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Last saved by: Jennie Butler
Company: FDA

FOOD AND DRUG ADMINISTRATION

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	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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	VACCINES AND RELATED BIOLOGICAL PRODUCTS

	ADVISORY COMMITTEE

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	MEETING

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	FRIDAY

	JANUARY 28, 2000

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		The meeting was held at 8:00 a.m. in the Versailles I and II rooms of the Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Harry B. Greenberg, Chair, presiding.
MEMBERS PRESENT:
		HARRY B. GREENBERG, M.D., Chair
		KATHRYN M. EDWARDS, M.D., Member
		MARY K. ESTES, Ph.D., Member
		STEVE KOHL, M.D., Member
		ROBERT S. DAUM, M.D., Member
		KWANG SIK KIM, M.D., Member

MEMBERS PRESENT (continued):
		WALTER L. FAGGETT, M.D., Member
		DIANE E. GRIFFIN, M.D., Ph.D., Member
		BARBARA LOE FISHER, Member
		NANCY CHERRY, Executive Secretary

INVITED PARTICIPANTS:
		ROBERT COUCH, M.D.
		NANCY COX, M.D.
		THEODORE EICKHOFF, M.D.
		L. PATRICIA FERRIERI, M.D.
		THOMAS FLEMING, Ph.D.
		CHARLES HOKE, JR., M.D.
		EDWIN KILBOURNE, M.D.

	C-O-N-T-E-N-T-S
	PAGE

Call to Order, Introductions
Administrative Matters	5

Presentation of Plaques to Retiring
VRBPAC Members	7

Introduction of Members	8

Open Public Hearing

Introduction by Dr. Levandowski	10

Discussion of U.S. Surveillance
	Dr. Fukuda	15

	Questions and Answers	27

Discussion of World Surveillance and Strain Characterization, Dr. Cox	41

	Questions and Answers	67

Presentation by Dr. Canas on the Armed Forces	72

	Questions and Answers	77

Presentation by Dr. Hampson on the Southern
   Hemisphere	78

	Questions and Answers	87

Presentation by Dr. Zambon on the United
Kingdom	93

	Questions and Answers	99

Presentation by Dr. Nerome on Japan	101

Discussion of Vaccine Responses
	Dr. Levandowski	108

Discussion of Availability of Strains and
	Reagents, Mr. Offringa	119

Comments from Manufacturers by Dr. Slusaw	122

	C-O-N-T-E-N-T-S (cont.)
	PAGE

Discussion of Options for Strain Selection
	Dr. Levandowski	127

Committee Discussion	136

Open Public Hearing	147

Committee Discussion (cont.)	148

Open Public Hearing Description of
Laboratory of Pediatric and Respiratory
Virus Diseases Activities, Dr. Carbone	165

