UNITED STATES OF AMERICA

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

(8:37 a.m.)

DR. FREAS: Good morning. Before we officially start the meeting, I would like to go around and introduce to the members of the public those committee members that are seated at the head table.

Starting on the right-hand side of the room, we have Dr. David Markovitz, Professor, Division of Infectious Diseases, University of Michigan Medical Center. Sitting next to him is Dr. Walter Dowdle, Senior Public Health Consultant, The Task Force for Child Survival and Development. Next we have Dr. Judith Goldberg, Director, Division of Biostatistics, New York University School of Medicine.

Next we have Dr. Ruth Karron, Associate Professor, Johns Hopkins University School of Hygiene and Public Health. Next we have Dr. Walter Royal, Associate Professor of Medicine, Morehouse School of Medicine. Next we have Dr. Monica Farley, Professor of Medicine, Emory University School of Medicine.

Next we have Pamela McInnes, Deputy Director, Division of Microbiology and Infectious Diseases, NIH. Next we have Ms. Cindy Lyn Province, Associate Director, Bioethics Center of St. Louis. Next we have Dr. Bruce Gellin, Director, National Vaccine Program.

Next we have ‑‑ joining with us this morning Dr. Stephen Phillips, Director, Deployment Medicine and Surveillance, Office of the Assistant Secretary of Defense. Next, to the Chairman of this committee, Dr. Gary Overturf, Professor, Pediatrics and Pathology, University of New Mexico School of Medicine.

Next we have Dr. Philip LaRussa, Professor of Clinical Pediatrics, Columbia Presbyterian Hospital. Next we have Dr. Martin Myers, Co-Director, Public Health Policy and Education, Sealy Center for Vaccine Development, University of Texas Medical Branch. Next we have Dr. Bonnie Word, Assistant Professor of Pediatrics, Baylor College of Medicine, Texas Children's Hospital.

Next we have Dr. Peter Palese, Chairman and Professor, Department of Microbiology, Mount Sinai School of Medicine. Next we have Dr. Arnold Monto, Professor at the University of Michigan. Next we have Dr. Ted Eickhoff, Professor of Medicine, University of Colorado Health Sciences Center.

Next is our non-voting industry representative, Dr. Michael Decker, Vice President, Scientific and Medical Affairs, Aventis Pasteur. Next we have Dr. Nancy Cox, Chief, Influenza Branch, Center for Disease Control and Prevention. And at the end of the table we have Dr. Reverend Levandowski ‑‑ Dr. Roland Levandowski ‑‑ excuse me ‑‑

(Laughter.)

‑‑ okay, from FDA.

I would like to welcome all of you here.

CHAIRMAN OVERTURF: I'd like to call the ‑‑ I'd like to welcome you back for the second day of this VRBPAC meeting.

At this time, we have an opportunity for an open public hearing, and I request that anybody who would like to make a statement to please make their way to a microphone. Please announce who you are and any groups that you may represent.

Okay. Since we have nobody who is approaching the microphone, I assume that there is nobody wanting to address the committee during the open public hearing. So we will proceed to the questions for this committee meeting, and that is the options for the strain selection for the 2004-2005 influenza vaccine, and I'll turn the meeting over to Dr. Levandowski.

DR. LEVANDOWSKI: Okay. Thank you.

Good morning, everybody. I'll just plunge right into this, and actually this should say options for Influenza A H1N1 and H1N2, or just Influenza A H1.

Just to summarize, I'll try to summarize information from yesterday as a reminder of what we were looking at for each of the strains, and then go through options that are possible for strain selection.

The H1N1 and H1N2 viruses ‑‑ of course there have been relatively few of these viruses isolated during this season. The isolates have come mainly from sporadic cases that have been in the Americas, Asia, and Europe, but there have been some outbreaks. I don't know if we emphasized that. There have been outbreaks of Influenza A H1N1 and H1N2 in Iceland and the Ukraine during this past season.

The HA on most of the H1 strains antigenically are similar to the current vaccine strain, which is A/New Caledonia/20/99, and the H1 virus is generally seen to be well inhibited by antisera from people who have been immunized with the current vaccines that contain A/New Caledonia/20/99.

In addition to that, we have high growth reassortants for A/New Caledonia/20/99 that are available or used in current manufacturing, and all of that is very well worked out at this time. So the first option for this ‑‑ for the H1 strain is to retain the New Caledonia/20/99 virus.

And in favor of that, as I mentioned, most of the recent H1 viruses are antigenically very close in nature to the hemagglutinins. They're very close in nature antigenically to the A/New Caledonia vaccine strain.

The current vaccines, of course, appear to be well matched to the HA of the current strains, and the manufacturing has worked out and the yield is very predictable. I'm not in favor of that. The con here is that there have been relatively few strains to look at for analysis.

The second option for this, of course, is to change to use a more recent H1N1 virus, and in favor of that there is the possibility that a more recent strain might provide a closer match with hemagglutinins and the neuraminidases of the contemporary strains.

But against that the new strain is not likely to be superior in terms of immunogenicity or efficacy compared to the current vaccine strain, and there aren't ‑‑ the manufacturing issues have not really been worked out for any strains at this point.

And the third option, of course, always is to defer the recommendation. In favor of that might be that there could be analysis of more contemporary strains if those were identified, and maybe that would make a closer match for the hemagglutinin and neuraminidase of next year's vaccine. But against that is the fact that it appears that there will be little new information that's forthcoming, since there are so few H1N1 viruses that are causing disease.

So moving on for the H3N2 viruses, by way of review, of course everyone knows that the Influenza A H3N2 viruses have predominated globally since September of 2003. The HA on most of these strains are antigenically distinguishable from the current vaccine strain, which is A/Panama/2007/99, and they are more closely related to the A/Fujian/411/2002 strains.

At this point, the influenza season appears to be declining in the northern hemisphere, and, of course, we also know that the majority of the strains that are ‑‑ that have been isolated are not that well inhibited by antisera produced against the current vaccines in people.

There are ‑‑ at this point, there are high growth reassortants of the ‑‑ of A/Fujian/411/2002-like strains, and that includes, as we heard yesterday, reassortants for A/Wyoming/3/2003 and A/Kumamoto/102/2002. And we know that those grow reasonably well.

So for H3N2, again, the first option would be to retain the A/Panama strain as the vaccine strain. And in favor of that, of course, the manufacturing is very well worked out, and it's very highly predictable. But against that we know that the HA of most of the H3N2 viruses are antigenically distinguishable from the current vaccine strain. And serological tests with current vaccines indicate that the majority of strains are not very well inhibited by antiserum from people who are immunized with the Panama strain.

And also, as we know, the H3N2 influenza viruses are often responsible for significant morbidity and mortality, and I think that was highlighted in Maria Zambon's talk.

So the second option for H3N2 is to choose a more recent H3N2 virus, and in favor of that a more recent strain could provide a closer match with the hemagglutinin and neuraminidase of contemporary strains. There are high growth reassortants for Fujian/411-like viruses available for manufacturing, and they appear to be reasonable in terms of their yield. And, again, reason to do this is because H3N2 viruses are often responsible for more significant morbidity and mortality.

Against this we don't really know that a new strain would actually provide superior immunogenicity or efficacy compared to the current vaccine strain, and we wouldn't know that until the vaccine was actually made and used.

The third option, of course, would be to defer the recommendation. In favor of that it might give us time to look at some other strains, and a different, more recent strain might provide a closer match with other contemporary H3N2 viruses in terms of the hemagglutinin and neuraminidase.

And, again, because the H3N2 viruses are associated with significant morbidity and mortality, that might be something to consider. Against that there is already a lot of information about how the H3N2 viruses have evolved during this current season, and it seems very unlikely that we're going to get any additional information in the next few weeks that would really add to what we already know about the current ‑‑ the majority of the current strains. And we don't really know whether another strain would be superior in terms of efficacy for vaccine production.

So for Influenza B ‑‑ again, to summarize ‑‑ the Influenza B viruses that have been circulating are in both of the known HA ‑‑ two known HA lineages. Strains that are in the vaccine HA lineage ‑‑ that is, the Victoria/287-like viruses ‑‑ seem to be antigenically very similar to the current vaccine strain, which is B/Hong Kong/330/2001-like virus.

Strains in the other HA lineage ‑‑ that is, the B/Yamagata/16/88 lineage, however, are the predominant viruses, and those have been represented by the reference strain B/Shanghai/361/2002.

Even though the Influenza B viruses have not been the predominant viruses in the recent months, strains similar to the B/Shanghai/361 virus have been isolated in many parts of the world. So they're out there circulating widely.

And although this B/Shanghai/361/2002 virus is related to previous vaccine strains, that and similar viruses are antigenically distinguishable from the previous B/Yamagata HA lineage viruses that were used in vaccines.

There is a little bit of evidence that the Influenza B viruses that are similar to B/Shanghai/361 are less well inhibited by antisera from people who have been immunized with vaccines that contained the virus in the same lineage, but even more so it's very apparent that the current vaccines do not inhibit these newer viruses as well.

And it's particularly obvious in looking at antisera from children where there's a true dichotomy, where there's a pretty reasonable vaccine response to the vaccine strain, but really no cross-reactive antibodies against the other HA lineage.

And we also have heard that there are some ‑‑ there are a number of candidate viruses in the B/Shanghai/361/2002 category that are available for potential vaccine use. But we don't really have a lot of information about those at this point, because they've only just recently been distributed to ‑‑ some of them have been recently distributed to manufacturers for evaluation.

So we don't really know exactly what their growth characteristics are going to be, although we heard from Greg Slusaw that the B/Jilin strain at least seemed to be a moderate strain in terms of its growth on early ‑‑ very early examination.

So the options for Influenza B ‑‑ one, we could retain the B/Hong Kong/330/2001-like virus, which is the current vaccine strain. For that manufacturing is very well defined, and it's very predictable. Against that at the moment the predominant strains are not in the same HA lineage, and those strains have been found in many parts of the world at this point.

Also against that, Influenza B viruses that are not in the vaccine HA lineage are not that well inhibited by post-infection and post-immunization antisera. And in particular, as I mentioned, the immunologically naive young children ‑‑ sera from immunologically naive young children who get the current vaccine don't seem to inhibit the B/Yamagata lineage viruses at all.

So the second option is to use a more recent Influenza B virus, and in favor of that the vaccines might provide better coverage for the currently circulating Influenza B viruses. There are several candidate strains that have been identified, and those are being examined right now.

Against that a new strain, you know, might not provide superior immunogenicity, and use of a new Influenza B strain could cause some difficulties in manufacturing, since we don't really have a lot of information at this point.

And then, finally, the third option, of course, is to defer the recommendation. And in favor of that that would provide more time to evaluate these candidate vaccine strains, and that might permit us to find the best match for a strain that matches the contemporary hemagglutinin and neuraminidases. Against that we don't really know whether a new strain really would be ‑‑ how much better that would be in terms of its actual use.

And so I'll stop there, and just remind the committee that the question is, of course, what strains should be recommended for the antigenic composition of the 2004-2005 influenza virus vaccine that we'll be using in the United States?

And the answer to this question should, of course, be based on the epidemiology and antigenic characteristics of the viruses, serologic responses, and availability of candidate strains for use. And I can answer a few questions, if there are ‑‑ if you want me to.

CHAIRMAN OVERTURF: Are there any questions for Dr. Levandowski? Yes.

DR. FARLEY: This is on the same track as yesterday's questions about B virus. This is for H1 virus, Influenza A H1. The numbers that we had in the handout were very, very small, as you've referred to. I think we only had 10 that showed the responsiveness to the previous vaccine sera.

If we look at the other WHO sites, does that give us reassurance that everything ‑‑ the additional numbers that that might bring in were also responsive?

DR. LEVANDOWSKI: Maybe Nancy can ‑‑

DR. FARLEY: Sort of a question for Nancy.

DR. LEVANDOWSKI: Maybe Nancy Cox would like to answer that.

DR. COX: Sure. This is Nancy Cox. The only significant outbreaks that have occurred since October have been in the Ukraine and Iceland. Those ‑‑ isolates from those outbreaks were analyzed by the WHO Collaborating Center in London, and the antigenic characteristics of those viruses were very similar or identical to the antigenic characteristics of the viruses that we've displayed in our table.

So I think that although the numbers are really small, if you look back at the previous time interval, which was during the southern hemisphere influenza season, that data also is reassuring that, you know, what we have ‑‑ we've looked at what is available, and it is very consistent data that we're seeing from all centers with small numbers of viruses, and the viruses are very well inhibited by antiserum to the New Caledonia vaccine strain.

CHAIRMAN OVERTURF: Are there other questions for Dr. Levandowski?

At this time, I think I should open up the discussion. And what I would prefer to do is to have a discussion regarding each selected strain, and we'll open it up with the H1N1 strain. And then after that we can vote on that strain and the recommendations, and then that will be followed by a discussion by each strain in sequence.

Is there any discussion regarding H1N ‑‑ further discussion about H1N1 strains? Any comments?

Well, the options ‑‑ the options for the H1N1 strain is to either retain the current New Caledonian strain or to go to a more recent strain or to defer the recommendation. And so those are your three options when we polled the committee on a vote.

And so I will start with David and have you go around the table and all state your vote.

DR. MARKOVITZ: Yes. David Markovitz. I would like to indeed vote to retain the current New Caledonia strain. Strains like the current circulating viruses are all very similar to this, and it's up and running and in production, and so it seems fairly clear that that's the way we should go.

DR. DOWDLE: Walter Dowdle. And I would vote to retain the current Caledonian strain.

DR. GOLDBERG: Judith Goldberg. I vote to retain it.

DR. KARRON: Ruth Karron. I'd vote to retain the A/New Caledonia strain.

DR. ROYAL: Walter Royal. I vote to retain the A/Caledonia strain.

DR. FARLEY: Monica Farley. I vote to retain it.

DR. McINNES: Pamela McInnes. I vote to retain the A/New Caledonia/20/99-like virus in the current vaccine.

MS. PROVINCE: Cindy Province. I vote to retain the current strain.

DR. GELLIN: Bruce Gellin. I also vote to retain the current New Caledonia strain.

DR. PHILLIPS: Steve Phillips. On behalf of Department of Defense, I vote to retain.

CHAIRMAN OVERTURF: This is Gary Overturf. I also would retain the current New Caledonia strain.

DR. LaRUSSA: Phil LaRussa. I vote to retain.

DR. MYERS: Martin Myers. Retain.

DR. WORD: Bonnie Word. Vote to retain.

DR. PALESE: Peter Palese. Retain, please.

DR. MONTO: Arnold Monto. Retain.

DR. EICKHOFF: Ted Eickhoff. I think there's an echo in this room.

(Laughter.)

Vote to retain. This is the easy one.

CHAIRMAN OVERTURF: Nobody wanted to buck a trend.

DR. FREAS: Just for the record, I'd like to announce that we're at the end of the voting members of the table, but we do ask industry for their opinion.

DR. DECKER: The industry applauds the wisdom of the committee.

(Laughter.)

CHAIRMAN OVERTURF: Is there any further comment? I think there's a unanimous vote to retain the New Caledonian strain for the H1N1 Influenza A.

The second issue is regarding the H3N2 strain, and I'll open this issue up to discussion again. And, again, there are three alternatives for that. One is, of course, to ‑‑ to use a more recent influenza A/Fujian strain or to retain the A/Panama strain or to defer this decision as well.

So I think those are the three options that we'll be voting on, and I'll open this up for discussion at this point. Is there any discussion?

Yes, Martin.

DR. MYERS: I guess it's a ‑‑ like on the last one, I have a question for Nancy. Some of the recent isolates were ‑‑ that you showed yesterday in your table were less reactive against the Fujian. Is there further drift that you anticipate occurring?

DR. COX: We have looked very carefully at recent viruses, and we really concentrated on looking at viruses that are in slight ‑‑ those slightly different genetic groups that have the changes at 126 in one group, or the change ‑‑ and the changes at 197 ‑‑ sorry, 193 and 227 in the other group.

And we haven't found that those viruses are antigenically distinguishable from the Fujian-like viruses. So we're seeing low avid viruses have a tendency to group together in the 193/227 group, but some of those viruses that are not as well inhibited by the Fujian antiserum are also not well inhibited by any of the other antisera. So we just think those are low avid viruses.

So I don't ‑‑ in answer to your question, the short answer is we don't, at the moment, see anything that looks like a definable antigenic variant from Fujian.

CHAIRMAN OVERTURF: The one thing that was troubling to me yesterday a little bit in the data ‑‑ and maybe I was misinterpreting it ‑‑ it seemed to me that there was a fair amount of heterogeneity in the serological neutralization of A/Fujian. Is that ‑‑ was that a correct interpretation? Or do you feel it was fairly uniform among the A/Fujian-like isolates that in the sera was fairly representative, fairly neutralizing? Do you understand the question?

DR. LEVANDOWSKI: You mean from the human serologies.

CHAIRMAN OVERTURF: Yes.

DR. LEVANDOWSKI: Well, I think we saw some variability. I tried to point that out. Maybe I didn't do such a good job. I think generally what we saw for most of the sera examined in most of the laboratories was that the majority of the A/Fujian-like viruses are not well inhibited by current vaccine antisera.

CHAIRMAN OVERTURF: Okay.

DR. LEVANDOWSKI: But they ‑‑ I think we can see that there is ‑‑ there is some heterogeneity there, too, that is a little bit reflective of ‑‑ of what is seen with the ferret serum. And we didn't emphasize that, but there are some ‑‑ there were some of the low reactor type strains that were included in the serologies. And just as they were low reacting in ‑‑ with the ferret sera, they were very low reacting with the human sera as well.

So it's ‑‑ there is that heterogeneity that is out there, and I don't know that that can answer your concern except to say that, yes, I think you are correct in interpreting it as ‑‑ as there is some variability in the results, not only from lab to lab but between the viruses themselves.

CHAIRMAN OVERTURF: Is there any further discussion regarding the issue of the H3N2 strain selection? Again, I will repeat, I think the three options is either to defer this, to retain the A/Panama strain, or to elect to proceed to an A/Fujian-like H3N2 strain for the 2004-2005 season.

So with that, I think we can probably, again, poll the committee for a vote. And this time, to give David a break, I will start with Ted.

DR. EICKHOFF: Thank you. I truly think this is the other easy one. The next one won't be this easy. But I think certainly based on the data that Roland and Nancy have presented, I think it's time for an update. So I would recommend that we switch strains and move to an A/Fujian-like strain. There are two candidates available that are said to grow moderately well or grow well in eggs.

There's another issue that I'll just put out on the table. I think there is an issue of public perception here that we should be aware of. If we voted to retain the current A/Panama strain, I think there would be a certain loss of credibility ‑‑

(Laughter.)

‑‑ on the part of this panel. Hence, I would vote to update to an A/Fujian-like strain.

DR. MONTO: Arnold Monto. I agree. We need to move to the A/Fujian-like strains. I think that everything is in place for their manufacture, which I think is probably going to come on second. And, again, I totally agree that if we didn't do it, we'd have a lot of explaining to do.

DR. PALESE: Peter Palese. I vote for switching to the Fujian strain, which we should have probably done last year.

(Laughter.)

DR. WORD: This is Bonnie Word. I would agree for the switch to the Fujian-like strain based on the information presented here.

DR. MYERS: I agree.

DR. LaRUSSA: Phil LaRussa. I vote to switch.

CHAIRMAN OVERTURF: I also vote to switch. I also think there is not just the issue of credibility, but I think there is a broader issue in terms of vaccine acceptability. I think when one vaccine seems to perform poorly, or that's the public perception, I think it hurts all vaccines. And being a vaccine advocate, I would really like to make sure that we choose the optimal strain. So I also would vote for a change to A/Fujian.

DR. PHILLIPS: Steve Phillips. We vote to change.

DR. GELLIN: Bruce Gellin. I also vote to change to the Fujian.

MS. PROVINCE: Cindy Province. I vote to change to A/Fujian.

DR. McINNES: Pamela McInnes. Given that we are supposed to take into account data, along with a degree of pragmatism in our decisionmaking, I vote to change to an A/Fujian-like strain.

DR. FARLEY: Monica Farley. I vote to change to the Fujian-like strain.

DR. ROYAL: Walter Royal. I vote to switch to the Fujian strain.

DR. KARRON: Ruth Karron. I vote to change to an A/Fujian-like strain.

DR. GOLDBERG: Judith Goldberg. I vote to switch to the A/Fujian strain.

DR. DOWDLE: Well, I'm not going to start a new trend at this late date. But ‑‑ but ‑‑ this is Walter Dowdle. I would like to point out, though, that I think the data that we've seen so far it's just a little too early to decide how well the Panama strain performed last year.

You know, I think we shouldn't leave here without recognizing that we've got a lot more data coming in, and the studies that we've seen in this country at least were not designed to really evaluate the current strain. So we need to keep this in mind. I don't think that it ‑‑ based on past evidence, there's no reason to believe that this was a disaster at all, because past evidence just simply didn't point that direction.

Having said that, I think we also always agree to try to have the closest match we can get, and it's clearly Fujian.

DR. MARKOVITZ: Yes. David Markovitz. I'd like to agree completely with what Walter said and vote to switch to the Fujian-like strain.

CHAIRMAN OVERTURF: Dr. Decker, would you like to make a comment for industry?

DR. DECKER: We're ready to get to work making it.

CHAIRMAN OVERTURF: Again, that's another unanimous vote to change to the A/Fujian strain. And we'll proceed onward, then, to the selection for an Influenza B strain.

It seems to me, again, there are really three options here. Again, one is to retain the current strain, the second one is to proceed to substitute with a B/Yamagata-like virus, or, again, to defer the recommendation. And so I will now open this issue up to discussion.

Dr. McInnes.

DR. McINNES: Thank you. I'd like to ask a question, please, of Nancy.

Nancy, the data that you shared about the B strains ‑‑ I think it was pretty clear that of what you have, the B/Yamagata-like strains are dominating, and you showed that the two ‑‑ that the strains you have are most either like the B/Shanghai/361 or the B/Jilin/20. And I still don't know if it's 2003 or 2002. Is it 2003 at the end? That's not my question, but is it B/Jilin/20/2003?

DR. COX: 2003.

DR. McINNES: Okay. And that the data from the October '03 through what you currently have from the three collaborating centers, you had 49 B isolates total, of which 46 were B/Yamagata and three would be Victoria-like.

DR. COX: That's correct. And I can add a bit more data that is from Canada. And so the numbers now are 57 total B's, 52 of which are Yamagata lineage and five of which are Victoria lineage.

DR. McINNES: Thank you. So my question was, given, I think, you also said there wasn't much B activity in, we presume, the collaborating centers, is it ‑‑ is it a fair assumption that the collaborating centers have all of the B data we're going to be able to get for the foreseeable future? Or is there a likelihood ‑‑ are there viruses that have ‑‑ are in the collaborating centers or could be obtained that have not yet been looked at?

DR. COX: We have a few at CDC. But, again, it's relatively few that are in the pipeline. And certainly whatever data we can develop within the next few weeks would be available for the committee, should that be necessary.

It doesn't look to me ‑‑ we have ‑‑ I was checking the log-in sheets before I left. And although we've received a lot of packages, the majority of the viruses are actually A's, H3N2's. So it would be a limited amount of information.

CHAIRMAN OVERTURF: Nancy, of the additional strains over the 49 that you mentioned yesterday, and now the ones from Canada, what were the dates of recovery of those viruses?

DR. COX: They were all isolated between October and the current time. So they're all in that most recent time interval that you see on ‑‑ on our tables that we present.

DR. KARRON: One more ‑‑ one more question for Nancy. I know that sometimes that when we have an A year, we often have a ‑‑ we have B late in the season. Would we ‑‑ if we were going to have that happen in the northern hemisphere, would we already have seen that?

DR. COX: Influenza is full of surprises, as we all know. But we've been watching very closely for that second wave of activity, and we have ‑‑ and we sort of expected that we might see it for Influenza B viruses this year, since we had Victoria-like viruses circulating last year, quite a few school outbreaks, and so on and so forth.

But we haven't seen that increase in the proportion of the total isolates that are Influenza B. In fact, in past weeks we've seen very few B's isolated in the U.S., so we're not getting ‑‑ we're not getting that signal that we usually do when we have that second wave.

CHAIRMAN OVERTURF: Dr. Palese.

DR. PALESE: Could I ask whether we could fine-tune one of the options, so one is retaining it, one is changing, and the third one was to defer ‑‑ if I remember correctly, looking for the most recent isolate, the most ‑‑ I think that was the option in terms of deferring.

I would like to fine-tune this and say we defer, but really have only the choice between the Victoria and the Yamagata. That would give the manufacturer a chance to develop and gear up. They have the old strain ‑‑ to gear up the new one, and then a deferment would ‑‑ deferring would mean that we chose to wait, what we get in in the next couple of weeks or more ‑‑ three weeks or four weeks.

So, in other words, not sort of leaving the option completely open in terms of deferring, but rather say at the end of that period a decision will be made for either switching or retaining.

CHAIRMAN OVERTURF: Yes. This is very similar to what we did with the A strain last year, actually. Yes.

DR. DECKER: Just a suggestion of the refinement of that, or maybe this is what Peter was saying and I didn't understand it. But it would seem to me that the data are sufficiently well in hand to make a provisional choice, which would stand unless CDC, FDA, and the Chair elected to call another committee meeting.

In other words, instead of putting off your decision, I wonder if you can make a decision now, recognizing that you've got X period of time to revisit that, because we are waiting for reassortants to be made, and so on.

DR. PALESE: No, that was not what I meant. I really meant to leave it open, not to make a provisional decision.

DR. DECKER: Well, then, my impression was right, and Peter didn't say that. But I wanted to.

(Laughter.)

CHAIRMAN OVERTURF: Dr. Monto.

DR. MONTO: Yes. I would agree with what I thought was a refinement by Dr. Decker of the ‑‑ of Peter's remarks, because I think this is a critical decision, given the fact that, number one, there is so much divergence between the two lineages, and also the fact that we've experienced in the past situations where one lineage predominated in one part of the world and the other lineage predominated in another part of the world.

Correct me if I'm wrong, Nancy, but I think the B ‑‑ the B/Vics persisted in ‑‑ in Asia when we were having B/Yamagata a few years back. So the question I would have is: how many of these isolates are actually from the western hemisphere?

DR. COX: That would take me some time to dig through.

DR. MONTO: Just an impression.

DR. COX: But the majority of these isolates are from China and Japan and Thailand, and so on, rather than from the western hemisphere. So what we're seeing there is ‑‑ well, we ‑‑ you're absolutely correct in recalling that the B/Victoria viruses persisted in Asia, and particularly in China, for a number of years when they were detected nowhere else.

And then we had the continuing evolution of the Vic-like lineage, and then had its reemergence in the rest of the world. It's really ‑‑ because we've had co-circulation of the two lineages, it's really difficult to know exactly what's going to happen, particularly based on relatively small numbers. But the signal is there that the Yamagata lineages ‑‑ lineage is predominating actually globally.

CHAIRMAN OVERTURF: Dr. Goldberg.

DR. GOLDBERG: Yes. I mean, actually, what you're observing from the data that you have is that 91 percent of the observed isolates are Yamagata lineage. And if you just put a 95 percent confidence interval on that crudely, it's compatible with something between 83 percent and 100 percent, as the true underlying rate would lie within that interval.

So I think that with the data we have it would take a lot to overturn it. And if you don't expect very many more of these isolates, I think we're dealing with an issue that we have to make some informed judgment, recognizing all of the biases in the way we get the data.

CHAIRMAN OVERTURF: Yes. If you look at the current data, it sounds like we've only had three or four B isolates per week over the last season. And if we were to wait another two or three weeks, we might have another half dozen at best, unless something starts up, obviously, but I really think the chances that we will see new isolates is probably small. And I'm a little bit perplexed about how you would make a decision, unless you had five out of six isolates suddenly turn to A/Victoria ‑‑ I mean, B/Victoria.

Yes, Peter.

DR. MONTO: No, I think that's the dilemma, because we have seen, and almost consistently seen, late B seasons. But the problem is they may be, as Nancy is saying, that since nothing much is in the pipeline, it may be too late, even though we do ‑‑ we do see B activity in March and going into April. It's going to be too late, really, to ‑‑ given the need for time for analysis and the rest to ‑‑ to be able to say anything that we haven't been able to say today.

CHAIRMAN OVERTURF: Yes, Dr. Palese.

DR. PALESE: I just wonder whether these numbe