Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_
Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_
here is the transcript:
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS AND EVALUATION AND RESEARCH
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VACCINES AND RELATED BIOLOGICAL PRODUCTS
ADVISORY COMMITTEE
MEETING ON INFLUENZA VIRUS VACCINE
FORMULATION FOR 2003-2004
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TUESDAY,
MARCH 18, 2003
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The meeting was held in Conference Room A on the 11th Floor, 5515 Security Lane, at 10:30 a.m., Dr. David Stephens, Committee Chair, presiding.
This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly, the Food and Drug Administrations makes no representation as to its accuracy.
PRESENT:
DAVID S. STEPHENS, M.D. Chair
JODY SACHS, D.P.M. Executive Secretary
DENISE ROYSTER Committee Management
Specialist
MICHAEL A. DECKER, M.D., M.P.H. Member
PAMELA S. DIAZ, M.D. Member
JUDITH D. GOLDBERG, Sc.D. Member
RUTH A. KARRON, M.D. Member
SAMUEL L. KATZ, M.D. Member
DAVID M. MARKOVITZ, M.D. Member
AUDREY F. MANLEY, M.D., M.P.H. Member
GARY D. OVERTURF, M.D. Member
PETER PALESE, Ph.D. Member
JULIE PARSONNET, M.D. Member
WALTER ROYAL, III, M.D. Member
RICHARD J. WHITLEY, M.D. Member
CONSULTANTS PRESENT:
NANCY COX, Ph.D.
COLONEL BENEDICT DINIEGA, M.D.
WALTER DOWDLE, Ph.D.
THEODORE EICKHOFF, M.D.
BARBARA LOE FISHER
BRUCE GELLIN, M.D., M.P.H.
PAMELA McINNES, D.D.S.
MARTIN MYERS, M.D.
SPEAKERS:
ROLAND LEVANDOWSKI, M.D.
NANCY COX, Ph.D.
INDUSTRY PRESENT:
JOHN O'BRIEN PowderJect
LISA BISSETTE PowderJect
KATHLEEN COOLING MedImmune
C-O-N-T-E-N-T-S
Call to Order 3
Announcements 9
Open Session
Strain Selection for the Influenza Virus
Vaccine for 2003-2004
Introduction and Review
Dr. Levandowski, FDA 11
Additional Information, H3N2
Dr. Nancy Cox, CDC 29
Committee Discussion
Open Public Hearing 49
Recommendations for Influenza Virus
Vaccine for 2003-23004 67
Adjournment 70
P-R-O-C-E-E-D-I-N-G-S
10:37 a.m.
DR. STEPHENS: That's great. Welcome, Pam.
DR. DIAZ: Hi. Thanks. I may not be able to stay long. I'm sorry.
DR. STEPHENS: Just to get started, this is a follow-up to our meeting on influenza virus vaccine formulation for 2003 and 2004.
As most all of you know, we delayed recommendations concerning the H3N2 components, and that's the subject, a major subject, of this conference call and meeting. And I'll turn it over to Dr. Jody Sachs, who will call the roll and give us announcements.
DR. SACHS: Good morning. I'd like to go ahead and start with a roll call. I'll read your name and your affiliation and just, if you're here, say present. We do have a transcriber here, so this is for the public record. Thank you.
I'll start with our chair, Dr. David Stephens from Emory University School of Medicine?
DR. STEPHENS: Here.
DR. SACHS: Dr. Ruth Karron from Johns Hopkins University School of Hygiene and Public Health?
DR. KARRON: Here.
DR. SACHS: Dr. Michael Decker from Aventis. And he will be calling in later, so I'm going to skip over. Dr. Pam Diaz from Chicago Department of Public Health?
DR. DIAZ: Here.
DR. SACHS: Dr. Sam Katz from Duke University?
DR. KATZ: Here.
DR. SACHS: Dr. David Markovitz from University of Michigan Medical Center?
DR. MARKOVITZ: Here.
DR. SACHS: Dr. Audrey Manley from -- President Emeritus, Spelman College?
DR. MANLEY: Here.
DR. SACHS: Dr. Gary Overturf, University of New Mexico School of Medicine?
DR. OVERTURF: Here.
DR. SACHS: Thank you. Dr. Julie Parsonnet from Stanford University?
DR. PARSONNET: Here.
DR. ROYAL: Dr. Walter Royal, Morehouse School of Medicine?
DR. ROYAL: Here. Here.
DR. SACHS: Dr. Nancy Cox from the CDC?
DR. COX: Here.
DR. SACHS: Colonel Benedict Diniega?
COLONEL DINIEGA: Here.
DR. SACHS: From the Office of Assistant Secretary of Defense for Health Affairs. Dr. Walter Dowdle, from the Task Force of Child Survival and Development?
DR. DOWDLE: Here.
DR. SACHS: Dr. Theodore Eickhoff from the University of Chicago Health Centers?
DR. EICKHOFF: University of Colorado. Here.
DR. SACHS: Yes. I'm sorry. Dr. Pamela McInnes from the Division of Microbiology and Infectious Diseases, NIH?
DR. McINNES: Present.
DR. SACHS: Dr. Martin Myers, University of Texas Medical Branch?
DR. MEYERS: Here.
DR. SACHS: And I'm checking. Is Barbara Loe Fisher National Vaccine Information Center on?
(No response.)
DR. SACHS: Okay. Hopefully, she'll call in. The following people have told me that they will be calling in a little bit later, so we'll acknowledge them when they come on: Dr. Michael Decker from Aventis, who is our industry representative; Dr. Judith Goldberg; and Dr. Peter Palese; as well as Dr. Richard Whitley.
I'd also like to briefly say this welcome to the 95th meeting for the Vaccine and Related Biological Products Advisory Committee. Where I'm talking from right now, there is a speaker phone for public participation at the FDA, located at 5516 Security Lane in Conference Room A on the 11th floor, Suite 1113 in Rockville, Maryland.
This morning's session will consist of presentations and committee discussions that are open to the public as described in the Federal Register notice of March 5th, 2003.
Should a committee member get dropped from the telephone lines, simply call back at the number given, 1-888-655-9181, and ask to be connected to the pass code VRBPAC. The operator is under strict instructions only to connect committee members to this line. That number, again, if you're disconnected, just hang up and call back. If you have problems while I on the call, press star zero and the operator will help you.
I really wish that people would not use their hold button because if you're calling from a clinical center that has background music, it could be distracting to those remaining on the telephone line. If you'd like to use mute, please, I urge you to use star six. And if you'd like to speak, you have to press star six to get off the mute.
Since there are many lines connected, any background sound will decrease the quality of sound for everybody.
I'd like to remind everybody to please give your name before speaking. And I'd like now to introduce some of the FDA staff members who are participating at today's meeting. They are currently not at this location.
Dr. Karen Midthun is the Director of the Office of Vaccine Research and Review. Dr. Norman Baylor is the Associate Director for Regulatory Policy, Office of Vaccine Research and Review. Dr. Jerry Weir is the Director of the Division of Viral Products. Dr. Roland Levandowski is Medical Officer who will be presenting. Dr. Nancy Cox will also be presenting. She will be from CDC.
