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                 FOOD AND DRUG ADMINISTRATION

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        CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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            VACCINES AND RELATED BIOLOGICAL PRODUCTS

                       ADVISORY COMMITTEE

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                               MEETING

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                               FRIDAY

                        JANUARY 28, 2000

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                 The meeting was held at 8:00 a.m. in the

Versailles I and II rooms of the Holiday Inn, 8120

Wisconsin Avenue, Bethesda, Maryland, Dr. Harry B.

Greenberg, Chair, presiding.

MEMBERS PRESENT:

                 HARRY B. GREENBERG, M.D., Chair

                 KATHRYN M. EDWARDS, M.D., Member

                 MARY K. ESTES, Ph.D., Member

                 STEVE KOHL, M.D., Member

                 ROBERT S. DAUM, M.D., Member

                 KWANG SIK KIM, M.D., Member




                            NEAL R. GROSS
                    COURT REPORTERS AND TRANSCRIBERS
                        1323 RHODE ISLAND AVE., N.W.
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                                                                     2

MEMBERS PRESENT (continued):

                 WALTER L. FAGGETT, M.D., Member

                 DIANE E. GRIFFIN, M.D., Ph.D., Member

                 BARBARA LOE FISHER, Member

                 NANCY CHERRY, Executive Secretary



INVITED PARTICIPANTS:

                 ROBERT COUCH, M.D.

                 NANCY COX, M.D.

                 THEODORE EICKHOFF, M.D.

                 L. PATRICIA FERRIERI, M.D.

                 THOMAS FLEMING, Ph.D.

                 CHARLES HOKE, JR., M.D.

                 EDWIN KILBOURNE, M.D.




                           NEAL R. GROSS
                   COURT REPORTERS AND TRANSCRIBERS
                       1323 RHODE ISLAND AVE., N.W.
(202) 234-4433        WASHINGTON, D.C. 20005-3701     www.nealrgross.com
                                                                      3

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

Call to Order, Introductions
Administrative Matters ............................. 5

Presentation of Plaques to Retiring
VRBPAC Members ..................................... 7

Introduction of Members ............................ 8

Open Public Hearing

Introduction by Dr. Levandowski ................... 10

Discussion of U.S. Surveillance
      Dr. Fukuda .................................. 15

           Questions and Answers ....................... 27

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

           Questions and Answers ....................... 67

Presentation by Dr. Canas on the Armed Forces ..... 72

           Questions and Answers ....................... 77

Presentation by Dr. Hampson on the Southern
   Hemisphere ..................................... 78

           Questions and Answers ....................... 87

Presentation by Dr. Zambon on the United
Kingdom ........................................... 93

           Questions and Answers ....................... 99

Presentation by Dr. Nerome on Japan .............. 101

Discussion of Vaccine Responses
      Dr. Levandowski ............................ 108

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

Comments from Manufacturers by Dr. Slusaw ........ 122



                            NEAL R. GROSS
                    COURT REPORTERS AND TRANSCRIBERS
                        1323 RHODE ISLAND AVE., N.W.
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                                                                      4

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

Discussion of Options for Strain Selection
      Dr. Levandowski ............................ 127

Committee Discussion ............................. 136

Open Public Hearing .............................. 147

Committee Discussion (cont.) ..................... 148

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

           Questions and Answers ...................... 174




                            NEAL R. GROSS
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                                                                            5

 1                        P-R-O-C-E-E-D-I-N-G-S

 2                                                           (8:02 a.m.)

 3                    CHAIRMAN GREENBERG:         Good morning.        Good

 4   morning, everyone.          I'd like to welcome you to the

 5   second day of the VRBPAC meeting.                 I have no major

 6   annoucements, so, without further ado, I'm going to go

 7   to the boss here.

 8                    MS. CHERRY:        Good morning and welcome.

 9   Let me repeat an announcement I made yesterday because

10   I know that many of you in the audience are here for

11   the first time.       And that is if you are parked in the

12   parking lot across the street, Bethesda is diligent

13   about checking parking meters so don't get so wrapped

14   up in what you're hearing today that you forget and let

15   your meter go.

16                    And I have a conflict-of-interest statement

17   to     read:      "The    following       annoucement     addresses

18   conflict-of-interest          issues      associated     with       the

19   sessions of the Vaccines and Related Biological Products

20   Advisory Committee on January 28, 2000.                Based on the

21   agenda made available, it has been determined that the

22   committee discussions for the influenza virus vaccine

23   formulation for 2000-2001 and the briefing from the

24   Laboratory of Pediatric and Respiratory Virus Diseases



                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433         WASHINGTON, D.C. 20005-3701      www.nealrgross.com
                                                                                    6

 1   presents no potential for a conflict of interest.

 2                          The director of the Center for Biologics

 3   Evaluation and Research has appointed Doctors Robert

 4   Breiman, Robert Couch, Theodore Eickhoff, Patricia

 5   Ferrieri, Thomas Fleming, Charles Hoke, and Edwin

 6   Kilbourne as temporary voting members for the discussion

 7   of     the       flu    formulation.        In   the    event       that    the

 8   discussions involve specific products or firms not on

 9   the agenda and for which FDA's participants have a

10   financial interest, the participants are reminded of

11   the need to exclude themselves from the discussions.

12    Their recusals will be noted for the public record."

13                          With   respect      to    all        other    meeting

14   participants, we ask, in the interest of fairness, that

15   you state your name and affiliation and address any

16   current or previous financial involvement with any firm

17   whose products you wish to comment on.                       This includes

18   anyone who speaks in open, public hearing.

19                          I'll return the microphone.

20                          Okay, is Dr. Zoon here?

21                          CHAIRMAN GREENBERG:       Ah, good.       You're up.

22                          (Laughter.)

23                          That's an auspicious entrance.               This type

24   of thing is always fun, although sad, so I think Dr.



                                      NEAL R. GROSS
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                                                                               7

 1   Zoon is about to make a presentation of plaques to

 2   retiring VRBPAC members.               No problem.

 3                        DR. ZOON:     Well, this truly is a special,

 4   special honor.           I was coming down Rockville Pike this

 5   morning.          Of course a bus was stuck blocking two lanes

 6   of traffic.          So it never fails, when you're trying to

 7   be someplace on time.             But I said, I will not let that

 8   thwart me.          And then I go to the elevators here in the

 9   Holiday Inn and it nearly done me in.

10                        (Laughter.)

11                        So I think you can all relate to this.

12                        Well, it is my very, very dear pleasure to

13   present to Dr. Kathy Edwards a wonderful plaque.                       And

14   I would just like to, one, for her service on the VRBPAC.

15    And I'd just like to personally thank Kathy.                     I have

16   thoroughly enjoyed interacting, working with you, and

17   I want you to know you're not going to get away this

18   easy.        None of our members ever leave the committee.

19    They merely reinvent themselves in other ways.                        And

20   I think Ted is the true victim of this process.

21                        (Laughter.)

22                        So, with great pleasure and gratitude,

23   Kathy.           Thank you very, very much.

24                        (Applause.)



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                                                                             8

 1                    CHAIRMAN GREENBERG:           I'd just like to

 2   second that.      Actually, I don't think I was really aware

 3   that Kathy was going to leave.           Are you?      I don't think

 4   that's correct.        She's not leaving, is she?

 5                    (Laughter.)

 6                    So, yes.   So you've been a spectular member

 7   of the committee and we may lose our ability to say

 8   anything sensible if you really leave.                Oh, okay.        So

 9   Dr. Adimora also.        That's too bad.         So, will she get

10   the plaque?

11                    DR. EDWARDS:      She's already received the

12   plaque, yes.

13                    CHAIRMAN GREENBERG:        Okay.      Okay.

14                    I'd like, I guess, to go around the room

15   and have people introduce themselves, starting down

16   there with Diane, since Dixie isn't here.

17                    DR. GRIFFIN:       Diane Griffin from Johns

18   Hopkins School of Public Health.

19                    DR. ESTES:     Mary Estes, Baylor College of

20   Medicine.

21                    DR.   KOHL:     Steve      Kohl,     Oregon    Health

22   Science University.

23                    DR. KIM:      Kwang Sik Kim from Children's

24   Hospital, Los Angeles.



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                                                                                 9

 1                    DR.   FAGGETT:         Walt    Faggett,        American

 2   Preferred Provider, Washington, D.C.

 3                    MS. FISHER:     Barbara Loe Fisher, National

 4   Vaccine Information Center.

 5                    DR. EDWARDS:       Kathy Edwards, Vanderbilt

 6   University and, as I remineded everyone yesterday, I

 7   have the home of the Tennessee Titans.

 8                    CHAIRMAN GREENBERG:           Right.

 9                    (Laughter.)

10                    DR.   DAUM:      I'm    Robert       Daum     from      the

11   University of Chicago.          No commercial.

12                    (Laughter.)

13                    CHAIRMAN      GREENBERG:        Harry       Greenberg,

14   Stanford University and the Palo Alto VA Hospital.

15                    DR. LEVANDOWSKI:        Roland Levandowski from

16   the Center for Biologics Evaluation and Research.

17                    DR. EICKHOFF:     Ted Eickhoff, University of

18   Colorado.

19                    DR. FERRIERI:     Pat Ferrieri, University of

20   Minnesota Medical School, Minneapolis, and the team that

21   didn't make it.

22                    (Laughter.)

23                    DR. FLEMING:      Tom Fleming, University of

24   Washington, Seattle.



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                                                                              10

 1                    DR. COX:     Nancy Cox, Centers for Disease

 2   Control and Prevention.

 3                    DR. KILBOURNE:         Ed Kilbourne, New York

 4   Medical College.

 5                    DR. COUCH:      Bob Couch, Baylor College of

 6   Medicine, Houston, Texas, the former home of the

 7   Tennesee Titans.

 8                    (Laughter.)

 9                    CHAIRMAN GREENBERG:          Okay, now.         We now

10   have an open public hearing and I'd like to ask anybody

11   in the audience whether they have anything that they

12   would like to say to the committee or to the public.

13    I'm looking and not seeing any hands.             Is that correct?

14    Okay, if that's correct, the open and public hearing

15   is closed.

16                    Now we're going to start our session and,

17   as you all know, it's January so it's the flu session.

18    And Roland is now going to lead us through a discussion

19   of what's happening in flu to help inform us to try to

20   make some choices.       Roland.      And, Roland, I would simply

21   say to try to ask your speakers to be expeditious and

22   timely in informing us what's going on.

23                    DR. LEVANDOWSKI:         Okay.        Thank you, Dr.

24   Greenberg.       Can you all hear me?       Am I loud enough here?



                                 NEAL R. GROSS
                         COURT REPORTERS AND TRANSCRIBERS
                             1323 RHODE ISLAND AVE., N.W.
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                                                                                     11

 1    I can't tell from up here, so somebody will have to

 2   yell at me.           Okay?      It sounds like I'm getting some

 3   feedback now, so it's probably okay.

 4                       Thanks      again.        I'd     like        to    welcome

 5   everybody here and thank you all for coming on this kind

 6   of cold and chilly and icy day in Bethesda.                              As Dr.

 7   Greenberg has mentioned, we all know why we're here

 8   today.           We're here to begin the process of selecting

 9   the influenza virus strains that will be included in

10   vaccines prepared for the 2000-2001 season.                            As you're

11   probably aware, the match between the antigen in the

12   influenza          vaccine     and    the   circulating           strains       is

13   probably the most important feature in the potential

14   efficacy of inactivated vaccines for influenza.

15                       This overhead shows the question that we

16   would like to have answered by the committee.                            And the

17   question is the same one that we ask every year, that

18   is, what strains should be recommended for the antigenic

19   composition of the 2000-2001 inactivated influenza

20   virus vaccine?

21                       In     order      to     answer         the        question,

22   information is needed and we are prepared to supply

23   information this morning, although it may not be all

24   of the information that we would like to have.                            But we



                                      NEAL R. GROSS
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                                  1323 RHODE ISLAND AVE., N.W.
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                                                                               12

 1   will do this to assist in formulating the answer.

 2                    In the next overhead, just to remind people

 3   who may be a little bit new to this, the data that are

 4   needed includes, most importantly, information on the

 5   appearance of new influenza viruses.                     When those new

 6   viruses are identified and they have shown that they

 7   have new antigenic and genetic characteristics, how

 8   widespread they become helps in judging the urgency in

 9   considering       changing      a   component      of     the   vaccine,

10   because, obviously, it's something that we don't take

11   lightly and don't want to do if we don't need to.                         If

12   new strains have the capability for broad dissemination,

13   it's important to know whether or not current vaccines

14   are likely to provide some measure of protection.

15                    And, finally, if it appears likely that the

16   current vaccines could be suboptimal, then it's still

17   necessary to have some virus strains that grow well

18   enough to permit manufacture of vaccine within the

19   current constraints of time.

20                    The vaccines are actually being prepared

21   now.       They are being prepared now so that they can be

22   available        in    the     early     fall      to     ensure      that

23   administration of the vaccine is done before onset of

24   the influenza season in the following winter.



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                                                                                   13

 1                         Now this slide is a little bit out of date.

 2    I somehow misplaced the most recent one.                      But it's not

 3   too far off.           What I would like you to get out of this

 4   slide, this shows the production of influenza vaccine

 5   for the United States over the last 10 or so years.

 6   And you can see that that vaccine production has been

 7   rising.          This is what makes all of these deadlines quite

 8   important for the manufacturers.                        Vaccine is not

 9   produced in a single day.                  It takes many months to get

10   it ready and it takes many months for it to start to

11   get     out      for    public      use.      Currently,      the    vaccine

12   production is somewhere between 80 and 90 million doses

13   for the United States.               So that's quite a lot.

14                         So you can turn the overheads off, please.

15    Thank you.

16                         Okay,    so    the     balance    between        enough

17   information to choose wisely and enough time to make

18   the vaccine and deliver it is usually very difficult.

19    We're at that point in the year when there is an urgent

20   need to ensure the vaccine production goes forward.

21                         During the past year, recommendations were

22   made for vaccines that are currently in use and, in the

23   United States, the vaccines are trivalent and they

24   include          an     A/Sydney/5/97         (H3N2)        component;        an



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                                                                                  14

 1   A/Beijing/262/95             (H1N1)           component;          and          a

 2   B/Yamanashi/166/98 component.

 3                    In     September        of     1999,        that's      last

 4   September,       the      World     Health        Organization           made

 5   recommendations for influenza vaccines to be used in

 6   the Southern Hemisphere.                Those recommendations were

 7   for        vaccines      incorporating           an      A/Moscow/10/99

 8   (H3N2)-like        strain;         an      A/New         Caledonia/20/99

 9   (H1N1)-like strain; and a B/Beijing/184/93-like strain

10   which, in most cases, will be the B/Yamanashi/166/98

11   strain.

12                    I should make some mention about how those

13   recommendations have been implemented.                    And, actually,

14   they've not been implemented in the case of the A/Moscow

15   recommendation.             Although       much       work     went      into

16   developing       A/Moscow-like          reassortants,        it    was     not

17   possible to produce a virus that had both the growth

18   properties needed and, more importantly, the correct

19   antigenic characteristics.               As a result, World Health

20   Organization amended its recommendation to indicate

21   that an A/Sydney/5/97-like viruses and its reassortants

22   could still be used for the current manufacturing

23   campaign for the Southern Hemisphere.

24                    There may be some more information on that



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                                                                                     15

 1   in some presentations to come, but, in the interests

 2   of time, I'd like to get things moving.                      I just would

 3   remind all of our speakers that we are on a very, very

 4   tight schedule, as we usually are, and we'll all need

 5   to be somewhat brief and to get going.

 6                          So, initially, to give us information about

 7   U.S. surveillance, Dr. Keiji Fukuda from the Influenza

 8   Branch at CDC will begin.

 9                          DR. FUKUDA:        Thanks, Roland, and good

10   morning.          Usually I try to be very brief in presenting

11   the U.S. surveillance information.                       This morning, I

12   will be a little bit more involved, because some of the

13   features          of    this   season     which     I   think     need      some

14   explanation.

15                          In general, the 1999-2000 season has begun

16   relatively early compared with the last two seasons,

17   which were also H3N2 seasons.                   They have been similar

18   to the previous two seasons in terms of the percent of

19   respiratory specimens testing positive for influenza;

20   in the percent of patient visits for influenza-like

21   illness to sentinel physicians; and in the number of

22   states           reporting      either      widespread       or      regional

23   activity.

24                          However, pneumonia and influenza mortality



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                                                                                16

 1   levels have been unusually high this year.                   And there's

 2   also been an unusual amount of media interest.                         Last

 3   year, between October and March, CDC received a little

 4   over 400 calls from the media about influenza.                         This

 5   year, between October and January 26, about 850 to 900

 6   calls have come in from the media, and, largely, over

 7   a two to three week period.

 8                       In terms of the viruses which have been

 9   isolated in the U.S. so far, approximately 46,000;

10   47,000           respiratory     specimens        were      tested       for

11   respiratory viruses.             About 19 percent of these have

12   been      positive     for     influenza.        The      percentage       of

13   positive specimens peaked around week 51 and, as of week

14   three, which is the most current reporting week, ending

15   January 22, that percentage has fallen to 21 percent.

16                       There have been 8,736 influenza isolates.

17    A small number, 29, have been B viruses.                       The vast

18   majority have been Influenza A viruses.                     And, of the

19   2,084 A viruses which have been subtyped, again, the

20   vast majority have been Influenza A(H3N2) viruses.

21   There have been very few H1N1 viruses.

22                       In this slide here, this just graphically

23   depicts what I just went over.               Basically, you can see

24   that the number of influenza isolates peaked somewhere



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                                                                                 17

 1   around week 52.

 2                    Now in terms of the sentinel physician

 3   system, there are approximately 400 sentinel physicians

 4   who regularly report to the states and CDC and these

 5   sentinel physicians report on the number of patients

 6   coming in for influenza-like illness.                     We saw that the

 7   national rates of these visits peaked at around week

 8   52 at six percent and, as of week three, this has fallen

 9   to three percent.

10                    In terms of regions, the region which

11   reported the highest percentage was the West South

12   Central Region, consisting of Arkansas, Louisiana,

13   Oklahoma, and Texas.             And that reached a peak of 14

14   percent.         The    other     region    which     reached       a   high

15   percentage was the Pacific Region at nine percent, also

16   during week 52.         And, again, this graph here shows what

17   I just went over, showing that these sentinel physician

18   visits peaked around week 52 and that the percentages

19   have been coming down rapidly.

20                    Now in terms of estimated levels of either

21   widespread or regional activities from the state and

22   territorial       epidemiologists,          this    appears       to    have

23   peaked at around week two with 43 states reporting either

24   widespread or regional activity.                    And, again, this



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                                                                             18

 1   graph of the three clinical and virus activity markers

 2   basically show the same picture where activity appears

 3   to have peaked somewhere between the end of December

 4   and the first part of January.

 5                    However, when we look at the pneumonia and

 6   influenza mortality data from 122 cities, you can see

 7   that the peaking of that activity has been unusually

 8   high and you can see that there is also this blip early

 9   in the season.         And here are the levels.           During week

10   51, we had eight percent and this has increased, as of

11   week three, up to 11 percent.                  This is somewhat

12   provisional, because, for the most recent week, we

13   always have some missing data.               But the percentage

14   shouldn't change too much.          To put this in perspective,

15   in the previous three seasons, we have seen peaks of

16   8.8 percent, 9 percent, and 9.1 percent.

17                    Now    just   to    go     over      a   couple        of

18   considerations about P&I mortality.             In general, there

19   are some main factors which influence measurements of

20   P&I mortality.         One of these are the infectious agents

21   out there, and, in particular, the incidence and

22   prevalence of influenza virus infections.                    A second

23   thing is the virulence of influenze virus strains.                    And

24   then the incidence of other pathogens.



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                                                                                     19

 1                      In addition, there are a number of both

 2   protective         and     susceptibility         factors    out       in     the

 3   population.         And these things include things such as

 4   the overall levels of protective antibody in the

 5   population,         resulting        both    from     previous         natural

 6   infection as well as current levels of vaccine coverage.

 7    And then, as Roland mentioned, the vaccine match is

 8   an important factor and the effectiveness of the

 9   vaccine.          We also know that changing behaviors can

10   affect P&I mortality.               And then, finally, population

11   demographics and underlying characteristics are quite

12   important.         And then, finally, there are a number of

13   measurement issues which are important.

14                      Now      in    terms     of     influenza         viruses,

15   essentially,         we     do    not   measure      the    incidence           or

16   prevalence of these infections nationally each year.

17    And so this is really an unmeasured factor.                          And this

18   would be extremely difficult to come up with for a figure

19   each year.

20                      In terms of strain virulence, we can make

21   a couple of general and specific observations.                             Since

22   their appearance in 1968, in general, the H3N2 viruses

23   have       been    more      virulent       and    have     led      to     more

24   hospitalizations and P&I deaths than H1N1 and B viruses.



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                                                                         20

 1                    In terms of this season, specifically,

 2   because of the high P&I mortality, the New York City

 3   Department of Health pulled the death certificate

 4   records and went over them by hand to look and see whether

 5   there appeared to be any unusual diagnoses on the death

 6   certificates and did not see them.             And they also were

 7   able to break down the death certificates by age and

 8   compare some of the rates from last year to this year.

 9    And, again, we do not see an unusual distribution of

10   deaths by age.      So, as of right now, we do not have any

11   indication that there is an unusually virulent strain

12   out there.

13                    Now in terms of pathogens, you know that

14   each winter there are a number of other pathogens which

15   circulate, and this is certainly no exception.                      In

16   particular, this year, in parts of the country, the

17   curves for RSV virus and influenza viruses have really

18   been almost superimposable.

19                    Now in terms of population factors, there

20   are some things that I want to go into.               In terms of

21   overall levels of protective antibody, again, this is

22   a factor that we do not normally measure year-to-year.

23    Now in terms of vaccine coverage, as Roland showed,

24   the doses which have been produced in the country have



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 1   been increasing and, for the past year, as Roland

 2   mentioned, there has been approximately 80 to 90 million

 3   doses which have been distributed in the U.S.              In terms

 4   of vaccine match between what's in the vaccine and what's

 5   been circulating, it's really been very good this year.

 6                    And, in terms of vaccine effectiveness, at

 7   this point we do not have any specific data on vaccine

 8   effectiveness.       These will be available from a couple

 9   of different health maintenance care organizations, but

10   not until the end of summer.

11                    Now one of the things I want to point out

12   is that elderly age is a key risk factor for P&I

13   mortality.       And if we look at the data for H3N2 seasons

14   dating from 1968 up until the middle part of the 1990s,

15   you can see that the elderly have accounted for a high

16   proportion of P&I deaths each year.               So that, at this

17   point, they account for well over 90 percent of the P&I

18   deaths that we see each year.           Now when you look at the

19   numbers of people who are over the age of 65, they have

20   increased rather dramatically from 1950 to 1996, going

21   from about 12 million to almost 34 million people.

22                    Again, this graph here simply shows what

23   I just mentioned in a more graphic form.               But, again,

24   you can see that this has been a rather dramatic



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 1   increase.

 2                       Now what are some of the things which tell

 3   us that age is important?               Well, in this slide here,

 4   this upper part represents P&I mortality as measured

 5   from       the     National    Center      for    Health      Statistics

 6   databases.          This is complete national data here.                This

 7   bottom graph down here represents P&I mortality as

 8   measured by the 122 cities system.                   This is the data

 9   that we're currently talking about.

10                       And there are a number of similarities and

11   differences between these two curves which I won't go

12   into.        But one thing that I want to point out is that,

13   in both of these curves, here you see a somewhat increase

14   in baseline and here you see a somewhat increase in

15   baseline.          And we think that this is probably related,

16   in part, to the aging of the population.

17                       Now this is another complicated graph, but,

18   basically, there are two lines here.                      This upper line

19   here is P&I mortality in the Western part of the United

20   States.          And this other up-and-down curve down here is

21   P&I mortality in the Eastern part of the United States.

22    And, in general, you can see that P&I mortality is

23   generally higher in the West with higher peaks and a

24   higher baseline, and somewhat lower on the East Coast.



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 1                     Now when we look at the percent increase

 2   in the elderly population by region, you can see that

 3   the percentage in the 85 and year-old group has been

 4   particularly dramatic and the increase has been the

 5   highest in the Western part of the United States,

 6   followed by the South and by the Northeast and by the

 7   Midwest.         But the relationship between age and P&I

 8   mortality is not so straightforward and simple.                    When

 9   you look at the absolute numbers of elderly people, you

10   can see that the largest number of elderly people reside

11   in the South, whereas the lowest number reside in the

12   West.        So, again, there's the relationship between age

13   and P&I mortality, but it is not so straightforward.

14                     The other major issue I want to mention for

15   this season are some important measurement issues.

16   Now, in general, we look at two main data sources for

17   P&I mortality.         The first one is the so-called 122

18   cities mortality reporting system.                  And this system

19   reflects about one-third of all U.S. mortality.                    It's

20   a rapid death monitoring system and the results are

21   always considered preliminary.               Again, these are the

22   results that I showed you when I showed you that big

23   peak for the season.

24                     About two or three years later, we look at



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 1   the data from the National Center for Health Statistics.

 2    This is complete national data, but, unfortunately,

 3   they usually are not available for another two or three

 4   years after a calendar year.

