorrect, and someone wants to reconsider based on that, please speak now.
		Okay, with that having been done we'll move on to the open public hearing.  This is an opportunity for anyone in the audience who wishes to to address the Committee.  I don't think there's anyone scheduled.
		In want of such a Committee addressing folks, we're adjourned.  Thank you very much.
		(Whereupon, at 3:29 p.m., the meeting was concluded.)

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