And I'd also for the record like to acknowledge the following people who are on the call from industry: Dr. Sam Lee and Dr. Michael Decker are both from Aventis. Dr. Lisa Bissette and John O'Brien are from PowderJect and Evans.
I'd ask that committee members dock your cell phones, since it adds an unnecessary background noise to the line.
And I'd like to acknowledge Denise Royster. She is the Committee Management Specialist who is responsible for pulling this meeting off, and I am indebted to her.
At this point, I'd like to ask if there are any other FDA members that I left out. Please introduce yourself.
DR. EGAN: William Egan, Deputy Director for the Office of Vaccines.
DR. SACHS: Thank you. And Dr. Chris Mink, she's also from the FDA.
DR. MINK: I'm here also.
DR. GAGVETEN: Yeha, and I'm behind her. Sarah Gagveten from the --
MS. McCRACKEN: Kathy McCracken from -- also from -- and FDA.
DR. SACHS: Thank you. Are there any others? Okay.
I have a meeting statement that I'd like to read for public record.
The following announcement addresses the conflict of interest issues associated with the Vaccine and Related Biological Products Advisory Committee meeting on March 18th, 2003.
The Director of the Center for Biologics Evaluation and Research has appointed Dr. Nancy Cox, Dr. Walter Dowdle, Dr. Theodore Eickhoff, Dr. Bruce Gellin, Dr. Pamela McInnes, Dr. Martin Myers and Colonel Benedict and Ms. Barbara Fisher as temporary voting members for this meeting.
Based on the agenda, it has been determined that there are no products being approved at this meeting. The Committee participants have been screened for their financial interests to determine if any conflict of interest existed.
The Agency reviewed the agenda and all relevant financial interests reported by the meeting participants. The Food and Drug Administration prepared general matter waivers for the Special Government Employees participating in this meeting who required a waiver under 18 U.S.C. 208.
Because general topics impact on so many entities, it is not prudent to recite all potential conflicts of interest as they appear to each member. FDA acknowledges that there may be potential conflicts of interest, but because of the 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 participating in this meeting as a non-voting industry representative acting on behalf of regulated industry. Dr. Decker's appointment is not subject to 18 U.S.C. 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 today's committee discussions.
In the event that the discussions involve specific products or firms not on the agenda, and for the FDA participants have financial interests, the participants are reminded of their need to exclude themselves from the discussions. Their recusal will be noted for the public record.
With respect to all meeting participants, we ask in the interest of fairness that you state your name and affiliation and any current or previous financial involvement with a firm whose products you wish to comment upon. Waivers are available by written request under the Freedom of Information Act.
I'd now like to turn the meeting over to our chair, Dr. David Stephens. Thank you.
DR. EGAN: Jody, this is Dr. Egan. Is Dr. Gellin present?
DR. SACHS: He called me early this morning and said this morning and said that he was at a -- attending a conference that he was presenting at. He will be calling in, but he said it may be after we begin, maybe about eleven or so.
DR. EGAN: Okay. Thank you. I just wanted to clarify that.
DR. SACHS: And I'd also like to remind people that there are additional members calling in, Dr. Richard Whitley, Dr. Peter Palese, Dr. Judith Goldberg, as well Dr. Michael Decker, who will be calling in later.
DR. STEPHENS: Thank you very much, Jody. I think we will -- I want to remind members and consultants to announce your name before speaking. Otherwise, it's going to get real confusion. And I think we'll begin with Dr. Roland Levandowski updating us and reviewing our positions. Roland?
DR. LEVANDOWSKI: Okay. Thank you, Dr. Stephens. This is Roland Levandowski. I'm going to try to go over several things, and I'll just -- and actually both for Nancy and I just to get an idea of what the agenda items will be, I'm first going to give a brief statement about the situation with H5 influenza A viruses and atypical pneumonia for information purposes.
I'll then go on to review what's happened in terms of influenza strain selections. And I'd also like to restate what our question is for the committee. I think it's pretty obvious that the question is going to be what should be the H3N2 component of next year's influenza vaccines. And I'll restate that.
And when I'm done, Nancy Cox will provide the committee members with some updated surveillance on epidemiologic data. And then I intend to, and as usual, give information about -- or just a summary of what the options for recommendations could be at this point. And then turn it back to you, Dr. Stephens, for committee discussion on the actual recommendations.
So I'll just go right ahead and start getting in some information about H5 and atypical pneumonia. Since the last committee meeting, and at present time, of course there's been a lot of ongoing investigations related about the avian influenza and atypical pneumonia in Asia.
You're probably all aware that in February the Chinese Ministry of Health reported that there had been an ongoing outbreak of pneumonia in the Guangdong Province of southern China.
OPERATOR: Ms. Loe Fisher has joined.
DR. LEVANDOWSKI: The pneumonia there in China in Guangdong Province was described as being atypical, and it involved at least about 300 people, and there were five associated deaths that were reported.
Subsequently, the Chinese Ministry of Health attributed that outbreak to chlamydia pneumoniae, and they've stated also that the outbreak has ended there.
Because of that Chinese experience, the Hong Kong Department of Health had also been making particular efforts to look at all the cases of atypical pneumonia there to see if there was any type of pattern.
And initially, there was no particular etiology found in terms of atypical pneumonia until the beginning of March. And there was nothing that seemed to fit any particular clinical or epidemiologic pattern.
However, in February, in mid-February, there were two members of a Hong Kong family who were demonstrated to have been infected with an H5N1 influenza A virus of avian origin. That family, just to remind you, had visited relatives in Fujian, China, where the 8-year-old daughter of the family, of the visiting family, became ill with an acute respiratory disease and she died.
We don't really have any additional information on that family member, but a 9-year-old son of the family and the 33-year-old father also became ill, and when they returned to Hong Kong, the H5 influenza diagnosis was diagnosed.
Now, the son in that case recovered, but the father developed pneumonia and he died. And that death was -- seems to have been related to avian influenza.
The mother of the family also had an acute respiratory illness, but in her case a pair influenza virus was isolated and she recovered uneventfully.
Any relation between the atypical pneumonia in China and H5 is uncertain, but there have been no additional cases of H5 documented anywhere at this time.
Subsequently to discovery of the H5 influenza A virus and seem to be similar to what occurred in China in February, there have been cases of atypical pneumonia of an as yet unknown etiology in Hong Kong, Vietnam --
OPERATOR: Excuse me. Michael Decker is joining the conference.
DR. LEVANDOWSKI: And -- but the epidemiology in those cases suggest that there may be a contagious, infectious etiology.
The term that's being used by the World Health Organization to describe this illness is severe acute respiratory syndrome. And I think they're using that because it reflects the fact that the etiology is unknown, even though we think there might be a microbial origin, and also the fact that many of the individuals who have this illness do seem to have some type of severe pneumonia, even if it's not fatal. In fact, most of the cases, there seems to be some evidence of pneumonia.