 5                    Now this year for the 122 cities system,

 6   the P&I death case definition was changed.            The old case

 7   definition said that a P&I death consisted of influenza

 8   anywhere on the death certificate or pneumonia on part

 9   one.        For this season, the new case definition is

10   influenza anywhere on the death certificate or pneumonia

11   anywhere on the death certificate.            So you can see that

12   it's a somewhat broader case definition.               And so the

13   expected effect of this would be to increase the number

14   of P&I deaths.

15                    Here's the reason why that case definition

16   change was made.      Now over the past decade, WHO has been

17   working on revising ICD-9 coding to ICD-10 coding.                   In

18   January of 1999, ICD-10 coding was implemented in the

19   United States.       The effect of this on P&I deaths and

20   pneumonia death recording has been profound.               Based on

21   both NCHS projections and then confirmed by us, by

22   looking at some data from cities, this ICD-10 coding

23   change decreased P&I mortality and pneumonia mortality

24   by over 60 percent in the United States.



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 1                         This is a really dramatic change.                       And

 2   because of the drasticness of it, WHO may end up

 3   modifying this ICD-10 pneumonia coding.                           This is a

 4   process in discussion which is going on right now.

 5                         But, in the meantime, what we did for the

 6   122 cities case definition, was basically change the

 7   old case definition to something which would be called

 8   a multiple-cause-of-death case definition.                             And the

 9   importance of this is that the numerator data that we're

10   looking          at   this   year   is   based     on      this     new     case

11   definition.            That sinusoidal baseline which you look

12   at is based on the old case definition.                      That's based

13   on the previous five-year's worth of data.                        So we have

14   a difficulty there.

15                         So does the case definition change account

16   for this entire increase in P&I mortality?                          Well, the

17   answer is probably not.                  Here, again, you see two

18   different curves.             Now it turns out that in the 122

19   cities system, there are 29 cities that always were

20   reporting         a    so-called multiple-cause-of-death case

21   definition.             And so this change to the new case

22   definition really represents no change for them.                           Those

23   cities are represented by this solid curve here and you

24   can see that, in cities in which no case definition



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 1   change was made, we still see an increase in P&I

 2   mortality.

 3                     Now this dotted line down here actually

 4   represents the bulk of the data that we normally look

 5   at.      And in these I guess 93 cities down here which did

 6   make a change in their case definition, we also see that

 7   mortality has increased for this season.

 8                     So,    in    conclusion,      in      this     somewhat

 9   confusing picture, I think that we can say that three

10   out of the four surveillance systems have indicated that

11   activity levels have been similar to the previous two

12   Influenza        A(H3N2)      Sydney   seasons.         P&I     mortality

13   measurements definitely have been high and the full

14   explanation for this is uncertain at this point.

15                     We think that increasing aging of the

16   population is certainly an important factor and will

17   continue to be an important factor in the future.                           We

18   know that there was an important change in the case

19   definition, which we think increased the deaths that

20   were recorded.          But we also think that there are other

21   factors and some relationships between these factors

22   which, at this point, we don't fully understand.

23                     So, at this point, there are a number of

24   action steps which will be taken to understand this



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 1   phenomenon a little bit better.                During this season,

 2   there will be continued analysis of these P&I data and

 3   they will continue to be broken down in several different

 4   ways.        As I mentioned, vaccine effective estimates will

 5   be available at the end of the summer and we'll try to

 6   factor that in.         Normally we do not analyze the NCHS

 7   data until about two or three years later, but I think,

 8   because of this season, what we'll do is go ahead and

 9   obtain a subset of the data and try to do an analysis

10   and compare the results between NCHS and 122 cities data

11   more quickly.

12                     And then, finally, as usual, there will be

13   ongoing analysis of these viruses, trying to look and

14   see     whether    there's     anything      unusual    about      these

15   viruses, compared to the other Sydney viruses.

16                     So that was rather a hurried explanation

17   of all of this, but I'll take any questions if there

18   are any.

19                     DR. LEVANDOWSKI:       Okay.     Thank you, Keiji.

20    Dr. Greenberg, do you or the committee have any

21   questions or comments?

22                     CHAIRMAN GREENBERG:          Yes.     We have time

23   for a few questions.          Ms. Fisher.

24                     MS. FISHER:      Has there been any analysis



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 1   of the data with regard to how many of the individuals

 2   who died had been vaccinated either this year or in

 3   previous years?

 4                     DR. FUKUDA:       No.    Every year we receive

 5   anecdotal stories or reports of people who have been

 6   vaccinated and who have developed influenza or who have

 7   died.        And we also, every year, get viruses from those

 8   groups of people and look and see whether there's

 9   anything unusual about those viruses versus viruses

10   being isolated from other people.               But right now we do

11   not have specific data.

12                     MS. FISHER:     That's very important I would

13   think, to find out, you know, the vaccination status

14   of these people, both this year and in previous years.

15                     DR. FUKUDA:     Yes, that's one of the things,

16   when we do our vaccination effectiveness estimates,

17   that's one of the things that we've looked out and in

18   those calculations.

19                     CHAIRMAN GREENBERG:         Dr. Edwards and then

20   Dr. Daum.

21                     DR. EDWARDS:      Keiji, do you think that the

22   greater availability of the rapid diagnostic tests in

23   any way might increase the diagnosis and appreciation

24   that influenza is playing a role in some of the deaths?



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 1    Or do you think that that's not likely a role?

 2                     DR. FUKUDA:      I think that, you know, with

 3   the advent of the new rapid detection tests and the

 4   approval of the new anti-viral drugs, I mean certainly

 5   there has been a really greatly increased awareness of

 6   influenza.        You know, in looking over some of the data,

 7   from some places it appeared to us that perhaps influenza

 8   as a diagnosis was being coded a little bit more often

 9   than in other years, suggesting that people may be

10   thinking more about influenza.               But, again, you know,

11   we don't have that quantified and we don't have it

12   compared with other years right now.

13                     CHAIRMAN GREENBERG:         Dr. Daum and then Dr.

14   Ferrieri.

15                     DR. DAUM:     I wonder if you could comment

16   for me, as a non-influenza person, I was struck by the

17   vaccine uptake curve that you showed at the beginning

18   of your presentation with its dramatic rise in the number

19   of doses.        And, yet, looking at the data on occurrence

20   or mobidity or mortality, there doesn't seem to be any

21   kind of corresponding effect of that dramatic uptake.

22    You'd expect to see maybe some kind of downturn in some

23   parameter you showed.

24                     DR. FUKUDA:      Sure.



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 1                    DR. DAUM:     And I wonder, are we measuring

 2   the right things?        Are we looking at the right things?

 3    Or is this just not working?

 4                    DR. FUKUDA:        Sure.      This is something

 5   which comes up commonly.          Basically when we look at the

 6   data and we look at the increase in the elderly

 7   population versus the mortality rates, it appears that

 8   the mortality is decreasing in proportion to the

 9   increasing -- or the P&I mortality is not keeping up

10   with the increase in the elderly population.               But when

11   you look at these curves there, you don't really see

12   that effect because those curves are not adjusted for

13   the increasing elderly population.

14                    But this is a question which comes up a lot.

15    And the basic answer is, in fact, we do think that we

16   are seeing some effect from vaccination coverage.

17                    CHAIRMAN GREENBERG:           Dr. Ferrieri, Dr.

18   Kohl, and then Dr. Couch.

19                    DR. FERRIERI:      May I add to your anecdotes?

20    I direct a large microbiology laboratory and, although

21   it doesn't include the virology lab, I get all of the

22   feedback from that lab, as well as other information

23   in our institution from infection control.

24                    And this year I feel there's been a lot more



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 1   background noise in Influenza A-proven illness in a

 2   population highly immunized.              And I have a colleague

 3   in another institution, I don't have permission to use

 4   his name at this point, but he has at least 30 patients,

 5   normal people more like us, not the elderly, with proven

 6   virus, Influenza A isolates who had been documented to

 7   have immunization this year.             And I just hear more and

 8   more community physicians saying the same.

 9                     And so I'm having a hard time convincing

10   everyone who works for me and other people in the

11   hospital who say, well, I got immunized and I still got

12   sick.        And my rejoinder always is, well, you might have

13   died, so that's the good news, that you did not, you

14   know.

15                     (Laughter.)

16                     But what's your reaction?             And are you

17   getting a lot of that type of information that is

18   informal, if you will?

19                     DR. FUKUDA:      Sure.     You know, every year

20   we get a lot of informal information and a lot of calls.

21    And we get frequent calls every year about people who

22   have been immunized and who have developed either

23   confirmed influenza or influenza-like illnesses.

24                     But we also get calls on things like



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 1   outbreaks.       You know, we get lots of calls on that.

 2   And I think that we have gotten a lot of calls about

 3   immunized people who have developed influenza-like

 4   illness or confirmed influenza.                   By contrast, we

 5   haven't gotten that many calls about outbreaks occuring

 6   in the country.      And so that's something which has been

 7   noticeable to our group.

 8                    I can't really quantify those calls for you,

 9   but that was one of the reasons why we asked New York

10   City to take a look at the distribution of deaths by

11   age group, because, in talking with Marcy Leighton, she

12   said, in going out to the community and giving talks,

13   she had heard lots of comments from primary care

14   physicians saying we're seeing a lot of young people

15   coming in with this.         But, again, when we look at the

16   actual data and the breakdown, we don't see an unusual

17   hump of deaths in young people.             So I think, you know,

18   that's where it stands right now.

19                    CHAIRMAN GREENBERG:         Dr. Kohl.

20                    DR. KOHL:      Some of us elderly, although

21   they still consider us normal --

22                    (Laughter.)

23                    -- every year we ask about this year's

24   vaccine effectiveness.          And, of course, we can't tell



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 1   that.        So I'd like to ask you, in retrospect, do we have

 2   any data on last year's vaccine efficacy rates, since

 3   the viruses look like they are pretty much the same?

 4                     DR.   FUKUDA:        Yes.        We   got   vaccine

 5   estimates last year from a couple of different sources.

 6    The first estimate that we got was from outbreak out

 7   in California in an institution and, if I recall

 8   correctly, the vaccine effectiveness estimate from an

 9   outbreak was somewhere around 50 percent or so.                      And

10   this was, I think, in an elderly population.

11                     However, when we looked at the data that

12   was made available from the HMOs, from the health

13   maintenance care organizations at the end of the summer,

14   as far as I can recall, I think that that was lower,

15   around 40 percent or so.            I'd have to go back and see

16   what the actual figure was, but I think somewhere around

17   there.

18                     CHAIRMAN GREENBERG:         Dr. Couch.

19                     DR. COUCH:      Keiji, I don't want to claim

20   credit for this comment.               It came to me from Mark

21   LeForest.        But I thought it was interesting.            I'd ask

22   you to consider that he was suggesting this trend of

23   increase in pneumonia that had gone over in the past

24   few years and your suggestion of pneumonia/influenza



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 1   mortality increasing progressively is partly reflective

 2   of cost-reimbursement procedures requiring, over the

 3   course of years, a considerable improvement in the

 4   quality of the coding of discharged diagnosis and of

 5   death diagnosis than was true earlier.                So it's not a

 6   change in disease, but a change in the notification of

 7   disease.

 8                    DR. FUKUDA:     Yes.     I mean, I think that,

 9   you know, when we analyzed P&I hospitalization data,

10   that was clearly an issue.        I think that hospitalization

11   coding has really been affected a lot by reimbursement

12   practices.

13                    I'm less aware and less sure of whether

14   there has been that much of an effect on death coding

15   because of reimbursement practices.              My sense is that

16   if there is an effect it's less, but I'm not sure.

17                    DR. COUCH:     In both cases, the physician

18   is doing the coding, with the help of administrative

19   officials in the hospital.         But for the deaths, as well.

20                    CHAIRMAN GREENBERG:        Dr. Kilbourne.

21                    DR. KILBOURNE:     I just wonder.       When we're

22   talking about levels of projection of 40 to 50 percent

23   are those actually proven cases of influenza?

24                    DR. FUKUDA:      No.      These are clinically



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 1   defined cases of influenza.

 2                      DR. KILBOURNE:      Okay.     Because that's what

 3   you have to really look at, ultimately.

 4                      CHAIRMAN GREENBERG:         Dr. Cox.

 5                      DR. COX:     Yes.     I'd just like to comment

 6   that       those    were    effectiveness        estimates       against

 7   hospitalization in the elderly.

 8                      CHAIRMAN GREENBERG:         Dr. Kim and then Dr.

 9   Faggett and Estes and then we're done.

10                      DR. KIM:    Since you have viruses available,

11   do you have any information on in vitro activity of your

12   standard serum against those viruses?                     Whether, you

13   know, they are still active or, you know, activity

14   differs.

15                      DR. FUKUDA:      Well, I think that would be

16   some of the data that would be gone over subsequently.

17    So I think I'll just hold on that.                  You're going to

18   get more than enough.

19                      CHAIRMAN GREENBERG:         Dr. Faggett.

20                      DR.   FAGGETT:       A   little       clarification.

21   Were you saying that about one-third of the cases that

22   look like flu are really RSV?

23                      DR. FUKUDA:     No, no.     What I was saying was

24   that deaths for pneumonia and influenza reflect a number



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 1   of different factors and a number of different agents

 2   out there.       We know that influenza viruses are one of

 3   the main factors which affect it, but we also know that

 4   people can die from other viral agents.

 5                    And this year, for example, in some parts

 6   of the country, when you look at surveillance data for

 7   viruses such as respiratory syncytial virus, you know,

 8   the rise in those viruses has really been almost exactly

 9   the same as the rise in influenza viruses.                      And so,

10   again, we can't say what proportion of those P&I deaths

11   are due to RSV or mycoplasma or adenoviruses.                     But we

12   know that they're out there and that they play some role.

13                    DR. FAGGETT:      Before we went to that, this

14   year, was your impression that the RSV was affecting

15   more adults in a more virulent fashion, this year?

16                    DR.   FUKUDA:       No.       I   don't     have      any

17   information or any impression that the impact of RSV

18   has been different than in other years.                But I think

19   that, you know, traditionally we think of RSV as

20   impacting very young kids but I think it's clear that

21   they have some impact on the elderly also.

22                    CHAIRMAN GREENBERG:         Dr. Estes.

23                    DR. ESTES:      I'm a little concerned at the

24   answers about vaccine effectiveness.               So every year we



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 1   ask what was the vaccine effectiveness?                  And you say

 2   that next year by the end of the summer we'll hear what

 3   the data were for this year.             And yet, for last year,

 4   we don't seem to have good numbers for flu-proven cases.

 5    Are studies ongoing now that we really will get good

 6   data on vaccine effectiveness?

 7                    DR. FUKUDA:       No.     There is no ongoing

 8   program of vaccine effectiveness studies, looking at

 9   laboratory-confirmed cases.              I mean, these kind of

10   prospective studies, again, would be very expensive,

11   especially to have a laboratory component and we

12   certainly don't have any funding for those kinds of

13   studies.

14                    DR.   ESTES:       Well,     I   would       strongly

15   recommend that somebody reconsider this because at some

16   point we really need to know what the real vaccine

17   effectiveness is.

18                    CHAIRMAN GREENBERG:        Dr. Cox.

19                    DR.   COX:      Yes.        We've      had    similar

20   discussions for the last 10 years at least and probably

21   over the last 20 years.         And we would be delighted to

22   have the funding to do such studies.                  If it were made

23   available, we would be happy to organize those studies.

24    But the vaccines have been in use for such a long period



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 1   of time that, at the current time and the current funding

 2   base that we have, the best that can be done is to do

 3   a     retrospective     look     back     at    the     decrease           in

 4   hospitalizations among vaccinated individuals, using

 5   large databases and that type of study.                Because adding

 6   a laboratory component is very expensive.

 7                    Now in the future, there may be a couple

 8   of -- and maybe Kathryn would like to talk about

 9   this -- there may be a couple of studies which will be

10   done to look more generally at respiratory illnesses

11   and to integrate a laboratory component which could help

12   us     understand   the    contributions        of     the     different

13   respiratory agents during specific years.                    But, again,

14   you would want to have this as an ongoing study for a

15   number of years to really understand what's going on.

16                    CHAIRMAN GREENBERG:           Dr. Couch and then

17   Dr. --

18                    DR. COUCH:     Well, I just wanted to assure

19   Mary that we wouldn't want to trivialize that comment,

20   but it has been raised year after year after year.

21                    DR. ESTES:     But I think that's even worse

22   that's it has been raised for 10 years and --

23                    DR. COUCH:     But still nothing has been done

24   or has been put in force.           I find Nancy's comments to



                                 NEAL R. GROSS
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                                                                                39

 1   be very encouraging that maybe there is a possibility

 2   that some studies will be set up.

 3                     CHAIRMAN GREENBERG:         Dr. Daum and then Ms.

 4   Fisher and that will be the end of the comments.

 5                     DR. DAUM:      Yes, I just want to strongly

 6   reinforce Dr. Estes' comments.             I'm a relative newcomer

 7   to this process and this committee and already have heard

 8   several cries and outpourings for more information about

 9   this.        I'd be very happy to be informed by Dr. Cox or

10   anyone else as to what we can do to help.                To whom can

11   we send the message?          But we're doing an intervention

12   to 70 or 80 million people a year in this country and

13   what we know about how it's working is almost pitiful.

14    I mean, we just don't know enough about its performance.

15                     I would like to have a lot more information

16   and would like to encourage anybody who is in a position

17   to help to signal the urgency of this crucial health

18   problem and do something about it quickly.

19                     CHAIRMAN GREENBERG:          Ms. Fisher.

20                     MS.   FISHER:         This     has    to      be     done

21   immediately because there is a push to use flu vaccine

22   in children going on right now and it is not right that

23   we go forward with this kind of a recommendation for

24   children when we don't understand what's happening in



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                                                                                 40

 1   the general population.

 2                       DR. FUKUDA:        Actually, let me put the

 3   vaccine          effectiveness     question      in       somewhat     of     a

 4   different perspective.               There are many, many, many

 5   studies looking at vaccine effectiveness in small

 6   populations.          What we do not have -- and these are

 7   laboratory-based                  studies             looking               at

 8   laboratory-confirmed information.                  I think the issue

 9   of whether a vaccine is effective or not is not really

10   an issue.          I mean, there are just very large numbers

11   of studies addressing that question.

12                       What is not addressed is the national

13   vaccine effectiveness.              I mean, if you look at all

14   people in the United States and all of this vaccine,

15   what's the effect on this very large group of people?

16    And so that's the data which we do not have because

17   it's so expensive to collect.                But that's a different

18   issue, there.

19                       CHAIRMAN GREENBERG:         We're going to move

20   on, Dr. Couch.         I'm going to take the last word myself

21   and simply say that I think what you've heard here is

22   that -- and virtually everybody in this panel knows that

23   there is a huge history of documentation of vaccine

24   effectiveness at points in time in small studies.                         But



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                                                                                 41

 1   since flu is a moving target and things change, it would

 2   seem appropriate that there is a prospective, ongoing

 3   evaluation       because    there     is    the        potential        that

 4   effectiveness may be changing as flu changes.                     And some

 5   handle on that would probably be very useful.

 6                    Dr. Cox, your turn.

 7                    DR. LEVANDOWSKI:          All right.          Dr. Nancy

 8   Cox is the chief of the Influenza Branch at CDC and she's

 9   going to tell us about surveillance and antigenic

10   characterizations.

11                    DR. COX:    Thanks very much, Roland.                  I'll

12   try to move through the presentation very quickly.

13   There is rather a lot of information to cover and I would

14   suggest that anyone who is sitting too far in the back

15   to see move forward so that you can see.                   There are a

16   lot of slides that are fairly complex and may be

17   difficult to see.

18                    We're going to move from a U.S. picture of

19   influenza to the global picture of influenza.                   And we're

20   going to start with the viruses that we have the best

21   handle on at the moment.         So we're going to move through

22   the     different   groups     of   viruses       in    the     order       of

23   complexity and the number of questions that we have about

24   them.



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                                                                                    42

 1                     We're      going    to    start    this        year      with

 2   Influenza        A(H1N1)     strains.        This    overhead           simply

 3   indicates        by    the   number    of   pluses        that     you     have

 4   associated with a particular month in a particular area

 5   of the world the estimated extent of activity attributed

 6   to H1N1 viruses.

 7                     If we look at the activity that occurred

 8   between April 1999 and September 1999, which is mainly

 9   activity in the Southern Hemisphere, you'll see that

10   there was only sporadic H1N1 activity.                       We had only

11   sporadic isolates from various parts of the world.                         That

12   is also true for the period October 1999 to January 2000,

13   with the exception of Asia, where we know that during

14   December and January, particularly in Japan and you'll

15   hear more about this later, there was significant

16   activity caused by Influenza A(H1N1) viruses.

17                     Now if we look at the viruses themselves,

18   for those of you who have been here for the past two

19   years or past few years, you'll recall that we have two

20   antigenically and gentically distinct groups of H1N1

21   viruses which are circulating.                   The first group is

22   represented           here   by    A/Beijing/262/95              and      A/New

23   Caledonia/20/99 which you'll be hearing quite a bit

24   about today.



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                                                                             43

 1                      These two viruses belong to one genetic and

 2   antigenic group.          You can see that here we have the

 3   reference "antigen" and we have the post-infection

 4   ferret antisera titers.               The homologous titers are

 5   shown diagonally here in red and they're underlined.

 6    And we consider a fourfold difference in titer to be

 7   significant if it's reproducible from test to test.

 8                      Here you can see, first of all, that when

 9   we look at the relationship between the Beijing/262 and

10   New Caledonia strains, we see an asymmetric difference,

11   that is, we see a fourfold reduction in titer between

12   the     New      Caledonia   strain     against     the   Beijing/262

13   antiserum, but we don't see the reciprocal difference.

14    Nevertheless, when we look at a series of viruses, we

15   can clearly see that the Beijing/262 serum does not cover

16   this set of viruses down here as well as the New Caledonia

17   serum does.         So we have seen antigenic movement of the

18   what were formerly Beijing/262-like viruses so that

19   they're looking more like the New Caledonia antigenic

20   variant.

21                      Now, of course, circulating in some parts

22   of the world, close circulating in some parts of the

23   world and circulating separately in some parts of the

24   world, we have this older lineage of influenza viruses



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                                                                                44

 1   which are related to the Texas strain that was in the

 2   U.S. vaccine for a number of years.                       That group of

 3   viruses is represented by Johannesburg/96 and Moscow/13

 4   in this particular slide.              And you can see that these

 5   viruses          are    very      clearly        differentiable            by

 6   hemagglutination           inhibition      testing        from   the     New

 7   Caledonia and Beijing/262-like strains.

 8                      There was sporadic H1N1 activity in South

 9   America during their winter months, our summer months.

10    These viruses were isolated during May and July of '99.

11    And these strains from South America were clearly

12   related to the older Johannesburg and Moscow and the

13   Bayern/07 reference strain, which you will remember.

14                      Next slide, please.

15                      Here we have a slide showing some more

16   recent viruses.          And, in particular, I'd like to point

17   out some strains that were received from Dr. Nerome in

18   Japan where they're having a significant H1N1 outbreak.

19    We have the Kobe strain here and Sendai strain here.

20    And these viruses were isolated in November and

21   December of '99.           Once again, we see that the viruses

22   down here, and we have actually three viruses from North

23   America, one from Wisconsin and two from Canada, which

24   are      more     poorly     inhibited      by    antiserum       to     the



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                                                                                    45

 1   Beijing/262, but well inhibited by antiserum to the New

 2   Caledonia strain.

 3                           On this particular slide, we have the most

 4   recent Johannesburg/82-like strain that we've received

 5   listed at the bottom, antigen number 18.                      This is a virus

 6   from China and it just looks like a typical Johannesburg

 7   strain.

 8                           We're going to concentrate mainly on the

 9   bottom           part    of    this    slide     here.        And   just       to

10   demonstrate, I have actually the page number up on the

11   top, page number 11 in your packet.                    We had only 40 H1N1

12   strains that were isolated between April '99 and

13   September '99 to analyze in our laboratory.                         And only

14   a total of 11 strains that were isolated between October

15   and January.             Of the most recent strains, the majority

16   are in the Beijing/New Caledonia group and the majority

17   are New Caledonia-like.

18                           When we do the genetic analysis, we see that

19   here's the Beijing/262/95 strain and, of course, these

20   viruses do not remain very stable genetically; even if

21   they appear similar antigenically, they are marching

22   along and evolving with time.                     So here's our vaccine

23   strain and there are a number of conserved amino acid

24   changes between the Beijing strain and the currently



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                                                                                 46

 1   circulating strains on the same lineage.

 2                       Here's our New Caledonia strain.              And I've

 3   put red dots by a number of the viruses that you had

 4   seen on the HI table shown previously and these are

 5   strains that are well covered by the New Caledonia

 6   antiserum.           Down here shown in blue, we have the

 7   Bayern/Johannesburg lineage and you can see these

 8   viruses are also evolving, although, antigenically,

 9   they look very homogenous.

10                       We like to look at our sequence data in ways

11   that      are     fairly     simple     to    present.       What      we've

12   determined in the past that, oftentimes, strains which

13   have a sequence that is close to the consensus sequence

14   of the viruses circulating actually produce a ferret

15   serum with antibodies that are quite cross-reactive.

16    And so we like to look at the egg isolates that we have

17   because          those   are    the    strains     that     are   actually

18   considered to be vaccine candidates because we must have

19   strains that have been cast only in eggs in order to

20   go into the vaccine.              So we restrict our analysis here

21   to looking at strains that have a pure egg-passage

22   history.

