1

          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 BY TELECONFERENCE

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          FRIDAY,

          MARCH 10, 2000

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                    The meeting was held at noon in the Kennedy
          Room of the Holiday Inn, 8777 Georgia Avenue, Silver
          Spring, Maryland, Dr. Harry B. Greenberg, Chair,
          presiding.

          PRESENT:

          HARRY B. GREENBERG, M.D.           Chair
          ROBERT COUCH, M.D.                 Temporary Member
          ROBERT S. DAUM, M.D.               Member
          THEODORE EICKHOFF, M.D.            Temporary Member
          MARY K. ESTES, Ph.D.               Member  
          WALTER L. FAGGETT, M.D.            Member

          L. PATRICIA FERRIERI, M.D.         Temporary Member

          BARBARA LOE FISHER                 Member
          DIANE E. GRIFFIN, M.D., Ph.D.      Member
          CHARLES HOKE, JR., M.D.            Temporary Member
          ALICE S. HUANG, Ph.D.              Member
          EDWIN KILBOURNE, M.D.              Temporary Member
          STEVE KOHL, M.D.                   Member
          MARTIN MYERS, M.D.                 Temporary Member 

          DIXIE E. SNIDER, JR., M.D., M.P.H. Member
          DAVID S. STEPHENS, M.D.            Member
          NANCY CHERRY                       Executive Secretary
          DENISE ROYSTER                     Comm. Mgmt. Spec.

                                                                          2

                               A‑G‑E‑N‑D‑A
                                                          Page

          Teleconference Roll Call; Call to Order,
          Introductions, Administrative Matters . . . . . . .3

          Session 1 ‑ Open Session
          Completion of Formulation of Influenza Virus Vaccine
          for 2000‑2001

          Review of Current Situation, Dr. Roland 
          Levandowski, FDA. . . . . . . . . . . . . . . . . .5

          WHO Collaborating Laboratory Reports 1999‑2000
          Influenza Season, Dr. Alexander Klimov. . . . . . .9

          Additional Information on Serologic Results and
          Reference Strains, Dr. Roland Levandowski . . . . 29

          Options for Strain Selection, Influenza A, 
          Dr. Roland Levandowski. . . . . . . . . . . . . . 40

          Open Public Hearing . . . . . . . . . . . . . . . 47

          Committee Discussion and Voting . . . . . . . . . 47

          Options for Strain Selection, Influenza B,
          Dr. Roland Levandowski. . . . . . . . . . . . . . 52

          Open Public Hearing . . . . . . . . . . . . . . . 55

          Committee Discussion and Voting . . . . . . . . . 55

          Session 2 ‑ Open Session ‑ Vaccine Safety Action Plan

          Briefing, Dr. William Egan, FDA . . . . . . . . . 64

                                                                          3

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

     2                                            (12:03 p.m.)

     3              MS. CHERRY:  The following announcement

     4    addresses conflict of interest issues associated with

     5    the sessions of the Vaccines and Related Biological

     6    Products Advisory Committee on March 10, 2000.  

     7              Based on the agenda made available, it has

     8    been determined that the committee discussions for the

     9    influenza virus vaccine formulation for 2000‑2001 and

    10    the briefing of the vaccine safety action plan present

    11    no potential for a conflict of interest.  Dr.

    12    Alexander Klimov has been invited as a guest to

    13    participate in this discussion. 

    14              The Director of the Center for Biologics

    15    Evaluation and Research has appointed Drs. Claire

    16    Broome, Robert Couch, Theodore Eickhoff, Patricia

    17    Ferrieri, Charles Hoke, Edwin Kilbourne, and Martin

    18    Myers as temporary voting members for the discussion

    19    on the flu formulation.

    20              In the event that the discussions involve

    21    specific products or firms not on the agenda and for

    22    which FDA's participants have a financial interest,

    23    then the participants are reminded of the need to

    24    exclude themselves from the discussions.  Their

    25    refusals will be noted for the public record.

                                                                          4

     1              With respect to all other meeting

     2    participants, we ask in the interest of fairness that

     3    you state your name and affiliation and any current or

     4    previous financial involvement with any firm whose

     5    products you wish to comment on.

     6              Now, let me check one more time because I

     7    think somebody else came on the line.  Dr. Daum?  Dr.

     8    Faggett?

     9              DR. FAGGETT:  Dr. Faggett is here.

    10              MS. CHERRY:  Good.  Welcome.

    11              DR. FAGGETT:  Good morning.

    12              MS. CHERRY:  Dr. Kim.  Dr. Broome.  Okay. 

    13    Well, I hope they will join us as we go through. 

    14    That's all I have, Dr. Greenberg.

    15              DR. GREENBERG:  Okay.  Let me look at my

    16    agenda here.  What am I supposed to be doing next

    17    here, Nancy?  

    18              One note that I would like to just simply

    19    say to the advisory group around the telephones, that

    20    obviously it is harder to coordinate statements and

    21    questions in this venue then when we're in person.

    22    What I would just ask is that we all be tolerant of

    23    everybody else because it's complicated.  Also that

    24    you spend a little extra time formulating your

    25    question or your thought so that we do it as

                                                                          5

     1    efficiently as possible.

     2              I guess with that admonition, I will turn

     3    over the discussion to Roland who is going to review

     4    the current situation.

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

     6    Greenberg.  Good day to everybody.  I just would like

     7    to review a little bit about things that have happened

     8    in the past.  As you will recall, as the January

     9    meeting the committee recommended that the A/New

    10    Caledonia/20/99 strain would be used as the H1N1 virus

    11    for the 2000‑2001 influenza virus vaccine for the

    12    United States.

    13              However, at that time the recommendations

    14    for the H3N2 Influenza A and the Influenza B viruses

    15    were deferred so that additional information could be

    16    collected and analyzed.

    17              In February new information was presented

    18    and discussed at the World Health Organization and

    19    recommendations were made by WHO at that time.  I

    20    believe you should have gotten a copy of the WHO

    21    recommendations.  The WHO recommended as published in

    22    the February 25 "Weekly Epidemiologic Record" that

    23    vaccines for the 2000‑2001 influenza season of the

    24    northern hemisphere should contain an A/New

    25    Caledonia/20/99 H1N1 like strain, an A/Moscow/10/99

                                                                          6

     1    H3N2 like strain, and a B/Beijing/184/93 like strain.

     2              Those recommendations are the same as those

     3    that were previously made in September of 1999 for the

     4    southern hemisphere where that influenza season is

     5    about to begin and manufacturing has been

     6    accomplished.

     7              As you may know from previous discussions,

     8    the A/Moscow/10/99 H3N2 virus has been found to be

     9    unsuitable for vaccine manufacturing and that's

    10    because the wild‑type virus does not grow well enough

    11    and no suitable reassortant was obtained after

    12    considerable effort was expended in a number of

    13    laboratories to try to make a high‑growth reassortant.

    14              However, the A/Panama/2007/99 H3N2 virus is

    15    considered to be an A/Moscow/10/99 like strain and

    16    several high‑growth reassortants with potential for

    17    use in manufacturing have been produced.  That was

    18    also noted by WHO in their publication.

    19              The B/Yamanashi/166/98 virus, which is an

    20    B/Beijing/184/93 like strain is being used for

    21    manufacturing as the B strain in most areas of the

    22    world.

    23              Earlier this week on March 7 representatives

    24    of member countries of the European Agency for

    25    Evaluation of Medicinal Products met to complete their

                                                                          7

     1    recommendations for strains to be used in influenza

     2    virus vaccines next season in Europe.  

     3              European scientists from national regulatory

     4    authorities and manufacturing groups confirmed the

     5    selections that were made by WHO by choosing A/New

     6    Caledonia/20/99 as the H1N1 virus, A/Panama/2007/99 as

     7    the H3N2 virus, and B/Yamanashi/166/98.

     8              In the case of the A/Panama/2007/99 strain,

     9    five high‑growth reassortant viruses are being

    10    considered as potential vaccine candidates and it is

    11    expected that work will be completed in the next two

    12    weeks to determine which of those candidate viruses

    13    might be best suited for overall manufacturing

    14    purposes.

    15              Our purpose for today is to complete the

    16    recommendations for influenza virus strains to be used

    17    in vaccines for the United States during the upcoming

    18    season.  Specifically the committee and consultants

    19    are gathered on this teleconference to make

    20    recommendations for the H3N2 Influenza A virus and the

    21    Influenza B viruses.  I'll just read the questions as

    22    they are listed in the agenda.

    23              No. 1 is what strain should be recommended

    24    for the Influenza B component of the vaccine? 

    25    Question 2 is what strain should be recommended for

                                                                          8

     1    the Influenza A (H3N2) component of the vaccine.

     2              Having said that, unless there are some

     3    other comments from anybody, to begin we would like to

     4    provide some additional data for the committee's

     5    consideration starting with additional surveillance

     6    information from the CDC.  Standing by at CDC will be

     7    either Dr. Alexander Klimov or Dr. Nancy Cox to fill

     8    us in on information on surveillance.

     9              DR. FAGGETT:  Do we have this information in

    10    our packet?

    11              DR. LEVANDOWSKI:  Yes, that information

    12    should have been sent to all the committee members as

    13    part of the most recent package of information.  I

    14    would suggest that you do follow along with the

    15    handouts wherever possible.

    16              DR. GREENBERG:  Roland?

    17              MS. CHERRY:  It was faxed.

    18              DR. GREENBERG:  Roland, I assume this packet

    19    is the packet where the first page says CDC

    20    Information for FDA Advisory Panel March 10, and it's

    21    a 17‑page packet.  Is that correct?

    22              DR. LEVANDOWSKI:  That should be correct. 

    23    I'll just confirm that with the CDC colleagues.  

    24              Sasha?  Nancy?  Are you there?  Hello.

    25              MS. CHERRY:  CDC?

                                                                          9

     1              DR. KLIMOV:  Can you hear me?  Hello.

     2              MS. CHERRY:  Yes.

     3              DR. LEVANDOWSKI:  We're having trouble

     4    hearing you.

     5              DR. KLIMOV:  Can you hear me now?

     6              DR. LEVANDOWSKI:  Yes.

     7              DR. KLIMOV:  This is Dr. Klimov from CDC. 

     8    Nancy Cox is not available right now.  She might join

     9    us later.  Do you hear me clearly?

    10              DR. LEVANDOWSKI:  Yes.

    11              DR. KLIMOV:  Okay.  Should I start, Dr.

    12    Greenberg?

    13              DR. GREENBERG:  You should start but I asked

    14    a question which you could answer first, and that is

    15    I am assuming that the information that the panel 

    16    members will be following is in a packet that starts

    17    with something saying, "CDC Information for FDA

    18    Advisory Panel, March 10," and it is a 17‑page

    19    document?      

    20              DR. KLIMOV:  That's correct.

    21              DR. GREENBERG:  Okay.

    22              DR. KLIMOV:  I will start with brief update

    23    on the U.S. Surveillance and national influenza

    24    activities we can ignore in the U.S.  Most states or

    25    territorial epidemiologists reported widespread

                                                                         10

     1    influenza activities this week.  

     2              Only five of them reported original

     3    activity.  The proportion of patients with visits to

     4    sentinel physicians for influenza like illness is

     5    within the baseline level in the U.S.  You know there

     6    are issues (indiscernible).  I'm sorry.  Can you hear

     7    me?

     8              DR. LEVANDOWSKI:  Sasha, we're not hearing

     9    you because there was a lot of interference there for

    10    a second or so.  There was some sort of crunching

    11    noise.  Could you please repeat that?

    12              DR. KLIMOV:  So, as I said, the proportion

    13    of patients with visits to sentinel physicians for

    14    influenza like illness is within the baseline level in

    15    the whole U.S. now.  You also know from the January

    16    meeting that there are pharmacological issues existing

    17    for the pneumonia and influenza mortality.  This

    18    mortality is deeply down now but also is still

    19    slightly above the threshold for this period of the

    20    year.  

    21              The dominant one this year was Influenza A

    22    (H3N2).  You can look at the page 2 which has a graph

    23    indicating that the peak of the Influenza A (H3N2)

    24    activity was between first and second week of this

    25    year.  You could notice as well that at the very end

                                                                         11

     1    of this season there is an increasing number of

     2    Influenza A (H1N1).  Totally we received like 45 to 50

     3    Influenza A (H1N1) within the last five weeks.  I am

     4    going now to the page 4.  

     5              DR. KOHL:  Can I ask a question about that?

     6              DR. LEVANDOWSKI:  Dr. Kohl has a question,

     7    I think, for you Sasha.

     8              DR. KLIMOV:  Okay.

     9              DR. KOHL:  The H1N1 isolates, were they from

    10    a particular part of the United States?  Were they

    11    those Carolina/Kentucky isolates that are featured on

    12    the next page? 