	Questions and Answers	174

	P-R-O-C-E-E-D-I-N-G-S
	(8:02 a.m.)
		CHAIRMAN GREENBERG:  Good morning.  Good morning, everyone.  I'd like to welcome you to the second day of the VRBPAC meeting.  I have no major annoucements, so, without further ado, I'm going to go to the boss here.
		MS. CHERRY:  Good morning and welcome.  Let me repeat an announcement I made yesterday because I know that many of you in the audience are here for the first time.  And that is if you are parked in the parking lot across the street, Bethesda is diligent about checking parking meters so don't get so wrapped up in what you're hearing today that you forget and let your meter go.
		And I have a conflict-of-interest statement to read:  "The following annoucement addresses conflict-of-interest issues associated with the sessions of the Vaccines and Related Biological Products Advisory Committee on January 28, 2000.  Based on the agenda made available, it has been determined that the committee discussions for the influenza virus vaccine formulation for 2000-2001 and the briefing from the Laboratory of Pediatric and Respiratory Virus Diseases presents no potential for a conflict of interest.
		The director of the Center for Biologics Evaluation and Research has appointed Doctors Robert Breiman, Robert Couch, Theodore Eickhoff, Patricia Ferrieri, Thomas Fleming, Charles Hoke, and Edwin Kilbourne as temporary voting members for the discussion of the flu formulation.  In the event that the discussions involve specific products or firms not on the agenda and for which FDA's participants have a financial interest, the participants are reminded of the need to exclude themselves from the discussions.  Their recusals will be noted for the public record."
		With respect to all other meeting participants, we ask, in the interest of fairness, that you state your name and affiliation and address any current or previous financial involvement with any firm whose products you wish to comment on.  This includes anyone who speaks in open, public hearing.
		I'll return the microphone.
		Okay, is Dr. Zoon here?
		CHAIRMAN GREENBERG:  Ah, good.  You're up.
		(Laughter.)
		That's an auspicious entrance.  This type of thing is always fun, although sad, so I think Dr. Zoon is about to make a presentation of plaques to retiring VRBPAC members.  No problem.
		DR. ZOON:  Well, this truly is a special, special honor.  I was coming down Rockville Pike this morning.  Of course a bus was stuck blocking two lanes of traffic.  So it never fails, when you're trying to be someplace on time.  But I said, I will not let that thwart me.  And then I go to the elevators here in the Holiday Inn and it nearly done me in.
		(Laughter.)
		So I think you can all relate to this.
		Well, it is my very, very dear pleasure to present to Dr. Kathy Edwards a wonderful plaque.  And I would just like to, one, for her service on the VRBPAC.  And I'd just like to personally thank Kathy.  I have thoroughly enjoyed interacting, working with you, and I want you to know you're not going to get away this easy.  None of our members ever leave the committee.  They merely reinvent themselves in other ways.  And I think Ted is the true victim of this process.
		(Laughter.)
		So, with great pleasure and gratitude, Kathy.  Thank you very, very much.
		(Applause.)
		CHAIRMAN GREENBERG:  I'd just like to second that.  Actually, I don't think I was really aware that Kathy was going to leave.  Are you?  I don't think that's correct.  She's not leaving, is she?
		(Laughter.)
		So, yes.  So you've been a spectular member of the committee and we may lose our ability to say anything sensible if you really leave.  Oh, okay.  So Dr. Adimora also.  That's too bad.  So, will she get the plaque?
		DR. EDWARDS:  She's already received the plaque, yes.
		CHAIRMAN GREENBERG:  Okay.  Okay.
		I'd like, I guess, to go around the room and have people introduce themselves, starting down there with Diane, since Dixie isn't here.
		DR. GRIFFIN:  Diane Griffin from Johns Hopkins School of Public Health.
		DR. ESTES:  Mary Estes, Baylor College of Medicine.
		DR. KOHL:  Steve Kohl, Oregon Health Science University.
		DR. KIM:  Kwang Sik Kim from Children's Hospital, Los Angeles.
		DR. FAGGETT:  Walt Faggett, American Preferred Provider, Washington, D.C.
		MS. FISHER:  Barbara Loe Fisher, National Vaccine Information Center.
		DR. EDWARDS:  Kathy Edwards, Vanderbilt University and, as I remineded everyone yesterday, I have the home of the Tennessee Titans.
		CHAIRMAN GREENBERG:  Right.
		(Laughter.)
		DR. DAUM:  I'm Robert Daum from the University of Chicago.  No commercial.
		(Laughter.)
		CHAIRMAN GREENBERG:  Harry Greenberg, Stanford University and the Palo Alto VA Hospital.
		DR. LEVANDOWSKI:  Roland Levandowski from the Center for Biologics Evaluation and Research.
		DR. EICKHOFF:  Ted Eickhoff, University of Colorado.
		DR. FERRIERI:  Pat Ferrieri, University of Minnesota Medical School, Minneapolis, and the team that didn't make it.
		(Laughter.)
		DR. FLEMING:  Tom Fleming, University of Washington, Seattle.
		DR. COX:  Nancy Cox, Centers for Disease Control and Prevention.
		DR. KILBOURNE:  Ed Kilbourne, New York Medical College.
		DR. COUCH:  Bob Couch, Baylor College of Medicine, Houston, Texas, the former home of the Tennesee Titans.
		(Laughter.)
		CHAIRMAN GREENBERG:  Okay, now.  We now have an open public hearing and I'd like to ask anybody in the audience whether they have anything that they would like to say to the committee or to the public.  I'm looking and not seeing any hands.  Is that correct?  Okay, if that's correct, the open and public hearing is closed.
		Now we're going to start our session and, as you all know, it's January so it's the flu session.  And Roland is now going to lead us through a discussion of what's happening in flu to help inform us to try to make some choices.  Roland.  And, Roland, I would simply say to try to ask your speakers to be expeditious and timely in informing us what's going on.
		DR. LEVANDOWSKI:  Okay.  Thank you, Dr. Greenberg.  Can you all hear me?  Am I loud enough here?  I can't tell from up here, so somebody will have to yell at me.  Okay?  It sounds like I'm getting some feedback now, so it's probably okay.
		Thanks again.  I'd like to welcome everybody here and thank you all for coming on this kind of cold and chilly and icy day in Bethesda.  As Dr. Greenberg has mentioned, we all know why we're here today.  We're here to begin the process of selecting the influenza virus strains that will be included in vaccines prepared for the 2000-2001 season.  As you're probably aware, the match between the antigen in the influenza vaccine and the circulating strains is probably the most important feature in the potential efficacy of inactivated vaccines for influenza.
		This overhead shows the question that we would like to have answered by the committee.  And the question is the same one that we ask every year, that is, what strains should be recommended for the antigenic composition of the 2000-2001 inactivated influenza virus vaccine?
		In order to answer the question, information is needed and we are prepared to supply information this morning, although it may not be all of the information that we would like to have.  But we will do this to assist in formulating the answer.
		In the next overhead, just to remind people who may be a little bit new to this, the data that are needed includes, most importantly, information on the appearance of new influenza viruses.  When those new viruses are identified and they have shown that they have new antigenic and genetic characteristics, how widespread they become helps in judging the urgency in considering changing a component of the vaccine, because, obviously, it's something that we don't take lightly and don't want to do if we don't need to.  If new strains have the capability for broad dissemination, it's important to know whether or not current vaccines are likely to provide some measure of protection.
		And, finally, if it appears likely that the current vaccines could be suboptimal, then it's still necessary to have some virus strains that grow well enough to permit manufacture of vaccine within the current constraints of time.
		The vaccines are actually being prepared now.  They are being prepared now so that they can be available in the early fall to ensure that administration of the vaccine is done before onset of the influenza season in the following winter.
		Now this slide is a little bit out of date.  I somehow misplaced the most recent one.  But it's not too far off.  What I would like you to get out of this slide, this shows the production of influenza vaccine for the United States over the last 10 or so years.  And you can see that that vaccine production has been rising.  This is what makes all of these deadlines quite important for the manufacturers.  Vaccine is not produced in a single day.  It takes many months to get it ready and it takes many months for it to start to get out for public use.  Currently, the vaccine production is somewhere between 80 and 90 million doses for the United States.  So that's quite a lot.
		So you can turn the overheads off, please.  Thank you.
		Okay, so the balance between enough information to choose wisely and enough time to make the vaccine and deliver it is usually very difficult.  We're at that point in the year when there is an urgent need to ensure the vaccine production goes forward.
		During the past year, recommendations were made for vaccines that are currently in use and, in the United States, the vaccines are trivalent and they include an A/Sydney/5/97 (H3N2) component; an A/Beijing/262/95 (H1N1) component; and a B/Yamanashi/166/98 component.
		In September of 1999, that's last September, the World Health Organization made recommendations for influenza vaccines to be used in the Southern Hemisphere.  Those recommendations were for vaccines incorporating an A/Moscow/10/99 (H3N2)-like strain; an A/New Caledonia/20/99 (H1N1)-like strain; and a B/Beijing/184/93-like strain which, in most cases, will be the B/Yamanashi/166/98 strain.
		I should make some mention about how those recommendations have been implemented.  And, actually, they've not been implemented in the case of the A/Moscow recommendation.  Although much work went into developing A/Moscow-like reassortants, it was not possible to produce a virus that had both the growth properties needed and, more importantly, the correct antigenic characteristics.  As a result, World Health Organization amended its recommendation to indicate that an A/Sydney/5/97-like viruses and its reassortants could still be used for the current manufacturing campaign for the Southern Hemisphere.
		There may be some more information on that in some presentations to come, but, in the interests of time, I'd like to get things moving.  I just would remind all of our speakers that we are on a very, very tight schedule, as we usually are, and we'll all need to be somewhat brief and to get going.
		So, initially, to give us information about U.S. surveillance, Dr. Keiji Fukuda from the Influenza Branch at CDC will begin.
		DR. FUKUDA:  Thanks, Roland, and good morning.  Usually I try to be very brief in presenting the U.S. surveillance information.  This morning, I will be a little bit more involved, because some of the features of this season which I think need some explanation.
		In general, the 1999-2000 season has begun relatively early compared with the last two seasons, which were also H3N2 seasons.  They have been similar to the previous two seasons in terms of the percent of respiratory specimens testing positive for influenza; in the percent of patient visits for influenza-like illness to sentinel physicians; and in the number of states reporting either widespread or regional activity.
		However, pneumonia and influenza mortality levels have been unusually high this year.  And there's also been an unusual amount of media interest.  Last year, between October and March, CDC received a little over 400 calls from the media about influenza.  This year, between October and January 26, about 850 to 900 calls have come in from the media, and, largely, over a two to three week period.
		In terms of the viruses which have been isolated in the U.S. so far, approximately 46,000; 47,000 respiratory specimens were tested for respiratory viruses.  About 19 percent of these have been positive for influenza.  The percentage of positive specimens peaked around week 51 and, as of week three, which is the most current reporting week, ending January 22, that percentage has fallen to 21 percent.
		There have been 8,736 influenza isolates.  A small number, 29, have been B viruses.  The vast majority have been Influenza A viruses.  And, of the 2,084 A viruses which have been subtyped, again, the vast majority have been Influenza A(H3N2) viruses.  There have been very few H1N1 viruses.
		In this slide here, this just graphically depicts what I just went over.  Basically, you can see that the number of influenza isolates peaked somewhere around week 52.
		Now in terms of the sentinel physician system, there are approximately 400 sentinel physicians who regularly report to the states and CDC and these sentinel physicians report on the number of patients coming in for influenza-like illness.  We saw that the national rates of these visits peaked at around week 52 at six percent and, as of week three, this has fallen to three percent.
		In terms of regions, the region which reported the highest percentage was the West South Central Region, consisting of Arkansas, Louisiana, Oklahoma, and Texas.  And that reached a peak of 14 percent.  The other region which reached a high percentage was the Pacific Region at nine percent, also during week 52.  And, again, this graph here shows what I just went over, showing that these sentinel physician visits peaked around week 52 and that the percentages have been coming down rapidly.
		Now in terms of estimated levels of either widespread or regional activities from the state and territorial epidemiologists, this appears to have peaked at around week two with 43 states reporting either widespread or regional activity.  And, again, this graph of the three clinical and virus activity markers basically show the same picture where activity appears to have peaked somewhere between the end of December and the first part of January.
		However, when we look at the pneumonia and influenza mortality data from 122 cities, you can see that the peaking of that activity has been unusually high and you can see that there is also this blip early in the season.  And here are the levels.  During week 51, we had eight percent and this has increased, as of week three, up to 11 percent.  This is somewhat provisional, because, for the most recent week, we always have some missing data.  But the percentage shouldn't change too much.  To put this in perspective, in the previous three seasons, we have seen peaks of 8.8 percent, 9 percent, and 9.1 percent.
		Now just to go over a couple of considerations about P&I mortality.  In general, there are some main factors which influence measurements of P&I mortality.  One of these are the infectious agents out there, and, in particular, the incidence and prevalence of influenza virus infections.  A second thing is the virulence of influenze virus strains.  And then the incidence of other pathogens.
		In addition, there are a number of both protective and susceptibility factors out in the population.  And these things include things such as the overall levels of protective antibody in the population, resulting both from previous natural infection as well as current levels of vaccine coverage.  And then, as Roland mentioned, the vaccine match is an important factor and the effectiveness of the vaccine.  We also know that changing behaviors can affect P&I mortality.  And then, finally, population demographics and underlying characteristics are quite important.  And then, finally, there are a number of measurement issues which are important.
		Now in terms of influenza viruses, essentially, we do not measure the incidence or prevalence of these infections nationally each year.  And so this is really an unmeasured factor.  And this would be extremely difficult to come up with for a figure each year.
		In terms of strain virulence, we can make a couple of general and specific observations.  Since their appearance in 1968, in general, the H3N2 viruses have been more virulent and have led to more hospitalizations and P&I deaths than H1N1 and B viruses.
		In terms of this season, specifically, because of the high P&I mortality, the New York City Department of Health pulled the death certificate records and went over them by hand to look and see whether there appeared to be any unusual diagnoses on the death certificates and did not see them.  And they also were able to break down the death certificates by age and compare some of the rates from last year to this year.  And, again, we do not see an unusual distribution of deaths by age.  So, as of right now, we do not have any indication that there is an unusually virulent strain out there.
		Now in terms of pathogens, you know that each winter there are a number of other pathogens which circulate, and this is certainly no exception.  In particular, this year, in parts of the country, the curves for RSV virus and influenza viruses have really been almost superimposable.
		Now in terms of population factors, there are some things that I want to go into.  In terms of overall levels of protective antibody, again, this is a factor that we do not normally measure year-to-year.  Now in terms of vaccine coverage, as Roland showed, the doses which have been produced in the country have been increasing and, for the past year, as Roland mentioned, there has been approximately 80 to 90 million doses which have been distributed in the U.S.  In terms of vaccine match between what's in the vaccine and what's been circulating, it's really been very good this year.
		And, in terms of vaccine effectiveness, at this point we do not have any specific data on vaccine effectiveness.  These will be available from a couple of different health maintenance care organizations, but not until the end of summer.
		Now one of the things I want to point out is that elderly age is a key risk factor for P&I mortality.  And if we look at the data for H3N2 seasons dating from 1968 up until the middle part of the 1990s, you can see that the elderly have accounted for a high proportion of P&I deaths each year.  So that, at this point, they account for well over 90 percent of the P&I deaths that we see each year.  Now when you look at the numbers of people who are over the age of 65, they have increased rather dramatically from 1950 to 1996, going from about 12 million to almost 34 million people.
		Again, this graph here simply shows what I just mentioned in a more graphic form.  But, again, you can see that this has been a rather dramatic increase.
		Now what are some of the things which tell us that age is important?  Well, in this slide here, this upper part represents P&I mortality as measured from the National Center for Health Statistics databases.  This is complete national data here.  This bottom graph down here represents P&I mortality as measured by the 122 cities system.  This is the data that we're currently talking about.
		And there are a number of similarities and differences between these two curves which I won't go into.  But one thing that I want to point out is that, in both of these curves, here you see a somewhat increase in baseline and here you see a somewhat increase in baseline.  And we think that this is probably related, in part, to the aging of the population.
		Now this is another complicated graph, but, basically, there are two lines here.  This upper line here is P&I mortality in the Western part of the United States.  And this other up-and-down curve down here is P&I mortality in the Eastern part of the United States.  And, in general, you can see that P&I mortality is generally higher in the West with higher peaks and a higher baseline, and somewhat lower on the East Coast.
		Now when we look at the percent increase in the elderly population by region, you can see that the percentage in the 85 and year-old group has been particularly dramatic and the increase has been the highest in the Western part of the United States, followed by the South and by the Northeast and by the Midwest.  But the relationship between age and P&I mortality is not so straightforward and simple.  When you look at the absolute numbers of elderly people, you can see that the largest number of elderly people reside in the South, whereas the lowest number reside in the West.  So, again, there's the relationship between age and P&I mortality, but it is not so straightforward.
		The other major issue I want to mention for this season are some important measurement issues.  Now, in general, we look at two main data sources for P&I mortality.  The first one is the so-called 122 cities mortality reporting system.  And this system reflects about one-third of all U.S. mortality.  It's a rapid death monitoring system and the results are always considered preliminary.  Again, these are the results that I showed you when I showed you that big peak for the season.
		About two or three years later, we look at the data from the National Center for Health Statistics.  This is complete national data, but, unfortunately, they usually are not available for another two or three years after a calendar year.
		Now this year for the 122 cities system, the P&I death case definition was changed.  The old case definition said that a P&I death consisted of influenza anywhere on the death certificate or pneumonia on part one.  For this season, the new case definition is influenza anywhere on the death certificate or pneumonia anywhere on the death certificate.  So you can see that it's a somewhat broader case definition.  And so the expected effect of this would be to increase the number of P&I deaths.
		Here's the reason why that case definition change was made.  Now over the past decade, WHO has been working on revising ICD-9 coding to ICD-10 coding.  In January of 1999, ICD-10 coding was implemented in the United States.  The effect of this on P&I deaths and pneumonia death recording has been profound.  Based on both NCHS projections and then confirmed by us, by looking at some data from cities, this ICD-10 coding change decreased P&I mortality and pneumonia mortality by over 60 percent in the United States.
		This is a really dramatic change.  And because of the drasticness of it, WHO may end up modifying this ICD-10 pneumonia coding.  This is a process in discussion which is going on right now.
		But, in the meantime, what we did for the 122 cities case definition, was basically change the old case definition to something which would be called a multiple-cause-of-death case definition.  And the importance of this is that the numerator data that we're looking at this year is based on this new case definition.  That sinusoidal baseline which you look at is based on the old case definition.  That's based on the previous five-year's worth of data.  So we have a difficulty there.
		So does the case definition change account for this entire increase in P&I mortality?  Well, the answer is probably not.  Here, again, you see two different curves.  Now it turns out that in the 122 cities system, there are 29 cities that always were reporting a so-called multiple-cause-of-death case definition.  And so this change to the new case definition really represents no change for them.  Those cities are represented by this solid curve here and you can see that, in cities in which no case definition change was made, we still see an increase in P&I mortality.
		Now this dotted line down here actually represents the bulk of the data that we normally look at.  And in these I guess 93 cities down here which did make a change in their case definition, we also see that mortality has increased for this season.
		So, in conclusion, in this somewhat confusing picture, I think that we can say that three out of the four surveillance systems have indicated that activity levels have been similar to the previous two Influenza A(H3N2) Sydney seasons.  P&I mortality measurements definitely have been high and the full explanation for this is uncertain at this point.
		We think that increasing aging of the population is certainly an important factor and will continue to be an important factor in the future.  We know that there was an important change in the case definition, which we think increased the deaths that were recorded.  But we also think that there are other factors and some relationships between these factors which, at this point, we don't fully understand.
		So, at this point, there are a number of action steps which will be taken to understand this phenomenon a little bit better.  During this season, there will be continued analysis of these P&I data and they will continue to be broken down in several different ways.  As I mentioned, vaccine effective estimates will be available at the end of the summer and we'll try to factor that in.  Normally we do not analyze the NCHS data until about two or three years later, but I think, because of this season, what we'll do is go ahead and obtain a subset of the data and try to do an analysis and compare the results between NCHS and 122 cities data more quickly.
		And then, finally, as usual, there will be ongoing analysis of these viruses, trying to look and see whether there's anything unusual about these viruses, compared to the other Sydney viruses.
		So that was rather a hurried explanation of all of this, but I'll take any questions if there are any.
		DR. LEVANDOWSKI:  Okay.  Thank you, Keiji.  Dr. Greenberg, do you or the committee have any questions or comments?
		CHAIRMAN GREENBERG:  Yes.  We have time for a few questions.  Ms. Fisher.
		MS. FISHER:  Has there been any analysis of the data with regard to how many of the individuals who died had been vaccinated either this year or in previous years?
		DR. FUKUDA:  No.  Every year we receive anecdotal stories or reports of people who have been vaccinated and who have developed influenza or who have died.  And we also, every year, get viruses from those groups of people and look and see whether there's anything unusual about those viruses versus viruses being isolated from other people.  But right now we do not have specific data.
		MS. FISHER:  That's very important I would think, to find out, you know, the vaccination status of these people, both this year and in previous years.
		DR. FUKUDA:  Yes, that's one of the things, when we do our vaccination effectiveness estimates, that's one of the things that we've looked out and in those calculations.
		CHAIRMAN GREENBERG:  Dr. Edwards and then Dr. Daum.
		DR. EDWARDS:  Keiji, do you think that the greater availability of the rapid diagnostic tests in any way might increase the diagnosis and appreciation that influenza is playing a role in some of the deaths?  Or do you think that that's not likely a role?
		DR. FUKUDA:  I think that, you know, with the advent of the new rapid detection tests and the approval of the new anti-viral drugs, I mean certainly there has been a really greatly increased awareness of influenza.  You know, in looking over some of the data, from some places it appeared to us that perhaps influenza as a diagnosis was being coded a little bit more often than in other years, suggesting that people may be thinking more about influenza.  But, again, you know, we don't have that quantified and we don't have it compared with other years right now.
		CHAIRMAN GREENBERG:  Dr. Daum and then Dr. Ferrieri.
		DR. DAUM:  I wonder if you could comment for me, as a non-influenza person, I was struck by the vaccine uptake curve that you showed at the beginning of your presentation with its dramatic rise in the number of doses.  And, yet, looking at the data on occurrence or mobidity or mortality, there doesn't seem to be any kind of corresponding effect of that dramatic uptake.  You'd expect to see maybe some kind of downturn in some parameter you showed.
		DR. FUKUDA:  Sure.
		DR. DAUM:  And I wonder, are we measuring the right things?  Are we looking at the right things?  Or is this just not working?