The list of the countries that's affected by travelers who are coming from those areas in Asia has been growing, and that's also listed now by the WHO as including Germany, Canada, Switzerland and Thailand.
In the Thailand instances that were reported last week in Asia, there really appears to be mainly a clustering of the cases in hospital workers after they're exposed to an index case of a patient who has severe pneumonia.
In those instances, a high proportion of the exposed people have become ill and most of the instances of illness, the report is that there are pneumonia symptoms, which I think in most cases is also documented by X-Ray evidence of pneumonia.
The experience in Hong Kong, which is very well documented, also suggests that family members and others who may be in close contact with some of these patients may also be at risk and may develop symptoms.
The number of deaths, actually, however, related to this outbreak is very small. There are four that have been documented during the past week with the several hundred cases that are being investigated.
These cases are very -- they're very similar in many aspects. Exposure to the index case seems to result in symptoms in as short as two days, but can be somewhat longer.
And the clinical signs and symptoms are described as flu-like, with sore throat, fever, cough and, in many cases, this rapid progression to pneumonia seen on chest X-ray. There are some other peculiar lab findings, including thrombocytopenia and leukopenia.
And just one example of the index cases and here and what's happening in Asian. For the businessman who visited Shanghai, passed through Hong Kong on his way to Hanoi, when he arrived at Hanoi, became acutely ill, developed pneumonia, required ventilatory support and subsequently was transferred back to Hong Kong where he died.
In the meantime, in the hospital in Hanoi, approximately 40 of the healthcare workers became ill. Some of them have developed pneumonia and there's been at least death of a contact healthcare worker in Hanoi.
In Hong Kong, there have been many cases at one of the hospitals after exposure to that patient who was transferred back. However, there have been cases of illness with pneumonia symptoms at other hospitals and clinics.
And at this point, it's not clear that all of this is related to the same etiology, since there have been other cases of atypical pneumonia occurring in Hong Kong. So there may be multiple etiologies that are going on here, although there does seem to be a very distinct pattern for this severe acute respiratory syndrome.
What I'd really like to emphasize is that although there has been a high index of suspicion for avian influenza in the cases that have occurred, and there's been a very large amount of work done to try to identify an etiology, there's absolutely no evidence at this point that this that this syndrome that's occurring now that's being reported in the news media is related to influenza A of avian agency or in fact of any origin. There's no evidence that influenza is playing a role in that.
And maybe I should just stop there, Dr. Stephens, and see if you or anybody else wants to add any comments of questions.
DR. STEPHENS: Comments, questions?
DR. KATZ: This is Sam Katz. I guess my question would be, have they used any antivirals? I've read about antibiotics. Have they used antivirals, Ribavirin, Sotamovirin, any of the known antiviral agents in treating these patients?
DR. LEVANDOWSKI: Our understanding is that a number of different antimicrobial modalities have been used, including antibiotics for bacteria and also a number of different antiviral agents.
I don't know that I can tell you the list of antiviral agents. It does include also Tamiver and other anti-influenza agents. I'm not clear on what impact any of that has had. And I don't think I've seen reports that indicate what the outcomes might have been in any particular individual treated with any particular agent.
DR. KATZ: Thank you.
DR. STEPHENS: Other comments, questions?
DR. LEVANDOWSKI: Just to clarify, somebody here was asking me about being coy about saying that there was no evidence for influenza. It was looked for very actively, and there is no documentation for influenza. Again, very good laboratories that are involved in the investigation.
DR. MEYERS: Does that include serology, Roland? This is Marty.
DR. LEVANDOWSKI: I believe there is serologic studies going on as well. I don't know what the status of those is and I don't know exactly what is being looked for.
But I think that everything possible, any type of investigative modality, electron microscopy, PCD techniques, serologic techniques, histopathological examinations of tissues. All of those things are going on.
DR. ROYAL: That leads to my question. This is Royal. Any other organ systems known to be involved?
DR. LEVANDOWSKI: I am not clear on that either. It seems to be predominantly a pulmonary issue, but I'm not clear that there might not be some other types of abnormalities.
As I mentioned, there is thrombocytopenia that's been identified. I don't know what the implications of that would be. I don't believe that there has been evidence for something like encephalitis or hepatitis or renal disease.
But I'm not sure -- I'm not clear on what the ultimate cause of death is in the those people who have had the severe pneumonia. I believe it's respiratory death, but there may be other organ failures as well, as a part of that. And I don't know whether that indicates anything about the etiology.
DR. OVERTURF: This is Gary Overturf. Have there been epidemiologic clues in terms of index cases in particular, whether they have been primarily rural lifestyle as opposed to urban? You mentioned that the businessman, but I wonder if most of the cases have been rural as opposed to urban. Do we know that?
DR. LEVANDOWSKI: I think that the outbreaks as they are occurring are mainly in hospitals and involving healthcare workers, the ones that we know about, at least.
There are also the family members who are living in urban settings where these index cases are. And in the case of the businessman, I believe his time was spent in cities, but I don't know for sure that he didn't travel to some rural area. I'm not sure that anybody can give us that information at this point. A lot of these details are still being collected.
DR. MARKOVITZ: David Markovitz here. I wanted to know, what happened with the chlamydia aspect of this?
DR. LEVANDOWSKI: I believe that that might have been a serologic diagnosis that was made in retrospect, but again, I don't have all the information and I'm not privy to all the information that may be involved here. And I'm sort of speculating a little bit.
I don't think that we have other evidence -- I don't think we have direct evidence for chlamydia as a cause of infection. I had heard that there were some -- there was at least one case of atypical pneumonia in Hong Kong that might be attributed to a chlamydial infection, but I think that also was a serologic diagnosis.
So I don't know -- I don't believe that anybody suspects that that's the cause of what's going on.
OPERATOR: Excuse me. Richard Whitley has joined the conference.
DR. COX: Roland, I can probably just mention one thing that would clarify. The Chinese had looked extensively for a whole variety of --
DR. LEVANDOWSKI: Is this Nancy?
DR. COX: Sorry. This is Nancy Cox. The Chinese have looked for a whole variety of different pathogens in all the testing that they did. And they had some autopsy samples, which they examined microscopically.
And they had some EM's and so on. And they were identifying from some structures that they thought were chlamydia, but I think that folks here at CDC would feel that that kind of a diagnosis for chlamydia would be very difficult to make. And so -- but it was an EM that the Chinese had used, and that was the basis for they're saying it was chlamydia.
DR. PARSONNET: This is J. Parsonnet. Is there any -- do you know when the last new case was?
DR. COX: Today.
DR. PARSONNET: Today?
DR. LEVANDOWSKI: This is something that's still in evolution and I think we're not able to give too much more information than we already have. I don't think we actually -- I personally don't have any additional information that would be useful. And everything that we're getting here at FDA is coming from the WHO and the Hong Kong Department of Health website. And I think those who have an interest may find those websites helpful in keeping track of what's going on.
