MARCH 17, 2004



            The Advisory Committee met at 1:00 p.m. via a teleconference organized in Conference Room C of the Center for Biologics Evaluation and Research, Building 29B, 8800 Rockville Pike, Rockville, Maryland, Dr. Walter Royal III, Acting Chairman, presiding.


PRESENT: This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation as to its accuracy.


WALTER ROYAL III, M.D.     Acting Chairman

NANCY J. COX, Ph.D.       Consultant

MICHAEL D. DECKER, M.D.    Industry Representative

WALTER DOWDLE, Ph.D.      Consultant


MONICA M. FARLEY, M.D.     Member

JUDY D. GOLDBERG, Sc.D.    Consultant

RUTH A. KARRON, M.D.      Member

PHILIP S. LaRUSSA, Ph.D.   Member

PAMELA McINNES, D.D.S.     Consultant

ARNOLD S. MONTO, M.D.        Consultant

MARTIN MYERS, M.D.        Consultant

PETER PALESE, Ph.D.       Member


M.P.H., LTC(P)

BONNIE M. WORD, M.D.      Member

CHRISTINE WALSH, R.N.        Executive Secretary











Agenda                                        Page


Welcome - Chairman Royal                          3


Introductions - Christine Walsh                   3




Roland Levandowski                               11

Nancy Cox                                        14


Committee Discussion on Influenza B              26




                                         1:03 p.m.

            CHAIRMAN ROYAL:  Good afternoon.  I guess it's good afternoon to most of you.  My name is Walter Royal.  I am the Acting Chair for this teleconference, sitting in for Dr. Gary Overturf.  I would like to call this meeting to order.  Today's agenda will deal with recommendations pertaining to vaccines and related biological products.

            We will begin today's teleconference with announcements by Ms. Walsh from the FDA.

            MS. WALSH:  Thank you, Dr. Royal.  Good afternoon.  I am Christine Walsh, the executive secretary for today's meeting of Vaccines and Related Biological Products Advisory Committee.  I would like to welcome all of you to the 98th meeting of this Advisory Committee.  There's a speakerphone for public participation located here in Conference C of Building 29B on the NIH campus.  This afternoon's session will consist of presentations and Committee discussions that are open to the public, as described in the Federal Register notice of February 19, 2004.

            At this time, I would like to introduce the Committee members and ask if they acknowledge by saying, "Present," if they can hear me.  The Committee Acting Chair, Dr. Walter Royal, III, Associate Professor of Medicine Morehouse School of Medicine?

            MS. WALSH:  Present.

            MS. WALSH:  Our consumer representative, Cindy Lyn Province, R.N., M.S.N., Associate Director, Bioethics Center of St. Louis.

            Our non-voting industry representative, Dr. Michael D. Decker, Vice President, Scientific and Medical Affairs, Aventis Pasteur.

            DR. DECKER:  Present.

            MS. WALSH:  Dr. Monica M. Farley, Professor of Medicine, Department of Medicine, Emory University of School of Medicine.

            DR. FARLEY:  Present.

            MS. WALSH:  Dr. Ruth A. Karron, Associate Professor, Division of International Health, Johns Hopkins School of Hygiene and Public Health.

            DR. KARRON:  Present.

            MS. WALSH:  Dr. Philip S. LaRussa, Professor of Clinical Pediatrics, Columbia University.

            DR. LaRUSSA:  Present.

            MS. WALSH:  Dr. Peter Palese, Chairman and Professor, Department of Microbiology, Mt. Sinai School of Medicine.  Dr. Palese?

            Dr. Bonnie M. Word, Assistant Professor of Pediatrics, Baylor College of Medicine, Texas Children's Hospital Clinical Care Center.

            DR. WORD:  Present.

            MS. WALSH:  Now I would like to introduce our consultants for today's meeting.  Dr. Nancy Cox, Chief Influenza Branch, Center for Disease Control and Prevention.

            DR. COX:  I'm present.

            DR. PALESE:  Peter Palese joining.  I'm sorry I'm late.

            MS. WALSH:  Thank you, Dr. Palese.  We just called your name.  Dr. Walter Dowdle, Senior Public Consultant, The Task Force for Child Survival and Development.

            DR. DOWDLE:  Present.

            MS. WALSH:  Dr. Theodore Eickhoff, Professor of Medicine, Division of Infectious Diseases, University of Colorado Health Science Center.

            DR. EICKHOFF:  Present.

            MS. WALSH:  Dr. Bruce Gellin, Director, National Vaccine Program.

            Dr. Judith Goldberg, Director, Division of Biostatistics, New York University School of Medicine.

            DR. GOLDBERG:  Present.

            MS. WALSH:  Dr. Martin Myers, Co-Director, Public Health Policy and Education, Sealy Center for Vaccine Development, University of Texas Medical Branch.  Dr. Myers?

            Dr. Arnold Monto, Professor of Epidemiology, University of Michigan, School of Public Health.  Dr. Monto?

            Dr. Stephen Phillips, Director, Deployment Medicine and Surveillance Force, Health Protection and Readiness, Office of Assistant Secretary of Defense.

            DR. PHILLIPS:  Present.

            MS. WALSH:  Dr. Pamela McInnes, National Institute of Allergy and Infectious Diseases, Deputy Director, Division of Microbiology and Infectious Diseases, NIH.

            DR. McINNES:  Present.

            MS. WALSH:  Now I would like to introduce the influenza vaccine manufacturers that will be participating in this teleconference to answer any manufacturing questions.  Ken Guito, Aventis Pasteur, Incorporated.

            MR. LI:  Yes.  Sam Li from Aventis Pasteur.

            MS. WALSH:  Thank you very much.  Peter McBride, Chiron Corporation.

            MR. McBRIDE:  Present.

            MS. WALSH:  Bill Turner and Kathy Coelingh, MedImmune Vaccines, Incorporated.

            MS. COELINGH:  Present.

            MR. TURNER:  Present.

            MS. WALSH:  Thank you.  I would like to thank all Committee members, consultants and manufacturers for taking the time to join us today.  I also wish to thank Dr. Royal for agreeing to step into the Acting Chair role for today's meeting.

            I just want to go back, if I may.  Did Dr. Bruce Gellin join us?  Dr. Martin Myers?  Dr. Arnold Monto?  Cindy Lyn Province?

            (No response.)

            MS. WALSH:  Okay.  There are also two other members that could not participate with us today, and they are Dr. Gary Overturf, our Committee Chair, from University of New Mexico Medical Center, and Dr. David Markovitz, University of Michigan Medical Center.

            Now I would like to introduce some FDA Sieber staff members that will be participating in today's meeting and are currently seated in the room.  Dr. Karen Midthun, Acting Deputy Director for Medicine; Dr. William Egan, Acting Director, Office of Vaccines, Research and Review; Dr. Norman Baylor ‑‑

            PARTICIPANT:  No, he's not ‑‑

            MS. WALSH:  Okay.  Dr. Weir.

            PARTICIPANT:  No.

            MS. WALSH:  Okay.  Dr. Roland A. Levandowski, Supervisory Medical Officer, Laboratory of Pediatric and Respiratory Viral Diseases, Division of Viral Products, OVRR; and Denise Royster, Committee Management Specialist, VRBPAC Advisory Committee, who actually helped pull this whole meeting together, and I thank her for her hard work.

            I ask that all Committee members identify themselves each and every time they speak.  We do have a transcriber present who will need your assistance in order to accurately transcribe all comments to the appropriate Committee member.  I also ask that our Committee members not use cellular phones if possible since that does add extra unnecessary background noise to the line.  Should during the teleconference a noise occur in your office, we would appreciate it if you would use the mute button on your phone if you have that option.  We ask that you do not place us on hold, because many clinical centers do have background music that can be very distracting.

            I would now like to read into the public record the conflict of interest statement for this meeting.  The following announcement addresses conflict of interest issues associated with the Vaccine and Related Biological Products Advisory Committee meeting on March 17, 2004.  The Director for Biologics Evaluation and Research has appointed Drs. Walter Dowdle, Theodore Eickhoff, Bruce Gellin, Judith Goldberg, Pamela McInnes, Arnold Monto, Martin Myers and Stephen Phillips as temporary voting members for this meeting.  The Director of the Center for Biologics Evaluation and Research also has appointed Dr. Walter Royal as Acting Chair for this teleconference meeting.  Based on the agenda, it has been determined that there are no specific products being approved at this meeting.

            The Committee participants have been screened for their financial interests to determine if any conflicts of interest existed, the Agency reviewed the agenda and all relevant financial interests reported by the meeting participants.  The Food & Drug Administration prepared general matter waivers for participants who require a waiver under 18 USC 208.  Because general topics impact on many entities, it is not prudent to recite all potential conflicts of interest as they apply to each member.  FDA acknowledges that there may be potential conflicts of interest, but because of general nature of the discussions before the Committee, these potential conflicts are mitigated.

            We would like to note for the record that Dr. Michael Decker is a non-voting industry representative for this Committee acting on behalf of regulated industry.  Dr. Decker's appointment is not subject to 18 USC 208.  He is employed by Aventis and thus has a financial interest in his employer.  In addition, in the interest of fairness, FDA is disclosing that his employer, Aventis, is a manufacturer of a product that could be affected by the Committee discussions.

            Members and consultants are aware of the need to exclude themselves from the discussions involving specific products or firms for which they have not been screened for conflict of interest.  Their exclusion will be noted for public record.

            With respect to all other meeting participants, we ask in the interest of fairness that you address any current or previous financial involvement with any firm whose products you wish to comment upon.  Waivers are available by written request under the Freedom of Information Act.

            That ends the reading of the conflict of interest statement.  Dr. Royal, I turn the meeting over to you.

            CHAIRMAN ROYAL:  This is Dr. Royal.  Thank you very much.  At this time, we will move into our open discussions and begin with our first speaker, Dr. Roland Levandowski from the FDA.

            MR. MYERS:  Hello.  This is Marty Myers, I've joined you.

            MS. WALSH:  Thank you, Dr. Myers.

            MR. LEVANDOWSKI:  Okay.  Thanks, Dr. Royal.  I'll just go ahead and get started with a brief introduction before we hear some updated information from Nancy Cox.  Just to remind everybody and the Committee members that we had our first meeting on February 19 to discuss strain selection, and at that time we presented some fairly extensive information on surveillance of influenza viruses, circulation of new strains, serologic responses from people and strain availability for manufacturing.

            And as a result of the information that was presented to the Committee, the Committee recommended that for the 2004-2005 influenza vaccine that an A/New Caledonia/20/99 H1N1 strain should be retained as part of the vaccine, that the H3N2 influenza A component of the vaccine be changed to an A/Fujian/411/2002-like strain.  And the recommendation for the B strain was made provisionally but with the ‑‑ the provision was that we would come back to the Committee with additional information in the time between February 19 and the present to indicate whether there would be a need for a change in the recommendation.

            The recommendation that was made based on the information that was available to the Committee on February 19 was that the influenza B component of the vaccine should be changed to be a B/Shanghai/361/2002-like strain.

            In the interim, other things that have been happening, manufacturing has been continuing.  The Committee heard in February that manufacturers had already been manufacturing the A/New Caledonia strain, and,subsequently, based on the recommendation, the manufacturers have started working with an A/Fujian-like strain.  The actual strain that's being used for manufacturing vaccines is one called A/Wyoming/3/2003.  There are high-growth reassortants of that that had previously been developed and were available, and that manufacturing is going forward.

            Manufacturing for the B strain has not really begun in earnest yet.  There have been several influenza B viruses that have been distributed to manufacturers that fit the recommendation of B/Shanghai/361/2002-like.  Those are in evaluation and we have some preliminary information that suggests that the strains that are available seem to be moderate growth, but we don't have the full information on that, and it's not clear of the strains that are available which one might be the best one, but that work is going on too.

            The question that we would like the Committee to address today really focuses on the B strain and finalizing that.  And the question is does the Committee confirm its recommendation of February 19, 2004 to change to a B/Shanghai/361/2002-like strain of the B/Yamagata hemagglutinin lineage for vaccines to be used during the 2004-2005 season?  I think, Dr. Royal, that's all I really had to say as introductory remarks, and if you have ‑‑ you or the others have any questions, I'll try to answer them.

            CHAIRMAN ROYAL:  Thank you very much, Dr. Levandowski.  Do we have any questions before we move on?

            At this time, I'd like to ask Dr. Nancy Cox to come forward.


            DR. COX:  Thanks, Dr. Royal.  I'm having a little bit of difficulty hearing on my end.  Either there is quite a bit of wind or someone breathing into their handheld headset, so it's a little bit distracting, a little bit hard to heard on my end.  So if there's anything that can be done out there, that would be very helpful.

            MS. WALSH:  Excuse me, Dr. Cox.  This is Christine Walsh.  I would just ask that if you are not speaking, if you do have a mute available option, if you would please use that.  Dr. Cox, go ahead.

            DR. COX:  Okay.  Before we start going through the package of materials that was sent out, I'd first like to talk very briefly about surveillance data.  And just as we were mentioning about a month ago when we had our last meeting, activity was then winding down and has continued winding down even more.  So we are now below baseline for influenza-like illness surveillance for sentinel providers and for P&I mortality for the 122 U.S. cities.

            Very few influenza viruses have been isolated during the past month, but I'd just like to remind you that overall the 2003-2004 season over 100,000 respiratory specimens were tested for influenza.  Over 23,000 of those were positive for influenza, and this is a higher proportion.  This is about 22 percent, and it's a higher proportion overall than we've seen in some years.

            Of these that were positive for flu, 99.3 percent were influenza A and seven-tenths of one percent were influenza B.  For the influenza A viruses that were subtyped, 99.9 percent ‑‑

            MS. WALSH:  Excuse me, Dr. Cox.  I'm sorry, this is Christine Walsh.  We're hearing a beeping sound.  If somebody could ‑‑ oh, okay.  Are you there?

            DR. COX:  Yes.

            MS. WALSH:  Okay.  The beeping sound stopped, so maybe that ‑‑ that may help.  I'm sorry, Dr. Cox, go ahead.

            DR. COX:  Do I need to go back over anything?

            MS. WALSH:  If you please could.

            DR. COX:  Okay.  So I just mentioned that we had found below the baseline, both for the influenza-like illness surveillance conducted by the Sentinel providers and for P&I mortality for the 122 cities.  Very few influenza viruses have been isolated during the past month, but overall for the season out of over 100,000 respiratory specimens that were tested for a variety of respiratory pathogens, over 23,000 of those were positive for influenza.  Ninety-nine point three percent were positive for influenza A, and only 0.7 percent were positive for influenza B.  Of the influenza As that were identified, and not all of them were subtypes, but of those that were subtypes 99.9 percent were H3N2 and only two were H1 viruses.  So just as we had talked about a month ago, we had a very heavily predominant H3N2 year.

            At the current time, only local activity is being reported in Mississippi and Virginia.  A number of states are still reporting sporadic activity, which means they have influenza-like occurring and an occasion sporadic isolates being reported to them.  But activity, as I mentioned in my opening sentence, has really declined.  And, basically, we've been looking for an upsurge in influenza B isolates or influenza H1 isolates and absolutely have seen no sign yet that we're going to have a second wave of infections this year.  So in spite of the fact that the H3N2 activity occurred early and actually declined very early, we don't expect, based on our current data, to see a second wave.

            Okay.  If we could now turn to the CDC package of information that was provided to the Committee members, I'd like to walk you through this information.  I hope you've all had time to read the summary on Page 2.  I don't think I will need to go through that and read it to you, because you've probably had an opportunity to do that.

            On the second ‑‑ Page 3 of the handout, you will see an hemagglutinin inhibition table for influenza B viruses that we tested most recently.  And as we discussed in February, we have the two groups of viruses.  The Victoria lineage viruses are represented on the right hand side with blocks of yellow color, and the Yamagata lineage viruses are represented on the left hand side of the table, represented in green.  We have here a number of viruses from North America, including viruses from Canada.  The most recent virus I think that we have is one from Alaska that was isolated in mid-February.  Then we have a number of viruses from ‑‑ one from South America and then some from Asia.  Those are all Yamagata lineage viruses.

            At the bottom of the page for test antigens 25 through 33, you will see a block of viruses from Paraguay that were actually isolated in October and November.  When we got a recent shipment, didn't know these viruses were coming, but they were sort of cleaning out their season at the end of their year, and what became apparent in terms of looking at the isolation dates of the whole package of viruses that they had sent us the viruses were actually ‑‑ they had a late influenza season that started ‑‑ you know, normally, they're having their season during our summer months, and they had a late B outbreak starting mainly in September, going into October and just a couple viruses in November.

            And those ‑‑ so that was their previous ‑‑ these are the tail-end of their South American season, and the question always comes up as to whether viruses that are circulating in different places in the Southern Hemisphere indicate what viruses are going to circulate the following season in the Northern Hemisphere.  Clearly, in this particular case, for these Paraguayan viruses, they did not predict what was going to happen in terms of B circulation in North America because they were Victoria lineage viruses whereas in North America, both in the U.S. and in Canada, Yamagata lineage viruses predominated.

            Okay.  I think unless there are any questions on that page, I'll just mention that the viruses that we talked about before, namely the Shanghai/361 and the Jilin/20 strains, have antisera that covers a currently circulating strain on the Yamagata lineage well.

            DR. PALESE:  Peter Palese.  Can I ask you a question, please, Nancy?

            DR. COX:  Yes, certainly.

            DR. PALESE:  These Paraguayan strains, have they been associated with unusual virulence or are they ‑‑ is anything known about that?  In other words, are those more vicious viruses than what we have seen?

            DR. COX:  We can't say for sure, but, certainly, whenever there have been unusual outbreaks in Latin America, we have had calls from our colleagues at PAHO and they have ‑‑ there's something unusual going on.  And so, for example, when there was the outbreak El Salvador back in September we actually sent an EIS officer to help investigate that particular outbreak because there was reported increases in pediatric deaths.  So because ‑‑ I can't say with 100 percent certainty, but because we had no information that there was anything unusual going on either from our sources in Paraguay with our email contact or with PAHO, we, I think, could safely assume there was nothing very unusual about these.

            DR. PALESE:  But it was ‑‑ I mean the first isolate is from October 9, and the last one ‑‑

            DR. COX:  There were isolates from September but because the cutoff here ‑‑ because we're talking about ‑‑ we're presenting data for the period October onward.  So what we can see from looking at the whole package of information they sent is that this was the tail-end of their activity.  So the outbreak started earlier and this was the end of it.  But it went on in to November as evidenced by the two isolates from November.  So we can say that that may be somewhat unusual, just like our season this year was somewhat unusual because it started so early.  But it's certainly not out of bounds with what we know about Southern Hemisphere activity where in Australia or New Zealand or any of the countries in the Southern Hemisphere there can occasionally be outbreaks that go beyond the normal winter ‑‑ that go on into their spring.  Peter, does that help?

            DR. PALESE:  Thank you.  Thank you very much.

            CHAIRMAN ROYAL:  Thank you very much.  This is Dr. Royal.  Are there any other questions for Dr. Cox?

            DR. COX:  Okay.  So then I'll go on to Page 4, and what we have encapsulated on Page 4 is a result that we have for influenza B viruses that are actually antigenically characterized by us here at CDC.  We have now slightly different proportions of viruses that are Yamagata lineage and Victoria lineage because of some additional viruses that have come in and particularly the viruses from Paraguay.  But you can see that 65 percent of the viruses tested here at CDC are on the Yamagata lineage and 35 percent are on the Victoria lineage, shown in the green color.

            If we look then at the map on Page 5, and we were just ‑‑ we realize that this map isn't perhaps the more informative piece of information in the package, Page 6 is somewhat more informative, but we really wanted to try to give the Committee an idea of the countries where we've had either no reports of B isolates, where we have no data whatsoever for Bs or where we have B but we don't know ‑‑ and that's shown in orange ‑‑ which they are, whether they're Yamagata or Victorian, and that's because some of these countries actually do serology or use rapid tests and then they report based on that or they've been having a virus isolate that they can use for testing.

            The blue color indicates the countries where the Yamagata viruses only have circulated or where they have predominated.  This color shows where the Vic viruses have circulated only or have predominated.  But I think we should go on quickly to Page 6 because the impression that you get from Page 5 is that Yamagata strains are circulating more widely and predominating in more countries than the Vic viruses.  But to get the actual numbers, you can see on Page 6, and we did quite a bit of beating the bushes to get this data.

            So you can see that there were a couple of surprises in terms of B Victoria viruses circulating.  We had the 12 that we got from Paraguay from October onward, and, once again, these are viruses with isolation dates October 1 through March 10.  Okay.

            The second surprise was that we got an email from the WHO Collaborating Center in London, from  Alan Hay, and they had shortly after the WHO and FDA meetings received a package from South Korea that contained 19 B/Vic lineage viruses.  South Korea had a very, very heavy H3N2 season last year.  They had very little influenza-B last year and a heavy season with mainly H3, sort of like the season that we had in the U.S. this year.  So, anyway, that's what they were seeing.

            We were also able to get data from China, Thailand, Malaysia and Hong Kong and then some updated information from Japan.  Now, in all of the other Asian countries besides South Korea, you can see very clearly that the Yamagata lineage viruses are predominating.  So we do have a mixed picture as sometimes happens for influenza B viruses with these two different lineages circulating, but when we look at the numbers globally, we have 80 percent of the viruses on the Yamagata lineage, 20 percent on the Vic lineage, and when we look at the distribution on the somewhat simplistic maps that we presented on Page 5, there are more countries now, and we know the numbers are low for all, there are more countries, there's a greater geographic distribution of countries that have a predominance of the Yamagata-like viruses.  So the picture hasn't changed, it's changed a little bit, but overall the message is the same as it was a month ago.

            Now, just for completeness, we did include updated evolutionary trees for the HAs of viruses on the Yamagata lineage and the Victoria lineage and also the neuraminidase genes of viruses on both lineages.  I don't think it's really necessary for me to go through these dendograms in very much detail if you were able to print them out in color.  I just would like to note that the viruses that have the little hatchmark, the pound sign after them, are egg isolates and they also show up in blue if you printed it out in color so you can see where the egg isolates lie on the dendograms.

            So I think with that I will close and see if there are any additional questions.

            DR. EICKHOFF:  This is Ted Eickhoff.  Nancy, could I ask you an additional question?

            DR. COX:  Certainly.

            DR. EICKHOFF:  On Page 4, the color code doesn't seem to be quite the same as the color code on Page 3 since the Paraguay isolates are shown there in blue ‑‑ or green, rather, which on Page 3 represents the B Yamagata lineage.

            DR. COX:  Green?  I'm sorry, so the Paraguay viruses are shown in green on Page 4 ‑‑ oh, Page ‑‑ no, the color code isn't the same.  No, the color code ‑‑ it's mixed around.  So I apologize.  We should have kept the color code the same on Pages 3 and 4.  I'm with you now.  I'm sorry, I apologize for that.

            DR. EICKHOFF:  No, it was just confusing me a little bit.  So the color code is reversed on Page 4?

            DR. COX:  Correct.

            DR. EICKHOFF:  Okay.

            DR. MONTO:  Nancy, this is Arnold Monto.  The South Korea isolates seem rather out of line in many respects.  Do we know for sure that these were isolates from this past winter, and how does this compare with China over the border, because I know you get specimens in from Mukdin and places like that?

            DR. COX:  Yes.  These viruses were from this season.  Their isolation dates were November and December of '03.  The earliest one it was isolated in, let's see, toward the end of November, and then the rest of them are thread all the way through December.  And we just don't have any explanation for why South Korea has different strains than China, Thailand, Malaysia and Hong Kong, and Hong Kong, Japan and Mainland China all have data that corresponds very well, and Thailand as well.  So we just don't have an explanation for why South Korea is kind of sticking out there like a sore thumb.

            DR. LaRUSSA:  This is Phil LaRussa.  I have a question for you.  Do you get any information about whether the isolates are spread around the country or whether they're from a single outbreak?

            DR. COX:  The isolates from Korea are actually from six different cities.

            DR. LaRUSSA:  Okay.  Good.

            CHAIRMAN ROYAL:  Are there any other Committee questions for Dr. Cox at this time?  If not, we will move on to Committee discussion.  Does anyone have any comments or questions regarding questions for today?  Can everyone hear me, this is Dr. Royal.

            DR. COX:  Yes.

            CHAIRMAN ROYAL:  I hear some, I guess, airport noise around there.  At this time, we'll move on to the open public hearing.  Is there anyone from the public who would like to make a statement concerning matters addressed today?  Okay.

            MS. WALSH:  Dr. Royal, this is Christine.  I don't see anyone in the room.

            CHAIRMAN ROYAL:  Okay.  Well, thank you.  Well, in that case, ahead of schedule we will move on to specific Committee discussion concerning the recommendations for influenza B virus and also for ‑‑ I guess we need to address how to confirm our recommendations for the influenza A virus vaccine.

            MR. LEVANDOWSKI:  Dr. Royal?

            CHAIRMAN ROYAL:  Yes.

            MR. LEVANDOWSKI:  This is Roland Levandowski.  I don't think we were asking to have confirmation for the influenza A recommendations.  I think we had already had very good input from the Committee on that.  It was really to confirm the recommendation for influenza B today.

            CHAIRMAN ROYAL:  Okay.  Thank you for that correction.  Any discussion from the Committee?

            DR. KARRON:  Yes.  This is Ruth Karron.  I was just wondering if the industry representatives wanted to say anything more about the availability of the B/Shanghai/2002-like virus, as we heard a little from Dr. Levandowski, but I didn't know if they had any other specific comments.

            CHAIRMAN ROYAL:  Are there any comments from industry at this time?  Okay.  Well, if not ‑‑

            DR. PALESE:  Dr. Royal, Peter Palese.  Can I ask one other question, please?

            CHAIRMAN ROYAL:  Yes.  Go right ahead, please.

            DR. PALESE:  Okay.  Looking at the B/Shanghai in terms of its ability to interact or to neutralize the most recent B virus, there's actually quite a drop in terms of hemagglutination inhibition activity from the 2002 to the 2003 virus.  It looks actually that the Jiangsu/10/03 might almost be a better ‑‑ I'm just concerned because it looks like that the B/Shanghai may not be the best one.

            CHAIRMAN ROYAL:  Thank you.  Dr. Cox, do you have any comments?

            DR. COX:  Yes.  Peter, I'm glad you're looking at all of these carefully.  One of the things that always happens when we're working with a variety of strains is that we get different homologous titers with the sera and respective antigens.  So the homologous titer for the Jiangsu is higher and in that sense is more satisfactory and gives nice titers with some of the recent viruses.  The Shanghai has a twofold lower homologous titer than Jiangsu and the titers are correspondingly lower.  And so it's hard to know if that really is significant or not.  The viruses that are egg isolates have been circulated to the manufacturers, and so we're very keen to hear on the relative growth properties and the ability to manufacture to use the different egg isolates that have been circulated for production.  So I think going back to Ruth's question, it would be helpful to hear more from the manufacturers.

            DR. PALESE:  Yes.  But even the Jiangsu is also an egg isolate, so I mean the question is‑‑

            DR. COX:  That's why we need to hear from the manufacturer.

            DR. PALESE:  But if they never got the virus, they can't get any data.

            DR. COX:  They did.

            MR. LEVANDOWSKI:  This is Roland Levandowski.  We have distributed those viruses.  Some of them the manufacturers haven't really had enough time to work with yet to give us a lot of feedback, but just, Dr. Royal, if it's okay with you to comment on the question Dr. Palese's raising about the cross reactivity of the anti-sera.  They're actually looking down the Jiangsu column on Page 3 of the CDC handout, and it looks to me like it may not be as good in terms of cross reactivity as the Shanghai/361 anti-sera.  If you're looking at the homologous titer and the reductions there, I see two strains, antigens 13 and 14, which show a fourfold reduction with the Jiangsu serum, and I don't see that with the Shanghai/361 serum.  But I'm not sure that that even in and of itself means a lot, as I think Nancy Cox was trying to say.  I'm not sure that I would negate the use of Jiangsu because there are a couple of strains that seem to have a somewhat lower cross reactivity in this particular test.

            DR. COX:  Yes.  I guess, Peter, what I was trying to say is that when you look at the homologous titer it kind of is a toss-up between the two.

            MR. MYERS:  Nancy, it's Marty just following up on Peter's question.  When we look at a cross reaction in a human sera, what do you see?

            DR. COX:  Well, we haven't had any people who've been immunized with either of these viruses, so we really don't have a comparable way to look at it.

            MR. MYERS:  Well, I mean with last year's.

            DR. COX:  With last year's vaccine, we tested ‑‑ I'm going to have to flip back ‑‑

            MR. LEVANDOWSKI:  Well, Nancy, this is Roland again.  To help you out, last year's vaccine had a Hong Kong/330/2001-like B/Victoria/281 lineage hemagglutinin, and the cross reactivity, as I recall, was somewhat low for these B/Yamagata lineage strains, as you would expect.  I don't exactly recall what we saw with the use of the B/Victoria/504/2000/Yamagata-like strain from sera that we had from a couple of years ago, but I seem to recall that there was some reduction in antibody responses against the current B/Yamagata-like strains probably because there's been antigenic drift going on in those strains as well.

            DR. COX:  So the bottom line is that the serologies that we did are really not that informative, because we had the Vic-like antigens and we had tested Jilin and Jiangsu and there was not a good response.  They were equally poor, but it was not the right lineage vaccine strain to be able to say anything.

            MR. MYERS:  I understand.

            DR. EICKHOFF:  This is Ted Eickhoff.  Another question for Nancy.  You may have mentioned this but I simply didn't pay attention.  What were the dates of isolation of those South Korean strains?

            DR. COX:  South Koreans, yes, the dates of isolation were November and December.

            DR. EICKHOFF:  Of 2003.

            DR. COX:  Of 2003, correct.

            DR. EICKHOFF:  Thank you.

            DR. DECKER:  This is Michael Decker.  I've got a question for Roland and for Nancy.  And the question really relates to what level of detail do you want the Committee to go into?  I'm a little confused because I had the impression before the meeting started that our primary job today was to either reconfirm the tentative decision to go with the B/Yamagata lineage or to reverse that tentative decision and switch to a Victoria lineage, and I hear us now discussing fine details of specific strains, which is a conversation I wasn't expecting because in prior years what we've told the companies is ‑‑ we've told them what general type to go and we've allowed them to pick the specific production strains based on the performance of the candidate strains in their hands.  It sounds like now we're trying to pick the exact strain they're going to use for production, and is that what you really intend us to do?

            MR. LEVANDOWSKI:  Dr. Royal, this is Roland.  Should I respond to that?

            CHAIRMAN ROYAL:  Yes, please, go ahead.

            MR. LEVANDOWSKI:  Okay.  Well, as Dr. Decker is pointing out, in past years we have had from the Committee a general recommendation for a strain of which we should try to have an isolate that would be suitable for manufacturing that would meet the antigenic characterization for that particular strain.  And we have usually be successful with that strategy for finding a strain that will be a reasonable one for manufacturing and still meet the antigenic characteristics.  You're probably aware that most years we don't have the exact name strain from the recommendations in the vaccine, although occasionally that happens.  But the reason for that is that we do try to make sure that the manufacturers get a strain that's going to be useful for their purposes in terms of getting good yield.

            In this particular situation, I guess, from my point of view, I see that there are several strains that are available.  Those have been distributed to the manufacturers, and if everybody is okay with that, we would certainly like to give the opportunity for the manufacturers to pick from those strains that have the right antigenic characterization, which of those would be the one that give us the best yield so that we can use that for vaccine manufacturing.

            MR. LI:  This is Sam Li from Aventis Pasteur.  I think that process of selecting a prototype strain now and then working later to come back and decide what the actual vaccine strain would be is very suitable to our time frame.  We have candidates for at least three different strains, the B/Jilin, the B/Jiangsu and the B/Shanghai, that we've began initial work on.  Unfortunately, at this point, the data is still pretty early, so we don't have enough to make an actual determination of which one would be the best yielding.  So if we could follow that path, that would probably be the best for us.

            DR. PALESE:  Peter Palese.  I mean, clearly, I think there should be some understanding that not every B/Yamagata strain should be ‑‑ could be used.  For example, if I go back to the Page 3, we have the Sichuan/379 and that is also green and also posing for the same lineage, but, clearly, I mean that has tenfold lower interaction with the more recent one.

            MR. LEVANDOWSKI:  Dr. Palese?

            DR. PALESE:  Yes.

            MR. LEVANDOWSKI:  Let me answer that.  We don't have any intention to go back in time to an older strain of a different antigenic characteristic.  As you're pointing out, the Sichuan/379/99 strain is an older strain, and we don't actually think that would representative of the strains that we're talking about now, which I think we're characterizing generally as B/Shanghai/361/2002-like.  And Nancy may want to answer that too.

            DR. PALESE:  True, but I mean I just wanted to sort of clarify and maybe disagree with Dr. Decker in terms of what can be used or should be used by industry.

            DR. MONTO:  This is Arnold Monto.  According to what we've heard, industry now has three different B/Yamagata lineage viruses.  Can't we assume that the recommendation is going to be B/Shanghai-like and one of those will be the candidate for vaccine?

            MR. LEVANDOWSKI:  This is Roland again.  That would certainly be our ‑‑ what we would have anticipated doing.  That's what we would intend to do, yes.

            DR. COX:  And just if I could pipe in one more time, the viruses that we sent to Roland for distribution, the new B strains are all ones that we believe are acceptable, that fit into that B/Shanghai/361-like category, and we would not at all think that going backwards to the old Sichuan/379/99 strain would be sensible.

            MR. LI:  This is Sam Li again.  I also want to say to the Committee that based on the initial data we're confident that one of these strains that we're working with would be acceptable, so I just wanted to make sure the Committee felt comfortable that one of those three probably would be used for the vaccine.

            DR. DOWDLE:  Nancy, this is Walter Dowdle, and I'm sorry I don't have access to the tables, but if I could ask, would it not be fair to say that if you have a ‑‑ if all three of those viruses grow well, it is quite possible that they may not show the difference that you see as this sort of one shot HI test.  In fact, they could indeed be closer on later tests than they perhaps are now, and this could be within test error.

            DR. COX:  That's true, and ‑‑ I mean that is true.  Based on their genetic properties and the antigenic properties and the tests that we've done thus far, we believe that they are antigenically equivalent, the ones that we're talking about.

            DR. DOWDLE:  Right.  So I think we're talking about differences here that may turn out to be minimal if at all.

            DR. COX:  Right.  Correct.

            DR. DOWDLE:  Yes.  Thank you.

            DR. COX:  Yes.

            DR. DECKER:  This is Michael Decker again.  Correct me, Roland, if I'm wrong, but I believe is it not true that also in at least some prior years different manufacturers have had differing success with different strains, and the vaccine that's marketed is actually not always been the same strain from each manufacturer, but they've always been in the same antigenic group here?  In other words, we may find of the three strains you've recently distributed one manufacturer has their best success with one, another with another, and those manufacturers' specific choices all fall within the domain of choices that was approved by the Committee.

            MR. LEVANDOWSKI:  Yes, that's true.  In fact the current vaccine from this past year of the two manufacturers, each had a different influenza B, actual influenza B strain.  Aventis used B/Hong Kong/1434/2002, and Evans/Chiron used B/Hong Kong/330/2001.  I guess I should mention that Medimmune used B/Hong Kong/330/2001 as a strain for the live vaccine.  So, yes, we do anticipate that that may be a necessity, and if it will help manufacturing, if it significantly helps manufacturing, we're prepared to support that.

            DR. DECKER:  Then, Mr. Chairman, I would suggest that perhaps the question before us is whether we wish to reconfirm our B/Yamagata choice of last month or wish to move instead to Victoria, and if we wish to stay with Yamagata, do we wish to authorize FDA to move ahead with these three strains they sent to the manufacturers and allow the appropriate officials in the companies and at FDA to agree on the final choices.

            CHAIRMAN ROYAL:  Do we have any discussion concerning that recommendation?  Is anyone ‑‑

            PARTICIPANT:  Do we need a second?

            MS. WALSH:  Yes.

            PARTICIPANT:  I'll second.

            CHAIRMAN ROYAL:  All in favor?

            (Committee members vote aye.)

            CHAIRMAN ROYAL:  Okay.  So we now change the question.  Could you please restate that question, Dr. Decker?

            DR. DECKER:  It was a two-part.  Number one, does the Committee wish to reconfirm its tentative recommendation of last month that the influenza B component be changed to a B/Yamagata/1688 lineage, a B/Shanghai/361/2002-like strain?  That's part one.  And assuming that that question is answered in the affirmative, does the Committee then wish to authorize FDA and the companies to make appropriate choices among the candidate strains that have been circulated as to the specific strains used by each company for manufacture?

            CHAIRMAN ROYAL:  Are we prepared to vote?  First, I'd like to check to see if anyone new has joined the teleconference since we checked the roster?

            DR. MONTO:  Arnold Monto has joined.

            CHAIRMAN ROYAL:  Okay.  Great.  Dr. Gellin?  Dr. Myers?

            MR. MYERS:  Yes.

            CHAIRMAN ROYAL:  Mrs. Province?  Okay.  With that, I believe we are prepared to vote.  We'll start with Dr. Dowdle.

            DR. DOWDLE:  My vote is affirmative.  Do you want to do both ‑‑ do you want to consider both 1 and 2 as one or do them separately?

            CHAIRMAN ROYAL:  I think Number 2 will be contingent upon the outcome on 1, so if ‑‑

            DR. DOWDLE:  Okay.  Number 1 would be, yes, I agree.  Yes.

            CHAIRMAN ROYAL:  Okay.  Dr. Goldberg?

            DR. GOLDBERG:  Affirmative for Question 1 to change to the strain.

            CHAIRMAN ROYAL:  Okay.  Great.  Dr. Karron?

            DR. KARRON:  Yes, I agree that we should change the strain.

            CHAIRMAN ROYAL:  Okay.  I'm next, Dr. Royal, I do agree to change the strain.  Dr. Farley?  Are you still with us, Dr. Farley?  Okay.  We'll move on to Dr. McInnes.

            DR. McINNES:  I vote to confirm the recommendation made on February 19 to change the flu component to B/Yamagata/1688 lineage.

            CHAIRMAN ROYAL:  Okay.  Thank you very much.  Dr. Phillips?

            DR. PHILLIPS:  Yes.  I vote to the confirm the recommendation.

            CHAIRMAN ROYAL:  Okay.  Dr. LaRussa?

            DR. LaRUSSA:  I also vote to confirm the recommendation to change.

            CHAIRMAN ROYAL:  Okay.  Thank you.  Dr. Myers?

            MR. MYERS:  I vote to confirm the recommendation.

            CHAIRMAN ROYAL:  Dr. Word?

            DR. WORD:  I vote to confirm the recommendation.

            CHAIRMAN ROYAL:  Dr. Peter Palese?

            DR. PALESE:  Yes.

            CHAIRMAN ROYAL:  How do you vote?

            DR. PALESE:  Yes.

            CHAIRMAN ROYAL:  Thank you.  Dr. Monto?

            DR. MONTO:  Yes.

            CHAIRMAN ROYAL:  Okay.  And Dr. Eickhoff?

            DR. EICKHOFF:  Yes, vote to confirm.

            CHAIRMAN ROYAL:  Thank you very much.  Did we miss anyone?  Any further comments from the Committee or from FDA or CDC?  If not, we can adjourn today's teleconference.

            DR. KARRON:  Don't we have a second question?

            CHAIRMAN ROYAL:  Oh, the second question I thought was contingent upon the first.  Okay.  Well, we will do that separately.  Okay, the second question, that is to ‑‑ Dr. Decker, I did not write it down verbatim.  Could you go ahead and state the second question for us, please?

            DR. DECKER:  Does the Committee authorize FDA to work with the manufacturers to settle for each manufacturer on the final strain to be used within the guidelines that we just authorized?

            CHAIRMAN ROYAL:  Okay.  Great.  Okay.  Dr. Dowdle?

            DR. DOWDLE:  Yes.

            CHAIRMAN ROYAL:  Dr. Goldberg?

            DR. GOLDBERG:  Yes.

            CHAIRMAN ROYAL:  Thank you.  Dr. Karron?

            DR. KARRON:  Yes.

            CHAIRMAN ROYAL:  Dr. Royal, yes.  Dr. Farley?  Dr. McInnes?

            DR. McINNES:  Yes.

            CHAIRMAN ROYAL:  Dr. Phillips?

            DR. PHILLIPS:  Yes.

            CHAIRMAN ROYAL:  Dr. LaRussa?

            DR. LaRUSSA:  Yes.

            CHAIRMAN ROYAL:  Dr. Myers?

            MR. MYERS:  Yes.

            CHAIRMAN ROYAL:  Dr. Word?

            DR. WORD:  Yes.

            CHAIRMAN ROYAL:  Dr. Palese?

            DR. PALESE:  Yes.

            CHAIRMAN ROYAL:  Dr. Monto?

            DR. MONTO:  Yes.

            CHAIRMAN ROYAL:  And Dr. Eickhoff?

            DR. EICKHOFF:  Yes.

            MS. WALSH:  Excuse me, this is Christine Walsh.  Can you please repeat the Question Number 2 again?

            DR. DECKER:  Question Number 2 was does the Committee authorize FDA to work with the manufacturers to reach final agreement on the specific strain to be used by each manufacturer for manufacturing the B component of the 2004-5 vaccine in accord with or consistent with the recommendation that we just adopted that it be a B/Yamagata B/Shanghai/361/2002-like strain.

            MS. WALSH:  Thank you.

            CHAIRMAN ROYAL:  Okay.  Thank you very much.  Any further comments?  Christine, anything else?

            MS. WALSH:  Nothing that I know.

            CHAIRMAN ROYAL:  Okay.  Well, with that, we will adjourn today's teleconference.  Thank you all.

            MS. WALSH:  Thank you very much.

            (Whereupon, at 2:04 p.m., the FDA Teleconference was concluded.)