23                       And when we compare the New Caledonia strain

24   to the consensus sequence for the Beijing/262 lineage



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                                                                                      47

 1   of virus, we see that it has an identical sequence to

 2   the consensus sequence.                So perhaps this is one of the

 3   reasons          the     antiserum     is    covering        the     currently

 4   circulating strains on that lineage so well.

 5                           Next slide, please.

 6                           We also look at the neuraminidase -- not

 7   antigenically, perhaps we'll be doing that in the

 8   future -- but we do look at the neuraminidases of these

 9   viruses genetically.                 And, once again, we see our

10   vaccine strain is here and the neuraminidase of the New

11   Caledonia and one of its corresponding high-growth

12   reassortants is up here, so the neuraminidase is also

13   evolved.

14                           Next slide, please.

15                           When there are two lineages of viruses

16   within a given type or subtype, we like to keep track

17   of exactly what the geographic distribution is of the

18   viruses that have been identified.                      And here we have

19   the geographic distribution of the Beijing/262-like

20   lineage viruses that have circulated between October

21   '98 and January 2000.                 And you can see that they're

22   pretty           well    distributed      in    all    continents           where

23   surveillance occurs.

24                           I'm going to just show one overhead with



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                                                                              48

 1   the post-vaccination human serologies.                 Roland is going

 2   to be presenting a lot more data later, but this data

 3   did not get to Roland in time for him to incorporate

 4   it into his analysis.         So I would just like to show you

 5   that if we concentrate just on this column for the time

 6   being and look at the post-vaccination geometric mean

 7   titers against the vaccine strain Beijing/262 and

 8   against New Caledonia; a representative Japanese strain

 9   from the current outbreak in Japan; and a virus from

10   North America, the Canada virus, we see that we have

11   a greater than 50 percent reduction in post-vaccination

12   geometric mean titer for these representative strains.

13                    Next overhead, please.

14                    Again, if we look at an elderly population.

15    I neglected to mention that we were looking at healthy

16   adults in the previous slide.           If we look at the elderly

17   population, once again, if we look simply at the

18   post-vaccination geometric mean titers, we see at least

19   a 50 percent reduction for these strains, as compared

20   to the homologous titer that we observed for the vaccine

21   strain itself.

22                    We'll move very quickly onto the Influenza

23   B viruses.        The picture is a bit more complex for

24   Influenza B, but similar to the situation for Influenza



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                                                                                 49

 1   (H1N1) viruses.            We really have not had a great deal

 2   of Influenza B activity when we look globally, neither

 3   for the Southern Hemisphere winter nor for the Northern

 4   Hemisphere winter that's occurring now.

 5                       Next overhead, please.

 6                       Once again, we have two lineages of viruses

 7   circulating.         We have the so-called Yamagata lineage,

 8   which is represented here by Yamanashi, Beijing/184,

 9   and Harbin/07.          And then we have what we traditionally

10   have called the Victoria lineage, which is represented

11   here by Shangdong/07/97.             And it's very easy to see that

12   these            viruses     are       distinguishable,              easily

13   distinguishable,           using    hemagglutination          inhibition

14   tests with post-infection ferret sera.

15                       This was a test that was performed in early

16   November and we had some isolates from Tennessee that

17   had been collected in early October.                      And the vaccine

18   strain that we are currently using as our B component

19   is Yamanashi/166.           We see that, for these viruses, we

20   had good inhibition for the Tennessee strains and a

21   strain from Brazil that was also isolated in October.

22    This virus from Ohio had a fourfold reduction in titer

23   compared with the vaccine strain, but was only twofold

24   reduced when compared to the Beijing/184 prototype.



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                                                                           50

 1                    This test was done in early January of 2000.

 2    And as we continued to do more testing with the Bs,

 3   we started seeing a slightly different picture emerge.

 4    If we concentrate here on the titers that we're seeing

 5   against the B/Yamanashi ferret serum, we see that we

 6   have the Zagreb and New Caledonia strains, which are

 7   well-inhibited, and a number of strains that are just

 8   two fold down.

 9                    But then we have antigens 17 through 21

10   here, which had been received recently.                They've been

11   isolated in August and September of '99, but we've

12   received them rather recently.              We had three viruses

13   from Vietnam and two from Southern China.                  And very

14   clearly, these viruses were not well-inhibited by

15   antiserum to the Yamanashi.           They were still reasonably

16   well-inhibited by antiserum to the Beijing/184 and they

17   were clearly on the Yamanashi lineage, as confirmed by

18   sequence analysis and so on.

19                    We were very interested in looking at these

20   viruses in more detail.            We did multiple tests with

21   these to be sure that the HI values were reproducible.

22    And we chose one particular strain, that is this

23   Shenzhen/654 strain; put it into ferrets; and got a

24   ferret antiserum, which shows us quite clearly that we



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                                                                                     51

 1   have a new Influenza B variant.                    That is, we have a

 2   greater than fourfold reduction in titer when we're

 3   looking at the ability of the Yamanashi ferret antiserum

 4   to    inhibit         this   strain     and   we    have     a    reciprocal

 5   difference when we look at the ability of the Shenzhen

 6   antiserum to inhibit the Yamanashi virus.

 7                         Now as you can see, this test was just

 8   completed last Monday, right after the ferret was bled.

 9    And      so     we    haven't    had    a    chance    to       do   a    large

10   retrospective analysis to actually see how this Shenzhen

11   antiserum would perform against, for example, the

12   Tennesee strain and some of the other strains that you've

13   seen in previous tests.              So this is one of the next steps

14   that we'll be performing.                 But you can see that this

15   antiserum clearly inhibits these viruses much better

16   than the Yamanashi serum does.

17                         The other thing I should point out is that

18   the B/Johannesburg strain was also well-inhibited.                              In

19   our hands, it's well-inhibited both by the Yamanashi

20   antiserum and by the Shenzhen/654 antiserum.

21                         Next slide, please.

22                         We'll concentrate mainly on the bottom part

23   of this table, the frequency table.                    If we look at the

24   period between April '99 and September '99, we have



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                                                                             52

 1   analyzed a total of 97 strains.              Only 10 of those, or

 2   approximately 10 percent, have been Victoria-like and

 3   those are from Asia.         The majority of the strains are

 4   Beijing/Yamanashi-like or low to Yamanashi.                And you'll

 5   see a number of strains here, 16 in fact, all from Asia,

 6   which were low to Yamanashi.              And that includes the

 7   Shenzhen and some of the Vietnam strains.

 8                    If we look at the recent period, we've had

 9   relatively few Influenza B viruses to analyze.                      Only

10   a total of 14.      And we have one strain from Asia which

11   is low to Yamanashi.         We have two from the U.S. which

12   are low to Yamanashi.

13                    Okay.    This shows the molecular analysis

14   of the hemagglutinin genes of these strains.                        As I

15   mentioned, we can clearly distinguish these viruses

16   genetically.      This is the so-called Victoria lineage.

17    This is the so-called Yamagata lineage.                  Here's our

18   vaccine strain here, Yamanashi/16/98.                  And it's more

19   or less in the middle of the majority of strains that

20   we have analyzed.

21                    The new variant that I mentioned is located

22   up here and it's actually shown right here.                 There are

23   a number of specific amino acid changes between these

24   strains and these strains that could account for the



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                                                                             53

 1   differences in antigenicity.           And you'll note that this

 2   new group of viruses up here is more closely related

 3   to the previous vaccine strain Harbin/07/94 than it is

 4   to the Yamanashi/16/98.

 5                    Next slide, please.

 6                    We looked at the extent of amino acid

 7   difference between the egg isolates that we have for

 8   Influenza B/Beijing-like strains and the consensus

 9   sequence.        And you'll see that the Yamanashi vaccine

10   strain is actually very close to the consensus sequence.

11    And this has been the sublineage that has predominated

12   in most of the world in recent years.                  But, again, it

13   should be noted that we have a relatively small number

14   of strains.

15                    Next slide, please.

16                    And here we're looking at the separate

17   sublineage of Harbin-like strains.             And here we see that

18   the Shenzhen/654 has five amino acid differences,

19   compared to the consensus sequence for the sublineage.

20    Now part of the problem here is that we have relatively

21   few viruses that are in this lineage.              We don't do know

22   the significance of this new antigenic variant.                 We only

23   have a handful of viruses that are like this.                  We have

24   just received a package of strains from the National



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                                                                                  54

 1   Influenza Center in Beijing and all of the strains in

 2   that package are Influenza B strains, so we're very keen

 3   to look at those in detail and see if we can find similar

 4   viruses from other locations in China.

 5                      Next overhead, please.

 6                      If we look at the neuraminidase genes's

 7   evolutionary        relationships         about      the   B   Influenza,

 8   neuraminidase genes, once again, we see the Yamanashi

 9   strain, here sort of smack in the middle of the most

10   prevalent influenza virus strains that are circulating.

11    We'll need to sequence some additional neuraminidase

12   genes from these recent strains.                 We haven't been able

13   to complete those studies yet.                       Well, Shenzhen is

14   actually         done   here,     but   we    want    to   look      at    the

15   neuraminidases of some of the viruses from Vietnam and

16   the other Shenzhen strain to see if they cluster

17   together.

18                      Now just to remind you, we've been talking

19   about this for a number of years, but we need to keep

20   in mind that we do have these two separate lineages.

21    The vaccine for Europe and North America has contained

22   viruses from the Yamagata lineage, but the Victoria-like

23   viruses have continued to circulate in Asia.                        And the

24   red dots here on the map just show the locations of



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                                                                                    55

 1   B/Victoria-like strains isolated between October '98

 2   and January 2000.               And we really haven't seen these

 3   viruses          spread     outside      of    Asia,    which      is     quite

 4   surprising.

 5                       I   have     just    one    post-vaccine        serology

 6   exhibit to show you today.                    And, again, I'd like you

 7   to concentrate simply on this column, which shows the

 8   post-vaccination             geometric        mean   titer     against       the

 9   vaccine strain Yamanashi and some other representative

10   strains.         And I'd just like you to note that the titers

11   are markedly reduced for the B/Shenzhen/654 variant in

12   all of these different panels.

13                       Next overhead, please.

14                       And I said we were going to move through

15   the virus groups in order of increasing complexity and

16   now we're talking about H3N2 strains.                        When we look at

17   the influenza activity that has occurred worldwide, and

18   this is just an estimate of the extent of activity, but

19   it certainly contrasts markedly to the picture that we

20   saw for the B viruses and the H1N1 strains, you can see

21   that there was really significant activity due to H3N2

22   viruses in the Southern Hemisphere in South Africa,

23   Australia, and New Zealand and also on Central and South

24   America during their winter season.



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                                                                                   56

 1                          You can also see that there is significant

 2   influenza activity due to H3N2 viruses in the U.S.,

 3   Canada,          and    Europe.        And    there's        also   activity

 4   occurring in Asia, but it's not quite at the same

 5   intensity, at least insofar as we understand it.

 6                          Now looking at the HI reactions for the H3N2

 7   strains has been extremely interesting.                       All of us who

 8   have been watching the evolution of H3N2 viruses over

 9   the past few years would have predicted that Sydney-like

10   strains would not circulate for three years in a row.

11    That has not happened for H3N2 strains for a number

12   of years.

13                          We have looked in great detail and with

14   great care at whether or not the currently circulating

15   strains are indeed Sydney-like.                    Here I'm showing you

16   one particular batch of post-infection ferret serum.

17    We have checked three different batches made with serum

18   from five different ferrets.                      And we see the same

19   picture with all three batches of ferret serum to the

20   Sydney strain.

21                          This is a test that was performed in

22   mid-December and it is very representative of what we

23   had been seeing during November and the first part of

24   December, and that is to say that, regardless of whether



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 1   we were looking at viruses from the United States, which

 2   are shown here and with test antigens 7 through 12, or

 3   whether we were looking at viruses from Asia, shown here

 4   with test antigens 13 through 18, we were seeing a very

 5   good inhibition of these viruses with antiserum to the

 6   Sydney vaccine strain.

 7                    We    were    also    seeing     a      great   deal      of

 8   homogeneity, regardless of what serum we were looking

 9   at.       Here we have the Moscow/10 strain that Roland

10   mentioned earlier.          We were seeing very good inhibition

11   with this particular antiserum.                Here's another virus

12   that you'll hear about quite a bit.                        This is the

13   Panama/2007/99 strain and its antiserum was inhibiting

14   all of these strains very well.

15                    We have two high-growth reassortants that

16   were made against the Panama antiserum.                   The reason we

17   did that is that we saw that the Panama virus itself

18   had a fourfold in many tests, sometimes a twofold,

19   reduction in titer when compared to the homologous

20   Sydney titer.         So that's the reason that we went ahead

21   and made a ferret antiserum to this virus and then

22   high-growth reassortants were made.                   And the antisera

23   to these two high-growth reassorts, NIB-41 and 42,

24   inhibited the viruses that we were seeing early on quite



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 1   well.

 2                    Here we have another virus which is fourfold

 3   reduced, very reproducibly fourfold reduced in titer

 4   as compared to the Sydney homologous titer.                        And

 5   antiserum to that strain also inhibits these strains

 6   quite well.

 7                    Here we have viruses that were isolated

 8   during October and November from the U.S. and these

 9   strains were isolated a bit earlier, between April and

10   September of '99.

11                    Next overhead, please.

12                    You notice that this test was done a month

13   later in mid-January.          And this table is organized in

14   very much the same way.         It's fairly complex.       I'll try

15   to walk you through it.

16                    What we were seeing -- by this time, we had

17   identified another strain that was fourfold reduced in

18   titer to the Sydney antiserum that's shown here in

19   reference antigen number 6 Alaska/37/99.                   And, of

20   course, we made a ferret antiserum to that strain, so

21   that's the new antigen that's been introduced here.

22                    But if we concentrate first on this column

23   here, which shows the inhibition of viruses by the Sydney

24   antiserum, we see that, if we look at viruses from North



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 1   America, we have a number of viruses with a fourfold

 2   or greater reduction in titer against the Sydney strain.

 3    And if we look across here and look at how these viruses

 4   are inhibited by other antisera, what we tend to see

 5   is the viruses which are more poorly inhibited by the

 6   Sydney antiserum also tend to be more poorly inhibited

 7   by the other antiserum.

 8                      Now if we look at the viruses that we've

 9   received from other countries, we have a similar

10   pattern.         There are a number of strains which are very

11   well-inhibited         within      twofold     versus    the    Sydney

12   antiserum.         But we also have a viruses from Hong Kong

13   and one from Korea which are reduced in titer.

14                      I think I will go on to the next overhead,

15   rather than spend too much time there on that particular

16   one.       This is the latest test that we performed this

17   week and in this test we have one additional antigen

18   and ferret antiserum, the Shenzhen/510/99 strain.                    And

19   this was the most recent egg isolate that we had or one

20   of the most recent egg isolates that we had from Asia

21   and so we thought it would be a good idea, even though

22   it wasn't reproducibly reduced in titer with the Sydnedy

23   antiserum, we thought it would be a good idea to see

24   what kind of a profile we observed with antiserum



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 1   produced against this virus.

 2                       Once again, if we concentrate on column A,

 3   we'll see that there are strains from North America,

 4   which are very well-inhibited.                    These are strains

 5   isolated in primarily in December and January of this

 6   season.          And we also have some strains that are fourfold

 7   reduced in titer, compared to the Sydney antiserum.

 8   Again, these strains were isolated in October.                     If we

 9   look at viruses from abroad, we see a similar pattern.

10    We could find viruses which are reduced in titer.

11                       We had been looking quite closely at the

12   Panama antiserum and in many tests the Panama antiserum

13   performs as well if not better than the Sydney strain

14   in covering the currently circulating viruses.                  In this

15   test, it's not readily apparent.

16                       We haven't tested the Shenzhen antiserum

17   a great number of times.             I think we've only had it in

18   two large tests, but we do see that this Shenzhen

19   antiserum tends to cover almost all of the strains.

20   We only have one strain here, the Philippines/26/99

21   strain, which may be mentioned by others later, which

22   is reduced fourfold or greater in titer.

23                       So what I would like to just pause here and

24   mention is that we have a picture for the H3N2 viruses



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 1   that's a little bit complex.              We're really looking for

 2   a distinct new variant and we haven't seen one.                   We're

 3   looking for a variant where we have a fourfold reduction

 4   in titer that's symmetrical, that's going both ways.

 5    And if you look at this table carefully, you'll see

 6   that there are no strains here which give symmetrical,

 7   fourfold reductions in titer.

 8                      The viruses are reasonably homogeneous and

 9   when they are less well inhibited by the Sydney, they

10   tend to be less well inhibited by the other antisera.

11    The only antisera that we have at the moment, and we

12   have much less experience with it, but the only one that

13   we have that tends to give a significantly broader

14   pattern is this Shenzhen/510 antiserum.

15                      So in the past what we've always tried to

16   do is to find the new variant and really move to the

17   new variant.         But you could think about a variety of

18   strategies for updating vaccine components.

19                      You could think about, of course, you have

20   one strategy where you stay with the component that you

21   have in.         You could have one where you moved to a strain

22   that is somewhat different, for example the Shanghai/42

23   even though it isn't very representative of what's

24   circulating genetically.              Or you could try to just



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 1   follow and move where the viruses seem to be going

 2   genetically and move to the Panama strain.               Or you could

 3   try to surround the strains by moving to a strain that

 4   really you have a limited rationale for changing to,

 5   but the antiserum actually seems to cover better.                       So

 6   these are some of the ideas that we're exploring.

 7                      Next overhead, please.

 8                      Now I've shown you tables that have been

 9   selected to make certain points.                     This shows the

10   composite data for H3N2 viruses.                  If we look at the

11   viruses that were isolated between April '99 and

12   September '99, we have a total of 346 strains that we've

13   looked at and of those just about 11 and one-half percent

14   were fourfold or greater reduced in titer to the Sydney

15   strain.          If you look back at what was happening last

16   year, we also had about 10 percent of strains which were

17   reduced in titer to Sydney.             So it's really not a very

18   different picture from what we were seeing last year

19   or what we saw during the summer months.

20                      And the same thing is true of the period

21   October '99 to January 2000.                  Again, it's about 11

22   percent of the strains which are reduced in titer.

23                      The molecular picture is fairly complex.

24    I've put red dots by some of the viruses that you've



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 1   seen on your HI table.                Here's the Alaska/37, the

 2   Panama/2007.         Sydney vaccine strain, of course, is down

 3   here and the viruses have been evolving with time as

 4   we always expect at a molecular level.                   And here's the

 5   Moscow strain here up in this sublineage.                        And the

 6   Shenzhen/510 is here.

 7                      Now what I've done also here is to put a

 8   small green L by the strains which are low reactor in

 9   HI tests.         And what you'll see is that those so-called

10   low reactors, the viruses that are fourfold or greater

11   down in titer as compared to the homologous titer with

12   ferret serum, are scattered throughout the dendrogram.

13    They don't cluster together.                 So what we have is a

14   picture where we don't have a clearly emerging variant

15   of H3N2.         We have low reactors which are in each of these

16   different clades.

17                      Next overhead, please.

18                      If we look at the sequences of our egg

19   isolates or our possible vaccine candidate strains, as

20   compared to the consensus sequence that we've obtained

21   for strains circulating, we see that the Sydney vaccine

22   strain now has nine amino acid differences compared to

23   the      consensus     sequence.         Panama/2007       has     three.

24   Shenzhen/510 has five.              Another strain that's been



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 1   mentioned quite a bit or will be mentioned more in the

 2   future is Moscow/10, which has five.

 3                        The       relationships               between         the

 4   neuraminidases of these strains at a molecular level

 5   are also complex.               We have different subgroups of

 6   neuramidases that are circulating.                  And we see that the

 7   Panama neuraminidase is here in this clade while the

 8   Moscow and Shenzhen neuraminidases are up here in this

 9   clade.           Sydney neuraminidase is down here and there are

10   a number of amino acid changes that have occurred in

11   the neuraminidase.

12                        Next overhead, please.

13                        Now I'm going to finish up my talk with a

14   bit of an aside, but I know that the committee has had

15   a number of questions over the summer months about what

16   was going on in China with regard to Influenza A(H9N2)

17   infection that had been reported from Hong Kong and then

18   also from Guangdong Province in Southern China.

19                        The   story     that    you're        probably      most

20   familiar with is that that emerged from Hong Kong in

21   March of 1999 -- I apologize for the typo -- when H9N2

22   viruses were isolated from two hospitalized children

23   ages 4 years and 13 months.                      These children had

24   underlying health conditions that may have predisposed



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                                                                                 65

 1   them to more serious disease, nevertheless they were

 2   hospitalized.         Both of them recovered uneventfully and

 3   no further cases have been reported from Hong Kong.

 4                      The viruses were analyzed in detail and

 5   contain all avian genes, that is to say there was no

 6   reassortment between human strains that were close

 7   circulating at the time and these H9N2 viruses.                        Quite

 8   a lot of work occurred in Hong Kong to determine the

 9   source of the infection and it was already known that

10   some of the poultry were shedding H9N2 viruses, that

11   had antibody to H9N2 viruses.               And it was reported by

12   the Department of Health in Hong Kong that about 70

13   percent of the batches of poultry that they tested were

14   positive for antibody for H9 virus.

15                      After    an   investigation           in   which       CDC

16   participated extensively but which was led by the

17   Department of Health in Hong Kong, it was determined

18   that poultry are the likely source of infection and

19   serologic         studies    indicate      that     human      to      human

20   transmission is rare and inefficient, similar to the

21   picture that was seen for the H5N1 viruses.

22                      Isolation of H9N2 viruses was also reported

23   by Dr. Guo Yuanji at an international meeting in March

24   of 1999.         He reported that five H9N2 viruses had been



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 1   obtained from individuals who had accute respiratory

 2   disease in Guangdong Province.                    And the individuals

 3   were ill, actually, in December of 1998.

 4                         Subsequently, this work was published in

 5   the Chinese Journal of Experimental Clinical Virology

 6   and the title of the paper is "Discovery of Humans

 7   Infected by Avian Influenza A(H9N2) Viruses."                       The age

 8   of the patients ranged from 1 year to 75 years of age.

 9    And the severity of infection varied somewhat and there

10   wasn't a great deal of clinical information in the paper

11   that was published.

12                         The H9N2 viruses that were reported by Dr.

13   Guo are antigenically different from the ones that were

14   isolated         in    Hong    Kong.       And    I'll      show   you     the

15   relationships between these viruses on this slide.                           We

16   haven't actually received any of the viruses isolated

17   by Dr. Guo so we haven't been able to confirm his

18   analysis, but the viruses from Hong Kong are listed here,

19   antigens 3 through 6.               And we just have MDCK and egg

20   isolate pairs shown here.

21                         And you can see that these viruses that were

22   isolated from humans, whether in MDCK cells or chick

23   cells, are closely related to a reference avian virus

24   A/Quail/G1.           And we'll just call it G1 for the sake of



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 1   convenience.       So these viruses are closely related to

 2   this virus, which was isolated from the live bird market

 3   in Hong Kong during December of 1997 right before the

 4   slaughter of the chickens that was undertaken to

 5   eradicate H5 viruses.

 6                     The viruses that Dr. Guo has reported

 7   apparently are related to a reference avian strain

 8   Chicken/G9 which is shown here.               So it appears that

 9   there are two antigentically and, I'll show you in a

10   minute, genetically distinct groups of H9N2 viruses that

11   are circulating in poultry in Asia and both lineages

12   have shown the ability to jump from birds to humans.

13    Here I've just pointed out with red arrows the G9

14   reference strain and it's genetically and antigenically

15   from the G1 group that's shown here.

16                     I think that's my last overhead.

17                     CHAIRMAN GREENBERG:       Nancy, thank you very

18   much for a very complete talk.              Now that talk took a

19   little more time than the schedule Dr. Levandowski had

20   planned, but I think it was very complete and very

21   helpful.         What I would please ask is for the next

22   speakers, who I am sure have wonderful data to tell us,

23   that when it overlaps with what you've just heard, you

24   don't have to tell us again.            And, in order to try to



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                                                                                  68

 1   keep this on track, I would hope that, again, the next

 2   speakers really present the committee with the data that

 3   is important to make the decision for next year's

 4   vaccine.

 5                        I have time for one or two questions for

 6   Nancy.           Dr. Kim.

 7                        DR. KIM:      So it appears that, based on your

 8   H3N2 data, that it seems unclear why there seems to be

 9   an increase in influenza activity this year compared

10   to let's say last year.

11                        DR.    COX:       Yes,   the    viruses     that      are

12   circulating this year appear very similar to the strains

13   that have circulated during the previous two winters.

14    So it is unclear, first of all, why, based on past

15   observations, we haven't seen a new variant emerge.

16   And, secondly, why we would have an epidemic caused by

17   H3N2 rather than H1N1 or B when we would expect the

18   antibody levels to be lower to those two strains.

19                        CHAIRMAN GREENBERG:           Dr. Edwards.

20                        DR. EDWARDS:         I have a quick question.

21   When you're looking at hemogglutination inhibition with

22   the A/Alaska strain, making the antisera in ferrets,

23   it appeared that the neutralization of that homologous

24   strain was quite low whereas neutralization of other



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 1   viruses with that strain was higher.                    Does that happen

 2   frequently?

 3                      DR. COX:       That happens with viruses which

 4   we typically call "low avid."                  They just don't appear

 5   to bind antibody as efficiently as some other strains.