I believe that both of those sites, as soon as they have information that is credible and that they're confident in will put that -- make that information publicly available.
DR. STEPHENS: That's excellent. Why don't we go on, Roland, to the influenza H3N2 question?
DR. LEVANDOWSKI: Okay. So thanks, Dr. Stephens. Just as review, just to go over what the recommendations from the committee were in February when we last met, the committee had indicated that it was recommending that the H1N1 influenza A virus and the influenza virus B components of the vaccine should remain the same as they were.
And for H1N1 influenza A, that's A/New Caledonia/20/99. And for influenza B, that's a B/Hong Kong/330/01-like virus, which for us in the United States would mean either B/Hong Kong/330 or B/Hong Kong/1434/02 viruses.
For both of those strains, manufacturing has been in progress. And just as further review of what happened in February, the H3N2 influenza A recommendation was postponed because there was late breaking information about a new variant of influenza A H3N2, which is represented by some viruses forming a group that had signature amino acid substitutions at positions 155 and 156 of the hemagglutinin.
These viruses were antigenically distinguishable from the current strains. And we had information at that time that these new variant viruses were identified in Asia, including China, and also in North America and Europe.
We had information presented at the last meeting, which we won't review again, but just to reiterate, it shows that current vaccines produce antibodies that don't really inhibit many of these new viruses very well.
And at the time we met last, there were no isolates that were -- of those new antigenic variant viruses that were suitable for use in vaccine production.
After the postponement, we had some additional information through WHO. And I think you all are aware that WHO had also postponed its recommendation to try to identify whether it was possible to have a response to the new variant.
In the interim, there's been a lot of work that's gone on to try to find an isolate of one of these viruses that would be suitable for vaccine production. That hasn't happened, in spite of a lot of effort.
And because of that, the WHO recognizing that time is limited for vaccine production. And also the fact that many of the viruses have continued to be A/Panama/2007/99-like, recommended that for the northern hemisphere, that influenza virus vaccine should continue to have an H3N2 component that they would describe as A/Moscow/10/99-like. For us, that would be the equivalent of A/Panama/2007/99.
OPERATOR: Peter Palese has joined, please.
DR. LEVANDOWSKI: Okay. The WHO recommendations have been -- they were first published on the WHO website at the end of February. And on Friday, March 14th, the official weekly epidemiologic record publication of those came out, so those of you who would like to see that information directly also can access it at the WHO website.
Last week, early last week, the Committee on Proprietary Medicinal Products for the European Union met to consider what their influenza vaccine composition recommendations would be. And they announced at their meeting that they would be publishing recommendations, official recommendations, later this week that would be exactly the same as what the WHO had recommended, which would include an A/Moscow/1099-like virus, which again would mean A/Panama/2007/99.
So our main business today is really to complete the recommendations for the United States. And the question for the committee really is what influenza A H3N2 virus should be recommended for inclusion in the vaccine produced for the 2003/2004 influenza season.
Nancy Cox from CDC will be presenting some additional information on surveillance and epidemiology.
And again, before Nancy goes on, I should stop and see if you or any of the committee members have any questions about anything I've mentioned here.
DR. STEPHENS: Questions for Dr. Levandowski?
DR. MEYERS: What seems to -- this is Marty. What seems to be the problem in identifying the seed virus?
DR. LEVANDOWSKI: There aren't any seed viruses. And the problem is that it's not been possible to isolate a reference strain in eggs from one of the -- that is one of these new variant viruses. All of the isolates that we have to work with at this point are derived from tissue cultures of uncertain origins. They're the regular laboratory tissue cultures that are used for recovering viruses. And for the most part, that's MD -- laboratory grade MDCK virus tissue cultures.
DR. PALESE: Peter Palese. Can I ask -- well, maybe we should wait until Nancy has presented her data. But there -- I realize that there some New York strains. And wouldn't there be some throat washings available from these patients?
DR. LEVANDOWSKI: Maybe what I can say is that CDC and other WHO influenza centers are obtaining the original secretions to try to re-isolate these viruses. And as sometimes happens, these are -- they do not seem to replicate that well at all with at all in eggs. Even the tissue culture isolates are sometimes problematic.
DR. PALESE: I mean, clearly, I mean, I will say that I haven't seen an influenza virus which doesn't go in eggs, basically. I mean, it's difficult for me to understand that there are no throat washings available, particularly from American strains.
DR. COX: This is Nancy Cox. There are throat washings available, and we have very actively solicited the original particle specimens from our collaborating laboratories in Hawaii and military labs that have good access to very good specimens.
And we've actually inoculated approximately 20 or more of those into eggs, and have not been able to recover any, when normally we would. And we've also tried primary kidney cells, and we put fewer in because we just didn't have those going as long.
But we were not so far able to recover any in primary kidney cells. I'm sure if we had more time, that might be possible.
In addition to the work going on here, work has been proceeding at the other WHO collaborating centers with some of the national influenza centers, and it's just not been fruitful, and none of us really understand why. But I think there are probably some answers in the receptor binding area.
DR. STEPHENS: Nancy, I think -- why don't we go on with your comments at this point?
DR. COX: Okay. I'll try to be quite brief. The influenza activity in the United States is declining. It's pretty apparent from all of the graphs that we generate on a weekly basis that activity peak during the sixth week of the year, it comes -- but there still is a bit of epidemic level activity going on.
But certainly the intensity has declined, and our sentinel physicians data indicates we're almost down to background with respect to visits to the sentinel physicians for ILI.
Forty-five percent of the viruses that have been identified this season are influenza A isolates.
And 46 percent of those subtype, 82 percent of the subtype viruses are H1 and only 18 percent are H3. And of course, 55 percent of the isolates are influenza B.
I should say that influenza B predominated during the early part of the season, and now there are more influenza A isolates being identified during recent weeks.
But I think that the season has been unremarkable except for the outbreaks in schools, and those were primarily associated with influenza B viruses, but we also know that influenza A isolates were obtained from some of the school outbreaks.
The only -- and finally, the other thing worthy of mentioning -- and I'm sure some of you have seen some of this in the newspapers and various other places -- there have been a number of severe illnesses associated with influenza infections, and a number of deaths in children and others.
It's not so surprising to us here at CDC because we know that happens every year, but I think the number of reports has increased a bit because of the attention on -- by our peers and then the much greater efforts that are going into diagnosing various illnesses in this country now.
But there have also been some reports of encephalopathy associated with influenza infections in children. And those are all being followed up and investigated. And I'm sure you'll hear more about those in the future.
DR. WHITLEY: Nancy, excuse me. This is Rich Whitley. Children in the United States?
DR. COX: Yes, children -- I'm talking specifically about --
DR. WHITLEY: Okay.
DR. COX: So I think that really sort of covers what I would like to say about the activity in the United States.
I'd like the committee members to look at the frequency table, which is titled Influenza A(HSN2) Isolates Characterized by CDC.