    13              DR. KLIMOV:  The Kentucky isolates and

    14    Carolina isolates but not only from those regions.  We

    15    have them from Hawaii, Nevada, California, Wisconsin,

    16    Kentucky as you said, and North Carolina as well.

    17              DR. KOHL:  Thank you.

    18              DR. KLIMOV:  And the hemagglutination

    19    inhibition test presented on page 4 for Influenza H1N1

    20    viruses actually validates the decision which was made

    21    in January about H1N1 vaccine component.  As you can

    22    see from this table in two sort of difference frames,

    23    we have now in the United States two variations of

    24    Influenza H1N1 circulating.  The first group is so‑

    25    called Beijing/262‑like or we can call them now A/New

                                                                         12

     1    Caledonia‑like viruses.  This is antigenic and genetic

     2    group.  

     3              The other group of viruses we found in North

     4    Carolina and Kentucky.  They are similar to the

     5    previous year's Influenza H1N1 which circulated in the

     6    United States.  They belong to so‑called Bayern group

     7    or, according to the vaccine strain, to the

     8    A/Johannesburg/82/96 antigenic and genetic lineage.

     9              The Beijing/262‑like or New Caledonia‑like

    10    viruses, you can see that within this group

    11    Beijing/262 ferret antisera which is A antisera on

    12    this table will not cover well all new strains and in

    13    particular some strains from Hong Kong, Bangkok, and

    14    Philippines.  There is more than four point difference

    15    between the homologous titer and the titer against

    16    those (indiscernible).  At the same time you can see

    17    that New Caledonia/20 ferret antisera did well with

    18    all the viruses in this set.

    19              As you can see from the table also, the

    20    Johannesburg/82/96 or Bayern‑like viruses, are close

    21    to each other and to the previous years of

    22    Johannesburg/82.  I would like to remind you all that

    23    Johannesburg/82‑like viruses are distinct

    24    antigenically to the A/Beijing/262/95‑like viruses. 

    25    However, the Beijing/262 produces five types of

                                                                         13

     1    antibodies that cross‑react well with all

     2    A/Bayern/7/95‑like viruses.

     3              Now I'm going to move to the Influenza B

     4    viruses.  I would like to ask you to turn to page 6 of

     5    our package.

     6              PARTICIPANT:  It's difficult to hear you. 

     7    Could you speak up, please.

     8              DR. KLIMOV:  Okay.  I'm trying to speak as

     9    loud as I can.  Can you hear me?

    10              PARTICIPANT:  It's a bit better.

    11              DR. KLIMOV:  Okay.  I will try keeping

    12    louder.  This page 6 and the following page 7

    13    represent recent hemagglutination inhibition data on

    14    some recent viruses.  As you can see, most of those

    15    viruses continue to belong to B/Beijing/184/93 and

    16    B/Yamanashi/166/98 group.  

    17              The test on page 6 includes some recent

    18    viruses from China.  As you remember, during the

    19    January meeting we mentioned that we just received at

    20    that moment a package from China.  From the table on

    21    the page 6 you can see that some of those new viruses

    22    from China are poorly covered with Beijing/184

    23    antisera.

    24              As you remember during the January meeting

    25    we mentioned the Shenzhen/654/99 at that moment

                                                                         14

     1    possible variant which we hope will cover most of the

     2    viruses.  You can see from the table on page 6 this

     3    antisera (indiscernible) so it looks like the China

     4    has some new variations but there is no one particular

     5    group of viruses in this region.

     6              DR. GREENBERG:  There is somebody who is

     7    eating an apple into their phone or something.

     8              MS. CHERRY:  It may help if you put your

     9    phone on mute while you're listening.

    10              DR. KLIMOV:  Okay.  So page 7 represents the

    11    data which we received from Dr. Alan Hampson from

    12    London.  We have similar data, just his collection is

    13    a little bit wider.  The test includes recent viruses

    14    from Hong Kong.  I forgot to mention that

    15    unfortunately we do have just a few viruses from China

    16    so far.  We've had very few come to the U.S. this

    17    season.

    18              The table on page 7 clearly shows that the

    19    new virus is from Hong Kong definitely

    20    Yamanashi/166/98‑like and this Yamanashi antisera

    21    reacts well with the strains from that region.

    22              The next page 8 presents data ‑‑

    23              PARTICIPANT:  Sasha, can I ask a question? 

    24    Do we have much epidemiologic information yet about

    25    the Shangdong/07 being so far out?

                                                                         15

     1              DR. KLIMOV:  Not too much actually.  We are

     2    talking more about what I call B/Victoria‑like

     3    viruses.  We did not receive this virus from China but

     4    we do know that some countries like Japan and Taiwan

     5    do have B/Victoria‑like viruses with the

     6    B/Beijing/184.  As you all know, the B/Victoria‑like

     7    viruses are in the United States for many, many years.

     8              PARTICIPANT:  Thank you.

     9              DR. KLIMOV:  Page 8 represents the

    10    evolutionary relationships among Influenza B

    11    hemagglutinin genes.  This is about the same shown to

    12    you all at the January meeting except new viruses on

    13    the top of the tree, Shenzhen/652, Shenzhen/654.  The

    14    majority of recent viruses are within the bottom part

    15    of this tree.  In other words within the

    16    B/Yamanashi/166 genetic group.  They are genetically

    17    close to B/Yamanashi.

    18              The viruses on the top of this figure which

    19    I mentioned is from so‑called Harbin/7/94 genetic

    20    sublineage.  I should mention that viruses from this

    21    sublineage wasn't found in the United States.  They

    22    continue to circulate a little bit in China but even

    23    in China they have more B/Yamanashi‑like viruses at

    24    this moment genetically.

    25              The next table on page 9 is actually the

                                                                         16

     1    same table we have shown during the January meeting

     2    but we put this in the package just to remind you all

     3    that B‑Yamanashi/166/98 virus is the closest virus to

     4    so‑called consensus amino acid sequence of the

     5    hemagglutinin.  

     6              You can see, for example, that Beijing/184

     7    has 9 amino acid differences.  Harbin/7/94, which used

     8    to be the same strain for several years, has 12 amino

     9    acid differences but B/Yamanashi/166/98 still has only

    10    2 amino acid differences from the consensus sequence. 

    11    This is an indication that we do not have considerable

    12    antigenic change of the hemagglutinin of recent

    13    Influenza B viruses.

    14              If you have questions about Influenza B

    15    please go ahead.  Otherwise, I will go to Influenza A

    16    (H3N2) viruses.

    17              Okay.  Influenza A (H3N2) virus.  We have a

    18    few which is similar to what we saw during the January

    19    meeting or before January meeting.  Most of the

    20    viruses are still close to Sydney/05/97, Moscow/10/99,

    21    and Panama/2007/99.

    22              If you look at the hemagglutination

    23    inhibition table on page 11 of your package, you can

    24    see that the viruses are close to Sydney, Moscow, and

    25    Panama.  But at the bottom part of the table, you can

                                                                         17

     1    see that there are some new viruses.  

     2              For example, in this particular case, from

     3    Indiana, Texas, Florida, which are low to Sydney/05 to

     4    the homologous side.  Also you can see that there is

     5    a tendency that Moscow antisera or Panama antisera

     6    cover those new viruses better than Sydney/05 antisera

     7    does.

     8              The next table on page 12 includes some new

     9    viruses from U.S. and other areas.  This also

    10    represents the data of hemagglutination inhibition

    11    activity caused by ferret antisera raised against

    12    several Panama high‑growing reassortants.  Those

    13    reassortants are so‑called Resvir‑16, Resvir‑17 as

    14    prepared in Dr. Levandowski's lab, and also NIB‑41

    15    which was prepared by Dr. John Wood in London.

    16              Once again, from this table you can see at

    17    the bottom of the table there are some recent viruses

    18    which are low to Sydney/05 antisera but they are

    19    followed pretty well with Moscow/10 or Panama/2007

    20    antisera most of them.

    21              Also this table shows that antigenically all

    22    three high‑growing reassortants are similar to each

    23    other and acceptable by their antigen as potential

    24    vaccine reassortant.  They work as well as wild‑type

    25    Panama virus does.

                                                                         18

     1              The next page, page 13, represents a genetic

     2    evolutionary relationships data among recent Influenza

     3    A (H3N2) viruses.  You can see that definitely the

     4    viruses of this subtype are undergoing genetic

     5    changes.  They are quite high now from Sydney/5/97

     6    genetically.  

     7              In the middle of this graph you can find

     8    Panama/2007/99 virus.  Actually, all recent viruses

     9    belong either to the A/Panama/2007 branch on this tree

    10    or to the branch which is on the top of this picture.

    11    I should mention that antigenically those viruses from

    12    those top two branches it is impossible to distinguish

    13    between them.  As I said, antigenically they are

    14    pretty similar to A/Panama/2007.  

    15              If you move to the next page 14, you can see

    16    that Panama/2007/99 is the virus which is one of the

    17    closest to the consensus amino acid sequence of the

    18    hemagglutinatinin of recent Influenza A (H3N2)

    19    viruses.  For example, the Sydney/5/97 had 9 amino

    20    acid differences from the consensus.  Panama/2007 had

    21    just 3 amino acid differences which actually provides

    22    additional support to Panama as a potential vaccine

    23    candidate from our point of view.

    24              The last page of the package, page 15,

    25    presents the data on evolution of the neuraminidase

                                                                         19

     1    genes of recent influenza viruses.  You can see from

     2    this graph the new variations of Influenza A viruses

     3    like reassortants 16, 17, etcetera.  

     4              They belong to a sublineage which is

     5    different from the sublineage of where the Sydney/5/97

     6    neuraminidase is.  In other words, the neuraminidase

     7    of recent viruses is genetically different from the

     8    neuraminidase of Sydney/5/97‑like viruses.

     9              As a sort of conclusion about the H3 part of

    10    my presentation, I should repeat that antigenically

    11    and genetically the data which we gained after the

    12    January meeting are similar to what we have shown

    13    during the January meeting about vaccine selections. 

    14    Genetically we definitely see that the new age of

    15    Influenza H3 antiviruses are most harm in comparison

    16    to Sydney/5/97 vaccine strain.

    17              Also, I would like to mention that we may

    18    sort of vary on how many viruses we received this year

    19    from people who were vaccinated.  We call them vaccine

    20    tailors.  How data indicate that if two years ago we

    21    received approximately 3.8 percent of viruses from

    22    vaccinated people.  Last year we received 4.1 percent

    23    of strains from people who were vaccinated.  

    24              This year this figure is double so in this

    25    season 47 of 542 viruses we received so far.  It was

                                                                         20

     1    9 percent, 8.7 percent of viruses we received from

     2    people who were vaccinated this last year.  We do not

     3    ask specifically people to send us the knowledge of

     4    viruses circulated from vaccine tailors so this is

     5    just random figures which we have.

     6              Probably I will stop here and ready to

     7    answer your questions.

     8              MS. FISHER:  This is Barbara Fisher.  I have

     9    a question.

    10              DR. LEVANDOWSKI:  Yes.

    11              MS. CHERRY:  Go ahead.

    12              MS. FISHER:  Okay.  Sorry.  What you're

    13    saying then is that those who were vaccinated and came

    14    down with the flu, we don't know which strain was

    15    associated with that failure?

    16              DR. KLIMOV:  You know, my most cases,

    17    antigenically those viruses are pretty close to Sydney

    18    to Moscow to Panama, the recent viruses.  Genetically

    19    they are withdrawn.

    20              MS. FISHER:  I have one more question.  In

    21    the last meeting you talked, or someone talked about

    22    increased mortality associated with the flu this

    23    season.  Do we have anymore data about the health and

    24    vaccination history of those who died including their

    25    ages?

                                                                         21

     1              DR. KLIMOV:  This data is still in the

     2    collection stage.  I know that our edit section is

     3    working on this right now but I do not have any

     4    finalized data about this issue.

     5              DR. GREENBERG:  Let's clarify something just

     6    for the record here because I'm not sure I understand

     7    the response.  It was my impression that the data that

     8    was stated was that this year ‑‑

     9              PARTICIPANT:  You're breaking up, Harry.  We

    10    can't hear you.

    11              DR. GREENBERG:  Is that better?  Sasha, hold

    12    on a second.  What I heard you say was that this year

    13    approximately 9 percent of the isolates sent to the

    14    CDC appeared to come from people who were vaccinated

    15    as opposed to the past two years where approximately

    16    4.5 percent came from people who were vaccinated.

    17              DR. KLIMOV:  It's about 4 percent.

    18              DR. GREENBERG:  You said nothing that I am

    19    aware of of differences in sequence or antigenicity of

    20    the two types of isolates.  I think that was what Ms.

    21    Fisher was asking.

    22              DR. KLIMOV:  Okay.  Once again, the tables

    23    which are in our package indicate that we do see a

    24    definite percentage of viruses which are low to Sydney

    25    now.

                                                                         22

     1              DR. GREENBERG:  Sasha, the question is are

     2    those viruses specifically obtained from people who

     3    were vaccinated?

     4              DR. KLIMOV:  Okay.  Every year we receive

     5    some number of viruses.  We made a query how many ‑‑

     6    when we receive some viruses in some cases they have

     7    a remark that the virus was from a vaccine tailor or

     8    from vaccinated person.  When we made these

     9    calculations, we realized that this year ‑‑

    10              DR. GREENBERG:  Sasha, you're not listening

    11    I don't think.  I understand what you're saying.

    12              PARTICIPANT:  Harry, permit me.  It's just

    13    a simple question.  Are the isolates from vaccinees

    14    the same as from none vaccinees?