		DR. FUKUDA:  Sure.  This is something which comes up commonly.  Basically when we look at the data and we look at the increase in the elderly population versus the mortality rates, it appears that the mortality is decreasing in proportion to the increasing ‑‑ or the P&I mortality is not keeping up with the increase in the elderly population.  But when you look at these curves there, you don't really see that effect because those curves are not adjusted for the increasing elderly population.
		But this is a question which comes up a lot.  And the basic answer is, in fact, we do think that we are seeing some effect from vaccination coverage.
		CHAIRMAN GREENBERG:  Dr. Ferrieri, Dr. Kohl, and then Dr. Couch.
		DR. FERRIERI:  May I add to your anecdotes?  I direct a large microbiology laboratory and, although it doesn't include the virology lab, I get all of the feedback from that lab, as well as other information in our institution from infection control.
		And this year I feel there's been a lot more background noise in Influenza A-proven illness in a population highly immunized.  And I have a colleague in another institution, I don't have permission to use his name at this point, but he has at least 30 patients, normal people more like us, not the elderly, with proven virus, Influenza A isolates who had been documented to have immunization this year.  And I just hear more and more community physicians saying the same.
		And so I'm having a hard time convincing everyone who works for me and other people in the hospital who say, well, I got immunized and I still got sick.  And my rejoinder always is, well, you might have died, so that's the good news, that you did not, you know.
		(Laughter.)
		But what's your reaction?  And are you getting a lot of that type of information that is informal, if you will?
		DR. FUKUDA:  Sure.  You know, every year we get a lot of informal information and a lot of calls.  And we get frequent calls every year about people who have been immunized and who have developed either confirmed influenza or influenza-like illnesses.
		But we also get calls on things like outbreaks.  You know, we get lots of calls on that.  And I think that we have gotten a lot of calls about immunized people who have developed influenza-like illness or confirmed influenza.  By contrast, we haven't gotten that many calls about outbreaks occuring in the country.  And so that's something which has been noticeable to our group.
		I can't really quantify those calls for you, but that was one of the reasons why we asked New York City to take a look at the distribution of deaths by age group, because, in talking with Marcy Leighton, she said, in going out to the community and giving talks, she had heard lots of comments from primary care physicians saying we're seeing a lot of young people coming in with this.  But, again, when we look at the actual data and the breakdown, we don't see an unusual hump of deaths in young people.  So I think, you know, that's where it stands right now.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  Some of us elderly, although they still consider us normal ‑‑
		(Laughter.)
		‑‑ every year we ask about this year's vaccine effectiveness.  And, of course, we can't tell that.  So I'd like to ask you, in retrospect, do we have any data on last year's vaccine efficacy rates, since the viruses look like they are pretty much the same?
		DR. FUKUDA:  Yes.  We got vaccine estimates last year from a couple of different sources.  The first estimate that we got was from outbreak out in California in an institution and, if I recall correctly, the vaccine effectiveness estimate from an outbreak was somewhere around 50 percent or so.  And this was, I think, in an elderly population.
		However, when we looked at the data that was made available from the HMOs, from the health maintenance care organizations at the end of the summer, as far as I can recall, I think that that was lower, around 40 percent or so.  I'd have to go back and see what the actual figure was, but I think somewhere around there.
		CHAIRMAN GREENBERG:  Dr. Couch.
		DR. COUCH:  Keiji, I don't want to claim credit for this comment.  It came to me from Mark LeForest.  But I thought it was interesting.  I'd ask you to consider that he was suggesting this trend of increase in pneumonia that had gone over in the past few years and your suggestion of pneumonia/influenza mortality increasing progressively is partly reflective of cost-reimbursement procedures requiring, over the course of years, a considerable improvement in the quality of the coding of discharged diagnosis and of death diagnosis than was true earlier.  So it's not a change in disease, but a change in the notification of disease.
		DR. FUKUDA:  Yes.  I mean, I think that, you know, when we analyzed P&I hospitalization data, that was clearly an issue.  I think that hospitalization coding has really been affected a lot by reimbursement practices.
		I'm less aware and less sure of whether there has been that much of an effect on death coding because of reimbursement practices.  My sense is that if there is an effect it's less, but I'm not sure.
		DR. COUCH:  In both cases, the physician is doing the coding, with the help of administrative officials in the hospital.  But for the deaths, as well.
		CHAIRMAN GREENBERG:  Dr. Kilbourne.
		DR. KILBOURNE:  I just wonder.  When we're talking about levels of projection of 40 to 50 percent are those actually proven cases of influenza?
		DR. FUKUDA:  No.  These are clinically defined cases of influenza.
		DR. KILBOURNE:  Okay.  Because that's what you have to really look at, ultimately.
		CHAIRMAN GREENBERG:  Dr. Cox.
		DR. COX:  Yes.  I'd just like to comment that those were effectiveness estimates against hospitalization in the elderly.
		CHAIRMAN GREENBERG:  Dr. Kim and then Dr. Faggett and Estes and then we're done.
		DR. KIM:  Since you have viruses available, do you have any information on in vitro activity of your standard serum against those viruses?  Whether, you know, they are still active or, you know, activity differs.
		DR. FUKUDA:  Well, I think that would be some of the data that would be gone over subsequently.  So I think I'll just hold on that.  You're going to get more than enough.
		CHAIRMAN GREENBERG:  Dr. Faggett.
		DR. FAGGETT:  A little clarification.  Were you saying that about one-third of the cases that look like flu are really RSV?
		DR. FUKUDA:  No, no.  What I was saying was that deaths for pneumonia and influenza reflect a number of different factors and a number of different agents out there.  We know that influenza viruses are one of the main factors which affect it, but we also know that people can die from other viral agents.
		And this year, for example, in some parts of the country, when you look at surveillance data for viruses such as respiratory syncytial virus, you know, the rise in those viruses has really been almost exactly the same as the rise in influenza viruses.  And so, again, we can't say what proportion of those P&I deaths are due to RSV or mycoplasma or adenoviruses.  But we know that they're out there and that they play some role.
		DR. FAGGETT:  Before we went to that, this year, was your impression that the RSV was affecting more adults in a more virulent fashion, this year?
		DR. FUKUDA:  No.  I don't have any information or any impression that the impact of RSV has been different than in other years.  But I think that, you know, traditionally we think of RSV as impacting very young kids but I think it's clear that they have some impact on the elderly also.
		CHAIRMAN GREENBERG:  Dr. Estes.
		DR. ESTES:  I'm a little concerned at the answers about vaccine effectiveness.  So every year we ask what was the vaccine effectiveness?  And you say that next year by the end of the summer we'll hear what the data were for this year.  And yet, for last year, we don't seem to have good numbers for flu-proven cases.  Are studies ongoing now that we really will get good data on vaccine effectiveness?
		DR. FUKUDA:  No.  There is no ongoing program of vaccine effectiveness studies, looking at laboratory-confirmed cases.  I mean, these kind of prospective studies, again, would be very expensive, especially to have a laboratory component and we certainly don't have any funding for those kinds of studies.
		DR. ESTES:  Well, I would strongly recommend that somebody reconsider this because at some point we really need to know what the real vaccine effectiveness is.
		CHAIRMAN GREENBERG:  Dr. Cox.
		DR. COX:  Yes.  We've had similar discussions for the last 10 years at least and probably over the last 20 years.  And we would be delighted to have the funding to do such studies.  If it were made available, we would be happy to organize those studies.  But the vaccines have been in use for such a long period of time that, at the current time and the current funding base that we have, the best that can be done is to do a retrospective look back at the decrease in hospitalizations among vaccinated individuals, using large databases and that type of study.  Because adding a laboratory component is very expensive.
		Now in the future, there may be a couple of ‑‑ and maybe Kathryn would like to talk about this ‑‑ there may be a couple of studies which will be done to look more generally at respiratory illnesses and to integrate a laboratory component which could help us understand the contributions of the different respiratory agents during specific years.  But, again, you would want to have this as an ongoing study for a number of years to really understand what's going on.
		CHAIRMAN GREENBERG:  Dr. Couch and then Dr. ‑‑
		DR. COUCH:  Well, I just wanted to assure Mary that we wouldn't want to trivialize that comment, but it has been raised year after year after year.
		DR. ESTES:  But I think that's even worse that's it has been raised for 10 years and ‑‑
		DR. COUCH:  But still nothing has been done or has been put in force.  I find Nancy's comments to be very encouraging that maybe there is a possibility that some studies will be set up.
		CHAIRMAN GREENBERG:  Dr. Daum and then Ms. Fisher and that will be the end of the comments.
		DR. DAUM:  Yes, I just want to strongly reinforce Dr. Estes' comments.  I'm a relative newcomer to this process and this committee and already have heard several cries and outpourings for more information about this.  I'd be very happy to be informed by Dr. Cox or anyone else as to what we can do to help.  To whom can we send the message?  But we're doing an intervention to 70 or 80 million people a year in this country and what we know about how it's working is almost pitiful.  I mean, we just don't know enough about its performance.
		I would like to have a lot more information and would like to encourage anybody who is in a position to help to signal the urgency of this crucial health problem and do something about it quickly.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  This has to be done immediately because there is a push to use flu vaccine in children going on right now and it is not right that we go forward with this kind of a recommendation for children when we don't understand what's happening in the general population.
		DR. FUKUDA:  Actually, let me put the vaccine effectiveness question in somewhat of a different perspective.  There are many, many, many studies looking at vaccine effectiveness in small populations.  What we do not have ‑‑ and these are laboratory-based studies looking at laboratory-confirmed information.  I think the issue of whether a vaccine is effective or not is not really an issue.  I mean, there are just very large numbers of studies addressing that question.
		What is not addressed is the national vaccine effectiveness.  I mean, if you look at all people in the United States and all of this vaccine, what's the effect on this very large group of people?  And so that's the data which we do not have because it's so expensive to collect.  But that's a different issue, there.
		CHAIRMAN GREENBERG:  We're going to move on, Dr. Couch.  I'm going to take the last word myself and simply say that I think what you've heard here is that ‑‑ and virtually everybody in this panel knows that there is a huge history of documentation of vaccine effectiveness at points in time in small studies.  But since flu is a moving target and things change, it would seem appropriate that there is a prospective, ongoing evaluation because there is the potential that effectiveness may be changing as flu changes.  And some handle on that would probably be very useful.
		Dr. Cox, your turn.
		DR. LEVANDOWSKI:  All right.  Dr. Nancy Cox is the chief of the Influenza Branch at CDC and she's going to tell us about surveillance and antigenic characterizations.
		DR. COX:  Thanks very much, Roland.  I'll try to move through the presentation very quickly.  There is rather a lot of information to cover and I would suggest that anyone who is sitting too far in the back to see move forward so that you can see.  There are a lot of slides that are fairly complex and may be difficult to see.
		We're going to move from a U.S. picture of influenza to the global picture of influenza.  And we're going to start with the viruses that we have the best handle on at the moment.  So we're going to move through the different groups of viruses in the order of complexity and the number of questions that we have about them.
		We're going to start this year with Influenza A(H1N1) strains.  This overhead simply indicates by the number of pluses that you have associated with a particular month in a particular area of the world the estimated extent of activity attributed to H1N1 viruses.
		If we look at the activity that occurred between April 1999 and September 1999, which is mainly activity in the Southern Hemisphere, you'll see that there was only sporadic H1N1 activity.  We had only sporadic isolates from various parts of the world.  That is also true for the period October 1999 to January 2000, with the exception of Asia, where we know that during December and January, particularly in Japan and you'll hear more about this later, there was significant activity caused by Influenza A(H1N1) viruses.
		Now if we look at the viruses themselves, for those of you who have been here for the past two years or past few years, you'll recall that we have two antigenically and gentically distinct groups of H1N1 viruses which are circulating.  The first group is represented here by A/Beijing/262/95 and A/New Caledonia/20/99 which you'll be hearing quite a bit about today.
		These two viruses belong to one genetic and antigenic group.  You can see that here we have the reference "antigen" and we have the post-infection ferret antisera titers.  The homologous titers are shown diagonally here in red and they're underlined.  And we consider a fourfold difference in titer to be significant if it's reproducible from test to test.
		Here you can see, first of all, that when we look at the relationship between the Beijing/262 and New Caledonia strains, we see an asymmetric difference, that is, we see a fourfold reduction in titer between the New Caledonia strain against the Beijing/262 antiserum, but we don't see the reciprocal difference.  Nevertheless, when we look at a series of viruses, we can clearly see that the Beijing/262 serum does not cover this set of viruses down here as well as the New Caledonia serum does.  So we have seen antigenic movement of the what were formerly Beijing/262-like viruses so that they're looking more like the New Caledonia antigenic variant.
		Now, of course, circulating in some parts of the world, close circulating in some parts of the world and circulating separately in some parts of the world, we have this older lineage of influenza viruses which are related to the Texas strain that was in the U.S. vaccine for a number of years.  That group of viruses is represented by Johannesburg/96 and Moscow/13 in this particular slide.  And you can see that these viruses are very clearly differentiable by hemagglutination inhibition testing from the New Caledonia and Beijing/262-like strains.
		There was sporadic H1N1 activity in South America during their winter months, our summer months.  These viruses were isolated during May and July of '99.  And these strains from South America were clearly related to the older Johannesburg and Moscow and the Bayern/07 reference strain, which you will remember.
		Next slide, please.
		Here we have a slide showing some more recent viruses.  And, in particular, I'd like to point out some strains that were received from Dr. Nerome in Japan where they're having a significant H1N1 outbreak.  We have the Kobe strain here and Sendai strain here.  And these viruses were isolated in November and December of '99.  Once again, we see that the viruses down here, and we have actually three viruses from North America, one from Wisconsin and two from Canada, which are more poorly inhibited by antiserum to the Beijing/262, but well inhibited by antiserum to the New Caledonia strain.
		On this particular slide, we have the most recent Johannesburg/82-like strain that we've received listed at the bottom, antigen number 18.  This is a virus from China and it just looks like a typical Johannesburg strain.
		We're going to concentrate mainly on the bottom part of this slide here.  And just to demonstrate, I have actually the page number up on the top, page number 11 in your packet.  We had only 40 H1N1 strains that were isolated between April '99 and September '99 to analyze in our laboratory.  And only a total of 11 strains that were isolated between October and January.  Of the most recent strains, the majority are in the Beijing/New Caledonia group and the majority are New Caledonia-like.
		When we do the genetic analysis, we see that here's the Beijing/262/95 strain and, of course, these viruses do not remain very stable genetically; even if they appear similar antigenically, they are marching along and evolving with time.  So here's our vaccine strain and there are a number of conserved amino acid changes between the Beijing strain and the currently circulating strains on the same lineage.
		Here's our New Caledonia strain.  And I've put red dots by a number of the viruses that you had seen on the HI table shown previously and these are strains that are well covered by the New Caledonia antiserum.  Down here shown in blue, we have the Bayern/Johannesburg lineage and you can see these viruses are also evolving, although, antigenically, they look very homogenous.
		We like to look at our sequence data in ways that are fairly simple to present.  What we've determined in the past that, oftentimes, strains which have a sequence that is close to the consensus sequence of the viruses circulating actually produce a ferret serum with antibodies that are quite cross-reactive.  And so we like to look at the egg isolates that we have because those are the strains that are actually considered to be vaccine candidates because we must have strains that have been cast only in eggs in order to go into the vaccine.  So we restrict our analysis here to looking at strains that have a pure egg-passage history.
		And when we compare the New Caledonia strain to the consensus sequence for the Beijing/262 lineage of virus, we see that it has an identical sequence to the consensus sequence.  So perhaps this is one of the reasons the antiserum is covering the currently circulating strains on that lineage so well.
		Next slide, please.
		We also look at the neuraminidase ‑‑ not antigenically, perhaps we'll be doing that in the future ‑‑ but we do look at the neuraminidases of these viruses genetically.  And, once again, we see our vaccine strain is here and the neuraminidase of the New Caledonia and one of its corresponding high-growth reassortants is up here, so the neuraminidase is also evolved.
		Next slide, please.
		When there are two lineages of viruses within a given type or subtype, we like to keep track of exactly what the geographic distribution is of the viruses that have been identified.  And here we have the geographic distribution of the Beijing/262-like lineage viruses that have circulated between October '98 and January 2000.  And you can see that they're pretty well distributed in all continents where surveillance occurs.
		I'm going to just show one overhead with the post-vaccination human serologies.  Roland is going to be presenting a lot more data later, but this data did not get to Roland in time for him to incorporate it into his analysis.  So I would just like to show you that if we concentrate just on this column for the time being and look at the post-vaccination geometric mean titers against the vaccine strain Beijing/262 and against New Caledonia; a representative Japanese strain from the current outbreak in Japan; and a virus from North America, the Canada virus, we see that we have a greater than 50 percent reduction in post-vaccination geometric mean titer for these representative strains.
		Next overhead, please.
		Again, if we look at an elderly population.  I neglected to mention that we were looking at healthy adults in the previous slide.  If we look at the elderly population, once again, if we look simply at the post-vaccination geometric mean titers, we see at least a 50 percent reduction for these strains, as compared to the homologous titer that we observed for the vaccine strain itself.
		We'll move very quickly onto the Influenza B viruses.  The picture is a bit more complex for Influenza B, but similar to the situation for Influenza (H1N1) viruses.  We really have not had a great deal of Influenza B activity when we look globally, neither for the Southern Hemisphere winter nor for the Northern Hemisphere winter that's occurring now.
		Next overhead, please.
		Once again, we have two lineages of viruses circulating.  We have the so-called Yamagata lineage, which is represented here by Yamanashi, Beijing/184, and Harbin/07.  And then we have what we traditionally have called the Victoria lineage, which is represented here by Shangdong/07/97.  And it's very easy to see that these viruses are distinguishable, easily distinguishable, using hemagglutination inhibition tests with post-infection ferret sera.
		This was a test that was performed in early November and we had some isolates from Tennessee that had been collected in early October.  And the vaccine strain that we are currently using as our B component is Yamanashi/166.  We see that, for these viruses, we had good inhibition for the Tennessee strains and a strain from Brazil that was also isolated in October.  This virus from Ohio had a fourfold reduction in titer compared with the vaccine strain, but was only twofold reduced when compared to the Beijing/184 prototype.
		This test was done in early January of 2000.  And as we continued to do more testing with the Bs, we started seeing a slightly different picture emerge.  If we concentrate here on the titers that we're seeing against the B/Yamanashi ferret serum, we see that we have the Zagreb and New Caledonia strains, which are well-inhibited, and a number of strains that are just two fold down.
		But then we have antigens 17 through 21 here, which had been received recently.  They've been isolated in August and September of '99, but we've received them rather recently.  We had three viruses from Vietnam and two from Southern China.  And very clearly, these viruses were not well-inhibited by antiserum to the Yamanashi.  They were still reasonably well-inhibited by antiserum to the Beijing/184 and they were clearly on the Yamanashi lineage, as confirmed by sequence analysis and so on.
		We were very interested in looking at these viruses in more detail.  We did multiple tests with these to be sure that the HI values were reproducible.  And we chose one particular strain, that is this Shenzhen/654 strain; put it into ferrets; and got a ferret antiserum, which shows us quite clearly that we have a new Influenza B variant.  That is, we have a greater than fourfold reduction in titer when we're looking at the ability of the Yamanashi ferret antiserum to inhibit this strain and we have a reciprocal difference when we look at the ability of the Shenzhen antiserum to inhibit the Yamanashi virus.
		Now as you can see, this test was just completed last Monday, right after the ferret was bled.  And so we haven't had a chance to do a large retrospective analysis to actually see how this Shenzhen antiserum would perform against, for example, the Tennesee strain and some of the other strains that you've seen in previous tests.  So this is one of the next steps that we'll be performing.  But you can see that this antiserum clearly inhibits these viruses much better than the Yamanashi serum does.
		The other thing I should point out is that the B/Johannesburg strain was also well-inhibited.  In our hands, it's well-inhibited both by the Yamanashi antiserum and by the Shenzhen/654 antiserum.
		Next slide, please.
		We'll concentrate mainly on the bottom part of this table, the frequency table.  If we look at the period between April '99 and September '99, we have analyzed a total of 97 strains.  Only 10 of those, or approximately 10 percent, have been Victoria-like and those are from Asia.  The majority of the strains are Beijing/Yamanashi-like or low to Yamanashi.  And you'll see a number of strains here, 16 in fact, all from Asia, which were low to Yamanashi.  And that includes the Shenzhen and some of the Vietnam strains.
		If we look at the recent period, we've had relatively few Influenza B viruses to analyze.  Only a total of 14.  And we have one strain from Asia which is low to Yamanashi.  We have two from the U.S. which are low to Yamanashi.
		Okay.  This shows the molecular analysis of the hemagglutinin genes of these strains.  As I mentioned, we can clearly distinguish these viruses genetically.  This is the so-called Victoria lineage.  This is the so-called Yamagata lineage.  Here's our vaccine strain here, Yamanashi/16/98.  And it's more or less in the middle of the majority of strains that we have analyzed.
		The new variant that I mentioned is located up here and it's actually shown right here.  There are a number of specific amino acid changes between these strains and these strains that could account for the differences in antigenicity.  And you'll note that this new group of viruses up here is more closely related to the previous vaccine strain Harbin/07/94 than it is to the Yamanashi/16/98.
		Next slide, please.
		We looked at the extent of amino acid difference between the egg isolates that we have for Influenza B/Beijing-like strains and the consensus sequence.  And you'll see that the Yamanashi vaccine strain is actually very close to the consensus sequence.  And this has been the sublineage that has predominated in most of the world in recent years.  But, again, it should be noted that we have a relatively small number of strains.
		Next slide, please.
		And here we're looking at the separate sublineage of Harbin-like strains.  And here we see that the Shenzhen/654 has five amino acid differences, compared to the consensus sequence for the sublineage.  Now part of the problem here is that we have relatively few viruses that are in this lineage.  We don't do know the significance of this new antigenic variant.  We only have a handful of viruses that are like this.  We have just received a package of strains from the National Influenza Center in Beijing and all of the strains in that package are Influenza B strains, so we're very keen to look at those in detail and see if we can find similar viruses from other locations in China.
		Next overhead, please.
		If we look at the neuraminidase genes's evolutionary relationships about the B Influenza, neuraminidase genes, once again, we see the Yamanashi strain, here sort of smack in the middle of the most prevalent influenza virus strains that are circulating.  We'll need to sequence some additional neuraminidase genes from these recent strains.  We haven't been able to complete those studies yet.  Well, Shenzhen is actually done here, but we want to look at the neuraminidases of some of the viruses from Vietnam and the other Shenzhen strain to see if they cluster together.
		Now just to remind you, we've been talking about this for a number of years, but we need to keep in mind that we do have these two separate lineages.  The vaccine for Europe and North America has contained viruses from the Yamagata lineage, but the Victoria-like viruses have continued to circulate in Asia.  And the red dots here on the map just show the locations of B/Victoria-like strains isolated between October '98 and January 2000.  And we really haven't seen these viruses spread outside of Asia, which is quite surprising.
		I have just one post-vaccine serology exhibit to show you today.  And, again, I'd like you to concentrate simply on this column, which shows the post-vaccination geometric mean titer against the vaccine strain Yamanashi and some other representative strains.  And I'd just like you to note that the titers are markedly reduced for the B/Shenzhen/654 variant in all of these different panels.
		Next overhead, please.
		And I said we were going to move through the virus groups in order of increasing complexity and now we're talking about H3N2 strains.  When we look at the influenza activity that has occurred worldwide, and this is just an estimate of the extent of activity, but it certainly contrasts markedly to the picture that we saw for the B viruses and the H1N1 strains, you can see that there was really significant activity due to H3N2 viruses in the Southern Hemisphere in South Africa, Australia, and New Zealand and also on Central and South America during their winter season.
		You can also see that there is significant influenza activity due to H3N2 viruses in the U.S., Canada, and Europe.  And there's also activity occurring in Asia, but it's not quite at the same intensity, at least insofar as we understand it.
		Now looking at the HI reactions for the H3N2 strains has been extremely interesting.  All of us who have been watching the evolution of H3N2 viruses over the past few years would have predicted that Sydney-like strains would not circulate for three years in a row.  That has not happened for H3N2 strains for a number of years.
		We have looked in great detail and with great care at whether or not the currently circulating strains are indeed Sydney-like.  Here I'm showing you one particular batch of post-infection ferret serum.  We have checked three different batches made with serum from five different ferrets.  And we see the same picture with all three batches of ferret serum to the Sydney strain.
		This is a test that was performed in mid-December and it is very representative of what we had been seeing during November and the first part of December, and that is to say that, regardless of whether we were looking at viruses from the United States, which are shown here and with test antigens 7 through 12, or whether we were looking at viruses from Asia, shown here with test antigens 13 through 18, we were seeing a very good inhibition of these viruses with antiserum to the Sydney vaccine strain.
		We were also seeing a great deal of homogeneity, regardless of what serum we were looking at.  Here we have the Moscow/10 strain that Roland mentioned earlier.  We were seeing very good inhibition with this particular antiserum.  Here's another virus that you'll hear about quite a bit.  This is the Panama/2007/99 strain and its antiserum was inhibiting all of these strains very well.
		We have two high-growth reassortants that were made against the Panama antiserum.  The reason we did that is that we saw that the Panama virus itself had a fourfold in many tests, sometimes a twofold, reduction in titer when compared to the homologous Sydney titer.  So that's the reason that we went ahead and made a ferret antiserum to this virus and then high-growth reassortants were made.  And the antisera to these two high-growth reassorts, NIB-41 and 42, inhibited the viruses that we were seeing early on quite well.
		Here we have another virus which is fourfold reduced, very reproducibly fourfold reduced in titer as compared to the Sydney homologous titer.  And antiserum to that strain also inhibits these strains quite well.
		Here we have viruses that were isolated during October and November from the U.S. and these strains were isolated a bit earlier, between April and September of '99.
		Next overhead, please.
		You notice that this test was done a month later in mid-January.  And this table is organized in very much the same way.  It's fairly complex.  I'll try to walk you through it.
		What we were seeing ‑‑ by this time, we had identified another strain that was fourfold reduced in titer to the Sydney antiserum that's shown here in reference antigen number 6 Alaska/37/99.  And, of course, we made a ferret antiserum to that strain, so that's the new antigen that's been introduced here.
		But if we concentrate first on this column here, which shows the inhibition of viruses by the Sydney antiserum, we see that, if we look at viruses from North America, we have a number of viruses with a fourfold or greater reduction in titer against the Sydney strain.  And if we look across here and look at how these viruses are inhibited by other antisera, what we tend to see is the viruses which are more poorly inhibited by the Sydney antiserum also tend to be more poorly inhibited by the other antiserum.
		Now if we look at the viruses that we've received from other countries, we have a similar pattern.  There are a number of strains which are very well-inhibited within twofold versus the Sydney antiserum.  But we also have a viruses from Hong Kong and one from Korea which are reduced in titer.
		I think I will go on to the next overhead, rather than spend too much time there on that particular one.  This is the latest test that we performed this week and in this test we have one additional antigen and ferret antiserum, the Shenzhen/510/99 strain.  And this was the most recent egg isolate that we had or one of the most recent egg isolates that we had from Asia and so we thought it would be a good idea, even though it wasn't reproducibly reduced in titer with the Sydnedy antiserum, we thought it would be a good idea to see what kind of a profile we observed with antiserum produced against this virus.
		Once again, if we concentrate on column A, we'll see that there are strains from North America, which are very well-inhibited.  These are strains isolated in primarily in December and January of this season.  And we also have some strains that are fourfold reduced in titer, compared to the Sydney antiserum.  Again, these strains were isolated in October.  If we look at viruses from abroad, we see a similar pattern.  We could find viruses which are reduced in titer.
		We had been looking quite closely at the Panama antiserum and in many tests the Panama antiserum performs as well if not better than the Sydney strain in covering the currently circulating viruses.  In this test, it's not readily apparent.
		We haven't tested the Shenzhen antiserum a great number of times.  I think we've only had it in two large tests, but we do see that this Shenzhen antiserum tends to cover almost all of the strains.  We only have one strain here, the Philippines/26/99 strain, which may be mentioned by others later, which is reduced fourfold or greater in titer.
		So what I would like to just pause here and mention is that we have a picture for the H3N2 viruses that's a little bit complex.  We're really looking for a distinct new variant and we haven't seen one.  We're looking for a variant where we have a fourfold reduction in titer that's symmetrical, that's going both ways.  And if you look at this table carefully, you'll see that there are no strains here which give symmetrical, fourfold reductions in titer.
		The viruses are reasonably homogeneous and when they are less well inhibited by the Sydney, they tend to be less well inhibited by the other antisera.  The only antisera that we have at the moment, and we have much less experience with it, but the only one that we have that tends to give a significantly broader pattern is this Shenzhen/510 antiserum.
		So in the past what we've always tried to do is to find the new variant and really move to the new variant.  But you could think about a variety of strategies for updating vaccine components.
		You could think about, of course, you have one strategy where you stay with the component that you have in.  You could have one where you moved to a strain that is somewhat different, for example the Shanghai/42 even though it isn't very representative of what's circulating genetically.  Or you could try to just follow and move where the viruses seem to be going genetically and move to the Panama strain.  Or you could try to surround the strains by moving to a strain that really you have a limited rationale for changing to, but the antiserum actually seems to cover better.  So these are some of the ideas that we're exploring.
		Next overhead, please.
		Now I've shown you tables that have been selected to make certain points.  This shows the composite data for H3N2 viruses.  If we look at the viruses that were isolated between April '99 and September '99, we have a total of 346 strains that we've looked at and of those just about 11 and one-half percent were fourfold or greater reduced in titer to the Sydney strain.  If you look back at what was happening last year, we also had about 10 percent of strains which were reduced in titer to Sydney.  So it's really not a very different picture from what we were seeing last year or what we saw during the summer months.
		And the same thing is true of the period October '99 to January 2000.  Again, it's about 11 percent of the strains which are reduced in titer.
		The molecular picture is fairly complex.  I've put red dots by some of the viruses that you've seen on your HI table.  Here's the Alaska/37, the Panama/2007.  Sydney vaccine strain, of course, is down here and the viruses have been evolving with time as we always expect at a molecular level.  And here's the Moscow strain here up in this sublineage.  And the Shenzhen/510 is here.
		Now what I've done also here is to put a small green L by the strains which are low reactor in HI tests.  And what you'll see is that those so-called low reactors, the viruses that are fourfold or greater down in titer as compared to the homologous titer with ferret serum, are scattered throughout the dendrogram.  They don't cluster together.  So what we have is a picture where we don't have a clearly emerging variant of H3N2.  We have low reactors which are in each of these different clades.
		Next overhead, please.
		If we look at the sequences of our egg isolates or our possible vaccine candidate strains, as compared to the consensus sequence that we've obtained for strains circulating, we see that the Sydney vaccine strain now has nine amino acid differences compared to the consensus sequence.  Panama/2007 has three.  Shenzhen/510 has five.  Another strain that's been mentioned quite a bit or will be mentioned more in the future is Moscow/10, which has five.
		The relationships between the neuraminidases of these strains at a molecular level are also complex.  We have different subgroups of neuramidases that are circulating.  And we see that the Panama neuraminidase is here in this clade while the Moscow and Shenzhen neuraminidases are up here in this clade.  Sydney neuraminidase is down here and there are a number of amino acid changes that have occurred in the neuraminidase.
		Next overhead, please.
		Now I'm going to finish up my talk with a bit of an aside, but I know that the committee has had a number of questions over the summer months about what was going on in China with regard to Influenza A(H9N2) infection that had been reported from Hong Kong and then also from Guangdong Province in Southern China.
		The story that you're probably most familiar with is that that emerged from Hong Kong in March of 1999 ‑‑ I apologize for the typo ‑‑ when H9N2 viruses were isolated from two hospitalized children ages 4 years and 13 months.  These children had underlying health conditions that may have predisposed them to more serious disease, nevertheless they were hospitalized.  Both of them recovered uneventfully and no further cases have been reported from Hong Kong.
		The viruses were analyzed in detail and contain all avian genes, that is to say there was no reassortment between human strains that were close circulating at the time and these H9N2 viruses.  Quite a lot of work occurred in Hong Kong to determine the source of the infection and it was already known that some of the poultry were shedding H9N2 viruses, that had antibody to H9N2 viruses.  And it was reported by the Department of Health in Hong Kong that about 70 percent of the batches of poultry that they tested were positive for antibody for H9 virus.
		After an investigation in which CDC participated extensively but which was led by the Department of Health in Hong Kong, it was determined that poultry are the likely source of infection and serologic studies indicate that human to human transmission is rare and inefficient, similar to the picture that was seen for the H5N1 viruses.
		Isolation of H9N2 viruses was also reported by Dr. Guo Yuanji at an international meeting in March of 1999.  He reported that five H9N2 viruses had been obtained from individuals who had accute respiratory disease in Guangdong Province.  And the individuals were ill, actually, in December of 1998.
		Subsequently, this work was published in the Chinese Journal of Experimental Clinical Virology and the title of the paper is "Discovery of Humans Infected by Avian Influenza A(H9N2) Viruses."  The age of the patients ranged from 1 year to 75 years of age.  And the severity of infection varied somewhat and there wasn't a great deal of clinical information in the paper that was published.
		The H9N2 viruses that were reported by Dr. Guo are antigenically different from the ones that were isolated in Hong Kong.  And I'll show you the relationships between these viruses on this slide.  We haven't actually received any of the viruses isolated by Dr. Guo so we haven't been able to confirm his analysis, but the viruses from Hong Kong are listed here, antigens 3 through 6.  And we just have MDCK and egg isolate pairs shown here.
		And you can see that these viruses that were isolated from humans, whether in MDCK cells or chick cells, are closely related to a reference avian virus A/Quail/G1.  And we'll just call it G1 for the sake of convenience.  So these viruses are closely related to this virus, which was isolated from the live bird market in Hong Kong during December of 1997 right before the slaughter of the chickens that was undertaken to eradicate H5 viruses.
		The viruses that Dr. Guo has reported apparently are related to a reference avian strain Chicken/G9 which is shown here.  So it appears that there are two antigentically and, I'll show you in a minute, genetically distinct groups of H9N2 viruses that are circulating in poultry in Asia and both lineages have shown the ability to jump from birds to humans.  Here I've just pointed out with red arrows the G9 reference strain and it's genetically and antigenically from the G1 group that's shown here.
		I think that's my last overhead.
		CHAIRMAN GREENBERG:  Nancy, thank you very much for a very complete talk.  Now that talk took a little more time than the schedule Dr. Levandowski had planned, but I think it was very complete and very helpful.  What I would please ask is for the next speakers, who I am sure have wonderful data to tell us, that when it overlaps with what you've just heard, you don't have to tell us again.  And, in order to try to keep this on track, I would hope that, again, the next speakers really present the committee with the data that is important to make the decision for next year's vaccine.
		I have time for one or two questions for Nancy.  Dr. Kim.
		DR. KIM:  So it appears that, based on your H3N2 data, that it seems unclear why there seems to be an increase in influenza activity this year compared to let's say last year.
		DR. COX:  Yes, the viruses that are circulating this year appear very similar to the strains that have circulated during the previous two winters.  So it is unclear, first of all, why, based on past observations, we haven't seen a new variant emerge.  And, secondly, why we would have an epidemic caused by H3N2 rather than H1N1 or B when we would expect the antibody levels to be lower to those two strains.
		CHAIRMAN GREENBERG:  Dr. Edwards.
		DR. EDWARDS:  I have a quick question.  When you're looking at hemogglutination inhibition with the A/Alaska strain, making the antisera in ferrets, it appeared that the neutralization of that homologous strain was quite low whereas neutralization of other viruses with that strain was higher.  Does that happen frequently?
		DR. COX:  That happens with viruses which we typically call "low avid."  They just don't appear to bind antibody as efficiently as some other strains.  So occasionally, when we put one of those strains into ferrets, we find a ferret antiserum that inhibits the homologous virus less well than it does the other viruses, which bind antibody better.
		DR. EDWARDS:  Would they be not very good ones to select as vaccine strains?  Or are ferrets and humans not alike?
		DR. COX:  We tend to try to stay away from those strains if possible.
		CHAIRMAN GREENBERG:  Two more questions.  That's it.  Dr. Faggett and then Dr. Couch.
		DR. FAGGETT:  With the H9N2 virus, was that a mutation in terms of the one reported first and Dr. Guo's?  And was there an implication that this person-to-person capacity for Dr. Guo's virus?
		DR. COX:  I'm sorry.  I'm not sure I understand your question.
		DR. FAGGETT:  For H9N2.
		DR. COX:  Right.  The H9N2 viruses that are circulating in the poultry in Asia ‑‑
		DR. FAGGETT:  Right.
		DR. COX:  There are two distinct lineages.
		DR. FAGGETT:  Okay so no mutation there, just very distinct to start with.
		DR. COX:  That's right.
		DR. FAGGETT:  Okay.
		DR. COX:  Distinct to start with.
		DR. FAGETT:  Right.  But did Dr. Guo's reported virus have any potential for person-to-person transmission?
		DR. COX:  We really don't know very much about those viruses and epidemiologic studies comparable to those done in Hong Kong haven't been done yet, although Dr. Guo has done some serum surveys.
		CHAIRMAN GREENBERG:  Last question, Dr. Couch.
		DR. COUCH:  Just a couple quickly, Nancy.  One is a lot of, including Dr. Kilbourne, are pleased to see the emphasis coming on on neuraminidase and looking forward to antigenicity data that you said you're working on for the future.
		But the puzzle is on everybody's part, as you've indicated, is why three years in a row of A/Sydney?  And one suggestion that you've made that may have contributed is perhaps the neuraminidase are different and that, in the presence of a high population immunity and the absence of neuraminidase in it, perhaps this antibody and this virus has a little better ability to survive.  So I think that will be interesting.
		You've emphasized the low reactor frequencies and I can't remember from past years that ‑‑ see you said it was 10 percent all the way across the years period.  It that about the usual?  Or is there a higher frequency this year?
		And my last question relates to Influenza B.  Any outbreak or epidemiologic data to go with the Shenzhen strains?
		DR. COX:  I'm not sure what you're ‑‑ your first question was more of a comment than a question, I think.  Yes, why three years?
		DR. COUCH:  Well, I just wanted you to speculate a little bit.  You didn't mention the neuraminidase as a possibility.
		DR. COX:  Right.  Right.  We're going to ‑‑ yes.  Neuraminidase is a possibility.  We're going to be looking at that in much greater detail, trying to sequence more neuraminidase genes and eventually trying to set up some antibody neuraminidase inhibition tests.  And we're also going to be looking at internal genes as well, just in case.
		DR. COUCH:  Have previous low reactor frequencies been low, 1 or 2 percent, versus 10 or 11 now?
		DR. COX:  It depends on the year, but 10 percent is not unusual because there's just a degree of hetereogeneity among viruses circulating that causes us to see this kind of picture.  What we expect to see when a new variant is really emerging is an increase over time.  So 5 percent, 10 percent, 30 percent, and so on and then predominance of that new antigenic subtype.
		And the third question was?
		CHAIRMAN GREENBERG:  The last question was on B.
		DR. COX:  On B we don't really have very good epidemiologic information about the significance of the strains that have come to us from China, but we'll be following up on that and trying to get as much information as possible.
		CHAIRMAN GREENBERG:  I'd like to move on now and we have a series of speakers.  Dr. Canas.  And what'd I like to say is for each of you, you've got a maximum of 10 minutes and then a hook is coming out.
		DR. LEVANDOWSKI:  I need to reinforce what Dr. Greenburg said.  We're severely behind schedule by about 45 minutes so all the speakers need to be very succinct.
		Linda Canas is the chief of diagnostic and pyrology at Brooks Air Force Base.  She's with the Department of Defense and she has information that overlaps with the surveillance data that's been presented by CDC.
		CHAIRMAN GREENBERG:  And when you have overlapping data, just say you've learned this already.  You don't have to present it again.
		DR. LEVANDOWSKI:  Okay, I meant "supplements."
		(Laughter.)
		DR. CANAS:  Good morning.  DOD is very interested in maintaining the health of the men and women in the armed forces and respiratory disease, of course, rates very high on this.  For over 20 years now, the Air Force has conducted influenza surveillance.
		It's been a successful program and it's now operated through the Global Emerging Infectious Disease Office out of Washington and is tri-service.  Each of the services has their own portion.  The Air Force still continues mainly in the overseas and stateside surveillance by sentinel base.
		Now last year I went through a detailed process of how this works and let's just through it very briefly so you know what we do.  We do have sentinel sites that are set up around the world.  Throat cultures are collected from the physicians of anyone presenting with a case definition meeting respiratory illness.  These are sent to us generally by FedEx to our laboratory in San Antonio where we do traditional laboratory methods and isolate whatever virus we get.
		We are looking for influenza, but it's a clinical test in our labs so we report whatever we do get and get this information back to the public health officers at the bases.  We then go on to do any molecular tests and hemagglutination inhibition subtypings in our lab and also send on to Dr. Cox's lab at CDC.
		And just to give you an idea of where all of these different sites are, we do have them set up around the world.  We have two that are proposed.  Agreements have been signed and we should, hopefully, start getting some specimins from Uganda pretty soon.  Bolivia is also supposed to come on line.  The stateside bases, our military bases, have been chosen ‑‑ training sites where people are coming together, points of entry into the country, and our overseas sites.  My handout didn't get here, so it lists all of these and their countries and states to give you an idea that we do have a pretty broad range.
		One of the most exciting additions has been in collaboration with Army and Navy research labs in overseas areas where we've been able to get specimens from Nepal and Thailand for several years now.  This summer we ran into practical problems getting specimens into the country, but I think that's finally all worked out.  We are expecting another shipment shortly from them.  They say they are having some significant outbreaks.
		South America has been particularly prolific in sending specimens.  They've been very excited about the program.  I understand now that the National Police is going to be involved in getting supplies out and getting them back to us.  And, as I mentioned, Bolivia in South America and Uganda will be coming on line very shortly.
		Our graphs of what's been going.  You will notice that we have a signficant respiratory increase this season and that is very true in the military population.  But it's unique.  We're getting a lot of background parainfluenza.  Our program is not designed for RSV, but we have a uniquely military consideration with adenoviruses in our recruit population.  So the majority of those isolates have been adenovirus as opposed to influenza.
		There's been very little influenza isolated in the recruit population.  And this is true for all services.  And those that have been influenza cases have been in the new recruits who really haven't had time to develop an immunity yet.  So we're not seeing influenza in the recruit population.
		In the active duty population as a whole, we do see it.  We're trying to do some vaccine efficacy studies.  We know we have a unique population here.  They are required, the active duty are required, to be vaccinated.  We can track their records; we can track their travel; we can track their medical history, but it takes money.  So we're trying to do the retrospective studies of matching up vaccination and travel histories with the laboratory case definitions and this is an ongoing process.  It is one of our priorities to try to get true vaccine efficacy studies down the line.
		In Asia, we are just now beginning to see a real increase in samples coming out of Asia.  We've had one H1 out of Hawaii and that has been a New Caledonia.  We had one H1 just last week out of New Jersey.  And we've had two Bs in the Pacific and just last week we got a B out of Oklahoma.  Everything else we've seen has been H3N2.
		One of the things in the Pacific that we're trying to get off the ground is surveillance on board aircraft carriers in the Navy.  And we can have more access to places like Singapore and those places, but that, again, is still in development.
		Most of the European surveillance is done through the Army at Landstuhl and there were some technical difficulties and I wasn't able to get that information.  Everything we've seen, which has been ‑‑ we've had several from Turkey lately; a few from England and Germany.  They've all been H3.
		And just a summary of our numbers are very similar to what you've already seen.  We're seeing a big increase.  It has been an early season, but it hasn't been anything particularly unusual in our experience and H3 is predominate across-the-board.  We are expecting shipments from South America and Nepal shortly, but we have nothing to contribute on that at this point.
		We're just getting all our molecular work on line.  We've got some nice new equipment and we expect to be able to start contributing more information and being able to compare that to the libraries that are set up with CDC and other places and contribute to that knowledge.  But this is our program as we have it right now.
		CHAIRMAN GREENBERG:  Thank you and thank you for finishing quickly.  Roland.
		DR. LEVANDOWSKI:  Actually, I have a question about the B strains.  Are any of the strains that have been isolated by the military B/Victoria-like, particularly from the Pacific Rim or from Thailand?
		DR. CANAS:  Well, we've had very few and even those we had last year have all been very nice 184s, the Beijing.
		CHAIRMAN GREENBERG:  Dr. Kilbourne.
		DR. KILBOURNE:  What is the current vaccine coverage in the military?  It used to be very complete.
		DR. CANAS:  It's considered to be 90 percent by all studies.
		DR. KILBOURNE:  So, in essence, when you're seeing the adenoviruses emerging, you've just subtracted flu, do you think?
		DR. CANAS:  Well, adeno ‑‑ of course, you know, we had an adeno vaccine that's no longer available, so that has just increased a lot but we are looking for both.  But not too much in the recruits, we're not getting much flu.  But in the population ‑‑ and the adeno is in the recruit population as opposed to the population at large and it hasn't translated into the civilian communities around them either.
		CHAIRMAN GREENBERG:  Okay.  Any other questions?  Okay, well let's move on to Dr. Hampson.  And, Dr. Hampson, the same admonition.
		DR. LEVANDOWSKI:  Right.  Alan Hampson is one of the directors of the WHO Influenza Center in Melbourne and he has some information about what's happening recently in the Pacific and the Southern Hemisphere.
		DR. HAMPSON:  Okay.  Just very quickly to outline the collection of strains that we've had in the last 12 months or 13 months and just showing you our collection network, which is mainly Australia, New Zealand, and into Thailand and some lesser percentage of viruses from some of the Asian countries.
		And just to show you quickly that in Australia and New Zealand, we have the typical temperate climate distribution of viruses.  This one's in weeks.  One in months.  And during the course of this season, we've had Influenza A and Influenza B scattered throughout the season.  Maybe a slightly increasing tendency towards Influenza B towards the end there.
		Whereas in New Caledonia and Thailand, these are more typical of the tropical distribution where we see virus throughout the year.  In the case of New Caledonia, we tend to see outbreaks occurring at sporadic intervals.  Interesting this year, we've had two outbreaks of Influenza A.  The first purely H3 and the second purely H1.  And here's the New Caledonia strain Nancy was talking about and some later Influenza B.
		And if we quickly have a look at the distribution of the Influenza As, the greater percentage have been H3N2 with a very small percentage of H1N1, again just paralleling what Nancy has told you.  Then showing you that all of the H1N1 viruses that we have seen for the year fall into this Beijing lineage and are very well-inhibited by the antiserum against this new virus isolate that we achieved earlier in the year, the New Caledonia strain.
		And just to show you a difference table from minoesets from the Beijing virus showing this characteristic distribution of a number of minoeset differences.  And these are persisting in very recent isolates, including some which we've just received in the last week from the Philippines.
		With the Influenza Bs, the greatest majority of our strains have been the B/Beijing lineage.  A very small number of B/Shangdong viruses.
		Next.
		And the important thing to note is that the only place that we had this B/Shangdong or the B/Victoria lineage of viruses from was Thailand.  We didn't see it anywhere else in Asia.  We had expected this year that we might.  And, then again, it only occurred in the first part of the year and you will have noticed in that earlier graph that we've had quite a reasonable amount of Influenza B activity later in the year in Thailand and these were all B/Beijing/184 lineage.  So this change to the B/Victoria strain has changed back again to 184-type of strains in Thailand.
		Now our results with the Type B, the recent Type B/Beijing/184 lineage viruses has been maybe just a little different from Nancy's in that the viruses that we're seeing are better neutralized overall ‑‑ some of the viruses are around fourfold down against the B/Beijing/184 virus antiserum.  Certainly many of them are twofold down.  A number of them are fourfold down against ‑‑ two-to-fourfold down against the Yamanashi antiserum.  And in all cases these viruses are much better neutralized by two recent isolates, the South Australia/05 and Johannesburg/05.
		And I've just put in the dendrogram to show all the ones marked in blue are our recent 1999 isolates and they are fairly closely grouped.  The current vaccine strain, Yamanashi here, the previous vaccine strain, B/Harbin there, and the typical isolates that we're seeing now neutralized by these two antisera against B/South Australia and B/Johannesburg.  So there is drift going on with those viruses.
		And we've had a look at some post-vaccination seriological responses and we are seeing a significant reduction against viruses of this type in vaccines containing the Yamanashi virus.  So we've got reduction in B/Johannesburg.  These are younger and older adults here.  And in the youngest here, but not in the oldest here from Australia for some reason at this stage, we've seen a significant reduction against the new strain, the B/Shenzhen strain that Nancy referred to in her talk.
		We are seeing an intriguingly different picture with the H3N2 viruses.  I've divided them up here into low reactors.  These are strains that are ‑‑ I'm sorry.  That should say "low reactor" on this group here.  These are strains that are fourfold down in reaction with Sydney antiserum.  These are the standard Sydney-type strains which Nancy's already shown you.  And we've selected some out which appear to be more strongly reactive with Moscow antiserum and with a particular monoclonal antibody that we use which differentiates the Moscow virus.  So we have a much wider split of these viruses than Nancy showed you in her results.
		And just to show you some selected results.  These are not by distribution in terms of numbers, but just some selected results to show you the type of range of reactivity we get from strains that react strongly with all of our antisera.  Just occasional strains which react extremely poorly, very low titers, with all of our antisera.
		Now just to stress that most surveillance is done with cell-grown viruses these days rather than egg-isolated viruses, we went back and took a number of the clinical samples for which we had these low-reacting strains and reisolated the viruses directly in eggs and made the comparison.  And what you can see here is the cell-egg pair, or the egg-cell pair.  We've shown it for both the type strain, the reference strain A/Sydney.
		And you can see there is a difference there in reaction with antiserum.  And, in fact, all the way down this column where the virus has been significantly low in its reaction as a cell-grown isolate with the Sydney antiserum, when we've grown it in eggs, the reaction is increased quite significantly.  Many of these viruses are more reactive, as you will see, with the A/Moscow antiserum.  So there seems to be some degree of influence here on the cell culture system having been used to isolate these viruses.
		And I just put in one dendrogram here to show you with the A/Sydney virus at this point, virtually all of our recent isolates have fallen in this part of the dendrogram, close to the A/Panama strain which Nancy has mentioned and fairly well away from the Moscow/10 strain, which has also been mentioned as a potential vaccine strain.
		Now I don't expect you to be able to read this in terms of the difference table for the amino acids in these viruses, but what we did was to take a number of viruses.  The ones marked in yellow are the ones that are normal reactors in our HI test.  The ones marked in pink are the ones that are low reactors.  And I've marked here three in red at the top which are extremely low reactors with A/Sydney antisera and our other antisera.
		And just looking across at where we've colored the amino acid differences.  And these are all common amino acid differences across these groups.  There is absolutely nothing emerges, as Nancy said previously, to show a genetic difference that relates to this low reactivity.  There is some intriguing difference here that's not explained by the hemagglutinin sequence.
		But one thing we did do was to have a look at a number of these viruses and I apologize for the poor scan here of this electromicrograph.  But it does show fairly dramatically what we did see.  In a small number of viruses that we looked at where we took the very low-reacting strains, put them under the EEM.  Took normal strains.  And the thing that was outstanding, we saw these huge aggregates of virus in the viruses that were low reactors.  And I'm sure that Dr. Kilbourne will probably tell us that there's someting defective about the neuraminidase in these viruses which is giving us this reaction.  We haven't been able to investigate that yet.
		A quick look at the H3N2 strains.  You will have seen at the bottom of one of Nancy's HI tables a virus known as the Philippines/26 strain which is reacting very, very poorly with the antisera raised against A/Sydney virus.  These are just normalized to 100 percent in all cases.  But some lowering with this Shanghai/42 strain which you mentioned.  No lowering with the Moscow/10, in our hands.  And lowering with a number of other recent isolates.
		Now there has been mention made of the A/Moscow strain that was selected for vaccine production in the Souther Hemisphere.  And it became a real rod for our backs when we tried to work on this strain because when we took the earliest reassortant that we had which was one made in Australia, this IVR-112, we found to our surprise that it had a dilution mutation and the adjacent amino acid change because of the triplet that are being cut out here in an antigenic site, in antigenic site B.
		And just to go on with a number of reassortants that were made in the efforts to produce a suitable vaccine strain, as I'll show you in a moment, this correlated with antigenic differences.  Essentially everything that we have seen from that virus in terms of reassortants has had genetic differences and fairly significant genetic differences from the wild-type virus.
		We also did fine with the virus that we were working with.  In fact, had changes from the original sequence that had been distributed by CDC.  And, clearly, when we looked at our original sequences, we found evidence that these viruses were mixed.  So this was a mixed population of viruses obviously throwing off mutants as it went.
		And here's an example of two of these reassortants showing some difference in the reaction of their antisera that were produced against them, against the A/Sydney virus and clearly losing the advantage that had been seen here with the Moscow and quite dramatically seeing the change with a number of our recent low-reacting strains.
		This Victoria/390 and Brisbane/156 are strains which we've used as markers when we found that we had this genetic change in the virus to have a look and see whether it was having a significant effect.  And it certainly was.  It was certainly causing a significant reduction in the potence of the antiserum losing any advantage from putting that strain in the vaccine.
		Next slide.
		And, again, when we went on further and had a look at one further reassortment listed here to sera against that reassortant, seeing exactly the same sort of thing.  Even though this virus did not have a dilution in it, it had other mutational changes.  And so we did not come up with a virus that produced any sort of advantage seen with the original Moscow antiserum and maybe in part the breadth of reactivity of the Moscow antiserum may have due, and this is my speculation, to that being a mixed virus infection at the outset.
		CHAIRMAN GREENBERG:  Thank you very much.  Roland.
		DR. LEVANDOWSKI:  I've got another question, if I can ask it.  The experience with the Moscow strain, does that have any significance for what's being seen with low-reacting strains generally amongst the H3N2s?  Is that sort of one example of what may be going on elsewhere?
		DR. HAMPSON:  We haven't seen any evidence that they mixed in terms of their genetics.  We have found a couple of strains which clearly are, one Philippino strain which had a very low reactivity which clearly had quasi-species in it.  But the others we haven't and, now that you mention it, maybe we should go back and have a look a little more closely at some of those.
		DR. LEVANDOWSKI:  Well, I'm just wondering if that's state-of-the-art for H2N3 viruses today.
		DR. HAMPSON:  Possible.
		CHAIRMAN GREENBERG:  Diane.
		DR. GRIFFIN:  I was intrigued with the differences you saw between the cell-grown and the egg-grown viruses.  And the vaccine is grown in eggs and those are egg-grown viruses.  I assume most isolates are probably made in cells.  And are most of the viruses used for testing in these wide variety of tests we're seeing grown in human, I assume these are human, cells?
		DR. HAMPSON:  No.  They're MDCK cells for a canine kidney cell line that we grow the viruses in.
		DR. GRIFFIN:  They're MDC ‑‑ oh, I see.
		DR. HAMPSON:  The interesting thing is that we retain our reference panels and this is uniform across the WHO system.  Our reference panels are in-grown viruses with antisera prepared against those in-grown viruses because we are using these are the basis for looking for vaccine strains.
		Unfortunately, the isolates that come to us are cell-grown viruses and sometimes when we go back and reisolate these viruses in eggs because they've looked interesting and looked like a vaccine candidate, we finish up with a virus which is different.  The receptors on the cells, the MDCK cells, and the receptors on the egg embryo cells are different and there is a receptor-driven selection of influenza viruses.  This may, in part, explain some of this low avidity reaction that we've seen, that Nancy described.
		DR. GRIFFIN:  I guess what I am really most interested in is what the virus is like that's actually from the person before it's isolated.  You know, just because if there was any possibility that that was somehow different than the vaccine, that that might help explain some of the things we're seeing.  Has anybody done direct sequencing prior to isolation?
		DR. HAMPSON:  Yes, they have.  And the answer is that, generally, what we see in direct sequencing is viruses that have the same sequence as the cell-grown viruses rather than the egg-grown viruses.  And there was a proposal a number of years ago that, in fact, we should be looking at cell-isolated viruses as the starting strains for vaccine.  And, in fact, there have been a number of meetings on that.  It poses a number of regulatory issues which haven't been solved as yet.
		CHAIRMAN GREENBERG:  Nancy, you want to answer this specific issue, correct?
		DR. COX:  Yes.
		CHAIRMAN GREENBERG:  Nancy Cox.
		DR. COX:  We have been looking at sequences specifically for host-mediated changes since the late '80s when a lot of the data first came out where isolates were sequenced directly so a clinical specimen was obtained and the HA sequence was sequenced ‑‑ was obtained directly from that rather than after isolation.
		And so when we look at strains that are candidate strains, we're always keeping in mind what we know about host-mediated selection.  And when we see that a virus that comes out of eggs that has a particular amino acid difference from the majority of strains that are circulating, we want to be sure that we don't have an antigenic difference that's conferred by that change.  This is always taken into account as much as possible.
		CHAIRMAN GREENBERG:  Dr. Kilbourne, is this directly on point?
		DR. KILBOURNE:  It's directly on the point.
		CHAIRMAN GREENBERG:  Okay.
		DR. KILBOURNE:  Because I think a very important consideration comes up here and that is that it is very arbitrary what we define as Moscow/10 or anything else.  Will the real virus stand up?  Because we're dealing in each instance with a heterogeneous quasi-species mixture and, out of our reassortment procedures, we will fish different variants.  And I think it's hard to say whether those variants which seem to be artificants of reassortment are the true representative or not.
		We go back to wild-type a lot.  What is wild type?  It's a mixture anyway.  So I think it's, well not to overemphasize these differences unless we really show they're antigenically significantly different.
		CHAIRMAN GREENBERG:  Okay, last question is Dr. Couch.
		DR. COUCH:  Alan, that was a great deal of data in a big hurry.  And between last night at 11:00 getting this and what you said, it's a little trouble here.  Will you tell me, remind me, if Australia has had H3N2, or the Southern Hemisphere, H3N2 epidemics three years in a row as we did?  And what your thoughts are about A/Moscow, low-reactivity strains and low aggregation as being a reasonable explanation for our third year in a row.
		DR. HAMPSON:  Yes, we've had A/Sydney for three years in a row.  The outbreak this year was not quite so significant as the previous years.  Last year was a very serious outbreak.  This year was a moderate outbreak.  And the preceding year we did have A/Sydney in the population.  It was mixed at that stage with the previous strain A/Nanchang.
		I'm perplexed by why we've had this virus repeatedly in the population.  I don't understand it and we're still trying to come to terms with our findings here with these low-reactive strains and exactly what is contributing to this.  It's far more dramatic than we have seen in the past, but it's more dramatic than what Nancy is seeing and so there's clearly some difference in our surveillance or our test system which is throwing this up a little more than she is seeing at CDC.
		CHAIRMAN GREENBERG:  Okay.  I'd like to move on to Dr. Zambon.  And, Dr. Zambon, again, as expeditious as you can be.
		DR. LEVANDOWSKI:  Dr. Maria Zambon is from the Public Health Laboratory Service in London.  And I think you probably have seen in the news that London, and England in particular, have been having a fairly severe influenza season.  And we would be most interested to know about what's happening there.
		DR. ZAMBON:  Thank you very much.  Just like in the United States, in the United Kingdom, we have a number of different measures of influenza activity.  The one that we pay most attention to is based on sentinel physician recording from a sentinel physician network, which is based on monitoring some 800,000 to 1 million people in the United Kingdom and new episodes of influenza-like illness are recorded.
		This is described as the RSGP, standing for the Royal College of General Practitioners, weekly consultation rates for influenza and influenza-like illness.  Shown here is the last 10 years index and you will see that, in the United Kingdom, the way in which we describe our influenza activity could be described as arbitrary in some ways, but I hope you will see what I mean when I describe a little bit further.
		We know that our baseline for influenza runs to round about 50.  And we describe anything in the consultation index below 50 per 100,000 as baseline activity.  Anywhere between 50 and 200 we describe as normal seasonal activity in that we recognize influenza circulates every year.  Somewhere between 200 and 400 we describe as higher-than-expected seasonal activity.  And anywhere that's greater than 400 we describe as epidemic activity in order to reflect a severe year's worth of influenza.
		The last time that we had a very serious influenza epidemic in the United Kingdom was the season for 1989-1990, which is also recognized worldwide as being a very severe influenza season.  This year, 1999-2000, we would describe what we saw as higher-than-expected seasonal activity.  And this peak here, which is now on the downturn, is probably a slight underestimate in that some of the figures obtained were obtained over the Christmas period.
		Next slide, please.
		The GP practices involved in influenza community surveillance, some of those GP practices which do the influenza monitoring clinically also submit swabs to us and they are a very valuable source of isolates.
		Next slide, please.
		The distribution of those GPs reflects the major urban areas and the population density.  The thing that we can say for this year, which is a reflection of some of the press activity that you may have heard about, is that the major consultation index, major consultations took place or the peak of consultations took place in the elderly, which is a reflection, therefore, probably, of impact on the health care system and hospital bed utilization.
		Importantly, when we look at the isolates, our isolates are derived either from community sources or from hospital sources, about half and half, and we see different distributions.  The hospital isolates come primarily from the elderly or young children, whereas the community isolates come from the bulk of the population, that is the young and middle-aged.
		Next slide, please.
		Our death data ‑‑ this is as up-to-date as we have ‑‑ suggests that we have, so far, a very similar season to last year, which was reasonably severe in death terms.  We estimate in the United Kingdom that there are some 10,000 to 12,000 excess deaths associated with an H3N2 season every year.  And last year, as you know, was an H3N2 season.  This year, so far in the United Kingdom, it has been exclusively H3N2 and our death data look very similar to last year.
		Next slide.
		Now I won't spend too much time on this because many of the points have already been made.  We see our viruses really, the majority of them, react reasonably well with Sydney/5, although we do have some low reactors.  In general terms, where we have used Moscow/10 antiserum, we see slightly better reactivity with the Moscow antiserum, but maybe not enough to make a substantial amount of.
		Next slide, please.
		The proportion of isolates with decreased reactivity, those fourfold or less to Sydney, has stayed relatively constant, I think, over the portion of the season that we've analyzed so far, and is rather similar to the proportion that we saw last year.
		Next slide, please.
		And, in sequence terms, the only reason for my showing you this is to perhaps point out, we've had a bit of discussion from the panel, the question of vaccinated individuals who subsequently go on to develop influenza.  I'd just like to draw your attention here to this strain, England/650/99, which has come from a vaccinated individual.
		The only point that I would note here is that we do have an additional creation of a potential glycosulation which makes that virus slightly different to the others that we've looked at this season.  But we have actually seen that virus strain circulating from individuals who have not been vaccinated.  We saw that at the end of last season.  So it makes the point very nicely that the viruses that you recover from vaccinated individuals, at least as far as their HA1 is concerned, may not be any different to what's seen circulating in the population.
		Next slide.
		And, indeed, when we look at our viruses, they are clustered very closely together and closely with other viruses that we saw towards the back end of last season.
		Next slide.
		We've had three Influenza B strains so far, all of which have come in late December or early January.  And the HI data are, therefore, not what I'd describe as robust in the sense that there's only been one HI test.  We see, in general, that the viruses are Beijing-like, although this most recent virus in this single HI test shows a slightly reduced reactivity to the Beijing/184 and the B/Yamagata serum.
		Next slide, please.
		Although when we actually look at the sequence analysis, we can see no reason why that should be particularly.
		Next slide, please.
		So, in summary, for the United Kingdom influenza surveillance, we've had widespread influenza activity over this last season.  We've had predominately H3N2 strains circulating.  Our clinical activity is all related to H3N2.
		We've had one imported case of H1N1, which came from a lady who'd returned from a cruise in the Caribbean.  And we would actually describe this as a New Caledonia-like strain, although we cannot get at it genetically for various technical reasons.
		The majority of our strains are Sydney/5-like and we see a small percentage with reduced reactivity to A/Sydney/5 with a fixation of some mutation as compared to our '98 and '99 viruses.  And we clearly do not have any molecular correlate for the low-reacting strains that we see.  We've had the recent onset of Influenza B circulation and a relatively small number of Influenza B viruses have actually been assessed.  And I'll leave it at that.
		CHAIRMAN GREENBERG:  Thank you very much.  Roland.  Dr. Faggett.
		DR. FAGGETT:  Yes.  In your data, your 1998 experience appeared to be below normal.  How do you account for that dip in your numbers?  Was it increased immunizations or ‑‑
		DR. ZAMBON:  Sorry, I'm not sure I understood the question.  1998 and 1999.
		DR. FAGGETT:  Your chart shows a below-normal incidence of influenza.  Did I read that correctly?
		DR. ZAMBON:  No, that's not ‑‑ you mean for the '98-'99 season?
		DR. FAGGETT:  Right.
		DR. ZAMBON:  No, that's not correct.
		DR. FAGGETT:  That dip in '98.
		DR. ZAMBON:  That's the '97-'98 season.
		DR. FAGGETT:  Right, okay.
		DR. ZAMBON:  So this is the '98-'99 season.
		DR. FAGGETT:  Right.  Okay.  Right.  That dip.  How do you account for that?  That's a very significant dip.
		DR. ZAMBON:  We had very little influenza circulating in that year.  And, if I recall correctly, that was predominately an Influenza B season.
		DR. FAGGETT:  So there was no increased immunization or anything like that?
		DR. ZAMBON:  No.  Rather like the United States, we've seen a progressive increase in the amount of vaccine put out, but what is clear in the United Kingdom is that we do not necessarily have data about how well vaccine is targeted to the at-risk populations.  And where that has been looked at, we have some very disappointing figures to suggest that the at-risk population only 40 to 50 percent of those are actually receiving vaccines.  So even though a lot of vaccine is going out, it's not necessarily getting to those that most need it.
		DR. FAGGETT:  Yes.  We have that same experience.
		CHAIRMAN GREENBERG:  Okay.  If there's no other questions, we'll move on to the last speaker before the break and that's Dr. Nerome.
		Dr. Nerome, Roland will introduce you in a second, but, again, 10 minutes.
		DR. LEVANDOWSKI:  Okay.  Dr. Kuniaki Nerome is from the Laboratory of Respiratory Viruses at NIH in Tokyo.  And, as you heard, they've had quite a different experience there this year, with H1N1 viruses, from most of the rest of the world.  And we'd very much like to hear that information.
		DR. NEROME:  If possible, I would like to express to Dr. Levandowski from FDA and Dr. Nancy Cox from CDC thanks for their invitation to attend this important meeting and present influenza activity in Japan.
		May I have my first slide, please.
		In Japan, co-circulation of the H3N2 and B viruses were repeated this sick season.  This is the first half was Hong Kong and second half was the B viruses.  The end saw a small peak caused by the B virus Victoria-like strain.  So, in Japan, two types of B viruses coincided in the second half of the season.
		Next slide, please.
		This is the total number of virus isolated last season in Japan.  9,373 viruses isolated in Japan in last season.  They are divided into three antigenic groups.  The first one with H1 subtype.  There are 1.13 percent.  The second type H3N2 viruses, corresponding to 57.2 percent.  The third type are the B viruses.  The diversity divided into, evolutionary, the Yamagata-like lineage.  So, only in Japan, two types of unrelated viruses co-circulated last season.  In this season, this was a quite different.
		Next slide, please.
		And you are looking at this visual of a B virus strain.  This indicate as two viruses in different parts of the west part of Japan, the center of a part of Japan in Hokkaido.  And this red indicates co-circulating H3N2 and H1N1 viruses, but only two prefectures isolated the H1N1 viruses.
		Next slide, please.
		And this is the original H1N1 and H3N2.  And co-circulating, H3N2, H1, and B viruses.  You can see here, Japan experienced co-circulation of the H3N2 and H1N1 viruses.
		Next slide, please.
		This is a number of virus in isolation reported at weekly intervals.  You can see here strains started in isolation with H3N2 viruses here in mid-October, like this.  You see here a sharp increase in the number of virus isolation H3N2 viruses.  In parallel, H1N1 were also isolated in many parts of Japan country here.  You can see here a co-circulation with H1N1 and H3N2 viruses.  Co-circulating only in Japan.
		Next slide, please.
		This is a table explaining of the H1N1 viruses.  You can see a HI index showing titer of 640.  On the basis of this HI pattern, please look down here.  Most of the viruses, you have the high titer 160.  This is the Hiroshima strain.  And the Nagoya strain also you have the high titer to 160.  In several strains here you can see a 40, 20, and 80.  And a Beijing antiserum inhibited very weakly these second virus here.  You can see here there's two type of antigenic variants co-circulating in Japan.
		Next slide, please.
		I can summarize here, because the letters are very small, very hard to see the small letters.  This is variant.  They have the high titer to Beijing strain.  And it is saying that this may be belonging to a Beijing-like variant.  And the second is Sendai-H.  Sendai-H is in Chiba strain.  You have the high titer to Beijing and Chiba belonging to a distinct antigen group.
		Next slide.
		There we have sequencing of 10 strains here.  On the basis of the antigen sequencing, Beijing/262 strain like this.  This is New Caledonia strain.  One amino acid difference between the Beijing like this.  Only one amino acid.  And this is the Bayern/07/95 strain.  There are 12 to 13 amino acid differences between them.  These amino acid differences only molecules belonging to antigenic site A and B.
		This is changing of H1N1 viruses because here a changing of viruses has evolved since 1998 two crossed like this.  This recent Japanese variant belongs to indicated by New Caledonia-like strain.  For example, this first variant belongs to Japanese New Caledonia-like strain.  And this indicates a Beijing-reactive strain.  The remaining strains are similar evolutionarily to the B/Beijing-like strain.
		This is H3N2 viruses you can see here.  The majority of the H3N2 viruses are reactive to Chiba-reactive strain.
		And only one strain
		I'll summarize here.  Japanese have seen two viruses, separating into two distinct other groups.  The first one reacted to the -like strain like this.  Chiba and inhibited it weakly, this strain. And the second group you can see here, Osaka and Hiroshima Yamagata, reacting to high titer reactive strain here.
		And now this is a second group of the antigen variant, Fukushima and Sendai/H and Yoshima/H.  and Chiba were inhibited very weakly against strain like this.  And this to Sendai/H reacted with high titer to -like strain.
		We also completed a analysis of this Sydney-like strain and another variant, Moscow like this.  The six differences you can see here.  And this is constructed from HA genes here.  Our indicator, Moscow-like strain, branched across it here.  The second one, strain.  They are distantly related to each other.  The majority of this strain belonged to this branch, indicating it is a Moscow-like strain.
		This is the only one B viruses isolated in Japan.  This is a Shangdong and Beijing were not reactive to this.  But this is one of the varieties reactive with a high titer to Beijing like this.  It is interesting that -- 
		This is also comparing and Yamagata and Yamanashi and Shangdong-like strains.  Between Shangdong-like strains, two obvious differences can be seen here between Yamanashi and Yamagata strains.
		This is also then the  You see Beijing here.  You see Yamanashi.  You see Shangdong-like strain here. They are quite different from each other.  Shangdong-like branch indicator, belongs to a different evolutionary lineage.
		In conclusion, our total number isolated around 278 strains were isolated in Japan.  H1 is 731, corresponding to 57.3 percent.  H3 is 546 isolated and B only one.
		In conclusion, as a result of what we followed up with virological surveillance, a total 1,278 viruses were isolated in Japan in this season.
		Second, of the total isolated, 731 corresponded to 57.3 percent was identified and they were separated into two distinct antigenic groups.  The first variant was similar to the A/Beijing/262.  And the second variant was indistinguishable from A/New Caledonia/29/90 strain.  This result suggests to us to change H1N1 vaccine strain from A/Beijing/262 to current epidemic strains such as A/New Caledonia strain.
		Third, the rest of 546 corresponding to 42.7 percent were H3N2 viruses and 93.5 percent of them were A/Sydney/5/97-like variant.  I am wondering if Sydney/5/97 viruses will still cause outbreak as a major epidemic strain in the forthcoming winter months.  Having considered, we may cancel A/Sydney/15/97 as a vaccine strain and consider the use of current epidemic strain in 2000-2001 season.
		Fourth, regarding the vaccine strain of Influenza B viruses, we need, Japanwide, more information because we isolated only one strain in the season.
		Finally, H5N1 and H9N2 viruses still co-circulate in poultry and wild birds in Southern China.  Additionally, co-circulation of H9N2, classic swine H1N1, and human H3N2 viruses in swine population in Southern China suggest to us that influenza in the world in the 21st century may encounter the crucial issue.
		Thank you very much.
		CHAIRMAN GREENBERG:  Thank you very much, Dr. Nerome.  Roland, do you have any questions?  Are there any questions of the panelists for Dr. Nerome.  If not, we'll take a break.  And I'm going to try to catch up a little bit here, so I would like for all of you to be back at ‑‑ it's now 10:34 by my watch.  10:50 I'd like you to be back and Roland will start.
		(Recess.)
		CHAIRMAN GREENBERG:  Okay.  I'd like to continue with Dr. Levandowski talking to us about vaccine responses.
		DR. LEVANDOWSKI:  Okay.  Thank you, Dr. Greenburg.
		Some of the material I'm going to cover has been mentioned in passing in some of the other presentations.  I'd like to point out that we haven't really gotten all of the information that we would like to have and, as was pointed by Nancy Cox, there are some serologic studies that I don't have reflected in the material that's been handed out only because that information is so new.  We tried to do the best we can to have as much up-to-date data as possible.
		CHAIRMAN GREENBERG:  Hold on.  People with cell phones are in big trouble.
		(Laughter.)
		Especially if they're FDA staff.
		(Laughter.)
		DR. LEVANDOWSKI:  Okay.  So I'll continue.  I'm going to talk about the 1999 vaccine studies.  For the convenience of the committee and anybody who has one, the handouts include all the overheads that are going to be used to present the serologic responses.  What I'm going to try to do is to summarize the information that's contained in materials that have come from a number of different sources and have been provided for committee review.
		I should point out that the serologic data do reflect this ongoing very major international collaborative effort.  And it's greatly facilitated and largely possible because of the commitment by the World Health Organization and its influenza centers to collecting information.
		If we can go to the first overhead, it should be page two in the handout.  This overhead shows the serum panels that are used for the serologic studies, which include three separate sets of serum panels from adults and elderly in Australia, Europe, and the United States.  The vaccines used for immunization are shown on the table, I hope.
		And I call your attention to the vaccine that was used in Australia, which includes as the B component B/Harbin/07/94.  Data for the Influenza B viruses for the Australian sera are being presented since they provide quite a lot of information that's very similar to the data from vaccines containing the B/Yamanashi/166/98 strain.
		The laboratories participating and performing the serologic testing include the WHO Influenza Center in Melbourne, Australia; the National Institute for Biological Standardization and Control in London; the Centers for Disease Control and Prevention in Atlanta; and the Center for Biologics Evaluation and Research in Bethesda.  The labs share these sets of sera, as shown, and it accounts for approximately 175 serum pairs.
		Next overhead, please.  This is on page three; it should be.
		This slide shows the H1N1 antigens that were used for serologic testing for the material that are presented.  Not every one of these antigens was used by all the laboratories, but they were used in different places to try to explore a variety of new antigens.  A core of the antigens is, however, tested in each of the laboratories and that's used as a comparison between the laboratories since there are known technical differences between each of our labs in terms of serologic testing.
		The serologic studies have been performed in two separate campaigns coinciding with the World Health Organization recommendations for the Southern Hemisphere in September of 1999 and the current evaluation of influenza viruses.  The antigens shown include representative strains for both of the H1N1 lineages that are circulating and it includes strains related to the A/Beijing/262 strain, which is the current vaccine strain and the A/Bayern/07/95-like strains.
		Next overhead, which is page four.
		This overhead shows results obtained in September 1999 from two of the participating laboratories using a panel of sera from elderly in Europe.  The table includes data on geometric mean titers; the percent greater than or equal to 32 or 40 for the titers; and the percent fourfold rises.  The data that are shown here are from the Center for Biologics at the top and from WHO Melbourne at the bottom.  And the vaccine strain was A/Beijing/262/95.
		The vaccine used was immogenic and it produced homologous antibody responses.  In this particular instance, the A/New Caledonia and the A/Nanchang are A/Beijing/262-like strains and the A/Johannesburg is a Bayern/07/95-like strain.  In both cases, the A/Beijing/262 vaccine produced antibodies that cross-reacted well with the Johannesburg strain.  However, the other Beijing/262-like strains were not well-inhibited by the sera produced in response to the vaccine antigen.  In both of these instances, there was a reduction in the geometric mean titer of more than 50 percent.
		Next overhead, which is page five.
		This overhead shows results that were obtained in January of this year from two of the laboratories using a panel of sera from adults in Europe.  These data are from NIBSC at the top and from CDC at the bottom.  The vaccine strain, again, was A/Beijing/262/95.  A/New Caledonia; A/Madrid; A/Wisconsin; A/Nanchang; and A/Peru are all A/Beijing/262-like strains.  And A/Johannesburg ‑‑ and I hope I'm right on all these because I'm a little confused myself ‑‑ A/Hong Kong; and A/Argentina are Bayern/07/95-like strains.
		Again, the vaccine elicited good responses to the vaccine antigen and to the A/Bayern-like strains, but the response to the new A/Beijing/262-like strains was reduced by more than 50 percent in most of the instances.
		Next overhead, which is page six.
		Moving on, this slide shows the Influenza B viruses that were used for serological testing.  The antigens shown include representative strains for both of the B lineages that are circulating and includes strains that are related to B/Harbin/07/94 or B/Yamanashi/166/98, the vaccine strains.  And to the B/Victoria/287-like strains.  For the most part, these serologies have been done with ether-treated Influenza B antigens, but there are some exceptions but I'm not going to go into that on these slides.
		Next overhead on page 7.
		This overhead shows the results that were obtained in September '99 using a panel of sera from adults in Australia.  The data are from CBER at the top and from the World Health Organization, Melbourne, at the bottom.  The data demonstrate that the current vaccine strain produces antibodies at somewhat reduced titers for some of the newer B/Yamanashi-like strains.  For the B/South Australia strain, for example, there is more than a 50 percent reduction in titer shown as compared to the vaccine or vaccine-like strain.
		In addition, as has been previously seen for several years, the antibody titers are extremely low against the newer B/Victoria-like strains, such as B/Shangdong/07/97 and B/Sichuan/40/99.
		Next overhead which is page eight.
		This overhead shows results that were obtained in January of this year using a panel of sera from adults in the United States.  The data are from CDC at the top and from the WHO Melbourne at the bottom.  These data demonstrate that the current vaccine produces antibodies that cross-react reasonably well with other new B/Yamanashi-like strains such as B/Tennessee/4/99 and B/Shanghai/180/99.  However, antibody titers are reduced by more than 50 percent against the B/Shenzhen/654/99 strain, which, again, is in the same lineage as the current vaccine stain, B/Yamanashi/166.  And I think you can see that in both of these serum panels, that there's a fairly marked reduction for that particular strain.
		Next overhead, which is page nine.
		This overhead shows results that were obtained, again, in January of this year using a panel of sera from the elderly in the United States and the data are from the CDC at the top and from the Center for Biologics at the bottom.  The data, again, demonstrate the current vaccine strain produces antibodies that cross-react reasonably well with many of the newer influenza viruses that are in the B/Yamanashi lineage. But, in the CDC data, again, you can see that the titers for the B/Shenzhen/654 virus are markedly reduced as compared to the vaccine strain.
		We're going to skip over page 10.  Go to page 11.
		This overhead shows the H3N2 influence viruses used for serologic testing.  And, actually, this doesn't even show all the viruses that have been used, but I included most of them here.  The antigens chosen, again, are currently circulating strains that are representative of these A/Sydney/5/97-like strains that are the current vaccine strain and also strains that appear to be less well inhibited by ferret antisera raised against the A/Sydney strain.
		I think we'll skip over to page 13.  And this overhead shows results that were obtained in January of this year using a panel of sera from elderly in the United States.  The data are from the Center for Biologics at the top and from WHO Melbourne at the bottom.  And what they show is that the responses to the newer H3N2 strains were, for the most part, similar to the vaccine strain.  However, a notable exception to this is, for the A/Philippines ‑‑ and I guess I've got a typo there.  I think this is supposed to be "'99" ‑‑ that the A/Philippines/26/99 strain shows a very marked reduction which is more than twofold in the test that was done at WHO in Melbourne.
		Next overhead, which is page 14.
		This overhead shows results, again, that were obtained in January of this year using a panel of sera from adults in Europe and the data are from CDC at the top and from NIBSC at the bottom.  These data demonstrate reductions in titer against some of the newer viruses, including the A/Moscow/10/99 strain; the A/Shanghai/42/99 virus; and the A/Panama strain.  The data from NIBSC also indicate that there are good antibody titers against the A/Shenzhen/510/99 strain.
		Okay, skip ahead to page 16 and I'll try to put this into a summary form.  The following tables show the frequency with which we found new test antigens given a 50 percent or greater reduction compared to the current vaccine strain.  50 percent is used here as an arbitrary breakpoint since it does represent a twofold reduction, which in geometric mean titer terms is fairly substantial.
		The data included in this table are for antigens that were tested in more than one lab where possible, but antigens that were tested in a single lab are included where they are of particular interest.  I've not included everything that's been done here.  It should be noted that not all of the testing has been completed, so there are, obviously, some holes in some of these tables we're going to see.  In this particular table, the antigen at the top is one of the Bayern/07-like strains and all the others are Beijing/262-like strains.
		I'd just like to call your attention to the last columns here, for the moment, although you can look at the individual data as well.  But the data for the Johannesburg strain indicates that that strain was quite well-inhibited by antisera in all of the tests that were done from sera that were collected using current vaccine strains.  Somewhat paradoxically, if you look at all the A/Beijing/262 lineage viruses, including the A/New Caledonia; the A/Nanchang; A/Peru; A/Wisconsin; and A/Madrid, on average there were reductions that were greater than 50 percent overall, as shown at the end, here.  And, in some instances, they were quite substantial, in some of the serum panels that were tested.
		Next overhead, please, which is page 17 in the handout.
		This slide shows summary data for the Influenza B viruses.  The top two strains here are B/Victoria-like strains.  The bottom six strains are like the vaccine strain B/Yamanashi.  Some of these B/Yamanashi-like viruses appear to be less well-inhibited by sera from persons who have been immunized with the current vaccines.  However, many of the strains do not appear to be well-inhibited at all, which suggests that some antigenic drift may be going on.
		And I just call your attention to some of theses strains that have been tested in multiple laboratories.  In particular, the B/Shenzhen/654/99, which Nancy Cox mentioned as being a new variant virus.  As expected, the B/Victoria lineage viruses were not well-inhibited by the current vaccines and there's more uniformity in finding, really, the most marked reduction in antibody titers for those strains as compared to the vaccine strain.  That's not news; that's what we've been seeing over the last several years.
		Next overhead on page 18 will show summary data for the H3N2 viruses.  All of these strains are related to the Sydney vaccine strain, but the table includes some of the strains that are less well-inhibited by ferret sera A/Sydney.  The most marked reductions in this table are for the Shanghai/42/99 strain and for the A/Philippines strain.  In both of those instances, there's a substantial, greater than 50 percent, reduction in titer.  But you can see that there's sort of variability amongst these strains from really not much reduction in the tests that have been done so far to really quite marked reduction.
		Okay, so slides off.  So, in summary, the vaccines that were used for the clinical studies were immunogenic in the populations tested.  And for all of the three vaccine component strains, there is some evidence of antigenic drift, which is probably most notable or most obvious for the H1N1 virus strains, which represent drift variance, I guess, or drift of a sort from the current vaccine strain.  As we've known for several years, the B/Victoria lineage persists and the current vaccines are probably of limited protection against those strains.
		And that's all I've got to say.  I'll stop there.  I hope we're getting back on time.  And if there are any questions, I'll be happy to try to answer them.
		CHAIRMAN GREENBERG:  Panel members, do you have any questions for Roland?  Okay, if there are no questions, we will move on to availability of strains and reagents by Mr. Offringa.
		MR. OFFRINGA:  If I could have the first overhead.
		I'm just going to give a brief overview of the vaccine strains, current candidate strains, and potency reagent availability.  I'll start with the H1N1 strains.  The current vaccine strain is A/Beijing/262/95.  The reassortant used for vaccine production is X-127, which has a high-yield growth character.
		There is one H1N1 candidate strain which is A/New Caledonia/20/99.  This is also in the Beijing/262 lineage.  There are two reassortants available for New Caledonia:  IVR-116 and X-139.  The IVR-116 has a moderate-to-high yield growth character and the X-139 has a moderate yield growth character.  The IVR-116 reassort is currently being used to produce vaccine for the Southern Hemisphere.
		I'll continue with the B strains.  The current B vaccine strain is B/Yamanashi/166/98, which is in the Yamagata lineage.  Influenza B reassortants are not available, so the wild-type strain is used for vaccine production and this wild-type strain has a moderate yield and growth character.  There's currently one candidate strain distributed to manufacturers, which is B/Johannesburg/5/99, also in the Yamagata lineage.  Unfortunately, all manufacturers have experienced a very low yield with this strain.
		And I'll continue with the H3N2 strains.  The current vaccine strain is A/Sydney/5/97.  There are two reassortants being used for vaccine production:  IVR-108 and RESVIR-13.  Both of these reassortants have a moderate-to-high yield growth character.
		We also, again, have one candidate strain distributed to manufacturers, the A/Panama/2007/99, which is a Sydney-like strain.  There are several reassortants distributed to manufacturers:  the NIB-41 and NIB-42.  Both of these strains exhibit a moderate yield growth character.  And then we have recently isolated two Panama reassortants in our laboratory:  RESVIR-16 and RESVIR-17.  We are going to distribute these to manufacturers next week and hope to get some information on their growth character shortly.
		I'll move on to availability of potency reagents.  For all current vaccine strains, the Yamanashi/166/98; A/Beijing/262/95; and Sydney/5/97, we have reagents available.  We are currently also distributing New Caledonia IVR-116 reagents from the Therapeutic Goods Administration in Australia, which are being used for testing of Southern Hemisphere vaccine.  And our IVR-116 reagents will be available by February.  If any other strains are chosen, those reagents would not be available until May at the earliest.
		If there are any questions?
		CHAIRMAN GREENBERG:  Thank you very much.  Panel have any questions?  Okay.  We're moving on to manufacturers' comments and this is Dr. Slusaw.
		DR. SLUSAW:  Thank you.  Roland noted I had 30 seconds so that he could get the agenda back on track.
		(Laughter.)
		I don't envy the task before the committee today of selecting the strains for the next influenza vaccine season.  It's really, I guess, all about balancing and trying to find the best antigenic match for the strains you anticipate will be circulating during the next season, yet selecting strains that also have appropriate growth characteristics so that they are practical to use to make vaccine.  And also doing that selection in a timely fashion which allows the manufacturers time to produce the required vaccine within the timeframe that it's needed.
		There are several critical key pieces of the puzzle that have to fit together to support vaccine manufacturing.  The first is egg supply.  In the U.S., the flu vaccine manufacturers probably consume about a half million eggs per day during a six-to-eight month period while the monovalent concentrates are being manufactured each season.  The good news is that this is a pretty predictable process and we have a fine-tuned and robust system in place that ensures the availability of embryonated eggs for vaccine manufacturing.
		Something that we're talking about a little bit more today is selection of seed viruses and also another component of that, preparation of high-growth reassortants.  And it would not be possible to produce the numbers of doses we talked about for last year, for example, 80 to 90 million doses, without the availability of high-growth reassortants prepared by Dr. Levandowski's and Dr. Kilbourne's laboratories as well as laboratories in Europe and Australia.
		And then, finally, the third critical piece is the availability of the potency test reagents.  Until we have prepare the reference antiserum and the reference antigen and those reagents have been calibrated, we have several disadvantages.  One is that we don't know precisely the amount of vaccine we're manufacturing.  Although we can estimate that number, it can be off by quite a bit.  So we run the risk of producing too much or not enough of a particular component.  And, of course, until we can measure the potencies, we can't formulate the trivalent vaccine so the rest of that process is dependent on having the potency test reagents completed.
		A bit of a timeline to illustrate a normal flu vaccine manufacturing season, if there is any such thing.  Generally the process begins about a year in advance when the egg suppliers order their birds to support the egg supply for the following vaccine season.  These pullets are housed usually in October or November, and this is really the only time during the year when an egg supply is not available.
		An ongoing process that usually begins sometime in fall and continues through the early part of the year is receiving candidate seed viruses.  And, kind of in parallel with that, the preparation of high-growth reassortants.  Now this is, of course, one of the first stages where surprises can come up and things can begin to go wrong.  An example is what we've heard this morning with the A/Moscow reassortant, for example.  There's a bit of black magic involved and things don't always turn out as expected.
		The manufacturers hope to come away from this meeting with at least the first strain selection at this time.  Two would be nice, but I think in a typical year we expect one.  And then following at about four week periods, the second and finally the third strain selection.
		As the strains are selected, production of the monovalent components of the vaccine proceed.  Many manufacturers, both in the U.S. and some in Europe, actually start production of the monovalents in January, before the official strain selection.  And that's a bit of a risk.  We can make educated guesses based on the latest surveillance data at the time, but it's a bit of a risk that must be undertaken in order to support the number of vaccine doses that must be manufactured in the time period.
		The next surprise in the process, of course, can occur at the stage of producing the vaccine components.  Although we receive the candidate strains and have an opportunity to evaluate and test them a bit, especially on small-scale, once those strains are scaled up to large-scale production, there may be surprises with the growth characteristics or the purification properties of the virus that can affect the yields and the final availability of doses.  And then, of course, in the same timeframe, the preparation of the potency test reagents for SRID testing.
		Then normally we would expect to bulk the first vaccine in the beginning of June and then after the appropriate testing and release is completed, the license is generally issued the first week in July and vaccine distribution will begin.  And that'll proceed through about the first or second week in October.  And, especially in recent years, this has become kind of a hard cut-off date and any vaccine that's available after that time period generally either won't be sold or will be returned by the customers.
		I wanted to try to put together a little bit of an illustration about some of the things that begin to go wrong if strain selection is delayed for any reason.  And, of course, it pushes out the timeframes for the availability of the candidate viruses as well as the high-growth reassortants.
		And in this illustration, supposing third strain selection is pushed out a months or so, one of the first bad things that happens is there may be a gap in production of the monovalent concentrates at this point.  If a manufacturer has made all of the required first and second strain, rather than overproduce something that won't be needed, we may actually have to wait until the third strain is available and then resume production.  The downside of that, of course, is that the chickens and the egg supply can't be turned off, so manufacturers and egg suppliers have to absorb that cost of, say, a half million eggs per day, which are essentially just be discarded.
		Then, of course, this gap in production here can translate into an extended production cycle at the end of the program.  And, again, that can also delay the availability of the SRID testing reagents and pushing out the bulk vaccine preparation and perhaps the license issuing.  And the really critical factor here is that we lose this window of opportunity for vaccine distribution and continue to distribute vaccine as normal, but rather than just simply pushing out the timeframe into the November part of the year, these vaccine doses essentially won't be used by the marketplace.
		Any questions or comments?
		CHAIRMAN GREENBERG:  Panel?  It's clearly a treadmill.  Okay.  If not, thank you very much.  And now Roland's going to lead us in ‑‑ yes?  There is a short break, but you just broke.  You're strong.  We don't need it.
		DR. LEVANDOWSKI:  Okay.  I would like to lay out what we see as some options for the 2000 to 2001 influenza vaccine composition and just go over the different possibilities here.
		Okay.  Take that off.  We're not ready for that.
		(Laughter.)
		Influenza A viruses of the H1N1 and H3N2 subtypes and also Influenza B viruses have continued to circulate in human populations and there's been discussion here in the past about eliminating one or more of the components of the vaccine, but I think what we heard today is that all three strains that are currently in the vaccine and more are alive and kicking out there.  Therefore, the first thing to consider is what the valency of the vaccine should be and I would argue that the vaccine should continue to be a trivalent vaccine.
		As far as the Influenza A viruses, the H1N1 types, strains similar to the A/Beijing/262/95 strain have now been found in all areas of the world and what we've seen this morning is that those strains are undergoing antigenic drift.  The human serologic responses suggest that the current vaccines are immunogenic, but that the predominant new A/Beijing/262/95-like viruses are poorly inhibited.
		The vaccine candidate strains, such as the A/New Caledonia/20/99 are currently available and being used for production for vaccines for the Southern Hemisphere.  So there is some manufacturing experience with that strain as well.  So options.
		Now the first overhead, the options for the H1N1 viruses.
		The first option would be to maintain the current vaccine strain.  In favor of that is that the current vaccines appear to be highly immunogenic.   And, in addition, manufacturing is well-defined and it's predictable at this point from having had the experience.
		Against that are that the strains are demonstrating antigenic drift and those antigenic drift strains have been found in all parts of the world.  In addition, heterologous serologic responses to the H1 deletion strains are clearly reduced.
		So another option, on the next overhead, for the H1N1 viruses, would be to change the current vaccine strain to a more recent strain.  And in favor of that, the more strain could possibly provide a better antigenic match with the current H1N1 strains that are circulating.  In addition, there are vaccine candidate strains, such as this A/New Caledonia/20/99, that are available and they've been used for manufacturing vaccines for the Southern Hemisphere.  Against that, we don't really have information on the immunogenicity of a New Caledonia-like vaccine.
		So the third possibility would be, for the H1 strains, to defer this selection to accumulate some more data.  In favor of that is that there may be some additional data that would further refine and clarify the position.  But against that is that it doesn't appear that it's likely that there will be much more information coming in over the next several weeks because there have not been, except for Japan, there have not been a lot of H1 strains that have been isolated.
		Okay.  Overhead off.
		For the Influenza B viruses, the strains of Influenza B in the Yamagata/16/88 lineage have predominated, with strains that are similar to the current vaccine strain, which is B/Yamanashi/166/98, islated in the Americas, Europe, Africa, Australia, Asia, and essentially the whole world.  A new variant in that lineage has been identified just in the last week.  And therefore its possible significance has not really been assessed completely.  Strains of the B/Victoria/287 lineage continue to appear in Asia, as has been true for several years, but the relative frequency of these strains appears to be diminishing at this type.
		The sera from people who are immunized with the current vaccines inhibit some of the current B/Yamanashi-like viruses well, as previously current vaccines did not produce antibody responses to the B/Victoria/287-like strains.  And I should add that some of the B/Yamanashi-like strains are also not well-inhibited by the current vaccines.
		There's limited information at this time on other vaccine candidates, as we just heard.  However, the strain that has been examined really does not appear to grow very well and, for that reason, would probably not be a very desirable candidate.
		So the options for B, the first overhead here, the first option, of course, is to maintain the current vaccine strain.  And in favor of this would be that most of the strains worldwide are similar to the current vaccine strain.  The vaccines appear to be immunogenic and, again, manufacturing is well-defined and predictable.  But against that is that recent Yamanashi-like strains are not clearly well-inhibited by the post-immunization antisera.
		So the next option would be, again, to change the current vaccine strain to a more recent B/Yamanashi-like virus.  In favor of that is that the vaccines could be antigenically closer to the current Influenza B viruses.  But, against that, we don't really know that there would be a clear advantage based on any antigenic characterization that's been done so far and there really are no superior alternate vaccine candidate strains at this time.
		So option three is, again, to defer to accumulate more data.  In this case, in favor of this option would be that there are more data that are likely to be available in the next two-to-three weeks, including analysis of these new Chinese Influenza B viruses that have been sent to CDC recently.  Against that is that additional data may not really alter what the current considerations are, once all the information is in.
		You want to take the overhead off?
		For the Influenze H3N2 A viruses, there is antigenic heterogeneity that's continuing among these strains, as there has been in the past year or more.  And approximately 10 to 15 percent of the strains are antigenically distinguishable from the A/Sydney/5/97 vaccine strain.  And, again, that heterogeneity has been found widely, not only in the United States, but in most areas of the world.
		From that information, there is not a clear antigenic or genetic pattern to suggest a group of antigenic variance that might become the predominant one.  The antisera to some of these newer H3N2 strains appear to inhibit many of the current strains reasonably well, but serologic responses are reduced against some of the recently emerging and antigenically divergent strains.  Although vaccine candidate strains and high-growth reassortants for some of these are available, it's not clear that the vaccine candidates currently available will offer an antigenic advantage.
		So, again, the options for the H3N2 virus.  The first option would be to maintain the current vaccine composition and that was a strategy that was used last year in view of much of the similar kind of information.  In favor of this would be that manufacturing is well worked out and the yield is predictable.  But against that is that there is this antigenic heterogeneity and 10 to 15 percent of the new H3N2 viruses are distinguishable, readily distinguishable, from the A/Sydney/5/97 strain.
		Some of these recent strains are not well-inhibited by post-immunization antisera.  And the current vaccine strain has been in use for the past two seasons and the A/Sydney-like strains have predominated for the past three years, which is a distinctly unusual situation to be in, particularly for the H3N2 strains.  That's really unprecedented in the last 20 years or more.
		So the options for the H3N2 virus.  Again, the first option is that we could maintain the current vaccine composition and in favor of that is that manufacturing is well worked out and the yield is predictable.  But against that, there is antigenic heterogeneity and 10 to 15 percent of the new viruses are distinguishable from the A/Sydney strain.  The most recent strains are not well-inhibited by post-immunization antiserum and the current vaccine strain has been ‑‑ did I say this already?  What am I doing?  Sorry.
		CHAIRMAN GREENBERG:  It's okay.  We're slow learners.
		(Laughter.)
		DR. LEVANDOWSKI:  Pardon me.
		So option two.  This is what I really meant to say.  We could change the current vaccine strain to more recent.  And in favor of that, 10 to 15 percent of the recent strains are poorly inhibited.  It could be possible to achieve a better antigenic match with the recent strains.  And there are some alternative strains that are available for production.
		Against that would be that the choice of the strain could benefit from additional epidemiologic, serologic, and manufacturing information.  We really don't have all the data in that we'd like to have.  It's not clear that the available strains are superior to the current vaccine strain, however.  And there is little information on the potential for vaccine production with any of these new strains, except for a very little bit of information for these Panama reassortants that's been mentioned.
		So the final option of these four is number three, which is to defer to accumulate more data.  And in favor of that, there will probably be significantly more data for these more recent strains over the next two to three weeks.  And since the H3N2 strain is the one that's most likely to cause significant mobidity and mortality, this choice is one that should be really very carefully made.  Against that, of course, is always that the additional data may not alter what we know from the current conditions, considerations.
		So I'll stop there.
		CHAIRMAN GREENBERG:  Roland, that was a very clear, at least to me, delineation of options.  Now I'm sure the committee will come up with some other options, but that was very helpful to me.  And I think we had planned for discussion after lunch, but I think we have some time now and I think it would be wise to see how far we get in discussion.  So I'm going to open that up for discussion.  And you can sit here, but I suppose most of the questions will be ‑‑ Dr. Estes first.
		DR. ESTES:  I have one question that hasn't been brought up yet today.  We have a new potential factor in flu variation and that's the introduction of neuraminidase inhibitors this last year.  And I wonder are there studies that are looking at flu coming out of areas where these inhibitors are being used extensively to be sure that we're not putting a new pressure, there will be a new virus that's now going to pop up in the next month or so?  I'd just like to hear people's opinions.  Others must be worrying about this.
		CHAIRMAN GREENBERG:  Anybody with expertise can answer that.  Dr. Cox.
		DR. COX:  I can at least give a partial answer.  This has been of concern because the viruses that are resistant to the neuraminidase inhibitors have been found to have mutations both in the neuraminidase itself and also in the hemagglutinatin and, of course, the concern is that you might be driving antigenic change.  But it also should be stated right up front that it's much more difficult to generate resistant strains to the neuraminidase inhibitors than it is to the older antivirals, symantodyne and rhymantodyne.
		So the manufacturers are now working together to set up a susceptibility network and they will be looking not only at field strains, which are collected by CDC and other WHO colloborating centers, but they will also be attempting to obtain isolates from individuals before treatment and after treatment to look at changes that occur.  So I think that monitoring should be sufficiently good to give us a good idea of what's going on.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  This is sort of a general question, but to what extent does mass vaccination versus targeting high-risk groups contribute to antigenic drift of strains included in the vaccine every year?
		CHAIRMAN GREENBERG:  Again, anybody of our experts who wants to answer questions, I think.  Roland, do you want to tackle that?
		DR. LEVANDOWSKI:  Well, I don't think I have a good response for it, but when you're saying the term "mass vaccination," I don't believe we've used what's really mass vaccination in the United States at any point.  Possibly the closest thing to that experience would be in Japan where all the children were immunized for some number of years, all the school children.  But I don't know that there are, from any studies done there, that there was any impact on epidemiology of spread of influenza.  I'm not sure whether Dr. Nerome would have any comments on that or Dr. Cox.
		MS. FISHER:  I wasn't speaking of children.  I was thinking the increase in the elderly and in healthy individuals.
		DR. LEVANDOWSKI:  Yes.
		MS. FISHER:  Does it put pressure on the strains in the vaccine to change?
		CHAIRMAN GREENBERG:  Dr. Cox is looking like she wants to answer.
		DR. COX:  I don't think that there's any way to give a definitive answer.  But such a small proportion of the world's population is vaccinated at the present time that we would not expect that vaccination could be contributing significantly to antigenic drift.  Many of the new strains do emerge from Asia and immunization rates in Asia, with influenza vaccine, are very low.
		DR. LEVANDOWSKI:  There may be some data from the pre-immunization era.  We've only used influenza vaccine since the 1940s and there are studies looking back, seroarcheology, to see what had happened.
		And I believe Dr. Daudle has published some paper describing one of the events that was originally thought to be an antigenic shift, that is a complete change in hemagglutinin being more like a substantial antigenic drift some time near the end of the 1800s, beginning of the 1900s.  I don't remember the exact epidemic or outbreaks that are described from that paper but it has been described previously that there are major antigenic changes that occur, short of an antigenic shift that would cause a pandemic within influenza viruses in the past.
		CHAIRMAN GREENBERG:  I think, just for me, Dr. Cox's answer was a compelling one that the world is susceptible to influenza and the amount of vaccine given to the world at this point is very small compared to the amount of people who are infected.  But it's an interesting question.
		Dr. Daum and then Dr. Kohl.
		DR. DAUM:  I'm actually very interested in that question and would like to sort of push the envelope a little bit further.  Leaving the world aside for a moment and focusing just on the United States where we're distributing 70 or 60, I don't know the exact number, million doses of vaccine a year and we have very little B activity, relatively speaking, very little H1 activity, relatively speaking and lots and lots of H3 activity, relatively speaking.  We've had this Sydney-like H3 member of the trivalent vaccine in the last few years.  And couldn't we make any inferences at all about the kinds of viruses that are circulating and the types of vaccines the committee has chosen in years past?
		For example, one might say, in a naive way, the B vaccine works great; the H1 vaccine works great; and the H3N2 is not working because it's still circulating, despite 60 or 70 million doses of vaccine being circulated.
		So I'm wondering, is there anything to be gained from what we've done with previous vaccines and what's actually been circulating in the community in spite of or in concert with this large vaccination effort?
		CHAIRMAN GREENBERG:  Dr. Cox.
		DR. COX:  I think that what we're seeing with regard to circulation of H3N2 viruses versus B and H1 is a reflection of what's occurring globally.  I mean, if you remember the first slide that I put up for each of the different groups of viruses, what we were seeing in the United States or what we're seeing in the United States is pretty representative of what we're seeing globally.  And the vaccine coverage in the United States is higher than it is in many other regions of the world.
		So I think it's very difficult to say that we're not having H1N1 because the vaccine is working well or we're not having B because the vaccine is working well.  It's a very complex interaction of the host, the immune background, and the virus itself, how transmissable it is, how different antigenically it is, and so on.  And those host and virus factors are what determine which strains circulate.
		I think we have a tremendous amount to learn and there are some very interesting modeling techniques that we'd like to use to try to help us understand the way viruses are changing and the epidemiology of the circulation of the different strains.
		DR. HOKE:  Thank you.  One population that is immunized in what might be called a mass way is the military recruit populations and they are universally immunized against influenza and carefully monitored for respiratory diseases rates.  It has an important impact on training.  And when rates exceed a certain threshhold, investigations are conducted.
		We've long recognized that if there were strains of influenza that circulated that, for example, against which vaccine could not protect, that that would be a very good sentinel population in which that would happen.  And, to my knowledge, the kind of instance that you inferred that there might be a sudden shift in that population, highly immunized as a sort of source of a new strain that emerged under pressure, I don't know that that's ever happened.  I haven't combed back through the data.
		But I should say, on the other side, that, through the use of influenza vaccine in association with adenovirus vaccine, that respiratory disease rates in military recruits are suppressed to very, very low levels.  And this is really a population that would be highly susceptible to transmission of respiratory viruses.  So that, you know, anecdotes of isolates from people who had been immunized notwithstanding, I think that the almost complete suppression of influenza in military recruits under a universal immunization policy is rather compelling information about the effectiveness of the immunization.
		CHAIRMAN GREENBERG:  I would guess also that recruits are a somewhat isolated population, especially isolated to children more than the general population, which might help the vaccine work a little better.
		DR. HOKE:  Well, that would depend on where the training force post was, but generally they are embedded in communities.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  I don't know if this is premature, but I think I, for one, feel we can start focusing on some of these viral selections and, to use a phrase earlier, one is a no-brainer, I think.  And the no-brainer is the H3N2.  It looks like we should hold off on that selection pending, quote, "significant new data."
		CHAIRMAN GREENBERG:  I want to make sure that ‑‑ if the panel feels that they've asked enough questions to help Roland give recommendations, I'm not against moving ahead with that.  Roland, is that okay with you?  And we can start with each one.
		Are there any further questions from anybody in the panel?  Dr. Couch.
		DR. COUCH:  Well, mine was just a question for clarification that I neglected to ask Dr. Hampson.  Just to be sure I understood that all of the Influenza B experience in Thailand and in New Zealand and in the Southern Hemisphere was the Yamanashi-like virus, not anything related to the B/Shenzhen that's now being considered as perhaps something different.
		DR. HAMPSON:  No, there we haven't any of the Shenzhen-like virus.
		DR. COUCH:  So those would fit with the previous classification of these.
		DR. HAMPSON:  Yes, the B viruses that we have found throughout our area of surveillance are the B/Yamanashi-like viruses.  We're showing some percentage of them with a degree of drift, react about two to fourfold down with the B/Yamanashi antiserum.  And more closely related to the B/Johannesburg is our current updated reference strain.
		CHAIRMAN GREENBERG:  Dr. Ferrieri.
		DR. FERRIERI:  I just want to second what Dr. Kohl said.  We will have more data in about two to three to four weeks about alternative strains and so I don't know that we need extensive discussion on the H3N2 status.
		CHAIRMAN GREENBERG:  Well, what I would, since I think everybody feels they're ready to go, I think I'll just move around and we can take one virus at a time.  I'm going to switch to the left-hand side of the table here.
		(Laughter.)
		And I see somebody, an expert in influenza down there.  So, Dr. Couch, why don't we start with the ‑‑ does everybody want to start with the big guy, H3N2?  Because I've had two people say let's start with the H3N2 and our recommendation there.  Is that okay with the panel?  We'll start with that component and what we think?
		I think we were presented by Roland three possibilities.  One, to recommend staying with the current.  Two, to identify a new candidate.  And, as best I can tell, there's only one candidate that could be identified at this moment and that's the Panama reassortant that is there.  Or, three, to wait some period of time while more serology and analysis of new viruses is done.  And we were told that since ‑‑ and Roland clearly, I think, tipped his hand as to what he thought since he said this is by far the most important, usually the most important virus and the most information we could have, the better-off we'll be.
		So I will start with you as to what you're recommendations would be.
		DR. COUCH:  Well, I will do one and then let's move down the table on the left.  How about that for the others?
		Well, actually, I'd like to first of all compliment industry on their efforts, which those of us who've got institutional memories know that industry used to be relatively intolerant of not making all three decisions at this time.  And that was always extremely difficult.  And then they gave us one.  And now they're giving us three.  So we really only have to make one for sure at this time and they've set up a schedule that we've all certainly got to try and live by.
		And so I think that's a major improvement over the way, if you want to go back 10, 15 years, the way these decisions were made in the past.  And so I think they ought to be complimented for that accommodation to make this decision a little bit more definitive.
		So if you want to start with the three, I guess I'd consider that ‑‑
		CHAIRMAN GREENBERG:  Could I interrupt for one second?  I am told ‑‑ excuse me, this is my parliamentary naivete.  But before we start voting from the panel, I was supposed to ask for public comment and I apologize to the public.  This is purely my inability to follow schedule correctly.  Please step up to a microphone and identify yourself.
		MR. RUBIN:  Yes, Mr. Chairman.  I'm Fred Rubin.  I've worked for Aventis Pasteur.  We are one of the manufacturers of influenza vaccine.
		I think one consideration that hasn't been mentioned here.  I'm sure some people know it, but maybe not everybody and that's that the ACIP at its October meeting voted to lower the high-risk age group to 50 and that, I think, constitutes a sizeable additional population of people.  And so the challenge is being put to industry to produce vaccine a little bit more than there's been in past years.  So rather than this being a trivial piece of information, I think it's a highly significant piece of information.
		If that policy, which they've voted on, is implemented, it's going to mean that we have to produce, in industry, you know between 25 and 40 million additional doses.  I could be off by, you know, a million or two here or there.
		So I think the putting off of the decision could have some impact.  So I think it's important for you to keep that in mind.  Even though you have to pick the right strain, we also have to provide enough vaccine for all these people.  And if we don't have time to do it, a policy that's voted on and then you can't implement it has terrible repercussions.
		CHAIRMAN GREENBERG:  That's very helpful.  And since I am now in the high-risk group ‑‑
		(Laughter.)
		‑‑ sort of startling to me.
		DR. COUCH:  Did you get your vaccine this year?
		CHAIRMAN GREENBERG:  No.  Are there any other comments from the public?  If not, again, I apologize for not having done that before.
		Dr. Couch, back to you.
		DR. COUCH:  Well, what I usually do ‑‑ I started it, actually, many years ago ‑‑ was what Roland put up there first.  I put down my strain, epidemiologic vaccine, and availability and mark my crosses on these things.  And I've been doing the same thing here I always do.
		And he, of course, enunciated all of the considerations very clearly.  And I've got a bunch of question marks and only one plus across under H3.  And it's a clear note and deferral is, as Dr. Kohl indicated, I suspect, based on where we stand right now, perhaps the last decision.  And if we hold to the industry schedule, that will be an April decision.  But we can decide whether one or the other is ready to go with the next decision.
		It's not the only one I think we have to defer, but H3 should be deferred.
		CHAIRMAN GREENBERG:  Dr. Hoke.
		DR. HOKE:  Am I supposed to talk about H3 or pick another one?
		CHAIRMAN GREENBERG:  Yes, we're doing H3 into now moving along on that one.
		DR. HOKE:  Yes, I agree with that.  I agree with that.
		CHAIRMAN GREENBERG:  So, for the record, Dr. Hoke agrees to defer decisionmaking for the time being on H3N2.  Dr. Kilbourne.
		DR. KILBOURNE:  Well, I think we have a population that's saturated with H3N2 right now.  I have not seen evidence today of any prospective strains that look as if they're going to be significantly antigenically different, so I think you have not only a well-vaccinated population, but one fraught with the disease itself.  So I suspect that even if one of those new strains were to come into the population next year and we stuck with Sydney, we'd still be okay.  Because there's enough cross-reactivity among strains so I think we could be comfortable.
		CHAIRMAN GREENBERG:  So, was that a vote to use Sydney now?
		DR. KILBOURNE:  That would be my vote.  Maybe I'm jumping ahead, but certainly it could be deferment as far as I'm concerned.
		CHAIRMAN GREENBERG:  So would you say to defer, pending new information?  Or do you say we have enough information at this moment to choose?
		DR. KILBOURNE:  In my view, we have enough to choose.
		CHAIRMAN GREENBERG:  Okay.
		DR. KILBOURNE:  But others may not agree, so I don't want to ‑‑
		CHAIRMAN GREENBERG:  No, that's the whole point of voting.  Dr. Couch.
		DR. COUCH:  Could I ask Ed a question?  What if we get antigenicity data on the neuraminidase and there are major differences between Sydney and say a couple of the recent strains?  Just in the neuraminidase.
		DR. KILBOURNE:  Then you put in a new neuraminidase.
		(Laughter.)
		CHAIRMAN GREENBERG:  I think Dr. Kilbourne has said that his vote is that there's enough information now to say that the manufacturers should go ahead with the current Sydney vaccine, that we do not have to wait.  Am I putting it ‑‑ did I not interpret what you said correctly?
		DR. KILBOURNE:  You did.
		CHAIRMAN GREENBERG:  Okay.  Thank you.  Dr. Cox.
		DR. COX:  My view is that, because we have H3N2 circulating widely now and there's always a delay between the time the viruses are isolated and sent to the state health departments or the intermediate labs and then on to the international collaborating centers, it would really be prudent for us to defer this particular recommendation and accumulate as much information as possible.
		CHAIRMAN GREENBERG:  Okay.  Dr. Ferrieri.
		DR. FERRIERI:  I support deferral and suggest that exploring not just the Panama strains, but the Shenzhen/510/99, although I may have missed some point.  But the antisera and inhibition of all of the new strains look superb for that, with a rare exception.
		CHAIRMAN GREENBERG:  Dr. Eickhoff.
		DR. EICKHOFF:  Well, I support deferral and yet I'm reasonably confident that, when we can defer no longer, we're going wind up with A/Sydney back in the vaccine.
		CHAIRMAN GREENBERG:  Dr. Daum.
		DR. DAUM:  I must confess to be having a difficult time with this.  I'm persuaded that deferral for the period of time talked about would still give manufacturers enough time to prepare properly for the season.  And, given that and the possible availability of new information in a timely way, why not have new information?
		But I share Dr. Eickhoff's view.  I don't think there's going to be likely to be a change here and I'm not sure we have enough confidence in what the new information's going to be that's going to drive that.
		CHAIRMAN GREENBERG:  Dr. Edwards.
		DR. EDWARDS:  I would vote for deferral.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  I don't feel comfortable making this decision.  I would defer to Dr. Cox and others.  However, I do want to make a statement.
		I do think some attention has to be paid to increased mortality among those who got flu this year, particularly looking at what their vaccination status was.  And, also, you know, as flu vaccine coverage increases, especially among the elderly and healthy persons under 65 in the U.S., perhaps there should be an investigation of whether vaccinated persons are losing cell-mediated immunity acquired from natural infection and are becoming more vulnerable to both vaccine-strain flu infection and increased mortality from the flu complications such as pneumonia caused by other infectious organisms.
		CHAIRMAN GREENBERG:  Dr. Faggett.
		DR. FAGGETT:  Yes.  I really appreciate the input from Dr. Couch and other experts and do vote for deferment.  I would agree, though, that I would hope that the manufacturers do have enough inventory to take care of the 50, that new age group, as well.  And I think it's probably, in our patient population in my community, we do have a lot more interest now, so I think we're going to have an increased demand.  Now we're in for that age 50, other places are going to be wanting it, too.
		CHAIRMAN GREENBERG:  Dr. Kim.
		DR. KIM:  I also support deferral, although I respect Dr. Kilbourne's comment that we may not be able to see any considerable difference in that sense.  I think since the Moscow strain was not, indeed, feasible, then, again, the strains like the Panama, you know, appear to be appealing and, again, in addition to Sydney strain.  So I think those options need to be continued to be explored.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  Defer.
		CHAIRMAN GREENBERG:  Dr. Estes.
		DR. ESTES:  I support deferral.  I also think it's prudent to get as much information as possible and I am concerned about the pressure of the use of the new antiviral as to whether that's going to end up changing this hemagglutinin, which would only affect the A strains.
		CHAIRMAN GREENBERG:  And Dr. Griffin.
		DR. GRIFFIN:  I think we need the maximum amount of information before this choice is made and so we should defer.
		CHAIRMAN GREENBERG:  Okay.  And for the record, I also vote defer.  And I think, in fact, I am heartened by the fact that, as Roland said, that the A/Sydney there's two years of experience and we, I would assume, have some ability to defer because that is already in the bank, so to speak, and manufacturing can be done relatively efficiently.  So if it ends up, as Dr. Kilbourne thinks, that that turns out to be the strain, we have it and we have a lot of experience making that vaccine.  Not me, but ‑‑
		DR. KILBOURNE:  I'm not unhappy with this decision.
		CHAIRMAN GREENBERG:  Yes.  And your point was clear.
		DR. COUCH:  Well, I might say that I think Ed is correct.  I mean, the view that some of us might have been taking, which is in agreement with his that that may well be the decision, but I'm more comfortable backing into it rather than charging out there.
		CHAIRMAN GREENBERG:  And I think everybody understands that there is no real difference with Dr. Kilbourne.  He was just looking into the future more than we were.
		Well, I think we have time for perhaps at least beginning to talk about one other strain or even more.  So, Dr. Couch, I know you said you didn't want to start off the next one, but, you know, you have many years of influenza experience.
		DR. COUCH:  Oh, no.  There are other people down here.  You're pinpointing me a little bit too much.
		CHAIRMAN GREENBERG:  So I'm going to pick the strain.
		DR. COUCH:  Good.
		CHAIRMAN GREENBERG:  Let's go with the next one, with the H1N1 strain.
		DR. COUCH:  I was going to say, you know, let me select one and then let me try to defer the other one, if I may.
		(Laughter.)
		My H1 chart has plusses all the way across and that is what was once again highlighted and described very nicely by Roland and that is that we should change the H1 ‑‑
		CHAIRMAN GREENBERG:  Could you use your microphone a little bit more?  I'm having a little trouble hearing you.
		DR. COUCH:  That my little chart I told you I make has plusses all the way across on H1 and so we need to recommend a change in the strain and the obvious change is to New Caledonia.  And the reasons for that were enunciated very nicely by Roland.
		CHAIRMAN GREENBERG:  Okay.  Fine.  Dr. Hoke.
		DR. HOKE:  Perhaps I needed to hear Dr. Levandowski again, because I actually had not been so certain that ‑‑ but, of course, Dr. Couch always seems to, you know, sound definite.  Sounds like he knows exactly what he's talking about.
		I had written at the bottom of my chart to stay with the A/Beijing.  And so I'll just say that I had written that down, because it wouldn't be right to change my mind just because you said that.  But perhaps there will be some more discussion on that.
		CHAIRMAN GREENBERG:  So you can reconsider after you hear all of this.  This isn't the SATs.  Dr. Kilbourne.
		DR. KILBOURNE:  I think, all other things being equal, I would opt for the New Caledonia or something like it.  I think there's enough evidence of a drift there so that we should be concerned about it.
		CHAIRMAN GREENBERG:  Dr. Cox.
		DR. COX:  I agree with going with New Caledonia.  And I know that not everyone else in the room could see Dr. Nerome HI tables very clearly, but I happen to have hard copies and it was really gratifying to see that he has several pages of recently isolated H1N1 viruses from their outbreak and they're all very well covered by the New Caledonia virus.
		CHAIRMAN GREENBERG:  And Dr. Hoke, I'm sure, is among us who couldn't see that data.  Dr. Ferrieri.
		DR. FERRIERI:  Well, I support New Caledonia based on all of the data presented today, but what we don't have is immunogenicity data that should be generated within a relatively short time, so we need a backup plan if that data is negative and perhaps Roland can comment on that.  But that's clearly the best choice for us to go to if everything works out.
		CHAIRMAN GREENBERG:  Dr. Eickhoff.
		DR. EICKHOFF:  I concur, based, I think in large part, on the data from Japan.
		CHAIRMAN GREENBERG:  Dr. Daum.
		DR. DAUM:  I concur and don't have anything to add to what's been said.
		CHAIRMAN GREENBERG:  Dr. Edwards.
		DR. EDWARDS:  I would vote for New Caledonia.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  I defer to the CDC.
		CHAIRMAN GREENBERG:  Dr. Faggett.
		DR. FAGGETT:  That New Caledonia has a good ring.  I support New Caledonia.
		(Laughter.)
		CHAIRMAN GREENBERG:  Dr. Kim.
		DR. KIM:  I support a New Caledonia strain, particularly with the data that Dr. Cox just shared.  I think that's a real issue.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  I support the New Caledonia, but I'm a little concerned about isolates 16 to 20, the South American isolates that looks like we're not as well ‑‑ is that correct?  That they weren't as well neutralized?
		DR. COUCH:  Yes.  I've noted the same thing.  But South America, so far, is A/Bayern-like.
		DR. COX:  Yes.
		DR. COUCH:  But that may be a result of the number of strains that you've had in hand and on your world chart, it stood out as the only one that had not seen the H1 change, the only major ‑‑
		DR. COX:  Peru had.  Peru had, previously, had New Caledonia-like strains.  And, in fact, those strains that you're mentioning are Bayern-like.  And if you recall, the vaccination studies indicate that viruses related to Bayern are well-covered by the Beijing/262 vaccine.
		DR. KOHL:  Well, then I'll withdraw that comment.
		CHAIRMAN GREENBERG:  Dr. Estes.
		DR. ESTES:  Well, I think the New Caledonia looks like a good candidate.  Again, because of my concern about the new pressure on this virus, I just wondered if we would be wise to wait to be sure that we have typed other viruses that are just coming out now to be sure that there are no other changes.  And maybe I'm being ‑‑ so I was actually going to suggest deferring this.  But, obviously, depending on what the discussion is about the B component ‑‑
		CHAIRMAN GREENBERG:  You've got to do them in order, so what is your vote, Dr. Estes?
		(Laughter.)
		DR. ESTES:  Actually, I vote to defer.
		CHAIRMAN GREENBERG:  Okay.  Dr. Griffin.
		DR. GRIFFIN:  I think we have sufficient information.  I think we have the most information on this; put it this way.  We've got to make a choice on one of the three and so New Caledonia.
		CHAIRMAN GREENBERG:  Okay.  And, for the record, I would pick New Caledonia as well.  And I agree with what Diane said, that this was the one that, for me, I thought we had the most information.
		I would like a clarification on something that Dr. Ferrieri raised.  And that is when a strain is switched, as we are recommending now, how frequently do we have immunogenicity data on what we are switching to at the time we make our decision?
		DR. LEVANDOWSKI:  Generally, it's very unusual to have access to any data before a vaccine is made.  We've been in the position once or twice in the past 10 years where there have been some experimental vaccines that were made when some new variants had been identified at an early point.  It's not so easy to get those vaccines made, but they would, if we could have them, would provide very important pieces of information, just to be sure.
		Most of the time, I think we've been okay.  And it seems like the vaccines are immunogenic, given the fact that measuring immunogenicity is sometimes a little bit tricky.  But we, you know, we don't usually have that information.
		I suppose it's possible at some point, as we're, both Southern Hemisphere and Northern Hemisphere are using the same vaccines, that it might be possible to get some earlier information, but probably not in time for us to make a recommendation here.
		CHAIRMAN GREENBERG:  Because, of course, Dr. Ferrieri's question was critically important, you would hate to switch to a vaccine that was not immunogenic.  I just was trying to figure out how, if you were making a new one, you would necessarily have that information.
		Okay.  It's now noon and, since this committee is hot, I think we should just go on to H3N2 while it's fresh ‑‑ I mean ‑‑ excuse me ‑‑ to B while it's fresh in some of our minds and make our decision.  And so, Bob, despite the fact that you were, you know, I let you off the hook and then you bit, so do you want to start off with B again?  Or should I ‑‑
		DR. COUCH:  I'll make a proposal then, because I ‑‑ the only concern that's been emphasized very well is ‑‑ well, let me back up a minute and say last year, you know, we do guesses, you see.  And we thought, well, gee, we've had H3N2 two years in a row.  We've got to start worrying about B.
		And so we fine-tuned the B and it turned out that we had another H3N2 epidemic.  And so now we've got three of them behind us and, unless H1 does something a little bit unexpected, B should be here next year.  So that we're back in that same position.
		And do we need to fine-tune it?  I'd say the data says we don't need any fine-tuning.  So the question is whether we need to change the B strain.  And I think Nancy emphasized very well that, gee, we've got a whole potload of new viruses coming in.  Shenzhen's out in front of us.  The epidemiologic data is not in-hand.  And so the B information that we want for the definitive decision to stay with Yamanashi versus consider something else is not yet in-hand.
		So it's another deferral.  I actually suspect that that one will be the February decision and H3 will be the March, but they could be reversed.  But I think it's in the deferral status also.
		CHAIRMAN GREENBERG:  Okay.  Thank you.  Dr. Hoke.
		DR. HOKE:  That is my choice also.
		CHAIRMAN GREENBERG:  Dr. Kilbourne.
		DR. KILBOURNE:  I would move for deferral.
		CHAIRMAN GREENBERG:  Dr. Cox.
		DR. COX:  I concur.
		CHAIRMAN GREENBERG:  Dr. Ferrieri.
		DR. FERRIERI:  I support that.  And Nancy Cox said there would be more data from Chinese strains in two to three weeks or Roland said that.  I'm concerned that the other candidates to date have demonstrated low yield in vitro, so we may end up having to go back to Yamanashi, though.
		CHAIRMAN GREENBERG:  Okay.  Dr. Eickhoff.
		DR. EICKHOFF:  I concur.
		CHAIRMAN GREENBERG:  Dr. Daum.
		DR. DAUM:  Same.
		CHAIRMAN GREENBERG:  Dr. Edwards.
		DR. EDWARDS:  Deferral.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  No comment.
		DR. FAGGETT:  Dr. Faggett defers.
		CHAIRMAN GREENBERG:  You vote for deferral?  Yes.  Dr. Kim.
		DR. KIM:  Defer.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  Defer.
		CHAIRMAN GREENBERG:  Dr. Estes.
		DR. ESTES:  I agree.
		CHAIRMAN GREENBERG:  Dr. Griffin.
		DR. GRIFFIN:  I also agree.
		CHAIRMAN GREENBERG:  And, for the record, I also agree.
		So I'd like to thank the panel for dealing in a very logical way with a very complicated system.  Of course we punted on two decisions, which was, I think, the logical thing to do.
		So, because of scheduling issues, I'd actually like you ‑‑ it turns out that it would be easiest for us to continue a little while longer and hold your hunger in place.  We're going to have 10 minutes of open public meeting which Nancy and Dwight, I just ask whether there's any public ‑‑ is there anybody in the public out there who wishes to say something?  Okay.  Well, in which case, then, there is nobody.
		So, then, we're going to have 10 minutes of talk from Dr. Carbone and then we'll adjourn and we will have then ended the public component of this meeting.  Kathy, come on up.  So we're just switching gears here and Dr. Carbone is going to talk, describe to us the activities of the Laboratory of Pediatric and Respiratory Virus Diseases.
		DR. CARBONE:  Hi.  Actually, today I'm going to describe the two subsections of the laboratory that I head.  And that's the Neurovirulence Unit, which is my research group, and Dr. Judy Beeler's research group, the Antigen Immune Response Team.
		Next slide, please.
		Just to illustrate the two.  This is Dr. Beeler's group in yellow.  This is my group in yellow here.  This is the rest of the laboratory.  Of course, the noted Dr. Levandowski is part of our group; Dr. Atreya; and associated members.  This group here is an academic group that's working in collaboration with my group at the FDA.  I just want to point out that these two new candidates have just arrived in the laboratory, so the work that I'll be describing is really the result of Mr. Rubin, Dr. Pletnikov, Ms. Jones just arrived, and myself.
		Next slide, please.
		Just to give you a little introduction to the Laboratory of Pediatric and Respiratory Viral Diseases, we regulate the new research on vaccines that are innoculated into virtually every person in the United States, either as an adult or a child.  That includes influenza, measles, mumps, rubella, rotavirus, and polio virus vaccines.  That's, sum total, about 100 million doses per year.
		Over the time since I arrived to head the lab in 1996, at the present time in 1999 or now 2000, we have had an increase in IND reviews of twofold PLAs and supplements of fivefold, but we've managed to increase our scientific publications by twofold.  And I'm very proud of the laboratory for that reason.
		One of the reasons, despite about a 50 percent decrease in research funding for the laboratory, is that there have been successful applications for outside funding.  And we have the National Vaccine Program Office.  Dr. Zoon, the Center Director's Target Award.  And we also have our collaborations with academia and the Office of Women's Health at the FDA to thank for these outside funds to continue our research.
		Next slide.
		So Dr. Beeler and myself, as an introduction, we deal with licensed vaccines.  We have a new collaboration with Dr. Levandowski's group that I'll describe later.  Dr. Beeler has been working on measles for many years.  We've been working on mumps since my arrival at the FDA.  We also work on two viruses there.  Dr. Beeler and Dr. Atreya work on two viruses:  RSV and human parainfluenza virus III.  They're not currently vaccines, but they're in research program.
		And then, of course, the laboratory has cross-cutting programs which include neurovirulence and human immune responses that we serve as references and act on these areas for the entire division.
		Next slide.
		So just briefly I'm going to describe in two minutes my program and follow with Dr. Beeler's.  Time does not permit us, obviously, to get into much detail so I hope I don't leave everyone too much in the dark.  But, in general, when I arrived, I had an interest in neurological disease and viruses.  And virus vaccines, of course, have been associated with many neurological diseases.  And part of our job is to determine which of those associations are causal and which are coincidence.
		In some cases, there's clearly a causal association between certain types of mumps vaccine strains and meningitis; Ural B vaccine, Leningrad III, and Sophia, none of which were licensed in the United States.  Polio vaccine has clearly been associated with the polio the disease.  Measles vaccine has rarely been described in cases of encephalitis.  There are issues of varicella vaccine and questions of latency for this virus in the nervous system.
		And then there are several areas that are of great concern to the public and, as yet, the data are not available to know whether this is a causal or a coincidence and more work needs to be done to determine it, but publications have come from the outside, non-FDA and non-government publications, trying to associate the measles, mumps, rubella vaccine and autism; hepatitis B vaccine and multiple sclerosis; and a host of other neurological diseases.
		Next slide.
		So in my laboratory, we've developed a very multi-disciplinary group to study virus-induced neurological disease and brain development.  Because if we're going to determine whether vaccines are safe for use in the population in regards to their infection and damage to the nervous system, it's important to understand how viruses affect the brain.
		Because we deal with so many pediatric diseases, we do something that's actually very rare in the United States and that's we look at developmental milestones in terms of virus-infected brains.  Now typically people have for years been looking at neurovirulence assays in adult animals.  We actually look in the developing nervous system and look for developmental brain damage, which may be more pertinant to the pediatric and newborn populations.
		We actually have data of neurochemistry, serotonin changes in the brain, neuroimmunology, we look at cytokines.  We have indicates of brain developmental gene up regulation and infection.  And now we have some data which show that sometimes adverse events associated with wild-type virus infection in the brain are dependent upon genetic background of the animal.  We use a rat model for these.
		We also, in the rat model, have studied behavior as sort of an outcome.  This is a very, actually a very sensitive outcome for developmental brain damage.  And have determined abnormalities from wild-type virus infections with social/play behaviors, cognizant deficiencies, and anxieties and other emotional disorders.  In addition, we've been able to describe anatomical differences.
		We use all this information that we gather with the wild-type viruses to try and develop effective vaccine neurovirulence assays to make sure that the vaccines that we use are safe.
		Next slide.
		Thus far, the accomplishments specifically in the laboratory ‑‑ and I'm sorry I don't have time to show you data, so I've referenced them if anybody would like the references.  With our emphasis on brain developmental damage, we've been able, with the strong involvement of Mr. Rubin in my laboratory, we've had several publications on mumps virus neurovirulence assay development trying to get to a small animal assay and avoid the use of primates if possible.  This was just returned with very favorable review, so I suspect this will be accepted.  We are now starting influenza virus and an HPIV3 neurovirulence experiments.
		Mechanism and pathogenesis of virus-associated developmental brain damage, as I described in the previous slide, has resulted in a host of publications coming directly out of my laboratory or collaborations with Dr. Katz and Dr. Plata-Salaman.
		And we also have published early last year the first animal model for autism or autistic-like disease associated with neonatal brain damage due to a virus infection.  We used Borna disease virus as our agent.  And Dr. Pletnikov, a very talented instructor, has published several publications on this model, following our previous 10 years of work.  He's has done some tremendous work.
		Next slide.
		So now I'll move into Dr. Beeler's program.  She's also done some slides here and they're very abbreviated, but I'll try to do my best, due to time constraints.  Dr. Beeler has an excellent program in virus-host cell interactions.  And she is looking at particularly a virus attachment, two RSV proteins F and G.  They are important in attachment in cell fusion.
		And the particular interest in this area is ‑‑ she's currently got an excellent post-doctoral fellow, Dr. Feldman, working in this area ‑‑ is that this is a look at antibody-mediated immune responses to prevent infection and spread of the virus.  In other words, if we can find the RSV receptor and the virus attachment sites, there may be ways to target the vaccine to prevent, actually, the virus from even entering the cell or to block the receptor rather than neutralize the virus per se.
		This is very exciting work and it's very unique.  The RSV receptor has not been defined.
		The next slide.
		You'll see that this work has resulted in both collaborative and publications coming directly from Dr. Beeler's lab, as well as many submitted publications.  And the work is continuing nicely.  She also has a nice collaborative publication on human immune response to RSV.
		Next slide.
		Dr. Beeler has a program on measles as well and has just recently, with Ms. Audet in her laboratory, published a paper in Biologicals.  It was recorded by an international group that there was pestivirus contamination of measles vaccine and Dr. Beeler did a very nice careful study which demonstrates, no pestivirus contamination.  It was a very well-designed study and, like I said, just got accepted into Biologicals.
		She has a very interesting line of research that she's been working on when time permits on measles vaccine associated thomboytopenia resulted in a publication in '96 and another manuscript in preparation.  It's a very interesting publication with very interesting work which suggests that certain factors in cell substrates may cause immune responses that result in anti-platelet antibodies.  Excellent work.
		Next slide.
		She provided this slide and I put it up here to illustrate that in many cases we hear about leveraging resources, both inside and outside the FDA, and through leveraging resources in these multiple collaborations that Dr. Beeler has initiated or been asked to participate in studies, it has tremendous impact in the research world through her collaborations as well.
		Thank you very much.
		CHAIRMAN GREENBERG:  Thank you very much, Dr. Carbone.  I'd just like to editorialize briefly.  As all the panel knows over at least the last couple of years that I've been on it, the FDA-CBER research has been really cut to the bone as far as what their research support is and it's sort of amazing that you and your colleagues continue to be able to be productive in what is an inhospitable situation.
		Are there any specific questions for Dr. Carbone before I ask you folks a question about how to proceed?  Dr. Estes.
		DR. ESTES:  I'd like to ask Dr. Carbone, I mean, your laboratory has been very successful at leveraging resources.  Do you have a specific mechanism that has helped you?  Is there something unique about what you're doing that has been successful in this that would be of benefit for us to know about?
		DR. CARBONE:  Well, the applications to the NVPO, the Office of Women's Health, Center Director's Target Award are open to everyone.  There have been some instances, because I came from academia and was permitted to maintain a part-time academic position at a university, then, through that mechanism, I am able to be a collaborator on NIH-RO1 funding with approval of NIH and the FDA.  They got together.  And they have done this in the past.  It's done at the CDC.  It's done at veteran's hospitals.  I can't serve as the primary investigator, but I can collaborate on grants.  And that is a very helpful mechanism.
		DR. ESTES:  Thank you.
		CHAIRMAN GREENBERG:  Dr. Kohl.
		DR. KOHL:  Dr. Carbone, I want to congratulate you.  I was very impressed by what you've been able to do in the last three or four years.  I guess my question is is there anything you desperately need that would help you further in your efforts?
		DR. CARBONE:  Oh, boy.
		(Laughter.)
		Christmas.  I think it's what we don't need.  That's the problem.  But I think that I would say that the one major problem has been the shrinkage in FTEs at CBER.  And that has necessitated some very drastic measures.  We've been lately discussing sharing technicians and rotating them through because there aren't sufficient technicians for everyone to utilize.  And that makes it difficult because of the review work we do requires that there be support in the laboratory.
		So FTEs for technical positions would be very important.  And this pertains to every laboratory in the division.  This is not just my laboratory.
		And the second thing would be a somewhat reliable or sustainable source of funding for the research.  We've taken some pretty drastic cuts.  And, unlike an NIH-RO1 mechanism, which I had an RO1 for 10 years, on the outside, we get funded year-to-year.  And that makes it very difficult to maintain a program as opposed to the three-to-five year continuous funding you'll get from an RO1.
		So, really, more funding and more personnel.  I think that the CBER environment is extremely supportive and talented.  The administration and management is very supportive of the research program.  We're dealing, I think, with external issues.
		CHAIRMAN GREENBERG:  Ms. Fisher.
		MS. FISHER:  Yes, I'm curious because there is a lot of publicity about record amount of money that is being allocated to HHS for scientific research.  Why is the FDA's research program somehow not getting a part of this pie?  I mean, am I ‑‑
		DR. CARBONE:  That's a little above my area.
		MS. FISHER:  Well, I mean, I don't understand.
		CHAIRMAN GREENBERG:  I think when Dr. Goldman addresses us in closed session, I think that's a spectacular question to ask him.
		DR. CARBONE:  Yes.  That's a good person to ask.
		CHAIRMAN GREENBERG:  Dr. Carbone, probably doesn't ‑‑ if you have a speculation, feel free.
		DR. CARBONE:  No, I really wouldn't.
		CHAIRMAN GREENBERG:  I would invite you to leave it to the people who can take more heat.
		DR. CARBONE:  Yes.  I'm down here looking up.  That's all I am.
		CHAIRMAN GREENBERG:  Okay.  Any other questions?  I would simply say one thing that just because Dr. Carbone and her colleagues have been successful, that should not indicate that anybody I think on this committee thinks that the current level of support is appropriate.  I would say this, if anything, your success has occurred despite what's happened to you, not because of it.
		Okay.  You have a choice here as a committee.  We can move right now into closed session and review the lab.  Or you can go for lunch and come back and we can move into closed session and review the lab.  I'm happy either way, but I want to give people on the committee the ‑‑ I think Dr. Griffin, who ran the review of this lab, says it will be quite expeditious to do that.  So she votes closed session.  The rest of you?
		Okay.  So I'm dismissing the audience and the consultants, with tremendous gratitude.  And you all did a great job.
		(Whereupon, the proceedings went off the record and resumed in Closed Session.)

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