And you saw a similar table during my presentation in February. And we simply updated this to have the most recent figures for viruses that we've tested here.
The thing that I'd like you to note is that we now have about 25 percent of the isolates, H3 isolates that have been -- that were obtained between October and March -- that is to say they have isolation dates between October 2002 and March 2003 -- that have reduced titres to the Panama strain.
If you look more closely at where those viruses have come from, they're predominately from Asia. And that reflects the viruses that we were talking about. That number of 35 low reactor -- viruses that we were discussing at the meeting in February, where we were focusing on some of the viruses from China, Japan and Korea.
DR. KARRON: Nancy, this is Ruth Karron. I have a question about this table, and actually how it relates to the previous table that we received in this packet, that has sera/anti-sera data on it.
The A/Fujian-like viruses would not be low reactors, is that correct? They seem to have very high homologous titres but equivalent HI titres to the A/Panama-like viruses.
DR. COX: No, that's not correct.
DR. KARRON: Okay.
DR. COX: Some of the Fujian-like viruses have very low titres to Panama.
DR. KARRON: Oh. So my question is this a -- can we then assume -- does this table indicate what proportion of Fujian-like or --
DR. COX: No --
DR. KARRON: Not at all?
DR. COX: This table does not. This table is looking overall at the number of viruses that are reduced fourfold or greater in titre to the Panama antiserum, compared to the homologous titre to the Panama.
We haven't sequenced all of those viruses, that we don't know -- I don't know off the top of my head what proportion of those viruses would have the 155/156 changes.
DR. MEYERS: Nancy, this is Marty. Given the difficulty in recovering the variant in both primary kidney and in eggs, do you think the proportion might be higher, that this may underestimate? It's a difficult one to culture?
DR. COX: We don't really know if this is difficult to culture in MDCK cells. That's where the original isolations are typically done nowadays. And we don't really have a feeling that they're hard to grow on MDCK. Their titres are a little bit lower, but the isolation seems to be fine. The isolation rate seems to be fine.
DR. PALESE: Nancy, you would still say that the --
DR. STEPHENS: Is this Peter?
DR. PALESE: Peter Palese. Yeah, sorry. That the Fujian-like virus is represented as a heralding virus at the end of this year, and most likely, if you wouldn't have a problem in terms of having an isolated virus, you would recommend A/Fujian-like to be the next strain, is that correct?
DR. COX: If we were able to isolate a virus, and if we had an egg isolate with the right property for production of vaccines, then yes, we probably would recommend that strain for the next vaccine. And we would probably think that would be a good way to go.
DR. PALESE: Thank you.
DR. COX: I think that it isn't quite as clearcut. I mean, influenza HI tests are not quite as clearcut as we would like them to be. And we do have isolates that have the 155 and 156 change that are well inhibited by Panama, and we have a large number of them which are not well inhibited by Panama.
I think that the other issue is that when the lab in the UK has tested the viruses coming in from Europe, and they have been having increasing H3 activity over the past several weeks in Europe.
Alan Hayes, who is the WHO Center Director there in London, has said that a fairly significant number of those viruses are in fact not so well inhibited by the Fujian antiserum as he would have expected.
And so I think that we felt because a lot of the H3 activity in North America has been late, we still don't know what the significance of the Fujian variant is.
DR. PALESE: The other -- Peter Palese again -- if we look at the table you gave us, in New York, Alaska, Missouri isolates, they are, in terms of the ferret antiserum, they are at least ten times better with the Fujian ferret sera G, for example, as compared to the Moscow.
So that would indicate, you know, that these American ones here, I mean, we would have tenfold less vaccine than we could have, as compared to changing the -- not changing the strain.
DR. COX: Yeah. I think that there are a lot of different ways to interpret these tables, and I don't want to get into too much detail. I mean, what we're really looking at is the homologous titre for Panama, and then we're looking down -- we're looking to see how many -- what proportion of viruses have a fourfold reduction in titre, or greater reduction.
And then because some of these Fujian-like viruses, which would be the viruses represented by antisera G, H, I, J and K, because they have higher homologous titres, they tend to look much better down the row. But if you take into account the higher homologous titres, there are -- you can see that there are significant reductions in titre for some of these viruses down at the -- these antigens down at the end of the table.
I'm sorry. I probably wasn't very clear on that, but I think you can probably get what I mean.
DR. STEPHENS: Are there other questions for Nancy?
DR. KARRON: This is Ruth Karron again. I just had a question about whether we know anything about the severity of illness associated with A/Fujian-like strains?
And specifically, do we know anything about the cases of encephalopathy this year in children, and what strain of influenza those were associated with?
DR. COX: Yeah. We know that the H1N1, H1N2 and B viruses have all been associated with severe influenza cases and with some of the encephalopathy cases.
DR. EICKHOFF: This is Ted for Nancy. Is there any data in human sera, people immunized with the A/Panama and how well A/Fujian viruses are inhibited?
DR. COX: I'll turn that over to Roland, actually.
DR. EICKHOFF: Okay.
DR. LEVANDOWSKI: Yeah. The question is about current vaccines, I understand, right? About whether they produce antibodies that cross react well with these Fujian-like strains?
DR. EICKHOFF: Correct.
DR. LEVANDOWSKI: And it's not perfect, as it never is when you're looking at serologic results. But there are a number of strains that were looked at in different laboratories, in which there seem to be significant reductions in antibody responses to these viruses that have the 155, 156 amino acid substitution.
It wasn't perfect, but as I said, it usually never is. But there is -- we did see several strains that seemed to have reduced antibody titres, or that antibody titres against those were reduced as compared to the vaccine strain.
DR. EICKHOFF: Yeah. Thank you.
DR. STEPHENS: This is David Stephens. A further question about options, Roland, and potentially Nancy. It sounds like from a practical perspective, there really isn't an option at this point, in the sense that we don't have A/Fujian-like strain that can go grow in eggs. That's correct? And therefore, we're a bit stuck at this point.
What about the issue of a supplemental vaccine?
DR. LEVANDOWSKI: This is Roland. I'll try to address that. That's been tried in the past. There was an experience in 1986. The A Taiwan/186 H1N1 virus was recognized only very late in the year ads a new variant. It was about March, I believe.
There was a lot of work that was done to try to make a supplemental vaccine to target certain populations. Actually, it was young people who were the biggest concern.
And the problem there was that the vaccine, although manufacturers worked very hard to produce it, it was only available very late toward the end of November. And therefore, there wasn't a lot of use of the vaccine.
There was a little bit of confusion on the part of providers -- and I know that because I was one of them at the time -- on who actually should be immunized.
And so overall, I'd say the experience was not very positive in terms of the turnaround time and getting the vaccine to those who needed it.
But the fact is, the positive aspect of that was that it was possible to do that. Of course, that was at a time when there was quite a lot less vaccine being used. There were about 20 million doses of vaccine being produced per year at that point, and a lot less vaccine at use as compared to today.