    15              DR. KLIMOV:  In general, yes.  In general,

    16    yes.

    17              DR. GREENBERG:  Thank you.  Because that was

    18    what Ms. Fisher, I think, was asking and, I think,

    19    your answer confused me.  Okay.

    20              DR. KLIMOV:  Okay.  I'm sorry.

    21              DR. GREENBERG:  Go on.

    22              PARTICIPANT:  I have two questions.  I have

    23    to say I am not terribly impressed with differences

    24    away from the Sydney in terms of antigenicity.  If you

    25    look at page 12 again and compare Sydney/5 at the top

                                                                         23

     1    as A with NIB‑41, which I gather is a Panama

     2    reassortant, I don't see really significant

     3    differences among those ferrets here.  

     4              I think you probably only used a couple of

     5    ferrets per observation point.  Don't you?  I just

     6    wonder that we're always moving too fast here and

     7    relying more on sequence and antigenicity,

     8    antigenicity being the definitive thing as far as I'm

     9    concerned still.  The tendency is interesting but

    10    probably academic in terms of protection.

    11              DR. KLIMOV:  As you can see from the table

    12    on page 12, there is a four‑fold difference one way

    13    between Sydney and Panama but not the other way,

    14    between Panama and Sydney as you can see on this

    15    particular table but we don't see this in all the

    16    tests so it's a one‑way difference between Sydney and

    17    Panama‑like viruses.

    18              Yes, indeed, there is no dramatic difference

    19    between Sydney and, let's say, Panama for example. 

    20    But as you can see, nonetheless, from the table on

    21    page 12 on the bottom part quite a number of viruses

    22    on this table are more than four‑fold down to Sydney

    23    but not to Moscow and not to Panama but all of them

    24    are reacting extremely well with Panama or Moscow. 

    25    The percentage of low reactors to Panama or to Moscow

                                                                         24

     1    is lower than percentage of low reactors to Sydney.

     2              PARTICIPANT:  Yes, but the group I would be

     3    concerned about, which would be numbers 20 through 28,

     4    the data looks very much the same to me as I scan

     5    those data in terms of protection by any of those ADCD

     6    antisera at the top.

     7              DR. KLIMOV:  Exactly.  That's what I'm

     8    saying.  Antigenetically all reassortants with Resvir‑

     9    16, 17, and NIB‑41 are similar to wild‑type Panama

    10    virus.

    11              PARTICIPANT:  As far as I'm concerned, it

    12    becomes academic about changing away from Sydney even

    13    though our instincts tell us probably why.  I have one

    14    other question, Sasha.  Do you have any information

    15    about the neuraminidase antigenicity?  You've shown us

    16    a genetic tree there.  Is there any information about

    17    any significant antigenic differences among those N2s?

    18              DR. KLIMOV:  We don't have this here at CDC

    19    but there is data which indicated antigenic properties

    20    of recent neuraminidase are different from the

    21    Sydney/5‑like neuraminidase.

    22              PARTICIPANT:  I see.  That might begin to

    23    explain some of the differences you will be seeing

    24    this year in terms of vaccine failure.  Are you going

    25    to be looking for that?

                                                                         25

     1              DR. KLIMOV:  That's correct.

     2              PARTICIPANT:  Okay.

     3              DR. LEVANDOWSKI:  Okay.  This is Roland

     4    Levandowski.  Are there other questions?

     5              DR. KOHL:  Yes, this is Kohl.  I'm a little

     6    concerned about the H1N1 at the end of the season. 

     7    And also about the isolation of a considerable number

     8    of low neflodation strains from the southern part of

     9    the United States.  

    10              DR. KLIMOV:  As to the first question, the

    11    number of H1N1 viruses in the United States in the

    12    recent weeks, it's hard to predict right now will it

    13    continue to increase.  We do know that Japan, Taiwan

    14    had wide outbreaks of H1N1 viruses this season.  We do

    15    know that Canada, for example, had in recent weeks

    16    also outbreaks of Influenza A (H1N1) viruses.   

    17              Once again, it's difficult to say whether

    18    it's going to be what we call a wide base and small

    19    peak at the end of the season but this is the fact

    20    right now.  There is an increasing number of H1N1

    21    viruses which we did not see before during the

    22    preceding weeks of the influenza season.

    23              DR. KOHL:  And a portion of those H1N1s will

    24    not be well covered by this strain we chose in

    25    January.

                                                                         26

     1              DR. KLIMOV:  It is well covered.  It is well

     2    covered.

     3              DR. LEVANDOWSKI:  Dr. Kohl, let me just ‑‑

     4    can I clarify?  This is Roland Levandowski.  Can I

     5    clarify?  You're looking at the table from page 4 and

     6    you are referring to the antigens No. 17 through 21?

     7              DR. KOHL:  Correct.

     8              DR. LEVANDOWSKI:  Those antigens are really

     9    Johannesburg/82/96‑like strains.  I think we should

    10    emphasis that the CDC's ferret antisera are very good

    11    at detecting the difference between those two

    12    lineages, between the Beijing/262 vaccine lineage and

    13    the older Johannesburg/82/96 lineage.  

    14              We're not presenting the data here but we

    15    have data from people who have been immunized which

    16    indicate very well that the antibodies produced in

    17    response to Beijing/262 and people do cross‑react very

    18    well with those Johannesburg/82/96‑like strains.

    19              Although we don't have data on these

    20    specific strains, I think we would expect that we

    21    would see the same if we did the serologies with

    22    those.  Partly that would be because most people have

    23    been exposed in the past to the Johannesburg/82/96‑

    24    like strains.

    25              DR. KOHL:  Thank you very much.

                                                                         27

     1              DR. COUCH:  That data is in your handout.

     2              DR. LEVANDOWSKI:  I wasn't really going to

     3    emphasis it later.

     4              DR. COUCH:  But the concern arises and it's

     5    covered by your serology table.

     6              DR. LEVANDOWSKI:  Okay.  This is Roland

     7    again.  Are there other questions or comments?

     8              DR. DAUM:  Bob Daum speaking from Chicago.

     9              MS. CHERRY:  Hi.  Welcome, Dr. Daum.

    10              DR. DAUM:  Welcome to you.  Hi.  In terms of

    11    failure isolates, return to that for just a moment. 

    12    Two questions.  First of all, do we know anything

    13    about the reporting system or the likelihood that

    14    someone would send you an isolate from a failure

    15    patient versus a nonfailure patient and has that

    16    possibly changed in the last three years?

    17              Secondly, I may have blanked but did you

    18    give us any breakdown by serotype of the failure

    19    isolates?

    20              DR. KLIMOV:  As to the first question, there

    21    is not actually a system of sending us viruses

    22    specifically for people who failed to be protected

    23    with the vaccine immunization so they us randomly.  As

    24    I mentioned before, we do not request specifically to

    25    send us data from such patients.

                                                                         28

     1              MS. CHERRY:  Dr. Klimov, you are being hard

     2    to hear.  Can you speak up?

     3              DR. KLIMOV:  Okay.  Okay.  Is this better?

     4              MS. CHERRY:  Yes.

     5              DR. KLIMOV:  Okay.  Once again, we do not

     6    have any specific system of tracking viruses from

     7    vaccinated people, just people that sent us what they

     8    consider to be interesting to send.  Once again, there

     9    is no specific system.  Just, as I said, we notice

    10    that this year the percentage seems to be higher than

    11    two years ago.

    12              As to the second question, I didn't quite

    13    understand what you mean about serotyping.  They are

    14    all H3N2.

    15              DR. GREENBERG:  Again, I think it's

    16    important for all of us ‑‑

    17              PARTICIPANT:  You're breaking up again.

    18              MS. CHERRY:  Harry, we're losing you.

    19              DR. GREENBERG:  I would just like to make

    20    sure that everybody once questions are answered try to

    21    ask a new question because it's hard enough to pay

    22    attention to this thing, at least on my phone, because

    23    it's breaking up so much.  Are there any more

    24    questions?

    25              DR. COUCH:  Harry, Bob Couch.  As long as

                                                                         29

     1    you've stopped for a moment, I'm going to have to

     2    leave the call in about 10 minutes.  I am responsible

     3    for our noon conference.  Just in general, I think

     4    Ed's points are well taken but I think the decisions

     5    are fairly straightforward but it's probably too early

     6    for an opinion.  In 10 minutes from now I'm going to

     7    leave you but if you want me to say anything at that

     8    time, feel free.  Otherwise, I'll try to join you if

     9    you're still going when it's over.

    10              DR. GREENBERG:  Okay.  I might since you

    11    have a lot of experience and probably ‑‑

    12              DR. COUCH:  You've got other people there

    13    that do, too, though.

    14              DR. GREENBERG:  No, no.  I might ask you

    15    your opinion so if you could just indicate when you

    16    are about to leave.

    17              DR. COUCH:  Okay.  Okay.

    18              DR. GREENBERG:  Roland.

    19              DR. LEVANDOWSKI:  Okay.  If there are no

    20    further questions, then we'll just continue.  I would

    21    like to get some information, just some refresher

    22    information about serologic responses and the

    23    availability of strains and reagents.  I will try not

    24    to take too long.  I'll refer you to the handout from

    25    the Center for Biologics that is dated current to

                                                                         30

     1    March 7, 2000.  I don't want to call your attention to

     2    too many tables in there but I will call your

     3    attention to a few.

     4              I don't have a handout that has all the

     5    individual serologic studies that were done from the

     6    participating labs to save space so the ones that are

     7    included in the handout are just intended to give some

     8    examples for people who wanted to take a look at them.

     9              My main goal is going to be to try to

    10    summarize the work that has been done by the four labs

    11    that are involved in doing serologic testing; CDC in

    12    Atlanta, WHO Melbourne in Australia, National

    13    Institute for Biological Standardization and Control

    14    in London, and CBER‑FDA in Bethesda.  

    15              Overall I would like to point out that this

    16    collaboration is very extensive and labor intensive. 

    17    The effort is to try to collect as much information as

    18    we can on the performance of vaccines with respect to

    19    antibodies that will inhibit recently identified

    20    strains relative to the current vaccine strain.  You

    21    will see on these tables that we've got more than 50

    22    different influenza viruses that we've taken a look at

    23    this year.  I'll call your attention to some specific

    24    ones.

    25              A lot of the information has been previously

                                                                         31

     1    described.  I'm not going to talk about the H1N1

     2    strains at this point.  I'm going to restrict my

     3    remarks to the H3N2 and the B viruses.  There's a

     4    table on page 3 of the handout which indicates the

     5    H3N2 Influenza A viruses that have been examined and

     6    you'll see if you look at that that the list is very

     7    extensive.  It includes strains from all of the

     8    antigenic and genetic backgrounds that have been

     9    identified.  

    10              In particular, the list includes some

    11    viruses that were collected during the current

    12    influenza season in the United States such as the

    13    A/Michigan/27/99 and the A/California/32/99, as well

    14    as some strains that are genetically more closely

    15    related to the A/Moscow/10/99 and A/Panama/2007/99

    16    such as the A/Victoria/358/99 and A/Philippines/26/99

    17    strains.

    18              If you'll turn to the summary table, which

    19    on page 16 of the handout, you'll see a table that

    20    shows a number of serologic tests that were done

    21    indicating whether a 50 percent or greater reduction

    22    in antibody titer occurred as compared to the

    23    A/Sydney/597 vaccine strain.  Here again we're using

    24    the 50 percent or greater reduction as a cut‑off point

    25    since it represents a two‑fold reduction in titer.

                                                                         32

     1              In some instances on this table, the tests

     2    were done with the Resvir‑13 A/Sydney/597 reassortant

     3    that was used in the vaccine.  In some instances the

     4    wild‑type A/Sydney/597 virus was used for comparison.

     5              You'll notice that there is some variability

     6    in the results between the laboratories but in several

     7    instances the majority of tests indicate that there is

     8    a 50 percent or greater reduction in the antibody

     9    titers such as the results for A/Victoria/358/99 and

    10    A/Philippines/26/99.

    11              In other instances there is little or no

    12    reduction such as with the A/Michigan/27/99 strain and

    13    with the A/Shenzhen/510/99 strain.  Overall we think

    14    that the results indicate that the current H3N2

    15    Influenza A vaccine strain is imperfect in its

    16    coverage of recently circulating influenza viruses.

    17              Turning to the ‑‑ I'll just continue and if

    18    there are questions, I'll take them all at the end I

    19    think.  Turning to Influenza B, the table on page 4,

    20    flipping back to page 4, indicates the viruses that

    21    were used for serologic testing.  You'll note that

    22    most emphasis was placed on viruses that are similar

    23    to the current vaccine strain which is

    24    B/Yamanashi/166/98.  The strains tested are

    25    representative of a wide geographic range and they

                                                                         33

     1    include the new variant B/Shenzhen/654/99.