 6    So occasionally, when we put one of those strains into

 7   ferrets, we find a ferret antiserum that inhibits the

 8   homologous virus less well than it does the other

 9   viruses, which bind antibody better.

10                      DR. EDWARDS:         Would they be not very good

11   ones to select as vaccine strains?                   Or are ferrets and

12   humans not alike?

13                      DR. COX:       We tend to try to stay away from

14   those strains if possible.

15                      CHAIRMAN GREENBERG:             Two more questions.

16    That's it.            Dr. Faggett and then Dr. Couch.

17                      DR. FAGGETT:         With the H9N2 virus, was that

18   a mutation in terms of the one reported first and Dr.

19   Guo's?           And    was    there    an    implication    that      this

20   person-to-person capacity for Dr. Guo's virus?

21                      DR. COX:          I'm sorry.         I'm not sure I

22   understand your question.

23                      DR. FAGGETT:         For H9N2.

24                      DR. COX:       Right.     The H9N2 viruses that are



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 1   circulating in the poultry in Asia --

 2                        DR. FAGGETT:       Right.

 3                        DR. COX:     There are two distinct lineages.

 4                        DR. FAGGETT:        Okay so no mutation there,

 5   just very distinct to start with.

 6                        DR. COX:      That's right.

 7                        DR. FAGGETT:       Okay.

 8                        DR. COX:      Distinct to start with.

 9                        DR. FAGETT:        Right.      But did Dr. Guo's

10   reported virus have any potential for person-to-person

11   transmission?

12                        DR. COX:      We really don't know very much

13   about            those   viruses      and     epidemiologic      studies

14   comparable to those done in Hong Kong haven't been done

15   yet, although Dr. Guo has done some serum surveys.

16                        CHAIRMAN GREENBERG:           Last question, Dr.

17   Couch.

18                        DR. COUCH:      Just a couple quickly, Nancy.

19    One is a lot of, including Dr. Kilbourne, are pleased

20   to see the emphasis coming on on neuraminidase and

21   looking forward to antigenicity data that you said

22   you're working on for the future.

23                        But the puzzle is on everybody's part, as

24   you've indicated, is why three years in a row of



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 1   A/Sydney?        And one suggestion that you've made that may

 2   have contributed is perhaps the neuraminidase are

 3   different and that, in the presence of a high population

 4   immunity and the absence of neuraminidase in it, perhaps

 5   this antibody and this virus has a little better ability

 6   to survive.          So I think that will be interesting.

 7                        You've     emphasized       the      low    reactor

 8   frequencies and I can't remember from past years

 9   that -- see you said it was 10 percent all the way across

10   the years period.          It that about the usual?         Or is there

11   a higher frequency this year?

12                        And my last question relates to Influenza

13   B.     Any outbreak or epidemiologic data to go with the

14   Shenzhen strains?

15                        DR. COX:    I'm not sure what you're -- your

16   first question was more of a comment than a question,

17   I think.         Yes, why three years?

18                        DR. COUCH:      Well, I just wanted you to

19   speculate        a    little    bit.      You   didn't     mention      the

20   neuraminidase as a possibility.

21                        DR. COX:      Right.       Right.     We're going

22   to -- yes.       Neuraminidase is a possibility.            We're going

23   to be looking at that in much greater detail, trying

24   to sequence more neuraminidase genes and eventually



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 1   trying to set up some antibody neuraminidase inhibition

 2   tests.           And we're also going to be looking at internal

 3   genes as well, just in case.

 4                        DR. COUCH:        Have previous low reactor

 5   frequencies been low, 1 or 2 percent, versus 10 or 11

 6   now?

 7                        DR. COX:     It depends on the year, but 10

 8   percent is not unusual because there's just a degree

 9   of hetereogeneity among viruses circulating that causes

10   us to see this kind of picture.                 What we expect to see

11   when a new variant is really emerging is an increase

12   over time.           So 5 percent, 10 percent, 30 percent, and

13   so on and then predominance of that new antigenic

14   subtype.

15                        And the third question was?

16                        CHAIRMAN GREENBERG:        The last question was

17   on B.

18                        DR. COX:     On B we don't really have very

19   good epidemiologic information about the significance

20   of the strains that have come to us from China, but we'll

21   be following up on that and trying to get as much

22   information as possible.

23                        CHAIRMAN GREENBERG:         I'd like to move on

24   now and we have a series of speakers.                      Dr. Canas.      And



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 1   what'd I like to say is for each of you, you've got a

 2   maximum of 10 minutes and then a hook is coming out.

 3                      DR. LEVANDOWSKI:         I need to reinforce what

 4   Dr. Greenburg said.            We're severely behind schedule by

 5   about 45 minutes so all the speakers need to be very

 6   succinct.

 7                      Linda Canas is the chief of diagnostic and

 8   pyrology at Brooks Air Force Base.                         She's with the

 9   Department of Defense and she has information that

10   overlaps         with    the    surveillance       data      that's      been

11   presented by CDC.

12                      CHAIRMAN GREENBERG:             And when you have

13   overlapping data, just say you've learned this already.

14    You don't have to present it again.

15                      DR.      LEVANDOWSKI:             Okay,       I      meant

16   "supplements."

17                      (Laughter.)

18                      DR. CANAS:         Good morning.          DOD is very

19   interested in maintaining the health of the men and women

20   in the armed forces and respiratory disease, of course,

21   rates very high on this.                For over 20 years now, the

22   Air Force has conducted influenza surveillance.

23                      It's been a successful program and it's now

24   operated through the Global Emerging Infectious Disease



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 1   Office out of Washington and is tri-service.                      Each of

 2   the services has their own portion.             The Air Force still

 3   continues        mainly   in   the     overseas        and     stateside

 4   surveillance by sentinel base.

 5                     Now last year I went through a detailed

 6   process of how this works and let's just through it very

 7   briefly so you know what we do.               We do have sentinel

 8   sites that are set up around the world.                Throat cultures

 9   are collected from the physicians of anyone presenting

10   with a case definition meeting respiratory illness.

11   These are sent to us generally by FedEx to our laboratory

12   in San Antonio where we do traditional laboratory

13   methods and isolate whatever virus we get.

14                     We are looking for influenza, but it's a

15   clinical test in our labs so we report whatever we do

16   get and get this information back to the public health

17   officers at the bases.         We then go on to do any molecular

18   tests and hemagglutination inhibition subtypings in our

19   lab and also send on to Dr. Cox's lab at CDC.

20                     And just to give you an idea of where all

21   of these different sites are, we do have them set up

22   around the world.          We have two that are proposed.

23   Agreements have been signed and we should, hopefully,

24   start getting some specimins from Uganda pretty soon.



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 1    Bolivia is also supposed to come on line.                The stateside

 2   bases, our military bases, have been chosen -- training

 3   sites where people are coming together, points of entry

 4   into the country, and our overseas sites.                   My handout

 5   didn't get here, so it lists all of these and their

 6   countries and states to give you an idea that we do have

 7   a pretty broad range.

 8                       One of the most exciting additions has been

 9   in collaboration with Army and Navy research labs in

10   overseas areas where we've been able to get specimens

11   from Nepal and Thailand for several years now.                        This

12   summer we ran into practical problems getting specimens

13   into the country, but I think that's finally all worked

14   out.       We are expecting another shipment shortly from

15   them.            They say they are having some significant

16   outbreaks.

17                       South    America      has     been    particularly

18   prolific in sending specimens.                    They've been very

19   excited about the program.               I understand now that the

20   National Police is going to be involved in getting

21   supplies out and getting them back to us.                    And, as I

22   mentioned, Bolivia in South America and Uganda will be

23   coming on line very shortly.

24                       Our graphs of what's been going.            You will



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 1   notice that we have a signficant respiratory increase

 2   this season and that is very true in the military

 3   population.        But it's unique.        We're getting a lot of

 4   background parainfluenza.            Our program is not designed

 5   for RSV, but we have a uniquely military consideration

 6   with adenoviruses in our recruit population.                   So the

 7   majority of those isolates have been adenovirus as

 8   opposed to influenza.

 9                     There's been very little influenza isolated

10   in the recruit population.             And this is true for all

11   services.        And those that have been influenza cases have

12   been in the new recruits who really haven't had time

13   to develop an immunity yet.                  So we're not seeing

14   influenza in the recruit population.

15                     In the active duty population as a whole,

16   we do see it.       We're trying to do some vaccine efficacy

17   studies.         We know we have a unique population here.

18   They are required, the active duty are required, to be

19   vaccinated.        We can track their records; we can track

20   their travel; we can track their medical history, but

21   it takes money.       So we're trying to do the retrospective

22   studies of matching up vaccination and travel histories

23   with the laboratory case definitions and this is an

24   ongoing process.         It is one of our priorities to try



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 1   to get true vaccine efficacy studies down the line.

 2                         In Asia, we are just now beginning to see

 3   a real increase in samples coming out of Asia.                           We've

 4   had one H1 out of Hawaii and that has been a New

 5   Caledonia.            We had one H1 just last week out of New

 6   Jersey.          And we've had two Bs in the Pacific and just

 7   last week we got a B out of Oklahoma.                       Everything else

 8   we've seen has been H3N2.

 9                         One of the things in the Pacific that we're

10   trying to get off the ground is surveillance on board

11   aircraft carriers in the Navy.                   And we can have more

12   access to places like Singapore and those places, but

13   that, again, is still in development.

14                         Most of the European surveillance is done

15   through the Army at Landstuhl and there were some

16   technical difficulties and I wasn't able to get that

17   information.              Everything       we've     seen,      which       has

18   been -- we've had several from Turkey lately; a few from

19   England and Germany.              They've all been H3.

20                         And just a summary of our numbers are very

21   similar to what you've already seen.                        We're seeing a

22   big increase.           It has been an early season, but it hasn't

23   been anything particularly unusual in our experience

24   and      H3      is   predominate      across-the-board.             We     are



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 1   expecting         shipments     from    South    America    and      Nepal

 2   shortly, but we have nothing to contribute on that at

 3   this point.

 4                      We're just getting all our molecular work

 5   on line.         We've got some nice new equipment and we expect

 6   to be able to start contributing more information and

 7   being able to compare that to the libraries that are

 8   set up with CDC and other places and contribute to that

 9   knowledge.         But this is our program as we have it right

10   now.

11                      CHAIRMAN GREENBERG:           Thank you and thank

12   you for finishing quickly.               Roland.

13                      DR.   LEVANDOWSKI:           Actually,    I    have      a

14   question about the B strains.                Are any of the strains

15   that have been isolated by the military B/Victoria-like,

16   particularly from the Pacific Rim or from Thailand?

17                      DR. CANAS:       Well, we've had very few and

18   even those we had last year have all been very nice 184s,

19   the Beijing.

20                      CHAIRMAN GREENBERG:          Dr. Kilbourne.

21                      DR. KILBOURNE:       What is the current vaccine

22   coverage in the military?              It used to be very complete.

23                      DR. CANAS:          It's considered to be 90

24   percent by all studies.



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 1                          DR. KILBOURNE:     So, in essence, when you're

 2   seeing           the     adenoviruses       emerging,         you've      just

 3   subtracted flu, do you think?

 4                          DR. CANAS:    Well, adeno -- of course, you

 5   know, we had an adeno vaccine that's no longer available,

 6   so that has just increased a lot but we are looking for

 7   both.            But not too much in the recruits, we're not

 8   getting much flu.            But in the population -- and the adeno

 9   is in the recruit population as opposed to the population

10   at large and it hasn't translated into the civilian

11   communities around them either.

12                          CHAIRMAN GREENBERG:           Okay.       Any other

13   questions?             Okay, well let's move on to Dr. Hampson.

14    And, Dr. Hampson, the same admonition.

15                          DR. LEVANDOWSKI:       Right.        Alan Hampson is

16   one of the directors of the WHO Influenza Center in

17   Melbourne and he has some information about what's

18   happening recently in the Pacific and the Southern

19   Hemisphere.

20                          DR. HAMPSON:     Okay.     Just very quickly to

21   outline the collection of strains that we've had in the

22   last 12 months or 13 months and just showing you our

23   collection network, which is mainly Australia, New

24   Zealand, and into Thailand and some lesser percentage



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 1   of viruses from some of the Asian countries.

 2                     And just to show you quickly that in

 3   Australia and New Zealand, we have the typical temperate

 4   climate distribution of viruses.              This one's in weeks.

 5    One in months.        And during the course of this season,

 6   we've       had   Influenza    A   and    Influenza     B     scattered

 7   throughout the season.             Maybe a slightly increasing

 8   tendency towards Influenza B towards the end there.

 9                     Whereas in New Caledonia and Thailand,

10   these are more typical of the tropical distribution

11   where we see virus throughout the year.                 In the case

12   of New Caledonia, we tend to see outbreaks occurring

13   at sporadic intervals.             Interesting this year, we've

14   had two outbreaks of Influenza A.              The first purely H3

15   and the second purely H1.           And here's the New Caledonia

16   strain Nancy was talking about and some later Influenza

17   B.

18                     And if we quickly have a look at the

19   distribution of the Influenza As, the greater percentage

20   have been H3N2 with a very small percentage of H1N1,

21   again just paralleling what Nancy has told you.                       Then

22   showing you that all of the H1N1 viruses that we have

23   seen for the year fall into this Beijing lineage and

24   are very well-inhibited by the antiserum against this



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 1   new virus isolate that we achieved earlier in the year,

 2   the New Caledonia strain.

 3                    And just to show you a difference table from

 4   minoesets        from    the     Beijing       virus   showing      this

 5   characteristic distribution of a number of minoeset

 6   differences.       And these are persisting in very recent

 7   isolates, including some which we've just received in

 8   the last week from the Philippines.

 9                    With    the     Influenza       Bs,   the   greatest

10   majority of our strains have been the B/Beijing lineage.

11    A very small number of B/Shangdong viruses.

12                    Next.

13                    And the important thing to note is that the

14   only place that we had this B/Shangdong or the B/Victoria

15   lineage of viruses from was Thailand.                  We didn't see

16   it anywhere else in Asia.             We had expected this year

17   that we might.          And, then again, it only occurred in

18   the first part of the year and you will have noticed

19   in that earlier graph that we've had quite a reasonable

20   amount of Influenza B activity later in the year in

21   Thailand and these were all B/Beijing/184 lineage.                      So

22   this change to the B/Victoria strain has changed back

23   again to 184-type of strains in Thailand.

24                    Now our results with the Type B, the recent



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 1   Type B/Beijing/184 lineage viruses has been maybe just

 2   a little different from Nancy's in that the viruses that

 3   we're seeing are better neutralized overall -- some of

 4   the viruses are around fourfold down against the

 5   B/Beijing/184 virus antiserum.             Certainly many of them

 6   are twofold down.        A number of them are fourfold down

 7   against -- two-to-fourfold down against the Yamanashi

 8   antiserum.       And in all cases these viruses are much

 9   better neutralized by two recent isolates, the South

10   Australia/05 and Johannesburg/05.

11                    And I've just put in the dendrogram to show

12   all the ones marked in blue are our recent 1999 isolates

13   and they are fairly closely grouped.                     The current

14   vaccine strain, Yamanashi here, the previous vaccine

15   strain, B/Harbin there, and the typical isolates that

16   we're seeing now neutralized by these two antisera

17   against B/South Australia and B/Johannesburg.                 So there

18   is drift going on with those viruses.

19                    And    we've      had      a     look     at       some

20   post-vaccination seriological responses and we are

21   seeing a significant reduction against viruses of this

22   type in vaccines containing the Yamanashi virus.                        So

23   we've got reduction in B/Johannesburg.                     These are

24   younger and older adults here.               And in the youngest



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 1   here, but not in the oldest here from Australia for some

 2   reason at this stage, we've seen a significant reduction

 3   against the new strain, the B/Shenzhen strain that Nancy

 4   referred to in her talk.

 5                    We are seeing an intriguingly different

 6   picture with the H3N2 viruses.                 I've divided them up

 7   here      into   low    reactors.         These    are     strains     that

 8   are -- I'm sorry.          That should say "low reactor" on this

 9   group here.       These are strains that are fourfold down

10   in reaction with Sydney antiserum.                        These are the

11   standard Sydney-type strains which Nancy's already

12   shown you.       And we've selected some out which appear

13   to be more strongly reactive with Moscow antiserum and

14   with a particular monoclonal antibody that we use which

15   differentiates the Moscow virus.                   So we have a much

16   wider split of these viruses than Nancy showed you in

17   her results.

18                    And just to show you some selected results.

19    These are not by distribution in terms of numbers, but

20   just some selected results to show you the type of range

21   of reactivity we get from strains that react strongly

22   with all of our antisera.            Just occasional strains which

23   react extremely poorly, very low titers, with all of

24   our antisera.



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 1                       Now just to stress that most surveillance

 2   is done with cell-grown viruses these days rather than

 3   egg-isolated viruses, we went back and took a number

 4   of     the       clinical   samples     for    which      we    had      these

 5   low-reacting          strains     and    reisolated        the       viruses

 6   directly in eggs and made the comparison.                      And what you

 7   can see here is the cell-egg pair, or the egg-cell pair.

 8    We've shown it for both the type strain, the reference

 9   strain A/Sydney.

10                       And you can see there is a difference there

11   in reaction with antiserum.              And, in fact, all the way

12   down this column where the virus has been significantly

13   low in its reaction as a cell-grown isolate with the

14   Sydney antiserum, when we've grown it in eggs, the

15   reaction is increased quite significantly.                           Many of

16   these viruses are more reactive, as you will see, with

17   the A/Moscow antiserum.               So there seems to be some

18   degree of influence here on the cell culture system

19   having been used to isolate these viruses.

20                       And I just put in one dendrogram here to

21   show you with the A/Sydney virus at this point, virtually

22   all of our recent isolates have fallen in this part of

23   the dendrogram, close to the A/Panama strain which Nancy

24   has mentioned and fairly well away from the Moscow/10



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 1   strain, which has also been mentioned as a potential

 2   vaccine strain.

 3                    Now I don't expect you to be able to read

 4   this in terms of the difference table for the amino acids

 5   in these viruses, but what we did was to take a number

 6   of viruses.      The ones marked in yellow are the ones that

 7   are normal reactors in our HI test.               The ones marked

 8   in pink are the ones that are low reactors.                 And I've

 9   marked here three in red at the top which are extremely

10   low reactors with A/Sydney antisera and our other

11   antisera.

12                    And just looking across at where we've

13   colored the amino acid differences.             And these are all

14   common amino acid differences across these groups.

15   There is absolutely nothing emerges, as Nancy said

16   previously, to show a genetic difference that relates

17   to this low reactivity.             There is some intriguing

18   difference       here   that's       not     explained       by      the

19   hemagglutinin sequence.

20                    But one thing we did do was to have a look

21   at a number of these viruses and I apologize for the

22   poor scan here of this electromicrograph.             But it does

23   show fairly dramatically what we did see.                In a small

24   number of viruses that we looked at where we took the



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 1   very low-reacting strains, put them under the EEM.               Took

 2   normal strains.        And the thing that was outstanding,

 3   we saw these huge aggregates of virus in the viruses

 4   that were low reactors.         And I'm sure that Dr. Kilbourne

 5   will probably tell us that there's someting defective

 6   about the neuraminidase in these viruses which is giving

 7   us this reaction.        We haven't been able to investigate

 8   that yet.

 9                    A quick look at the H3N2 strains.         You will

10   have seen at the bottom of one of Nancy's HI tables a

11   virus known as the Philippines/26 strain which is

12   reacting very, very poorly with the antisera raised

13   against A/Sydney virus.          These are just normalized to

14   100 percent in all cases.          But some lowering with this

15   Shanghai/42 strain which you mentioned.                No lowering

16   with the Moscow/10, in our hands.               And lowering with

17   a number of other recent isolates.

18                    Now there has been mention made of the

19   A/Moscow strain that was selected for vaccine production

20   in the Souther Hemisphere.            And it became a real rod

21   for our backs when we tried to work on this strain because

22   when we took the earliest reassortant that we had which

23   was one made in Australia, this IVR-112, we found to

24   our surprise that it had a dilution mutation and the



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 1   adjacent amino acid change because of the triplet that

 2   are being cut out here in an antigenic site, in antigenic

 3   site B.

 4                    And   just     to   go   on   with    a   number        of

 5   reassortants that were made in the efforts to produce

 6   a suitable vaccine strain, as I'll show you in a moment,

 7   this         correlated     with      antigenic        differences.

 8   Essentially everything that we have seen from that virus

 9   in terms of reassortants has had genetic differences

10   and fairly significant genetic differences from the

11   wild-type virus.

12                    We also did fine with the virus that we were

13   working with.       In fact, had changes from the original

14   sequence that had been distributed by CDC.                           And,

15   clearly, when we looked at our original sequences, we

16   found evidence that these viruses were mixed.                   So this

17   was a mixed population of viruses obviously throwing

18   off mutants as it went.

19                    And here's an example of two of these

20   reassortants showing some difference in the reaction

21   of their antisera that were produced against them,

22   against the A/Sydney virus and clearly losing the

23   advantage that had been seen here with the Moscow and

24   quite dramatically seeing the change with a number of



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 1   our recent low-reacting strains.

 2                     This Victoria/390 and Brisbane/156 are

 3   strains which we've used as markers when we found that

 4   we had this genetic change in the virus to have a look

 5   and see whether it was having a significant effect.

 6   And it certainly was.              It was certainly causing a

 7   significant reduction in the potence of the antiserum

 8   losing any advantage from putting that strain in the

 9   vaccine.

10                     Next slide.

11                     And, again, when we went on further and had

12   a look at one further reassortment listed here to sera

13   against that reassortant, seeing exactly the same sort

14   of thing.        Even though this virus did not have a dilution

15   in it, it had other mutational changes.                 And so we did

16   not come up with a virus that produced any sort of

17   advantage seen with the original Moscow antiserum and

18   maybe in part the breadth of reactivity of the Moscow

19   antiserum may have due, and this is my speculation, to

20   that being a mixed virus infection at the outset.

21                     CHAIRMAN GREENBERG:         Thank you very much.

22    Roland.

23                     DR.   LEVANDOWSKI:           I've     got    another

24   question, if I can ask it.               The experience with the



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 1   Moscow strain, does that have any significance for

 2   what's being seen with low-reacting strains generally

 3   amongst the H3N2s?       Is that sort of one example of what

 4   may be going on elsewhere?

 5                    DR. HAMPSON:     We haven't seen any evidence

 6   that they mixed in terms of their genetics.                We have

 7   found a couple of strains which clearly are, one

 8   Philippino strain which had a very low reactivity which

 9   clearly had quasi-species in it.               But the others we

10   haven't and, now that you mention it, maybe we should

11   go back and have a look a little more closely at some

12   of those.

13                    DR. LEVANDOWSKI:       Well, I'm just wondering

14   if that's state-of-the-art for H2N3 viruses today.

15                    DR. HAMPSON:     Possible.

16                    CHAIRMAN GREENBERG:        Diane.

17                    DR. GRIFFIN:       I was intrigued with the

18   differences you saw between the cell-grown and the

19   egg-grown viruses.        And the vaccine is grown in eggs

20   and those are egg-grown viruses.           I assume most isolates

21   are probably made in cells.         And are most of the viruses

22   used for testing in these wide variety of tests we're

23   seeing grown in human, I assume these are human, cells?

24                    DR. HAMPSON:     No.    They're MDCK cells for



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 1   a canine kidney cell line that we grow the viruses in.

 2                    DR. GRIFFIN:     They're MDC -- oh, I see.

 3                    DR. HAMPSON:    The interesting thing is that

 4   we retain our reference panels and this is uniform across

 5   the WHO system.        Our reference panels are in-grown

 6   viruses with antisera prepared against those in-grown

 7   viruses because we are using these are the basis for

 8   looking for vaccine strains.

 9                    Unfortunately, the isolates that come to

10   us are cell-grown viruses and sometimes when we go back

11   and reisolate these viruses in eggs because they've

12   looked interesting and looked like a vaccine candidate,

13   we finish up with a virus which is different.                        The

14   receptors on the cells, the MDCK cells, and the receptors

15   on the egg embryo cells are different and there is a

16   receptor-driven selection of influenza viruses.                    This

17   may, in part, explain some of this low avidity reaction

18   that we've seen, that Nancy described.

19                    DR. GRIFFIN:     I guess what I am really most

20   interested in is what the virus is like that's actually

21   from the person before it's isolated.                 You know, just

22   because if there was any possibility that that was

23   somehow different than the vaccine, that that might help

24   explain some of the things we're seeing.                Has anybody



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 1   done direct sequencing prior to isolation?

 2                     DR. HAMPSON:        Yes, they have.              And the

 3   answer is that, generally, what we see in direct

 4   sequencing is viruses that have the same sequence as

 5   the     cell-grown     viruses     rather     than      the     egg-grown

 6   viruses.         And there was a proposal a number of years

 7   ago that, in fact, we should be looking at cell-isolated

 8   viruses as the starting strains for vaccine.                       And, in

 9   fact, there have been a number of meetings on that.

10   It poses a number of regulatory issues which haven't

11   been solved as yet.

12                     CHAIRMAN GREENBERG:          Nancy, you want to

13   answer this specific issue, correct?

14                     DR. COX:    Yes.

15                     CHAIRMAN GREENBERG:         Nancy Cox.

16                     DR. COX:    We have been looking at sequences

17   specifically for host-mediated changes since the late

18   '80s when a lot of the data first came out where isolates

19   were sequenced directly so a clinical specimen was

20   obtained and the HA sequence was sequenced -- was

21   obtained directly from that rather than after isolation.