We had that discussion earlier in February, about what the implications of an additional strain would be. And because manufacturers currently are -- for the amount of demand they have -- working pretty much up until September or October to get the number of doses produced, to add another strain into that mix at a late time would, whatever number of doses of that additional strain were produced, would take away from the total number of doses that could be made in the regular trivalent vaccine that might be already in production.
Any other questions about that, Dr. Stephens?
DR. STEPHENS: Well, I guess, the concern, certainly my concern, and I think many of the committee members, is are we going to see the emergence of the 155, 156 variants and how can we potentially deal with the possibility.
Obviously, there will be continued work, as I understand it, to try to get these strains to grow, which is the first step.
It's -- given the issue of SARS and this issue of the emergence of a new H3N2 -- I think we're all -- I mean, I think that's certainly a concern of me and many of the other members of the committee.
DR. PALESE: Peter Palese. Can I just ask one question? As we're saying, concerns, you know, that they are not doing the bets -- that they are not recommending the best solution in terms of the efficacy of the vaccine.
The New York Strains, like 2003 and the Hawaii one, et cetera, what happens -- they be isolating MDCK cells -- when they are being put into eggs, do they grow sufficiently high?
DR. COX: Yes. If those MDCK isolates are subsequently packed in eggs, they grow okay. It's just a matter of not being able to get the original clinical material to grow an egg.
So we very carefully inoculated both the amnion and the allantoid cavity, and we used the same techniques that have been used previously with great success. And it's just not working this time. And as I said before, we don't know why.
DR. PALESE: But you have good growing viruses of the Fujian -- of Fujian kind?
DR. COX: They grow quite well in MDCK cells, and if you put those subsequently into eggs, they will grow.
DR. PALESE: Let me then ask sort of the -- this is posed to Dr. Levandowski, sort of a challenging question. So the viruses would be available. They would grow. And the problem is that they have been in the MDCK cell line, where we don't know exactly what the -- they're not approved cell lines.
However, I mean, what happens if we have a virus isolate which was from a presentation to have HIV, hepatitis B, hepatitis C and three other unknown viruses, and we would then still accept that this is being purified for an -- egg passage? And would allow it for vaccine production?
I mean, I'm not really convinced that just because it was the MDCK cells, we should make 80 million doses where we know that the H3 is not good. And just because -- I mean, we have the unknown of a patient.
I mean, there may be all kinds of isolates in a patient. And just by having it filled in an -- egg, rather than purifying it afterwards ten times, I just -- I mean the regulatory people have to make the final decision, and they don't have to accept our recommendation.
But for me, it would look that this -- that we are sort of not making the best vaccine decision, if we don't allow the Fujian type to be part of this new formulation.
DR. LEVANDOWSKI: Well, if you're asking for a response -- this is Roland -- I think that we're not alone here in this respect. I think we're in concert with most of the other -- in fact, all of the other regulatory authorities that I'm familiar with.
The concern that you're expressing, that we don't know necessarily everything there is to know about every donor of every virus, I think is true. Many of these viruses do come from otherwise healthy people, but we never really know what all they might have.
And you're right. We have put some sort of hope in use of eggs over the years that a lot of mammalian type advantageous agents might not replicate.
But I think the concerns about MDCK and in particular MDCK as they exist in laboratories that are doing the isolation, there are other concerns related to other materials that might be introduced. If the materials are used to support the tissue cultures, the possibility of cross contamination with other agents and so on.
I don't think I'm answering you entirely, but I think I'm expressing what all the regulatory agencies worldwide have been concerned about in terms of MDCK and in non-qualified cell lines in the laboratories that are using those.
The historical artifact is that eggs were the first way that influenza viruses were isolated and we're kind of still living with that.
DR. STEPHENS: Okay. Other comments, questions, for Dr. Levandowski or Dr. Cox?
DR. MEYERS: One other question. This is Marty, again. One of the questions that came up at the last meeting was the timetable for reagents and -- which is of course not dependent upon eggs replication. What would be the timetable on having reference reagents available if there was opportunity to continue to find a more appropriate feed virus?
DR. LEVANDOWSKI: Well, the reference -- this is Roland again -- the reference reagents are dependent upon the actual feed virus. They need to match up with whatever is going to be displaced, as much as possible.
And in fact, the reference antigen that's used to preparation, the comparison is really a vaccine that's produced in eggs. We still are somewhat dependent there.
It is true that it would be possible to consider influenza virus in some other manner for use as antigen, but the fact is that it requires a large volume, a very large volume of antigens, so it's not really practical to think about setting up tissue culture flasks in order to get enough virus to have -- to produce the antigen.
The timeframe is still the same, from the time we have the strain at hand until the reagents could be made, if everything was already set to go. It would be about two months.
And if you're asking if -- are we within that timeframe now, we are today, but shortly, we will not be. In past years, our recommendations had been finalized in March. That doesn't mean that reagents weren't in preparation prior to that.
I think we started as late as early April in making reagents and still been able to provide them by the time they're necessary for testing the potency of the third strain of the vaccine, so that the formulation can begin.
But until we have the actual strain, we really aren't able to do much of anything.
DR. DECKER: This is Michael Decker. You know, it's very frustrating to be in this situation, and I hear that from everybody on the committee, because it's obvious that we would prefer to make the switch if we could. But it's also clear to me that trying to do so is likely to cause more problems than it will help.
In terms of the best protection for the United States population, the perfect vaccine, arriving in insufficient quantities and late, will protect fewer people than the less perfect vaccine arriving abundantly and on time. And that's exactly the situation I think that we have.
The match between the Fujian strains and the A/Panama is not ideal, but it's not bad. And we're probably better off at this point, given the fact that there is no commercially usable, industrial strain, but just going ahead, sighing, and taking the Panama.
DR. PALESE: Peter Palese. I mean, I can see from a commercial standpoint of view, it is sort of easier and probably less complicated to stick with the old formulation. But this is now 1998. This is a five years old strain, the -- and I feel that for safety, in terms of purifying it through egg passages -- I mean the weighing of a slight risk versus a much better vaccine.
And I'm not sure that I really agree that we should just forget about the H3. And there are ways, I believe, with some -- I mean, that we have much better technology now to look whether there are adventitious agents, one, and I don't see a real problem in having one MDCK passage.
I mean, it's a tradition from the regulatory people, but on the other hand, I mean, why we could even make it from -- viruses now. And I just don't feel that we should -- if we have the technological abilities to make better vaccines, then we should make them, rather than sticking to old regulatory rules.
DR. DOWDLE: This is Walter Dowdle. Could I ask Nancy to give us some sense of the urgency in the network for isolating such a virus and growing such a virus in eggs? Because I would assume that the same issues are going to be coming up very shortly for the southern hemisphere as well.
So I would assume there's a considerable amount of urgency, but if you could sort of relate that to us, I'd appreciate it.
DR. COX: Certainly, Walt. This is Nancy and thanks for that question.
There is a lot of urgency, and so there's been a lot of -- with the National Influenza Center. And I know from speaking with Allan Hayes the other say, that he's been trying to work with all the European labs, and some of those are very good.