     2              The summary on page 17, flipping back one

     3    more time, shows the number of serologic tests that

     4    were done that showed a 50 percent or greater

     5    reduction in antibody titer as compared to the

     6    B/Yamanashi/166/98 vaccine strain or its equivalent. 

     7    Again, the results are somewhat mixed.  For the new

     8    variant strain B/Shenzhen/654/99, for example, the

     9    geometric mean titers were reduced by more than 50

    10    percent in the majority of tests.

    11              In addition, results for B/South

    12    Australia/5/99 were also reduced.  In looking at other

    13    strains that are similar to that one such as the

    14    B/Shanghai/180/99 and the B/Johannesburg/5/99 there

    15    was little or no evidence of reduced titers.

    16    Taken all together the results indicate that antigenic

    17    changes that are occurring can be detected in some

    18    cases including in the case of this variant B strain.

    19              That's really all I have to say about the

    20    serologies at this point.  If there are questions,

    21    I'll take them.

    22              One further comments would be that these

    23    data are really not so different from what we were

    24    discussing in January, although there was a lot of

    25    additional information that was collected.  If there

                                                                         34

     1    aren't any questions about that, then I'll just go on

     2    and make a few comments about the availability of

     3    strain reagents.

     4              The Influenza A/New Caledonia/20/99 (H1N1)

     5    high‑growth reassortant virus, the IVR‑116, is

     6    currently being used for manufacturing.  Information

     7    on the yield of the strain suggest it to be a

     8    moderately high yielding strain.  For the benefit of

     9    manufacturers, the specific antisera and antigen for

    10    performing the potency test for A/New Caledonia will

    11    be available from the Center for Biologics within the

    12    next two weeks.

    13              The antigen is in the last stages of

    14    calibration for use and both it and the specific sheep

    15    antiserum are being prepared for distribution even

    16    today as we're speaking.  These reagents are available

    17    at an earlier time this year than usual for a new

    18    strain because of efforts to support manufacturing for

    19    vaccines being distributed in the southern hemisphere

    20    and we think that's actually a good thing for helping

    21    us smooth out the difficulties with making strain

    22    changes.

    23              There are five high‑growth reassortants of

    24    the A/Panama/2007/99 (H3N2) virus that are being

    25    evaluated.  As Sasha Klimov was pointing out, all of

                                                                         35

     1    these appear to be antigenically equivalent.  Even

     2    though he didn't have all five listed in the table,

     3    they are all antigenically equivalent.  Two of these

     4    appear to be higher yielding than the others. 

     5              Additional information is being gathered on

     6    those to determine whether one or the other of those

     7    strains might be better suited to downstream

     8    processing which is an issue also.

     9              Potency reagents are not currently available

    10    for the Panama/2007 strain, although immunization of

    11    sheep has been begun in anticipation that strain might

    12    be a potential vaccine candidate.  Potency reagents

    13    for the A/Panama/2007 strain would not be available

    14    until sometime in May which is typical time for these.

    15              Of course, we do have the reagents for the

    16    A/Sydney strain currently available and in the event

    17    that a Panama strain was chosen for manufacturing,

    18    those reagents could be used in the interim, although

    19    they would be expected to give a falsely high estimate

    20    of how much vaccine was being produced.

    21              The B/Yamanashi/166/98 virus and potency

    22    reagents are currently available.  However, here we

    23    don't have as much of a choice in terms of the

    24    practical issues.  Work that's been done earlier in

    25    the United States and Europe with the

                                                                         36

     1    B/Johannesburg/599 strain and in Australia with the

     2    B/South Australia/599 strain suggest that neither of

     3    those strains would be suitable for manufacturing

     4    because of their poor growth characteristics.  Really

     5    we don't have any other candidate, Yamanashi‑like

     6    strains at this time.

     7              One further comment about the

     8    B/Shenzhen/654/99 strain is that working with it in

     9    the laboratory it seems to have, at least in some

    10    laboratories, some unusual properties in that when the

    11    antigen is split with ether whereas normally we would

    12    expect the hemagglutinin titer to increase

    13    substantially it sometimes goes down and that's a

    14    little bit concerning.

    15              That's all that I have to say about the

    16    strains and reagents unless there are some questions

    17    or comments.        

    18              DR. FAGGETT:  One question.  This is Dr.

    19    Faggett in Washington.  You said there were two

    20    strains that had a high yield because they were

    21    antigenically ‑‑ there were two strains of those?

    22              DR. LEVANDOWSKI:  We're talking about the

    23    A/Panama/2007/99 reassortants that I believe you are

    24    referring to.  Those two strains are designated as

    25    Resvir‑17 and NIB‑41.  They are both reassortants that

                                                                         37

     1    were produced using the A/Panama/2007/99 virus as the

     2    wild‑type parent.

     3              PARTICIPANT:  Roland, has just one high‑

     4    yield reassortant on the New Caledonia been

     5    distributed to manufacturers?

     6              DR. LEVANDOWSKI:  That has been and at this

     7    point we don't anticipate using any others mainly

     8    because of the issues about making the reagents

     9    specific for the strain.  We have noticed in past

    10    years recently that there can be some differences in

    11    the behavior of the behavior of the potency reagents

    12    for different isolates, even though when they are

    13    related by the wild‑type parent.  

    14              PARTICIPANT:  I just wondered if in the

    15    manufacturer's hands if you looked at the other New

    16    Caledonia candidates they might be higher yielding.

    17              DR. LEVANDOWSKI:  I believe there may be

    18    some information on that but I don't have it at hand.

    19              PARTICIPANT:  Okay.  

    20              DR. SNIDER:  Roland, this is Dixie Snider. 

    21    You went over it rather fast, at least with regard to

    22    the B reassortants that might be available.  What I

    23    took away was that there was no B/Yamanashi strains

    24    that were viable.  Then you started talking about

    25    Shenzhen I lost you.

                                                                         38

     1              DR. LEVANDOWSKI:  I'm sorry.  I do tend to

     2    talk pretty fast when I'm excited like I am today. 

     3    There are no reassortants for the B strains at this

     4    point.  The manufacturers rely entirely on the wild‑

     5    type strain and in producing vaccine that often is one

     6    of the biggest problems, to get a wild‑type influence

     7    of B virus that grows well.

     8              What I meant to point out but maybe didn't

     9    do well enough was that the strains that have been

    10    examined by manufacturers so far which include the

    11    Johannesburg/599 and the South Australia/599 did not

    12    appear like they would be of practical use in

    13    manufacturing.  

    14              The Shenzhen/654 strain has not been

    15    examined as far as I know but, as I was mentioning,

    16    there are some concerns that come out of just the

    17    laboratory testing of the strain about whether that

    18    would be a suitable strain or not.

    19              DR. COUCH:  Harry, would you permit me?  Bob

    20    Couch.

    21              DR. GREENBERG:  It would be my pleasure.

    22              DR. COUCH:  I will just be brief and I'm

    23    sure you'll have other discussions and there may be

    24    different views as well.  I think probably our

    25    decisions are not very complicated.  

                                                                         39

     1              Regarding B, I would like to have known more

     2    about the influence of the B strain variation and the

     3    epidemiology of what's going on in China with regard

     4    to questions like Shenzhen and South Australia, but I

     5    think our information otherwise is fairly

     6    straightforward that I would recommend that we stay

     7    with B/Yamanashi again for the coming year.

     8              Regarding the H3N2, I agree with Ed.  I

     9    don't think it's absolutely clear that there is a

    10    distinct change that requires a change.  But, on the

    11    other hand, as he said, I think we have that as a knee

    12    jerk response and I think we need a little fine tuning

    13    if that's what we have in store on the H3N2.  

    14              I'd feel a little bit better with Panama in

    15    view of the suggested changes in the neuraminidase as

    16    well even though we don't have antigenistic data.  I'm

    17    a little more comfortable with changing that H3N2 and

    18    Panama looks like our best bet in that regard.  That

    19    would be my recommendation on H3N2.

    20              DR. GREENBERG:  Thank you very much, Bob.

    21              DR. COUCH:  And I'll have to run.

    22              DR. GREENBERG:  Okay.  Have a good noon

    23    meeting.

    24              DR. COUCH:  Thanks.

    25              MS. CHERRY:  Thanks, Dr. Couch.

                                                                         40

     1              DR. GREENBERG:  Roland, back to you.

     2              DR. LEVANDOWSKI:  Okay.  Are there other

     3    questions at this point?  If there weren't, I would be

     4    prepared to make a summary of this and give some

     5    options for what the strain choices might be.

     6              MS. CHERRY:  Please do.

     7              DR. GREENBERG:  Yes.

     8              DR. LEVANDOWSKI:  For the 2000‑2001

     9    influenza vaccine, just to summarize the information

    10    about the H3N2 and the Influenza B viruses starting

    11    with the H3N2 Influenza A.

    12              In the case of the H3N2 Influenza A viruses,

    13    it's pretty clear that antigenic drift is continuing. 

    14    Most of the strains are antigenically similar to the

    15    A/Sydney/597 and A/Panama/2007/99 strains.  However,

    16    we have some evidence that suggest that the

    17    neuraminidase of the more recent strains is different

    18    from that of the current vaccine strain which is

    19    A/Sydney/597.  That can be debated some.

    20              Ten to 15 percent of the strains, no matter

    21    what the choice is, are not well inhibited by the

    22    ferret sera but those low reactors, as we emphasized

    23    in January, don't fall into any particular genetic

    24    background.  

    25              Whereas the CDC normally receives 2 to 3

                                                                         41

     1    percent of its influence isolates from persons who are

     2    immunized, this year the percent seems to be higher,

     3    about 9 percent of the isolates, which is a

     4    substantial increase from people who got this year's

     5    vaccine and nevertheless were infected.  That was

     6    without particular effort to try to collect those

     7    strains.

     8              Some of the H3N2 viruses are not very well

     9    inhibited by antisera from people who are immunized

    10    with the current vaccines that contain the

    11    A/Sydney/5/97 strain.  Again, the current vaccine

    12    strain, A/Sydney/5/97, has been around already for two

    13    years which is quite a long time by modern standards

    14    for an H3N2 strain given the continuous antigenic

    15    drift.

    16              Finally, the high‑growth reassortants of

    17    A/Panama/2007/99 are available.  They appear to grow

    18    well.  It looks like they would be possible to use in

    19    manufacturing.  

    20              The options for the H3N2 strain, the first

    21    option would be, of course, to continue to use the

    22    current vaccine strain which is A/Sydney/5/97.  In

    23    favor of that, I would say that the manufacturing is

    24    very well worked out and the yield is highly

    25    predictable.  In addition, many of the viruses this

                                                                         42

     1    year are A/Sydney/5/97‑like.

     2              Again that is that there is antigenic drift

     3    that is continuing.  The vaccine strain, again, is

     4    relatively old for an H3N2 strain.  More than the

     5    usual number of H3N2 isolates are from persons who are

     6    immunized with the current vaccine.  A consistent

     7    minority of all the strains, however, are not well

     8    inhibited by the sera produced against the current

     9    vaccine.  

    10              This brings me to the second option and I

    11    think there are only two here.  The second option is

    12    to change the current vaccine to a strain that is more

    13    representative of the currently circulating viruses

    14    such as the A/Panama/2007/99.  In favor of that a more

    15    recent strain would provide a closer match with the

    16    hemagglutinin and the neuraminidase of contemporary

    17    strains.  

    18              There are some alternative high growth

    19    reassortants that could be chosen.  Against that we

    20    really don't know that a new strain would be superior

    21    in coverage for the low reactors in terms of its

    22    comparison to A/Sydney.

    23              Turning to the Influenza B viruses ‑‑

    24              DR. GREENBERG:  Roland?

    25              DR. LEVANDOWSKI:  Yes.

                                                                         43

     1              DR. GREENBERG:  Do you want to do both of

     2    these and then have discussion or do you want to have

     3    any discussion about your H3N2 and then have a vote on

     4    that?

     5              DR. LEVANDOWSKI:  If it's simpler to go

     6    ahead with the H3N2, I think that might be the way to

     7    go if that's what you're suggesting.

     8              DR. GREENBERG:  It's up to you but I think

     9    that might be simpler since it's totally fresh and you

    10    just went through the options and people can ask you

    11    a question and then we can vote.

    12              DR. LEVANDOWSKI:  Okay.  That's perfectly

    13    fine with me.

    14              DR. GREENBERG:  Are there any further

    15    clarifications that anyone would like of Roland or

    16    anybody else?

    17              DR. SNIDER:  Well, Harry, this is Dixie.  I

    18    was just going to mention that this week's MMWR also

    19    points out that although this past season has not been

    20    out of line with the kinds of epidemics we've had in

    21    the past five seasons, it has been shall we say one of

    22    the more severe seasons.  I think that is also a

    23    factor that would indicate to me that it would be wise

    24    to try to keep up with this drift if it continues to

    25    occur.

                                                                         44

     1              DR. GREENBERG:  Thank you, Dixie.  Does

     2    anybody have anything else to say before we call a

     3    vote?

     4              DR. FAGGETT:  This is Walt Faggett.  That

     5    would be pushing towards changing the Sydney, right? 

     6    Is that what you're saying?

     7              DR. SNIDER:  Yes.

     8              DR. FAGGETT:  So that 9 percent probably was

     9    due to that.

    10              DR. SNIDER:  Yeah, and what I'm saying is

    11    that we had other indicators of the severity of the

    12    epidemic during this past year.  Although we've seen

    13    numbers like we've seen this past year in some

    14    previous seasons, you would have to say it was a bad

    15    season.

    16              DR. GREENBERG:  Okay.

    17              MS. CHERRY:  Dr. Greenberg, I think it's

    18    only fair we open the floor for an open public hearing

    19    before we vote.

    20              DR. GREENBERG:  Okay.

    21              DR. KOHL:  This is Dr. Kohl.  I would just

    22    like to comment before we do that.  I'm more concerned

    23    in the H3N2 story in that, as was mentioned, this will

    24    be the third year we have a Sydney‑like virus in the

    25    vaccine.  Last year was a more severe epidemic and

                                                                         45

     1    would possibly suggest that the vaccine maybe wasn't

     2    working quite as well, although that is jumping a

     3    little bit.

     4              The problem, of course, is that we don't

     5    have another virus to go to that looks like it's a

     6    leading candidate.  I think there is some concern in

     7    our two options.

     8              DR. GREENBERG:  I agree with you, Dr. Kohl. 

     9    Of course, I don't think there has ever been a flu

    10    season where anybody knowing the way flu works doesn't

    11    have some concern.  Are there any other questions or

    12    comments?

    13              DR. FERRIERI:  This is Pat Ferrieri, Harry. 

    14    I just wanted to echo some of the concerns about the

    15    current ‑‑ if we would retain the Sydney/597.  I'm

    16    totally opposed to doing that based on the background

    17    noise that we've been hearing on clinical failures. 

    18    I think we do have a reasonable substitute.

    19              DR. GREENBERG:  Thank you, Pat.  Anybody

    20    else want to weigh in before we open it up to the

    21    public?

    22              DR. ESTES:  This is Mary Estes.  I concur

    23    with Pat.

    24              DR. GREENBERG:  Thank you, Mary. 

    25              DR. EICKHOFF:  This is Ted Eickhoff.  I will

                                                                         46

     1    take a contrary position and simply point out it's

     2    really stretching the science considerably to infer

     3    that the severity of the outbreak this year was due to

     4    continuing antigenic drift.  It may have been but

     5    there certainly may have been other factors also.

     6              Furthermore, that 9 percent figure for

     7    strains submitted from "vaccine failures" is subject

     8    to a whole lot of selection by us about which we know

     9    very little or nothing.

    10              DR. KILBOURNE:  This is Ed Kilbourne.  I

    11    agree with Ted absolutely on both points.  I also have

    12    to say that I'm in agreement with that and also with

    13    the way Bob Couch analyzed the situation.  I think I'm

    14    particularly disturbed by the evidence of possible

    15    neuraminidase change.  I would probably go along with

    16    change.

    17              DR. GREENBERG:  Thank you both, Dr. Eickhoff

    18    and Dr. Kilbourne.  Are there any other comments?

    19              MS. FISHER:  I have one comment.  Barbara

    20    Fisher.  I think there has to be a more competent

    21    investigation into genetic and other differences in

    22    those individuals who suffer vaccine failure and those

    23    who don't, those who die from the flu and those who

    24    don't.  It may be that we're talking about something

    25    that has to do with the individual versus the vaccine.

                                                                         47

     1              DR. KLIMOV:  This is Dr. Klimov.  That is

     2    exactly what we are doing right now.  We tried to

     3    investigate as much as we can about the history of

     4    some vaccine failures as well as about the genetic

     5    characteristics of those viruses.

     6              DR. GREENBERG:  Thank you, Ms. Fisher and

     7    Sasha.  Any other comments?  Okay.  

     8              Nancy, you said you had people there in the

     9    audience who might want to make a comment?

    10              MS. CHERRY:  Well, I think it's only fair

    11    before we take a vote.

    12              DR. GREENBERG:  Yeah.  We can't see who's

    13    there.

    14              MS. CHERRY:  If there is anyone in the room

    15    that would like to make a comment, we do have some

    16    microphones.  Well, I do not see a rush to the

    17    microphone so I guess we can proceed.

    18              DR. GREENBERG:  Okay.  Nancy, could you call

    19    a roll call vote because you know who's currently here

    20    and who is not and I don't.

    21              MS. CHERRY:  Well, there are a few I'm not

    22    sure of but let's start ‑‑ well, do we need a motion,

    23    Harry?

    24              DR. GREENBERG:  Yeah.  I am going to make a

    25    motion, I guess, which is that ‑‑ we can go on to a

                                                                         48

     1    second motion if this doesn't work, and that is I make

     2    a motion that we recommend that the H3N2 component of

     3    the coming year's vaccine be switched to the

     4    Panama/2007/99‑like virus.

     5              PARTICIPANT:  I second that.

     6              DR. GREENBERG:  Is that okay?

     7              PARTICIPANT:  Second.

     8              DR. GREENBERG:  Thank you.  So that's the

     9    motion.

    10              MS. CHERRY:  Okay.  Now, I will go down the

    11    list then and read them off.  Dr. Kohl.

    12              DR. KOHL:  I agree.  

    13              MS. CHERRY:  Dr. Huang.

    14              DR. HUANG:  I agree.

    15              MS. CHERRY:  Dr. Daum.

    16              DR. DAUM:  I agree and wonder if it's

    17    possible to consider a more outreaching collection of

    18    viruses from failure patient strategy to avoid the

    19    selection bias that I think Ted Eickhoff rightly

    20    raised as a possible concern.

    21              MS. CHERRY:  Okay.  Dr. Stephens.

    22              DR. STEPHENS:  I agree.

    23              MS. CHERRY:  Dr. Faggett.

    24              DR. FAGGETT:  I agree.

    25              MS. CHERRY:  Ms. Fisher.

                                                                         49

     1              MS. FISHER:  I abstain.

     2              MS. CHERRY:  Okay.  Dr. Kim, are you there? 

     3    Okay.  He's not.  Dr. Estes.

     4              DR. ESTES:  I agree.

     5              MS. CHERRY:  Dr. Snider.

     6              DR. SNIDER:  I agree.

     7              MS. CHERRY:  Dr. Griffin.

     8              DR. GRIFFIN:  I agree.

     9              MS. CHERRY:  Dr. Greenberg.  Obviously you

    10    agree.  It was your motion.

    11              DR. GREENBERG:  Just to be contrary I could

    12    change my mind.

    13              MS. CHERRY:  Don't do that across 3,000

    14    miles.  Dr. Broome, are you there?  No.  Okay.  Dr.

    15    Eickhoff.

    16              DR. EICKHOFF:  I support the update.  I

    17    agree.

    18              MS. CHERRY:  Okay.  Dr. Ferrieri.

    19              DR. FERRIERI:  I agree.

    20              MS. CHERRY:  Dr. Myers.

    21              DR. MYERS:  I agree.

    22              MS. CHERRY:  Dr. Katz.

    23              DR. KATZ:  I agree.

    24              MS. CHERRY:  Dr. Hoke.

    25              DR. HOKE:  I agree.

                                                                         50

     1              MS. CHERRY:  Dr. Couch is gone but we had

     2    his.  And Dr. Kilbourne.

     3              DR. KILBOURNE:  Yes.

     4              DR. GREENBERG:  I have a question.  This may

     5    be procedural.  I would like a clarification.  Ms.

     6    Fisher?

     7              MS. FISHER:  Yes.

     8              DR. GREENBERG:  On the abstention is your

     9    abstention ‑‑ the vote was how to pick a new influenza

    10    strain and I'm just curious whether your abstention is

    11    you're feeling that you don't have enough 

    12    information ‑‑

    13              PARTICIPANT:  I wasn't voting on that.  I

    14    was voting on ‑‑

    15              DR. GREENBERG:  No, no.  I was speaking to

    16    Ms. Fisher.

    17              MS. FISHER:  My abstention is I don't feel

    18    comfortable participating in the vote.  I just don't

    19    think that it is something that I can vote on at this

    20    point.

    21              DR. GREENBERG:  Is that because you don't

    22    think there should be an influenza vaccine?

    23              MS. FISHER:  Oh, no.

    24              MS. CHERRY:  Harry, it's all right.  I don't

    25    think she really needs to explain.

                                                                         51

     1              DR. GREENBERG:  Okay.

     2              MS. FISHER:  It was not that at all.  Just

     3    that I don't feel comfortable participating in this

     4    decision.

     5              DR. GREENBERG:  Okay.

     6              PARTICIPANT:  Dr. Greenberg, I'm sorry but

     7    I was voting on what I thought was a motion to approve

     8    a change.

     9              DR. GREENBERG:  Yes.

    10              PARTICIPANT:  You're stating a lot of other

    11    things in your repetition of that motion.  I just want

    12    to be sure I wasn't voting on a lot of things

    13    including problems of selection and so forth.

    14              DR. GREENBERG:  No, I think, as I understand

    15    it, you were simply voting on the motion which was to

    16    change next year's strain to A/Panama/2007/99‑like

    17    strain.

    18              PARTICIPANT:  Okay.

    19              DR. GREENBERG:  So, as I understand it,

    20    we've completed one half of our selection.  Now,

    21    Roland, I would love you to go through the pluses and

    22    minuses of our questions for the B.

    23              DR. LEVANDOWSKI:  Okay.  I think the B

    24    selection may make itself but let me just summarize

    25    what information we have.

                                                                         52

     1              The antigenic drift is clearly continuing in

     2    Influenza B viruses as well.  Most of the strains

     3    worldwide are related to the current vaccine strain

     4    which is B/Yamanashi/166/98.  Within that group there

     5    is a new variant represented by the B/Shenzhen/654/99

     6    but it's not really clear how extensively that strain

     7    is spreading.  I don't think we have good information

     8    to suggest that it is at this point but it's just a

     9    little bit fuzzy.

    10              There is no evidence that the spread of the

    11    B/Victoria/287‑like strains and it's my understanding

    12    that those appear to be declining in frequency at the

    13    present time, although they are still being found in

    14    some parts of Asia where they had been found

    15    previously.

    16              Some Influenza B viruses that are related to

    17    the current vaccine strain are not well inhibited by

    18    antisera from people who are immunized with the

    19    current vaccines that contain the B/Yamanashi/166/98

    20    strain.  However, the B/Johannesburg/5/99 and B/South

    21    Australia/5/99 strains that were identified as being

    22    potentially capable of giving broad coverage for most

    23    of the Influenza B viruses don't grow very well and

    24    they would not be good choices for manufacturing.

    25    We don't really have other additional vaccine

                                                                         53

     1    candidate strains at this time.

     2              The options for Influenza B, the first

     3    option would be to retain the current vaccine strain

     4    which is B/Yamanashi/166/98.  In favor of that, again,

     5    most of the Influenza B viruses are clearly related to

     6    the current vaccine strain.  In addition,

     7    manufacturing is well defined and it's predictable.

     8              Contrary, or on the negative side, there is

     9    a new variant strain that has been recently identified

    10    and we're not always sure where those things are

    11    going.  Some of the Yamanashi‑like strains are also

    12    not well inhibited by the post‑immunization antisera.

    13              That leads me to the second option.  The

    14    second option would be to change the current vaccine

    15    strain to a more recent B/Yamanashi‑like strain.  In

    16    favor of that would be that the vaccines might provide

    17    broader coverage for the currently circulating

    18    Influenza B viruses.  Contrary to that is that there

    19    aren't any true alternate vaccine candidate strains

    20    and those that have been looked at really are not

    21    going to be adequate for large scale manufacturing.

    22              Those are the options and if there are

    23    questions or ‑‑

    24              DR. GREENBERG:  Roland, can I ask you a

    25    question?  It seems to me you've postulated a

                                                                         54

     1    hypothetical option but not a real option.  A

     2    hypothetical option is actually not an option.  If I

     3    understand it correctly, there is no chance to change

     4    because we don't have anything to change to.  Is that

     5    correct or do I have it wrong?

     6              DR. LEVANDOWSKI:  I think we can always make

     7    an attempt to catch up with a strain that is

     8    identified as being a significant new variant that

     9    really requires a response.  In the past you might

    10    remember that in 1986 there was a new H1N1 virus that

    11    was identified only toward the end of March and an

    12    attempt was made to make vaccines for that.  

    13              It's very, very difficult this late in the

    14    year for manufacturers actually to turn around and

    15    gear up to make a change for a strain they haven't had

    16    a chance to work with yet.  From a practical point of

    17    view, I would say that if there were great urgency to

    18    do so, we would certainly want to make the attempt to

    19    do it.  

    20              Given the current circumstances where we

    21    don't have information that suggest that great

    22    urgency, I think it would be hard to postpone the

    23    decision to try to fine some other strain which also

    24    might turn out not to grow very well.

    25              DR. GREENBERG:  Okay.  Are there any other

                                                                         55

     1    questions?  

     2              MS. CHERRY:  I guess then let's open the

     3    floor again in case anyone wishes to comment here

     4    before the vote.

     5              PARTICIPANT:  Question on the floor.

     6              MS. CHERRY:  Again, I do not see anyone. 

     7    I'm sorry.  Who had ‑‑

     8              DR. HUANG:  May I make a motion?  This is

     9    Alice.

    10              DR. GREENBERG:  Yes, Alice.  Make a motion.

    11              MS. CHERRY:  Alice?

    12              DR. HUANG:  I would like to move that we

    13    remain with the current vaccine strain, the Yamanashi,

    14    for the B.

    15              DR. SNIDER:  Second.

    16              MS. CHERRY:  Who was that?

    17              DR. SNIDER:  Dixie.

    18              MS. CHERRY:  Okay.

    19              DR. GREENBERG:  Okay.  We have a motion.

    20              MS. CHERRY:  Would you like me to read the

    21    list?

    22              DR. GREENBERG:  Yes, please.

    23              DR. FERRIERI:  May I ask a question first,

    24    Harry?

    25              DR. GREENBERG:  Sure.

                                                                         56

     1              DR. FERRIERI:  Does this permit the ‑‑ does

     2    exclude the possibility of choosing a recent isolate

     3    of B/Yamanashi to use as Roland suggested or does this

     4    confine us to the precise strain used in this year's

     5    vaccine?

     6              DR. GREENBERG:  Roland, could you answer

     7    that?

     8              DR. LEVANDOWSKI:  Yes, I will.  Yes, it

     9    would require us.  We would be using what's the

    10    current vaccine strain.  It would not be another

    11    similar strain.

    12              DR. GREENBERG:  No, I think what Pat asked

    13    was does this mean if all of a sudden a new B isolate

    14    appeared two days from now that clearly looked very

    15    different and looked like the right choice, would we

    16    not be able to change?  Isn't that what you were

    17    asking, Pat?

    18              DR. FERRIERI:  Yes, that, you know, has

    19    relationship genetically to B/Yamanashi but it's a

    20    recent isolate that has some evidence of drift.  You

    21    hinted, Roland, that we might use that as an option.

    22              DR. LEVANDOWSKI:  Well, I guess I would have

    23    to answer that by saying that I don't really know of

    24    another strain at this point that has qualities that

    25    from the outset would make it look suitable for

                                                                         57

     1    manufacturing.  I think that's what I was trying to

     2    point out, that we have made an attempt to find some

     3    egg isolates of newer Influenza B viruses that might

     4    be suitable for manufacturing and we've not been able

     5    to do that.

     6              DR. SNIDER:  Roland, this is Dixie.  Isn't

     7    there another issue here which would be that if we

     8    came up with another B strain, we would have all three

     9    new components?  How long would that take to

    10    manufacture?

    11              DR. LEVANDOWSKI:  Well, that issue I wasn't

    12    going to get into but, yes, it would be somewhat

    13    difficult for manufacturers to change all three

    14    strains in one year if it's not really necessary.  If

    15    it were necessary, we would make an attempt to do that

    16    but it would mean that vaccines would be delayed for

    17    a longer period of time than it normally takes to

    18    produce them.  It would be difficult to make that

    19    change.  

    20              Although this year we are in a somewhat

    21    different situation where we have for the first strain

    22    that was selected as a different strain we were able

    23    to get reagents together at an earlier time.

    24              DR. SNIDER:  Right, for the southern

    25    hemisphere.  But, nevertheless, I mean, that is an

                                                                         58

     1    issue I think that is important to have on the table.

     2              DR. GREENBERG:  Are there any other

     3    comments?

     4              PARTICIPANT:  Yeah.  Roland, is there still

     5    work ongoing looking for a more suitable B isolate

     6    that will grow?

     7              DR. LEVANDOWSKI:  I don't know of the actual

     8    work that's going on.  I do know that all of the WHO

     9    influenza centers are continuously examining strains

    10    that come in and I believe that our colleagues from

    11    CDC could answer if they thought they had found any

    12    additional strains up to this point that might be

    13    candidates.  

    14              I don't believe that's true.  One of the

    15    difficulties for us is finding strains that are egg

    16    isolates.  In current times a lot of the strains that

    17    come in for antigenic characterization are from tissue

    18    culture isolates which we have not really found

    19    suitable for manufacturing.

    20              PARTICIPANT:  So you're saying that it's

    21    extremely unlikely within the next month, for

    22    instance, that there will emerge a candidate that

    23    could be used in manufacturing the vaccine.

    24              DR. LEVANDOWSKI:  I think it's not too

    25    likely but it's possible.  I mean, it's always

                                                                         59

     1    possible that a new strain will be identified.

     2              PARTICIPANT:  And is it possible, Harry, for

     3    us as a committee to leave that door open?

     4              DR. GREENBERG:  I assume.  That was the

     5    original question to Roland who opened this situation. 

     6    I assume that it's always possible to alter what's

     7    going into the vaccine assuming that epidemiologic

     8    information has changed.  This is simply, I think, our

     9    best recommendation at this point in time.

    10              PARTICIPANT:  Well, this is an unusual

    11    situation.  I think it sounds like we have

    12    epidemiological information that there are new Bs out

    13    there that would be better covered by a virus but we

    14    don't have one that grows well enough to cover it.

    15              DR. GREENBERG:  I thought we do not have

    16    compelling evidence of a new B variant.  That's the

    17    issue, that there is some noise out there and it might

    18    be that a new B one is what we want but it's not an

    19    overwhelming picture.

    20              Roland, can you clarify this for me and the

    21    committee?

    22              DR. LEVANDOWSKI:  I'll try to answer that. 

    23    The B/Shenzhen/654/99 strain does represent apparently

    24    ‑‑ if Dr. Klimov and Dr. Cox are available, they will

    25    need to comment, too, but I believe we should view

                                                                         60

     1    that as a true new variant of Influenza B virus.  What

     2    we don't really have evidence of at this point is that

     3    that strain is spreading and displacing the majority

     4    strains which are still quite clearly

     5    B/Yamanashi/166/99‑like but that could change, as

     6    always, that the epidemiology is always moving on.

     7              PARTICIPANT:  Roland, a B/Shenzhen isolate

     8    would also cover the B/Yamanashi‑like isolate?

     9              DR. LEVANDOWSKI:  Dr. Klimov will probably

    10    want to comment on this but from his tables, and I'm

    11    not sure which page that's on at this point to tell

    12    you the truth, I think suggest that the B/Shenzhen

    13    strain would not necessarily produce at least a ferret

    14    sera that covers all the B/Yamanashi strains that

    15    well.  In fact, it might not be a good choice for that

    16    reason.

    17              DR. GREENBERG:  That was my impression. 

    18    Even if such a ‑‑

    19              DR. KLIMOV:  On page 6 you can see the table

    20    which includes the Shenzhen/654/99 ferret antisera. 

    21    You can see that this antisera definitely do not work

    22    well against new viruses.  Still Yamanashi seems to be

    23    the best one that works reasonably well with the

    24    majority of viruses circulating at this moment.

    25              DR. GREENBERG:  Okay.  Thank you for

                                                                         61

     1    clarifying that.  Are there more questions?  I think

     2    then we can if we don't have anymore questions ‑‑

     3    Nancy, I take it nobody in the open hearing got up?

     4              MS. CHERRY:  No one has.  Let me give them

     5    one last chance.  No, no one is rising from their

     6    seat.

     7              DR. GREENBERG:  So we have a motion from

     8    Alice.  Nancy, can you call the roll call?

     9              DR. FAGGETT:  And repeat the motion, please.

    10              DR. GREENBERG:  The  motion from Alice, I

    11    think, if I have it right, Alice, and correct me, was

    12    that we recommend that we stay with the current

    13    B/Yamanashi virus for the coming season, the 166/98.

    14              DR. HUANG:  That's right, Harry.

    15              MS. CHERRY:  Okay.  Here we go.  Dr. Kohl.

    16              DR. KOHL:  I support the motion.

    17              MS. CHERRY:  Dr. Huang, obviously.  Dr.

    18    Daum.

    19              DR. DAUM:  Support. 

    20              MS. CHERRY:  I'm sorry?          

    21              DR. DAUM:  I support the motion.

    22              MS. CHERRY:  Okay.  Dr. Stephens.

    23              DR. STEPHENS:  I support the motion.

    24              MS. CHERRY:  Dr. Faggett.

    25              DR. FAGGETT:  I support the motion.

                                                                         62

     1              MS. CHERRY:  Ms. Fisher.

     2              MS. FISHER:  I abstain.

     3              MS. CHERRY:  Okay.  Dr. Kim.  Dr. Estes.

     4              DR. ESTES:  I agree.

     5              MS. CHERRY:  Dr. Snider.

     6              DR. SNIDER:  Yes.     

     7              MS. CHERRY:  Dr. Griffin.

     8              DR. GRIFFIN:  I agree.

     9              MS. CHERRY:  Dr. Greenberg.  

    10              DR. GREENBERG:  I agree.

    11              MS. CHERRY:  Dr. Broome.  Dr. Eickhoff.

    12              DR. EICKHOFF:  I agree.

    13              MS. CHERRY:  Dr. Ferrieri.

    14              DR. FERRIERI:  I agree.

    15              MS. CHERRY:  Dr. Myers.

    16              DR. MYERS:  I agree.

    17              MS. CHERRY:  Dr. Katz.

    18              DR. KATZ:  I agree.

    19              MS. CHERRY:  Dr. Hoke.

    20              DR. HOKE:  I agree.

    21              MS. CHERRY:  Dr. Couch is gone.  Dr.

    22    Kilbourne.  Dr. Kilbourne?  Dr. Kilbourne?

    23              DR. KILBOURNE:  I agree.  I'm sorry.  I was

    24    muted.

    25              MS. CHERRY:  Okay.

                                                                         63

     1              DR. GREENBERG:  Thank you for being so mute.

     2              DR. KILBOURNE:  It rarely happens.

     3              MS. CHERRY:  That's the end of the voting.

     4              DR. GREENBERG:  Okay.  I would like to thank

     5    all of you for moving through that so expediously.

     6              Nancy, as I look at the agenda, correct me

     7    if I'm wrong, we now have something that says Open

     8    Session, Vaccine Safety Action Plan.

     9              MS. CHERRY:  Yes.  As we move into that,

    10    that will be Dr. Egan speaking.  I want to remind the

    11    committee that we did not screen you for this because

    12    this was to be a case where we are giving you

    13    information rather than asking you for advice so there

    14    was no conflict of interest screening.  You certainly

    15    are welcome to ask questions but, again, our sign is

    16    not hanging out for advice.

    17              DR. GREENBERG:  Nancy.

    18              MS. CHERRY:  Yes.

    19              DR. GREENBERG:  I'm just going to ask my

    20    other committee members.  I know I have to just get up

    21    for a minute or two and I just wondered whether we

    22    could take like a three minute break to let anybody do

    23    anything they need to do before Dr. Egan gets started.

    24              MS. CHERRY:  Absolutely.

    25              DR. GREENBERG:  Is that okay, folks?

                                                                         64

     1              PARTICIPANT:  Good idea.

     2              PARTICIPANT:  Sure.

     3              DR. GREENBERG:  Okay.

     4              MS. CHERRY:  And when Dr. Greenberg gets

     5    back then we will reconvene.

     6              DR. GREENBERG:  I have about a hundred yard

     7    run.  If we can get this wound up and people can get

     8    on their way, that would be terrific.

     9              (Whereupon, at 1:29 p.m. off the record

    10    until 1:36 p.m.)

    11              DR. GREENBERG:  We should probably get

    12    started.

    13              DR. EGAN:  Thank you.  As I just mentioned,

    14    what I'm planning to do is just give a little bit of

    15    an update to the committee about the Department's

    16    vaccine safety action plan and implementation plan.  

    17              MS. CHERRY:  Can you hear him well enough?

    18              PARTICIPANT:  Yes.

    19              DR. EGAN:  Although concerns about safety

    20    have always attended the use of vaccines, these

    21    concerns have loomed somewhat larger in recent years. 

    22    The increased number of vaccinations that are

    23    available and that are required is obviously one of

    24    the reasons for this increased concern about safety.

    25              Paradoxically, also the very success of

                                                                         65

     1    vaccines is another reason.  The diseases that

     2    vaccines have been designed to prevent are gone and

     3    are no longer perceived as much of a threat as before. 

     4    Attention thus turns to the adverse events that may

     5    accompany vaccines.

     6              On this overhead I've listed a number of

     7    vaccine concerns.  Most of these concerns are fairly

     8    recent, Hib vaccines and diabetes, for examples.  Some

     9    of them are quite old, the progressive vaccinity that

    10    accompanied smallpox.  Some of these are clearly

    11    linked to vaccination.  Oral polio vaccine and vaccine

    12    associated paralytic polio as an example.

    13              Others are not clearly linked.  Measles and

    14    autism for example.  Some may be very specific to the

    15    vaccine strain as with mumps vaccine and aseptic

    16    meningitis.  This has been linked to the Urabe strain

    17    but not to the Jeryl Lynn strain that is in use in the

    18    United States.

    19              This is a small list of concerns that have

    20    been expressed in recent years concerning vaccine

    21    safety.  I can list a good number of additional

    22    concerns and put up many, many more slides. 

    23    Assessments of these concerns certainly need to be

    24    done.  However, these take resources and these

    25    resources are limited and prioritizations need to be

                                                                         66

     1    made.

     2              I would like to make a few points about

     3    these concerns.  These safety issues can stem from the

     4    vaccine itself.  For example, again, VAPP and polio or

     5    aseptic meningitis and the Urabe strain of the mumps

     6    vaccine.  They can stem from an adventitious agent in

     7    the vaccine.  For example, SV40 that was found in the

     8    oral polio vaccine.  They can stem from additives or

     9    adventitious materials that are found in the vaccine.

    10              Some recent work in our own laboratories

    11    indicate that the thrombocytopenia that is associated

    12    with the measles vaccine may derive from an

    13    adventitious protein that is a protein from cell

    14    substrate that is present in the vaccine.

    15              One can also look at adverse events due to

    16    LPS, DNA, antibiotics and what have you, that make

    17    their way into the vaccine.  For some of these

    18    concerns causality has been established.  For some the

    19    most evidence is against them.  For some the evidence

    20    is uncertain.

    21              What is certain, however, is that an

    22    increased emphasis needs to be placed on and increased

    23    resources need to be devoted to vaccine safety

    24    activities.  We need to better address the problems

    25    that are or may be associated with vaccines.  We need

                                                                         67

     1    to do this in a prospective fashion and retrospective

     2    fashion. 

     3              The vaccine safety implementation plan is a

     4    departmental plan to address this need.  It also

     5    includes a component on vaccine communication.  The

     6    plan itself arose as a result of a report that was

     7    presented to Secretary Shalala from the task force on

     8    Safer Childhood Vaccines.  The Secretary then directed

     9    the National Vaccine Program Office to develop an

    10    action plan for implementing the needs that were

    11    addressed in the report.

    12              This was done through the National Vaccine

    13    Program Office's interagency group.  This is a group

    14    of various Government agencies including the NIH, the

    15    FDA, CDC, and HRSA.  This interagency group, which was

    16    co‑chaired by myself and Dan Salomon, developed a

    17    vaccine safety action plan.  This was presented to the

    18    National Vaccine Advisory Committee and later to the

    19    Surgeon General, Dr. David Satcher, the Dep. Sec. of

    20    HHS, Mr. Kevin Thurm.

    21              This Vaccine Safety Action Plan, which is

    22    extremely comprehensive, evolved into the vaccine

    23    safety implementation plan which was more of a focused

    24    and immediate implementation of the action plan.  Our

    25    highest priority activities were identified and, to

                                                                         68

     1    the extent possible, plans were made to implement

     2    these in the current fiscal year.

     3              I will note that stable funding for this

     4    plan is being pursued.  However, this is a quite

     5    difficult issue and whether this gets done through the

     6    vaccine trust or by setting up an additional trust

     7    fund or through continuing funding through the normal

     8    allocation process is still not settled.

     9              There are five goals that have been

    10    identified for the vaccine safety action plan.  These

    11    are given on the current overhead which is to increase

    12    effort to detect potential vaccine safety problems. 

    13    Two is to improve the response to and understanding of

    14    vaccine safety concerns.  To improve the risk

    15    management of vaccines in clinical settings.  To

    16    increase and improve communications about vaccine

    17    risks and benefits.  To obtain and maintain a state of

    18    the art vaccine supply.

    19              This vaccine safety implementation plan was

    20    chaired by Dr. Roger Bernier.  The development of this

    21    implementation plan was chaired by Dr. Roger Bernier

    22    from the CDC's National Immunization Program and done

    23    through the National Vaccine Program.

    24              Let me say a few words about some of the

    25    immediate action steps that were identified and these

                                                                         69

     1    are on the following overheads.

     2              With regard to detecting potential safety

     3    problems, the most immediate needs were to improve

     4    laboratory testing of vaccines and evaluate vaccine

     5    safety and purity, and to develop new approaches for

     6    the presence of unknown or previously undetected

     7    agents in vaccines.  An example of the latter is, for

     8    example, one could develop generalized PCR methods not

     9    for specific viruses but for families of viruses.

    10              With regard to improving response and

    11    understanding of vaccine safety concerns, it was

    12    thought there was a need to evaluate the VAERS reports

    13    more adequately to improve scientific understanding of

    14    the reports and to carry out a more timely review of

    15    newly hypothesized vaccine safety concerns.  

    16              For example, have a standing board or

    17    committee, presumably investigative scientists outside

    18    of the Government, that could be presented with a

    19    vaccine safety concern and they could make some

    20    assessment of how important it would be to immediately

    21    investigate that concern or if the evidence didn't

    22    support it that well.  Then to study possible causal

    23    links between vaccines and specific diseases in

    24    expanded vaccine safety data link population.

    25              With regard to improving risk management of

                                                                         70

     1    vaccines in clinical settings, we felt it was very

     2    important to finalize the decision rules for vaccine

     3    policies so that any unnecessary repeat doses are not

     4    administered, to update the standards for pediatric

     5    immunization practices, and to include a focus on

     6    safety related issues and practices.

     7              With regard to increasing improved

     8    communication, the need to improve the exchange of

     9    information between healthcare providers and parents. 

    10    That's healthcare providers on all levels.  And for

    11    obtaining and maintaining state of the art vaccine

    12    supplies and to develop safer alternatives for current

    13    vaccines.  This could include both the vaccines

    14    themselves and excipients or adjuvant that are used in

    15    these vaccines.  For example, changing preservatives,

    16    different preservatives; changing adjuvants, for

    17    example, from aluminum to another type of adjuvant.

    18              That's the plan in a nutshell.  I think

    19    there is much that we need to do to make vaccines

    20    safer and to promote the safe use of these vaccines. 

    21    If I could just close with a quote from Sir Graham

    22    Wilson from his classic book, The Hazards of

    23    Immunization.  

    24              I quote, "It is for us and for those who

    25    come after us to see that the sword which vaccines and

                                                                         71

     1    antisera have put into our hands is never allowed to

     2    tarnish through over confidence, negligence,

     3    carelessness, or want of foresight."  Thank you.

     4              DR. GREENBERG:  Thank you, Bill, for an

     5    excellent presentation.  I guess now I would open it

     6    up to committee members who have any questions of

     7    Bill.

     8              DR. FAGGETT:  Harry, Walt Faggett.  One

     9    question.   Excellent presentation.  The matter of

    10    stable funding, you mention it's going to be stable

    11    but you don't give the source.  I'm not clear how

    12    stable it's going to be if you don't have a source of

    13    funding at this point.

    14              DR. SNIDER:  Harry, this is Dixie.  I wanted

    15    to make an observation about that.  As a federal

    16    official I hope I don't step over the line but there

    17    has been a lot of difficulty, Walter, and everyone

    18    else, in trying to nail down some stable funding.

    19              Through all of these meetings we have really

    20    had no major problems in convincing people that this

    21    is an important thing for us to be doing.  I mean, all

    22    of us, the agencies involved and all professional

    23    societies and so forth.  

    24              The situation is such that those who are

    25    concerned about having adequate money for vaccine

                                                                         72

     1    purchase are obviously in this environment from which

     2    we are having new vaccines come on line that are

     3    higher priced than earlier vaccines, are very

     4    concerned about trying to redirect funds from vaccine

     5    purchase to vaccine safety.  

     6              Those who are concerned about having

     7    adequate funds available for vaccine compensation are

     8    understandably reluctant to have any of those funds

     9    reprogrammed for vaccine safety.  Those who are

    10    concerned about this are concerned about increasing

    11    appropriations for vaccines.

    12              CDC has this year reprogrammed some of its

    13    money to increase our efforts on vaccine safety but

    14    they fall far short of what is needed.  I think there

    15    is some real concern about how we get over the hump in

    16    terms of getting some resources.

    17              As some of you may know, there has been an

    18    interest in reducing.  Since the vaccine compensation

    19    has a goodly amount of money in it, there has been

    20    some interest in reducing the excise tax on vaccines

    21    and some discussion of redirecting some excise tax

    22    money into a vaccine safety arena but that would take

    23    some legislative action which is obviously difficult

    24    to pull off.

    25              DR. GREENBERG:  Thank you, Dixie.

                                                                         73

     1              DR. EGAN:  I would just like to say thank

     2    you very much for that response, Dixie.  My comments

     3    about seeking stable funding was seeking stable

     4    funding specifically for vaccine safety because we

     5    don't have the ability, the monies, to redirect

     6    existing funds from existing activities such as the

     7    vaccine purchaser.

     8              MS. FISHER:  Barbara Fisher here.  I think

     9    the vaccine safety plan is a really good first step to

    10    addressing some of the outstanding concerns about

    11    vaccine safety, but I think it might be useful to take

    12    another look at the conclusions of three reports

    13    issued by the Institute of Medicine in 1991 and '94,

    14    particularly those talking about the lack of research

    15    investigating the biological mechanisms underlying

    16    adverse events following natural infection as well as

    17    immunization.  

    18              Also to review the report of the April 1,

    19    1996, Institute of Medicine Vaccine Safety Forum

    20    Workshop, which also identified biological mechanism

    21    and research needs.

    22              I know that the greatest concern to parents

    23    right now is the lack of scientific information on the

    24    cumulative effect of multiple antigens on the

    25    developing immune and neurological system,

                                                                         74

     1    particularly and potentially genetically susceptible

     2    populations.  In other words, those children who may

     3    be susceptible to developing autoimmunity or immune‑

     4    mediated neurological dysfunction.  

     5              Further, whether some of this might be

     6    influenced by genetic recompenation caused by exposure

     7    to viruses and other toxins including additives in

     8    vaccines, as you mentioned, Dr. Egan, like mercury and

     9    aluminum.  There is private money being raised right

    10    now to fund this kind of research.  

    11              I think that if the FDA takes the lead, it

    12    would have public support because it would pave the

    13    way for development of screening techniques to

    14    identify high‑risk children and it would lead to

    15    modification of that policy to make them safer.  I

    16    just would like to say, however, that the suggestion

    17    of taking money from the funds, the trust fund, that

    18    was set up for vaccine‑injured children would be

    19    vigorously opposed.  

    20              I think the other funding sources need to be

    21    identified, but I think there would be public support

    22    for it especially if the CDC and FDA and NIH makes

    23    this a priority that the funding the vaccine safety

    24    research, particularly basic science research, is a

    25    priority in our society.  You will receive grants or

                                                                         75

     1    support for that but there will be opposition to using

     2    the trust fund money.

     3              DR. EGAN:  Thank you, Mrs. Fisher, for those

     4    comments.  I would like to add that in the vaccine

     5    safety action plan there were a number of items that

     6    related to many of the issues that you brought up,

     7    particularly looking for susceptible populations,

     8    investigating the realm of adverse events and genetic

     9    susceptibility to those adverse events.

    10              The particular action steps that I put up

    11    here were those ones that we could begin immediately

    12    this year.  Those very, very difficult studies on

    13    genetics with adverse events are certainly elements of

    14    the action plan.  Thank you.

    15              DR. GREENBERG:  Are there any other comments

    16    from the panel?

    17              DR. KATZ:  Harry, I would like to make three

    18    comments.  Is that all right?

    19              DR. GREENBERG:  Yes.  Could you identify

    20    yourself?

    21              DR. KATZ:  Sam Katz.  Three comments and two

    22    for Bill.  The first one is scientific in accuracy. 

    23    When you talk about SV40 you limited it to OPV.  SV40

    24    was found in IPV also.

    25              DR. EGAN:  My mistake, Sam.  I meant to say

                                                                         76

     1    IPV because it never was in the licensed OPV.  It was

     2    only in the IPV.  Thank you for correcting that.

     3              DR. KATZ:  Secondly, I don't know if this is

     4    for publication or just this meeting but it is

     5    sometimes misleading.  You made the statement that

     6    diseases are gone.  Only smallpox is gone.  We know

     7    very well that diphtheria continues in eastern Europe,

     8    that measles is in the Netherlands, that polio is in

     9    Sub‑Saharan and much of Asia.  We mislead the public

    10    when we say the diseases are gone.  They are gone from

    11    the United States but not from the world.  No place is

    12    further than a jet plane ride away from wherever one

    13    sits today.

    14              DR. EGAN:  Thank you for that comment. 

    15    Certainly for many of these, barring smallpox, they

    16    are seen.  There's a case or two of diphtheria every

    17    year in the U.S.  Measles has reemerged and so on.  My

    18    point was more that they are not prevalent and

    19    immediate to everybody as they were and not everybody

    20    was seeing the devastation.

    21              DR. KATZ:  Our worst enemy sometimes.  A

    22    third question for Ms. Fisher.  I sat the last few

    23    years on the Advisory Commission on Child Vaccines. 

    24    It runs very effectively.  The commission is made up

    25    of parents and of attorneys who prosecute these cases

                                                                         77

     1    and only a couple of physicians and nurses.  

     2              Basically they have done an excellent job in

     3    rewarding appropriate cases that have been adjudicated

     4    by medical experts and reviewed very carefully. 

     5    Nevertheless, with the current excise tax they've had

     6    more than enough money to pay all the claims that were

     7    adjudicated.  With the trust funds it has continued to

     8    increase over a billion dollars that just sits there.

     9              It isn't even used to compensate these

    10    families because they get enough funds from the excise

    11    tax.  I think that still stands without anyway eroding

    12    the compensation program as a possible avenue for

    13    safety which seems to me perfectly compatible.  It's

    14    what the program is set up for.

    15              MS. FISHER:  Barbara Fisher here.  A GAO

    16    report has just been issued in the last few months

    17    looking at the implementation of the National

    18    Childhood Vaccine Injury with respect to the

    19    compensation program.  

    20              Congress is taking a look at it and I think

    21    that there are still outstanding questions about the

    22    rules for compensation and the way it is being

    23    implemented and whether or not in the future there

    24    will be an opportunity for more awards if the terms

    25    under which compensation are given are changed.  

                                                                         78

     1              I think it's a mistake to assume that the

     2    excess amount that is now in the trust fund is not

     3    going to be utilized in the future and a terrible

     4    precedent would be set to go into that fund and use it

     5    for any other purpose than what Congress originally

     6    intended it for in 1986 which is to compensate

     7    vaccine‑injured children.

     8              DR. EGAN:  This is Bill Egan.  I think that

     9    the point here is that we need stable funding for

    10    vaccine safety research.  I don't think we are going

    11    to settle in this meeting where that's going to come

    12    from.  The issue is that the stable funding is needed

    13    and a variety of sources are being discussed and

    14    debated.  I think we've just heard some of the points

    15    that have been made in that debate.

    16              DR. GREENBERG:  Hold on a second.  I would

    17    like to get some other panel members who might have

    18    something to say involved here.

    19              DR. MYERS:  Harry, this is Marty.  Could I

    20    add something from the National Vaccine Program

    21    perspective?

    22              DR. GREENBERG:  Yeah.

    23              DR. MYERS:  I think the point that Bill was

    24    making is a very important one, that the Department is

    25    looking at a variety of options and the trust fund is

                                                                         79

     1    only one of the many that the Department has been

     2    considering for stable funding.  

     3              It's understood that stable funding is

     4    necessary but the process is likely to take some time

     5    given the manner in which appropriations are managed

     6    and decisions are made concerning long‑term funding of

     7    initiatives such as this.  

     8              What this implementation plan that Bill has

     9    been describing is those things we thought were so

    10    urgent they shouldn't wait for that process and the

    11    different agencies, as Dixie said, reprogrammed funds

    12    to help support these activities of which CDC, NIH,

    13    FDA, and NDPO with its unmet funding have done to get

    14    a number of these enhanced safety activities

    15    initiated.  

    16              For example, one of the ones that Bill

    17    mentioned was there is contracting underway with

    18    potential external review groups to consider timely

    19    reviews and hypothesized vaccine safety concerns,

    20    somebody that would be outside of Government.

    21              Another that was discussed extensively at

    22    the recent NVAC meeting was a workshop to identify and

    23    discuss more effective approaches to vaccine benefits

    24    and risk communications which is going to occur in the

    25    fall.  I think this is looked at as we're getting

                                                                         80

     1    started the issue of stable funding is very important

     2    but it won't come quickly.

     3              DR. GREENBERG:  Thank you, Marty.  Are there

     4    any members who have not yet spoken who would like to

     5    add something?  Are there any members who have spoken

     6    who would like to add something?

     7              DR. FAGGETT:  Harry, Walt Faggett.  Just one

     8    quick one for Bill Egan.  Do you have a budget

     9    projection on what is needed for some of the very

    10    impressive activities you are planning for vaccine

    11    safety?

    12              DR. EGAN:  For the whole package these are

    13    really very, very rough estimates.  For everything

    14    combined it's numbers on the order of up to $50

    15    million dollars per year.  Activities like, you know,

    16    the vaccine safety data link which is absolutely

    17    essential in all of these.  Those are very, very

    18    expensive computer systems to keep up.  They cost

    19    millions of dollars per year.

    20              DR. FAGGETT:  They are mandated under 2010

    21    so that should give you some hope.

    22              DR. SNIDER:  Harry, this is Dixie.  I have

    23    a question for Bill or Marty or anyone who has been

    24    involved in thinking about vaccine safety

    25    implementation plan.  Getting back to this committee.

                                                                         81

     1              The question would be what could this

     2    committee do as part of its role in helping to move

     3    vaccine safety issues forward?  Are there other

     4    specific ‑‑ is there a specific charge or some

     5    specific recommendations coming out of this Planning

     6    Activity Board or the Vaccine and Related Biological

     7    Products Advisory Committee?

     8              DR. EGAN:  Dixie, I think this presentation

     9    right now was simply to advise the committee of what

    10    was going on within the Department.  I think the

    11    individual members can always act on their conscience

    12    and act as advocates for whatever they see fit.  We

    13    weren't asking for any kind of action at this time. 

    14    This was simply a briefing or update.

    15              MS. FISHER:  I have a question.  Barbara

    16    Fisher.  Is it allowed under committee rules for

    17    individual members of the committee to meet with FDA

    18    staff to review concerns about priorities, for

    19    example, on this plan?  Is it appropriate or is it

    20    allowed under the rules for committee members, for

    21    example, like me to meet with an FDA staff to

    22    communicate the parent concerns and priorities or what

    23    they think priorities are for vaccine safety?

    24              DR. EGAN:  Mrs. Fisher, it's allowed and

    25    appropriate for anyone, member of the committee or

                                                                         82

     1    not, to call me, to meet with FDA to express their

     2    concerns, and to give us their opinions and advice.

     3              MS. FISHER:  Thank you.

     4              DR. MYERS:  Harry, just to respond to Dixie

     5    and your query.  It would seem to me like the NVAC

     6    would be useful to have the advisory committee go on

     7    record in support of a stable long‑term funding.

     8              DR. GREENBERG:  I think we've been ‑‑

     9              OPERATOR:  Conference operator.  How may I

    10    help you?

    11              MS. CHERRY:  I'm sorry.  We're still

    12    meeting.

    13              DR. MYERS:  To Mrs. Fisher, in addition to

    14    the FDA one of the attempts of this workshop this fall

    15    is to ‑‑ one of the specific objectives is to

    16    establish meaningful mechanisms for meaningful

    17    discussions to address various concerns by a variety

    18    of different constituents.  I think participation in

    19    that would be very useful.

    20              DR. GREENBERG:  Thank you, Marty.  I would

    21    like to make a comment myself.  This is simply as a

    22    panel member, not as a chair.  That is that this is to

    23    me an incredibly important area.  I think all of you

    24    as panel members, and many of you who are scientists,

    25    need to realize that there is going to have to be

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     1    priorities set even in such an important area as

     2    safety as to where you are going to get the most

     3    benefit and where you need to put your biggest efforts

     4    and where other efforts go.  

     5              To some degree because this is such a hot

     6    potato that's hard because everything is important

     7    but, as you've heard, there's not money for anything

     8    it sounds like.  What I would ask of all of you is to

     9    think is this wonderful list that Bill presented, is

    10    this what is needed for vaccine safety?  

    11              Begin to think in your own mind where we are

    12    going to get the most improvement most quickly and

    13    what are longer terms and perhaps slower investments

    14    and share that information or that thought with Bill. 

    15    I think it's a very ‑‑ it's easy to say we are all for

    16    safety but it's pretty hard to figure out exactly what

    17    is the most important thing to do, the next most

    18    important thing to do.  That requires a lot of

    19    thought.

    20              DR. EGAN:  Just let me emphasize, too, that

    21    this plan is a departmental plan and all of the

    22    agencies that are part of the interagency group of the

    23    National Vaccine Program.  I would also like to thank

    24    again Dr. Roger Bernier from CDC who worked so very,

    25    very hard to develop this implementation plan which I

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     1    simply present today.

     2              DR. GREENBERG:  I would imagine that a

     3    number of you are beginning to get antsy so I would

     4    like to know if there are any other questions of Bill

     5    or thoughts?

     6              DR. KOHL:  Harry, Dr. Kohl.  Would it be

     7    appropriate to have a committee motion to strongly

     8    urge stable funding for this plan?

     9              DR. GREENBERG:  As far as I'm concerned,

    10    that's just fine.  Nancy, are there any prohibitions

    11    of that?

    12              MS. CHERRY:  Well, this was unplanned and I

    13    don't know where the motion will go from here.

    14              DR. GREENBERG:  Well, I'm not sure where it

    15    will go either.

    16              MS. CHERRY:  I mean, you can go on record as

    17    making that motion.

    18              DR. GREENBERG:  I'm happy to be on record as

    19    we've been a number of times in the past on record for

    20    stable funding for the research mission of the FDA. 

    21    It's never clear to me where those motions go either.

    22              DR. FAGGETT:  Walt Faggett.  I'd like to

    23    second that motion.

    24              DR. GREENBERG:  Okay.  Why don't you just

    25    quickly take a vote.

                                                                         85

     1              MS. CHERRY:  Okay.  Shall I go down the list

     2    again?

     3              DR. GREENBERG:  Yeah.

     4              MS. CHERRY:  Okay.  Kohl.

     5              DR. KOHL:  Yes.

     6              MS. CHERRY:  Huang.  She's gone. Daum.

     7              DR. DAUM:  Yes.

     8              MS. CHERRY:  Stephens.

     9              DR. STEPHENS:  Yes.

    10              MS. CHERRY:  Faggett.

    11              DR. FAGGETT:  Strongly agree.

    12              MS. CHERRY:  Okay.  Fisher.

    13              MS. FISHER:  Yes, strongly agree but oppose

    14    any use of the trust funds for the children.

    15              MS. CHERRY:  Okay.  Kim.  He never made it. 

    16    Estes.

    17              DR. ESTES:  Yes.

    18              MS. CHERRY:  Snider.

    19              DR. SNIDER:  Abstain.

    20              MS. CHERRY:  Abstain?  Okay.  Griffin.

    21              DR. GRIFFIN:  Yes.

    22              MS. CHERRY:  Greenberg.

    23              DR. GREENBERG:  Yeah.

    24              MS. CHERRY:  Broome.  Eickhoff.

    25              DR. EICKHOFF:  I agree.

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     1              MS. CHERRY:  Ferrieri.  Dr. Ferrieri?  Okay. 

     2    Dr. Myers.

     3              DR. MYERS:  Abstain.

     4              MS. CHERRY:  Katz.

     5              DR. KATZ:  Agree.

     6              MS. CHERRY:  Hoke.  Couch is gone. 

     7    Kilbourne.  Gone.

     8              DR. GREENBERG:  So we are beginning to lose

     9    people so I would like to ‑‑

    10              MS. CHERRY:  Well, not all of those were

    11    actually ‑‑

    12              DR. GREENBERG:  Yes.

    13              MS. CHERRY:  Some of those were temporary

    14    voting members.

    15              DR. GREENBERG:  I totally understand.  I

    16    would like to get everybody's ‑‑ let everybody express

    17    their opinion but if we don't have any more opinions,

    18    maybe we could move towards closure here.

    19              MS. CHERRY:  Okay.  Before we do, we need to

    20    open the floor one more time.

    21              DR. GREENBERG:  I understand that, Nancy. 

    22    I'm trying to see whether there are any more comments

    23    on Dr. Egan's presentation.  No?  Great.  So, Nancy,

    24    can you check the floor there.

    25              MS. CHERRY:  Okay.  Would anyone like to

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     1    address the committee?  I guess not.  Back to you, Dr.

     2    Greenberg.

     3              DR. GREENBERG:  Okay.  I think the safety

     4    issue is obviously incredibly important.  Without

     5    safety we will not ‑‑ without real safety and the

     6    perception of safety we will not have utilization of

     7    vaccines the way they should be used.  I think we all

     8    need to think long and hard about it and how to

     9    improve it.  

    10              Bill, that was a good first start. Again, I

    11    suggest all of you to think about ideas that you have

    12    and to relay those to Bill.  Are there any last

    13    comments on safety?  

    14              If not, I would like to thank all of you for

    15    joining on this telephone conference.  It worked fine. 

    16    I know you are all very disappointed that you could

    17    not spend the last two days in Washington but you'll

    18    just have to live with that.

    19              MS. CHERRY:  We did have nice weather had

    20    you come.

    21              DR. GREENBERG:  Okay.

    22              MS. CHERRY:  I would like to thank everyone

    23    also, particularly for the abrupt change in plans. 

    24    Thank you for being flexible enough to go along with

    25    us.

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     1              DR. GREENBERG:  Okay.  Thanks again and I

     2    guess we'll be seeing you in May.

     3              MS. CHERRY:  Okay.

     4              (Whereupon, at 2:13 the teleconference was

     5    concluded.)

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