22                     And so when we look at strains that are

23   candidate strains, we're always keeping in mind what

24   we know about host-mediated selection.                  And when we see



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 1   that a virus that comes out of eggs that has a particular

 2   amino acid difference from the majority of strains that

 3   are circulating, we want to be sure that we don't have

 4   an antigenic difference that's conferred by that change.

 5    This is always taken into account as much as possible.

 6                        CHAIRMAN GREENBERG:           Dr. Kilbourne, is

 7   this directly on point?

 8                        DR. KILBOURNE:      It's directly on the point.

 9                        CHAIRMAN GREENBERG:         Okay.

10                        DR. KILBOURNE:         Because I think a very

11   important consideration comes up here and that is that

12   it is very arbitrary what we define as Moscow/10 or

13   anything else.           Will the real virus stand up?                Because

14   we're dealing in each instance with a heterogeneous

15   quasi-species mixture and, out of our reassortment

16   procedures, we will fish different variants.                             And I

17   think it's hard to say whether those variants which seem

18   to     be        artificants    of   reassortment          are     the     true

19   representative or not.

20                        We go back to wild-type a lot.          What is wild

21   type?        It's a mixture anyway.            So I think it's, well

22   not to overemphasize these differences unless we really

23   show they're antigenically significantly different.

24                        CHAIRMAN GREENBERG:          Okay, last question



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 1   is Dr. Couch.

 2                     DR. COUCH:     Alan, that was a great deal of

 3   data in a big hurry.          And between last night at 11:00

 4   getting this and what you said, it's a little trouble

 5   here.        Will you tell me, remind me, if Australia has

 6   had H3N2, or the Southern Hemisphere, H3N2 epidemics

 7   three years in a row as we did?             And what your thoughts

 8   are about A/Moscow, low-reactivity strains and low

 9   aggregation as being a reasonable explanation for our

10   third year in a row.

11                     DR. HAMPSON:      Yes, we've had A/Sydney for

12   three years in a row.           The outbreak this year was not

13   quite so significant as the previous years.               Last year

14   was a very serious outbreak.             This year was a moderate

15   outbreak.        And the preceding year we did have A/Sydney

16   in the population.         It was mixed at that stage with the

17   previous strain A/Nanchang.

18                     I'm perplexed by why we've had this virus

19   repeatedly in the population.               I don't understand it

20   and we're still trying to come to terms with our findings

21   here with these low-reactive strains and exactly what

22   is contributing to this.            It's far more dramatic than

23   we have seen in the past, but it's more dramatic than

24   what Nancy is seeing and so there's clearly some



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                                                                                  94

 1   difference in our surveillance or our test system which

 2   is throwing this up a little more than she is seeing

 3   at CDC.

 4                        CHAIRMAN GREENBERG:          Okay.       I'd like to

 5   move on to Dr. Zambon.                And, Dr. Zambon, again, as

 6   expeditious as you can be.

 7                        DR. LEVANDOWSKI:       Dr. Maria Zambon is from

 8   the Public Health Laboratory Service in London.                            And

 9   I think you probably have seen in the news that London,

10   and England in particular, have been having a fairly

11   severe           influenza   season.        And    we      would   be    most

12   interested to know about what's happening there.

13                        DR. ZAMBON:       Thank you very much.              Just

14   like in the United States, in the United Kingdom, we

15   have a number of different measures of influenza

16   activity.           The one that we pay most attention to is based

17   on     sentinel        physician     recording       from     a    sentinel

18   physician network, which is based on monitoring some

19   800,000 to 1 million people in the United Kingdom and

20   new episodes of influenza-like illness are recorded.

21                        This is described as the RSGP, standing for

22   the Royal College of General Practitioners, weekly

23   consultation rates for influenza and influenza-like

24   illness.           Shown here is the last 10 years index and you



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                                                                               95

 1   will see that, in the United Kingdom, the way in which

 2   we describe our influenza activity could be described

 3   as arbitrary in some ways, but I hope you will see what

 4   I mean when I describe a little bit further.

 5                     We know that our baseline for influenza runs

 6   to round about 50.             And we describe anything in the

 7   consultation index below 50 per 100,000 as baseline

 8   activity.        Anywhere between 50 and 200 we describe as

 9   normal seasonal activity in that we recognize influenza

10   circulates every year.             Somewhere between 200 and 400

11   we describe as higher-than-expected seasonal activity.

12    And anywhere that's greater than 400 we describe as

13   epidemic activity in order to reflect a severe year's

14   worth of influenza.

15                     The last time that we had a very serious

16   influenza epidemic in the United Kingdom was the season

17   for 1989-1990, which is also recognized worldwide as

18   being a very severe influenza season.                       This year,

19   1999-2000,        we     would     describe       what    we    saw       as

20   higher-than-expected seasonal activity.                   And this peak

21   here, which is now on the downturn, is probably a slight

22   underestimate in that some of the figures obtained were

23   obtained over the Christmas period.

24                     Next slide, please.



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                                                                         96

 1                    The GP practices involved in influenza

 2   community surveillance, some of those GP practices which

 3   do the influenza monitoring clinically also submit swabs

 4   to us and they are a very valuable source of isolates.

 5                    Next slide, please.

 6                    The distribution of those GPs reflects the

 7   major urban areas and the population density.           The thing

 8   that we can say for this year, which is a reflection

 9   of some of the press activity that you may have heard

10   about, is that the major consultation index, major

11   consultations took place or the peak of consultations

12   took place in the elderly, which is a reflection,

13   therefore, probably, of impact on the health care system

14   and hospital bed utilization.

15                    Importantly, when we look at the isolates,

16   our isolates are derived either from community sources

17   or from hospital sources, about half and half, and we

18   see different distributions.             The hospital isolates

19   come primarily from the elderly or young children,

20   whereas the community isolates come from the bulk of

21   the population, that is the young and middle-aged.

22                    Next slide, please.

23                    Our death data -- this is as up-to-date as

24   we have -- suggests that we have, so far, a very similar



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                                                                             97

 1   season to last year, which was reasonably severe in death

 2   terms.           We estimate in the United Kingdom that there

 3   are some 10,000 to 12,000 excess deaths associated with

 4   an H3N2 season every year.             And last year, as you know,

 5   was an H3N2 season.            This year, so far in the United

 6   Kingdom, it has been exclusively H3N2 and our death data

 7   look very similar to last year.

 8                       Next slide.

 9                       Now I won't spend too much time on this

10   because many of the points have already been made.                      We

11   see our viruses really, the majority of them, react

12   reasonably well with Sydney/5, although we do have some

13   low reactors.           In general terms, where we have used

14   Moscow/10 antiserum, we see slightly better reactivity

15   with the Moscow antiserum, but maybe not enough to make

16   a substantial amount of.

17                       Next slide, please.

18                       The proportion of isolates with decreased

19   reactivity, those fourfold or less to Sydney, has stayed

20   relatively constant, I think, over the portion of the

21   season that we've analyzed so far, and is rather similar

22   to the proportion that we saw last year.

23                       Next slide, please.

24                       And, in sequence terms, the only reason for



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                                                                          98

 1   my showing you this is to perhaps point out, we've had

 2   a bit of discussion from the panel, the question of

 3   vaccinated individuals who subsequently go on to develop

 4   influenza.       I'd just like to draw your attention here

 5   to this strain, England/650/99, which has come from a

 6   vaccinated individual.

 7                    The only point that I would note here is

 8   that we do have an additional creation of a potential

 9   glycosulation which makes that virus slightly different

10   to the others that we've looked at this season.                    But

11   we have actually seen that virus strain circulating from

12   individuals who have not been vaccinated.              We saw that

13   at the end of last season.           So it makes the point very

14   nicely that the viruses that you recover from vaccinated

15   individuals, at least as far as their HA1 is concerned,

16   may not be any different to what's seen circulating in

17   the population.

18                    Next slide.

19                    And, indeed, when we look at our viruses,

20   they are clustered very closely together and closely

21   with other viruses that we saw towards the back end of

22   last season.

23                    Next slide.

24                    We've had three Influenza B strains so far,



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                                                                                  99

 1   all of which have come in late December or early January.

 2    And the HI data are, therefore, not what I'd describe

 3   as robust in the sense that there's only been one HI

 4   test.            We see, in general, that the viruses are

 5   Beijing-like, although this most recent virus in this

 6   single HI test shows a slightly reduced reactivity to

 7   the Beijing/184 and the B/Yamagata serum.

 8                       Next slide, please.

 9                       Although when we actually look at the

10   sequence analysis, we can see no reason why that should

11   be particularly.

12                       Next slide, please.

13                       So, in summary, for the United Kingdom

14   influenza surveillance, we've had widespread influenza

15   activity           over     this      last     season.         We've       had

16   predominately H3N2 strains circulating.                      Our clinical

17   activity is all related to H3N2.

18                       We've had one imported case of H1N1, which

19   came from a lady who'd returned from a cruise in the

20   Caribbean.          And we would actually describe this as a

21   New Caledonia-like strain, although we cannot get at

22   it genetically for various technical reasons.

23                       The       majority       of     our      strains       are

24   Sydney/5-like and we see a small percentage with reduced



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                                                                               100

 1   reactivity to A/Sydney/5 with a fixation of some

 2   mutation as compared to our '98 and '99 viruses.                          And

 3   we clearly do not have any molecular correlate for the

 4   low-reacting strains that we see.               We've had the recent

 5   onset of Influenza B circulation and a relatively small

 6   number of Influenza B viruses have actually been

 7   assessed.         And I'll leave it at that.

 8                      CHAIRMAN GREENBERG:         Thank you very much.

 9    Roland.         Dr. Faggett.

10                      DR. FAGGETT:     Yes.     In your data, your 1998

11   experience appeared to be below normal.                      How do you

12   account for that dip in your numbers?                Was it increased

13   immunizations or --

14                      DR.   ZAMBON:        Sorry,     I'm      not    sure      I

15   understood the question.             1998 and 1999.

16                      DR.   FAGGETT:          Your     chart         shows      a

17   below-normal incidence of influenza.                     Did I read that

18   correctly?

19                      DR. ZAMBON:     No, that's not -- you mean for

20   the '98-'99 season?

21                      DR. FAGGETT:      Right.

22                      DR. ZAMBON:      No, that's not correct.

23                      DR. FAGGETT:      That dip in '98.

24                      DR. ZAMBON:      That's the '97-'98 season.



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                                                                          101

 1                    DR. FAGGETT:     Right, okay.

 2                    DR. ZAMBON:    So this is the '98-'99 season.

 3                    DR. FAGGETT:     Right.     Okay.     Right.      That

 4   dip.        How do you account for that?              That's a very

 5   significant dip.

 6                    DR. ZAMBON:     We had very little influenza

 7   circulating in that year.          And, if I recall correctly,

 8   that was predominately an Influenza B season.

 9                    DR. FAGGETT:      So there was no increased

10   immunization or anything like that?

11                    DR. ZAMBON:     No.    Rather like the United

12   States, we've seen a progressive increase in the amount

13   of vaccine put out, but what is clear in the United

14   Kingdom is that we do not necessarily have data about

15   how well vaccine is targeted to the at-risk populations.

16    And where that has been looked at, we have some very

17   disappointing figures to suggest that the at-risk

18   population only 40 to 50 percent of those are actually

19   receiving vaccines.        So even though a lot of vaccine

20   is going out, it's not necessarily getting to those that

21   most need it.

22                    DR. FAGGETT:       Yes.      We have that same

23   experience.

24                    CHAIRMAN GREENBERG:        Okay.     If there's no



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                                                                           102

 1   other questions, we'll move on to the last speaker before

 2   the break and that's Dr. Nerome.

 3                      Dr. Nerome, Roland will introduce you in

 4   a second, but, again, 10 minutes.

 5                      DR.   LEVANDOWSKI:         Okay.      Dr.   Kuniaki

 6   Nerome is from the Laboratory of Respiratory Viruses

 7   at NIH in Tokyo.         And, as you heard, they've had quite

 8   a different experience there this year, with H1N1

 9   viruses, from most of the rest of the world.                   And we'd

10   very much like to hear that information.

11                      DR. NEROME:      If possible, I would like to

12   express to Dr. Levandowski from FDA and Dr. Nancy Cox

13   from CDC thanks for their invitation to attend this

14   important meeting and present influenza activity in

15   Japan.

16                      May I have my first slide, please.

17                      In Japan, co-circulation of the H3N2 and

18   B viruses were repeated this sick season.                 This is the

19   first half was Hong Kong and second half was the B

20   viruses.         The end saw a small peak caused by the B virus

21   Victoria-like strain.             So, in Japan, two types of B

22   viruses coincided in the second half of the season.

23                      Next slide, please.

24                      This is the total number of virus isolated



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                                                                                  103

 1   last season in Japan.             9,373 viruses isolated in Japan

 2   in last season.           They are divided into three antigenic

 3   groups.          The first one with H1 subtype.            There are 1.13

 4   percent.          The second type H3N2 viruses, corresponding

 5   to 57.2 percent.             The third type are the B viruses.

 6   The       diversity       divided       into,      evolutionary,             the

 7   Yamagata-like lineage.               So, only in Japan, two types

 8   of unrelated viruses co-circulated last season.                                In

 9   this season, this was a quite different.

10                       Next slide, please.

11                       And you are looking at this visual of a B

12   virus strain.           This indicate as two viruses in different

13   parts of the west part of Japan, the center of a part

14   of     Japan       in   Hokkaido.         And    this      red     indicates

15   co-circulating H3N2 and H1N1 viruses, but only two

16   prefectures isolated the H1N1 viruses.

17                       Next slide, please.

18                       And this is the original H1N1 and H3N2.

19   And co-circulating, H3N2, H1, and B viruses.                          You can

20   see here, Japan experienced co-circulation of the H3N2

21   and H1N1 viruses.

22                       Next slide, please.

23                       This is a number of virus in isolation

24   reported at weekly intervals.                You can see here strains



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                                                                            104

 1   started          in   isolation     with    H3N2     viruses   here      in

 2   mid-October, like this.              You see here a sharp increase

 3   in the number of virus isolation H3N2 viruses.                           In

 4   parallel, H1N1 were also isolated in many parts of Japan

 5   country here.           You can see here a co-circulation with

 6   H1N1 and H3N2 viruses.              Co-circulating only in Japan.

 7                         Next slide, please.

 8                         This is a table explaining of the H1N1

 9   viruses.         You can see a HI index showing titer of 640.

10    On the basis of this HI pattern, please look down here.

11    Most of the viruses, you have the high titer 160.                   This

12   is the Hiroshima strain.                And the Nagoya strain also

13   you have the high titer to 160.               In several strains here

14   you can see a 40, 20, and 80.                And a Beijing antiserum

15   inhibited very weakly these second virus here.                   You can

16   see      here     there's     two    type    of    antigenic   variants

17   co-circulating in Japan.

18                         Next slide, please.

19                         I can summarize here, because the letters

20   are very small, very hard to see the small letters.

21   This is variant.            They have the high titer to Beijing

22   strain.          And it is saying that this may be belonging

23   to a Beijing-like variant.              And the second is Sendai-H.

24    Sendai-H is in Chiba strain.                You have the high titer



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                                                                            105

 1   to Beijing and Chiba belonging to a distinct antigen

 2   group.

 3                      Next slide.

 4                      There we have sequencing of 10 strains here.

 5    On the basis of the antigen sequencing, Beijing/262

 6   strain like this.           This is New Caledonia strain.              One

 7   amino acid difference between the Beijing like this.

 8    Only one amino acid.              And this is the Bayern/07/95

 9   strain.          There are 12 to 13 amino acid differences

10   between them.           These amino acid differences only

11   molecules belonging to antigenic site A and B.

12                      This is changing of H1N1 viruses because

13   here a changing of viruses has evolved since 1998 two

14   crossed like this.              This recent Japanese variant

15   belongs to indicated by New Caledonia-like strain.                     For

16   example, this first variant belongs to Japanese New

17   Caledonia-like          strain.         And     this     indicates         a

18   Beijing-reactive strain.              The remaining strains are

19   similar evolutionarily to the B/Beijing-like strain.

20                      This is H3N2 viruses you can see here.              The

21   majority         of   the   H3N2     viruses      are    reactive        to

22   Chiba-reactive strain.

23                      And only one strain

24                      I'll summarize here.          Japanese have seen



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                                                                                 106

 1   two viruses, separating into two distinct other groups.

 2    The first one reacted to the -like strain like this.

 3    Chiba and inhibited it weakly, this strain. And the

 4   second group you can see here, Osaka and Hiroshima

 5   Yamagata, reacting to high titer reactive strain here.

 6                       And now this is a second group of the antigen

 7   variant, Fukushima and Sendai/H and Yoshima/H.                              and

 8   Chiba were inhibited very weakly against strain like

 9   this.        And this to Sendai/H reacted with high titer to

10   -like strain.

11                       We    also    completed      a   analysis       of    this

12   Sydney-like strain and another variant, Moscow like

13   this.        The six differences you can see here.                  And this

14   is constructed from HA genes here.                          Our indicator,

15   Moscow-like strain, branched across it here.                                The

16   second one, strain.              They are distantly related to each

17   other.           The majority of this strain belonged to this

18   branch, indicating it is a Moscow-like strain.

19                       This is the only one B viruses isolated in

20   Japan.           This is a Shangdong and Beijing were not

21   reactive to this.              But this is one of the varieties

22   reactive with a high titer to Beijing like this.                              It

23   is interesting that --

24                       This is also comparing and Yamagata and



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                                                                                 107

 1   Yamanashi          and     Shangdong-like         strains.           Between

 2   Shangdong-like strains, two obvious differences can be

 3   seen here between Yamanashi and Yamagata strains.

 4                      This is also then the          You see Beijing here.

 5    You see Yamanashi.                 You see Shangdong-like strain

 6   here.       They    are     quite      different     from     each     other.

 7   Shangdong-like branch indicator, belongs to a different

 8   evolutionary lineage.

 9                      In conclusion, our total number isolated

10   around 278 strains were isolated in Japan.                      H1 is 731,

11   corresponding to 57.3 percent.                  H3 is 546 isolated and

12   B only one.

13                      In conclusion, as a result of what we

14   followed up with virological surveillance, a total 1,278

15   viruses were isolated in Japan in this season.

16                      Second,        of    the    total        isolated,       731

17   corresponded to 57.3 percent was identified and they

18   were separated into two distinct antigenic groups.                          The

19   first variant was similar to the A/Beijing/262.                             And

20   the second variant was indistinguishable from A/New

21   Caledonia/29/90 strain.                This result suggests to us to

22   change H1N1 vaccine strain from A/Beijing/262 to current

23   epidemic strains such as A/New Caledonia strain.

24                      Third, the rest of 546 corresponding to 42.7



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                                                                                108

 1   percent were H3N2 viruses and 93.5 percent of them were

 2   A/Sydney/5/97-like              variant.         I   am     wondering        if

 3   Sydney/5/97 viruses will still cause outbreak as a major

 4   epidemic strain in the forthcoming winter months.

 5   Having considered, we may cancel A/Sydney/15/97 as a

 6   vaccine strain and consider the use of current epidemic

 7   strain in 2000-2001 season.

 8                        Fourth, regarding the vaccine strain of

 9   Influenza           B    viruses,     we    need,      Japanwide,        more

10   information because we isolated only one strain in the

11   season.

12                        Finally,     H5N1     and    H9N2      viruses     still

13   co-circulate in poultry and wild birds in Southern

14   China.           Additionally, co-circulation of H9N2, classic

15   swine H1N1, and human H3N2 viruses in swine population

16   in Southern China suggest to us that influenza in the

17   world in the 21st century may encounter the crucial

18   issue.

19                        Thank you very much.

20                        CHAIRMAN GREENBERG:          Thank you very much,

21   Dr. Nerome.             Roland, do you have any questions?                 Are

22   there any questions of the panelists for Dr. Nerome.

23    If not, we'll take a break.                 And I'm going to try to

24   catch up a little bit here, so I would like for all of



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                                                                                109

 1   you to be back at -- it's now 10:34 by my watch.                        10:50

 2   I'd like you to be back and Roland will start.

 3                    (Recess.)

 4                    CHAIRMAN GREENBERG:            Okay.         I'd like to

 5   continue with Dr. Levandowski talking to us about

 6   vaccine responses.

 7                    DR. LEVANDOWSKI:           Okay.        Thank you, Dr.

 8   Greenburg.

 9                    Some of the material I'm going to cover has

10   been      mentioned     in   passing      in   some      of    the      other

11   presentations.         I'd like to point out that we haven't

12   really gotten all of the information that we would like

13   to have and, as was pointed by Nancy Cox, there are some

14   serologic studies that I don't have reflected in the

15   material that's been handed out only because that

16   information is so new.            We tried to do the best we can

17   to have as much up-to-date data as possible.

18                    CHAIRMAN GREENBERG:           Hold on.       People with

19   cell phones are in big trouble.

20                    (Laughter.)

21                    Especially if they're FDA staff.

22                    (Laughter.)

23                    DR. LEVANDOWSKI:         Okay.     So I'll continue.

24    I'm going to talk about the 1999 vaccine studies.                         For



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                                                                              110

 1   the convenience of the committee and anybody who has

 2   one, the handouts include all the overheads that are

 3   going to be used to present the serologic responses.

 4    What I'm going to try to do is to summarize the

 5   information that's contained in materials that have come

 6   from a number of different sources and have been provided

 7   for committee review.

 8                        I should point out that the serologic data

 9   do     reflect       this   ongoing      very    major     international

10   collaborative effort.             And it's greatly facilitated and

11   largely possible because of the commitment by the World

12   Health           Organization    and   its    influenza      centers       to

13   collecting information.

14                        If we can go to the first overhead, it should

15   be page two in the handout.                  This overhead shows the

16   serum panels that are used for the serologic studies,

17   which include three separate sets of serum panels from

18   adults and elderly in Australia, Europe, and the United

19   States.           The vaccines used for immunization are shown

20   on the table, I hope.

21                        And I call your attention to the vaccine

22   that was used in Australia, which includes as the B

23   component B/Harbin/07/94.                Data for the Influenza B

24   viruses for the Australian sera are being presented



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 1   since they provide quite a lot of information that's

 2   very similar to the data from vaccines containing the

 3   B/Yamanashi/166/98 strain.

 4                    The       laboratories          participating           and

 5   performing       the     serologic      testing      include     the     WHO

 6   Influenza Center in Melbourne, Australia; the National

 7   Institute for Biological Standardization and Control

 8   in     London;    the      Centers     for     Disease      Control      and

 9   Prevention in Atlanta; and the Center for Biologics

10   Evaluation and Research in Bethesda.                      The labs share

11   these sets of sera, as shown, and it accounts for

12   approximately 175 serum pairs.

13                    Next overhead, please.               This is on page

14   three; it should be.

15                    This slide shows the H1N1 antigens that were

16   used for serologic testing for the material that are

17   presented.       Not every one of these antigens was used

18   by all the laboratories, but they were used in different

19   places to try to explore a variety of new antigens.

20   A core of the antigens is, however, tested in each of

21   the laboratories and that's used as a comparison between

22   the     laboratories        since    there     are   known     technical

23   differences between each of our labs in terms of

24   serologic testing.



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 1                       The serologic studies have been performed

 2   in two separate campaigns coinciding with the World

 3   Health Organization recommendations for the Southern

 4   Hemisphere         in     September       of   1999    and    the   current

 5   evaluation of influenza viruses.                      The antigens shown

 6   include representative strains for both of the H1N1

 7   lineages that are circulating and it includes strains

 8   related to the A/Beijing/262 strain, which is the

 9   current vaccine strain and the A/Bayern/07/95-like

10   strains.

11                       Next overhead, which is page four.

12                       This overhead shows results obtained in

13   September          1999      from     two      of   the      participating

14   laboratories using a panel of sera from elderly in

15   Europe.          The table includes data on geometric mean

16   titers; the percent greater than or equal to 32 or 40

17   for the titers; and the percent fourfold rises.                            The

18   data that are shown here are from the Center for

19   Biologics at the top and from WHO Melbourne at the

20   bottom.          And the vaccine strain was A/Beijing/262/95.

21                       The vaccine used was immogenic and it

22   produced         homologous       antibody      responses.          In    this

23   particular         instance,        the   A/New     Caledonia       and    the

24   A/Nanchang         are     A/Beijing/262-like          strains      and    the



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                                                                            113

 1   A/Johannesburg is a Bayern/07/95-like strain.                   In both

 2   cases, the A/Beijing/262 vaccine produced antibodies

 3   that cross-reacted well with the Johannesburg strain.

 4    However, the other Beijing/262-like strains were not

 5   well-inhibited by the sera produced in response to the

 6   vaccine antigen.        In both of these instances, there was

 7   a reduction in the geometric mean titer of more than

 8   50 percent.

 9                    Next overhead, which is page five.

10                    This   overhead     shows      results    that      were

11   obtained in January of this year from two of the

12   laboratories using a panel of sera from adults in Europe.

13    These data are from NIBSC at the top and from CDC at

14   the       bottom.       The    vaccine        strain,     again,       was

15   A/Beijing/262/95.               A/New     Caledonia;         A/Madrid;

16   A/Wisconsin;        A/Nanchang;         and     A/Peru       are       all

17   A/Beijing/262-like strains.             And A/Johannesburg -- and

18   I hope I'm right on all these because I'm a little

19   confused myself -- A/Hong Kong; and A/Argentina are

20   Bayern/07/95-like strains.

21                    Again, the vaccine elicited good responses

22   to the vaccine antigen and to the A/Bayern-like strains,

23   but the response to the new A/Beijing/262-like strains

24   was reduced by more than 50 percent in most of the



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                                                                            114

 1   instances.