And we have been thinking ahead to the southern hemisphere decisions, of course. And so we're continuing to work as, you know, as intensively as we possibly can on this issue.
And a lot of discussions have also gone into trying to use reverse genetics to make vaccine strains that would be -- that would have the Fujian-like hemagglutinin neuraminidase.
That brings up a lot of additional intellectual property issues and so on. But I think there are laboratories which are going ahead and trying to make these vaccine strains and qualified cell lines, and they would be suitable vaccine strains.
And, you know, certainly here at CDC, we're going to continue our efforts to isolate appropriate viruses, both using tissue culture, the primary kidney cells, and eggs.
And, you know, I just can't -- you know, it's hard to -- we all feel very -- that this is a very urgent issue. We've all been working on this very intensively for what seems like a very long time. We're very disappointed that we haven't been able to obtain an egg isolate or an appropriate isolate. So I don't know what to say.
The other centers are doing the same. Our colleagues in Japan had felt that they had what would be an appropriate egg isolate, but it turned out that that virus had an earlier passage in MDCK cells, and so that it was not deemed to be appropriate in regulatory terms.
So there's been really, you know, very -- you know, I don't want to say frantic -- but a very intensive effort around the globe to try to solve this problem.
DR. DECKER: This is Michael Decker again. Let me remind the committee that the issue is not simply obtaining an isolate. Even if that could be done, that is hardly the end of the issue. The goal is not to have an isolate in the laboratory but to have millions of doses of vaccine.
In 2000, when we had the flu supply debacle, we already had the isolate by this point in time. If we had the isolate today, we would still have to obtain a high growth reassortment. We'd have to be able to take that into egg production. We would have to await FDA's producing the reagents to test potency.
In 2000, those reagents became in May. Production was already ahead of the point where it is this year. And when the product was tested, it was found that the yield from the industrial process was much lower than had been anticipated. And volumes of available vaccine would only be half to two-thirds of what had been planned.
All those pitfalls still lie ahead of us this year. And if you elect to try to go for this new strain, even if you could snap your fingers and make an isolate tomorrow, you haven't removed the risk of those other pitfalls.
And I just have to wonder: A strain that can't be isolated in the world's best labs, are you sure it's going to be easy to grow in industrial volumes in eggs?
DR. STEPHENS: Okay. I think we need to move now to at least having a brief -- or if there's any open public discussion. Jody, do you want to introduce that?
DR. SACHS: Sure. At this part o the FDA Advisory Committee meeting procedure, we are required to hold an open public hearing for those members of the public who are not on the agenda, and who would like to make a statement concerning matters pending before the committee.
I have not received any requests at this time. Is there anyone in the room who would like to address the committee at this time?
DR. STEPHENS: I would like to hear from the PowderJect/Evans Group, if they want to make any comments about this issue.
DR. O'BRIEN: (Poor connection) Actually -- Michael Decker's concerns -- difficulties in flu production. The earlier start we get, obviously the better. This will be a significant delay, and therefore it would jeopardize the number of doses which could be made available for a year.
I think I've mentioned before, it's got to be a balance between the total number of doses that can protect a certain number of people and that they are effective. And someone's got to find that balance, obviously.
DR. STEPHENS: Are there other comments, other questions?
DR. SACHS: I would like to thank the participants at the open public hearing. And at this time, if there's no other comments in the open public hearing, I'd like to turn the meeting back over to you, Dr. Stephens. Thank you.
DR. STEPHENS: Okay. I think that we're now coming to kind of final discussion and recommendations for the vaccine. I would like to make sure that there are no additional questions.
I just have one further question from a regulatory standpoint. And Roland has given his comments, but are there other FDA comments about the use of an MDCK variant for vaccine production?
DR. MIDTHUN: I guess -- this is Karen Midthun, FDA. I just think that, you know, it is a tumorigenic cell line. It's not previously used in any vaccine production.
That's something that would really have to be very closely considered and characterized to determine, whether that was an acceptable cell substrate for something to have been passage through.
DR. STEPHENS: The practicalities, though, make that a long-term process, I would guess?
DR. MIDTHUN: I'm sorry. Could you --
DR. STEPHENS: I'm sorry. The practicalities of making those determinations are a -- not something that can be solved quickly?
DR. MIDTHUN: That's correct.
DR. STEPHENS: Okay. Roland, I think it would be helpful just to restate the question for the committee at this point and your opinions about options.
DR. LEVANDOWSKI: Okay. I'd be happy to restate the question. It's very straightforward. The question for the committee is what should be the H3N2 influenza component of the influenza vaccine to be used in 2003/2004.
And if you'd like me to, I'd just -- I can give a sort of a summary about the information. And I think it covers some of what has already been discussed.
But I think it probably is worthwhile reiterating some of the points in terms of what the options are that are available to us at this point, if that's okay, Dr. Stephens?
DR. STEPHENS: Yes, that's fine.
DR. LEVANDOWSKI: Okay. So, you know, as we've talked about or as we've done typically in our meetings, there -- actually, there are probably three options.
The first one here is that we could keep the same strain. We would continue to use A/Panama/2007/99 strain as the vaccine virus. And actually in favor of that, still the majority of the viruses that are being isolated are A/Panama/2007/99-like characterization of their hemagglutinins.
We know that manufacturing is worked out and the yield is very predicable. And as we also heard, some -- what would be against continuing to use the same strain for the vaccine would be that there is an increasing proportion of recent H3N2 viruses that are not well inhibited by post-infection or post-immunization antisera.
Highly consistent between the strains. There is some variation, as I mentioned. Many of these recent viruses, however, do seem to have signature amino acid changes, which suggest that a variant is developing.
And there's evidence that that new variant can spread. It's been identified in Europe and Norway and the United Kingdom, there are isolates.
There may be others that are coming because we're not entirely finished with the surveillance and epidemiology. There are isolates from Asia, from China, Japan and Korea. And there are also isolates from North America, both the United States and Canada.
And as has been pointed out when we see new strains, they often tend to spread rapidly in susceptible populations when there's a herald wave phenomena, in particular where there's a large increase in the number of the new variants. Sometimes that following year, we see those becoming the predominant strains.
And, of course, are concern is that the H3N2 influenza viruses are highly associated with morbidity and mortality.
That brings me to the second option, of course, is to try to change the vaccine strain. And in favor of that would be that these new variants are spreading geographically and they have been causing illness, and that a large portion of the population may be susceptible to those strains.
We would like to suspect that a new strain would provide a closer match with the hemagglutinin and neuraminidase of the contemporary strain.
But the fact is that we don't always known whether a new strain, even if it is supposedly a better antigenic match, will provide any superior coverage to the current strain. We only find that out in retrospect, after the vaccine is produced.
And of course, also not in favor of trying to make a change is the fact that we really do not have a suitable influenza virus in hand that could be used for manufacturing, and there's absolutely no information about what difficulties might arise in manufacturing.
The third option usually is to postpone the decision, but we're at that point in time where there will probably not be a lot of additional helpful information that we'll be able to provide. And manufacturing really does need to proceed at this point in time.
I guess I can stop there, Dr. Stephens, and ask if there are questions or comments.
DR. STEPHENS: Questions, comments?
DR. MEYERS: Well, it's probably not answerable, but I'd just like to ask Nancy about the serology and other tests that have been run on these -- on this severe acute respiratory syndrome, and whether she is comfortable that this is not an H3N2 that is just being difficult to cultivate in vitro?
DR. COX: Okay. I think I can address that very efficiently. We're sure -- we don't have a lot of appropriately collected sera yet. More is coming in. But a lot of work on -- and again, some of the best labs in the world looking by PCR, culture and using a whole variety of different antibodies that are pegged to different groups of influenza. And so far, everything is negative for flu.
DR. MEYERS: Thank you.
DR. STEPHENS: Okay. Well, I think there doesn't sound like there's further questions at this point. And I --
DR. PALESE: Peter Palese. Can I ask one other question?
DR. STEPHENS: Yes, please.
DR. PALESE: So what would happen, for example, if the committee recommended change? And the FDA doesn't have to accept that recommendation, is that correct?
DR. COX: Yes, that's correct. You're advisory to us.
DR. PALESE: Okay.
DR. STEPHENS: Okay. Well, I think, if there are no further comments, we will take -- I think this is correct, Jody -- a roll call vote on this issue.
DR. COX: Yes, that's correct. But you need to present which question you're asking for the vote.
DR. STEPHENS: The question is what strain, what H3N2 strain, should be recommended for antigenic composition of the 2003/2004 inactivated influenza virus vaccine. I think that's correct, isn't it, Roland?
OPERATOR: Karen Cox is joining.
DR. LEVANDOWSKI: Yes.
DR. STEPHENS: I think we'll pretend like we're having a similar seating chart to what we had on the 20th of February, and would start with Dr. Katz. Doctor, I'll put you on the spot today. Sam? Is he still -- is Sam Katz still here?
DR. COX: He might be on mute. Well, we can move on and try to pick him up later.
DR. STEPHENS: Right.
OPERATOR: Excuse me. Bruce Gellin has joined the conference.
DR. COX: Great. Thank you.
DR. STEPHENS: Dr. Meyers?
DR. MEYERS: Well, I'm very uncomfortable in -- in that I really think we have an emerging new clave and we don't have a seed virus. And so I guess we're better to have an H3N2 in there. And so I guess I would vote to stick with the same strain.
DR. STEPHENS: And so you're voting for a A/Panama/2007/99 recommendation, is that correct?
DR. MEYERS: Correct.
DR. STEPHENS: Okay. Dr. McInnes?
DR. McINNES: A pragmatic recommendation for me was, I think, less than ideal, but I would go
A/Panama/2007/99.
DR. STEPHENS: Dr. Eickhoff?
DR. EICKHOFF: Well, I will cast my vote as did Marty Meyers, retain the present strain. But for the first time in many years of participating in these deliberations, I must add I am very uncomfortable with that recommendation.
DR. STEPHENS: Is Dr. Gellin here?
DR. GELLIN: Yeah, I just dialed in. I think -- I don't think I can weight in, since I didn't benefit from the discussion.
DR. STEPHENS: Okay. David --
DR. KATZ: This is Sam Katz. I stepped out of the door to grab a quick other call when you called my name, but --
DR. STEPHENS: Well, we called you first.
DR. KATZ: I know, that was what I was afraid of. You did that through all the last meeting, too.
DR. STEPHENS: Well, you were at the end of the table on the chart, so I'm just following protocol.
DR. KATZ: I just wanted you to know I was here for the whole call and I missed that last 30 seconds when you called me. But I would have to go along in -- reluctantly, but with -- I don't see a practical alternative -- voting to stick with the Panama.
DR. STEPHENS: Dr. Cox?
DR. COX: I agree with what Sam said. A/Panama, but, you know, I think we all have concerns.
DR. STEPHENS: Sure. Walt Dowdle?
DR. DOWDLE: Panama.
DR. STEPHENS: Peter Palese?
DR. PALESE: I feel very strongly that we should change the strain to the Fujian-like. And it's based on the fact that, one, there is a herald wave. It's a good indicator that this will be the next strain.
And two, that I feel that the slight risk of the egg passage, I think can be, with scientific means, can be gauged or estimated by passaging it five, six times through embryonated eggs. I feel that it is better in the long run to have a good vaccine or a better vaccine, where the H3 component is really effective, then having just a potential very, very minimal risk in terms of a formaldehyde treated vaccine. So I would like to vote for a change.
DR. STEPHENS: Knowing that there is no current candida at this point?
DR. PALESE: I -- okay. I disagree with -- I mean, this virus -- this virus are going well in embryonated eggs. We were told by Dr. Levandowski that the timeframe, if we had a virus on March 18th, that this will be enough to get all the reagents.
Otherwise, I mean, there was no point in delaying it. I mean, our February meetings was predicated on the fact that if there is some more evidence in three weeks later, that we would have a choice of what we -- a good, a better reason to choose one or the other.
And I just feel that one passage of MDCK cells is not necessarily where we should jeopardize 80 million doses and also give the influenza virus vaccine a bad name because many people may get sick.
DR. MIDTHUN: This is Karen Midthun -- I would just like to reiterate that at this point, it really would not be possible to qualify whatever MDCK line has been used.
And so in that the issue that Dr. Stephens raised before, you know, it's not that there isn't something that, you know, we can't consider. It's just that one really needs to know a lot about the cells that were used. They need to be qualified, characterized, to really address the different safety issues that we feel need to be addressed.
So I just thought that might be helpful to others, to have that information.
DR. PALESE: Look, I mean, that's sort of a decision on the FDA -- I mean, I think one can make a reasonable argument that we don't know what kind of adventitious agents are in human isolate as well, and that we are perfectly happy to accept that.
I mean, we're not asking for manufacturing vaccines in MDCK cells, but rather be sure that what is put into embryonated eggs is as pure as be free from adventitious agent as we can, with the best of our technology, assure at this point.
So I think the question whether it's an FDA approved cell line or not, I mean, is sort of -- I mean, we are not -- I don't think anyone use MDCK cells to produce 80 million doses.
DR. STEPHENS: Okay. I think that your position is clear. Let's move to Dr. Markovitz.
DR. MARKOVITZ: Yes. I would have to vote for retaining the A/Panama.
But I also would like to go on record as urging that we have an exploration of these issues that Dr. Palese has raised, so that if we have this in the future, perhaps we'll be able to move more expeditiously.
DR. STEPHENS: Dr. Diniega?
COLONEL DINIEGA: This is Ben Diniega from Health Affairs. I vote to retain the A/Panama, but agree with the need to continue efforts to try to get the Fujian-like strains grown on eggs.
DR. STEPHENS: Dr. Royal? Dr. Royal? Dr. Manley? Hello? