UNITED STATES OF AMERICA

	FOOD AND DRUG ADMINISTRATION

	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

	VACCINES AND RELATED BIOLOGICAL PRODUCTS

	ADVISORY COMMITTEE 

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	MEETING

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	TUESDAY, 

	JANUARY 30, 2001

		The meeting was held at 9:00 a.m. in the Versailles Rooms I, II, and III of the Bethesda Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, DR. ROBERT DAUM, Acting Chair, presiding.
PRESENT:

	MARY K. ESTES Ph.D.
	STEVE KOHL, M.D.
	KWANG SIK KIM, M.D.
	ALICE S. HUANG, Ph.D.
	ROBERT S. DAUM, M.D.
	DIXIE E. SNIDER JR., MDD., M.P.H.
	SAMUEL L. KATZ, M.D. 
	DAVID STEPHENS, M.D.
	DIANE E. GRIFFIN, M.D., Ph.D.
	AUDREY F. MANLEY, M.D., M.P.H.
	PAMELA DIAZ, M.D.
	BARBARA LOE FISHER
	JUDITH D. GOLDBERG, D., S.c.D
	WALTER L. FAGGET, M.D.

PRESENT: (cont.)

	NANCY CHERRY
	Executive Secretary

	DENISE ROYSTER
	Committee Management Specialist

CONSULTANTS PRESENT (voting):

	PATRICIA FERRIERI, M.D.
	EDWIN KILBOURNE, M.D.
	MARTIN MYERS, M.D.

GUESTS PRESENT:

	NANCY COX, Ph.D.
	COLONEL BENEDICT DINIEGA, M.D.
	MICHAEL DECKER, M.D., M.P.H
	DR. LANCE RODEWALD, CDC
	DR. WENDY KEITEL
	DR. KEIJI FUKUDA, CDC
	DR. ALEXANDER KLIMOV, CDC
	MS. LINDA CANAS, DOD
	MR. ALAN HAMPSON
	DR. JOANNA ELLIS

FDA REPRESENTATIVES PRESENT:

	DR. KATHRYN ZOON
	DR. KAREN MIDTHUN
	MR. ZHIPING YE
	DR. ROLAND LEVANDOWSKI
	
MANUFACTURER REPRESENTATIVES:

	DR. GREG SLUSAW, PhRMA
	MR. JOHN O'BRYAN, EVANS VACCINE
	MR. RICHARD HJORTH, WYETH

	I‑N‑D‑E‑X

AGENDA ITEM	PAGE

Call to Order/Welcome	4
	Dr. Robert Daum, Acting Chair

Introduction of Committee	4

Conflict of Interest Statement	6
	Tara P. Turner, Pharm.D.
	Executive Secretary, AVAC

Introduction and Updates
	Dr. Roland Levandowski, FDA	8
	Dr. Lance Rodewald, CDC	30
	Dr. Wendy Keitel, Baylor	60

Presentation to Retiring Members
	Dr. Katherine Zoon	81

U. S. Surveillance  	85
	Dr. Keiji Fukuda, CDC

World Surveillance and Strain Characterization
	Dr. Nancy Cox, CDC	95

Molecular Characterization of Strains
	Dr. Alexander Klimov, CDC	108

Additional reports 
	Ms. Linda Canas, DOD	117
	Mr. Alan Hampson, WHO	134
	Dr. Joanna Ellis	148

Vaccine Responses
	Dr. Roland Levandowski, FDA	156

Availability of Strains and Reagents
	Mr. Zhiping Ye, FDA	189

Comments from Manufacturers 
	Mr. Greg Slusaw	201

Options for Strain Selection
	Dr. Nancy Cox	220

Committee Discussions and Recommendations	240

	P-R-O-C-E-E-D-I-N-G-S
	(9:05 a.m.)
		CHAIR DAUM:  Good morning, the meeting is officially in session.  For people that don't like surprises, Dr. Zoon will not come at 8:15 to give plaques to retiring VRBPAC members, but will rather come about 9 o'clock. 
		So we will proceed with the Agenda and begin hearing about influenza issues, and then take a break before Dr. Zoon's presentation, and a photo-op, if you will, of the VRBPAC committee at the same time.
		We will begin with the usual introductions of the committee.  And, Dr. Snider, I can barely see you out  there.  Maybe it is my glasses, but we will maybe ask you to start, and we will go around the table and introduce ourselves.
		DR. SNIDER:  Dixie Snider, Associate Director for Science, Centers for Disease Control and Prevention.
		DR. STEPHENS:  David Stephens, Emory University, Atlanta.
		DR. KIM:  Kwang Sik Kim, Johns Hopkins.
		DR. GRIFFIN:  Diane Griffin, Johns Hopkins.		
		DR. HUANG:  Alice Huang, California Institute of Technology.
		DR. KOHL:  Steve Kohl, Oregon Health Sciences University.
		DR. MANLEY:  Audrey Manley, Spellman College.
		DR. DIAZ:  Pamela Diaz, Chicago Department of Public Health. 
		MS. FISHER:  Barbara Loe Fisher, National Vaccine information center.
		DR. ESTES:  Mary Estes, Baylor College of Medicine.
		DR.  FERRIERI:  Patricia Ferrieri, University of Minnesota Medical School, Minneapolis.
		DR. MYERS:  Martin Myers, National Vaccine Program Office.
		DR. GOLDBERG:  Judith Goldberg, NYU School of Medicine.
		DR. KILBOURNE:  Ed Kilbourne, New York Medical College.
		DR. DINIEGA:  Ben Diniega, Department of Defense health Affairs.
		DR. COX:  Nancy Cox, CDC Atlanta.
		DR. DECKER:  Michael Decker, Aventis Pasteur in Vanderbilt University.
		DR. LEVANDOWSKI:  Roland Levandowski, Center for Biologics.
		CHAIR DAUM:  And I'm Robert Daum from the University of Chicago.  Thank you. 
		We will now move on to Nancy Cherry, who will advise us of conflicts of interest.
		MS. CHERRY:  Well, first of all I will comment that we are happy to have Dr. Daum as Acting Chair today.  Also, you may or may not know that FDA is in the process of appointing industry representatives to each of the committees. 
		And, today, we have Dr. Decker acting as a guest, but in that capacity for our Committee. 
		My final announcement is for any of you that are parked at the public parking lots across the street where you feed the meters with many quarters, please be vigilant, because the Montgomery County's finest are also vigilant.
		The following announcement addresses conflict of interest issues associated with the meeting of the Vaccines and Related Biological Products Advisory Committee of January 30th, 2001.
		Based on the agenda made available, it has been determined that the committee discussions for the influenza virus vaccine formulation present no potential for a conflict of interest.
		The Director of the Center for Biologics Evaluation and Research has appointed Drs. Theodore Eickhoff, Patricia Ferrieri, Edwin Kilbourne and Martin Myers, as temporary voting members for the discussion on the selection of strains to be included in the influenza virus vaccine for the 2001-2002 season.
		And I would add that we are sorry that Dr. Eickhoff could not be with us today.
		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 any current or previous financial involvement with any firm whose products you wish to comment on.
		And I will now turn it back to Dr. Daum.
		CHAIR DAUM:  Thank you, Nancy.  I think we will move, without further ado, right into the topic of the day, the strain selection for influenza virus vaccine. 
		And we will begin with a trilogy of presentations that may be broken, as I mentioned by plaque presentations and photo ops.  And we will call on Dr. Levandowski of the FDA to introduce us to the topic, and present us some information about what has happened since last year.
		DR. LEVANDOWSKI:  Thank you, Dr. Daum.  I would like to welcome everybody here to this meeting.  And, as usual, there is lots of excitement, not the least of which is getting all of this together. 
		We are trying to present, or use, some new technology here, and hope that this is going to work.  However, if our power point doesn't work I think everybody is prepared with either slides or overheads to back this up, so we will just dive in and get started.
		As everybody knows we are here today to begin the process of selecting the influenza virus strains that are going to be included in the vaccines prepared for 2001-2002 in the United States. 
		The question to be answered by the committee is shown on this slide, and it is the same one we ask every year, and that is, what strain should be recommended for inclusion in the inactivated vaccine for the coming year.
		In formulating an answer to that question I think it is helpful to review a few facts about the currently approved inactivated influenza virus vaccines.  Inactivated influenza vaccines act primarily to induce the production of antibodies.
		The hemagglutinins and the neuraminidases of the incorporated influenza virus  in current vaccines are concentrated, and partially purified, to remove extraneous material derived from the eggs in which the vaccines are produced.
		Although antibodies to both the hemagglutinin and the neuraminidases may be protective, influenza virus vaccines are standardized currently only for the content of hemagglutinin. 
		And, therefore, the greatest emphasis is placed on the viral hemagglutinin and in the selection.  However, the neuraminidase receives consideration since it, too, may add to the protective efficacy of vaccines. 
		Since the use of the first inactivated vaccines in the 1940s, it has been very clear that one of the most important predictors of vaccine efficacy is the match of the vaccine virus with the influenza viruses that are causing infections.
		What has also been made clear, with yearly epidemics and pandemics, is that influenza virus have great scope for antigenic diversification.
		Ongoing random mutations of the hemagglutinin and the neuraminidase, which we refer to as antigenic drift, and exchange of entire genes with other influenza viruses that we refer to as antigenic shift, both participate in influenza virus evolution.
		It may also be helpful to the committee's deliberations to consider answers to the questions shown on this slide.  Most importantly it is necessary to know if new influenza virus is revolving in nature.
		An extensive global network exists to collect and analyze information, throughout the year, as we are going to hear shortly, from colleagues at CDC and other national and international institutions, this morning.
		When new viruses are identified, and they almost always are, the extent of geographic distribution helps to judge the urgency in changing the composition of the vaccine.  Often antigenic variants appear, but sometimes they are dead end branches on the evolutionary tree.
		As we've seen in the case of some influenza B viruses in Asia, in the recent past, they may even be spread in a geographic location without subsequent globalization of those strains.
		Of course we have seen, also, just the opposite with influenza A viruses transported freely and rapidly across hemispheres by modern travel habits.
		If new strains can disseminate widely it is useful to know whether current vaccines are likely to produce some measure of protection.  If it appears that current vaccines could be suboptimal, then it is still necessary to consider whether there is a strain that is suitable to permit large scale manufacture of vaccine within the perennial constraints of time.
		We are prepared to assist, this morning, by supplying information in each of these areas.  Customarily there is a brief review of the previous year's experience. 
		However, this year we are going to expand on the review of the production year just past.  As everyone is, undoubtedly, aware there was a serious and unprecedented delay in distribution of influenza virus vaccines in the United States during the production season that is just ending.
		It is now possible to state with certainty that the amount of vaccine produced for distribution in the United States during 2000 was similar to the amount produced and distributed in 1999.
		However, by all reports the disruption to the accustomed schedule for use of influenza virus vaccines in the fall months has been severe.  Even though there appears to be sufficient vaccine to supply the existing demand, the lack of vaccine at the time it was expected for use, in effect, was perceived as a shortage.
		And just as it takes months of planning and effort to make the vaccine, it also takes a huge effort, and many weeks, to administer more than 70 million doses of vaccine in this country.
		This slide helps to demonstrate the magnitude of the delay.  And to give some perspective, here, the data are included for 1998 and 1999 when similar total amounts of vaccine were produced.
		The data are presented here as the cumulative percent of the total amount of influenza virus vaccine that was submitted to the Center for Biologics Evaluation and Research for testing and release.
		The green bars here are information for 1998.  The blue bars are information for 1999, and the red ones are the information for 2000.
		What you can see is that in all three years, in June there was some vaccine that was produced for release, or it was prepared for release by that time.
		However, more than 50 percent of the vaccine was prepared by August in both 1998 and 1999.  While the 50 percent point was not reached until October in the year 2000.
		You will note that October is also the month when nearly one hundred percent of the vaccine had been prepared in 1998 and 1999.  That one hundred percent point was not reached until the end of November, to the beginning of December in this year, in the 2000 season.
		In effect it took about six to eight weeks longer to prepare vaccine.  And nearly 50 percent of the vaccine was ready for market only after October and November when most practitioners and recipients are now very well accustomed to using vaccine in accordance with recommendations from the Advisory Committee for Immunization Practices at CDC.
		The causes of the delay have been reported previously, and I've listed them here.  Although there have been several other instances in which one or another vaccine manufacturer experienced an event that delayed manufacturing, there has never been an occurrence when three of the four licensed manufacturers were delayed at the same time.
		I think that is the real answer to what happened during this past year. 
		At two of the manufacturers, Parkdale Pharmaceuticals and Wyeth deviations from good manufacturing practices were discovered during FDA inspections of facilities. 
		One of those manufacturers, Wyeth, was able to make corrections in time to permit production of vaccine.  Although the vaccine distribution began late in 2000.
		The other manufacturer, Parkdale, was not able to complete their corrections in a timely manner, and they withdrew from further production. 
		Another manufacturer, Aventis Pasteur, experienced early difficulties with one of the two new viruses included in the vaccine.  And I want to emphasize that there were two new strains that were recommended for the past year.
		I think that sometimes has been missed in some of the reports, or some of the conversations. 
		Although the A/Panama/2007/99 strain grew quite well in eggs, the early yield through the process, as is often true for new strains, was low.  However, as is usually true for all manufacturers of influenza vaccines adjustments were made in handling the virus, and eventually satisfactory yields were obtained.
		Unfortunately manufacturing is not only labor, but it is also time intensive.  And time lost is just simply not regained.  During the months that followed the recognition of the situation, FDA, CDC, NIH, and the manufacturers all worked together to develop strategies to minimize the impact of the delay, and to maximize the production and use of vaccine. 
		In order to give a further explanation of the public health service activities that went on, I'm first going to present some additional data on production. 
		Following that, Dr. Lance Rodewald, from the National Immunization Program, will discuss some of the CDC activities related to vaccine supply and distribution during 2000.
		And, finally, Dr. Wendy Keitel of Baylor College of Medicine in Houston will discuss clinical studies that were sponsored by the National Institutes of Allergy and Infectious Diseases during the past year, to re-evaluate dose response of inactivated influenza virus vaccines. 
		This slide shows an abbreviated version of the influenza vaccine production cycle.  And here I've placed the vaccine use at the top of this little pyramid, since that is what most people see from the production effort.
		What is not always obvious for everybody is that there is a continuous effort and a lot of work that goes on to support the preparation and use of the vaccine.  And that is what is shown in blue and in black at the bottom of the slide, here.
		Working down from the top, the vaccine can't be distributed until it is produced, obviously. Trivalent vaccine is formulated, however, from monovalent components that are produced individually from virus strains having different optimal conditions for growth and purification.
		The amount of trivalent vaccine is limited by the poorest yielding strain, as is often pointed out to us by manufacturers.  So a great deal of their effort goes into development of seed viruses.
		The seed viruses are proprietary for each manufacturer, and they are produced by carefully controlled consecutive passage and eggs.  Although each seed virus is unique, all seed viruses are antigenically identical to the referenced strains from which they are derived.
		Those referenced strains are recommended by the actions we are undertaking here today.  And although the recommendations occur somewhat point events, they really are supported by all that shown below on the slide, here, underneath the recommendations occur at specific time intervals.
		But the activities to support that are going on, basically, continuously.
		Manufacturers use only strains consistent with the recommendations.  But it is sometimes possible to have more than one choice, either from different appropriate wild type viruses, or from multiple high-growth reassortent viruses that are produced specifically to support manufacturing of vaccine at large scale.
		The global activities needed to prepare for the recommendations in northern hemisphere countries in January through March, and in the souther hemisphere countries in September through November, help to focus attention and to smooth out the vaccine preparation in many ways, mainly by forcing us to get busy.
		Well before the recommendations are made, however, surveillance by CDC and other WHO laboratories identify potential new reference influenza viruses, and it is possible to explore the potential of those new strains for use in producing vaccines well before any of the committee meetings occur.
		This slide shows the most recent recommendations.  The recommendations on the left are the ones that were made by this committee for the 2000 production year.  And the recommendations on the right are those that were made by the World Health Organization for the 2001 production year in the southern hemisphere.
		Please note that the recommendations for the H3N2 strain, and the H1N1 strain, which were new for the 2000 vaccine in the United States, are the same as those recommended for 2001 in the southern hemisphere.
		In fact the WHO recommendations for the southern hemisphere in 1999 that preceded our 2000 recommendations also included an A/Moscow-like and an A/New Caledonia-like strain.
		The current effective recommendations differ only in the B strain, which has been updated in the southern hemisphere to include a newer strain, the B/Sichuan/3799 strain, and the actual strains that are being used for manufacturing right now are the B/Johannesburg 599, and the B/Victoria 504/2000 strain.
		This slide shows the timing by month of the year of distribution of strains for the last five new strains that were recommended by this committee since 1998. 
		The blue filled squares denote reference viruses that were distributed to manufacturers, and the red filled squares denote potency reagents that were distributed for vaccine manufacturing.
		The little yellow bars in between indicate the months during which strain recommendations are mad in the United States, just for reference.
		What you can see from this slide by Gestalt is that for the two new strains that are recommended for 2000, distribution of the referenced viruses and the potency reagents was as early, or earlier than for previous new strains. 
		For the A/Panama/2007/99 recommendation four newly prepared high growth reassortants with hemagglutinin and neuraminidase from the A/Panama/2000/799 virus were distributed to manufacturers by the end of January. 
		The reassortant viruses that were named NIB41, NIB42, Resvir 16 and Resvir 17, were examined carefully by manufacturers, and the strains selected for use, which is called Resvir 17, was chosen by manufacturers in the United States and Europe as the best one of the four available for manufacturing on the basis of the growth and the yield in small scale purification.
		However, it should be noted that manufacturers can get an accurate forecast of yield only when the specific potency reagents are made available.  And in the case of the A/Panama/2007/99 strains, the reagents were not available until May of 2000.
		This slide shows some of the intensity of the work in developing new seed viruses for current vaccine strains during the first year the strains were included in the vaccine. 
		So for the A/Panama, and A/New Caledonia strain, those were first used in the year 2000, and the B/Yamanashi strain was first used in 1999.
		What I'm showing is an overlap of those years just for comparison as to what happened during the actual calendar years.
		The red bars here indicate when the A/Panama/2007/99 seed viruses were submitted to the Center for Biologics for release.  And what can be seen is that work to develop the A/Panama seed viruses was completed earlier, and over a shorter time interval as compared to the either the A/New Caledonia, or the B/Yamanashi strains. 
		What this suggests is that overall optimization of the A/Panama seed virus was not unusual difficult over all, it just takes time, as it always does for these things.
		And I think it is important for people to recognize that this also doesn't happen just at one time point, it occurs over a period of time that there is work going on to make improvements continuously.
		This slide provides information on the production of monovalent vaccine components during 1998, 1999, and 2000.  The results are presented as a percent.  Each monovalent type represented out of the total number of monovalent lots that were submitted for the particular calendar year to the Center for Biologics. 
		The results that are shown in light blue, you probably can't see it at the back, indicate the strains that were new within the given calendar year.
		So in 1998 A/Beijing and A/Sydney were new, and in 1999 B/Yamanashi was new, and in 2000 A/New Caledonia and A/Panama are new strains. 
		Although there might have been some early difficulty with the A/Panama strain, the data overall did not suggest an unusual difficulty with this A/Panama strain, as compared to other strains, either within the same year, or compared to the previous two years experiences with another H3N2 strain, the A/Sydney/597 strain.
		In fact, if you look a it, in all three years more effort, that is, more total lots of vaccine manufactured ultimately went into producing either the H1N1 influenza strain, or the influenza B strain that was needed for producing the influenza H3N2 strain.
		This isn't to minimize that there are difficulties with all these things, but it does show that some of the time, here, was not really -- it was not universal for all of the manufacturers. 
		This slide shows the number of trivalent lots that were submitted for release to the Center for Biologics over the past decade.  And what is obvious is that vaccine production has been increasing by approximately two-fold over the decade.
		In 1990 it was probably equivalent to approximately 40 million doses.  And more recently that equates to about 80 million doses per year that have been manufactured.
		More directly relevant for today's discussion, now that manufacturing has been completed for the 2000 year, the number of lots of vaccine produced for 2000 compares very favorably with the total produced for the year before.
		So, in summary, I think what we can say from this experience is that we can expect that there are going to be delays of shortages of production, delays occur at multiple manufacturers at one time.
		And this really points out the need for having multiple parallel streams of product.  The constraints of time and the need for all events to fall into place make production of influenza virus vaccine a delicately balanced system that requires great collaboration between the government and industry. 
		Temporary problems with the new vaccine strain and time needed to implement good manufacturing practices both contributed to the delay and distribution of vaccine in 2000.
		And significantly these events have led to one of the affected manufacturers to withdraw from producing influenza vaccine. 
		In most other ways, however, the experience in 2000 was really pretty typical of influenza manufacturing, generally, with all of the usual kinds of stresses.  
		And I will stop there and ask if you have any questions or comments.
		CHAIR DAUM:  We have something unusual, on my experience on this committee, is we have the luxury of some time.
		Would anybody like to ask some questions of Dr. Levandowski before we go on?  Dr. Kohl?
		DR. KOHL:  Could you specify what you mean by problems with good manufacturing practices?
		DR. LEVANDOWSKI:  Well, there are procedures and processes that are put into place that are, if they are used, will guarantee that there will be consistency in manufacturing, and that the product that is manufactured is wholesome and meets all the requirements of a product under licensing requirements in the United States. 
		DR. KOHL:  That is not quite the answer I was looking for.
		This is a process of producing influenza vaccine, is not a new process, it is something that has been going on for many years.  And I presume it is roughly the same process every year.
		What was special about this year that two companies had problems that were severe enough to stop their production? 
		DR. LEVANDOWSKI:  Well, what I can say is what I had stated before, I think.  That there are -- there were deviations from procedures that are put into place to ensure that the product is made in a consistent manner, and that it does meet all the standards for purity, potency, and so on.
		I am afraid that is probably all I can say.
		CHAIR DAUM:  Dr. Katz, welcome Dr. Katz, you didn't get to introduce yourself earlier.
		DR. KATZ: Well, I was at the meeting yesterday, and I mistook the beginning of time this morning.
		I wondered what efforts or progress have been made in getting away from production in ovo, and getting into an in vitro system for production of virus and vaccine? 
		DR. LEVANDOWSKI:  Globally there has been quite a lot of interest in production of vaccines and tissue cultures, and also by methods that would avoid, or would be more similar to making a purified protein.
		Those are in development.  When those might become realities is unclear.  There are a whole set of issues that are related to cell substrates, issues that are related to safety parameters, and issues that are related to having a setup that will, in terms of the viruses that are required to make the vaccine, they still need to have seed viruses.
		For example, the tissue culture system for making vaccine, all of those things need to be put into place and worked out.  
		And there is, I guess what I can say in the general sense, is that there is an awful lot of work going on looking at that, to see whether that has any advantages, either in terms of  efficacy of vaccine, or in smoothing out production of vaccine.   And it is going on around the world.
		CHAIR DAUM:  Dr. Snider?
		DR. SNIDER:  Yes.  Roland, could you tell us if Parkedale has made public their intentions with regard to producing influenza vaccine in the coming year, and the amount of doses that they normally produce?
		Or if you can't, is there a company representative who could tell us that? 
		DR. LEVANDOWSKI:  I don't know if there are any company representatives in the audience this morning.  But what I can say is that Parkedale has made press releases that indicate their intention is not to produce influenza virus vaccine.
		And I believe I've also seen press releases discussing what actions they would take to discontinue all of their activities in that regard.
		CHAIR DAUM:  I guess the follow-up question that is sort of implicit in what Dr. Kohl and Snider are hinting at, is how do you see what the occurrences this year as impacting long term issues of vaccine supply, and having enough manufacturers to ensure an adequate flow of product in a timely way?
		DR. LEVANDOWSKI:  Well, I think that it points out what we already knew about the system.  And we use the term fragile, it really is a very fragile system. 
		We ask these manufacturers to do what is really a very difficult task.  They basically have to make a new vaccine every year.  And this product has become very widely available, and really very relatively inexpensive.
		Quite honestly it doesn't make a lot of money for manufacturers.  And in that sort of situation I think what we've seen for pharmaceutical products, generally, is that if they are not profitable, the companies really have other incentives to move on to something else.
		I think that is the concern.  And this is not new in terms of companies making decisions to remove themselves from manufacturing inactivated influenza vaccines.  
		The technology is old, but it still is a fairly expensive activity, or venture to get into the market, and to have to start up and meet all of the requirements that we expect for modern vaccines. 
		And just because of all those difficulties, the relatively low profitability, as compared to other things, other exhibits of companies that left influenza vaccine production are really numerous.
		There are probably more manufacturers that have quit making influenza virus vaccines than are still making those vaccines.  And I can name some other companies like Merck, Letterly, Lilly, and there are probably a few more.  Merrill National was a company that eventually became a company that is still in existence, but this is really quite an important issue that needs to be addressed.
		And I hope that we can address it fully here this morning, to tell you the truth.
		CHAIR DAUM:  Other questions?  
		DR. KILBOURNE:  Could I make a comment?  Maybe it is appropriate for later rather than now.  But I think we may be becoming a little obsessive about how good an antigenic match we have to have.
		After all we are talking about drift.  And if we look at some of the data I have seen in this material furnished, if you compare the AN1 strains, the New Caledonia, and the Beijing 262, which was used for about four years, the coverage as reflected by vaccine response is not all that different. 
		I wonder whether one of the things we should consider is whether in a year where it is obvious, early on, that there are production difficulties, we might relax a little bit on the strictness of the antigenic demands here.
		CHAIR DAUM:  Do you want to comment on that? 
		DR. LEVANDOWSKI:  Well, I think I would just restate what I stated to begin with, and I think Dr. Kilbourne was maybe involved with the FM1 strain was the strain that led to initiating all of these activities, recognizing that antigenic drift could make vaccines relatively ineffective.
		DR. KILBOURNE:  Well, that is a unique situation, as far as I've been able to tell, and I'm putting together a paper on that right now, in that the magnitude of change in four years, there was something greater than we've see since.
		Whether Nancy would argue with that or not I don't know. 
		CHAIR DAUM:  Thank you, Dr. Kilbourne, thank you Dr. Levandowski.  I think we will move on at this point, and hear from Dr. Lance Rodewald, Director of the Immunization Services Division, the National Immunization Program at CDC.  Welcome.
		DR. RODEWALD:  Thank you, and thank you for the invitation to come and speak about some of the programmatic responses that we had towards the flu supply  problems this year.
		I'm in the Immunization Services Division at the National Immunization Program at CDC, and we are the main programmatic arm of the Immunization Program.  And so we do the lion's share of our work is with routine childhood vaccination, so this is a little bit different. 
		The scope of my talk will be to talk a little bit about what we were worried about, what was done by Public Health Service and CDC, and others, and then what has happened so far, from our perspective, and some of the programmatic lessons that we've learned, and continue to learn.
		The basic chronology we had is that if you look at the one year time line from January 1st through December 31st of this year, is the notification in mid-March of CDC possible enforcement actions, leading to the recognition that there may very well be not only a delay, but also a severe shortfall in the number of doses that will be produced.
		There was an MMR, MMWR, announcing the delay with the possible sever shortage of vaccine production.  And then there was the ACIP recommendations for the delay scenario.
		So it was recognized that there would not be a major shortfall between the middle MMWR and the ACIP recommendations, but that the delay would definitely occur.
		What we were mainly worried about, of course, are death and disease, and hospitalizations from influenza.  For each million doses that were not given to elderly patients, this would translate into 900 deaths and 1,300 hospitalizations.
		The estimates of supply from the FDA were not reassuring, as I mentioned earlier, and as Roland had mentioned.  And we are also worried that the vaccine supply is a bit dependent on the manufacturer, because they had different timings of when they came to market.
		And so if I was in a nursing home, for example, depending on which manufacturer, I may have my vaccine earlier or later in the season.   And, of course, the other thing is that this is primarily, and almost entirely, a private sector distribution, manufacturing and distribution system. 
		The other thing that we are worried about is how do we target vaccine in case there is a shortage, how do we really make sure that vaccine is given to those at highest risk of death and hospitalization.
		I would like to talk a little bit about what was done, and I would like to go over six points.  Number one is after, and basically remember that there is not a large adult vaccination infrastructure, public health infrastructure, it is largely a private system. 
		One of the things that we did is to communicate with our partners, the federal agencies, of course, and Dr. Levandowski had weekly conference calls with the CDC where he indicated what the most recent and current information was about the vaccine supply.
		We had conference calls with public health and private provider organizations.  For example, the Association of State and Territorial Health Offices, the American College of Physicians, and other provider organizations. 
		We purchased a guarantee of a production of more vaccine, and I will get into that in a moment.  This is the nine million doses of vaccine that we guaranteed production of.  
		We developed a website, I will get into that in a little bit, for exchange of information, and possible exchange, facilitating exchange of vaccine.  We had some new knowledge generation to help with this season.	
		We created, based on the new knowledge, some good practices material, and we conducted a media campaign.
		The federal contract for influenza vaccine production, I will talk a little bit about the time line for that, we contracted for the production of nine million doses of influenza vaccine, and these were doses that would not have been made available without the contract. 
		This was, in other words, doses of vaccine that were produced in excess of what was planned by the companies. 
		The availability, we could not get vaccine that would be available prior to mid-December in 2000, so this is really late season vaccine, and safety net vaccine in case there was a sever shortage.
		The prices turned out to be, through the contract, three dollars for public sector, five dollars for private sector.  And, significantly, there was a public health priority on the purchase of this vaccine. 
		The purpose of the public health priority was to implement the AICP's targeting policy, and the purchase was done by application only.  The applications were reviewed, ranked and prioritized by an algorithm that basically discussed, of this purchase, what percentage do you think will go to high risk patients, those at greatest risk of death, and hospitalization.  The applications were made to Aventis.
		The chronology here, if you take a look at the basic chronology that is on the bottom, and then the yellow bars here indicate where the funds were certified to procure the production of the nine million doses.
		And between that and the red bar, later on in the season, the red arrow later on in the season, at the time the funds were certified, there was still the distinct possibility that there could be a serious shortfall in the number of doses of vaccine. 
		And this prompted the purchase, and really sort of forced the purchase of the safety net vaccine, in case there was a serious shortage.
		Between that yellow bar and the next red arrow, it turned out that there would not be a serious shortfall if you add in the addition of the nine million doses.
		The website started taking orders, where you see the middle yellow bar, and vaccine began shipping on time in mid-December.
		The website that we developed really indicated several things.  One of them was -- the purpose was to indicate vaccine availability as the season progressed.  The intent was to link providers with vaccine, to those without vaccine, knowing that there was going to be an unevenness in distribution. 
		The website was for information only, because this was not a site where we would sell vaccine.  Vaccine was available from either manufacturers, or wholesalers.  This vaccine was put on the website.
		There were also links to states that were willing to redistribute vaccine within their state.  And we were pleased that all states agreed to provide contacts for redistribution of vaccine, in case that became necessary.
		Initially when the site went up there was no vaccine on the website, and then later on the vaccine from the nine million doses went up there.  We had anticipated that the website would become more valuable as the season would progress.
		The second component of the website was information, links to the ACIP, and MMWR statements, links to news, surveillance information, and other things.
		And then the third part was to provide helpful material for providers.  For example, brochures to discuss flu vaccination with their Petitioners, which I will get into in a moment.
		There were two pieces of new knowledge that we worked on generating this year.  There were provider based studies conducted by Gary Freed and his colleagues at the University of Michigan, that included focus groups of family physicians, and internists.
		And this was followed by the focus group driven quantitative survey of the same two groups.  We wanted to find out what it was that providers could look to CDC for during this flu season, and also to look a little bit at their capacity for targeting vaccination.
		One of the things that we found out, from many of the providers that this survey was conducted, right around October 1st was the midpoint of the quantitative survey.
		And what we found out is that many of the providers who had gotten limited shipments of their vaccine, had implemented a targeting policy, although this was challenging.
		Also we found out that only one-fourth of the physicians, with no difference between family physicians and internist, really had ability to target vaccination through reminder and recall systems. 
		We also did studies, these are focus group studies, targeted at the general public.  And the intent on this was to understand some of the barriers to vaccination, and some of the motivating factors for vaccination. 
		And one of the things we found out, we found out several things, that in the public's eye there is a very discreet vaccination season, and if that is missed, that is going to be problematic.
		There was a real non-perception of self-identification of high risk.  A 70 year old would say, that vaccine can't be for me, I'm healthy, it is really for the frail elderly, and I think there is a lot of merit to that, to feeling healthy, and not feeling like I'm a frail person.
		There was a real willingness for all patients, adults, young adults and elderly adults, to protect others through vaccination of themselves.  So if they said, well I'm not really particularly at high risk, because I'm healthy, but I'm willing to be vaccinated in order to prevent me from catching the disease and transmitting it to somebody who is at high risk.
		We developed several one page brochures for physician use.  These fliers, as Gary Freed told us, were very desirable, according to the physicians in the focus group in the surveys.
		The messages for these were developed through the public focus groups about barriers to get vaccinated, how to overcome them, what were some of the motivating factors.
		Three brochures were finalized and distributed it.  And they identified, number one, how can we identify, am I at high risk and do I need to be vaccinated, either for medical reasons, or for age related reasons.
		The second brochure was a reminder not to delay getting vaccinated if a patient is at high risk.  And the third was to reinforce the idea that one individual's vaccination protects not only him or herself, but also protects others who need to be protected.
		The brochures were made widely available through HCFA's peer review organizations, provider organizations, and internet distribution. 
		The media campaign was conducted by Harrison, Maldonado and Associates.  The target audiences are listed here, African-American individuals, Hispanic-American individuals, and the general population.
		The outlets were through TV, radio, and transit ads.  The materials that were developed were made available to partner groups through the same channels that we had the brochures made available, and there was a two phase campaign that was conducted.
		In mid-November the message was to help identify those that were at risk of serious disease, to self-identify, and to make sure that they seek vaccination. 
		And the second part, that was conducted in December, was a remainder that it is not too late to be vaccinated, keeping in mind that there will be a distribution of vaccine, and that the delay doesn't mean that you don't want to have vaccination conducted later into the season.
		I would like to go into a little bit of what happened so far.  Of course, as the FDA predicted, and with -- I think their timing was practically down to the nanosecond, the delay was very much as they predicted.
		The media campaigns were conducted, and they were conducted on time.  As Roland had mentioned, the total vaccine supply was similar to last year.  This time related shortage really occurred, and time related shortage really occurred.
		And time related shortage is, if I need the vaccine today, and I don't have it, a delay is a very uncomfortable feeling, it is really a shortage in time.
		The variation on timing and order fulfillment was very problematic this year.  One of the common complaints that we had heard is that there is a grocery store, or a drugstore that is conducting a campaign over here, yet I'm a pulmonologist, and I can't get influenza vaccine for my patients. 
		This was brought home several times, and in several different ways to us, this variation in timing of order fulfillment was very problematic, and this led to many upset immunization providers.
		Many vaccination campaigns, as Roland had mentioned, were delayed and some were canceled.  And the spot vaccine prices rose and fell.  Third party redistributors of vaccine charged higher prices in the midseason, and then these prices fell, again, as vaccine became available  when the delay was being resolved.
		The vaccine that we procured production of, with Aventis, was available on schedule, but it did not sell well.  And I would like to indicate this a little bit here.  One of the things between the extremes of the yellow arrows here, is an indication of the inelasticity of the pipeline, where it takes a certain amount of time that really can't be shortened, between procurement of production, and actual shipping of vaccine. 
		And so even though this was safety net vaccine, it would have been more valuable had it been available early in the season, but that is really not biologically possible. 
		Again, the CDC procured vaccine was safety net vaccine.  There were many orders of intent to purchase when the website went up.  These, of course, were prioritized by the algorithm, and the peak ordering was 4.5 million doses of an intent to purchase.
		But those who purchased were allowed to not follow through on the order if, for example, we had discouraged people from double ordering vaccine, or ordering sort of a security or safety net vaccine, in case their order didn't come through from the delay.
		But we think that really happened a fair amount this year, because most of the 4.5 million doses that were ordered were canceled.  Purchasers could withdraw intent.  The total that we have sold and distributed so far is 1.5 million doses, or 16 percent of the nine million doses.
		There are a large number of programmatic lessons that we have learned, and are learning, and I'm sure that we are going to continue to learn, and I suspect I'm going to learn a fair amount today, also.
		Number one, this is something that you all know, and know very well, and we are learning not only for this vaccine, but perhaps for other vaccines, is how fragile the vaccine supply really is.
		The second lesson is that vaccine must be available on time in the public's eye, and the tremendous amount of time it takes to plan campaigns, and plan immunization events of delayed vaccine is very problematic to deal with.
		The third major lesson is just how completely private the system really is.  I mean, if you take a look in contrast with, for example, CDC's childhood immunization program, where approximately 50 or so percent of the vaccine goes to federal contracts, a very small amount of the vaccine for influenza probably one or two percent goes through federal contracts. 
		The distribution itself is also private.  Third party distributors are very prominent in there, and they develop clientele lists, and usual customers, for who gets their vaccine. 
		Many of the distributors, and some providers, have early contracts, contracts may be being made this month, next month, and into March.  These early contracts sometimes have penalty clauses for failure to deliver the vaccine on time.
		And if the -- for example, if the vaccine is going to be delayed, if it is not going to be delayed, usually the penalty clause is not going to be an issue.
		But in a delay it makes it very difficult to consider trying to redistribute vaccine to those in greatest need.
		Physician ordering behavior is probably going to be difficult to change.  Again, there is sort of a routine ordering, going back to the same distributor, and it may be difficult to really change habits to order earlier, or to have more influenza immunization providers.  I think there is going to be a lot of challenges there.
		We had very limited ability to influence a private market.  And we think that one of the other lessons is that we need to engage private sector much earlier, and as early as possible, as we can do that. 
		Vaccine demand, of course, is time sensitive, and that is sort of the theme of this talk.  And I think in Roland's talk, also.
		Matching supply and demand is very difficult.  For example, right now, there is a surplus of vaccine. 
		Another lesson that we are learning is that targeting vaccine is difficult, and requires change in behavior on provider parts.  It is also going to, probably, require state and local public health infrastructure to help target vaccination efforts to steer vaccine to get more involved in immunization programs, and to help create the demand in the right time, for the season.
		Private sector capabilities that are currently not available will also be required.  With only 15 percent of physicians being able to implement, identify patients at high risk of, and recommended for vaccination, that leaves 75 percent of the providers without that capability.
		And, of course, that is very problematic for targeting efforts.  And a major lesson that is learned, and I think was not a surprise lesson, is that effective communications are critical.
		I would like to leave you with one last set of thoughts.  And we were fortunate, this year, for several reasons.  Number one is that we did not have an early influenza season.
		Of the last 18 seasons four of them peaked in December.  And so we are lucky that that didn't happen this year.  The time sensitive shortage, if there was an early season, would have had much more impact on hospitalizations and death.
		The total supply this year, we are fortunate because the total supply this year was similar to last year.  Had we had a severe shortage there would have been much, much more difficulty.
		And, of course, we are fortunate because this was not a pandemic year.  I think you can imagine what would have happened if this was a pandemic year.
		And with that I would like to stop and I would be happy to try and answer questions, if possible. 
		CHAIR DAUM:  Thank you very much, Dr. Rodewald, for an informative presentation.  We will take a few questions.  Dr. Fagget, welcome.  You didn't get to introduce yourself. 
		DR. FAGGET:  Walter Fagget, private practice here in Washington. 
		Lance, really an outstanding report.  And I just want to say, from the private practice sector, that we really appreciated the outstanding job that CDC did.
		And I think it points out, as you say, how important effective communication is in a timely fashion.  Your information did help us get the word out to colleagues and patients very well. 
		My question, you mentioned the private -- the public health and infrastructure, state infrastructure.  How responsive were they in terms of, and how helpful were they in getting the information out, and how much was available to you nationally?
		DR. RODEWALD:  That is a very good question.  One of the -- if you take a look at, for example, our 317 grants program to states, a very small percentage, it is by and large a childhood program.  Very small percentage of that goes for adult vaccination program. 
		The state immunization programs try to help, as much as possible, and do as much as they could do with the limited resources that they had.  For example, all states really provided a contact information, and telephone coverage for redistribution of vaccine, should that become necessary.
		But the real work of communicating with providers, making lists of all the nursing homes, calling all the nursing homes, did you get your vaccine, is it on time, which manufacturer did you, or not which manufacturer, but in case there was a manufacturer that dropped out, for example, did you order from that manufacturer. 
		Doing all of that legwork, that capacity really wasn't there.  I think communicating with providers, individual providers, and state level provider organizations is something that we would like to see happen if the capacity was there at the state and local level. 
		It is not so much the actual  delivery of the vaccines.  For example, the childhood vaccination program is largely private, also, in terms of the delivery side of it.  
		The public health department delivery is only about 15 to 20 percent.  However, it is the assurance role that public health has to make sure that vaccine goes to those individuals in greatest need.
		That is, I think, the part that needs to happen.  And I think people did as well as they could, but the resources were limited.
		CHAIR DAUM:  Dr. Stephens, then Dr. Kohl.
		DR. STEPHENS:  Some of this sounds like the California power shortage.  
		Do you have any data on who got the vaccine first, and in what order groups received it?
		DR. RODEWALD:  We don't, yet.  That is a good question.  We don't yet, but the National Vaccine Program Office funded an evaluation so that we can take a look.
		There was an agreement with the manufacturer to try to help us trace down who got the doses of vaccine and the nine million doses, so that we can try to understand that better.
		Now, one of the questions is, is how  -- that information is going to be very helpful in the future, and it may help us target vaccination efforts, or help to understand distribution efforts in the future.
		But because the -- I think the results would probably be very different if there was a serious shortage.  All nine million doses got snapped up right away, because there wasn't enough vaccine. 
		So I think one of the things we need to learn, and one of the things we realize, is that we have to understand sort of the epidemiology of the influenza vaccine distribution system much better than we do.
		So I think your question is good. We are fortunate that we have some studies that will try to look at that.  And, of course, it is too early now, because the vaccine is still for sale.
		In fact, it stops being for sale tomorrow, and the evaluation will be for this spring.
		CHAIR DAUM:  Dr. Kohl, and then Dr. Diaz.
		DR. KOHL:  I find myself in a high risk group, because I have grey hair.  And I went to my private practitioner and he said, sorry, we don't have any, go to the shopping center, which is where I was immunized, and my wife.
		And I guess my question is, yes, we dodged the big bullet this year, and it was kind of scary.  If this had been a bad flu year we wouldn't be discussing this as impassionately as we are, and I suspect there would be blood on the floor.
		Taking advantage of that, what is going to change so that a profit motivated distribution system can respond to serious shortfalls, which sounds like they will occur predictively in the future as well. 
		DR. RODEWALD:  Obviously that is a very good and key question.  One of the things that is interesting is that sort of these non-traditional sites have really become quite prominent in the vaccination system for adults.
		And when we talk to the -- to companies that put on large vaccination efforts, they say that they really do try very hard to target vaccination to the high risk patients, and give figures up in the 60 percent.
		I see you shaking your head, and I think that your skepticism is appropriate, because we don't really know how well you can target this. 
		One example, this gets back to communicating early, and trying to understand the distribution system a little bit better.  The American Medical Association has proposed to bring the manufacturers and distributors together in a conference to take a very hard look at this season, how we can improve things next season.
		There are a number of ideas that will be developed.  I think that these early contracts with penalty clauses are kind of challenging, because that really locks in a system that if one manufacturer drops out, or can't produce, or has a very delayed production, it is very difficult to re-steer vaccine. 
		And so whether or not we could develop example contract specifications that might provide a way out of a penalty clause, or something like that, I don't know. 
		I think that a variety of ideas need to be explored.  And so we are looking to, looking forward to the American Medical Association taking some of that on in terms of bringing the private sector together.
		There are a number of discussions on what is the proper role of public health, how much of an infrastructure really is needed.  I think your question also gets to Dr. Fagget's question, in terms of, you know, what is it that the public health would do, are there authorities that exist that would need to be used, or not used in these situations? 
		And these discussions are happening and ongoing.  And I think that this season, I like how you put it, we dodged a bullet, or perhaps the bullet was mis-aimed, and we are lucky that we didn't have to dodge too much, because we are not that nimble, I guess, over here.
		And we are very worried about this happening again in the future.
		CHAIR DAUM:  Pam?
		DR. DIAZ:  Lance, I wanted to make a couple of comments.  One, in particular, you mentioned the effect of communications.  And I really wanted to comment that I thought the CDC did a superb job this year of communicating, as has already been mentioned.
		What was going on with flu season, and what kinds of things should be done, we were able to take that and then relay that forward.  So I applaud you for that, for those efforts.
		Likewise my comments have been -- regarding distribution I think have already been heralded by other members.  But certainly some kind of a targeted distribution versus a redistribution seems inherently more stable in the sense that there is not a third party involved in the redistribution.
		There will always be some redistribution, I'm sure, of vaccine based on need, selective targeted need in various areas.  But, nonetheless, I think some of the problems we experienced were very much associated with difficulties in getting the vaccine once it was available, from the manufacturer, actually into our hands.
		And, finally, I was curious about your comments about contracts with clauses in them.  Because I'm aware of quite the opposite situation, such as that of ordering and being bound to a contract that has no clause, and henceforth really unable to take advantage of the nine million doses, or a parcel of that, due to being bound to paying for vaccine that was already ordered.
		DR. RODEWALD:  That is interesting, that is a helpful comment, because we hadn't really, you know, I don't think we've really discussed it from sort of that end of the beneficial side of the lock-in, in there.  That is interesting.
		DR. DIAZ:  And it was limited funds, and only a certain amount of funds, once one gets locked into a contract, regardless of the delay, and perhaps availability elsewhere.
		About the only thing that can be done in that sense is swap, give me some now, as soon as we get ours we will give it back, which is exactly what we put in place.
		DR. RODEWALD:  Right.  And swapping is problematic because you have to be able to pay attention to the cold chain, and all of the --
		DR. DIAZ:  Exactly.
		CHAIR DAUM:  Take a comment from Dr. Estes, Dr. Decker, and then we have to move on.
		DR. ESTES:  My comment was triggered by Dr. Kilbourne's earlier statement, and I have a question about what is the shelf life of these vaccines, and since we now are in a situation where we have surplus, has anyone been discussing the possibility that should we face a situation like this again, even though it may not be the best match, that perhaps we could have vaccine set aside from the previous year, that it could at least begin to be used for the highest risked population?
		DR. RODEWALD:  Yes, the latter part, these discussions are going on.  And what I would like to turn it to, your first question, to somebody that has more of the technical knowledge of what the shelf life of the vaccine would be, and looking to Nancy, Keiji, or Roland.
		CHAIR DAUM:  Anybody sitting at the table want to comment on that? 
		DR. LEVANDOWSKI:  I will take a stab at it.  Influenza vaccines have an expiration date on them that is artificial, right now.  I think everybody knows that.  The date that is put on vaccines for expiration for non-military use is June 30th.
		And the reason for that is to try to avoid confusion when new vaccines become available.  We could debate whether the changes are always necessary, as Dr. Kilbourne was raising earlier.
		But if there is a change that is a significant one in the vaccine, I think we would prefer to see the most current antigens being used.
		And so that is, I believe, the rationale, the best rationale for the expiration date of June 30th.  But we do know, and manufacturers can provide information on that, probably that the vaccines have stability for quite a bit longer time.
		It is not a perfect vaccine, it is not stable forever, by any means.  But during the period of time that the vaccine is in use, by and large, it is stable.
		And probably for at least six months or maybe even longer afterward, according to the way the vaccines are produced now.  I would be quick to point out that there have been some unexpected difficulties with specific vaccines, and you may recall that we had a product recall of the Parke Davis vaccine in 1996.
		And that was because of a stability problem that was recognized, very early, with one of the components.  But that is being monitored continuously, so it would be possible to have information that could be useful in trying to support any kind of policy that might be developed for use of a vaccine longer than the current expiration date.
		CHAIR DAUM:  Dr. Decker, and then I think we are going to move on.
		DR. KILBOURNE:  I just want to comment that even if there is no vaccine left, you still have the seed which you know is operative under production conditions.
		So that even if it is necessary to start over again, and rush in 94 strain, or something like that, it is still a potential advantage.  
		I wouldn't minimize the importance of the antigenic match, I don't mean to do that.  But I think we may have reached a time in an emergency situation in which we have to make that kind of a trade off.
		And I think the shelf life is probably far longer than is allowable.  We've extracted antigens, potent antigens, from leftover bulk stocks of vaccine manufacturers, years afterwards, five years later to get antigens for biochemical studies.
		CHAIR DAUM:  Dr. Decker, please.
		DR. DECKER:  I would like to just follow up on a couple of comments with respect to the most recent issue, another alternative that can be considered, that I haven't heard mention is CDC could elect to release the unused portion of the CDC's component for use elsewhere in the world.
		In the southern hemisphere, for example, where we don't run into issues of it being expired, and where the investment can be recouped, and the vaccine can do some good.
		Coming back now to the issues Steve raised, because they are obviously pressing on everybody's mind, although this was an unprecedented situation, and the particular constellation of circumstances one hopes won't arise again, companies falling out at the same time there is a difficult to grow strain.
		Still, it could happen, we want to be prepared.  In that regard a couple of things that I wanted to take note of. 
		The first is I had a clear sense, as the flu season evolved, that the system was adapting.  Just as the manufacturers were learning how to make the vaccine, the distribution system, and private practitioners were learning how to deal with this delayed arrival of vaccine. 
		And I noticed it seemed to be much more common in the latter months, than in the earlier months, that those third party distributors, who did have supplies of vaccine because of their locked-in contracts, and so on, were shifting their distribution, and in many cases handing vaccine over to the public system, or to nearby hospitals for distribution, rather than through the systems they originally planned.
		So one thing I think that we should not lose sight of is that there are multiple elements of our current distribution system, that have been learning how to handle this, and we need to keep working on that, and training them how to deal with this.  I think that will improve things.
		Another thing that I know that Aventis is doing, in order to dramatically reduce the likelihood of vaccine not being able to get the high risk persons, is that henceforth there will be a new distribution system in which everyone who seeks vaccine will get only part of their order in the first part of the season, which is specifically flagged as being for use for high risk persons.
		And then as the pipeline fills with available product everybody's orders will be filled.  So we won't have the situation that happened this year, where those who happened to have the earliest orders got everything, and then those who got in line late got nothing until supply caught up.
		That was, I think, one of the major problems.  And it happened that way because no one had ever faced this situation before, and we didn't know it was going to happen.
		But I think this is a major step towards avoiding this type of situation in the future.
		CHAIR DAUM:  Thank you, Michael.  I would like to move on at this point and introduce Dr. Wendy Keitel, Associate Professor of molecular virology and microbiology, at Baylor, who will share some new, interesting information with us.
		DR. KEITEL:  Good morning, excuse me for must a moment while I get this straightened out.
		Thank you very much for giving me this opportunity to present the results of a clinical trial that we conducted this summer in response to the delay and potential shortage of influenza vaccine. 
		I think Drs. Levandowski and Rodewald have painted a picture of the environment in which plans for this study were made.
		The title is shown here, Evaluation of Immunogenicity of a Half Dose of Trivalent Inactivated Influenza Virus Vaccine in Healthy Adults.  And I will refer to this as the half dose study.
		By way of introduction, we stand on some very broad shoulders with regard to the evaluation of dose response to influenza virus vaccines.  And going back 40 or 50 years it is very clear that increasing the dose of vaccine will increase the immune response to influenza virus vaccine.
		Some of the earlier studies are more difficult to evaluate because of the method for determining the antigenic content.  But since SRID, or radio immunodiffusion was introduced for assessing antigenic content, studies that evaluate a broad enough range of dose have clearly shown that increasing the dose of vaccine will increase the immune response.	
		So over the last 30 years, or so, a number of studies have done evaluating doses between two and a half micrograms of influenza virus hemagglutinin, up to 405 micrograms of hemagglutinin. 
		There has been some discussions that doses differing as little as two-fold do not result in enhanced immunogenicity, but I think the bottom line is that with a large enough sample size, with two to three fold increase dose you would be able to show a difference in immune response.
		But the question then becomes, would the reduction in immunogenicity be significant, and could one actually user a lower dose of influenza virus vaccines in a circumstance where there is a clear shortage of vaccine. 
		Before I proceed I would like to acknowledge the participants in the study.  As you can see, a large number of people, as well as agencies, made contributions to this effort.  The six vaccine and treatment evaluation units, and the respiratory pathogens research unit of the Baylor College of Medicine, sponsored by the NIH enrolled the clinical subjects.
		Evans provided the Medeva vaccine, and statistical support was provided by EMMES, the FDA, CDC also made valuable contributions to the design and analysis of the trial.
		Notably lacking on this slide is the project officer who oversaw this entire effort, Lind Lambert, and I would like to make a special acknowledgement of her contribution, as well as that of John Trainer, who was the principal investigator for the trial, but unfortunately was unable to present the results of the trial today.
		We enrolled subjects between the ages of 18 and 49 who had no medical indication to receive an influenza vaccine.  For this reason pregnant women, now recommended to receive vaccine, were excluded from participation.
		The upper age limit for inclusion in the trial was set at 49 because of the recent decision to target individuals between the ages of 50 and 64.
		The vaccine was commercial subvirion trivalent inactivated vaccine containing this year's antigens, and each one half mil dose, or full dose, standard dose of vaccine contained approximately 15 micrograms of hemagglutinin of each of the three strains contained in the vaccine. 
		The study was a multicenter, open label, blinded clinical trial.  That is, the subjects were not informed of the magnitude of the dose they were receiving, but the vaccine administrator and investigators were aware of half and full dose administration.
		Participants were stratified according to their receipt of trivalent vaccine within the preceding three years.  And the reason for this was because it is very clear that immune responses to influenza vaccine will differ depending on receipt of recent vaccine. 
		After stratification they were randomized to receive a single full dose containing the 15 microgram per dose, or half dose, containing approximately seven and a half micrograms of each strain per dose, into the deltoid muscle.
		Although primary end point of the trial was not to asses differences in reactogenicity between a full dose and a half dose, we did have an interest in collecting some type of information about how well the vaccine was tolerated.
		So subjects were asked to complete a diary card asking them about questions in the injection site, and overall systemic reactions.
		Blood samples were collected immediately prior to immunization, and three weeks after immunization, for determination of HAI antibody levels, and these assays were conducted in both the CDC and the FDA labs on the samples.
		For the rest of the presentation I will use the CDC data to display the results.  However, I would like to emphasize that, as has been shown, frequently there are very strong correlations between  CDC and FDA results.	
		The end points of the trial were to asses immune responses, and the following parameters were assessed.  The percent of subjects achieving a titer of at least 1 to 40 in their post-immunization sample, was determined.
		And, historically, levels of 1 to 32, or 1 to 40, depending on the laboratory, have been considered immunization goals, because of their correlation with protection against influenza. 
		The geometric mean titer and percent of subjects with four fold or greater titer rises in serum antibody also were determined.  However, percent with rise was not considered a primary end point.
		Based on a consensus among the investigators, and other influenza experts, we established what we considered to be acceptable immunogenicity in the half dose group, when compared with the full dose group.
		For the percent achieving a so-called protective titer, we considered a difference of 20 percent, or less, between the two to be acceptable.  That is percent in the high dose group -- excuse me, percent in the full dose group, minus percent in the half dose group.
		For the geometric mean titer of ration of less than, or equal to 1.5, was considered acceptable.  And for a percent with rise a difference, once again, of 20 percent or less was considered acceptable.
		Now, the study used a similarity design to compare responses in the full dose and the half dose groups.  And the sample size of 420 subjects per group was considered necessary to conclude that the response to the half dose was adequate, if the geometric mean titer was no less than 67 percent in the full dose group.
		So you heard a little bit about the concept that was proposed early in June.  The subject were beginning enrollment at the end of July.  By the end of August the full cohort, within three and a half weeks or so, the full cohort of subjects had been enrolled, data were analyzed, and results reported to the ACIP by the beginning of October. 
		And this slide shows you the enrollment by stratum.  Stratum 1, shown in triangles, were subjects who had recently received inactivated vaccine and stratum 2 had not received an influenza vaccine, ever, or at least within the past 3 years.
		And you can see, approximately, equal numbers were enrolled into each of the two strata.  And in total 1,009 subjects were enrolled over this period of time, three of whom were not evaluable.
		The vaccine was extremely well tolerated, as has been shown in numerous clinical trials. The most common side effect was some discomfort at the injection site.  
		You will note that about 50 percent of subjects receiving either the half dose, or the full dose of vaccine experienced no injection site reactogenicity.  And among the 50 percent or so that did, most of this was characterized as mild.
		There was a very low rate of systemic complaints, and no differences between individuals receiving the full dose or the half dose.
		Now, as has been demonstrated previously, and shown again here, there was a statistically significant increase in the minor injection site discomfort in the subjects who received the higher dose of vaccine, and not shown on the slide is the fact that subjects who received vaccine for the first time actually had a little bit significantly more reactogenicity. 
		Post-immunization geometric mean titers against each vaccine antigen, here H1, H3, and influenza V are shown in this slide.  Geometric mean titer is shown on the Y axis.  Once again, half dose is shown as a white bar, and full dose is shown as a blue bar.
		We have stratified here because of the significant differences between previously vaccinated and not previously vaccinated, into these two groups.  And I would like to point out that, in general, the geometric mean titers were similar, levels achieved were similar.
		However, statistically significant differences between subjects given full dose, and half dose, were observed for H1N1, H3N2, and previously vaccinated, and for H3N2 antigen in subjects who were not previously vaccinated.
		Now, when you combine these groups together, and treat them as individuals getting half dose, or a full dose of vaccine, there was statistically significant differences in the mean titers for all three antigens.
		Subjects achieving a so-called protective titer three weeks after immunization, is shown here, once again percent achieving this titer is shown on the Y axis, and the three antigens are shown here on the X axis.
		And you will see that the vaccine was highly immunogenic and the majority of subjects achieved protective titers against each influenza antigen, and when vaccine strata are combined there are no significant differences between the groups.
		Finally present with a significant response to vaccine is shown on this slide.  And this is where the biggest difference is between the two strata can be observed.  And you will note that in subjects who have been recently vaccinated with influenza virus vaccine, the percent of response is much lower than among subjects who have not recently received an influenza virus vaccine.
		And, from my point of view more importantly, in this panel, we see that there were significant differences in response rates against all three antigens among subjects who had been previously or recently immunized.
		So, finally, these data have been combined into a single slide to put them in the context of what we had defined as acceptability criteria.  In the first panel the percent achieving a protective titer, second the ratio of post-vaccination geometric mean titers, and then the third, the percent with the four-fold rise.  This, for the reasons I've described, being a secondary end point.
		Remember we accepted a difference of 20 percent between the two dose groups, and for a percent with rise, and percent with protective titer.  So in these two panels the Y axis is the percent difference between the two vaccine groups.
		So that for HN1N, there was about a four percent difference in the percent achieving protective titer.  And the one sided upper 95 percent confidence limit is shown here.
		So this falls well below our -- what we consider to be an acceptable immune response among subjects given the half dose, when compared with subjects given the full dose.
		And the same holds true for HVN2 influenza B.  In the center panel the GMT ratio, that is the full dose GMT over the half dose GMT, I will remind you that we had set a ratio of 1.5 as being acceptable in the study sample size.  This determined based on the power to detect this kind of a difference. 
		So, in summary, overall the half dose of vaccine was less immunogenic than the full dose among healthy younger adults.  And the immune responses to the half dose met preset acceptability criteria for all three antigens.
		So then the question becomes one of in the event of a true vaccine shortage, would a half dose of vaccine administered to twice as many people provide greater benefits than a full dose of vaccine administered to half as many people? 
		I would like to show some very preliminary data regarding a decision and analysis that was conducted in collaboration with Scott and Donald Berry of Berry Associates.
		And I will need an overhead to do this. 
		(Pause.)
		DR. KEITEL:  During the -- can you all hear me, is this one?
		During the period between 1983 and 1987 the Influenza Research Center at Baylor and Houston my colleagues and I conducted a randomized control perspective clinical trial of commercial inactivated influenza virus vaccine.
		And the goal of the study was to determine whether repeated annual immunization with influenza vaccine continued to provide protection.
		Although the public health policy had been to administer influenza virus vaccine, annually, some studies in British boarding schools had suggested that the protection conferred by subsequent doses of inactivated vaccine was inferior when compared with the first dose of vaccine given.
		So this clinical trial was designed to test the public health policy.  And each year subjects were enrolled and randomized to receive other placebo or inactivated vaccine, which in this case was commercial whole virus influenza virus vaccine.
		Once the subject had been assigned, randomized to receive vaccine, then for subsequent years they were given vaccine, so that we had cohorts of individuals with successively increasing numbers of annual immunization.
		Subjects enrolled into the study were monitored, prospectively, during the winter season, and were evaluated for the occurrence of any febrile and/or respiratory illness during influenza seasons, which was determined by means of intensive virologic surveillance in the community conducted, and surveillance conducted in our laboratory. 
		At the time of illness evaluation a sample of respiratory secretions was collected and cultured for influenza viruses.  Blood samples were collected at that time, and several weeks later, to determine whether an immune response had developed to the influenza virus, so that we had five successive seasons of illness assessments, paired blood samples.
		In addition we collected blood samples before and one month after immunization to assay for the level of antibodies to vaccine antigens.  
		Now, after the epidemic strain for each year had been identified, and characterized, then blood samples were tested, again, for immune responses to the epidemic variant.
		So that we had blood samples to the vaccine variant, to the epidemic variant, on subjects enrolled in this trial.
		Each year between 600 and 1,000 subjects were enrolled into the trial.  So that what we ended up with was a large number of sera in which the antibody levels, after immunization, or prior to the epidemic, could be used to determine the level of antibody which would confer protection against influenza. 
		Now, these are not particularly new data, but these constitute a very large data set.  A number of investigators previously had reported either under field conditions, or in the circumstance of artificial or experimental challenged with well typed influenza virus that levels between 32 and 64, or 40, or whatever, were associated with significant protection against influenza. 
		So the -- I show you, in this overhead, the data set between '83 and '87, and I show you, in each year -- in some years we had two strains.  But in these preliminary analysis we only have the results for one strain in each epidemic season. two H1N1, three H3N2, and one influenza B epidemic.
		Parenthetically, during this period we had what we would consider suboptimal match between vaccine and epidemic strains.  We had seven epidemic strains, and in two out of the seven we had good antigenic match, in the A/Philippines epidemic, and the A/Taiwan epidemic.
		Now, this -- what is shown here is the attempt to develop a model which would predict the likelihood of being infected based on the pre-season antibody level. 
		Drs. Berry have used a bazian approach to develop a model so that we could use the data collected in the clinical trial to predict what the outcome might be if we chose various immunization strategies.
		So shown here is the plots of the five epidemic strains, the proportion of subjects experiencing influenza over the season, as a function of log base to titer, and their post-immunization sample.
		And this relationship has been observed previously, but now has been modeled.  And without getting into the details of the model, I would like to show you the results of a preliminary analysis, decision analysis, looking at different strategies.
		So, let's say there had been a huge vaccine shortage, the question is, well could we, for those healthy younger people, who elect to be vaccinated, could we safely recommend a half a dose of vaccine as opposed to a full dose of vaccine? 
		And so shown here are various dosing strategy.  No one is vaccinated, everyone gets what we consider the optimal dose, half receive a full dose, all receive a half dose.
		And so these are estimated cases, or tac rates per 1000 using some CDC data.  And over in this column are shown the extra cases, if you had elected to use any of these particular dosing strategies.
		So if everybody received a full dose, if you compare this with all who receive a half dose, you can see the number of extra cases, per thousand, is five.
		So that it would be better to give everyone a half dose than the circumstance of using a regular does of vaccine, and giving it to half as many people, where 43 extra cases of influenza per thousand might occur.
		So we were fortunate in this season that we did not have to utilize the half dose vaccine, but I think we are beginning to look at ways that in the event there were true shortage of influenza vaccine we might approach, one strategy might be to offer a lower dose than is ordinarily recommended.
		But before I leave you with that thought, I would like to emphasize our concern about extrapolating the results of this trial to other populations, older individuals, and persons who are at high risk of death and complications following influenza. 
		It has clearly been demonstrated that as we age, and as we develop underlying medical conditions, the immune response to inactivated vaccine declines.
		And so  our group has really been interested in moving the other direction, rather than reducing the dose of influenza vaccine to consider increasing the dose of vaccine. 
		This is one of the number of strategies which include agivents, topical immunization, increasing the dose, and so forth.  And this is the result of a small clinical trial in which we compared the immunogenicity of subvirion vaccine with that of purified influenza virus hemagglutinin in similar doses, 15, 45, and 135 micrograms of purified influenza A, H1, and one antigen.  In this case it was A/Taiwan.	
		And this we conducted in a healthy elderly population that would show, even with very small numbers of subjects, that has a significant dose response with increasing antigen content, both in the serum, and not shown as well as in respiratory secretions.  Thank you. 
		CHAIR DAUM:  Thank you very much, Dr. Keitel.  There are one or two burning questions on the part of the committee.  We will go with Ms. Fisher and Dr. Ferrieri.
		MS. FISHER:  Do you know why there was not as strong an immune response in those who had received the vaccine, flu vaccine previously, versus those for whom it was the first dose?
		DR. KEITEL:  There are several potential reasons for this.  And I would say that the first is pre-immunization antibody titer.  And when, actually the data that I've just described, if you do a multi-varied analysis, the pre-immunization antibody level is a significant predictor of responding to vaccine, as is age, and dose.
		The second caveat that I would like to point out is that subjects enrolled into this trial, reported verbally whether they had received a flu vaccine within the preceding several years.
		And they were not randomized to receive yes or no.  So there is, possibly, an element of cohort effect, as well. 
		MS. FISHER:  Pre-vaccine antibody titers, in other words, those who had had the flu, and had had antibodies to the strains, is that what you are saying?
		DR. KEITEL:  I'm sorry.  Individuals who had been recently immunized against influenza have significantly higher pre-immunization antibody levels.
		MS. FISHER:  Right.  I was asking why would there be less of an immune response for those who had been previously vaccinated, wouldn't there be a stronger immune response?
		DR. KEITEL:  My opinion is that the people who had been previously vaccinated start with a higher level of antibody, and that impairs their ability to respond to that dose of antigen.
		MS. FISHER:  But what does that say for the protectiveness of the vaccine in that year, for those who had been previously vaccinated, what does that say in terms of people who had been repeatedly vaccinated with flu vaccine, and their ability to mount a proper antibody response and indeed be immune that year?
		Am I not understanding this?
		DR. KEITEL:  In the clinical trial that we conducted we compared the post-immunization geometric mean titers among subjects who had been randomized at the time of entry into the trial, and got increasing numbers of annual immunizations. 
		The pre-immunization titers each year were higher among individuals who were previously vaccinated.  But the post-immunization geometric mean titers were similar for all years, and antigens, with the exception of one antigen, in the latter part of the study in 1997, 1998.
		So I think that when we look at responses to influenza vaccines we have to be careful about which parameter we are looking at.  One is a four-fold rise, and you are less likely to experience a four-fold rise in titer after immunization if you've been previously immunized.
		And the effect of previous immunization on the geometric mean titer has been variable in study to study.
		CHAIR DAUM:  We need to move on.  Dr. Ferrieri, please.
		DR.  FERRIERI:  Well, that was my question.  I thought that perhaps that one would have expected, as Ms. Fisher did, in the animistic response based on some of the homologies of these antigens.
		But in reflecting on this there are a number of other models in microbiology where pre-existing antibody titer may dampen the response.
		It asked a group A streptococcal disease where an ASO and anti-deanase B are blunted in those who had higher titers at the time of a new exposure to group A strep.
		So it isn't so illogical.  But I appreciate, you know, that you might have expected, perhaps, the opposite.
		CHAIR DAUM:  Dr. Kilbourne, very briefly.
		DR. KILBOURNE:  It is not so much an inability of these people to respond, it is an inability for you to perceive their response to the geometric progression.  That is what it boils down to.
		I mean, they are actually making lots of antibody.  But when you set yourself an arbitrary definition of four-fold increase, then they may not make it.  Yet they also may be losing higher affinity antibody.
		And, also, the question I have is whether the previous vaccine was a heterovariant immunization, in which case you would have the problem of regional antigenic sin, and animistic response directing response to the wrong direction in people previously immunized.
		CHAIR DAUM:  Thank you, Dr. Kilbourne.  Thanks to our three speakers this morning for what I thought was a very enlightening series of presentations.
		We would like to move on and call on Dr. Katherine Zoon who is the Director of the whole operation here, the Center for Biologics Evaluation and Research, to make some presentations to retiring members. 
		DR. ZOON:  It is a pleasure to be here.  Thank you, Bob.  
		This morning, as you know, we have several members of our committee who are retiring from the committee, in quotes.  And I think it is really very special for the public service that they have provided the FDA, and actually the American people, on these important discussions surrounding vaccine issues.
		And it is one opportunity that the Center has to officially recognize their important contribution.  So this morning, in appreciation of those members, I would like to recognize them, and provide some plaques.
		The first is to Dr. Mary Estes.  Mary, are you here?  Mary, I just want to say it has been a delight to have you on the committee, and I hope that we will see you in the future, to help us again with some important issues.  Thank you, so much.
		CHAIR DAUM:  Subsequent plaque recipients, please take note.
		(Applause.)
		DR. ZOON:  The next is to Dr. Alice Huang.  Alice, it has been a pleasure to work with you in many different avenues over our careers.  And, especially, thanks for your contribution to this committee.  Thank you very much.
		(Applause.)
		CHAIR DAUM:  Dr. Huang wanted to take a minute of committee meeting to say a few words, having received her plaque, and now might be a good time to do that. 
		DR. ZOON:  Great, thank you.  Please.
		DR. HUANG:  I just wanted to say that from all of my experience on a variety of committees, that this committee is the best staffed.  The staffing is not only most efficient, it always has a view towards cost effectiveness, as we can see in the no-frills meetings that we hold.
		(Laughter.)
		DR. HUANG:  So I want to thank you for this opportunity to have been able to serve with such a professional committee.  And I've also enjoyed working with the very knowledgeable colleagues that I've met here.
		(Applause.)
		DR. ZOON:  Alice, I'm not sure if you are saying we are cheap, or thrifty.  But we do serve coffee to the committee members, so I have to say that. 
		DR. KOHL:  The coffee is kind of weak.
		DR. ZOON:  And last, but not least, I have the honor of presenting two plaques to Dr. Harry Greenberg.  Harry has served on our committee, but as well has chaired our committee. 
		And, Harry, we really appreciate the service and leadership that you have provided to the VRBPAC in dealing with some very difficult issues over the past several years.
		So, one, I appreciate your service, and I hope your neck gets better.  Thank you. 
		DR. GREENBERG:  This is what happens if you mess around with the committee. 
		So, Alice really stole a little of my thunder.  I would like to say that I have rarely worked with a group of colleagues, that is the committee members, who are so dedicated, and so good at what they do.
		The public is well served by this group of people, and I would like to thank all of you who have been very helpful.
		Secondly, the staff is outstanding.  I can't single out all of you, but basically to a person the FDA staff is outstanding.  But, Nancy, who is sort of the point person who many of us interact with, really is the grease that keeps this thing going, and keeps all of us in good humor at times when our humor might be flagging.  So, thank you, NANcy.
		(Applause.)
		CHAIR DAUM:  Well, there is a tremendous groundswell of feeling that the committee -- a picture of the committee now needs to be taken.  So because of that we will now take advantage of that for a morning break.
		We will break for twenty minutes.  I have five to ten here in the eastern time zone, and we will resume at 10:15.  Committee members do not get to leave the room, however.  And please assemble over here to be arranged by our photographer for a quick photo op.
		(Whereupon, the above-entitled matter went off the record at 9:55 a.m.  and went back on the record at 10:20 a.m.)
		CHAIR DAUM:  I would like to call the committee back to order at this point, please.  We do have a little extra time on our hands today, but if we keep being somewhat lax in our time observance we may end up being behind the eight ball.
		So I would like to get moving.  We would like to move, again, to another series of three presentations regarding influenza, to get to a point where we can begin our deliberations.
		And we will begin with Dr. Fukuda from the CDC, who will enlighten us regarding U. S. surveillance.  Dr. Fukuda?
		DR. FUKUDA:  Thank you, Dr. Daum.
		In a couple of minutes what I would like to do is describe what has been going on this season, and then sort of put it in context to the last couple of seasons that we've had.
		I think, as all of you know, during the last number of seasons, these have been dominated by influenza A, H3N2 viruses, and they have been quite severe in terms of their clinical impact.
		The bottom line for this year, by contrast, we are really seeing a mixed viral season in the United States, similar to what is being seen in many other parts of the world.  And the clinical impact, so far, has been less than it has been in the previous seasons.
		Up here, on this slide, what we do is have the numbers from the World Health Organization, and National Respiratory Virus system of laboratories.  And basically between October, up until about January 20th, about 30,000 respiratory specimens have been tested for influenza viruses.
		And of these seven percent of them have been positive for influenza viruses, for about 2,239 isolates.  
		Now, among those influenza viruses about 73 percent, or three quarters of them have been influenza A viruses, and the remainder have been influenza B viruses. 
		Among the influenza A viruses, here are the influenza A viruses.  And among those 38 percent of those have been subtyped.  And of those which have been subtyped, the vast majority, 97 percent, are influenza A HN1N viruses. 
		So, again, we are seeing a mixed season, with a quarter of the viruses influenza B viruses, and among the remainder influenza A viruses, almost all  of them have been influenza A H1N1.
		And this slide here graphically shows, basically, the information that I just told you.  The green bars are the influenza B viruses, the yellow and the blue bars are the influenza A viruses.  These are un-subtyped A viruses, these viruses down here are influenza A H1N1.
		And, again, you see that there have been some H3N2 viruses, but very few.  
		Now, we saw, this line here represents the percent positive, cumulative percent positive percentage of the virus of the specimens that are positive for influenza A viruses. 
		And as of the most current week, right now, about 22 percent of the specimens coming into this system are testing positive for influenza viruses. 
		When you look at past seasons we typically peak somewhere between 19 percent and about 33 percent being positive for influenza viruses.
		This map here basically shows where A or B viruses are predominating in the country.  The red represents a predominance of influenza A viruses, the blue represents a predominance of influenza B viruses.
		So you can see that most -- in most parts of the country, A viruses are predominating.  But on the west coast, and somewhat on the east coast, we are seeing areas where B viruses are predominating.
		Now, another thing that we follow at CDC are the percentage of visits to a group of about 500 sentinel physicians.  And what percentage of those visits are for influenza-like illness.
		And, nationally, we are seeing that about three percent of visits to this group of sentinel physicians are for influenza-like illnesses.
		Again, in past seasons we have seen this peak up at about five to seven percent.  And in this map here, what we see are that the rates of visits to physicians for influenza virus, or influenza-like illness, vary by region.
		The darker blue states represent areas in which the percentage is higher, and the light blue states represent those areas in which the percentage is lower.
		So, again, on the west coast, around the Texas area, and in the mountain states, the percentages range from about four to seven percent.  And then in the remainder of the country they range about two to three percent.
		Now, another way that we asses influenza activity in the country is to get reports from each of the state and territorial epidimiologists.
		And for week three, the most recent week, 30 states are reporting either widespread or regional activity.  At the same time last year about 41 states, or 48 states were reporting either regional or widespread activity.
		And, again, this map gives a slightly different picture.  This is the reporting by the state and territorial epidimiologists.  The red states represent states in which activity is being termed widespread.  The blue states represent states in which activity is a step down, so-called regional activity.  And you can see it sort of scattered all over the country in no clear pattern.
		Finally, the last parameter that we follow is the -- are the rates of pneumonia and influenza deaths in the country.  You can see that in the previous four seasons, that we have had these pronounced and fairly large peaks in pneumonia influenza deaths in the country, going above the sinusoidal base line.	
		By contrast, in this season so far, we have not gone above the threshold for PNI deaths.  Again, sort of cementing the idea that we are having a milder season than we have had in the previous seasons.
		So to put this in context, again, this is a graph of the percent positive specimens coming into the WHO, the National Respiratory Enteric Virus lab system. 
		The blue graph represents what we saw last year, where we saw a larger number of isolates, and we saw a peak coming earlier in the season.
		In the current influenza season we are seeing a slower increase in the number of virus isolates, and in the percentage of positive specimens.  And we have not seen the peaking yet.
		So we don't really know whether this is going to continue up higher, whether it is going to plateau, or what it is going to do.  We just know we haven't seen the peaking yet.
		And, similarly, this graph here shows what the visits for influenza-like illness to the sentinel physicians was for last season.  That is this blue curve here.  And this red curve, here, represents what we are seeing so far this year in the United States. 
		So I will stop there.
		CHAIR DAUM:  Thank you very much, Dr. Fukuda.  Are there one or two committee questions?  Dr. Diaz, Dr. Goldberg, Dr. Katz, Dr. Kohl.
		DR. DIAZ:  Dr. Fukuda, just out of curiosity, the 30,000 plus specimens that have been looked at, at WHO referral labs, I'm always curious about the, in this case, 93 percent that are negative for influenza. 
		Is there any comments, epidemiologically, what those negatives represent, do they look for other viruses, or is it that they were tested as influenza positive locally, and yet the specimen didn't survive in making it to the laboratory; any knowledge of what those represent?
		DR. FUKUDA:  Yes.  It is probably a combination of both of those possibilities.  I think that probably some of these represent purely negative test results, because the swabs may have been taken too late to isolate any sort of pathogen.
		But if you look at surveillance reports, say from California, from Canada, from a number of other systems, it is clear that there are other viruses co-circulating in particular RSV viruses. 
		I think we haven't seen big peaks in the pair of influenza viruses.  But they are clearly out there.
		DR. DIAZ:  Likewise, I guess the reason for my comment is that with downsizing of laboratories, and the negative impact of doing viral cultures on a local level, I think that WHO and others may have to begin to take up the brunt of local surveillance by delving further into those negatives so that we know what kinds of viruses are circulating.
		DR. FUKUDA:  As an aside, one of the things that we have specifically been trying to do is to get money into those public health labs so that they can continue the viruses isolation.
		CHAIR DAUM:  Dr. Goldberg.
		DR. GOLDBERG:  I wanted to just make a comment about the discussion before the break.
		CHAIR DAUM:  We are having technical problems.  Can you speak way into the microphone, please?
		DR. GOLDBERG:  I just wanted to make a comment about the discussion before the break about the half dose study.  In the previously immunized subjects the titers are high at baseline.
		Which means, for example, if they have a titer of, let's say, 100 -- this is arbitrary, to have a four-fold increase they would have to exceed 400.  Whereas if someone had a titer of one, a four-fold increase is four.	
		So an absolute difference would be very small, but a percent, or a fold difference would be very large.  When you have levels of protective -- protective levels, it is unlikely that you can increase very much.
		And the goal is to maintain the level, and not so much to show an increase.  So I think it doesn't mean they are not protected at all, it means they have a level of protection, which is being built upon, but they can't increase very much in any terms.
		CHAIR DAUM:  Thank you. 
		DR. GOLDBERG:  So I just wanted to clarify that.  
		CHAIR DAUM:  I want to return to questions for Dr. Fukuda.  We have Dr. Katz, then Dr. Kohl, then we will move on.
		DR. KATZ:  Just a quick one. Do they represent the internist family physicians, pediatricians, mixtures thereof?
		The reason I ask is that we are seeing a lot of RSV on the east coast in among the pediatric population.  And yet that doesn't seem reflected in your respiratory illness.
		DR. FUKUDA:  Sam, Originally when the system was set up, it was set up exclusively with family practice physicians.  In the last couple of years it has really been opened up.
		So I think that pediatricians probably represent about a quarter to a third of the reporting physicians now, so that there are internists, family practitioners, pediatricians, OBGYNs.
		And you are right, these curves don't reflect RSV activity.  But, you know, if we were to pull out other data, clearly, there are a number of RSV viruses out there.
		Particularly, I think, the California State Health Department does a good job of showing concurrent activity in terms of those viruses, and flu viruses. 
		CHAIR DAUM:  Dr. Kohl, please.
		DR. KOHL:  Nice presentation, as usual.  Are there historical data that allow us to say that a late upswing in the curve means that it will be a milder season, or is it possible that it will be severe, but it is coming at us?
		DR. FUKUDA:  I guess the rule in flu is that, literally, anything is possible.  I mean, I think -- it is simply true.
		So I think that I would guess, I mean, I really hate guessing but I would guess that it is likely that we are going to continue to have lower clinical levels of activity.
		But clearly when you look, historically, you can see bimodal peaks, if H3 viruses begin to come out later in the season, as we've seen in Australia.  In Australia, initially, there is a predominance of H1 viruses, and then later on there is kind of an upsurge in H3 viruses. 
		If we see that in the United States we may see, you know, a double peaking of activity.  So it could be anything. 
		CHAIR DAUM:  Thank you very much, Dr. Fukuda.
		I would like to move on at this point with our influenza branch trilogy, and call on Dr. Cox, the chief of the influenza branch at CDC for our next presentation, World Surveillance and Strain Characterization.
		DR. COX:  Thanks very much.  We are moving on to the more technical aspects of our considerations this morning.  And I want people to try to follow along in the handout that has been distributed, in case you are not able to see the overheads here.
		We will be starting on page 9 and then progressing through.  Now, I am not going to present the CDC human serologic results today.  I'm going to leave the summary of that data up to Dr. Levandowski in his presentation.
		But if you have any specific questions about the CDC serologic data, please let me know.
		As usual I'm going to present the three groups of viruses in the order of the easiest, perhaps the easiest decision, you never know for sure, but perhaps the easiest decision, to the most difficult decision.
		And we are going to start today with influenza A H1N1 viruses.  First of all we will look at world-wide activity due to influenza H1N1 viruses by season.
		First we are looking at last winter's season, October '99 to March 2000, then we will look at what happened in the southern hemisphere, followed by what is now currently happening in the northern hemisphere, predominantly in the northern hemisphere.
		And I don't know, for some of you who have been on the committee for some time, if you will remember that we really had relatively little H1N1 activity world-wide for a number of years.
		But we saw that H1N1 activity was increasing in some parts of Asia during the northern hemisphere season.  This was followed by outbreaks and epidemics in South America during our summer.  And it is being followed by circulation of the same A/New Caledonia-like strains in the no in the United States, and Europe, mainly.
		We are continuing to see H1N1 activity in Asia, but there really are no striking outbreaks there that we know about.
		Now, we move to the next page of the handout, and we will start going through the hemagglutination inhibition test results.  I'm going to try to orient you to these tables.  I know that they are sometimes difficult to follow.
		We have tried to choose representative tables.  We, obviously, present a very small subset of the data that we develop over the year, to you, at this meeting. 
		We try to make it representative and to allow the data that we show to tell a story of what we've been seeing over the past year.
		If you remember back to last year's presentation, and previous presentations, you will recall that there are two antigenically and genetically distinct groups of influenza A H1N1 viruses that are circulating globally.
		The viruses that are predominating are related to the old Beijing/262 vaccine strain, but are much better represented by the New Caledonia 2099 current vaccine strain.
		In addition to these viruses, which are shown as tests, to viruses like these, which are shown as test antigens 6 through 18, we do have the old Johannesburg 8296-like viruses continuing to circulate in the United States, as well as in other areas of the world.
		Now, here we see one other viruses in our reference battery, up here, and that is the Hong Kong 1252 strain.  You can see that it had a titer that was reduced four-fold in comparison to the homologous titer for New Caledonia.
		And we found that it was reproducibly reduced four-fold, and so we put that virus into ferrets, since that indicates a significant antigenic variation.
		And then we developed a ferret serum which we were using to see if that particular ferret serum could distinguish differences among the currently circulating strains.
		This was not a particularly representative strain, it was simply one of the viruses that appeared to be somewhat different.  And we see that it doesn't, there is a bit higher homologous titer, but it really doesn't cover the current strains any better than New Caledonia.
		So the picture that we were seeing last summer with strains from the southern hemisphere, really had -- did not change in the early fall.  We see here we have strains from Texas, which has really provided a tremendous number of the H1N1 strains that we looked at so far.
		These strains are all clearly New Caledonia-like, with a small subset of viruses which are like the older Johannesburg 96 vaccine strain.
		So we should move through this table a bit more quickly.  The first thing I would like to point out is that we've added a different referenced strain here.  This time the A/Fujian/156/2000 strain, which was also used as a serology antigen.
		I should mention that the strains that have asterisks here were used in human serologic studies.
		Here we have another strain, this one from China, that was reduced in titer with the Nanchang ferret antiserum.  But the majority of the strains that are in this lineage of viruses are quite well inhibited by antiserum to the Nanchang virus.
		And where we have viruses from wide geographic distribution in the United States, one from the UK, and then a couple from China.  In addition, on this slide, we have some of the Johannesburg-like strains shown here, and those strains do not appear to have undergone antigenic drift, including this strain, A/England 192/2000, which was used in serology.
		This last table was produced very recently, on the 24th of this month, and actually has some of the most recent viruses that we have been able to test on it.
		Again we have a variety of strains from the United States, with a fairly good geographic distribution, along with one from France.  I think that is the only strain that is not a U. S. strain.
		And, once again, those that are in the New Caledonia lineage are very well inhibited by antiserum to New Caledonia.  The strains that are on the Johannesburg lineage continue to look Johannesburg-like.
		So in this overhead I'm going to summarize the antigenic properties of the viruses that we characterized.  And I think it will be most instructive if we just focus on the bottom half of this particular overhead.
		For the time period between April 2000, and September 2000, we analyzed 255 H1N1 viruses.  About 10 percent, actually 12 percent were Johannesburg-like, while the remaining viruses were related to the New Caledonia lineage.
		And of those that are in the New Caledonia lineage, the majority are really closely related, antigenically, to the vaccine strain.  That is true, that generally story is true, for the most recent period, even though we have fewer viruses that we have analyzed.
		We have 8 percent now, of viruses, which are Johannesburg-like.  The majority are New Caledonia-like, and are closely related to the vaccine strain.
		Now we are going to move onto the influenza AH3N2 strains.  As Keiji has mentioned, we really did have predominantly H3N2 viruses in the United States last year, as well as in many other countries throughout the world.
		During the season in the southern hemisphere we had a significant amount of H3N2 activity in some areas, but clearly the seasons were mixed in a number of countries. 
		The viruses that were circulating in the southern hemisphere were A/Panama/2007/99-like, that is like the recommended vaccine.  And although we have had little H3N2 activity globally during the period from October to January 2001, the viruses that we have analyzed are also A/Panama-like.
		Now, it is really fairly interesting to see how the antigenic patterns of viruses sort of change over time.  This particular test was done in November.  And it has a number of viruses from the southern hemisphere.
		These Brazilian viruses were isolated during our summer.  These viruses from China, they are all from south China, from Guangzhow and also from Hong Kong, were isolated during the spring and summer, and into the early fall months.
		What we can see is that with the ferret antisera that are produced to our reference antigens, which include the old A/Sidney/97 vaccine strain, Moscow/10, which is the recommended strain, Panama, which is in the vaccine, and then a couple of 2000 strains, we can see that the strains that we were looking at, during the summer, actually are well inhibited by antisera to all, against all of these reference antigens.
		Now we are looking at viruses that were isolated during October and November of this season.  And we see the same thing.  We see that these viruses are, indeed, very well inhibited by antisera to all of these reference strains. 
		There have been a few exceptions among the viruses that we've tested.  And one of those exceptions is shown here, in this table, with antigen 13, A/Fugian/140/2000, which is also a serology antigen.
		And we saw that there was a four-fold reduction in titer with both the Panama antiserum, and also with the Moscow antiserum.
		So if we summarize the antigenic information that we have you will notice that during the southern hemisphere season there were quite a few H3N2 viruses isolated and sent in for analysis. 
		The majority of those were either Sidney-like, or Panama-like.  And in some tests it is really difficult to tell them apart.  And there were only a few viruses, including the Fugian virus that I pointed out before, that were low to Panama.
		We only have a total of 13 viruses that we've looked at, from the isolated, during the period October to December 2000.  Of those ten are from the U. S., and one is from Canada.  And all of those viruses are clearly A/Panama-like.
		Now, we are going to move on to the influenza B activity picture.  Last year in the northern hemisphere we had relatively little influenza B activity.
		There was, however, some -- there were some outbreaks of influenza B in Asia, and certain Asian countries.  During the season, in the southern hemisphere, there was really relatively little influenza B activity, although a few isolates were obtained.
		And during the current influenza season in the northern hemisphere, Canada is having local outbreaks caused by influenza B, and Hong Kong, and a few other areas in Asia are reporting occasional outbreaks.  And there have also been a few outbreaks noted in Europe.  But, basically, the influenza B activity has been relatively low.
		Now, I need to mention, before I start out, for those of you who remember presentations in other years, that there are two very distinct lineages of influenza B viruses that have been circulating globally since about 1988, actually.
		The circulation of the B/Victoria-like viruses has really been much, much more limited.   And the circulation has been primarily in China, although Japan did have some significant activity caused by B/Victoria viruses a few years ago.
		On these overheads I won't have any viruses, any antigens that represent the B/Victoria lineage.  All the antigens here are representative of the -- what we use to call the Yamagada lineage, and we now call it the Yamanashi lineage, I guess.
		So what you can see here is a table which has, as reference antigens, B/Beijing/184, which is the recommended strain, Yamanashi, which is the strain that is actually in the vaccine; Johannesburg/599 which is a strain which has been used for production of vaccine in the southern hemisphere. 
		And then the B/Sichuan/379/99, which is a prototype reference strain for the new variants that we are seeing.  This is a typo, I apologize, it should say 40, not 49, I don't know how we missed that one.
		This is the picture that we were seeing through the summer and into the early fall in many of the tests that we did.  That is to say that the viruses were well inhibited by antiserum to the Beijing/184, recommended strain, and pretty well inhibited with antiserum to the B/Yamagada vaccine strain itself, although we were seeing a few viruses that had a four-fold reduction in titer.
		Those viruses that were four-fold reduced in titer to the Yamanashi strain were pretty well inhibited by antiserum to the B/Johannesburg and B/Sichuan variant strains.  They are very similar to each other, they are considered to be B/Sichuan-like.
		In this particular table we are moving on in time to viruses that were isolated during November and December.  We have a number of strains from North America here, and then we have a strain from Japan, and one from India, and a couple from Hong Kong.
		What we are seeing is that there are increasing numbers of viruses that have a four-fold reduction in titer with the Beijing/184 antiserum, as well as with the B/Yamagada vaccine strain.
		These viruses are still pretty well inhibited, are very well inhibited by antiserum to the Johannesburg and Sichuan antisera.
		This is another example of the reduction in titers that we are seeing for current strains.  We have a number of strains, again, from North America, and a number from South China.
		Once again we are seeing better reductions in titer, sorry, better inhibition with the antiserum to Johannesburg and Sichuan.  And we have antiserum to Victoria/504, which has also been used for production of vaccine in the southern hemisphere. 
		We have included an antigen from Japan, here in our reference battery, because this particular strain is being considered for production of vaccine in Japan.
		So I think I have one final table with the most current data that we have.  There are actually a couple of viruses from January, here.  So these are the most current data that we have on influenza B viruses.	
		And as you can see we do have many viruses that are reduced in titer with the Beijing/184, and the Yamagada/166 antisera.
		As I said before, the Sichuan antisera to this Sichuan-like strains, which are listed up here, they are all really fairly similar to Sichuan, do cover the current strains much better.
		So if I can summarize the antigenic properties of the influenza B viruses that have been isolated, first of all, during the southern hemisphere influenza vaccine season.
		You can see that the majority of strains were B/Beijing/B/Yamagada-like.  But that about 20 percent of strains were low to Beijing and Yamagada.
		That percentage has increased, the percentage of low strains has increased fairly substantially in recent months, so that at the current time we would say that about 72 percent of the strains that we are looking at, are reduced in titer to the Beijing/184 and Yamanashi reference strains. 
		I think that that concludes my presentation.   I do have overheads made for the serologies, but I think that it is better to consider all the serologic data together.
		CHAIR DAUM:  Thank you very much for a very clear, concise presentation, Dr. Cox.
		Are there one or two questions for Dr. Cox before we move on to our next presentation?
		(No response.)
		CHAIR DAUM:  Okay, thank you very much, Dr. Cox.  We will move on to Dr. Klimov to complete the influenza branch trilogy.
		DR. KLIMOV:  I would follow the same format Nancy presented to you, and all the pictures and tables I'm going to show you, you also can find in our package, in case you don't see some details.
		Again, I would follow the order Nancy used, H1s, H3s, and Bs.  And I'm going to show several phylogenetic trees, and for those who are not very familiar with the tress, I'm going to notice that --
		CHAIR DAUM:  This is page 14 of the CDC handout, to orient committee members. 
		DR. KLIMOV:  Yes, thank you very much.
		And I need to notice that the horizontal distance is essential for understanding the relationships between different strains.  They are placed in a vertical order just for convenience.
		Actually the vertical distances are not important, at all, to estimate the difference between different strains.  For example, the difference between this strain and that strain is like, you know, from here up to here, and from here up to here.  So it is only horizontal distance.
		But, essentially, it doesn't matter much because we will be talking about genetic groups.  So as to the H1N1 hemagglutinin genes evolution in recent times, in recent couple of years, you can see that the viruses which are here, are genetically quite moved now from the Beijing/262/95, which was previous vaccine strain.
		And still pretty much a similar to the vaccine strain which is just now New Caledonia/20/99.  The vast majority of viruses are close to the New Caledonia genetically.
		At the bottom you can see another genetic antigenic group of the viruses which Nancy mentioned.  This is viruses similar to A/Johannesburg/82/96.  And, as you remember, we have approximately nine or ten percent of viruses from this genetic antigenic group.
		Next slide, please.  I did mention we did see some so-called low reactors, but they do not grow in the phylogenetic tree in some particular groups.  So they are randomly distributed among the tree, in general.
		This is the table which shows the amino acid differences between some of those strains which could be potentially vaccine candidates, because they are grown in eggs.
		And so-called consensus sequence.  And usually this parameter we use as an additional parameter to see whether new strains are evolutionary moved from the vaccine strain.
		From the previous year's experience we know that the closer the sequence of the HA to the consensus sequence, the better in terms of inducing immune response, which would work with the majority of viruses. 
		So from this table you can see that A/New Caledonia/20/99, the vaccine strain is sort of the best match to the consensus sequence.
		Next slide, please. The neuraminidase genes is a gene coding for another surface antigen of the influenza virus.  And during recent years we started to monitor evolution of this gene, as well. 
		You can see from this slide that, again, the majority of viruses, the majority of neuraminidase genes of recent viruses are still pretty close to the vaccine strain A/New Caledonia.
		You can see, also, that these do have viruses from the Johannesburg, or we call this sometimes Bayern/95 group.  They form another group of the viruses.  So genetically we also have two groups of the neuraminidase genes.
		And the next table shows the amino acid differences between the consensus of the neuraminidase protein sequence, and several egg grown strains.  We can see that New Caledonia is not the best match to the consensus of the neuraminidase protein, but still not very far from the consensus, which is good sign in terms of vaccine. 
		So as a conclusion we can say that genetically, as well as antigenically, great majority of current strains are similar to the New Caledonia vaccine strain.
		H3 part, Nancy mentioned that we had very few, actually, H3 strains this year. And most of them are actually, all of them are still pretty close, genetically, to the A/Panama/2007/99 strain.
		In spite of existing of sort of couple of genetic groups, which are not diverged very much genetically, we do not see any difference, antigenic difference between those two groups.
		And also very, very few low reactors are randomly spread among the branches of this tree.
		Next slide shows amino acid differences between some egg grown viruses, and hemagglutinin protein consensus sequence.  So you can see that Panama/2007/99 is still the best match to the consensus sequence among viruses grown in eggs.
		The neuraminidase genes of most recent viruses belong to a group which we call a Moscow/10/99, which is genetically different from the A/Panama neuraminidase genetic group.
		It is obvious that some -- we still have some viruses belonging to the Panama neuraminidase genetic group, but the majority belong to so-called Moscow/10/99 genetic group.
		As I mentioned before, and as Nancy mentioned, it doesn't influence, at least so far, on the antigenic properties of the current viruses. 
		Next slide shows the table about the amino acid differences between the neuraminidase protein consensus and the Panama has 10 amino acid differences from the consensus.  And in this sense is not the best match to the neuraminidase protein consensus.
		As a conclusion we can say that, essentially, all current H3N2 strains are antigenically and by the HA genetically close to the A/Panama vaccine strain, also the neuraminidase gene belongs to another genetic group.
		AS to the evolution of influenza B viruses, Nancy mentioned that there are two genetic antigenic lineages of influenza B viruses, B/Victoria-like viruses, and previously we called them B/Yamagoto, or B/Beijing/184-like, or B/Yamanashi-like viruses. 
		So this tree includes exclusively viruses from the B/Beijing/184 or B/Yamanashi group, because we did not see B/Victoria, we didn't receive B/Victoria-like viruses in last almost year.
		You can see that this is Yamanashi current vaccine strain.  And you can see that the majority of viruses genetically are moved from the Yamanashi vaccine strain, and form a group along with the B/Sichaun/79?99 reference strain, which is the strain recommended for southern hemisphere, as you know. 
		So, by the way, we mentioned that in red you can see the viruses which are grown in eggs, and asterisks indicate the viruses which are used in the serology tests.
		The Beijing/184, or Yamanashi genetic group is also actually includes some another genetic sublineage, which we call B/Harbin/795 sublineage.  And -- I'm sorry, that is about -- yes, this group is B/Harbin/794 genetic lineage.
		We continue to see very few strains belonging genetically to this genetic group, but do not see any significant antigenic differences between those two groups.
		And the percentage of these groups, and the percentage of B/Harbin-like genetically, B/Harbin-like viruses is actually pretty low, it was about 7 percent during the summertime, and now it is about 90 percent total.
		As I mentioned, we do not see B/Victoria-like viruses at all.
		The next slide shows the amino acid difference table, which indicates that B/Yamanashi/166/98 is moved apart from the consensus sequence for the HA protein.  And, for example, Sichuan/379 reference strain represents better match to the consensus sequence of the hemagglutinin protein.
		As to the neuraminidase gene, again, we see that in general most viruses are not very far from the B/Yamanashi vaccine strain, but still they are forming a new sublineage similar to Sichuan/379 genetic group.
		In the terms of amino acid differences from the neuraminidase protein consensus, again, Yamanashi is moved quite far from the consensus, while Sichuan is one of the best matches in the sense of the neuraminidase protein sequence.
		I will probably stop it here.
		CHAIR DAUM:  Thank you, very kindly.  Questions from the committee for Dr. Klimov.  Dr. Ferrieri first, then Dr. Estes.
		DR.  FERRIERI:  Very brief question.  How very different is the HA1 sequence in B, from the AHA1, for example, are they like 75 percent different?
		DR. KLIMOV:  You mean H3 and H1?
		DR.  FERRIERI:  No, AH1 and BH1.
		DR. KLIMOV:  They have approximately not more than 30 percent of homology, as far as I remember, something like variable homology.
		DR.  FERRIERI:  Thank you. 
		CHAIR DAUM:  Dr. Estes, please.
		DR. ESTES:  With the introduction of the neuraminidase inhibitors do you have any evidence that that has influenced either neuraminidase or HA in terms of evolution of these viruses? 
		DR. KLIMOV:  Not so far.  And I know that there is a group of, information group of people, actually, who is trying to monitor what the percentage of the strains which may be resistant to the neuraminidase inhibitors after the licensing of these drugs in several countries.
		Not much attention paid yet to the possible influence of the possible drug resistance onto the antigenic properties.  But so far we don't see any dramatic changes.
		CHAIR DAUM:  Thank you very much, Dr. Klimov.
		What I would like to try and do, with the committee's pleasure, is to get through the next three presentations, and following that we will break for lunch, and then resume our session in the afternoon.
		The next speaker whose name I hope I'm not going to butcher is Linda C. Canas.  Is that how you say it?  Good, I did it.  Who is the chief of diagnostic virology at Brooks Air Force Base in the Department of Defense. 
		MS. CANAS:  Good morning.  The Department of Defense has a historic and even continuing interest in the surveillance of respiratory viruses.  It is absolutely essential that we know what is going on.
		CHAIR DAUM:  We need -- can you speak right into the mike, or can we get some more gain from it?
		MS. CANAS:  It is essential that we know what is going on from a public health standpoint in the military facilities.   The Air Force has long engaged in influenza surveillance, and recently it has become a tri-service program that has operated under the direction of the global emerging infection system here in Washington. 
		This program is tri-service, and it operates on two different levels.  The Navy in San Diego, under the Naval Health Research Center operates a population-based surveillance system. 
		They have, at the recruit centers, all of the recruit centers from all services collect a certain number of samples, each week, according to case definition, based on the population of that particular center.
		And these are analyzed to determine what is going on in that population.  At the Air Force Center at Brooks Air Force Base, we have surveillance sites that are set up, and we are basically just trolling for bugs.  Whatever we can find we are going to report and keep track of.
		Our interest is influenza, and that is what we are interested in, that is what our case definition is aimed for.  But we actually will report anything we find.
		And this is the process that I'm going to talk about today.  The data is from all three services.  What the Army collects from the medical treatment facilities, what the Navy collects from the recruit centers, and what our program collects. 
		But the process is what we do in San Antonio.  The epidimiologists and the laboratory personnel decide on sentinel sites each year, and how the program will be run, and information is then sent to the Surgeon General of the Air Force. 
		And because there is such emphasis on influenza prevention of illness, and we know that the vaccine is the single best way of preventing illness, it is a requirement that all active duty individuals be vaccinated annually.
		So the message that goes out, that directs this influenza program, will also name the sentinel sites that have been decided on, and we make sure they all have supplies and directions on how they are going to collect this. 
		The public health office is in charge, and they collect samples and send them to Brooks Air Force base, where they are worked up according to standard laboratory practices.
		And we do try to treat these as clinical samples, and get the results back as quickly as possible.  And they do go into a computer where they are sent back as patient results.  
		And in addition we send the results to the disease surveillance branch where they keep analysis, and make reports that public health office is notified in a timely manner what is going on at their base, so they can react with any interventions, and they get some feedback from the program so they can react to it.
		In addition we get to make lots of reports and presentations.  We do make -- take selected isolates and share those with CDC, because they have a much more detailed analysis, and they can see what is going on in our program compared with the rest of the programs, and decisions can be made at meetings like this one.
		This is a map of our current sites listed in the handout, they are actually named by location.  But I wanted you to see that we do have a global presence.  Most of it, of course, are from our military sites where we have people stationed, and we are seeing people in the treatment facilities. 
		But we've been able, under this tri-service arena, to be able to hook into the Army and Navy research centers in more remote locations of the  world where they also already have ongoing research projects, and have now instituted influenza surveillance.
		This has been very productive in Napal and Thailand, several sites in South America.  And it is a very -- the program is flexible, and we try to maximize our resources compared with everyone else, to see where surveillance is needed. 
		If it is already well surveyed, and we don't need it for our own public health issues, then we move on to other areas.
		We have recently been able to confirm that Honduras will be a collection site, they are going to be submitting samples.  This is especially exciting because we lost Howard Air Force base when we moved out of Panama.
		And as you've heard many times today, the A/Panama/2007 is the vaccine strain, and that did come from this program.  
		South America, too, has been very productive.  We were able to identify, early, the variant H1N1, which is now New Caledonia, was actually the second time in the Americas that this strain had been recognized.  So these remote sites are important.
		We have the possibility, probability, of bringing on Uganda.  Everything has been set up, we have the shipping organized.  There are still some political considerations there that will have to be considered and worked out.
		When we look at the number of samples that we received from all sites, compared to last year, it is a little bit deceiving.  It looks like our season, like everyone else's, has been much lower than last year.
		One of the confounding factors here is that last year the Air Force experienced an extremely overwhelming incidence of adino virus disease, respiratory adino virus.  And while that continues it is not quite as overwhelming as before.
		So in fact our number of samples that we are receiving for, other than adino virus, is almost higher than last year.  And there is a couple of reasons for this. 
		Namely, while we do have a dependent and retired population that we are conducting surveillance on, and they fit, in many cases, the fidicional risk groups, our main population of concern are the relatively young, healthy individuals. 
		This is not one that you all are considering, but we have to keep these people healthy.  Their readiness mission is what is important.  And the commanders have been very concerned, this past year, that they have been able to rely on the past in the vaccine, and this year they weren't going to have the vaccine. 
		And never knowing exactly for sure what the mission will be, and where these people will be sent, and what they will have to do on a daily basis.  There was a great deal of concern about the vaccine.  So there was a very heightened awareness of surveillance.  and we've received many specimens, a lower productivity, but many specimens this season.
		In North America, and I think our results are somewhat different from many others.  We've had nearly equal numbers of As and Bs, 45 percent of all the flus in North America have been B.  Let's see, I'm not sure that is exactly right.
		41 percent have been A, and 56 have been B in our North America.  And these are at the same places.  I've daily reported out As and Bs from the same locations.  It hasn't been a spotty thing.  We've seen it in California, we've seen it in Texas, we see it from the very beginning, in Alaska. 
		And that continues, this co-circulation.  We also have a lot of peri influenza and interal viruses that are going around.  So from workload standpoint in our laboratory, we are basically working these samples up for anything it could be, instead of ruling out what we've been seeing.
		Our numbers in the Pacific have so far been considerably less, but that is changing.  In the last couple of weeks we are starting to see a lot more activity in this area.
		We saw our first isolate of the season in September in Okinawa, and that was a flu B.  Those numbers have continued, in very low numbers, in Okinawa and in Hawaii.  We've seen a predominance of B.
		We've had virtually nothing from Japan, but Korea is suddenly starting to see influenza A.  We started getting isolates within the last two weeks, and I've had requests for more supplies because they are seeing more illness.
		Our numbers from Europe are quite low, very low numbers.  I'm not sure we can make a lot of prediction.  From that we've had 3 As and one B, from those.
		South America, I present, this information is maybe not timely for this committee.  But, again, I think it shows our more equal numbers of A and B that we are seeing from this area of the world.
		And, of course, when we talk about getting samples from South America, for these remote sites, they don't come very often.  So they are truly surveillant samples.  And the miracle is that we are getting five and six month old samples that we are able to get isolation.  And that has been exciting.
		We've also seen a good bit of adino viruses in South America, especially Argentina. 
		Nepal and Thailand has been especially exciting.  Last Tuesday, one week ago today, we received in our lab 59 samples.  And the pressure was on to get some information for this committee to look at.
		These samples ranged from collection dates clear back to March, but some of them were up to January, and a good many in November.  So there was some timely issue here.
		We did put them in culture but our molecular biologist randomly chose 16 samples and went in with just PCR directly out of the tube that we got in the lab.  And he was able to isolate two As and a B from those 16 samples.
		When I left on Friday, when I left the lab on Friday, we had confirmed those three types. And in all, in our first culture results, we have 18 isolates.  The majority of them are A, that is 30 percent recovery, which we are really quite excited about, and we still have the rest of this week before we would finish reporting out the viruses.
		If we look at the subtypes, like everyone else, we have a strong H1 season, much stronger B than we've seen in many years.  And, in my experience, the co-circulation in these As and Bs, especially at the same location, is unprecedented.
		The B started out early, and first, mainly in the Pacific and Alaska.  We had quite a bit of B in Alaska, to begin with.  That continues, even though the As have come up.
		The Bse in our HAI subtyping, using rabbit antisera, have been lower titers than we've seen in the past.  A great many of them are four-fold less than the reference strain that we are using in our laboratory. 
		The Pacific Rim still has low levels of B, but they've actually been matching fairly well.  H1s have matched very closely with the reference strain, and we do have a predominance of that, especially in North America.
		In the Pacific the H1 is much -- we do have more of the H1s, but we have H3, also.  And H3 is what we are seeing in the Pacific.  These new ones that we are just seeing in Korea, that we've just identified last week by PCR, those were H3.
		Now, whether that will continue I don't have any idea at this point.  But it is interesting that that group does seem to be coming up as H3.
		And, again, to emphasize the same thing that has been reported elsewhere, we've just flipped this year.  H1s we've seen very little of in the last several years, but it is the predominating strain.
		I would say that from a laboratory standpoint they are much easier to work with, so it doesn't bother me any.
		This chart didn't print out in your handout.  It was the nucleotide homology, looking at the hemagglutinin gene, and we did show very close homology, pretty much what Dr. Klimov reported earlier.
		I think that our results have shown that the current strains are covered quite nicely, the hemagglutinin strain.
		Mostly we have seen the H1 and the B, like other groups.  Perhaps our numbers are a little closer.  One reason for that could be because of the increased interest in surveillance.  Perhaps people who weren't quite as ill, and may be in the private sector, would not have sought medical attention, or actually getting cultured in our program, which would show more equal numbers. 
		The Nepal isolates have just come in, they are currently being analyzed.  Several of our isolates were collected in November, so they do have some timely aspect to what we are looking at here.  It does appear that if we can make a prediction from two of these isolates, both of those As were H1, nothing that was used, the H3N2 primers didn't pick up anything. 
		So we suspect that these are going to come down as H1s, like we've been seeing everywhere else.
		Would there be any questions? 
		CHAIR DAUM:  Thank you very much.  That was -- you win the special VRBP prize for technical effects, as well as a very lucid presentation.
		Dr. Huang?
		DR. HUANG:  I remain concerned about our surveillance, and I have a comment and a question, not only to you, but also to the CDC presenters this morning.
		The comment is that our surveillance on the African continent is still really poor, if it exists at all.  And I remain concerned that we don't have that, really, set up as well as we ought to.
		And I know that we do have a Navy lab in Egypt, and I didn't see if that was part of your distribution there, or not, if they are active in this surveillance.	
		The other is that in the past we have seen data from cruise ships in Alaska that we obtained swabs in Alaska, or around Australia, that we obtained swabs of in the summer months of August, September.
		And I'm wondering, I just don't see that any more, and I'm wondering if there is some reason that we haven't gone ahead to do that. 
		MS. CANAS:  We actually do collect all year round.  Our surveillance is annual, we have that data all year.  I just presented from September right here, but it pretty much agreed.
		Africa is particularly problematic.  We are trying to get in, we have every expectation to get in to Africa with our surveillance.  But, as I said, there are political considerations.
		Dr. Kelly is here if you would like him to address that. 
		CHAIR DAUM:  Could you identify yourself, Dr. Kelly?
		DR. KELLY:  I'm Pat Kelly, I'm the director of the DOD infectious program. 
		Separate from the program that Linda operates, our lab in Cairo does do influenza surveillance and sends specimens directly to Dr. Cox of CDC.  They currently are doing surveillance in Egypt and in Syria, and this year we will be bringing on line Yerubi.
		It is a great logistic challenge to do surveillance in some of these overseas area.  For example in Yerubi they had everything politically lined up, but there was no local source of liquid nitrogen the store the specimens in.
		To get specimens out of Nepal we actually have to ship dry ice in from Bangkok.  So there are some unusual logistic constraints.  We also are going to be starting, as Linda mentioned, this year new surveillance in Uganda.
		One interesting challenge that we have faced in some of these countries is ethical debates over whether it is appropriate to do flu surveillance.
		Uganda initially, their ethics -- they turned it down, because they said that we don't use flu vaccine in this country, and thus you should go somewhere where flu vaccine is used.  This is not a surveillance program that is going to benefit us.
		We ultimately negotiated with them and are providing them benefits that they find valuable.  But it is much more complicated in some of these places.
		CHAIR DAUM:  Thank you very much.  Dr. Ferrieri and Dr. Diaz.
		DR.  FERRIERI:  I am very glad that you mentioned, Ms. Canas, the other surveillance and the high prevalence you saw with peri influenza.  It is my impression in the twin cities we've had peri flu 3 that came in in November through December and parts of January, causing rather relatively severe illness in adults as well. 
		And so the impression of many people is that everything is flu, and it gives a bad rap in the general public to the efficacy of influenza viruses vaccine. 
		And so I can't emphasize too much the co-transmission of more than influenza virus during this season.  We now are into RSV with trickle peri flu, and adino virus is certainly out there as well. 
		CHAIR DAUM:  Dr. Diaz, please?  Thank you, Dr. Ferrieri.
		DR. DIAZ:  I think actually what you said goes back to my comment about those 93 percent of non-flu isolates, because it is important for people to understand when there are other viruses circulating, what they are, so that they can better understand influenza vaccine and how well it is protective.
		But my comments that I wanted to make was in regards to your comment about the cruise ships.  And perhaps somebody from CDC can correct me if I'm wrong.
		But I think that cruise ship data came not from necessarily surveillance that was being done on cruise ships at the time, but rather was prompted by outbreaks of influenza-like illness on those cruise ships at the time, and then an investigation. 
		CHAIR DAUM:  Are there more questions for Ms. Canas?
		(No response.)
		CHAIR DAUM:  We have a clarifying comment coming in regarding cruise ships.
		DR. FUKUDA:  Just to clarify.  In Alaska there were large regional outbreaks involving cruise ships and land travelers identified in 1998, summer.  Also in the summer of 1999.
		Interestingly this past year we haven't seen the same phenomena occur up there.  There have been a number of other outbreaks reported on cruise ships in different areas.  And so that general phenomena occurs.
		So I think that when we presented those earlier Alaska outbreaks, one of the outstanding questions has been whether this is sort of a change in pattern in that area, or not.  And I still think we don't know the answer to that, yet.
		CHAIR DAUM:  Thank you very kindly.
		DR. GRIFFIN:  Are the cruise ships like canaries, then?
		(Laughter.)
		DR. FUKUDA:  Well, someone has termed them large virtual populations.  And in a sense they are this very big populations of people from all over the world.  And a fire may ignite, or may not ignite in that population.
		CHAIR DAUM:  Dr. Griffin, if it is brief.
		DR. KIM:  Yes.  I just wondered if somebody else could clarify.  So we saw what the surveillance, and heard about the surveillance that the Armed Forces does in Africa as far as influenza is concerned.
		But I'm just curious about what the WHO is doing.  Clearly South Africa, we get a lot of samples from there, but -- and maybe from Egypt and the Mediterranean region, but how about the middle?
		DR. COX:  I will try to address that.  Basically it has been well recognized for some time that Africa really doesn't generate a lot of information for vaccine strain selection, with the exception of South Africa, and now Egypt that has come on line.
		It is, as Pat Kelly pointed out, extremely difficult to convince people to do surveillance in these countries, if they don't see that there is a direct benefit.
		And I think that what we saw in South America is illustrative of what we are likely to see in Africa.  When the countries get to a point where flu vaccine is on their radar screen there will be a very much increased interest in doing flu surveillance.
		So, basically, what we have to do in the interim is figure out where we can best put resources to expand knowledge about what is going on.  There are a number of efforts underway to try to see if there are ways to increase the amount of funding that might be available to try to enhance surveillance in some areas of the world that are less well served at the present time.
		CHAIR DAUM:  Thank you, Dr. Cox.  I would like to move on now to hear from Mr. Hampson, the director of the WHO Collaborating Center for Influenza in Melbourne.  Welcome.
		MR. HAMPSON:  Thank you Mr. Chair, it is always a pleasure to speak at this meeting, and maybe a little bit daunting, because I have to present, very briefly, some surveillance information, antigenic analysis, genetic analysis, and some serology.
		So if you would like I'm going to be Keiji Fukuda, Nancy Cox, Roland Levandowski, and I can't remember who the others -- Sasha Klimov all rolled into one.
		It is also a little daunting to see that the U. S. Military probably has more surveillance sites than we do.
		This is just to show you the area of our collection of samples at our center, which is one of the four WHO collaborating centers for influenza. 
		And I am going to give you just a little bit of epidemiology from the three main collecting areas that we have.  Australia, of course, from which you will see that looking at sentinel surveillance, this is influenza-like illness measured over a number of years in general practice, and virus isolations measured in laboratory studies.
		That, in fact, we did not have a very severe season during the year 2000, it was a substantial reduction of the previous years in both the total influenza-like illness, and in particular in the number of clinical isolates that we received last year.
		That was even more marked in New Zealand, where you see this yellow line showing the level of influenza-like illness in comparison with other recent years, and in particular in 1996, when there was a very severe outbreak, a very, very flat year of influenza in New Zealand.
		And this has been characterized through much of our surveillance area, showing that in New Zealand it was a mixture of influenza A and influenza B, with influenza A predominating.
		And in Thailand our other major collecting area, apart from an early outbreak, early during the year 2000, which was mainly H1, so there had been a shift already there to H1 influenza from predominantly H3 early in the year.
		Very little influenza in terms of isolates seen during the remainder of the year.  So I suspect that you are having a year, in North America, which is going to be very similar to what we've seen through a lot of the Pacific area.
		Just showing you where our viruses are collected from, principally from Australia, New Zealand, Thailand.  But we do have a spread of collection sites where we could receive some viruses from Singapore, South Africa, up into the Pacific region, New Caledonia, Malaysia, and occasional samples from Vietnam.
		We have recently received a shipment within the last two weeks from both Singapore and Vietnam.  And, interestingly, in comparison with the results that Dr. Canas just presented, all of those viruses appear to be H3 viruses. 
		This is the distribution of subtypes and types that we've seen during this last 12 month period.  In Australia H3 continued to predominate, although we did have a significant amount of influenza A H1, the second most prominent type was type B. 
		We missed the type B last year, we normally have a two year outbreak of influenza type B, we had had a very severe outbreak in 1997, we essentially missed our second year of the outbreak in 1999, and it seems to have come back this year.
		New Zealand H1 predominated but was similar in levels to the H3 with a minority of influenza B.  Throughout Asia, though, we have seen a predominance of H1, and approximately equal levels of H3 and B, and through the Pacific something similar, but with influenza B less prominent, there.
		Now, I'm showing you very, very restricted and representative tables of antigenic analysis of our H1 viruses.  I'm showing you that the great majority of strains that we have seen are very well neutralized by New Caledonia antiserum.  
		They are less well neutralized by the previous reference strain, antiserum Beijing/262, which was a previous vaccine strain, particularly when you look at the homologous titer of the sera, the Beijing being higher than the New Caledonia, with the New Caledonia producing very good protection.
		We are also putting, in some of our essays, a normal human serum pool, a post-vaccination pool, to have a look and see whether there is any sign of variants coming up which would be escaping vaccination.  And the pool is showing very good protective level against these recent isolates, and gives us comfort that the vaccine is working.
		A second set of H1 assays just showing that there are still some residual strains of this Bayern or Johannesburg type, which was mentioned previously by Dr. Cox, including this recent Texas strain, which we put into this assay.
		We have occasional unusual strains like this England strain, which is showing very low reactivity across both types of viruses, we don't understand this at the moment, but reassuringly neutralized by the human serum pool.
		But, again, we have a very good protection by the New Caledonia 20 strain, as shown by Dr. Cox, and by this variant from Japan.
		If we have a look at the overall analysis of the strains that we've seen this year, there have been very, very few Bayern strains, in fact all of these Bayern strains that we've seen came from a single outbreak in South Australia, and we have seen them nowhere else in our surveillance area.
		The greater majority of the virus isolates that we did analyze came from this January to August period with fewer in the September to January 2001 period.
		I apologize for this dendrogram, I did have it hyperlinked, but the technology didn't function properly and so you are going to have to see it in a slightly blurred fashion.
		But simply what I'm showing here, here is the reference vaccine strain, New Caledonia 20.  Here is the previous vaccine reference strain Beijing/262, and the viruses are falling quite close, genetically, to the New Caledonia strain.
		There is a tendency for them to have moved and to have broken into two separate claves, and the majority of recent viruses we are finding now in this upper clave.  But the difference is not great, and certainly while there is a genetic difference, there is not an antigenic difference. 
		As shown by Sasha also, the viruses, the recent viruses are staying very close to New Caledonia, genetically, in terms of the neuraminidase sequence.  I apologize, this 88 up here should be a 2000 virus, not an 88 virus. 
		So all the recent viruses are, again, close to the New Caledonia virus, with the exception of these very different viruses, such as the South Australia viruses, which remain in this Bayern or Johannesburg clave, which is quite different. 
		H3 influenza virus analysis has been very similar to recent years.  We've seen a move, a drift away from Sidney to this Moscow type of virus, or viruses represented as Moscow-like, the Panama vaccine strain, and these other three strains, which are antigenically very, very similar.
		We get possibly more than some of the other reference labs strains which are low, we call low reacting strains.  They react poorly right across the range of antisera that we have.
		When we sequence these viruses they don't show any outstanding features.  When we make antisera against them, they make antisera which are characteristic of these other recent strains. 
		So we refer to them as low avid viruses, and we haven't found a reason for this low avidity, as yet.
		They don't appear to be significant, though in terms of vaccine protectiveness, although they do, again, react very poorly with our pooled human serum.  So this is something that is ongoing further investigation in our lab at the moment.
		If we have a look at the representative strains that we've had over these two periods, January through August, prior to the WHO meeting in September, we saw a preponderance of Moscow-type of viruses, still some Sidney-type of viruses, and low reacting strains in both these groups.
		We've now moved, quite definitely, away from Sidney-type viruses to Moscow-like viruses, but with a fairly high percentage that I've just showed you of these low reacting strains. 
		When we have a look at the genetic analysis, the dendrograms, we found that these are broken into two major trees, as represented by the Panama vaccine strain, and viruses which are closer to the Moscow referenced strain.
		So there is a genetic difference between these two viruses, although the Panama antigenically represents the Moscow virus.  A number of the other strains that I showed you previously were also falling into this group, and we find that most of the recent isolates that we have seen from late in the year, and we did have isolates coming through into October and November in Australia/Asia are falling into this Panama group.
		On the other hand, with the neuraminidase antigen, and again similar to what Sasha showed you, the virus are clustering close to the Moscow with the neuraminidase than they are to Panama.  So, clearly, an ideal vaccine strain if we would take into account both antigens would be a virus that fell into this group, in terms of its neuraminidase, but into the Panama group in terms of its hemagglutinin.
		And when we have a look at the influenza B, I apologize if these colors did not come out very strongly.  We do see a more dramatic difference, I think, than some of the other labs, in terms of the differences between our Yamanashi serum, and the sera against these recent strains, the reference strain Sichuan, and the vaccine strain B/Johannesburg, which are producing excellent protection against very recent virus isolates.
		The Yamanashi is producing poor protection against a large number of our recent isolates, and in effect much poorer even than the reference strain, which are represented in the vaccine, the Beijing/184 strain.
		And we see that in the second set of HI assays here.  Yamanashi showing exceptionally poor titers in some cases, against some of the recent strains, less than one in twenty.  Whereas the Sichuan, the Johannesburg, and the alternative vaccine strain which has been used in some countries in the southern hemisphere, the B/Victoria/504.
		I will just mention, at this point, that these two vaccine strains were selected after trolling through many, many egg isolates of virus.  They were the best growing strains that we could find, and undoubtedly you will hear a little bit more in the future.
		But the general feedback has been that these viruses do not grow awfully well. 
		Again, dividing our analysis up over the two time periods prior to the WHO southern hemisphere meeting, we were labeling most of our viruses as B/Beijing viruses at that stage, because that was the reference strain.  We have only recently switched into the Sichuan type of viruses, and quite possibly a high percentage of these strains that we call B/Beijing-like were, in fact, closer to B/Sichuan, and certainly on dendrograms they appear that way.
		And since the September meeting clearly a major move to Sichuan-like viruses in the isolates that we have analyzed since that time.
		And, again, having looked at the dendrogram, we see that these fall into a number of subclaves.  Here is the Sichuan-like virus, quite distant now from the Yamanashi virus, and from the Harben virus, and Beijing/184 virus, which was the reference strain.
		So there has been quite a significant genetic move in these viruses.  They are falling into, maybe, three or four separate claves.  We've seen all of these this year, and I think the major virus grouping, in fact, is around this Sichuan group, or possibly with some recent isolates moving up into this slightly further separation.
		And the neuraminidase very, very similar.  Not as great a move as in the hemagglutinin but clearly a move in these recent virus isolates into the Sichuan grouping, and away from the Yamanashi, and quite distant from the previous reference strain, Beijing/184.
		Now, I put some tables of serology into the handouts that I provided, and they are always rather difficult to look at.  And I've tried to summarize, graphically here, a little bit of the information in that.  
		And I've selected simply the older adults, and simply two groups of sera, the U. S. sera, and the Australian sera.  And  I've show two parameters, especially the geometric mean titer which I've expressed in terms of a percentage of the homologous vaccine percentage, and that is the New Caledonia.
		And what we see, quite clearly here, is that the New Caledonia has been producing good antibodies to all except one recent strain that we've tested in this, this Texas/87 virus.
		We've also looked at the total number of people who have presumptive protective titer, that is a titer in one in forty, or above, in this elderly group.  And, again, we see with recent strains, and including this Texas virus, a high percentage of people with protective titers.
		The Australian sera is showing very similar results to the U. S. sera in this group.
		Looking at the H3s, and just pointing out that the U. S. recipients here received a vaccine containing the A/Panama virus, or A/Panama virus and a Moscow-like virus, so this is the one hundred percent starting point.
		I've referred back to Sidney in here, because the Australian recipients actually received a Sidney containing vaccine in view of the difficulties we had getting the Moscow-like virus into the vaccine for last year.
		Again, over recent times, and these are results taken up to the point where we made our decision on vaccine formulation in September, very good protection both in terms of GMT, relative to the vaccine virus, and to the level of protective antibody, certainly a high level, up around 80 percent of people achieving protective titers.
		And that was similar, regardless of whether the vaccine contained the A/Sidney virus, or the A/Moscow virus.  To our surprise, although we were forced to put in A/Sidney-type of virus into the vaccine we did achieve very good titers against the Panama virus, and against recent isolates.
		There are a couple of recent strains.  I think the Hong Kong/19223 virus was mentioned earlier on.  And we have a strain which is being distributed for serology, the Leon virus, which is showing some lowering.  And we probably need to investigate these further at the moment.
		But against the great majority of strains the vaccine has been shown very high protective levels.  Against influenza B, at the time that we did our initial studies, when we had a look at the initial studies, these were the strains that we tested for vaccinees receiving the Yamanashi vaccine, up until September, you can see quite a dramatic lowering in terms of geometric mean titer. 
		The lowering was not as dramatic, or the lowering was not really greatly significant in terms of total, numbers of people achieving a titer of one in forty.
		But I would point out that we used ether-split antigens in doing the serology.  And we really can't be completely sure, I don't think, that that is not influencing the outcome of this test, to some extent.
		What is interesting is the two most recent tests that we've done in the serology, two new viruses we've put in, in fact one of them vaccine strain, and the other recent Leicester isolate, we've seen a reversal of the trend that we had seen earlier.
		So with the Yamanashi containing vaccine there is an indication that it may be protective against these viruses.  We also are having a look at the influence of passage level of these viruses, because as we passage them on, it seems they might be more readily neutralized by antibodies.
		I think I'll stop there.  Any questions? 
		CHAIR DAUM:  Thank you very much for illuminating view of the other side of the world.  Do we have committee questions, input, comments?
		(No response.)
		CHAIR DAUM:  That means your presentation was crystal clear.  Thank you very kindly.
		For our last speaker before we will call on Dr. Joanna Ellis of the respiratory virus unit, public health laboratory service in London.
		DR. ELLIS:  Thank you.  I would like to thank the committee for giving me this opportunity to present the data from the UK.
		In the United Kingdom we use a number of indices to measure influenza activity.  But the data we put the most reliance on comes from the Royal College of General Practitioners.
		This organization coordinates about 100 sentinel physician practices throughout England and Wales, and collects all the data.  These practices represent about 800,000 of the population.
		The consultation rate is then calculated and is expressed as the rate per 100,000.  The levels that we use to describe, the baseline level is 50 and below.  Between 50 and 200 is described as normal seasonal activity.  If the consultation rate rises to 200 to 400, and that is higher than normal, and it has to be above 400 of 100,000 of the population to be described as epidemic.
		As you can see, for this season, the level of consultations has hardly risen up to the baseline level.  This is shown more clearly here, where we can see the consultation rates against weeks.
		We have a slight peak of activity here, week two.  This is last season's activity.  And when we compare the death rates, or causes notified to the office of National Statistics, we can see we have a very slight increase in the death rate, but much less than previous years, which correlates with the lower level of activity.
		A small subset of those 100 sentinel physicians also sent in samples for virological analysis.  These are patients who are presenting with influenza, or influenza-like illness.  
		The physicians then take a combined nose and throat swab, and send those by post to the National Influenza Lab in Collingdale.
		We test them by culture, and this year we've also been running a PCR test.  This is a multi-plex test which is able to determine whether we have influenza H1N1, H3N2, influenza B, or RSV in those samples from the community. 
		And these are results that we have to date.  Here is out OCGP consultation rate.  These grey ones are the total number of samples we received each week.  The green is the RSV positives by PCR.
		And, as you can see, these were detected first in the season, week 43.  And the yellow are the flu H1N1, which we detected later, and then some flu Bs much later on.
		But the point to take home from this is the RSV and flu circulating at the same time, they are still circulating now, in the community.  When we look at the As distribution of those that were PCR positive, we can see that RSV was found, perhaps as you would expect, in the under five age group, and again in some of these older age groups, whereas flu was not found in this younger age group, it was found more in the middle age group, but not in the elderly.
		We not only receive samples from the community, we also get samples from hospitals, that is public health laboratories, and national health laboratories, which have already been typed as influenza, and come in for further analysis. 
		So when we look at this, here again is our consultation rates.  And these are the community samples, these are posted by isolation this time, not by PCR.  And we also have our hospital isolates here.
		When we look at the types we, as others have already described, predominantly have influenza A H1N1, which came first in the season, at week 43, and then peaked here, about week one.  We do have it coming down here, and it is still coming down this week, from data that we have.
		And then the later emergence of the flu B, which co-circulating now with the flu A.  When we look at the As distribution of the isolates, first of all, looking at the community, we can see that we have a peak of isolation in the 15 to 44 age group, which is what we normally see in the community samples.
		For the hospital samples we have mainly in the under five age group, and usually not many in the over 65s  this year.
		For the regional distribution of the isolates we have about 20 practices that sent in serological samples, scattered throughout England and Wales.
		The isolates themselves have come from all over, quite a few from Scotland this year.  Of the about 7 or 800 samples that we've actually received, we've got mainly H1N1, and a few flu Bs, as well.  But we haven't detected any H3N2 this season.
		Looking at the antigenic characteristics of the strains, first of all the H1N1s, here is the New Caledonia vaccine strain, and corresponding antiserum.
		Most of our isolates have reacted well to New Caledonia, like these two here, and show a New Caledonia-like.  We have had a few isolates which have been like the older vaccine strain, A/Bayern/95, this one here, and one here.
		In fact we've had three isolates.  They've all been in children under two and a half years old, and they've all come from one area in Wales, in Swansea, so we think it is just a sporadic outbreak there.
		Looking at the phylogeny of the H1N1 viruses, this is the older A/Bayern strain, and this is where our small outbreak fits on the tree.  This is the New Caledonia vaccine strain, and the majority of our isolates are fitted here, closely related to New Caledonia.
		When we look at the influenza B strains this season, here is the B/Beijing, the B/Yamanashi, and the B/Sichuan/99 reference strain.  Most of our isolates are showing a reduced reactivity with Beijing, fairly good reactivity with Yamanashi, but show much better reactivity with the B/Sichuan reference strain.
		Some of the isolates which we are now receiving, the last one here is from December, are now showing a reduced reactivity with the Yamanashi.  
		This is the phylogeny for the influenza B viruses, the Beijing lineage here, this is the older Victoria lineage, which has been talked about this morning.  Here is the B/Yamanashi vaccine strain, and all our strains fit here, on the Yamanashi lineage, but are much more closely related to the B/Sichuan/99 strain.
		So, in conclusion, we can say this year we've had a low level of influenza activity, which has barely got to baseline levels.  And we have predominantly had the H1N1 strains circulating.  The majority of these A/New Caledonia-like antigenically and genetically, although we have had a small cluster of the Bayern-like viruses. 
		We have seen a later onset of flu B circulation, which have co-circulated with the H1N1s.  The majority of B/Yamanashi-like show much better reactivity with the B/Sichuan, and they are closely related genetically, as well, to the B/Sichuan.
		Thank you. 
		CHAIR DAUM:  Thank you very much.  Do we have questions, or comments for Dr. Ellis?  Dr. Katz?
		DR. KATZ:  Dr. Ellis, many of us are unfamiliar with what the recommendations and utilization of influenza virus vaccines are in the United Kingdom.  Can you comment on that?
		DR. ELLIS:  Yes, I can.  They are recommended for the high risk groups, but this year it has also been decided that all those who are age 65, also recommended to have influenza vaccine, whereas last season it was all those age 75 and over, who were recommended.
		And they've also set a target of 60 percent uptake in this first year, and that has already been reached.
		CHAIR DAUM:  Do you have any kind of overall distribution relative to the population, like we have in this country?  I mean, I think the order of magnitude is 70 million doses, is that right?  70 million out of 250 million, almost --
		DR. ELLIS:  No, the number of doses this year was increased, and it was increased to 10.8 million doses.  So nothing like the amount that you have, but it has been increased to match that increased coverage in the over 65 age group.
		CHAIR DAUM:  Other questions, comments?  Thank you very much, Dr. Ellis.
		I think at this point we will take a break for lunch.  I have been asked to announce, by Nancy, that there is an area for about 20 people reserved in the restaurant here in the Holiday Inn, on the first floor for committee and/or presentors to spend the lunch period, should they wish to do so.
		We will take lunch for an hour.  It is exactly noon, we will reassemble at one o'clock.  Thank you. 
		(Whereupon, at 12:00 p.m., the above-entitled matter was recessed for lunch.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	(1:05 p.m.)
		CHAIR DAUM:  Welcome, everybody, back from lunch.
		The first -- there are three more presentations by way of background.  And then we have Dr. Cox will lay out the options for strain selection, and then we will have committee discussion. 
		So we will begin, of course, with the three presentations, and ask Dr. Levandowski to come and present some of the serologic data for us.
		DR. LEVANDOWSKI:  Thank you very much.  I will get started here.
		I was just joking that after lunch is probably not the best time to be talking about serologic data, because I have to tell you, that having looked at this stuff for the last several days, even my eyes are sort of crossing, and I'm not sure that I'm going to be able to keep it all straight.  I hope I can do a reasonable job for you.
		I have, also, sort of a -- we've been having power point presentations, and some overheads, and I actually have a combined presentation where high tech meets low tech.  So some of this is going to be on power point, and that is probably going to be the easiest part to see.
		Some of it I had some hiccups in my computer, and I couldn't get my tables transferred, so you are going to have to bear with me with my overheads, please.
		What I'm going to try to do is really to summarize a lot of serological information that is relevant for the current strain selection process.  And the serologic data that I'm going to present has been put together pretty much by way of committee, and that committee is really the ongoing collaborative efforts at a number of centers that are being sponsored by, and facilitated by, the World Health Organization and, in particular, its Influenza Centers. 
		This should show the serum panels that have been used for serologic studies.  And these serum panels have been coming from adults and elderly people, in Australia, Europe, the United States, and now recently Japan.	
		So we are having a little bit of expansion of the geographic distribution of the sera that we have to look at. 
		This particular graphic shows where the people who have contributed the materials for use, and what we are all looking at.
		One thing I would point out to you is that as Alan Hampson mentioned earlier this morning, the vaccine that was in use in Australia during the time that these serologies were done, included as the H3N2 strain the A/Sidney/597.
		And, therefore, I'm actually not going to summarize the data from those parts of the clinical trial, but all of the other information from that should be of use.	
		The laboratories that are participating in performing these serologic studies include the World Health Organization Influenza Center in Melbourne, Australia; the National Institute for Biological Standardization and Control in London; the Centers for Disease Control in Atlanta, and the Center for Biologic Evaluation and Research in Bethesda.
		Between these four labs these sets of sera have been tested against a large range of antigens that are recent, over the last year.  And the overall number for the serum panels is approximately 200 serum preparers.
		The testing hasn't been completed in all the laboratories at this time.  But what I'm going to present to you is data that  is current to yesterday, in fact. 
		So if I can get the first, or second, or third overhead, I will just have to flip through them to find the right one.  That looks good.
		This is a listing of the H1N1 antigens that were used for serologic testing.  And what I should hasten to point out is that not every one of these antigens was used in every laboratory. 
		So there is a whole variety of new antigens that were examined at least by one laboratory.  However, there is a core of these antigens that was tested in each of the laboratories, and we can use that as some comparison.
		There are known technical differences between the laboratories, and you will see on these slides it will be obvious that for the same serum panels there are some differences in the absolute magnitude of the antibody titers.
		But, generally, those things tend to be proportional.  And, really, what we are trying to do here with examining these serologic responses is to have some comparison between the current vaccine strains and the newer antigens that are appearing.
		So that is really what we want to focus on, that difference within a laboratory between the vaccine strain and the new strains. 
		These serologic studies that will be included actually were done in several separate campaigns that coincided with other recommendations that were made during this last year.
		And here I think it shows, as was also pointed out, there have been two lineages of H1N1 influenza A virus that have continued to circulate, although the strains that are related to the Beijing/262/95 strain are the predominant ones at the moment.  There are still some A/Bayern/795, or as Nancy Cox mentioned, the Johannesburg/82/96, those are the same lineage of H1N1 influenza A.
		This overhead shows results that were obtained from two of the participating labs, using a panel of sera from adults in the United States.  And this table and the others that are like it will include data on the geometric mean titers pre and post immunization.
		The percent of the titers that were greater than, or equal to 32 or 40, as the kind of cutoff numbers that we look at, as Wendy Keitel had mentioned earlier in her excellent presentation, and also percent four-fold rises.
		I'm really going to concentrate more on the geometric mean titers as a way of indicating differences between the vaccine strain and the newer antigens.
		In this particular table the data at the top are from the CDC, and the data at the bottom are from the CBER lab.  And the vaccine strain for these studies was the A/New Caledonia/20/99 strain.
		In this particular instance the IVR/116 strain was used as the antigen for the testing.  What I can say is that in this case the vaccine used was immunogenic, and it produced homologous antibody responses.
		And all of the strains that are in this particular panel, with the exception of the A/England/192/2000 strain, and the Brazil, I'm sorry, the Chile/4795/2000 strain are -- all the rest of those strains are New Caledonia-like.
		In both cases the A/New Caledonia vaccine produced antibodies that crossreacted well with the Bayern-like strain.  And this is typical for what we have been seeing previously, as we've discussed this in the past.
		And although the New Caledonia-like strains were mostly pretty well inhibited by the sera produced in response to the vaccine antigen in testing done at the CDC you can see that there is some reduction in the results for the A/Fujian/156/2000 strain.
		In none of these instances was there as much as a 50 percent reduction in titer.  And I will mention, a little bit later, as I go through some summary tables, why we think that -- or why I'm mentioning the 50 percent reduction.
		This overhead shows results -- I should mention that I'm not going to go through every one of the serologic panels individually, I'm just going to give some examples that will highlight some differences, or some similarities.
		This particular overhead shows the results obtained from two of the laboratories using sera that were from the elderly in Japan.  The data at the top are from NIBSC, and at the bottom they are from WHO in Melbourne.
		The vaccine strain, again, was the A/New Caledonia strain.  And in this instance the wild type strain was used as the antigen.  Again, except for the England/192/2000 strains, the strains here were A/New Caledonia-like.
		And what I would say again is that for the most part the vaccine produced antibody responses that were pretty good against most of the -- or all of the antigens that were included.
		Moving on to the H3N2 viruses, this slide shows the viruses that were used for serologic testing.  And, again there is a whole range of them.  All of these strains are somewhat related, they are more modern versions of the Sidney/597 and its progeny lines in evolution.
		They are typical, I guess they are reasonably representative of the strains that were circulating during 2000, and although there is one strain that is listed as being from 1999.
		This overhead shows -- should show a panel of sera from adults in Europe.  And the data at the top are from the Center for Biologics, and the data at the bottom are from WHO in Melbourne.
		The current vaccine strain, in both instances, was the Panama/2007/99 strain, and in one lab the reassortant used in the vaccine was the -- it was the antigen for the serology, and in the other lab it was the wild type strain.
		What you can see in this particular instance is that in some instance, some of these, for some of these strains, as Alan Hampson had already pointed out earlier this morning, there are some reductions in the antibody responses of the newer strains as compared to the vaccine strain.
		That is not universally true.  Many of the strains seem to be covered quite well by the antibodies produced to the current vaccine, but there are some notable differences. 
		And in this particular instance there is more than a 50 percent reduction in the geometric mean titers for the Hong Kong/123/2000 strain and the Leon/1242/2000 strain, as compared to the vaccine antigen.
		This overhead shows the results obtained using a panel of sera from elderly in the United States.  Data at the top are from the CDC, and the data at the bottom are from Center for Biologics.
		A/Panama is, again, the vaccine strain, and both labs used the Resvir 17 strain as the antigen.  What I would say here is that, again, for the most part there are pretty -- there are reasonably good cross-reacting antibodies that were seen, but there are, again, some notable exceptions.
		In this case the A/Fujian/140/2000 strain shows more than a 50 percent reduction in the titer.  And similar to what we saw in the previous slide, there seems to be some reduction, although it is not as much as 50 percent, there is some reduction seen against the Hong Kong/1923/2000 strain.
		So moving on, then, to influenza B viruses.  You will notice that this list is somewhat longer than the previous two.  And it reflects, to some extent, the growing concerns about influenza B viruses, and changes that are occurring.
		For the serologies that were showing, just at the moment, we do not have any strains that are in the B/Victoria/287 lineage.  And that reflects the fact that they have become so few and far between.
		But there are strains here that represent, really, a very wide geographic distribution, and were included in the serologies the Sichuan/379/99-like strains, and the vaccine strains that are in use, and then some newer strains from around the world that would fall into the Sichuan/379/99 category.
		So this one, this overhead shows results for a panel of sera from elderly in Europe.  And the data are from WHO Melbourne at the top, and from CDC at the bottom.
		And the vaccine strain was B/Yamanashi/166/98 for both serum panels.  Here there are a number of viruses that are included, as I mentioned, looking at Johannesburg/599 and Sichuan/379/99.
		And in the case of these serologies reduced titers were found, actually, for nearly all of the antigens that were tested by the laboratories.  Reductions of 50 percent or greater were found for many of the recent viruses, including this B/Christ Church/2/2000 strain, the B/Zagreb/3578/99 strain, the B/Alaska/16/2000 strain, the B/Guangdong/120/2000 strain, and the B/Hong Kong/557/2000 strains. 
		And although, as Alan Hampson mentioned, there may be some other strains that are appearing, what you see from this is that for some of the tests that have been done, there seems to be sort of a general trend for reduced antibody titers against the influenza B strains, even though some of these differences are relatively modest.
		This overhead shows a panel of sera from elderly in Australia.  And the results are from WHO Melbourne at the top, and from the Center for Biologics at the bottom.  B/Yamanashi/166/98 was the vaccine strain, again. 
		And, again, these results demonstrate reductions in titer against all of the antigens that were tested.  A reduction of 50 percent or greater was shown only for the B/Christ Church/2/2000 strain in this particular run.
		But in all of the instances, again, there is a modest reduction against these viruses, including the B/Johannesburg/5/99, the Sichuan/379/99, and the B/Victoria/504/2000 strain.
		So to try to summarize this, and let me see if I can do this with high tech, again.  Does that look better?  This one is better?  We will go with this one, then.
		So to try to summarize this, there are some tables I'm going to present to try to pull together the data.  This does not include all of the strains that were shown.  But this will include strains for which multiple laboratories have some data. 
		And so in attempting to summarize this, these tables show the frequency with which we found new test antigens that gave a 50 percent or greater reduction compared to the current vaccine strain.
		And the reason I'm emphasizing 50 percent, because that represents a two-fold reduction, which in geometric mean titer terms is really quite marked.
		The data included in the table are for antigens that, as I said, were tested in more than one laboratory.  And that is important, too, because that reflects, generally, the interest in these strains, and their possible use as vaccine candidates.
		It should be noted that not all of the testing that we would want to do for these things has been completed at this point.  And actually I would like to start with a different slide, I would like to start with the H1.  
		So here we are showing the first -- the upper antigen shown here, the Wuhan/292 -- no, actually it is not going to work because some of it is cut off.  We will go back to the overhead.  Sorry.
		So if we can get the other slide that shows the H1s?  Thank you. 
		So the upper antigens here are New Caledonia-like, and the bottom two are Bayern/7, or Johannesburg/82/96-like, in the other lineage.  And what you see, by and large, for these strains concentrating, really, on the totals over here, for all the laboratories, is that for the most part there doesn't appear to be too many instances in which there was as much as a 50 percent reduction from the serum panels that were examined.
		And to take that one step further, to try to look at overall what the differences in magnitude were, again, there is a lot of variability.  But in most instances, at least for these strains that we are looking at here, including some of the newer A/New Caledonia-like strains, there is really not too much of a difference in overall titer.
		There may be some exceptions to that, in this particular instance, one of the laboratories found that there was more than a 50 percent reduction in all of the tests.  But, overall, sort of using the balance of the data to try and see the consistency here, it actually seems to fit in pretty well with what we see for the rest of the information. 
		So in general what I would say is that it doesn't seem to show a lot of reduction, the current vaccines seem to be pretty reasonable at producing antibodies against all of the H1N1 influenza viruses that are out there. 
		There are some exceptions that we can see some reductions.  But, overall, it seems to be pretty good.
		And if I took this one step further to try to reduce it, I would say that probably about ten percent of the tests, overall, for all of the serologic tests that were done, both shown here, and not shown here, showed some reduction for the H1N1.  So it was really relatively minor there.
		So if we can go to the H3N2.  Again, the same kind of table, trying to look at differences.  These strains are all related to, are in the same evolutionary pathway from Panama/2007, and here again, I would like to call your attention mainly to the totals here.
		And what you see is that for most of the strains that are included here, and there is a range of strains from different locations, really there is not too much in the way of reductions, and overall it is really relatively minor.
		So that for the most part I would say it looks like these strains are well covered by the current vaccines. 
		There are some exceptions, again.  The Fujian/140/2000 strain, and also the Hong Kong/1923/2000 strain, in different laboratories there were some reductions seen.
		But even factoring that in with all the overall data, again, it seems to be reasonably consistent with what is seen for the other strains.  And here, again, I would say that there are some reductions, but it is really pretty modest.
		And looking at all of the strains that we had of serologic testing on, again, it was in the range of about 10 percent of the tests that were done, showed a reduction of 50 percent or greater.
		And then, finally, for influenza B, again there weren't any strains that were in the other lineage, so these are all strains that are in the same lineage, same HA lineage as B/Yamanashi/166/98.
		But, now, calling your attention to the totals, whereas before we saw lots of zeros for 50 percent reductions, here we see lots of numbers.  And although it is not one hundred percent in homogenous in every test, still there is a somewhat different pattern being seen for influenza B, as compared to the other two strains. 
		And the magnitude of those differences also seem to be pretty consistent.  It is a little bit higher than for the H1N1, or for the H3N2, but it is not dramatic.  It certainly is nothing like what we would see if we did have B/Victoria/2/87-like strains on here, in which case we would see percent reductions on average of about 75 or 80 percent.
		So this is somewhat modest.  But still there is a fairly consistent pattern of seeing some reductions in some of the tests, in some of the laboratories. 
		And if I took all the tests that we did, or that we have information for, and did the same thing as with the H1N1 and the H3N2, here is about 20 percent of the serologic tests that show some reduction.
		So there is a little bit of a difference here as compared to the other two strains. 
		So in summary what I would say is that for the most part the current vaccines were immunogenic, they produced reasonably good antibody titers.  And in all three, for all three vaccine antigens we can see some evidence that is consistent with the antigenic drift that is going on in terms of reductions in titers.	
		But overall, for all three of the strains, it is relatively modest.  And if there is anything happening, it seems to be happening more with influenza B viruses, which is also consistent with the epidemiologic data that has been presented already.
		And I will stop there.
		CHAIR DAUM:  Thank you very much.  We have time for a question or two.
		DR. KIM:  I know this issue has been, I believe, asked in the past about any information on the pediatric data for any antibody responses?
		DR. LEVANDOWSKI:  We have not had access to pediatric serum panels for some period of time.  It is very difficult to obtain that, although it would be very, I think would agree, it would be very important information. 
		And one thing that we don't see from serologies in adults that we see in serologies from children, is the effect of not  having been previously infected or immunized, so you have a very clean baseline to work from, and very obvious differences when they are present.
		And with these particular serum panels I didn't emphasize that at all. But the panels from Europe this year included mostly sera that had very low titers against the vaccine strains to begin with, that the people who were being immunized either hadn't been immunized previously, or had very low titers.
		And so there was a very clean, from those particular serum panels, like in the pediatric sera, you would expect a very clean kind of difference. 
		But we agree that would be very important to have information on pediatric patients. 
		CHAIR DAUM:  Dr. Kohl, then Dr. Snider.
		DR. KOHL:  I'm sorry to be a little bit of a pain, but we ask that question every year, and we get the same answer every year.  And I'm not sure what the problem is.
		But influenza has a considerable health expense in children.  There is more and more data showing that it is a very significant problem.  There are large groups of at-risk children that are recommended to be immunized.  And yet every year we don't have information about the vaccine in children.
		Perhaps Dr. Myers, as part of the vaccine information, whatever that group is called these days, or you, but there are NIH-funded child immunization centers around the country, and I don't understand why some of these can't be plugged in to get us some relevant data. 
		DR. LEVANDOWSKI:  Well, I think you are right that it is possible to do it.  And FDA previously had its own contract for immunization of children, but it wasn't an issue of funding that resulted in termination of that contract. 
		So from whatever source we could get those sera I think we would be very, very interested to have them.  And there have been discussions about trying to collaborate in that way.
		DR. KOHL:  Is there anything the committee can do to help push that forward?
		DR. LEVANDOWSKI:  I think you've already done it by raising the issue.
		CHAIR DAUM:  Dr. Snider?
		DR. SNIDER:  Yes, Roland.  With regard to the information about serological responses to the influenza B vaccine strain, and the -- with the other B strains that have emerged, I guess I really haven't heard us, in the past, have any discussion around at what level of reduction we might be concerned.
		Is there any clinical data from years past when vaccine strains have not covered well, that would give us any guidance at what level we should be concerned?  And that is for you, Nancy, or anybody that might have any information. 
		DR. LEVANDOWSKI:  Right.  I guess I have to kind of grope a little bit to try to find some way to respond to that.   I think we haven't really used the serologic information to tell us that people aren't entirely being protected.
		I think we've been using the serologic data here to try to say that we are seeing, or we are not seeing differences in the strains that are out there in nature.
		We are using human serology as a way to back up what is being seen with animal serologic data.  And what I could say is that in past years this committee, when we have not -- even when there has been a difference in the animal serologic data, if we've not seen a very dramatic, or any change from human serologic data, particularly if there wasn't strong evidence that influenza viruses were spreading widely, we have not had -- the committee has not used that information to recommend a change in the strain.
		And I think the answer partly goes back, again, to -- I guess try to predict forward for a new antigen versus what we know from strains that we've already worked with is somewhat difficult.
		And just because we have had the experience where, with antigenic changes, the old vaccine does not seem to have performed very well.  I guess we don't really know exactly what to anticipate.  I guess we don't know what to anticipate from any vaccine that we produce until we use it.
		DR. SNIDER:  Thank you.  Just behind that question, I just wanted to express what I see here.  I think the influenza experts really have been helpful over the years in really telling us that this is as much an art as a science in terms of how you make these kinds of decisions.
		And I think we all recognize that.  But at the same time it would be nice to be thinking about if there are ways to make our decisions more quantitatively oriented, if there are ways to build models, or to use data in more quantitative ways that would be predictive.
		I realize that with influenza we are talking about an extremely difficult situation, because we are talking about different, three different strains of viruses, and different subtypes, and so forth.
		But it is just a plea for those who might be in a position, around the table, or in the audience, or elsewhere, to try to be thinking about how we might model this, and be more quantitative in our approach.
		CHAIR DAUM:  I would like to follow up on that a little bit, and try to feel the elephant from a different part.  And that is when these kinds of data are shown, I, a totally non-influenza expert have tried to keep my eye on this number of 40 that has been touted as a protective level. 
		And I wonder if that is a valid way to think, your opinion is whether that is a valid way to consider these reductions as leaving you above or below 40.	
		And, secondly, to maybe in a minute or a minute and a half or so, tell us where the number comes from, I mean, is it an etched in stone number, or is it just a feeling of the art?
		DR. LEVANDOWSKI:  Well, I wish some other people could help me out here.  But my understanding of that is that 1 to 32, or 1 to 40 came about from clinical studies that were looking at protection in the clinical trials that they were done in.
		There was a correlation between a titer of greater than 1 to 32, or 1 to 40.  And it wasn't perfect by any means.  I think in my own mind I think of it as a 50 percent end point titer of a sort, that you can expect a reasonable number of people will be protected if you hit that titer.  It doesn't mean that everybody is.
		And certainly I think that the argument would be that the higher the antibody titer, and going back to the argument about how high can you get, I think probably there is a maximum for each individual that can't be overcome.
		Well, how high is enough?  Well, as much as an individual can achieve.  And the 1 to 40 I think was useful for trying to make some sense out of use of vaccines, and whether there was protection.
		I emphasize the geometric mean titer for this presentation because, again, I think what we are trying to do here, because there are technical differences between laboratories, because there are technical differences for each antigen that we look at, that seems to me the most direct comparison between the vaccine strain and the newer antigens to get a sort of a feel for how different are they.
		And it really, again, is somewhat parallel to what is being done looking at the differences with the animal serologies, trying to get that same kind of information from human serologic results.
		I don't think we are trying to say that there is or there is not protection for anybody, based  on what we are getting on these serologies.  I don't think we are trying to make that leap with this data. 
		I think we are trying to use it as a way to sort out whether there are some differences in the antigens.  And I think the answer to whether this means that there is efficacy for the vaccine, I think that belongs in clinical trials, which you also have told us we should be doing.
		CHAIR DAUM:  Dr. Cox, did you want to make a comment, then Dr. Kilbourne.
		DR. COX:  What Roland said is true, that the studies that were done to look at the correlation between a high titer and protection indicated that at a titer of 40 or 32 you have protection from about 50 percent of people.  If you have titers of 80 then you have a greater proportion of people protected.
		And the higher the antibody titer the more likely it is that you will be protected from infection.  So these values aren't absolute.
		The other caution I would like to place on the table, when we are looking at serologic results for influenza B viruses is that we are using ether treated antigens.
		And by using ether treated antigens we really tend to obscure differences.  The titers are higher, but the differences between strains are smaller.  And the reason we use the ether treated antigen for influenza B viruses is that if we don't use ether treated antigens we have such low titers that we can't see differences, anyway.
		So it is a kind of compromise that we have to make.  But when you look at the data you have to realize that some of the differences that do exist between antigens may be obscured by the methodology.
		CHAIR DAUM:  Thank you.  Dr. Kilbourne, then Ms. Fisher.
		DR. KILBOURNE:  I think there is a great deal of validity to that 1 to 40, or 1 to 32 figure, because it is derived from, really, a very large number of studies in the military, sponsored by the late Influenza Commission, in which fairly comparable and uniform populations of young recruits have been studied.
		So at least within that kind of population it has some validity.  And I think it is just a useful check point.  Having said that I have to remind us all that every one of us sitting in this room has had different experience with influenza virus antigens, depending on the age of infection, depending on what array of viruses we've been presented with, either in vaccine or infectious form, depending on our HLA type, undoubtedly.
		So that, again, this matter of generalizing, we are talking about heterogenous population of virus particles in human beings.
		So I think that it is remarkable that we are able to come up with some kind of a figure such as that.  Remember that is a figure for hemagglutinin antigen alone, we haven't even talked about the neuraminidase and very seldom do.  That is also a contributory factor.
		CHAIR DAUM:  Thank you, Dr. Kilbourne.  Ms. Fisher?
		MS. FISHER:  Well, I would like to agree with Dr. Snider that we do need more information, the committee needs more information on the future upon which to base decisions to change a strain.
		But beyond that, because there has been so much attention paid to vaccining children with flu vaccine, it seems that there needs to be some systematic way of looking at different populations, and how, genetic populations, and how they respond to the flu vaccine, to make sure we are doing the best we can in terms of appropriately using the vaccine in appropriate populations.
		CHAIR DAUM:  Thank you very much.
		DR. KILBOURNE:  Could I add just one other thing?
		CHAIR DAUM:  Yes, certainly.
		DR. KILBOURNE:  I think that we could do what you suggest as an idea.  Studies could be mounted that would answer a lot of these questions much more precisely.
		But I think it would take enormous amount of money, and resources, and BTUs, to really bring this about.  What you would have to do, for example, is to take last year's vaccine and compare it directly with its antecedent, or its successor, and really look at the relative response in this kind of population.
		That takes hundreds and hundreds of people, and probably hundreds of investigators, as well.  And it is not entirely art versus science, it is just simply a matter of resources, really.
		And anything that this committee can do to harp on that will be very gratefully accepted.
		CHAIR DAUM:  Dr. Kohl?
		DR. KOHL:  This is directed to anybody, but I had Dr. Fukuda in mind.  I guess every year we question vaccine efficacy, and every year we talk about cases of virus isolated, or virus isolated from cases, and wonder what the percentage of those people have been immunized, what the viruses are, and if possible, what their antibody response was at the time of the viral isolation.
		Is there any chance we will get any of that data, or does any of that data exist from last year, for instance, to tell us how efficacious the vaccine was?
		And if there is a magic level 1 to 40.  And Dr. Kilbourne mentioned most of these data are from young healthy military recruits who, of course, aren't the population we are interested in primarily.
		Does it take a different titer of antibody to protect older individuals, kids, etcetera?
		DR. FUKUDA:  You know, I think that for -- we have talked about this for the last couple of years, and I think that it has been pretty clear, for a while, that it would be really useful to have annual vaccine efficacy studies done.
		And as you know the reality has been that sporadically there are vaccine effectiveness studies done, typically in outbreak situations.  And then more recently, over the last three years or so, the National Immunization program at CDC has been doing vaccine effectiveness studies using data from HMOs, but without actually being able to ascertain the vaccine status accurately.
		And these are clearly not efficacy studies.  And I think it basically has come down to what Ed has pointed out.  I mean, these things can be done, it is just freeing up the resources to do them has been enormously difficult.
		I mean, I think that any number of us here would love to see those studies done.  And it really does just come down to resources.  And so, will the resources be there?  I mean, clearly there is a lot of interest in the, you know, potential for live attenuated influenza vaccine, and so on.
		There have been efficacy studies done in support of those sorts of things, but that is clearly different than the kind of annual year round studies, I think, all of you would like to see done, and certainly we would like to see done.
		So that is the situation, I think. 
		CHAIR DAUM:  Dr. Ferrieri, please.
		DR.  FERRIERI:  Very briefly.  I would support those types of studies recognizing the financial limitations, because it might put to rest some of the anecdotal impressions that we've had on occasional years that the vaccine hasn't been, "as good as other years".  And last year was a year in point.
		And although there has been denial at many, many levels that there were breakthroughs, there are scientific people who claim that in their cities they had antigen test results in patients who had been vaccinated with influenza virus vaccine, who did have positive tests. 
		And there are all sorts of little pockets of unrest about this.  But we need to have answers to that, so that we don't just speculate, were there breakthroughs or not.
		CHAIR DAUM:  Dr. Cox, did you want to say something? 
		DR. COX:  I will try to make a brief comment about that.  I think that we, those of us who have been involved with influenza activities for a number of years, do recognize that every year we received influenza viruses that were isolated from people who are vaccinated.
		In some years we receive more viruses than other years, and we are not quite sure if that reflects a decrease in vaccine effectiveness, or whether there just is more flu going around, and so there are more people who have breakthroughs.
		I think that there is a wealth of literature, and a very long history, of studies which have shown influenza vaccine to be safe and effective in young adults, in elderly, and so on.
		But where we really don't have as much information is in children.  And I think that we have to try to have our resources focused on those studies that might be most useful in directing activities for the future, and also link into data that already exists, because it is probably impossible for us to mount vaccine efficacy studies every year in all the different groups that we would really like to see them in.
		CHAIR DAUM:  Dr. Ferrieri?
		DR.  FERRIERI:  Briefly.  At the ACAC meetings in the fall there was data presented that is no big surprise, but supporting the hospital admission rates of young children admitted with influenza, and the influenza complications.
		So it would be wonderful to have more data, because vaccination could have an enormous impact on health as well as health economics in young children.
		CHAIR DAUM:  I think it is -- I would like to congratulate the people who presented data today from all the agencies, and from international agencies as well, because I've been on this committee several years now, and I have never heard the influenza study of the year laid out as nicely as I thought it was today.	
		But at the same time I think this committee is trying to say something.  What I think we are trying to say, and the consensus that I hear around the table is that this is a health care intervention which we, as a society, have committed to, to the tune of 70 million doses a year.
		And that we are wondering, each year, whether the vaccine is working; we are wondering whether our children, who clearly have a bigger burden of disease than perhaps was realized before, are being protected by this. 
		And I don't -- there aren't too many health care interventions that are quite this massive.  And I think that it is time to ask our governmental health care agencies to initiate the process to commit the resources to this task, so that it gets done.
		I think the committee says the same things every year about what is missing.  And although I really mean it when I congratulate everybody that the presentations today were just really fine, we need these additional resources, we need this additional information. 
		And I would hope that when we plan our vaccine, or help you plan it next year, that someone has made a commitment to start moving this process forward.
		And with that we come to a very practical part of the study, and that is Dr. Ye Zhiping, I hope I'm not butchering his name, from the FDA, will tell us that no matter what vaccine we think  we would like to design, we need a sense of practicality here.
		And we will now hear about the availability of strains and reagents, before moving on to comments from the manufacturer representative. 
		MR. YE:  In a short presentation I will represent the status, as of today, of the potency reagents and candidate vaccine strains. 
		In terms of potency reagents the current vaccine is available for the vaccine is for H1N1 is New Caledonia/28/99.  For H3N2 is a Panama/20007/99, and for B is B/Yamanashi/166/98.
		In terms of candidate for the new strains choosing the reagent will be available in May, at the earliest.
		And in terms of the vaccine candidate, the current vaccine for New Caledonia, H1N1, this strain give you a moderate virus yield.  And the reassortant possessing protection antigen from New Caledonia, this reassortant giving you a high yield.
		And since the strain of New Caledonia is a predominant strain currently we don't have new antigenically divergent strain now.
		And in terms H3N2, still the Panama/2007 is the current vaccine.  And, again this one giving you moderate virus yield, and the reassortant give you a high yield. 
		And although there are another three reassortant, the three reassortant does not offer any advantage over this reassortant.  And the candidate for the new strain of the new vaccine is A/Ulan Ude/1/2000.
		And this strain give you moderate virus yield, and the reassortant give you a high yield.
		The final one is the B strain, the current vaccine for B strain, is the B/Yamanashi/166/98, and this strain give you a moderate virus strain.  And there are possible 3 candidate for B strain, getting the data from the protection serum generated from this virus against the new isolate strain.
		And one is B/Johannesburg/5/99.  Unfortunately this strain give you a low yield.  And the B/Victoria/504/2000, and this one give you moderate yield.
		Another one is B/Alaska/16/2000, and this one give you a low yield.  Again is for B strain we don't have a reassortant right now.  That is it, thank you. 
		CHAIR DAUM:  Thank you, Dr. Ye.  We have an opportunity for questions for Dr. Ye.  Dr. Estes, start us off.
		DR. ESTES:  You listed, on the B strains the current strain that gives a moderate yield, and then a candidate strain, the Johannesburg, that gave a moderate  yield.
		Are those moderate yields really considered sort of similar?
		MR. YE:  Yes, for B it is compared to A the B is usually four times lower than B, B four times lower than A.  So that strain is pretty close, around 200 by inhibition, hemagglutinin HA titer.
		DR. LEVANDOWSKI:  Can I make a comment, also?
		CHAIR DAUM:  Please.
		DR. LEVANDOWSKI:  Actually the B/Johannesburg strain is a very low yielding strain, if that is what your question was?  The B/Johannesburg/5/99, we had discussed that at last year's meeting in March. 
		The B/Victoria/504/2000 is somewhat better yielding.  We are calling it moderate, but it is really early days for that strain, and I don't think that we have certainty, although we may hear some information from the manufacturers about this. 
		And Zhiping did not really emphasize, but there have been, probably, 15 or so of those strains that have been sent off to manufacturers to take a look at, to get some information on growth characteristics.
		And I would say the good news is they are very homogenous, but the bad news is they are all pretty much low yielding.
		CHAIR DAUM:  So if that last slide flashed back up?  On the B strains, the yield at the bottom of the slide, so is Victoria truly better than the other two, or are you saying that is really open to question? 
		DR. LEVANDOWSKI:  Well, I think we don't know the full answer to that.  But I think from what we do know it is a better strain than B/Johannesburg/5/99, or any of the others.  It seems to be the one that we hear from manufacturers is the best of the bunch. 
		But that is not to say that it is as good as it could be, or as good as might be desired.
		CHAIR DAUM:  Dr. Ferrieri, I couldn't tell whether you wanted to make a comment, or not?
		DR.  FERRIERI:  No, I just wanted to emphasize the low yield of the B/Johannesburg, the impression given perhaps was that it was also moderate.
		CHAIR DAUM:  Dr. Kohl, then I think Dr. Myers, and Dr. Griffin.
		DR. KOHL:  The WHO has recommended for the southern hemisphere the Sichuan/379.  Are these all in the Sichuan/379 group?  I'm looking at the dendrogram, and I'm not -- the Vic looks like it is not quite in the group, or is that --
		DR. LEVANDOWSKI:  We might defer to Nancy, but my understanding is that we should consider the B/Victoria/504/2000 strain as a Sichuan/379/99-like strain.  And there are many others, too, that are in that category.
		DR. COX:  That is correct.  And we actually put quite a bit of effort into making egg isolates of B/Sichuan/3/79-like viruses, and have recently distributed some of these strains to the manufacturers. 
		So there are some additional strains that have gone out, but there are just no data yet on whether they are going to be any better than the existing ones.
		So we are trying to work through a whole series of strains that are B/Sichuan-like.
		CHAIR DAUM:  Dr. Myers, then Dr. Griffin.
		DR. MYERS:  I was just going to ask about the neuraminidase because if there is as much drift in the neuraminidase as there is in the hemagglutinin in the B strains, whether we should be considering that. 
		CHAIR DAUM:  Does anyone want to comment?
		DR. LEVANDOWSKI:  Well, maybe -- okay, I will jump in.
		CHAIR DAUM:  Thank you. 
		DR. LEVANDOWSKI:  The vaccines are really standardized, as I mentioned, for hemagglutinin and not for neuraminidase.  We would like for both the hemagglutinin and neuraminidase to match, if possible, or to be as good a match as possible. 
		As Dr. Kilbourne mentioned there may be some, and I did too, there may be some protection from the neuraminidase and this committee has told us, in the past, that they thought it would be best for both the hemagglutinin and/or neuraminidase to match up.
		What I would ask, as a question for Nancy Cox again, or for anybody else from one of the WHO flu centers, is how much difference is there, antigenically, in the neuraminidases for these Sichuan/379/99-like strains, is there a substantial difference? 
		DR. COX:  We don't know, we don't have neuraminidase inhibition tests for influenza B viruses.  Most labs have not been doing neuraminidase inhibition tests for almost eight to ten years now.
		We are actually putting quite a bit of effort into renewing efforts to do neuraminidase inhibition testing on H3N2 viruses.  But it is a difficult process to get the reassortants that you know, the proper reassortants to do the right kind of testing. 
		CHAIR DAUM:  Thank you, Dr. Cox.  Dr. Griffin?
		DR. GRIFFIN:  My question follows along the same line, but I was thinking of the H3N2, because there the neuraminidase definitely looks like it has drifted away.	
		I noticed that the Ulan Ude strain does have neuraminidase that is much closer to the drifted variety, or the current selection to the neuraminidase of the current strains. 
		And I guess not being an influenza virologist I wondered what the possibility was, just reassorting that neuraminidase into the current vaccine, H3N2 selection? 
		MR. YE:  Usually this neuraminidase antibody is not protective antibody compared to HA.
		DR. GRIFFIN:  I wasn't talking about changing the HA, I was going to leave the HA, and I was just going to add in the neuraminidase that was more closely related to the current strains.  But maybe that viruses would not grow, but I don't know. 
		DR.  FERRIERI:  The point is that it wouldn't matter because it wouldn't contribute much in the overall protection, is my understanding of the issue.
		DR. KILBOURNE:  I think that is a misunderstanding, it has been misrepresented by the last two speakers.  It is a very important contributor to influenza virus immunity.  And it simply has been ignored through the years because it is a test of measuring its antigenicity are somewhat difficult technically.
		But I think it is high time we pay attention to this.  They are doing this in Europe, a manufacturer over there.  There is not even a requirement, currently, that there be neuraminidase in the vaccine.  
		I think in view of our vastly mature animal studies, this is an intolerable position. 
		DR. GRIFFIN:  Not being able to measure it is not the same as not being important, it seems to me.
		DR.  FERRIERI:  Well, and given the newer agents out on the market that may have some impact on the disease suggests, again, its role.
		And so, I'm sorry, I didn't mean to diminish its importance, but I came away with the impression, from the previous discussants, that the HA antigen induced antibodies that may have been more protective.	
		Do you have evidence that if you inactivated the gene for HA that you could still achieve the same virulence of any of these influenza vaccines?
		DR. KILBOURNE:  HA is undoubtedly the dominant, more important antigen.  There is no question about that.  But why ignore the other surface glycoprotein, which is also contributing to antibody formation and immunity.
		And a further point about that, while I have the floor, briefly, is that if there is going to be a divergence of evolution of the HA and NA, as has been shown, then we have to be cognizant of this. 
		We might actually have to fabricate reassortants that are high yield, which are antigenic hybrids.  Snatching, as you suggest, the HA from one and the NA from another, that adds to the complexity of the whole formula, though, which nobody is anxious to do.
		But I think it has to be clearly stated and abundantly made in the literature that it is a very important antigen, and will protect by itself.  But it's infection from permissive immunization, which does not prevent infection, but it may prevent disease when given in adequate quantity, all by itself.
		CHAIR DAUM:  Dr. Huang?
		DR. HUANG:  I would like to focus us back on influenza B strains and the candidate strains that we have in front of us.
		I guess a very simplistic question, and I'm not sure why I don't understand this, is that if we already have the Sichuan/379/99 used as a reference viruses, why that isn't already one of the candidate strains? 
		DR. COX:  Simply because it doesn't grow satisfactorily for vaccine production.  It was the prototype reference strain that was first identified as being a variant.
		And so it has been used in HI tests, and in serologic tests for both the southern hemisphere recommendation and for our own considerations here.  But it just doesn't grow well. 
		CHAIR DAUM:  Dr. Levandowski wants to make a comment, and then Dr. Ferrieri.
		DR. LEVANDOWSKI:  It would be analogous to our previous vaccine, that our recommendation was actually for a B/Beijing/184/93-like strain, but we've been using something else since that recommendation was made.
		So the reference strain may not be the actual strain, and that has been true right along for vaccines. 
		CHAIR DAUM:  Dr. Ferrieri?
		DR.  FERRIERI:  I would like to go back to the serology studies with influenza B.  I must say I don't feel I've memorized all the data that you presented.
		But in focusing on the very at-risk population of the elderly, it would appear that the titers, post-vaccination, are rather comparable against B/Yamanashi, Victoria, and others.
		And the percent of four-fold rise, although not real impressive might be, again, supported by the fact that they had rather high pre-vaccination titers in the elderly, 60-some, 58, and so on.
		And so I fail to see, I would like you to refresh my memory, which has obviously been very transient, about the inadequacy, if any, of the serology responses, serologic responses to B/Yamanashi.
		I don't see a sufficient evidence for examining a seriously candidate strains, although I appreciate the antigenic studies.
		CHAIR DAUM:  Does someone want to tackle that one? Roland.
		DR. LEVANDOWSKI:  I tried to give the impression that there is evidence for antigenic drift as shown through the human serologic results.
		And what I said, I think, was that what we see is, for the most part, what would be considered moderate, a moderate difference between the current vaccine strain and the Sichuan/379/99-like strains, in all the strains that have been examined overall, in fact.
		There are some serum panels that were tested where there was a more dramatic decrease seen.  But, overall, as I tried to do, to put it into some larger context, I guess we would have to state that what we see is really a rather modest effect in terms of reduction of antibody responses against those newer strains. 
		But it is consistent with antigenic drift going on within influenza B strains.  And it is a more impressive, if you want to put it that way, but it is a more obvious difference for influenza B than it is for either the H1N1 or the H3N2 this year.
		CHAIR DAUM:  Dr. Griffin, and then what I think I would like to do is move on to the last two presentations.  We will then have all the cards on the table, and we can continue this discussion.  If you could wait, that would be great.
		Let's thank Dr. Ye, very much for his presentation, and call on Dr. Greg Slusaw, I hope I'm not ruining his name.  Thank you, I'm doing three for three today, from Aventis, to represent the manufacturer's point of view.
		DR. SLUSAW:  Thank you.  First of all just an administrative note on the agenda.  Today I will be representing Aventis Pasteur, not necessarily the views of PhRMA, and that is simply because all the PhRMA flu manufacturer members didn't have a chance to review the content of what I'm saying today.  So we will just leave it at that. 
		The members of this committee are, once again, faced with a difficult challenge of analyzing today's surveillance data, and projecting that into the future, and arriving at strain recommendations for the 2001-2002 flu vaccine formula.
		We sometimes euphemistically refer to this activity as fine tuning, or updating the vaccine formula.  And to the casual observer it may seem that this is a trivial exercise.
		But I think the manufacturer's experience, from last year, reminds us that it is not.  Each time we change the vaccine composition we undertake a risk.  And even though we typically change one or more of the components of the vaccine formula each year, and we are generally very successful at manufacturing vaccine, that doesn't change the fact that we are taking a bit of a gamble each time we do it.
		And even looking at antigenic drift, and changing to an antigenically similar strain, the growth and purification characteristics of that virus may be much different, and may have tremendous impact on our ability to manufacture vaccine. 
		The first overhead, please.  Really, there are a number of critical pieces that have to come together into this complex puzzle to manufacture vaccine each year. 
		But if I can just distill that down to some of the main components, obviously the first critical issue is our major raw material, having a reliable consistent supply embryonated eggs for vaccine production. 
		This is something that we anticipate each year, though, and we can work toward, and we actually have a very robust, and reliable system in place, to ensure that we have an adequate egg supply.
		Which for the 70 million doses being produced for the United States market, involves about half a million chicken eggs, per day, over about a six month period, for vaccine production. 
		The second critical element, strain selection, of course is the activity that we are involved with here today.  And this is very important, of course, for choosing strains with the proper growth characteristics, but also achieving that balance between the best antigenic match, and having suitable growth characteristics for vaccine production. 
		And, of course, part of strain selection involves having high growth reassortants available for the A strains, which is very critical to being able to produce a vaccine supply.
		And then the final critical piece of the puzzle is having SRID potency test reagents for any new strains that are included in the vaccine formula.
		And although we have various methods for estimating the amount of antigen we are producing, when we begin production of a new strain, it is not until we actually have those homologous SRD reagents that we know exactly how much we've manufactured, and we can begin to think about formulating the trivalent vaccine. 
		Next.  Actually Dr. Levandowski provided a good introduction to the manufacturing timelines and constraints this morning in his presentation.
		The flu vaccine manufacturing cycle actually begins about a year ahead of time, when the chickens are ordered for the following vaccine production cycle.  And that usually occurs in January for the following year.
		And those birds are moved into the houses and begin to lay eggs usually in the October to November time frame. 
		Something that is ongoing, even as we are completing the previous production cycle is we are receiving candidate seed viruses, both from the CDC and from the FDA.  And this is a time of very close cooperation between the FDA, CDC, and the manufacturers, to evaluate the growth characteristics of those virus, and ensure that any candidates that are identified for the formula are acceptable for vaccine production. 
		And also in parallel would be the identification of new strains, the preparation of high growth reassortants occurs.
		We generally plan to work on a time table beginning the first strain production in January, and followed on approximately monthly intervals with the second strain selection in February, generally perhaps after the WHO strain recommendations, and then finally, about a month later, the third strain selection in March.
		And during the entire January, usually July, August, about a six or eight month time frame, monovalent concentrate production is in progress, and also in tandem with that, the potency test reagents are being prepared for any new viral strains in the vaccine formula.
		Finally we attempt to target, usually the first week in June, for the first bulk vaccine preparation, and the manufacturer's license are generally issued the first week or so in July, and then immediately vaccine distribution begins, in a normal year, into the October time frame, this year, of course, was extended into November and December. 
		Finally we just had a lot of discussion about some of the B candidate strains, and I can assure you that Dr. Levandowski was correct when he mentioned that we received at least 12 or 15 potential B candidates to consider for this year.
		This is just a relative comparison of growth based on hemagglutination, simply chicken red blood cell hemagglutination testing.  And I've just standardized them all to be Johannesburg as a growth of one, so it is just relative growth.
		Also including in this graph B/Yamanashi, the previous northern hemisphere B strain.  So by this slide it is giving an indication of growth of some of the candidates that we've had sufficient time to do a little evaluation on, and it is not an attempt to lobby for any particular B strain at this point.
		But I think more to remind us that it is very important to consider the growth characteristics of each of these.  The B/Johannesburg is something we've had experience with in full scale production for Southern hemisphere. 
		And actually this ratio is about correct, it appears to yield about one-third to one-half the amount of the B/Yamanashi.  So based on that I would certainly consider the B/Johannesburg a low yielding strain.
		Likewise something like the B/Sichuan/379 appears to be similar.  Not that they are not potentially viable vaccine candidates, but there is an omen of risk there, again, because their growth characteristics may or may not improve with sufficient passages in eggs.
		And certainly something like B/Alaska, or B/Canada, which so far does not even grow under conditions that are similar to production conditions, I would have grave concern even considering one of those strains for the vaccine formula.
		So just to summarize, the main points are that the flu vaccine manufacturing cycle, from the manufacturer's perspective, depends on very close communication, cooperation, and I guess choreography between various agencies and the manufacturers, especially at this time of year.
		And the second take home message is that changes in the vaccine formula do introduce an element of risk, and naturally one change is not as bad as considering two changes, or in years where we've had a very complex surveillance data we have considered three changes in the past.	But that is an additive effect, the more changes, the more risk. 
		And, finally, the timing of strain selection is very critical to allow us to respond and adapt to any problems with growth of the strains, and adjust our processes to be able to manufacture  vaccines. 
		Any questions? 
		CHAIR DAUM:  You have an opportunity for questions for Dr. Slusaw.  Dr. Snider?
		DR. SNIDER:  Yes.  You mentioned subsequent passages.  But are there other things that you can do to try to improve the yield, and will be doing with these strains? 
		MR. SLUSAW:  Influenza vaccine manufacturing licenses are for the process.   And there is, generally, a lot of flexibility built into there, again acknowledging that the vaccine composition changes annually, and different strains may have different growth and purification characteristics.
		So that allows us some latitude, even within our existing licenses, to fine tune the process to adapt to any peculiarities of a given vaccine strain.
		And it is something that we do on an ongoing basis, in fact, whether a strain is a poor grower or not, it is something we do to optimize our process. 
		So rest assured there will be a lot of activity to try to maximize the growth and the vaccine availability for an strains that are selected.  But there still is that element of uncertainty as far as how successful we will ultimately be.
		CHAIR DAUM:  Dr. Griffin, then Dr. Fagget.
		DR. GRIFFIN:  So my previous question was going to be, does that mean that none of these candidate strains are good if Victoria is only moderate, and the others are low?
		But my reading of your graph is that Victoria is just as good as Yamanashi, which is the current vaccine strain as far as its yield.  Is that correct? 
		MR. SLUSAW:  Again, we are kind of extrapolating ability to produce vaccine from very limited data, just hemagglutination data.  So it gives some indication, and there is historical precedent that it is a somewhat valid way of anticipating how well they will behave.
		But it is almost like an order of magnitude guess.  I wouldn't assign too much weight to it.  But it does give us an indication.
		And, certainly, I wouldn't select a strain that had evidence of being an extremely poor grower, thinking it may get better.
		CHAIR DAUM:  Dr. Fagget, please.
		DR. FAGGET:  You were able to produce nine million doses in short order.  How were you able to do that, and this year if you have another problem, will you be able to do that again?  And how much did you lose?
		MR. SLUSAW:  I will answer the second question first, I don't know.  And, again, it was a combination of a lot of hard work, and persistence, and luck, that allowed us to ultimately be able to produce A/Panama in sufficient quantities.
		The downside of that was it took us many months of work, and it kind of resulted in late availability and late deliveries to finally achieve that. 
		But I suppose it was just as likely that we may still be working on it, and had never had some measure of success.
		CHAIR DAUM:  Before I call on Dr. Decker I would like to ask you, if you are not speaking on behalf of all the manufacturers today, then can you tell us how much confidence we can take from the fact that B/Victoria grows well in your hands, versus what the rest of the industry might say, or do we just not know anything about what they might say?
		MR. SLUSAW:  Actually we have representatives, colleagues from some of the other vaccine manufacturers, and perhaps one of them would like to address their experience with some of the B candidate strains. 
		CHAIR DAUM:  Before you do that I just might like to say that it would be helpful if the process of clearing had gone on, so that we could have one statement that was real clear, for the whole industry.  I don't know what went wrong.
		Could you identify yourself for us, please?
		MR. HJORTH:  This is Richard Hjorth from Wyeth laboratories.  And I think one reason that we didn't fully get together in this is that some of the data just came off yesterday.
		But we have been looking at slot blots, using a monoclonal antibody to B.  And we thought that might be an alternative way of quantitating, with everything on a level playing field, to look at these different isolates.
		And, of course, if you just pass an isolate once or twice it is hard to tell how it is ultimately going to yield.  But looking at early passage data we agree one hundred percent that Victoria is an excellent strain.  We also found B/Perth to be an excellent strain.
		And perhaps a third choice would be Shis loca, but I'm not sure that -- I think that was in your low category?
		MR. SLUSAW:  Yes, that is right.
		MR. HJORTH:  So at least we agree on Victoria and Perth.
		CHAIR DAUM:  Thank you very much, that is very helpful.  Now, Dr. Decker, I'm sorry.
		DR. DECKER:  Actually that worked out very well because now I have the same question for both gentlemen, which is does the slide you show of the tests you reported predicting possible growth characteristics, were similar tests done at this time last year, and if so, did they predict or fail to predict the problems with Panama?
		MR. SLUSAW:  A/Panama was an interesting situation.  And as Dr. Levandowski noted earlier this morning, I think we had five or six high growth reassortants of A/Panama to work with.
		And we chose, in the U. S. and globally, the reassortant which appeared to give the highest growth.  And even that, as we later found out, was not one hundred percent assurance that we would be able to produce sufficient quantities of vaccine. 
		So, really, until we get into full scale production of the strain it is difficult to anticipate what production yields will be like.  Many manufacturers have capability to simulate their processes on a small scale, and that may give some indication.
		But it is not until we actually get into it that we know where we are going to stand with viruses yields.
		CHAIR DAUM:  Thank you.  I have erred before, and didn't realize there is another industry representative out there.  Would you like to comment?  Please tell us who you are.
		MR. O'BRYAN:  Thank you very much.  My name is John O'Bryan from Evans Vaccines in UK.  I would just like to make another comment about the B strains.
		Firstly, we haven't had the whole range to look at, but we have worked with B/Johannesburg, and B/Victoria.  Again, obviously for the southern hemisphere. 
		We looked at the HA from the primary growth for sera.  I think we found a similar aspect that is being reported today.  We thought Victoria was higher growth than Johannesburg.
		But when we put Johannesburg through the whole of the production process, and Victoria through the whole of the production process, we actually found that at the end of the day the yield is still significantly lower than the B/Yamanashi, it is about 65 to 70 percent, in fact.
		CHAIR DAUM:  The yield of -- I just want to make sure I understand.  Victoria was lower than --
		MR. O'BRYAN:  Yes.
		CHAIR DAUM:  Thank you.  Are there other committee questions?  Dr. Kilbourne.
		DR. KILBOURNE:  I would just like to ask Greg, and other manufacturers, whether if there is something the industry can do, by reviewing past data, to see if you have some kind of phenotypic marker that might correlate with whatever your production criteria are.
		In other words, are there simple things like temperature sensitivity, susceptibility to detergent disruption, any of those things that go on during manufacturing that might allow you to, without taking each individual candidate into a pilot production, be helpful in feedback to those of us making reassortants as to what to look for, other than high yield?
		MR. SLUSAW:  Well, Dr. Kilbourne, if you have an idea what that phenotypic marker is I would love to hear more of your ideas.
		Actually it is something we tried to look at and many manufacturers, as I mentioned, can mimic their production process on small scale.  And that is really a useful tool for evaluating.
		But I'm aware of the experience with A/Panama of manufacturers who ran A/Panama through the process, even at moderate scale, tens of thousands of eggs, and thought everything looked fine at that point, only to find that when they went into full scale production the yields were disappointing.
		So it would be great to identify some kind of phenotypic characteristic that could be used as a proxy for final vaccine yields.  But I'm not sure what the perfect characteristic might be.
		CHAIR DAUM:  Thank you, Dr. Decker.
		DR. DECKER:  The last few answers have stimulated a conclusion in my mind that I want to articulate to give a chance to get it knocked down if it is wrong.
		But it sounds as though the current state of the art is that despite good attempts that might give clues as to which are the most promising strains, we don't really know until we are so late in the process, that it is very hard to recover from a problem.
		And that is what happened in the last year.  So that would seem to suggest, first, that we ought to have a clear benefit in mind when we recommend a change in strains to warrant that perhaps a reducible risk of running into production problems.
		And second the one tool that we seem to have that can help to manage this is to allow as much time as possible for the detection and correction of the problems in production.   So anything that can be done to move up the time table of strain selection, delivery of the validation antigens, and sera and so on, would seem to be our best safeguard as long as we are in the situation of even mini-production exercises not being able to accurately predict whether or not we will be able to produce vaccine in true industrial production scale.
		CHAIR DAUM:  Thank you.  Other comments before we move on?  Dr. Estes, then Dr. Kohl.
		DR. ESTES:  It is not clear to me, I heard that obviously there were problems with production of the A/Panama.  And yet in the end those were overcome.
		Do we know how they were overcome?  I mean, is there any information from that that gives us a hint?
		MR. SLUSAW:  I think, at least in our experience, there were not any tremendous mysteries with how they were overcome.  We tried many of the fixes in the process that we would have tried with any other low yielding strain.
		There are certain characteristics of low passage level reassortants, some morphological characteristics that might affect the purification efficiency, for example.
		And, really, just through optimizing the process, and additional egg passages, which of course take time, the problem basically was corrected.  But part of that is the selection process of developing new seed cultures for production. 
		And it is somewhat of a hit and miss kind of statistical exercise, and there is no assurance that after one week the problem can be solved.  It may take months, and there would be no resolution.
		So there was an element of chance involved.
		CHAIR DAUM:  Dr. Kohl?
		DR. KOHL:  I am thinking about how we make strain decisions, and typically having done this for three or four years now, we always pick the easiest one first, and say go with such and such to begin with, and then we will do the hard one as late as possible. 
		And this year that seems, again, like a fairly easy thing to do.  I wonder if that is backwards?  And if it looks like it is clear, at least, what is emerging, and that we do want to make a shift, if we can tell the -- maybe I'm putting the cart before the horse.
		But if we can tell the companies we want to shift to a Sichuan-like strain and leave it at that, and let them start playing early on, although it sounds like they are already playing early on.
		So we are basically doing that at this point.
		DR. GRIFFIN:  But I think the thing that made the changes hard, or the decisions hard, at least last year or before, because we didn't have enough data on the strains that were emerging during that year, and it was thought that another month's worth of collecting that kind of data -- I don't think we are in that situation this year.
		I think we have pretty clear indications on what the strain patterns are like without a lot of, maybe except for possibly H3N2, but without a lot of questions out there.
		DR. SNIDER:  Dr. Kohl, do you want to make a follow-up comment?
		DR. KOHL:  I would hope that we can make a more rapid kind of decision, maybe even pick all three at this meeting, and at least a general idea, and let the companies take it from there.
		CHAIR DAUM:  Thank you, Dr. Kohl.
		What I would like to do is move on and hear from Dr. Cox what the options are for strain selection.  And then continue in a slightly different guise, this discussion yet again.
		Thank you very much, Dr. Slusaw, and other pharmaceutical folks who commented.  While Dr. Cox is getting set up you may make one more comment.  Could you remind us who you are?
		MR. HJORTH:  Rich Hjorth, from Wyeth.
		CHAIR DAUM:  Thank you. 
		MR. HJORTH:  We find in general, though, that the yield in eggs is a pretty good indicator.  We knew last year that Panama was certainly going to be much worse than Sidney, but the change was made.
		But I say rarely is it, for us, is it a manufacturing problem.  If it is a better yielder in eggs, it usually works better through the process.
		CHAIR DAUM:  Thank you very much.  Dr. Cox?
		DR. COX:  I think we can move fairly quickly, and clearly, through the options for selection of strains this year.
		And for each group of viruses I'm going to start out with some bullet points, which will summarize the data, then I will go on to the three options that exist for each strain, either maintaining the same strain in the vaccine, updating the strain, and making a decision on that, or deferring the decision until a later time.
		And then I will be following with another sort of more general overall summary.
		For H1N1 viruses we can summarize by saying that little antigenic heterogeneity has been observed.  And that most strains are antigenically very similar to the New Caledonia vaccine strain.
		And in general the neuraminidase genes of current strains are also similar to the neuraminidase of the vaccine strain.  There are a few low reactors, as you will recall from the tables.  But they do not fall into one clear genetic group.
		And in addition to the viruses being less well inhibited by the ferret sera, we are -- we see the viruses are well inhibited by the ferret sera.
		We also see that in the human serologic studies, generally these new strains are quite well inhibited by serum of individuals who have been vaccinated with the New Caledonia vaccine strain.
		The current vaccine strain has been in the influenza virus vaccine for one year.  So option one is to maintain the current vaccine strain.  The pros are that the current vaccine strain is immunogenic, and well matched to currently circulating viruses. 
		Manufacturing is well defined and predictable, and we don't really have any new vaccine candidates available.  
		Against that position is the fact that a variant strain possibly could be identified in the next two to three weeks.  
		Option two is to update the current vaccine strain.  I had to sort of really dig, but I could come up with one pro.  We might be able to provide a closer genetic match to next year's viruses if we chose the correct sublineage, because you will recall that the HA is dividing out into two sublineages.
		But against that we can see, from our data, that there are no clear advantages based on antigenic characterization, or serologic results.  And we have no superior alternate vaccine candidates.
		We could defer to accumulate additional data, and we do know that there will be more data available in the next two to three weeks, including both genetic and antigenic analysis of some new Chines H1N1 viruses that have only just arrived.
		Against this we realize that additional data may not alter the current considerations since, so far, the global data have consistently indicated a good vaccine match.
		So in summary we can say that although influenza activity associated with H1N1 viruses has generally been low, world-wide in the past four years or so, significant H1N1 activity has occurred this season in the northern hemisphere, as well as during the southern hemisphere's season during our summer.
		The majority of current viruses are antigenically similar to a New Caledonia.  However, viruses similar to Johannesburg, the Johannesburg reference strain were also identified. 
		Human serologic responses suggest that the current vaccine strain is immunogenic, provides a good antibody response against current viruses from both antigenic and genetic groups.
		In summary for the H3N2 viruses, we see that little antigenic heterogeneity is observed.  And most strains are antigenically quite similar to A/Panama.
		The neuraminidase genes of many current strains fall into a different genetic group from Panama, but the low reactors, and there are a few of them, but only a few, do not fall into any particular genetic group.
		And the H3N2 viruses are generally well inhibited, not only by the ferret serum, but also by human post-vaccination serum.
		This current strain has also been in the vaccine for one year.  So we could maintain the current vaccine strain.  And the pros for this approach would be that the current vaccine strain is immunogenic, and well matched to currently circulating viruses, manufacturing is now well defined and predictable.
		And we have, perhaps, only one obvious new vaccine candidate, which has been mentioned so far, and that is Ulan Ude, which was considered during the southern hemisphere deliberations.
		Against this position is the possibility that a new variant might be identified in the next two to three weeks.  I should mention that we do not have any H3N2 viruses from China.  Apparently their activity has been mainly H1 and B over the past few months.
		Option two is to update the current vaccine strain.  We might provide a closer genetic match to the HA, but especially to the neuraminidase of next year's viruses. 
		Against this there is no clear advantage, based on antigenic characterization, or the serologic results that we have, acknowledging that we do not have results for the -- we do not have neuraminidase inhibition tests.
		The only clear vaccine candidate that we have is the Ulan Ude, which does have the correct "neuraminidase" but as I said, that was under consideration for the southern hemisphere recommendations, as well. 
		Option three is defer to accumulate additional data.  And one of the issues in favor of this position would be that since H3N2 viruses cause the most serious morbidity, and mortality, this particular choice should be made very carefully.
		And I think we've all always given a lot of attention to this particular vaccine component.  There will be a few additional pieces of data available within the next two to three weeks, but we have to recognize that at this point additional data may be insufficient to alter current considerations, since we haven't yet identified a new variant.
		So, in summary for the H3N2 viruses, we can say that in contrast to most recent years, this year few H3N2 viruses have been isolated globally.  Those few viruses are antigenically similar to A/Panama, the A/Panama vaccine strain. 
		And serologic responses suggest that the current vaccine strain is immunogenic and provides an equivalent antibody response against most current viruses, but you can find some exceptions to that. 
		For influenza B viruses we can see quite clearly that antigenic drift has been detected.  A new variant represented by B/Sichuan/379/99 has been identified as prototype variant strain.
		The neuraminidase genes of many current strains are generally similar to the vaccine strain, but are closer to the neuraminidase gene of the B/Sichuan.
		There is no evidence for circulation of B/Victoria lineage strains at the present time.  And B viruses are generally less well inhibited by ferret serum, and to some extent by human post-infection serum.  The current vaccine strain has been in the vaccine for two years.
		So we could maintain the current B vaccine strain.  Once again, the current vaccine strain is immunogenic, and manufacturing is well defined and predictable.
		Against this the current influenza B strains are not well inhibited by ferret serum to the vaccine strain, and so we would essentially not be able to say that we had a good match with the current vaccine. 
		Human serologic responses against some recent strains are somewhat reduced.  And egg isolates with appropriate antigenic properties are being evaluated as candidate vaccine strain. 
		And I think that, as I mentioned before, there are a number of additional strains that have been sent out for examination by the manufacturers. 
		Option two is to update the current vaccine strain.  In favor of this position would be that we would provide a better antigenic match with the current B strains, and that vaccine candidate strains, such as B/Johannesburg/599, and B/Victoria/504/2000 have been used to manufacturer vaccines for the southern hemisphere, where smaller number of doses are produced.
		Against this position would be that no data are now available on the immunogenicity of vaccines produced with any of these B/Sichuan-like candidates.  And we know that many recent influenza B egg isolates grow rather poorly.
		The third option, of course, is to defer in order to accumulate additional data.  In favor of this we do know that more data will be available in the next two to three weeks.  We have a number of viruses that are backlogged in our laboratory waiting for analysis, including some new Chinese influenza B viruses. 
		We will have more data available on the growth properties of the potential vaccine candidates.  And I suspect this data will be developing fairly regularly over the next few weeks.
		And then against deferral is that additional data may not alter current considerations.
		So in summary for influenza B viruses there is antigenic drift from the vaccine strain B/Yamanashi.  And most of the viruses that are reduced in titer to the B/Yamanashi serum are antigenically and genetically similar to the prototype reference strain B/Sichuan.
		Serologic responses suggest that the current vaccine strain is immunogenic, but it may provide a more limited response against some of the current B viruses. 
		And a great deal of work has been done since the southern hemisphere vaccine recommendations were issued to develop additional alternate vaccine candidates. 
		Thank you. 
		CHAIR DAUM:  Thank you very much, that was very succinct, and very clear.
		We have a moment or two for some questions.  Dr. Decker?
		DR. DECKER:  I have two questions.  The first one is, in any given year we might make a recommendation, and then events would unfold that indicate, within a month or two, that there is a serious new problem, and that recommendation needs to be revisited.
		What are the consequences of withdrawing and replacing a recommendation?  A related question is, let us contrast two scenarios.  And scenario one, five years in a row we make a recommendation in January, and one time it has to be changed in February or March.
		The other alternative is five years in a row we defer everything until February or March, and we never have to change our minds, we just don't speak them until we are sure.
		Which of those is better for the public health? 
		DR. COX:  Were you directing those questions to me?
		DR. DECKER:  It seemed like the subject of books, or articles --
		(Laughter.)
		DR. COX:  Yes, indeed.  And I think your first question could be better answered by folks from the FDA, since this is the committee. 
		DR. DECKER:  Or perhaps from the manufacturer, because if they start work, is it better to start work and start it over, than to do no work at all? 
		CHAIR DAUM:  Bring this man a mirror.  You are the manufacturer, I don't know, you tell me.
		DR. DECKER:  I'm not speaking as a manufacturer, I'm not here in that role.
		CHAIR DAUM:  Oh, okay.  Does anyone from FDA want to comment on this question?  Dr. Midthun.
		DR. MIDTHUN:  Karen Midthun, FDA.  I think part of the issue is, obviously, the more you know the more certain you can be about the recommendation you are making.  And that is offset also by the time factor.
		We all know that it is difficult to really gear up and get everything in line to get the influenza vaccine available for when we need it.
		And so I guess part of the issue is, if one were to make a recommendation based on the data available, and when one obtained additional data one said, maybe we need to reconsider this, the issue then becomes, and I guess my question would now be to the manufacturer, what kind of impact does that have.
		MR. SLUSAW:  I am still thinking about this one a little bit, because there are obviously pros and cons either way.
		Obviously having selections made earlier would be an advantage, even with the potential risk of having to make a change at some later point if new data were identified. 
		I guess one thing that I ask myself is, weighing all the risks and advantages here, what is the likelihood, in a given year, that we would need to make a later change.
		Because in the case where we had to make a change several months into the season, that could be catastrophic as well, I suppose, especially if we are starting with a new seed virus, something that we haven't prepared working seed, something that we haven't had a chance to evaluate, really puts us back several months away from monovalent concentrate production and ultimately vaccine production. 
		So it is really a trade-off, I think, either way.  But at least having things to work with earlier help to identify potential problems earlier, and perhaps correct and address those so that it makes working with those strains a bit easier, and more practical.
		CHAIR DAUM:  Thank you.  Dr. Midthun, and Dr. Kohl.
		DR. MIDTHUN:  I just want to make one comment.  I mean, certainly I think everyone would agree that it is best to make a recommendation as early as possible if one feels one has sufficient data. 
		CHAIR DAUM:  Thank you.  Dr. Kohl?
		DR. KOHL:  If there is not a change in the vaccine strain, are there potential manufacturing problems that crop up, or is it a slam dunk?  I mean, if you know we are doing last year's vaccine again, is that just very simple to do, or are there risks in that? 
		MR. SLUSAW:  Again, I think from a manufacturing standpoint it probably is a slam dunk, barring any natural disasters like avian influenza sweeping through the northeast.
		But as far as from a manufacturing standpoint, and the performance and predictability of purification of the viruses, I think it makes things a lot easier.
		CHAIR DAUM:  I am going to presume that the other two industry spokespeople would agree, or would now comment.  Dr. Manley?
		DR. MANLEY:  I am concerned about the time line.  We have heard several comments that the earlier we make the -- it is better to make a decision earlier.  I'm not sure yet that I understand what early is.
		This morning we saw some timelines that showed September, October, what is the optimum time to be making the decision for any given year?  And does someone know?
		CHAIR DAUM:  Dr. Cox seems willing to take that question on.  Thank you. 
		DR. COX:  Yes.  I think that we all are -- have been working for many years with a balance, and the balance is between giving the manufacturer sufficient time to produce the vaccine, and developing enough data so that we can have a pretty good picture of what is actually going on.
		And if we make the decision too early we simply will be stabbing in the dark.  So we can't make the decision any earlier than we've traditionally done so, I think, without a risk that we will make a decision before we have as much data as we would like.
		I think that one of the things that we have to remember is that until this year we've been on the same time cycle.  The manufacturers have been producing more vaccine each year, and we really hadn't stubbed our toes, so to speak, until this year when several things went wrong, not just in the manufacturing process itself.
		And so I think that we also have to keep in mind the global picture, and recognizing that many of the manufacturers do manufacture in a global environment, and export vaccine, and we import vaccine. 
		And if we have different strain recommendations in the United States to the rest of the world, this also will have implications for vaccine supply here, and for immunization of the military, and a variety of other things as well. 
		CHAIR DAUM:  Thank you, Dr. Cox.  Dr. Midthun, and Dr. Kohl.
		DR. MIDTHUN:  I just wanted to make the point that in general we do like to have vaccine available by September for distribution so that it can get out there, so that you can start immunizing the individuals whom you intend to immunize.
		And as such the process of manufacturer, from sort of getting going to getting it ready by September, usually takes in the order of about six months.
		So I think it is fair to say that you really want to start at the latest in March to be able to meet that September timeline.  And so if you can start a little bit before then, let's say February, then there is a little bit of additional margin in the event that certain problems arise, such as low yield growth of a particular vaccine strain.
		CHAIR DAUM:  Dr. Kohl.
		CHAIR DAUM:  Dr. Cox, you mentioned that the H3 selection was critically important because it is such a variant virus.  And you said there were possibly new pieces of information that might come in, in the next several weeks.
		Yet there are no new viruses, it sounds like, that are coming in.  What new information were you alluding to, and how important are they?
		DR. COX:  Actually there are a few viruses.  We don't have any from China, but there are viruses from Korea that have been collected through the military network.
		I believe that there are also some viruses from Thailand or Singapore that Dr. Hampson will be analyzing.  And we have just three or four additional H3N2 viruses from the United States, I think, that are waiting analysis. 
		So it will be a relatively small amount of data, but there will be a few pieces of data. 
		DR. KOHL:  And you foresee possible data that might change the current situation? 
		DR. COX:  It is really hard to say for sure.  I don't honestly anticipate any large change, but I would hate to tell the committee, no, there won't be a change.
		CHAIR DAUM:  Okay.  Dr. Ferrieri, then Dr. Stephens, then we are going to go to our open public hearing.  We are going to take a short break, and then continue this discussion in the form of dealing with the questions and the actual selection.
		Dr. Ferrieri, please.
		DR.  FERRIERI:  A couple of quick questions for Dr. Cox, or perhaps Dr. Kilbourne.
		Could you refresh our memories on the genetic sequencing, and what you are really doing, is this just interminous sequencing you are doing?
		And, secondly, my question is, do we know what the exact protective locus might be on either of these two genes, the HA or neuraminidase? 
		DR. COX:  Sure.  We are sequencing the entire HA1 domain of the hemagglutinin, which is the variable domain.  No, we do not know the exact protective locus.
		We are actually trying to focus on regions, or particular amino acids that have been demonstrated to be under positive selection, and have been working with a group in California to do some modeling in that regard, not only for the H3N2, which we've published on, but we are also moving to look at H1N1 and B viruses in similar manner.
		But we can't really, by sequencing, tell what is going on.  We use sequencing as an adjunct to the serologic information.  And when we see a virus that is reduced in titer in the serologic analysis, we actually look to see if we can find some signature amino acid changes that correspond to that antigenic change.
		DR.  FERRIERI:  What did it mean, then, if there were eight changes in the B virus, B neuraminidase, was that -- I mean, all the others were compared to B/Yamanashi. 
		So I was confused about, then, what the amino acid changes were for B/Yamanashi, in one of your tables, from CDC.  Is that some new variant of the B/Yamanashi compared to the B prototype B/Yamanashi, or what? 
		DR. GRIFFIN:  Those are changes from the consensus slides.
		DR. COX:  Yes, these are all compared to the consensus.  So that just indicates that there are eight changes between the consensus neuraminidase sequence, and that of the B/Yamanashi.
		DR.  FERRIERI:  Thank you. 
		CHAIR DAUM:  Thank you.  Dr. Stephens, please.
		DR. STEPHENS:  This is for Dr. Cox.  I'm still a bit confused about the H3N2 story, which we talked about a bit.  In terms of this neuraminidase drift, and even the drift towards more Moscow-like strains, is it your kind of recommendation that those drifts are not significant change of action?
		DR. COX:  You are asking about whether the change in neuraminidase between the --
		DR. STEPHENS:  I am asking about the general, what I perceive of as a general drift away from our Panama strains, to the more Moscow-like strains. 
		Is that, in fact, a correct interpretation of the data? 
		DR. COX:  The HA is actually well matched.
		DR. STEPHENS:  Okay.
		DR. COX:  It is the neuraminidase --
		DR. STEPHENS:  It is the neuraminidase --
		DR. COX:  Which is in a different genetic clave.
		DR. STEPHENS:  And you think that that is not necessarily an issue that we should concern ourselves with?
		DR. COX:  I think that this is an issue which is important.  I think that because the neuraminidase isn't actually quantitated in the vaccine, as the HA is, we are not holding the neuraminidase to the same standard in terms of the vaccine process.
		And, therefore, and because we recognize that the hemagglutinin is the primary antigen that provides protection, although antibody to neuraminidase is also important, I think we have really tended to focus much more on the hemagglutinin for fairly good practical reasons at the present time.
		That is not to say that we can't think about ways to improve the vaccine standardization in the future.
		CHAIR DAUM:  Thank you very much.  I would like to move on now to the open public hearing, then we will take a short break, and then we will come back and begin discussing the questions the FDA has asked us to consider today.	
		So I understand that there is one speaker in the open public hearing, and that we have a presentation of five minutes or less.  May we call on the individual now to speak?
		Is there anyone who wishes to speak at the open public hearing part of this session?
		(No response.)
		CHAIR DAUM:  Then I thank you very much.  This is the end of the public hearing part of this session.
		I would like to ask us to take a 15 minute break, it is 3:02.  We will reassemble at 3:17.
		(Whereupon, the above-entitled matter went off the record at 3:02 p.m.  and went back on the record at 3:22 p.m.)
		CHAIR DAUM:  I have asked Dr. Levandowski to put the question up on the screen for us.  
		The question that was passed out this morning is a little longer than that.  Which one is from the previous meeting?  This one.  We will go with what Roland says.
		So this is the question, and it has been the tradition of this committee, I think, to consider this antigen by antigen, beginning with H1N1, going then to H3N2, and going to B for a grand finale.
		So what I would like to do is to see if there is any more general discussion, or general comments that people would like to make before we begin consideration of the question. 
		We have had some pretty lively discussion, but if we need to have a little more, that is fine.  Dr. Decker, we need to have a little more.
		DR. DECKER:  Just briefly I want to go back and revisit one question I asked that I didn't get fully answered, that I thought would be helpful in the long run for us.
		And that is to ask the Aventis and Letterly reps to compare for us the impact on them of two alternate scenarios.  One is they are not given a recommendation until, say, March.  Therefore they don't do anything in serious furtherance of the recommendation, because it wasn't given.
		The other is they are given a recommendation in good faith at this time of the year, right now, but then a freight train comes roaring out of China bearing new information and people say, wait, we have to change that. 
		Now, would that latter scenario cause some damage, materially, over and above the effects of the simple delay until March?   So that question is addressed to the production representatives from the vaccine manufacturers. 
		CHAIR DAUM:  Is Dr. Slusaw still here, would he care to respond to the question?  I think I see him emerging from my visual field, into my visual field.
		MR. SLUSAW:  Greg Slusaw, Aventis Pasteur.  I think after considering the alternatives it would, obviously, be desirable to have the selection earlier, even with the risk of a potential change later in the process that would mean expending additional resources.
		But still assuming that it is relatively low risk, that the decision would ultimately be changed, it would probably be advantageous to be able to begin manufacturer earlier.
		CHAIR DAUM:  With the recognition that you are not representing the industry today, we had two other spokespeople from two different companies, would they care to comment on this very question? 
		MR. HJORTH:  Well, I think a lot would depend on how far we got with the other strain before the change were made.  If we were just doing is development that would be great.  If we were actually manufacturing, you know, that is -- those eggs are gone forever, you know, we've used them up.
		But it would depend on the relative yield.  If the new strain were a much better yielder, we would be happy to change and throw out two weeks of vaccine, or something like that. 
		So it is kind of hard to give a black and white answer, I think. 
		CHAIR DAUM:  So it just depends, sort of.  Thank you very much.  Other general questions before we begin H1N1 discussion?  Dr. Kim, please.
		DR. KIM:  Well, I guess one plea that I would like to make is that instead of hearing same kind of data although the presentation, as Dr. Daum indicated, that are much clearer or well done this time, but my plea is that instead of hearing the same kind every year, that perhaps we can have some additional information to those questions which have been raised during the discussion session, that there are no information available to those issues.
		Perhaps those issues can be incorporated so that, perhaps, we will have more data, and a little more, perhaps science into this process in future meetings. 
		CHAIR DAUM:  Thank you, Dr. Kim.  Other general comments?
		(No response.)
		CHAIR DAUM:  Good, let's move on, then.  We have the FDA's question of what strain, I'm going to interpolate to mean what H1N1 strain should be recommended for inclusion in next year's flu vaccine.
		And, Dixie, there you are in the hot seat to start our discussion, please.
		DR. SNIDER:  Actually I think for H1N1 that is an easy question, at least in my mind.  It seems to me that all the epidemiologic, serologic and genetic information we have been provided today suggests that we have a vaccine that is well matched.
		We don't have any evidence that it is not efficacious.  And, therefore, I would recommend, for the H1N1, that we leave in the current A/New Caledonia/20/99 strain.
		CHAIR DAUM:  Okay.  Dr. Stephens?
		DR. STEPHENS:  I would agree with that.  I think that, as Dixie has suggested, the data supports continued use of that strain.  We still have, I believe, seven to ten percent of the Johannesburg strain causing disease, and there is, obviously, some concern that we might identify something new quickly.
		But I think certainly for right now the New Caledonia strain would be my recommendation. 
		CHAIR DAUM:  Thank you very much.  Dr. Kim, please.
		DR. KIM:  I concur, New Caledonia should be the one for the next year.
		DR. GRIFFIN:  I agree, New Caledonia. 
		CHAIR DAUM:  We may have started out with a nice simple one to get the juices flowing here.  Dr. Huang?
		DR. HUANG:  Right.  This is a no-brainer.  I agree, too.
		CHAIR DAUM:  Steve?
		DR. KOHL:  The only reservation I have is Dr. Cox's comment that there is a shipment coming from China.  And I agree right now that New Caledonia looks like the best. 
		But my decision would be a little bit biased if we were sure which H3N2 we wanted to do at this point, and could recommend that first, with confidence.
		Then I would be for waiting a couple more weeks to do the H1N1 pending these new strains. 
		CHAIR DAUM:  I am not entirely sure I follow that.  Could you clarify for us, please?
		DR. KOHL:  Well, it sounds like the -- I'm jumping ahead, as usual.  But it sounds like the H3N2 story is a little simpler, actually, than the H1N1, because -- the H3N2 is more complicated?
		Well, it is more complicated, and this is why I'm jumping ahead, it is more complicated if the neuraminidase issue is a problem.  And I was hoping that Dr. Cox, possibly, could clear that up to begin with.
		Or do you want to wait for the H3N2?  What I'm saying is that my H1N1 decision is tempered somewhat by the H3N2 decision.  Because the only really new data we are expecting in the next couple of weeks is H1N1 new strains from China.
		And if there is a blast of new strains coming from China, as Nancy said is possible, that would really change what I would feel comfortable with.
		CHAIR DAUM:  How about if we go ahead and take your H1N1 decision, but allow you to revisit it, depending upon what the H3N2 decision is.
		DR. KOHL:  Okay.  Then it is New Caledonia. 
		CHAIR DAUM:  There.  Dr. Manley, please.
		DR. MANLEY:  I agree.  I think the New Caledonia is the strain that I would recommend.
		CHAIR DAUM:  Dr. Diaz?
		DR. DIAZ:  I likewise would agree.
		CHAIR DAUM:  Ms. Fisher?
		MS. FISHER:  I am going to abstain.
		CHAIR DAUM:  Could we flesh you out a little bit?  It sounds like there is a concern in your part that we haven't heard.
		MS. FISHER:  I just do not feel that I should be voting on this particular issue.  I don't feel backgrounded enough on it.
		CHAIR DAUM:  Thank you very much. Dr. Fagget, please.
		DR. FAGGET:  I agree with New Caledonia. 
		CHAIR DAUM:  Dr. Estes?
		DR. ESTES:  I agree that this is the simplest decision.  I think really the only issue, probably, on everyone's mind on the committee is that when we look at the isolations of the viruses, it is not clear if we've hit the top of the peak, or for the next two weeks that is going to increase, and there will be new viruses that appear there.
		But based on all the data that we have at the moment the recommendation, I think, should be to keep the New Caledonia as the H1N1. 
		CHAIR DAUM:  Thank you very much.  Dr. Ferrieri?
		DR.  FERRIERI:  I support the New Caledonia/20/99.  If Dr. Cox and colleagues find anything that is dramatically different, please let us know.
		CHAIR DAUM:  Thank you.  Dr. Myers?
		DR. MYERS:  I agree.
		CHAIR DAUM:  Dr. Goldberg?
		DR. GOLDBERG:  I agree.
		CHAIR DAUM:  And Dr. Kilbourne?
		DR. KILBOURNE:  Based on the information now on hand I certainly concur.
		CHAIR DAUM:  Thank you.  And FDA, there is a box here, but I presume that -- ignore that box, thank you very much.
		Then we have a consensus on issue number one, or question one in the way of H1N1. 
		DR.  FERRIERI:  What about your vote?
		CHAIR DAUM:  My vote is to keep the -- thank you, Dr. Ferrieri.  I actually totally concur.  I think maintaining the present strain is the right way to go.  And I will put my name on here.  My name is not on here, that is why I didn't call on me.
		(Laughter.)
		CHAIR DAUM:  I'm under fire here all the time, it is not easy.
		Let's move on to the next issue, the same question for the H3N2 candidate.  And ask the exact same question, and start with the same sequence.  Dr. Snider?  I'm sorry, Dr. Cox?
		DR. COX:  If I could just make a technical comment?  I realize, during the break, or it was brought to my attention during the break that there is some confusion about whether Panama and Moscow are considered to be antigenically similar.  They are.
		So I don't know if that was confusing some people or not.  But --
		DR. GRIFFIN:  For the HA?
		DR. COX:  The HA is antigenically similar.  The neuraminidase is not genetically similar.  We haven't tested its antigenic properties.
		CHAIR DAUM:  Thank you very much.  If there was confusion about that, it sounds clarifying.
		Dr. Snider, please.
		DR. SNIDER:  Harry always swap back and forth --
		(Laughter.)
		CHAIR DAUM:  And you saw what happened to him.
		DR.  FERRIERI:  I used to go back and forth, too, and I'm still here.
		CHAIR DAUM:  Well, good.  Dixie, listen, for the B we will not start with you, all right?
		DR. SNIDER:  H3N2 is a bit more complicated decision, a little bit less clearcut, I think. 
		First of all there have been fewer isolates this year.  I mean, it hasn't been an H3N2 season.  So the number of isolates that we have to evaluate is relatively limited.
		As I mentioned earlier, we expect that Dr. Cox and presumably some others will be getting some additional H3N2 isolates, although they won't be large in number, given the small number of H3N2 isolates this year, we are really less certain.
		And then there is the issue that was just mentioned about the neuraminidase match being not so good in terms of comparison with the consensus.
		And, therefore, there is some reason for concern.  Nevertheless I think I'm not completely convinced that we have a good alternative in hand right now.
		So I'm torn between saying let's wait and get the additional isolate information to make sure that there is nothing new that has popped up on the H3N2 scene versus staying with the current strain.
		And I'm not sure what -- how much additional information is going to be available in the next two to three weeks, or what impact a two to three week delay would have in making that decision, or if we would have to wait until a March meeting. 
		I'm sorry to bring that up at this particular point in time, but this is the point at which it came to mind.  I mean, we have very little information, and a little more information here might increase or decrease our level of comfort staying with the same strain.
		CHAIR DAUM:  So I am going to try to interpolate what I'm hearing, and that is that you are, at least, tentatively believing that we should remain with the same?
		DR. SNIDER:  Tentatively remain the same, but inclined, if it is not very problematic, to want to take into account what the new strains that will be looked at demonstrate.  And have the flexibility to make a change at that point, if there is something that shows up there that indicates there should be a change.
		But if pressed today, if someone said you have to make a decision today, I would say stick with the same strain, because I don't have an alternative that I want to offer that I think is a better option.
		CHAIR DAUM:  Well, I think the -- I think the practical thing to say back to that is that we are asking you to commit today.  At the same time I think everybody's mindful, at least I hope they are, CDC, FDA, and other agencies that are involved, of our comments that if there is a reason to be brought back to the table by a conference call, or a revisit to this issue, we would like to be consulted.
		But I think we are being asked to make the best decision we have.
		DR. SNIDER:  In that context --
		CHAIR DAUM:  With the available information. 
		DR. SNIDER:  In that context then, as of today, with the information I have today, then I think I would stick with the A/Panama/2007/99, I think is the one in the current vaccine. 
		CHAIR DAUM:  Dr. Stephens?
		DR. STEPHENS:  I basically agree with Dixie's comments.  I think that as of today our choice is the A/Panama/2007/99 strain.  I have the reservations about the neuraminidase issue which have been discussed.
		And also a point that was raised earlier, that didn't get a lot of attention, and I think it was by Dr. Hampson, concerning these low avidity viruses strains that are H3N2.  I would like to know more about those.
		But as of today the A/Panama strain seems the best choice.
		CHAIR DAUM:  Dr. Kim?
		DR. KIM:  I guess I concur with the previous two speakers.  With the given information available today that if I had to choose, then I think I have to choose the A/Panama with some constraints being outlined by the previous two speakers.
		DR. GRIFFIN:  I would agree that A/Panama is the best choice for today, with the caveat that I think that the H3N2 strain is the one that we have the most risk, that we might have to change it downstream if we got more important information on new strains that were emerging.
		And also would just like to raise the issue, since we know we will be choosing a strain where the neuraminidase is divergent from the strains that are currently circulating, or appear to be circulating in greater abundance, as to whether there is any way to design a study in order to be able to get some information that might shed light on whether having a neuraminidase match is or is not important in this kind of a context.
		And so I would just put that out as a thought.
		CHAIR DAUM:  Thank you very much.  Dr. Huang?
		DR. HUANG:  I think given the current information that there is drift in the N2, and not very much drift, if any, in the H3, that I would certainly stick with the H3, and certainly would not change H3 just because of the N2 drift.
		The other question of the low avidity, or the low reacting strains to the H3, is a bother.  And, obviously, one needs to keep an eye on it.  I think that Nancy Cox mentioned that for these strains, that if you looked at the N2 pattern, there wasn't any genetic consistency.  Correct me if I'm wrong, Nancy.
		DR. COX:  For the low reacting strains there was no consistency in which genetic group they fell out in, in terms of their HA.
		DR. GRIFFIN:  For the HA, for the N, right?  So, anyway, I come down to the fact that I agree that we should retain Panama.
		CHAIR DAUM:  All right.  Dr. Kohl?
		DR. KOHL:  Now I can get back to where I was going.  I agree with what everyone said.  I think right now the Panama looks like the best bet we have.
		But I think the pharmaceutical companies have to make a practical decision at this point.  They have to go in with one virus to their eggs that are being laid a half a million a day.
		And I guess I would ask Nancy, Dr. Cox, which one should they go with first and give themselves a month more of time on the other one?  Is it riskier to go with the H1, or is it riskier to go with the H2?  Or whatever. 
		Would you go with the Panama, or would you go with the Caledonia first?
		DR. COX:  I would, personally, most likely think that it would be safer to go with the New Caledonia, simply because we have more data, and it seems really solid at the moment.
		There could be some surprises with the strains coming from China, but because the picture has been so consistent I feel that we are standing on a firmer foundation with that subtype.
		DR. KOHL:  With that in mind, then, I would continue to support the New Caledonia first, as the committee has already decided.  And then presuming that we will go with the Panama, but we have a month of new data to come in before we have to make that decision firm.
		CHAIR DAUM:  I am going to put you down as a Panama/defer, and put that flavor in it.  Dr. Manley?
		DR. MANLEY:  In light of all that has been said I concur that we should proceed with Panama.  And that we would expect, certainly CDC and the FDA to be vigilant.
		And as you have said if there is indication that this needs to be revisited they would let us know.  But I would not defer, I think they should proceed.
		CHAIR DAUM:  Thank you.  Dr. Diaz, please.
		DR. DIAZ:  Based on my current understanding of the problem, I would concur and be, probably, in the category of continuing with the Panama with a slash defer, as you put it.
		I want to make sure that, I guess I'm a little bit confused about the issue.  And at least my current understanding of this particular situation, that I guess I'm asking is this correct in my understanding of this. 
		That the neuraminidase, the differences in the neuraminidase that we are seeing currently tend to fall more along the lines of the Moscow strain, and the Ulan Ude strain, but all three, Panama, Ulan, and Moscow, have similar hemagglutinin. 
		And that what we are trying to balance here is the question of whether we more selectively go after the neuraminidase change that we are seeing, that seems to be a trend.  Or whether we stick with the Panama strain which will, presumably, if the neuraminidase does not play that large a role in terms of protection, that by going with the A/Panama we will be able to protect ourselves a little bit in case some of that neuraminidase does not continue to progress along the same lines, and perhaps changes and picks up some other neuraminidase characteristics that are similar to other strains, but not necessarily the Moscow or the Ulan.
		CHAIR DAUM:  Does someone from CDC or FDA want to answer that? 
		DR. COX:  I think that we have, perhaps, injected a little bit of confusion into the process.  And I just want to emphasize, again, that when we are looking at hemagglutinin, and we have both antigenic and genetic data, when we look at neuraminidase we have only genetic data at the present time.
		And so we don't really know if those genetic changes confer antigenic differences on the viruses.  In the past, where we had choices, where we had already clearly decided that we needed to update the vaccine strain based on the HA, then we really tried to match, as closely as possible, the neuraminidase. 
		But we have never really changed strains based on the neuraminidase alone, I think.  So while we know that in genetic terms the Ula Ude and Moscow have a better matching neuraminidase, we really don't know what that means in terms of protection.
		DR. DIAZ:  That is a better clarification.  Again, I would state --
		CHAIR DAUM:  That is a very helpful comment.  Thank you, Dr. Cox.  So where do you come down?
		DR. DIAZ:  That we should stay with the A/Panama, but if something unusual comes down later that we could defer.  But, currently as of now, I would -- the A/Panama seems to be the best choice.
		CHAIR DAUM:  Thank you.  Ms. Fisher?
		MS. FISHER:  I am abstaining.
		CHAIR DAUM:  Thank you.  And for the same reason?
		Dr. Fagget?
		DR. FAGGET:  Based on the previous discussion I agree that Panama/2007/99 should be the choice at this time.
		CHAIR DAUM:  Thank you.  Dr. Estes?
		DR. ESTES:  I think based on what we have seen presented today I'm comfortable, I think the A/Panama would continue to provide protection. 
		Again, there is some concern about where are we on, are we at the peak, or is there going to be some other activity in this curve, because we haven't seen where the end of the curve is going.
		So that would be the only concern, particularly with the H3N2 viruses, which do cause more severe disease.  So I agree with everyone, but I think this FDA and CDC certainly should have the option to look at that again, and perhaps come back to us if something happens dramatically.
		And based on everything that has happened in the last several years, within the next two weeks you should know whether that peak is beginning to go down.
		CHAIR DAUM:  Thank you very much.  Dr. Ferrieri?
		DR.  FERRIERI:  I support staying with A/Panama/2007/99.  And based on the information we've heard, it would appear that the antisera to A/Panama neutralize some of these other strains that have been in for studies.
		My educated guess is we are not going to see many more H3N2s, and that we will end up staying with this one.  I say that for comfort for the manufacturers, and as you are dealing with all those eggs, I recommend you see the movie "Chicken Run".
		(Laughter.)
		CHAIR DAUM:  Thanks for the recommendation, Dr. Ferrieri.  Let's continue with Dr. Myers, please.
		DR. MYERS:  Like everybody else I would like more data, but I also don't think we are going to likely get much more for this season.  So I think that A/Panama makes the most sense.
		I think that the many comments about the discomfort about not knowing more about the contribution of neuraminidase in the vaccine is making everybody uncomfortable.  And I would hope we collect that data, so that we will make sure what its contribution is.
		CHAIR DAUM:  Thank you, Marty.  Dr. Goldberg, please.
		DR. GOLDBERG:  I would agree, and I would also echo that we should be collecting some information on the world of neuraminidase. 
		CHAIR DAUM:  Dr. Kilbourne?
		DR. KILBOURNE:  Well, first I apologize for being a source of discomfort. But on the other hand I'm glad to see a certain amount of discomfort after all these years, in recognition of the probable important of neuraminidase, and even a trivalent vaccine of the sort.
		Having said that, on the basis of Nancy Cox's reassurance that these are just different, at this point, in terms of sequence, rather than prove antigenic differences, I would certainly go along with retention of Panama.
		CHAIR DAUM:  And I would concur with what you said.  I would like to hear more, in  future years, about -- as I think Dr. Griffin suggested, and Dr. Kilbourne I think you are suggesting also, to hear more about what these antigenic -- excuse me, what these genetic changes mean in terms of understanding serology, and their importance in protection against disease.
		But I think right now we don't know how to factor that information in.  And I think that in terms of sending a clear signal to manufacturers so that we have a good vaccine supply next year, there is a lot of solid data to support the fact that Panama is a good choice, and I concur, therefore, with that. 
		And with that I will launch us into a more controversial area, I guess, and that is the consideration of the type B strain for next year.  And if I could be allowed, I would call upon my colleague, and former Chairman of the Committee, Dr. Ferrieri, to initiate the discussion, lest I go to Dr. Snider yet again.
		DR.  FERRIERI:  Well, very briefly, I think that we have seen data that there has been antigenic drift, and that of these variant strains that have been presented to us, the B/Sichuan is the prototype of such strains. 
		Although we see no evidence of these moving around in the population, there is the potential that they will, and we would be uncomfortable, I think, staying with the Yamanashi, whatever it is, 166/98.
		And so -- and I guess Roland has convinced me, and I reexamined the serologic responses, and I would use the adjective that they are somewhat reduced compared with the newer strains. 
		And so I think on the basis of data on current strains that might be available to us, and this is where I need correction, the B/Victoria of the A/Sichuan lineage, is that correct, Nancy?
		DR. COX:  Yes.
		DR.  FERRIERI:  And so -- and that gave moderate growth.  So I would make the recommendation that we -- everything works out perfectly in vitro that -- well, it is in vivo, eggs, sorry.  That we would go to B/Victoria/504/2000.
		CHAIR DAUM:  Thank you very kindly, Dr. Ferrieri.  Dr. Myers, please.
		DR. MYERS:  Let me be sure I understand also, Nancy, the B/Sichuan is of the same as --
		DR. COX:  B/Sichuan and B/Victoria are antigenically similar to each other, and would be considered equivalent strains, antigenically. And, therefore, in terms of the vaccine properties.
		DR. MYERS:  I guess what I tend to agree with what Dr. Ferrieri said.  I have a concern in that we hear that there is a great deal of activity in China that is B, and that we will have more information in a couple of weeks.
		We have spotty geographic activity which is predominantly New Caledonia in this country.  So while I tend to agree with what she is saying about the Victoria and Sichuan, the direction we should go, because we are seeing drift, I sure would like to know what those strains in China look like.
		I guess -- so I guess this is one I would probably suggest deferring for two to three weeks.  But if it is two months until there is another meeting, then I guess I would probably go with the Victoria.
		CHAIR DAUM:  Thank you very much.  Dr. Goldberg, please.
		DR. GOLDBERG:  I guess I would like to see more information, also.  In lieu of that, the Victoria.  But if there is a possibility of deferring anything, I would suggest we do that with this. 
		CHAIR DAUM:  I think that -- let's try and clarify this, because I think you have really two possible decisions to make, and we can certainly have discussion which one is the best.
		But one of them would be to say that you believe that a -- I mean, you believe either staying with the same strain, or changing to a prototype such as B/Victoria is what we should now recommend.
		The other option is, as Dr. Myers has done, is to say I make no recommendation, but rather defer.  I think the decision to pick a prototype now, either the existing Yamanashi strain, or the proposed change of Dr. Ferrieri and now Dr. Goldberg carries with it, and I hope Dr. Cox and Levandowski have heard us, that if something startling happens, or if there is some new information that this committee should consider, we would be delighted to, and in fact want to.
		And so that anybody who picks, let's just say B/Victoria, it carries with it that notion that we would like to be informed, and have an opportunity to discuss, again, within the limits of the practicality of the manufacturers, and the eggs, and the chickens, and all the things we've heard that go into this decision, we would like to hear about that. 
		Deferring, on the other hand means that I give no advice today, and I would like to not do anything until this new information is available in terms of advice. 
		So I would like people to consider that as they go around the table, and try to help with their best opinion.  Granted, it is not a perfect world, but it is where we live.
		DR.  FERRIERI:  Could I add to what I said?
		CHAIR DAUM:  Yes.
		DR.  FERRIERI:  It is implicit, in what I said, that it would obviously be influenced by new information, and that is the way it has always been in the past, and I don't doubt that we will be hearing from them again.
		CHAIR DAUM:  Dr. Midthun, did you want to comment?
		DR. MIDTHUN:  Yes, I just wanted to say that it might be helpful if people said we feel that we need to move away, if they feel we need to move away from the Yamanashi strain to say so, and then if they make that decision and then to say either I need more information before I can give a recommendation, or this is my recommendation. 
		And that way we would know, at least, if there is a fairly significant trend towards moving away from Yamanashi.
		CHAIR DAUM:  I'm going to ask FDA to understand that if a person such as Dr. Ferrieri says B/Victoria, we don't have to separately ask her if she wants to move away from Yamanashi.
		On the other hand if Dr. Myers says I wish to defer we will ask him whether he wishes to move away from Yamanashi, or he can't say anything to us right now.
		So, Dr. Myers, I'm going to dump this back in your lap.  Would you like to make no decision at all right now, or do you know that Yamanashi is not your recommendation, can you go any further than just defer?
		DR. MYERS:  I think I would say we need to move away from Yamanashi.
		CHAIR DAUM:  Thank you very much.  And, Dr. Goldberg, I have your vote recorded.  We will go to Dr. Kilbourne.
		DR. KILBOURNE:  Well, I would vote at this point to move to the Victoria.
		CHAIR DAUM:  Thank you very much.  We are going to do a loop the loop here, and pick up with Dr. Estes on this side of the table, and go up this way.
		DR. ESTES:  To me the data looks very clear that we need to move away from the Yamanashi probably to a B/Sichuan but I think that picking a specific strain today is too early.
		I think more information is needed, in particular how well these various candidates behave in eggs, and so forth.
		CHAIR DAUM:  Thank you very kindly.  Dr. Fagget?
		DR. FAGGET:  I need one clarification.  It would appear that B/Victoria is not isolated as much since April of this year.  Am I reading it correctly, that CDC has not really identified that as being present?
		DR. COX:  The strains, that is just the particular strain.  That strain itself was isolated in April.  I didn't check, but that is probably right.  But it is a B/Sichuan-like strain, or you could consider it the other way around, that B/Sichuan is Victoria-like, they are antigenically similar to each other.  Does that help?
		DR. FAGGET:  Yes, that helps.
		DR. COX:  So the viruses like B/Victoria have been isolated.
		DR. FAGGET:  Been isolated, okay.  Well, based on the discussion, and that clarification, I would agree to move away from Yamanashi and to the Victoria.
		CHAIR DAUM:  Thank you very kindly.  Ms. Fisher?
		MS. FISHER:  I abstain.
		CHAIR DAUM:  Is it for the same reason?
		MS. FISHER:  That is correct. 
		CHAIR DAUM:  Dr. Diaz?  Thank you, Ms. Fisher.
		DR. DIAZ:  I would move that we move away from the B/Yamanashi to the B/Victoria, obviously withstanding we need data that may come down the pike, but currently that would be my recommendation. 
		CHAIR DAUM:  Thank you very much.  Dr. Manley?
		DR. MANLEY:  I agree that we should move to the B/Victoria/504/2000.  And, again, that if both CDC and FDA would be vigilant, and if there is reason for us to revisit this in the next three or four weeks, that they would then notify the committee.  
		That would be my vote, thank you. 
		DR. KOHL:  I agree with the move away from Yamanashi to a Sichuan-like virus that grows well as determined by the manufacturer. 
		CHAIR DAUM:  Dr. Huang?
		DR. HUANG:  I agree with the move away from Yamanashi, and I would hold a decision on what strain to move to.
		CHAIR DAUM:  Thank you very much.  Dr. Griffin?
		DR. GRIFFIN:  I think this virus, I mean I think we have more information on the B viruses strains than we usually do, because there has been a lot of B virus around.  And it seems pretty clear to me that it has moved away from Yamanashi.
		So I would definitely agree that we should move to a strain, it is going to be easier to make one change, at least, at a time.  That we should move away to a new B strain, and Victoria right now looks like the one that grows the best.
		But if there should be a better one, that would be fine.
		CHAIR DAUM:  Dr. Kim, please.
		DR. KIM:  Yes.  I agree that we move away from Yamanashi for all the reasons that have been presented, and to a strain like Sichuan, again, the final selection of the strain will be determined based on the in vivo and other information available. 
		CHAIR DAUM:  I need to clarify that, I apologize.  I understand you want to move away from the Yamanashi.  But do you recommend B/Victoria today, or do you defer?
		DR. KIM:  Defer.
		CHAIR DAUM:  Okay, thank you.  Dr. Stephens?
		DR. STEPHENS:  I agree we should move to a Sichuan-like strain, the choice of which I think should be deferred.
		CHAIR DAUM:  Thank you very much.  And Dr. Snider?
		DR. SNIDER:  I agree that we should move away from Yamanashi, barring any unexpected events, such as trying to move away from it would substantially decrease vaccine supplies in the country.
		And, therefore, I would move to the Sichuan-like strain, probably Victoria, but I think since the manufacturers are still in the process of evaluating these, it is premature to be too definitive about that. 
		CHAIR DAUM:  Okay.  I'm going to record you to be B/Victoria, unless you correct me.  Would you like to be a move away from Yamanashi, defer; or would you like to be a B/Victoria?
		DR. SNIDER:  I think they are going to defer, anyway.  They are going to keep playing with this, and if it doesn't work --
		CHAIR DAUM:  Well, we would like your opinion. 
		DR. SNIDER:  My opinion is that they should choose what works best for them.
		CHAIR DAUM:  That sounds like defer to me.  I'm sorry -- I hope I'm not putting words in your mouth.
		DR. GRIFFIN:  But I guess I want to clarify, by defer are you implying that they have to come back to us to actually make the strain selection, or that they should defer until they have enough information that they have decided on the best strain?
		CHAIR DAUM:  That is a good question.  Let me ask Dr. Levandowski, or Dr. Cox's opinion about that. 
		DR. GRIFFIN:  I personally don't think this is where we have expertise.
		CHAIR DAUM:  It is a reasonable question. 
		DR. LEVANDOWSKI:  Well, I guess we are going to expect the committee to make a specific strain recommendation at some point.  I don't think we were expecting that the committee would have to name strains for all the strains today. 
		And that has been true in the past.  But I think that is what you've been telling us about, if we find some new information that we should expect -- and we are expecting, actually, to come back to the committee. 
		We would be -- we will be continuing to, as we have been, collecting information to try to inform the recommendation.  And we do want to come back with that information to you, and have you review it, and make the recommendation at the time that we think that we have as much information as we are going to have.
		So I guess I'm just getting a little confused, also, about the terminology that we are using.  But I guess what I have been hearing, and maybe you will let me go on with this, and tell me if I'm right.
		Everybody thinks that the strain selection for the H1N1 strain for New Caledonia is really the only choice, and that is where we should go, and the manufacturer should get busy, and they shouldn't expect to have any other changes, barring something really unusual happening.
		Whereas with the H3N2, where there is somewhat less information, and we are feeling uncomfortable because it is an important part of the vaccine, and for the B strain because we don't know enough about the performance for the manufacturers, that for those strains you are going to expect us to bring some more information back to you and then you will definitely make the recommendations.
		CHAIR DAUM:  On the other hand there was a lot of support for the current vaccine strain in the H3N2 situation. 
		DR.  FERRIERI:  We voted --
		DR. MIDTHUN:  Can I make a clarification?
		CHAIR DAUM:  Please.
		DR. MIDTHUN:  I guess, really, what I thought I heard was that the majority of the committee said we are comfortable going with the current H1N1, and the current H3N2, barring something that is so significant that materializes within the next couple of weeks, that we would then let you know about, so that you could reconsider.
		However, I think with the B what I'm hearing is that many of you are saying that everyone pretty much has said move away from the Yamanashi.  But in several instances people have said, we don't yet have enough information to make a recommendation. 
		So a deferral in that instance means we will definitely come back to you with information on, further information on B, and get your input on that.  That is how I interpret deferral.
		CHAIR DAUM:  I see three hands.  And before I call on them I want to say, give my own vote here.  And that is that I believe we should move away from the Yamanashi, and I'm pretty comfortable with B/Victoria as a choice.
		So I want to summarize by saying that the committee, that Dr. Midthun summarized the committee's views perfectly, I think, on the 2 A types.  And on the B type we are 16 in number voting, one abstention.  15 out of 16 want to move away from the Yamanashi.  Nine of those are able to name B/Victoria as the strain they are comfortable moving to, today; 6 are unable to name the strain they would like to move to today, and would require more information to make that decision.
		That is where things stand this minute.  And now we will have some more discussion about that.  Dr. Kohl, Dr. Stephens, and Dr. Snider.
		DR. KOHL:  I wonder if I could simplify it, possibly.  If we feel comfortable saying a B/Sichuan-like virus, depending on positive growth characteristics for whichever B/Sichuan-like viruses that is, I think that is what Nancy is suggesting.
		Because if tomorrow there is a virus that grows better than the Vic, but is still a B/Sichuan like virus, that would fit within our recommendations, and would not have to be a deferral.  Would that be simpler?
		CHAIR DAUM:  It would be simpler.  The question is, do all the people that wanted to defer agree with that?  Dr. Huang, do you? 
		DR. HUANG:  I do.
		CHAIR DAUM:  Dr. Estes, do you? 
		DR. ESTES:  Yes.
		CHAIR DAUM:  Dr. Myers, do you? 
		DR. MYERS:  Yes.
		CHAIR DAUM:  Dr. Kim, do you? 
		DR. KIM:  Yes.
		CHAIR DAUM:  Dr. Stephens?
		DR. STEPHENS:  Yes, that was going to be my point.
		CHAIR DAUM:  And Dr. Snider?
		DR. SNIDER:  Yes, that was going to be my point too, not to tie their hands.
		CHAIR DAUM:  I think we've helped considerably, thank you for whoever raised that point.
		DR. GRIFFIN:  And then on the other side, all the people who voted for B/Victoria would also be happy if there was another Victoria-like strain that grew better, and that would be better for manufacturing purposes.
		CHAIR DAUM:  I think that is true.  I think the concern about the Victoria is largely the manufacturing issues.  And so we should be able to say that as well.  
		Dr. Goldberg?
		DR.  FERRIERI:  It is actually just as good in manufacturing, it is as good as Yamanashi, probably.
		CHAIR DAUM:  We heard that from one company. 
		DR.  FERRIERI:  Sorry, you are right.
		CHAIR DAUM:  Dr. Goldberg?
		DR. GOLDBERG:  I guess I would propose that certainly my vote for B/Victoria would fit into a good Sichuan-like virus with good growth properties.  So I would change my vote to go with the other.
		CHAIR DAUM:  I think we have come to a nice closure on this.  Does anyone want to make any other points that haven't been made regarding this issue?
		Then I would like to adjourn the meeting today, and remind the committee members that tomorrow the good news is 9 o'clock is your starting time.
		(Whereupon, at 4:09 p.m. the above-entitled matter was concluded.)