 2                      Next overhead, which is page six.

 3                      Moving on, this slide shows the Influenza

 4   B viruses that were used for serological testing.                      The

 5   antigens shown include representative strains for both

 6   of the B lineages that are circulating and includes

 7   strains          that    are    related      to    B/Harbin/07/94        or

 8   B/Yamanashi/166/98, the vaccine strains.                   And to the

 9   B/Victoria/287-like strains.                For the most part, these

10   serologies have been done with ether-treated Influenza

11   B antigens, but there are some exceptions but I'm not

12   going to go into that on these slides.

13                      Next overhead on page 7.

14                      This overhead shows the results that were

15   obtained in September '99 using a panel of sera from

16   adults in Australia.             The data are from CBER at the top

17   and from the World Health Organization, Melbourne, at

18   the bottom.             The data demonstrate that the current

19   vaccine strain produces antibodies at somewhat reduced

20   titers for some of the newer B/Yamanashi-like strains.

21    For the B/South Australia strain, for example, there

22   is more than a 50 percent reduction in titer shown as

23   compared to the vaccine or vaccine-like strain.

24                      In addition, as has been previously seen



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 1   for several years, the antibody titers are extremely

 2   low against the newer B/Victoria-like strains, such as

 3   B/Shangdong/07/97 and B/Sichuan/40/99.

 4                           Next overhead which is page eight.

 5                           This    overhead     shows      results       that   were

 6   obtained in January of this year using a panel of sera

 7   from adults in the United States.                           The data are from

 8   CDC at the top and from the WHO Melbourne at the bottom.

 9    These           data    demonstrate        that      the    current    vaccine

10   produces antibodies that cross-react reasonably well

11   with       other        new     B/Yamanashi-like            strains    such     as

12   B/Tennessee/4/99                and     B/Shanghai/180/99.             However,

13   antibody titers are reduced by more than 50 percent

14   against the B/Shenzhen/654/99 strain, which, again, is

15   in the same lineage as the current vaccine stain,

16   B/Yamanashi/166.                And I think you can see that in both

17   of these serum panels, that there's a fairly marked

18   reduction for that particular strain.

19                           Next overhead, which is page nine.

20                           This    overhead     shows      results       that   were

21   obtained, again, in January of this year using a panel

22   of sera from the elderly in the United States and the

23   data are from the CDC at the top and from the Center

24   for      Biologics         at    the      bottom.       The     data,    again,



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 1   demonstrate          the     current      vaccine      strain       produces

 2   antibodies that cross-react reasonably well with many

 3   of     the       newer   influenza      viruses      that     are    in     the

 4   B/Yamanashi lineage. But, in the CDC data, again, you

 5   can see that the titers for the B/Shenzhen/654 virus

 6   are markedly reduced as compared to the vaccine strain.

 7                       We're going to skip over page 10.                    Go to

 8   page 11.

 9                       This overhead shows the H3N2 influence

10   viruses used for serologic testing.                         And, actually,

11   this doesn't even show all the viruses that have been

12   used, but I included most of them here.                       The antigens

13   chosen, again, are currently circulating strains that

14   are representative of these A/Sydney/5/97-like strains

15   that are the current vaccine strain and also strains

16   that appear to be less well inhibited by ferret antisera

17   raised against the A/Sydney strain.

18                       I think we'll skip over to page 13.                     And

19   this overhead shows results that were obtained in

20   January of this year using a panel of sera from elderly

21   in the United States.              The data are from the Center for

22   Biologics at the top and from WHO Melbourne at the

23   bottom.          And what they show is that the responses to

24   the newer H3N2 strains were, for the most part, similar



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                                                                       117

 1   to the vaccine strain.          However, a notable exception

 2   to this is, for the A/Philippines -- and I guess I've

 3   got a typo there.          I think this is supposed to be

 4   "'99" -- that the A/Philippines/26/99 strain shows a

 5   very marked reduction which is more than twofold in the

 6   test that was done at WHO in Melbourne.

 7                    Next overhead, which is page 14.

 8                    This overhead shows results, again, that

 9   were obtained in January of this year using a panel of

10   sera from adults in Europe and the data are from CDC

11   at the top and from NIBSC at the bottom.              These data

12   demonstrate reductions in titer against some of the

13   newer viruses, including the A/Moscow/10/99 strain; the

14   A/Shanghai/42/99 virus; and the A/Panama strain.                  The

15   data from NIBSC also indicate that there are good

16   antibody titers against the A/Shenzhen/510/99 strain.

17                    Okay, skip ahead to page 16 and I'll try

18   to put this into a summary form.            The following tables

19   show the frequency with which we found new test antigens

20   given a 50 percent or greater reduction compared to the

21   current vaccine strain.         50 percent is used here as an

22   arbitrary breakpoint since it does represent a twofold

23   reduction, which in geometric mean titer terms is fairly

24   substantial.



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 1                          The data included in this table are for

 2   antigens that were tested in more than one lab where

 3   possible, but antigens that were tested in a single lab

 4   are included where they are of particular interest.

 5   I've not included everything that's been done here.

 6   It should be noted that not all of the testing has been

 7   completed, so there are, obviously, some holes in some

 8   of these tables we're going to see.                    In this particular

 9   table,           the    antigen     at   the     top    is    one   of     the

10   Bayern/07-like             strains       and    all    the    others       are

11   Beijing/262-like strains.

12                          I'd just like to call your attention to the

13   last columns here, for the moment, although you can look

14   at the individual data as well.                    But the data for the

15   Johannesburg strain indicates that that strain was quite

16   well-inhibited by antisera in all of the tests that were

17   done from sera that were collected using current vaccine

18   strains.           Somewhat paradoxically, if you look at all

19   the A/Beijing/262 lineage viruses, including the A/New

20   Caledonia; the A/Nanchang; A/Peru; A/Wisconsin; and

21   A/Madrid, on average there were reductions that were

22   greater than 50 percent overall, as shown at the end,

23   here.            And,    in   some    instances,       they    were      quite

24   substantial, in some of the serum panels that were



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                                                                            119

 1   tested.

 2                    Next overhead, please, which is page 17 in

 3   the handout.

 4                    This slide shows summary data for the

 5   Influenza B viruses.          The top two strains here are

 6   B/Victoria-like strains.          The bottom six strains are

 7   like the vaccine strain B/Yamanashi.                  Some of these

 8   B/Yamanashi-like        viruses        appear         to    be       less

 9   well-inhibited by sera from persons who have been

10   immunized with the current vaccines.              However, many of

11   the strains do not appear to be well-inhibited at all,

12   which suggests that some antigenic drift may be going

13   on.

14                    And I just call your attention to some of

15   theses strains that have been tested in multiple

16   laboratories.       In particular, the B/Shenzhen/654/99,

17   which Nancy Cox mentioned as being a new variant virus.

18    As expected, the B/Victoria lineage viruses were not

19   well-inhibited by the current vaccines and there's more

20   uniformity in finding, really, the most marked reduction

21   in antibody titers for those strains as compared to the

22   vaccine strain.      That's not news; that's what we've been

23   seeing over the last several years.

24                    Next overhead on page 18 will show summary



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 1   data for the H3N2 viruses.                  All of these strains are

 2   related to the Sydney vaccine strain, but the table

 3   includes           some     of     the     strains       that       are      less

 4   well-inhibited by ferret sera A/Sydney.                              The most

 5   marked           reductions       in     this    table       are      for      the

 6   Shanghai/42/99 strain and for the A/Philippines strain.

 7    In both of those instances, there's a substantial,

 8   greater than 50 percent, reduction in titer.                            But you

 9   can see that there's sort of variability amongst these

10   strains from really not much reduction in the tests that

11   have been done so far to really quite marked reduction.

12                        Okay, so slides off.           So, in summary, the

13   vaccines that were used for the clinical studies were

14   immunogenic in the populations tested.                       And for all of

15   the three vaccine component strains, there is some

16   evidence of antigenic drift, which is probably most

17   notable or most obvious for the H1N1 virus strains, which

18   represent drift variance, I guess, or drift of a sort

19   from the current vaccine strain.                     As we've known for

20   several years, the B/Victoria lineage persists and the

21   current vaccines are probably of limited protection

22   against those strains.

23                        And that's all I've got to say.                 I'll stop

24   there.           I hope we're getting back on time.             And if there



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 1   are any questions, I'll be happy to try to answer them.

 2                     CHAIRMAN GREENBERG:         Panel members, do you

 3   have any questions for Roland?                Okay, if there are no

 4   questions, we will move on to availability of strains

 5   and reagents by Mr. Offringa.

 6                     MR. OFFRINGA:       If I could have the first

 7   overhead.

 8                     I'm just going to give a brief overview of

 9   the vaccine strains, current candidate strains, and

10   potency reagent availability.             I'll start with the H1N1

11   strains.            The       current      vaccine       strain         is

12   A/Beijing/262/95.          The reassortant used for vaccine

13   production is X-127, which has a high-yield growth

14   character.

15                     There is one H1N1 candidate strain which

16   is     A/New     Caledonia/20/99.         This    is    also   in     the

17   Beijing/262        lineage.       There    are    two   reassortants

18   available for New Caledonia:              IVR-116 and X-139.          The

19   IVR-116 has a moderate-to-high yield growth character

20   and the X-139 has a moderate yield growth character.

21    The IVR-116 reassort is currently being used to produce

22   vaccine for the Southern Hemisphere.

23                     I'll continue with the B strains.                   The

24   current B vaccine strain is B/Yamanashi/166/98, which



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 1   is in the Yamagata lineage.           Influenza B reassortants

 2   are not available, so the wild-type strain is used for

 3   vaccine production and this wild-type strain has a

 4   moderate yield and growth character.            There's currently

 5   one candidate strain distributed to manufacturers,

 6   which is B/Johannesburg/5/99, also in the Yamagata

 7   lineage.         Unfortunately,      all     manufacturers      have

 8   experienced a very low yield with this strain.

 9                    And I'll continue with the H3N2 strains.

10    The current vaccine strain is A/Sydney/5/97.                  There

11   are two reassortants being used for vaccine production:

12    IVR-108 and RESVIR-13.           Both of these reassortants

13   have a moderate-to-high yield growth character.

14                    We also, again, have one candidate strain

15   distributed to manufacturers, the A/Panama/2007/99,

16   which is a Sydney-like strain.                There are several

17   reassortants distributed to manufacturers:             the NIB-41

18   and NIB-42.      Both of these strains exhibit a moderate

19   yield growth character.           And then we have recently

20   isolated two Panama reassortants in our laboratory:

21   RESVIR-16 and RESVIR-17.           We are going to distribute

22   these to manufacturers next week and hope to get some

23   information on their growth character shortly.

24                    I'll move on to availability of potency



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                                                                           123

 1   reagents.          For   all    current    vaccine      strains,      the

 2   Yamanashi/166/98; A/Beijing/262/95; and Sydney/5/97,

 3   we have reagents available.                We are currently also

 4   distributing New Caledonia IVR-116 reagents from the

 5   Therapeutic Goods Administration in Australia, which

 6   are being used for testing of Southern Hemisphere

 7   vaccine.         And our IVR-116 reagents will be available

 8   by February.         If any other strains are chosen, those

 9   reagents would not be available until May at the

10   earliest.

11                     If there are any questions?

12                     CHAIRMAN GREENBERG:          Thank you very much.

13    Panel have any questions?             Okay.    We're moving on to

14   manufacturers' comments and this is Dr. Slusaw.

15                     DR. SLUSAW:      Thank you.     Roland noted I had

16   30 seconds so that he could get the agenda back on track.

17                     (Laughter.)

18                     I don't envy the task before the committee

19   today of selecting the strains for the next influenza

20   vaccine season.           It's really, I guess, all about

21   balancing and trying to find the best antigenic match

22   for the strains you anticipate will be circulating

23   during the next season, yet selecting strains that also

24   have appropriate growth characteristics so that they



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 1   are practical to use to make vaccine.                    And also doing

 2   that selection in a timely fashion which allows the

 3   manufacturers time to produce the required vaccine

 4   within the timeframe that it's needed.

 5                     There are several critical key pieces of

 6   the puzzle that have to fit together to support vaccine

 7   manufacturing.         The first is egg supply.            In the U.S.,

 8   the flu vaccine manufacturers probably consume about

 9   a half million eggs per day during a six-to-eight month

10   period while the monovalent concentrates are being

11   manufactured each season.              The good news is that this

12   is a pretty predictable process and we have a fine-tuned

13   and robust system in place that ensures the availability

14   of embryonated eggs for vaccine manufacturing.

15                     Something that we're talking about a little

16   bit more today is selection of seed viruses and also

17   another component of that, preparation of high-growth

18   reassortants.         And it would not be possible to produce

19   the numbers of doses we talked about for last year, for

20   example,         80   to   90     million       doses,    without       the

21   availability of high-growth reassortants prepared by

22   Dr. Levandowski's and Dr. Kilbourne's laboratories as

23   well as laboratories in Europe and Australia.

24                     And then, finally, the third critical piece



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                                                                                    125

 1   is the availability of the potency test reagents.                           Until

 2   we     have       prepare      the       reference    antiserum        and     the

 3   reference           antigen        and     those     reagents      have      been

 4   calibrated, we have several disadvantages.                         One is that

 5   we don't know precisely the amount of vaccine we're

 6   manufacturing.              Although we can estimate that number,

 7   it can be off by quite a bit.                      So we run the risk of

 8   producing too much or not enough of a particular

 9   component.           And, of course, until we can measure the

10   potencies, we can't formulate the trivalent vaccine so

11   the rest of that process is dependent on having the

12   potency test reagents completed.

13                        A bit of a timeline to illustrate a normal

14   flu vaccine manufacturing season, if there is any such

15   thing.           Generally the process begins about a year in

16   advance when the egg suppliers order their birds to

17   support the egg supply for the following vaccine season.

18    These           pullets     are    housed     usually        in   October       or

19   November, and this is really the only time during the

20   year when an egg supply is not available.

21                        An ongoing process that usually begins

22   sometime in fall and continues through the early part

23   of the year is receiving candidate seed viruses.                             And,

24   kind of in parallel with that, the preparation of



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 1   high-growth reassortants.               Now this is, of course, one

 2   of the first stages where surprises can come up and

 3   things can begin to go wrong.                An example is what we've

 4   heard this morning with the A/Moscow reassortant, for

 5   example.         There's a bit of black magic involved and

 6   things don't always turn out as expected.

 7                     The manufacturers hope to come away from

 8   this meeting with at least the first strain selection

 9   at this time.          Two would be nice, but I think in a typical

10   year we expect one.             And then following at about four

11   week periods, the second and finally the third strain

12   selection.

13                     As the strains are selected, production of

14   the monovalent components of the vaccine proceed.                     Many

15   manufacturers, both in the U.S. and some in Europe,

16   actually start production of the monovalents in January,

17   before the official strain selection.                  And that's a bit

18   of a risk.        We can make educated guesses based on the

19   latest surveillance data at the time, but it's a bit

20   of a risk that must be undertaken in order to support

21   the number of vaccine doses that must be manufactured

22   in the time period.

23                     The next surprise in the process, of course,

24   can     occur     at    the   stage     of   producing     the   vaccine



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                                                                         127

 1   components.       Although we receive the candidate strains

 2   and have an opportunity to evaluate and test them a bit,

 3   especially on small-scale, once those strains are scaled

 4   up to large-scale production, there may be surprises

 5   with the growth characteristics or the purification

 6   properties of the virus that can affect the yields and

 7   the final availability of doses.             And then, of course,

 8   in the same timeframe, the preparation of the potency

 9   test reagents for SRID testing.

10                     Then normally we would expect to bulk the

11   first vaccine in the beginning of June and then after

12   the appropriate testing and release is completed, the

13   license is generally issued the first week in July and

14   vaccine distribution will begin.              And that'll proceed

15   through about the first or second week in October.                And,

16   especially in recent years, this has become kind of a

17   hard cut-off date and any vaccine that's available after

18   that time period generally either won't be sold or will

19   be returned by the customers.

20                     I wanted to try to put together a little

21   bit of an illustration about some of the things that

22   begin to go wrong if strain selection is delayed for

23   any     reason.      And,   of   course,     it    pushes   out     the

24   timeframes for the availability of the candidate viruses



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 1   as well as the high-growth reassortants.

 2                        And in this illustration, supposing third

 3   strain selection is pushed out a months or so, one of

 4   the first bad things that happens is there may be a gap

 5   in production of the monovalent concentrates at this

 6   point.           If a manufacturer has made all of the required

 7   first       and     second    strain,     rather     than   overproduce

 8   something that won't be needed, we may actually have

 9   to wait until the third strain is available and then

10   resume production.             The downside of that, of course,

11   is that the chickens and the egg supply can't be turned

12   off, so manufacturers and egg suppliers have to absorb

13   that cost of, say, a half million eggs per day, which

14   are essentially just be discarded.

15                        Then, of course, this gap in production here

16   can translate into an extended production cycle at the

17   end of the program.             And, again, that can also delay

18   the availability of the SRID testing reagents and

19   pushing out the bulk vaccine preparation and perhaps

20   the license issuing.              And the really critical factor

21   here is that we lose this window of opportunity for

22   vaccine distribution and continue to distribute vaccine

23   as normal, but rather than just simply pushing out the

24   timeframe into the November part of the year, these



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 1   vaccine          doses    essentially       won't     be    used   by     the

 2   marketplace.

 3                       Any questions or comments?

 4                       CHAIRMAN GREENBERG:           Panel?     It's clearly

 5   a treadmill.         Okay.       If not, thank you very much.             And

 6   now Roland's going to lead us in -- yes?                      There is a

 7   short break, but you just broke.                    You're strong.          We

 8   don't need it.

 9                       DR. LEVANDOWSKI:          Okay.     I would like to

10   lay out what we see as some options for the 2000 to 2001

11   influenza vaccine composition and just go over the

12   different possibilities here.

13                       Okay.     Take that off.        We're not ready for

14   that.

15                       (Laughter.)

16                       Influenza A viruses of the H1N1 and H3N2

17   subtypes and also Influenza B viruses have continued

18   to circulate in human populations and there's been

19   discussion here in the past about eliminating one or

20   more of the components of the vaccine, but I think what

21   we heard today is that all three strains that are

22   currently in the vaccine and more are alive and kicking

23   out there.         Therefore, the first thing to consider is

24   what the valency of the vaccine should be and I would



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 1   argue that the vaccine should continue to be a trivalent

 2   vaccine.

 3                     As far as the Influenza A viruses, the H1N1

 4   types, strains similar to the A/Beijing/262/95 strain

 5   have now been found in all areas of the world and what

 6   we've seen this morning is that those strains are

 7   undergoing       antigenic      drift.             The    human      serologic

 8   responses        suggest      that     the    current        vaccines          are

 9   immunogenic,            but     that         the         predominant           new

10   A/Beijing/262/95-like viruses are poorly inhibited.

11                     The vaccine candidate strains, such as the

12   A/New Caledonia/20/99 are currently available and being

13   used for production for vaccines for the Southern

14   Hemisphere.       So there is some manufacturing experience

15   with that strain as well.               So options.

16                     Now the first overhead, the options for the

17   H1N1 viruses.

18                     The first option would be to maintain the

19   current vaccine strain.              In favor of that is that the

20   current vaccines appear to be highly immunogenic.

21   And, in addition, manufacturing is well-defined and it's

22   predictable        at    this    point        from        having      had      the

23   experience.

24                     Against that are that the strains are



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 1   demonstrating antigenic drift and those antigenic drift

 2   strains have been found in all parts of the world.                     In

 3   addition, heterologous serologic responses to the H1

 4   deletion strains are clearly reduced.

 5                    So another option, on the next overhead,

 6   for the H1N1 viruses, would be to change the current

 7   vaccine strain to a more recent strain.                 And in favor

 8   of that, the more strain could possibly provide a better

 9   antigenic match with the current H1N1 strains that are

10   circulating.       In addition, there are vaccine candidate

11   strains, such as this A/New Caledonia/20/99, that are

12   available and they've been used for manufacturing

13   vaccines for the Southern Hemisphere.                  Against that,

14   we don't really have information on the immunogenicity

15   of a New Caledonia-like vaccine.

16                    So the third possibility would be, for the

17   H1 strains, to defer this selection to accumulate some

18   more data.       In favor of that is that there may be some

19   additional data that would further refine and clarify

20   the position.        But against that is that it doesn't

21   appear that it's likely that there will be much more

22   information coming in over the next several weeks

23   because there have not been, except for Japan, there

24   have not been a lot of H1 strains that have been isolated.



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 1                     Okay.   Overhead off.

 2                     For the Influenza B viruses, the strains

 3   of Influenza B in the Yamagata/16/88 lineage have

 4   predominated, with strains that are similar to the

 5   current vaccine strain, which is B/Yamanashi/166/98,

 6   islated in the Americas, Europe, Africa, Australia,

 7   Asia, and essentially the whole world.                  A new variant

 8   in that lineage has been identified just in the last

 9   week.        And therefore its possible significance has not

10   really been assessed completely.                    Strains of the

11   B/Victoria/287 lineage continue to appear in Asia, as

12   has been true for several years, but the relative

13   frequency of these strains appears to be diminishing

14   at this type.

15                     The sera from people who are immunized with

16   the current vaccines inhibit some of the current

17   B/Yamanashi-like viruses well, as previously current

18   vaccines did not produce antibody responses to the

19   B/Victoria/287-like strains.               And I should add that

20   some of the B/Yamanashi-like strains are also not

21   well-inhibited by the current vaccines.

22                     There's limited information at this time

23   on other vaccine candidates, as we just heard.               However,

24   the strain that has been examined really does not appear



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 1   to grow very well and, for that reason, would probably

 2   not be a very desirable candidate.

 3                        So the options for B, the first overhead

 4   here, the first option, of course, is to maintain the

 5   current vaccine strain.               And in favor of this would be

 6   that most of the strains worldwide are similar to the

 7   current vaccine strain.                  The vaccines appear to be

 8   immunogenic and, again, manufacturing is well-defined

 9   and predictable.              But against that is that recent

10   Yamanashi-like strains are not clearly well-inhibited

11   by the post-immunization antisera.

12                        So the next option would be, again, to

13   change the current vaccine strain to a more recent

14   B/Yamanashi-like virus.               In favor of that is that the

15   vaccines could be antigenically closer to the current

16   Influenza B viruses.              But, against that, we don't really

17   know that there would be a clear advantage based on any

18   antigenic characterization that's been done so far and

19   there really are no superior alternate vaccine candidate

20   strains at this time.

21                        So option three is, again, to defer to

22   accumulate more data.               In this case, in favor of this

23   option would be that there are more data that are likely

24   to     be        available   in    the   next     two-to-three    weeks,



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 1   including analysis of these new Chinese Influenza B

 2   viruses that have been sent to CDC recently.                      Against

 3   that is that additional data may not really alter what

 4   the current considerations are, once all the information

 5   is in.

 6                    You want to take the overhead off?

 7                    For the Influenze H3N2 A viruses, there is

 8   antigenic heterogeneity that's continuing among these

 9   strains, as there has been in the past year or more.

10    And approximately 10 to 15 percent of the strains are

11   antigenically distinguishable from the A/Sydney/5/97

12   vaccine strain.        And, again, that heterogeneity has

13   been found widely, not only in the United States, but

14   in most areas of the world.

15                    From that information, there is not a clear

16   antigenic or genetic pattern to suggest a group of

17   antigenic variance that might become the predominant

18   one.       The antisera to some of these newer H3N2 strains

19   appear to inhibit many of the current strains reasonably

20   well, but serologic responses are reduced against some

21   of the recently emerging and antigenically divergent

22   strains.         Although   vaccine      candidate          strains      and

23   high-growth       reassortants       for    some       of    these       are

24   available, it's not clear that the vaccine candidates



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 1   currently available will offer an antigenic advantage.

 2                        So, again, the options for the H3N2 virus.

 3    The first option would be to maintain the current

 4   vaccine composition and that was a strategy that was

 5   used last year in view of much of the similar kind of

 6   information.                In      favor    of   this    would      be     that

 7   manufacturing is well worked out and the yield is

 8   predictable.           But against that is that there is this

 9   antigenic heterogeneity and 10 to 15 percent of the new

10   H3N2             viruses         are        distinguishable,           readily

11   distinguishable, from the A/Sydney/5/97 strain.

12                        Some      of    these    recent     strains      are     not

13   well-inhibited by post-immunization antisera.                           And the

14   current vaccine strain has been in use for the past two

15   seasons and the A/Sydney-like strains have predominated

16   for the past three years, which is a distinctly unusual

17   situation to be in, particularly for the H3N2 strains.

18    That's really unprecedented in the last 20 years or

19   more.

20                        So the options for the H3N2 virus.                   Again,

21   the first option is that we could maintain the current

22   vaccine composition and in favor of that is that

23   manufacturing is well worked out and the yield is

24   predictable.           But against that, there is antigenic



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 1   heterogeneity and 10 to 15 percent of the new viruses

 2   are distinguishable from the A/Sydney strain.                      The most

 3   recent            strains        are      not      well-inhibited            by

 4   post-immunization antiserum and the current vaccine

 5   strain has been -- did I say this already?                       What am I

 6   doing?           Sorry.

 7                        CHAIRMAN GREENBERG:             It's okay.         We're

 8   slow learners.

 9                        (Laughter.)

10                        DR. LEVANDOWSKI:           Pardon me.

11                        So option two.        This is what I really meant

12   to say.          We could change the current vaccine strain to

13   more recent.              And in favor of that, 10 to 15 percent

14   of the recent strains are poorly inhibited.                        It could

15   be possible to achieve a better antigenic match with

16   the recent strains.                And there are some alternative

17   strains that are available for production.

18                        Against that would be that the choice of

19   the strain could benefit from additional epidemiologic,

20   serologic, and manufacturing information.                       We really

21   don't have all the data in that we'd like to have.                       It's

22   not clear that the available strains are superior to

23   the current vaccine strain, however.                         And there is

24   little           information      on   the      potential    for    vaccine



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 1   production with any of these new strains, except for

 2   a very little bit of information for these Panama

 3   reassortants that's been mentioned.

 4                    So the final option of these four is number

 5   three, which is to defer to accumulate more data.                  And

 6   in favor of that, there will probably be significantly

 7   more data for these more recent strains over the next

 8   two to three weeks.         And since the H3N2 strain is the

 9   one that's most likely to cause significant mobidity

10   and mortality, this choice is one that should be really

11   very carefully made.        Against that, of course, is always

12   that the additional data may not alter what we know from

13   the current conditions, considerations.

14                    So I'll stop there.

15                    CHAIRMAN GREENBERG:          Roland, that was a

16   very clear, at least to me, delineation of options.

17   Now I'm sure the committee will come up with some other

18   options, but that was very helpful to me.              And I think

19   we had planned for discussion after lunch, but I think

20   we have some time now and I think it would be wise to

21   see how far we get in discussion.             So I'm going to open

22   that up for discussion.           And you can sit here, but I

23   suppose most of the questions will be -- Dr. Estes first.

24                    DR. ESTES:     I have one question that hasn't



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 1   been brought up yet today.                  We have a new potential

 2   factor in flu variation and that's the introduction of

 3   neuraminidase inhibitors this last year.                      And I wonder

 4   are there studies that are looking at flu coming out

 5   of     areas      where      these    inhibitors       are    being      used

 6   extensively to be sure that we're not putting a new

 7   pressure, there will be a new virus that's now going

 8   to pop up in the next month or so?                     I'd just like to

 9   hear people's opinions.               Others must be worrying about

10   this.

11                       CHAIRMAN         GREENBERG:             Anybody      with

12   expertise can answer that.                 Dr. Cox.

13                       DR. COX:       I can at least give a partial

14   answer.          This has been of concern because the viruses

15   that are resistant to the neuraminidase inhibitors have

16   been found to have mutations both in the neuraminidase

17   itself and also in the hemagglutinatin and, of course,

18   the concern is that you might be driving antigenic

19   change.          But it also should be stated right up front

20   that it's much more difficult to generate resistant

21   strains to the neuraminidase inhibitors than it is to

22   the older antivirals, symantodyne and rhymantodyne.

23                       So    the    manufacturers        are    now    working

24   together to set up a susceptibility network and they



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 1   will be looking not only at field strains, which are

 2   collected by CDC and other WHO colloborating centers,

 3   but they will also be attempting to obtain isolates from

 4   individuals before treatment and after treatment to look

 5   at changes that occur.               So I think that monitoring

 6   should be sufficiently good to give us a good idea of

 7   what's going on.

 8                        CHAIRMAN GREENBERG:        Ms. Fisher.

 9                        MS. FISHER:      This is sort of a general

10   question, but to what extent does mass vaccination

11   versus           targeting   high-risk      groups        contribute        to

12   antigenic drift of strains included in the vaccine every

13   year?

14                        CHAIRMAN GREENBERG:       Again, anybody of our

15   experts who wants to answer questions, I think.                    Roland,

16   do you want to tackle that?

17                        DR. LEVANDOWSKI:        Well, I don't think I

18   have a good response for it, but when you're saying the

19   term "mass vaccination," I don't believe we've used

20   what's really mass vaccination in the United States at

21   any      point.        Possibly     the    closest        thing   to    that

22   experience would be in Japan where all the children were

23   immunized for some number of years, all the school

24   children.           But I don't know that there are, from any



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 1   studies done there, that there was any impact on

 2   epidemiology of spread of influenza.                    I'm not sure

 3   whether Dr. Nerome would have any comments on that or

 4   Dr. Cox.

 5                      MS. FISHER:    I wasn't speaking of children.

 6    I was thinking the increase in the elderly and in

 7   healthy individuals.

 8                      DR. LEVANDOWSKI:       Yes.

 9                      MS. FISHER:     Does it put pressure on the

10   strains in the vaccine to change?

11                      CHAIRMAN GREENBERG:         Dr. Cox is looking

12   like she wants to answer.

13                      DR. COX:    I don't think that there's any

14   way to give a definitive answer.                  But such a small

15   proportion of the world's population is vaccinated at

16   the      present    time   that    we    would    not   expect      that

17   vaccination could be contributing significantly to

18   antigenic drift.        Many of the new strains do emerge from

19   Asia and immunization rates in Asia, with influenza

20   vaccine, are very low.

21                      DR. LEVANDOWSKI:       There may be some data

22   from      the    pre-immunization       era.      We've   only      used

23   influenza vaccine since the 1940s and there are studies

24   looking back, seroarcheology, to see what had happened.



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 1                    And I believe Dr. Daudle has published some

 2   paper describing one of the events that was originally

 3   thought to be an antigenic shift, that is a complete

 4   change in hemagglutinin being more like a substantial

 5   antigenic drift some time near the end of the 1800s,

 6   beginning of the 1900s.            I don't remember the exact

 7   epidemic or outbreaks that are described from that paper

 8   but it has been described previously that there are major

 9   antigenic changes that occur, short of an antigenic

10   shift that would cause a pandemic within influenza

11   viruses in the past.

12                    CHAIRMAN GREENBERG:         I think, just for me,

13   Dr. Cox's answer was a compelling one that the world

14   is susceptible to influenza and the amount of vaccine

15   given to the world at this point is very small compared

16   to the amount of people who are infected.              But it's an

17   interesting question.

18                    Dr. Daum and then Dr. Kohl.

19                    DR. DAUM:     I'm actually very interested in

20   that question and would like to sort of push the envelope

21   a little bit further.          Leaving the world aside for a

22   moment and focusing just on the United States where we're

23   distributing 70 or 60, I don't know the exact number,

24   million doses of vaccine a year and we have very little



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 1   B    activity,          relatively      speaking,      very    little        H1

 2   activity, relatively speaking and lots and lots of H3

 3   activity,         relatively         speaking.         We've    had      this

 4   Sydney-like H3 member of the trivalent vaccine in the

 5   last few years.             And couldn't we make any inferences

 6   at all about the kinds of viruses that are circulating

 7   and the types of vaccines the committee has chosen in

 8   years past?

 9                      For example, one might say, in a naive way,

10   the B vaccine works great; the H1 vaccine works great;

11   and      the     H3N2    is    not    working     because      it's     still

12   circulating, despite 60 or 70 million doses of vaccine

13   being circulated.

14                      So I'm wondering, is there anything to be

15   gained from what we've done with previous vaccines and

16   what's actually been circulating in the community in

17   spite of or in concert with this large vaccination

18   effort?

19                      CHAIRMAN GREENBERG:            Dr. Cox.

20                      DR. COX:        I think that what we're seeing

21   with regard to circulation of H3N2 viruses versus B and

22   H1 is a reflection of what's occurring globally.                               I

23   mean, if you remember the first slide that I put up for

24   each of the different groups of viruses, what we were



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 1   seeing in the United States or what we're seeing in the

 2   United States is pretty representative of what we're

 3   seeing globally.          And the vaccine coverage in the United

 4   States is higher than it is in many other regions of

 5   the world.

 6                       So I think it's very difficult to say that

 7   we're not having H1N1 because the vaccine is working

 8   well or we're not having B because the vaccine is working

 9   well.        It's a very complex interaction of the host, the

10   immune           background,     and    the     virus     itself,       how

11   transmissable it is, how different antigenically it is,

12   and so on.          And those host and virus factors are what

13   determine which strains circulate.

14                       I think we have a tremendous amount to learn

15   and there are some very interesting modeling techniques

16   that we'd like to use to try to help us understand the

17   way viruses are changing and the epidemiology of the

18   circulation of the different strains.

19                       DR. HOKE:     Thank you.      One population that

20   is immunized in what might be called a mass way is the

21   military recruit populations and they are universally

22   immunized against influenza and carefully monitored for

23   respiratory diseases rates.              It has an important impact

24   on     training.         And     when    rates    exceed    a    certain



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 1   threshhold, investigations are conducted.

 2                        We've long recognized that if there were

 3   strains of influenza that circulated that, for example,

 4   against which vaccine could not protect, that that would

 5   be a very good sentinel population in which that would

 6   happen.           And, to my knowledge, the kind of instance that

 7   you inferred that there might be a sudden shift in that

 8   population, highly immunized as a sort of source of a

 9   new strain that emerged under pressure, I don't know

10   that that's ever happened.                   I haven't combed back

11   through the data.

12                        But I should say, on the other side, that,

13   through the use of influenza vaccine in association with

14   adenovirus vaccine, that respiratory disease rates in

15   military recruits are suppressed to very, very low

16   levels.           And this is really a population that would be

17   highly           susceptible   to    transmission          of   respiratory

18   viruses.           So that, you know, anecdotes of isolates from

19   people who had been immunized notwithstanding, I think

20   that the almost complete suppression of influenza in

21   military recruits under a universal immunization policy

22   is       rather        compelling        information            about       the

23   effectiveness of the immunization.

24                        CHAIRMAN GREENBERG:          I would guess also



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 1   that recruits are a somewhat isolated population,

 2   especially isolated to children more than the general

 3   population, which might help the vaccine work a little

 4   better.

 5                     DR. HOKE:     Well, that would depend on where

 6   the training force post was, but generally they are

 7   embedded in communities.

 8                     CHAIRMAN GREENBERG:         Dr. Kohl.

 9                     DR.   KOHL:      I   don't     know      if   this      is

10   premature, but I think I, for one, feel we can start

11   focusing on some of these viral selections and, to use

12   a phrase earlier, one is a no-brainer, I think.                         And

13   the no-brainer is the H3N2.              It looks like we should

14   hold off on that selection pending, quote, "significant

15   new data."

16                     CHAIRMAN GREENBERG:         I want to make sure

17   that -- if the panel feels that they've asked enough

18   questions to help Roland give recommendations, I'm not

19   against moving ahead with that.               Roland, is that okay

20   with you?        And we can start with each one.

21                     Are   there    any    further         questions     from

22   anybody in the panel?           Dr. Couch.

23                     DR. COUCH:     Well, mine was just a question

24   for clarification that I neglected to ask Dr. Hampson.



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 1    Just to be sure I understood that all of the Influenza

 2   B experience in Thailand and in New Zealand and in the

 3   Southern Hemisphere was the Yamanashi-like virus, not

 4   anything related to the B/Shenzhen that's now being

 5   considered as perhaps something different.

 6                    DR. HAMPSON:     No, there we haven't any of

 7   the Shenzhen-like virus.

 8                    DR. COUCH:     So those would fit with the

 9   previous classification of these.

10                    DR. HAMPSON:     Yes, the B viruses that we

11   have found throughout our area of surveillance are the

12   B/Yamanashi-like       viruses.           We're       showing      some

13   percentage of them with a degree of drift, react about

14   two to fourfold down with the B/Yamanashi antiserum.

15    And more closely related to the B/Johannesburg is our

16   current updated reference strain.

17                    CHAIRMAN GREENBERG:        Dr. Ferrieri.

18                    DR. FERRIERI:     I just want to second what

19   Dr. Kohl said.      We will have more data in about two to

20   three to four weeks about alternative strains and so

21   I don't know that we need extensive discussion on the

22   H3N2 status.

23                    CHAIRMAN GREENBERG:        Well, what I would,

24   since I think everybody feels they're ready to go, I



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 1   think I'll just move around and we can take one virus

 2   at a time.         I'm going to switch to the left-hand side

 3   of the table here.

 4                          (Laughter.)

 5                          And I see somebody, an expert in influenza

 6   down there.             So, Dr. Couch, why don't we start with

 7   the -- does everybody want to start with the big guy,

 8   H3N2?        Because I've had two people say let's start with

 9   the H3N2 and our recommendation there.                        Is that okay

10   with the panel?             We'll start with that component and

11   what we think?

12                          I think we were presented by Roland three

13   possibilities.             One, to recommend staying with the

14   current.          Two, to identify a new candidate.                    And, as

15   best I can tell, there's only one candidate that could

16   be identified at this moment and that's the Panama

17   reassortant that is there.                  Or, three, to wait some

18   period of time while more serology and analysis of new

19   viruses is done.                And we were told that since -- and

20   Roland clearly, I think, tipped his hand as to what he

21   thought since he said this is by far the most important,

22   usually          the     most     important     virus       and    the      most

23   information we could have, the better-off we'll be.

24                          So I will start with you as to what you're



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 1   recommendations would be.

 2                       DR. COUCH:      Well, I will do one and then

 3   let's move down the table on the left.                    How about that

 4   for the others?

 5                       Well, actually, I'd like to first of all

 6   compliment industry on their efforts, which those of

 7   us who've got institutional memories know that industry

 8   used to be relatively intolerant of not making all three

 9   decisions at this time.             And that was always extremely

10   difficult.          And then they gave us one.            And now they're

11   giving us three.           So we really only have to make one

12   for sure at this time and they've set up a schedule that

13   we've all certainly got to try and live by.

14                       And so I think that's a major improvement

15   over the way, if you want to go back 10, 15 years, the

16   way these decisions were made in the past.                       And so I

17   think        they    ought     to    be    complimented        for      that

18   accommodation to make this decision a little bit more

19   definitive.

20                       So if you want to start with the three, I

21   guess I'd consider that --

22                       CHAIRMAN GREENBERG:        Could I interrupt for

23   one second?           I am told -- excuse me, this is my

24   parliamentary naivete.              But before we start voting from



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 1   the panel, I was supposed to ask for public comment and

 2   I apologize to the public.             This is purely my inability

 3   to follow schedule correctly.                  Please step up to a

 4   microphone and identify yourself.

 5                       MR. RUBIN:       Yes, Mr. Chairman.          I'm Fred

 6   Rubin.           I've worked for Aventis Pasteur.           We are one

 7   of the manufacturers of influenza vaccine.

 8                       I think one consideration that hasn't been

 9   mentioned here.          I'm sure some people know it, but maybe

10   not everybody and that's that the ACIP at its October

11   meeting voted to lower the high-risk age group to 50

12   and that, I think, constitutes a sizeable additional

13   population of people.               And so the challenge is being

14   put to industry to produce vaccine a little bit more

15   than there's been in past years.                 So rather than this

16   being a trivial piece of information, I think it's a

17   highly significant piece of information.

18                       If that policy, which they've voted on, is

19   implemented, it's going to mean that we have to produce,

20   in    industry,        you   know    between     25   and   40    million

21   additional doses.            I could be off by, you know, a million

22   or two here or there.

23                       So I think the putting off of the decision

24   could have some impact.              So I think it's important for



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 1   you to keep that in mind.             Even though you have to pick

 2   the right strain, we also have to provide enough vaccine

 3   for all these people.            And if we don't have time to do

 4   it, a policy that's voted on and then you can't implement

 5   it has terrible repercussions.

 6                       CHAIRMAN GREENBERG:         That's very helpful.

 7    And since I am now in the high-risk group --

 8                       (Laughter.)

 9                       -- sort of startling to me.

10                       DR. COUCH:     Did you get your vaccine this

11   year?

12                       CHAIRMAN GREENBERG:          No.      Are there any

13   other comments from the public?                    If not, again, I

14   apologize for not having done that before.

15                       Dr. Couch, back to you.

16                       DR. COUCH:      Well, what I usually do -- I

17   started it, actually, many years ago -- was what Roland

18   put up there first.          I put down my strain, epidemiologic

19   vaccine, and availability and mark my crosses on these

20   things.          And I've been doing the same thing here I always

21   do.

22                       And he, of course, enunciated all of the

23   considerations very clearly.               And I've got a bunch of

24   question marks and only one plus across under H3.                        And



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 1   it's a clear note and deferral is, as Dr. Kohl indicated,

 2   I suspect, based on where we stand right now, perhaps

 3   the last decision.            And if we hold to the industry

 4   schedule, that will be an April decision.                   But we can

 5   decide whether one or the other is ready to go with the

 6   next decision.

 7                     It's not the only one I think we have to

 8   defer, but H3 should be deferred.

 9                     CHAIRMAN GREENBERG:          Dr. Hoke.

10                     DR. HOKE:      Am I supposed to talk about H3

11   or pick another one?

12                     CHAIRMAN GREENBERG:            Yes, we're doing H3

13   into now moving along on that one.

14                     DR. HOKE:     Yes, I agree with that.          I agree

15   with that.

16                     CHAIRMAN GREENBERG:            So, for the record,

17   Dr. Hoke agrees to defer decisionmaking for the time

18   being on H3N2.         Dr. Kilbourne.

19                     DR. KILBOURNE:         Well, I think we have a

20   population that's saturated with H3N2 right now.                   I have

21   not seen evidence today of any prospective strains that

22   look       as    if   they're     going     to     be    significantly

23   antigenically different, so I think you have not only

24   a well-vaccinated population, but one fraught with the



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 1   disease itself.         So I suspect that even if one of those

 2   new strains were to come into the population next year

 3   and we stuck with Sydney, we'd still be okay.                   Because

 4   there's enough cross-reactivity among strains so I think

 5   we could be comfortable.

 6                     CHAIRMAN GREENBERG:          So, was that a vote

 7   to use Sydney now?

 8                     DR. KILBOURNE:          That would be my vote.

 9   Maybe I'm jumping ahead, but certainly it could be

10   deferment as far as I'm concerned.

11                     CHAIRMAN GREENBERG:          So would you say to

12   defer, pending new information?               Or do you say we have

13   enough information at this moment to choose?

14                     DR. KILBOURNE:        In my view, we have enough

15   to choose.

16                     CHAIRMAN GREENBERG:          Okay.

17                     DR. KILBOURNE:        But others may not agree,

18   so I don't want to --

19                     CHAIRMAN GREENBERG:          No, that's the whole

20   point of voting.          Dr. Couch.

21                     DR. COUCH:        Could I ask Ed a question?

22   What if we get antigenicity data on the neuraminidase

23   and there are major differences between Sydney and say

24   a    couple      of   the   recent      strains?         Just   in     the



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 1   neuraminidase.

 2                    DR. KILBOURNE:         Then you put in a new

 3   neuraminidase.

 4                    (Laughter.)

 5                    CHAIRMAN GREENBERG:        I think Dr. Kilbourne

 6   has said that his vote is that there's enough information

 7   now to say that the manufacturers should go ahead with

 8   the current Sydney vaccine, that we do not have to wait.

 9    Am I putting it -- did I not interpret what you said

10   correctly?

11                    DR. KILBOURNE:       You did.

12                    CHAIRMAN GREENBERG:           Okay.     Thank you.

13   Dr. Cox.

14                    DR. COX:    My view is that, because we have

15   H3N2 circulating widely now and there's always a delay

16   between the time the viruses are isolated and sent to

17   the state health departments or the intermediate labs

18   and then on to the international collaborating centers,

19   it would really be prudent for us to defer this

20   particular       recommendation       and    accumulate     as     much

21   information as possible.

22                    CHAIRMAN GREENBERG:         Okay.     Dr. Ferrieri.

23                    DR. FERRIERI:         I support deferral and

24   suggest that exploring not just the Panama strains, but



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 1   the Shenzhen/510/99, although I may have missed some

 2   point.           But the antisera and inhibition of all of the

 3   new strains look superb for that, with a rare exception.

 4                        CHAIRMAN GREENBERG:         Dr. Eickhoff.

 5                        DR. EICKHOFF:      Well, I support deferral and

 6   yet I'm reasonably confident that, when we can defer

 7   no longer, we're going wind up with A/Sydney back in

 8   the vaccine.

 9                        CHAIRMAN GREENBERG:         Dr. Daum.

10                        DR. DAUM:     I must confess to be having a

11   difficult time with this.              I'm persuaded that deferral

12   for the period of time talked about would still give

13   manufacturers enough time to prepare properly for the

14   season.           And, given that and the possible availability

15   of new information in a timely way, why not have new

16   information?

17                        But I share Dr. Eickhoff's view.             I don't

18   think there's going to be likely to be a change here

19   and I'm not sure we have enough confidence in what the

20   new information's going to be that's going to drive that.

21                        CHAIRMAN GREENBERG:         Dr. Edwards.

22                        DR. EDWARDS:      I would vote for deferral.

23                        CHAIRMAN GREENBERG:         Ms. Fisher.

24                        MS. FISHER:        I don't feel comfortable



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 1   making this decision.              I would defer to Dr. Cox and

 2   others.          However, I do want to make a statement.

 3                       I do think some attention has to be paid

 4   to increased mortality among those who got flu this year,

 5   particularly looking at what their vaccination status

 6   was.        And, also, you know, as flu vaccine coverage

 7   increases, especially among the elderly and healthy

 8   persons under 65 in the U.S., perhaps there should be

 9   an investigation of whether vaccinated persons are

10   losing cell-mediated immunity acquired from natural

11   infection and are becoming more vulnerable to both

12   vaccine-strain flu infection and increased mortality

13   from the flu complications such as pneumonia caused by

14   other infectious organisms.

15                       CHAIRMAN GREENBERG:         Dr. Faggett.

16                       DR. FAGGETT:       Yes.     I really appreciate

17   the input from Dr. Couch and other experts and do vote

18   for deferment.         I would agree, though, that I would hope

19   that the manufacturers do have enough inventory to take

20   care of the 50, that new age group, as well.               And I think

21   it's       probably,     in    our    patient     population      in     my

22   community, we do have a lot more interest now, so I think

23   we're going to have an increased demand.                  Now we're in

24   for that age 50, other places are going to be wanting



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 1   it, too.

 2                    CHAIRMAN GREENBERG:         Dr. Kim.

 3                    DR. KIM:    I also support deferral, although

 4   I respect Dr. Kilbourne's comment that we may not be

 5   able to see any considerable difference in that sense.

 6    I think since the Moscow strain was not, indeed,

 7   feasible, then, again, the strains like the Panama, you

 8   know, appear to be appealing and, again, in addition

 9   to Sydney strain.        So I think those options need to be

10   continued to be explored.

11                    CHAIRMAN GREENBERG:         Dr. Kohl.

12                    DR. KOHL:     Defer.

13                    CHAIRMAN GREENBERG:         Dr. Estes.

14                    DR. ESTES:      I support deferral.            I also

15   think it's prudent to get as much information as possible

16   and I am concerned about the pressure of the use of the

17   new antiviral as to whether that's going to end up

18   changing this hemagglutinin, which would only affect

19   the A strains.

20                    CHAIRMAN GREENBERG:         And Dr. Griffin.

21                    DR. GRIFFIN:      I think we need the maximum

22   amount of information before this choice is made and

23   so we should defer.

24                    CHAIRMAN GREENBERG:          Okay.     And for the



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 1   record, I also vote defer.          And I think, in fact, I am

 2   heartened by the fact that, as Roland said, that the

 3   A/Sydney there's two years of experience and we, I would

 4   assume, have some ability to defer because that is

 5   already in the bank, so to speak, and manufacturing can

 6   be done relatively efficiently.             So if it ends up, as

 7   Dr. Kilbourne thinks, that that turns out to be the

 8   strain, we have it and we have a lot of experience making

 9   that vaccine.      Not me, but --

10                    DR. KILBOURNE:      I'm not unhappy with this

11   decision.

12                    CHAIRMAN GREENBERG:        Yes.      And your point

13   was clear.

14                    DR. COUCH:    Well, I might say that I think

15   Ed is correct.      I mean, the view that some of us might

16   have been taking, which is in agreement with his that

17   that may well be the decision, but I'm more comfortable

18   backing into it rather than charging out there.

19                    CHAIRMAN GREENBERG:       And I think everybody

20   understands that there is no real difference with Dr.

21   Kilbourne.       He was just looking into the future more

22   than we were.

23                    Well, I think we have time for perhaps at

24   least beginning to talk about one other strain or even



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 1   more.        So, Dr. Couch, I know you said you didn't want

 2   to start off the next one, but, you know, you have many

 3   years of influenza experience.

 4                     DR. COUCH:     Oh, no.     There are other people

 5   down here.       You're pinpointing me a little bit too much.

 6                     CHAIRMAN GREENBERG:         So I'm going to pick

 7   the strain.

 8                     DR. COUCH:     Good.

 9                     CHAIRMAN GREENBERG:        Let's go with the next

10   one, with the H1N1 strain.

11                     DR. COUCH:     I was going to say, you know,

12   let me select one and then let me try to defer the other

13   one, if I may.

14                     (Laughter.)

15                     My H1 chart has plusses all the way across

16   and that is what was once again highlighted and described

17   very nicely by Roland and that is that we should change

18   the H1 --

19                     CHAIRMAN GREENBERG:          Could you use your

20   microphone a little bit more?                 I'm having a little

21   trouble hearing you.

22                     DR. COUCH:     That my little chart I told you

23   I make has plusses all the way across on H1 and so we

24   need to recommend a change in the strain and the obvious



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 1   change is to New Caledonia.           And the reasons for that

 2   were enunciated very nicely by Roland.

 3                    CHAIRMAN GREENBERG:          Okay.    Fine.       Dr.

 4   Hoke.

 5                    DR. HOKE:     Perhaps I needed to hear Dr.

 6   Levandowski again, because I actually had not been so

 7   certain that -- but, of course, Dr. Couch always seems

 8   to, you know, sound definite.               Sounds like he knows

 9   exactly what he's talking about.

10                    I had written at the bottom of my chart to

11   stay with the A/Beijing.          And so I'll just say that I

12   had written that down, because it wouldn't be right to

13   change my mind just because you said that.             But perhaps

14   there will be some more discussion on that.

15                    CHAIRMAN GREENBERG:        So you can reconsider

16   after you hear all of this.          This isn't the SATs.          Dr.

17   Kilbourne.

18                    DR. KILBOURNE:      I think, all other things

19   being equal, I would opt for the New Caledonia or

20   something like it.       I think there's enough evidence of

21   a drift there so that we should be concerned about it.

22                    CHAIRMAN GREENBERG:        Dr. Cox.

23                    DR. COX:      I agree with going with New

24   Caledonia.       And I know that not everyone else in the



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 1   room could see Dr. Nerome HI tables very clearly, but

 2   I happen to have hard copies and it was really gratifying

 3   to see that he has several pages of recently isolated

 4   H1N1 viruses from their outbreak and they're all very

 5   well covered by the New Caledonia virus.

 6                    CHAIRMAN GREENBERG:           And Dr. Hoke, I'm

 7   sure, is among us who couldn't see that data.                           Dr.

 8   Ferrieri.

 9                    DR.   FERRIERI:          Well,      I    support       New

10   Caledonia based on all of the data presented today, but

11   what we don't have is immunogenicity data that should

12   be generated within a relatively short time, so we need

13   a backup plan if that data is negative and perhaps Roland

14   can comment on that.       But that's clearly the best choice

15   for us to go to if everything works out.

16                    CHAIRMAN GREENBERG:          Dr. Eickhoff.

17                    DR. EICKHOFF:      I concur, based, I think in

18   large part, on the data from Japan.

19                    CHAIRMAN GREENBERG:          Dr. Daum.

20                    DR. DAUM:     I concur and don't have anything

21   to add to what's been said.

22                    CHAIRMAN GREENBERG:          Dr. Edwards.

23                    DR.   EDWARDS:       I      would       vote   for     New

24   Caledonia.



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 1                        CHAIRMAN GREENBERG:         Ms. Fisher.

 2                        MS. FISHER:      I defer to the CDC.

 3                        CHAIRMAN GREENBERG:         Dr. Faggett.

 4                        DR. FAGGETT:      That New Caledonia has a good

 5   ring.        I support New Caledonia.

 6                        (Laughter.)

 7                        CHAIRMAN GREENBERG:         Dr. Kim.

 8                        DR. KIM:    I support a New Caledonia strain,

 9   particularly with the data that Dr. Cox just shared.

10    I think that's a real issue.

11                        CHAIRMAN GREENBERG:         Dr. Kohl.

12                        DR. KOHL:     I support the New Caledonia, but

13   I'm a little concerned about isolates 16 to 20, the South

14   American isolates that looks like we're not as well -- is

15   that correct?          That they weren't as well neutralized?

16                        DR. COUCH:       Yes.       I've noted the same

17   thing.           But South America, so far, is A/Bayern-like.

18                        DR. COX:     Yes.

19                        DR. COUCH:     But that may be a result of the

20   number of strains that you've had in hand and on your

21   world chart, it stood out as the only one that had not

22   seen the H1 change, the only major --

23                        DR. COX:    Peru had.       Peru had, previously,

24   had New Caledonia-like strains.                   And, in fact, those



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 1   strains that you're mentioning are Bayern-like.                     And

 2   if you recall, the vaccination studies indicate that

 3   viruses related to Bayern are well-covered by the

 4   Beijing/262 vaccine.

 5                    DR. KOHL:     Well, then I'll withdraw that

 6   comment.

 7                    CHAIRMAN GREENBERG:        Dr. Estes.

 8                    DR. ESTES:    Well, I think the New Caledonia

 9   looks like a good candidate.               Again, because of my

10   concern about the new pressure on this virus, I just

11   wondered if we would be wise to wait to be sure that

12   we have typed other viruses that are just coming out

13   now to be sure that there are no other changes.                     And

14   maybe I'm being -- so I was actually going to suggest

15   deferring this.      But, obviously, depending on what the

16   discussion is about the B component --

17                    CHAIRMAN GREENBERG:        You've got to do them

18   in order, so what is your vote, Dr. Estes?

19                    (Laughter.)

20                    DR. ESTES:    Actually, I vote to defer.

21                    CHAIRMAN GREENBERG:        Okay.     Dr. Griffin.

22                    DR. GRIFFIN:      I think we have sufficient

23   information.      I think we have the most information on

24   this; put it this way.         We've got to make a choice on



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 1   one of the three and so New Caledonia.

 2                     CHAIRMAN GREENBERG:         Okay.     And, for the

 3   record, I would pick New Caledonia as well.              And I agree

 4   with what Diane said, that this was the one that, for

 5   me, I thought we had the most information.

 6                     I would like a clarification on something

 7   that Dr. Ferrieri raised.             And that is when a strain

 8   is switched, as we are recommending now, how frequently

 9   do we have immunogenicity data on what we are switching

10   to at the time we make our decision?

11                     DR. LEVANDOWSKI:          Generally, it's very

12   unusual to have access to any data before a vaccine is

13   made.        We've been in the position once or twice in the

14   past 10 years where there have been some experimental

15   vaccines that were made when some new variants had been

16   identified at an early point.             It's not so easy to get

17   those vaccines made, but they would, if we could have

18   them,        would   provide      very     important     pieces        of

19   information, just to be sure.

20                     Most of the time, I think we've been okay.

21    And it seems like the vaccines are immunogenic, given

22   the fact that measuring immunogenicity is sometimes a

23   little bit tricky.         But we, you know, we don't usually

24   have that information.



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 1                      I suppose it's possible at some point, as

 2   we're, both Southern Hemisphere and Northern Hemisphere

 3   are using the same vaccines, that it might be possible

 4   to get some earlier information, but probably not in

 5   time for us to make a recommendation here.

 6                      CHAIRMAN GREENBERG:            Because, of course,

 7   Dr. Ferrieri's question was critically important, you

 8   would       hate   to    switch     to   a   vaccine       that   was     not

 9   immunogenic.        I just was trying to figure out how, if

10   you were making a new one, you would necessarily have

11   that information.

12                      Okay.       It's now noon and, since this

13   committee is hot, I think we should just go on to H3N2

14   while it's fresh -- I mean -- excuse me -- to B while

15   it's fresh in some of our minds and make our decision.

16    And so, Bob, despite the fact that you were, you know,

17   I let you off the hook and then you bit, so do you want

18   to start off with B again?                Or should I --

19                      DR. COUCH:         I'll make a proposal then,

20   because I -- the only concern that's been emphasized

21   very well is -- well, let me back up a minute and say

22   last year, you know, we do guesses, you see.                         And we

23   thought, well, gee, we've had H3N2 two years in a row.

24    We've got to start worrying about B.



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 1                        And so we fine-tuned the B and it turned

 2   out that we had another H3N2 epidemic.                      And so now we've

 3   got three of them behind us and, unless H1 does something

 4   a little bit unexpected, B should be here next year.

 5    So that we're back in that same position.

 6                        And do we need to fine-tune it?                  I'd say

 7   the data says we don't need any fine-tuning.                            So the

 8   question is whether we need to change the B strain.

 9   And I think Nancy emphasized very well that, gee, we've

10   got      a       whole   potload     of    new    viruses       coming       in.

11   Shenzhen's out in front of us.                   The epidemiologic data

12   is not in-hand.            And so the B information that we want

13   for the definitive decision to stay with Yamanashi

14   versus consider something else is not yet in-hand.

15                        So it's another deferral.                  I actually

16   suspect that that one will be the February decision and

17   H3 will be the March, but they could be reversed.                            But

18   I think it's in the deferral status also.

19                        CHAIRMAN GREENBERG:            Okay.       Thank you.

20   Dr. Hoke.

21                        DR. HOKE:      That is my choice also.

22                        CHAIRMAN GREENBERG:           Dr. Kilbourne.

23                        DR. KILBOURNE:        I would move for deferral.

24                        CHAIRMAN GREENBERG:           Dr. Cox.



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 1                     DR. COX:       I concur.

 2                     CHAIRMAN GREENBERG:            Dr. Ferrieri.

 3                     DR. FERRIERI:         I support that.        And Nancy

 4   Cox said there would be more data from Chinese strains

 5   in two to three weeks or Roland said that.                 I'm concerned

 6   that the other candidates to date have demonstrated low

 7   yield in vitro, so we may end up having to go back to

 8   Yamanashi, though.

 9                     CHAIRMAN GREENBERG:            Okay.     Dr. Eickhoff.

10                     DR. EICKHOFF:          I concur.

11                     CHAIRMAN GREENBERG:            Dr. Daum.

12                     DR. DAUM:        Same.

13                     CHAIRMAN GREENBERG:            Dr. Edwards.

14                     DR. EDWARDS:         Deferral.

15                     CHAIRMAN GREENBERG:            Ms. Fisher.

16                     MS. FISHER:         No comment.

17                     DR. FAGGETT:         Dr. Faggett defers.

18                     CHAIRMAN        GREENBERG:           You    vote       for

19   deferral?        Yes.     Dr. Kim.

20                     DR. KIM:       Defer.

21                     CHAIRMAN GREENBERG:            Dr. Kohl.

22                     DR. KOHL:        Defer.

23                     CHAIRMAN GREENBERG:            Dr. Estes.

24                     DR. ESTES:        I agree.



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 1                      CHAIRMAN GREENBERG:         Dr. Griffin.

 2                      DR. GRIFFIN:      I also agree.

 3                      CHAIRMAN GREENBERG:         And, for the record,

 4   I also agree.

 5                      So I'd like to thank the panel for dealing

 6   in a very logical way with a very complicated system.

 7    Of course we punted on two decisions, which was, I

 8   think, the logical thing to do.

 9                      So,   because    of    scheduling     issues,       I'd

10   actually like you -- it turns out that it would be easiest

11   for us to continue a little while longer and hold your

12   hunger in place.         We're going to have 10 minutes of open

13   public meeting which Nancy and Dwight, I just ask whether

14   there's any public -- is there anybody in the public

15   out there who wishes to say something?                   Okay.      Well,

16   in which case, then, there is nobody.

17                      So, then, we're going to have 10 minutes

18   of talk from Dr. Carbone and then we'll adjourn and we

19   will have then ended the public component of this

20   meeting.         Kathy, come on up.       So we're just switching

21   gears here and Dr. Carbone is going to talk, describe

22   to us the activities of the Laboratory of Pediatric and

23   Respiratory Virus Diseases.

24                      DR. CARBONE:        Hi.     Actually, today I'm



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 1   going to describe the two subsections of the laboratory

 2   that I head.       And that's the Neurovirulence Unit, which

 3   is my research group, and Dr. Judy Beeler's research

 4   group, the Antigen Immune Response Team.

 5                     Next slide, please.

 6                     Just to illustrate the two.           This is Dr.

 7   Beeler's group in yellow.            This is my group in yellow

 8   here.        This is the rest of the laboratory.         Of course,

 9   the noted Dr. Levandowski is part of our group; Dr.

10   Atreya; and associated members.              This group here is an

11   academic group that's working in collaboration with my

12   group at the FDA.        I just want to point out that these

13   two new candidates have just arrived in the laboratory,

14   so the work that I'll be describing is really the result

15   of Mr. Rubin, Dr. Pletnikov, Ms. Jones just arrived,

16   and myself.

17                     Next slide, please.

18                     Just to give you a little introduction to

19   the Laboratory of Pediatric and Respiratory Viral

20   Diseases, we regulate the new research on vaccines that

21   are innoculated into virtually every person in the

22   United States, either as an adult or a child.                     That

23   includes influenza, measles, mumps, rubella, rotavirus,

24   and polio virus vaccines.           That's, sum total, about 100



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 1   million doses per year.

 2                        Over the time since I arrived to head the

 3   lab in 1996, at the present time in 1999 or now 2000,

 4   we have had an increase in IND reviews of twofold PLAs

 5   and supplements of fivefold, but we've managed to

 6   increase our scientific publications by twofold.                          And

 7   I'm very proud of the laboratory for that reason.

 8                        One of the reasons, despite about a 50

 9   percent decrease in research funding for the laboratory,

10   is that there have been successful applications for

11   outside funding.               And we have the National Vaccine

12   Program Office.             Dr. Zoon, the Center Director's Target

13   Award.            And we also have our collaborations with

14   academia and the Office of Women's Health at the FDA

15   to thank for these outside funds to continue our

16   research.

17                        Next slide.

18                        So     Dr.     Beeler      and     myself,     as      an

19   introduction, we deal with licensed vaccines.                      We have

20   a new collaboration with Dr. Levandowski's group that

21   I'll describe later.                Dr. Beeler has been working on

22   measles for many years.                 We've been working on mumps

23   since my arrival at the FDA.                We also work on two viruses

24   there.           Dr. Beeler and Dr. Atreya work on two viruses:



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 1    RSV and human parainfluenza virus III.                   They're not

 2   currently vaccines, but they're in research program.

 3                       And then, of course, the laboratory has

 4   cross-cutting programs which include neurovirulence and

 5   human immune responses that we serve as references and

 6   act on these areas for the entire division.

 7                       Next slide.

 8                       So just briefly I'm going to describe in

 9   two minutes my program and follow with Dr. Beeler's.

10    Time does not permit us, obviously, to get into much

11   detail so I hope I don't leave everyone too much in the

12   dark.        But, in general, when I arrived, I had an interest

13   in     neurological       disease      and   viruses.      And     virus

14   vaccines, of course, have been associated with many

15   neurological diseases.               And part of our job is to

16   determine which of those associations are causal and

17   which are coincidence.

18                       In some cases, there's clearly a causal

19   association between certain types of mumps vaccine

20   strains and meningitis; Ural B vaccine, Leningrad III,

21   and Sophia, none of which were licensed in the United

22   States.          Polio vaccine has clearly been associated with

23   the polio the disease.            Measles vaccine has rarely been

24   described in cases of encephalitis.                  There are issues



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 1   of varicella vaccine and questions of latency for this

 2   virus in the nervous system.

 3                     And then there are several areas that are

 4   of great concern to the public and, as yet, the data

 5   are not available to know whether this is a causal or

 6   a coincidence and more work needs to be done to determine

 7   it, but publications have come from the outside, non-FDA

 8   and non-government publications, trying to associate

 9   the      measles,    mumps,      rubella      vaccine    and   autism;

10   hepatitis B vaccine and multiple sclerosis; and a host

11   of other neurological diseases.

12                     Next slide.

13                     So in my laboratory, we've developed a very

14   multi-disciplinary          group       to    study     virus-induced

15   neurological disease and brain development.                    Because

16   if we're going to determine whether vaccines are safe

17   for use in the population in regards to their infection

18   and damage to the nervous system, it's important to

19   understand how viruses affect the brain.

20                     Because we deal with so many pediatric

21   diseases, we do something that's actually very rare in

22   the United States and that's we look at developmental

23   milestones in terms of virus-infected brains.                         Now

24   typically        people   have    for    years    been    looking       at



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 1   neurovirulence assays in adult animals.                        We actually

 2   look in the developing nervous system and look for

 3   developmental brain damage, which may be more pertinant

 4   to the pediatric and newborn populations.

 5                    We actually have data of neurochemistry,

 6   serotonin changes in the brain, neuroimmunology, we look

 7   at cytokines.      We have indicates of brain developmental

 8   gene up regulation and infection.               And now we have some

 9   data which show that sometimes adverse events associated

10   with      wild-type     virus    infection       in      the    brain      are

11   dependent upon genetic background of the animal.                             We

12   use a rat model for these.

13                    We also, in the rat model, have studied

14   behavior as sort of an outcome.            This is a very, actually

15   a very sensitive outcome for developmental brain damage.

16    And have determined abnormalities from wild-type virus

17   infections       with       social/play      behaviors,          cognizant

18   deficiencies,         and    anxieties       and      other      emotional

19   disorders.       In addition, we've been able to describe

20   anatomical differences.

21                    We use all this information that we gather

22   with the wild-type viruses to try and develop effective

23   vaccine neurovirulence assays to make sure that the

24   vaccines that we use are safe.



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 1                        Next slide.

 2                        Thus far, the accomplishments specifically

 3   in the laboratory -- and I'm sorry I don't have time

 4   to show you data, so I've referenced them if anybody

 5   would like the references.               With our emphasis on brain

 6   developmental damage, we've been able, with the strong

 7   involvement of Mr. Rubin in my laboratory, we've had

 8   several publications on mumps virus neurovirulence

 9   assay development trying to get to a small animal assay

10   and avoid the use of primates if possible.                       This was

11   just returned with very favorable review, so I suspect

12   this will be accepted.              We are now starting influenza

13   virus and an HPIV3 neurovirulence experiments.

14                        Mechanism         and        pathogenesis              of

15   virus-associated           developmental        brain      damage,     as     I

16   described in the previous slide, has resulted in a host

17   of publications coming directly out of my laboratory

18   or collaborations with Dr. Katz and Dr. Plata-Salaman.

19                        And we also have published early last year

20   the first animal model for autism or autistic-like

21   disease associated with neonatal brain damage due to

22   a virus infection.            We used Borna disease virus as our

23   agent.           And Dr. Pletnikov, a very talented instructor,

24   has published several publications on this model,



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 1   following our previous 10 years of work.                  He's has done

 2   some tremendous work.

 3                       Next slide.

 4                       So now I'll move into Dr. Beeler's program.

 5    She's also done some slides here and they're very

 6   abbreviated, but I'll try to do my best, due to time

 7   constraints.          Dr. Beeler has an excellent program in

 8   virus-host cell interactions.                 And she is looking at

 9   particularly a virus attachment, two RSV proteins F and

10   G.     They are important in attachment in cell fusion.

11                       And the particular interest in this area

12   is -- she's currently got an excellent post-doctoral

13   fellow, Dr. Feldman, working in this area -- is that

14   this is a look at antibody-mediated immune responses

15   to prevent infection and spread of the virus.                   In other

16   words, if we can find the RSV receptor and the virus

17   attachment sites, there may be ways to target the vaccine

18   to prevent, actually, the virus from even entering the

19   cell or to block the receptor rather than neutralize

20   the virus per se.

21                       This is very exciting work and it's very

22   unique.          The RSV receptor has not been defined.

23                       The next slide.

24                       You'll see that this work has resulted in



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 1   both collaborative and publications coming directly

 2   from Dr. Beeler's lab, as well as many submitted

 3   publications.         And the work is continuing nicely.                     She

 4   also has a nice collaborative publication on human

 5   immune response to RSV.

 6                       Next slide.

 7                       Dr. Beeler has a program on measles as well

 8   and has just recently, with Ms. Audet in her laboratory,

 9   published a paper in Biologicals.                 It was recorded by

10   an     international        group     that   there        was   pestivirus

11   contamination of measles vaccine and Dr. Beeler did a

12   very       nice     careful      study    which     demonstrates,             no

13   pestivirus contamination.                It was a very well-designed

14   study       and,    like   I     said,    just    got     accepted        into

15   Biologicals.

16                       She has a very interesting line of research

17   that she's been working on when time permits on measles

18   vaccine          associated      thomboytopenia         resulted        in      a

19   publication          in    '96     and     another        manuscript          in

20   preparation.         It's a very interesting publication with

21   very interesting work which suggests that certain

22   factors in cell substrates may cause immune responses

23   that result in anti-platelet antibodies.                          Excellent

24   work.



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 1                      Next slide.

 2                      She provided this slide and I put it up here

 3   to illustrate that in many cases we hear about leveraging

 4   resources, both inside and outside the FDA, and through

 5   leveraging resources in these multiple collaborations

 6   that      Dr.    Beeler   has    initiated       or      been     asked       to

 7   participate in studies, it has tremendous impact in the

 8   research world through her collaborations as well.

 9                      Thank you very much.

10                      CHAIRMAN GREENBERG:         Thank you very much,

11   Dr. Carbone.         I'd just like to editorialize briefly.

12    As all the panel knows over at least the last couple

13   of years that I've been on it, the FDA-CBER research

14   has been really cut to the bone as far as what their

15   research support is and it's sort of amazing that you

16   and your colleagues continue to be able to be productive

17   in what is an inhospitable situation.

18                      Are there any specific questions for Dr.

19   Carbone before I ask you folks a question about how to

20   proceed?         Dr. Estes.

21                      DR. ESTES:      I'd like to ask Dr. Carbone,

22   I mean, your laboratory has been very successful at

23   leveraging resources.           Do you have a specific mechanism

24   that has helped you?            Is there something unique about



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 1   what you're doing that has been successful in this that

 2   would be of benefit for us to know about?

 3                    DR. CARBONE:     Well, the applications to the

 4   NVPO, the Office of Women's Health, Center Director's

 5   Target Award are open to everyone.             There have been some

 6   instances,       because   I   came     from    academia     and     was

 7   permitted to maintain a part-time academic position at

 8   a university, then, through that mechanism, I am able

 9   to be a collaborator on NIH-RO1 funding with approval

10   of NIH and the FDA.        They got together.          And they have

11   done this in the past.         It's done at the CDC.        It's done

12   at veteran's hospitals.          I can't serve as the primary

13   investigator, but I can collaborate on grants.               And that

14   is a very helpful mechanism.

15                    DR. ESTES:     Thank you.

16                    CHAIRMAN GREENBERG:         Dr. Kohl.

17                    DR.   KOHL:        Dr.    Carbone,     I   want       to

18   congratulate you.        I was very impressed by what you've

19   been able to do in the last three or four years.               I guess

20   my question is is there anything you desperately need

21   that would help you further in your efforts?

22                    DR. CARBONE:      Oh, boy.

23                    (Laughter.)

24                    Christmas.      I think it's what we don't



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 1   need.        That's the problem.        But I think that I would

 2   say that the one major problem has been the shrinkage

 3   in FTEs at CBER.          And that has necessitated some very

 4   drastic measures.         We've been lately discussing sharing

 5   technicians and rotating them through because there

 6   aren't sufficient technicians for everyone to utilize.

 7    And that makes it difficult because of the review work

 8   we do requires that there be support in the laboratory.

 9                      So FTEs for technical positions would be

10   very important.          And this pertains to every laboratory

11   in the division.          This is not just my laboratory.

12                      And the second thing would be a somewhat

13   reliable or sustainable source of funding for the

14   research.         We've taken some pretty drastic cuts.             And,

15   unlike an NIH-RO1 mechanism, which I had an RO1 for 10

16   years, on the outside, we get funded year-to-year.                    And

17   that makes it very difficult to maintain a program as

18   opposed to the three-to-five year continuous funding

19   you'll get from an RO1.

20                      So,   really,       more     funding    and      more

21   personnel.          I think that the CBER environment is

22   extremely supportive and talented.                The administration

23   and management is very supportive of the research

24   program.         We're dealing, I think, with external issues.



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 1                    CHAIRMAN GREENBERG:         Ms. Fisher.

 2                    MS. FISHER:     Yes, I'm curious because there

 3   is a lot of publicity about record amount of money that

 4   is being allocated to HHS for scientific research.                    Why

 5   is the FDA's research program somehow not getting a part

 6   of this pie?      I mean, am I --

 7                    DR. CARBONE:       That's a little above my

 8   area.

 9                    MS.   FISHER:       Well,     I      mean,    I   don't

10   understand.

11                    CHAIRMAN GREENBERG:           I think when Dr.

12   Goldman addresses us in closed session, I think that's

13   a spectacular question to ask him.

14                    DR. CARBONE:     Yes.      That's a good person

15   to ask.

16                    CHAIRMAN GREENBERG:        Dr. Carbone, probably

17   doesn't -- if you have a speculation, feel free.

18                    DR. CARBONE:     No, I really wouldn't.

19                    CHAIRMAN GREENBERG:        I would invite you to

20   leave it to the people who can take more heat.

21                    DR. CARBONE:     Yes.      I'm down here looking

22   up.      That's all I am.

23                    CHAIRMAN GREENBERG:           Okay.          Any other

24   questions?       I would simply say one thing that just



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 1   because Dr. Carbone and her colleagues have been

 2   successful, that should not indicate that anybody I

 3   think on this committee thinks that the current level

 4   of support is appropriate.               I would say this, if

 5   anything, your success has occurred despite what's

 6   happened to you, not because of it.

 7                    Okay.      You   have     a   choice   here     as     a

 8   committee.       We can move right now into closed session

 9   and review the lab.         Or you can go for lunch and come

10   back and we can move into closed session and review the

11   lab.       I'm happy either way, but I want to give people

12   on the committee the -- I think Dr. Griffin, who ran

13   the review of this lab, says it will be quite expeditious

14   to do that.      So she votes closed session.           The rest of

15   you?

16                    Okay.   So I'm dismissing the audience and

17   the consultants, with tremendous gratitude.                  And you

18   all did a great job.

19                    (Whereupon, the proceedings went off the

20   record and resumed in Closed Session.)

21

22

23

24



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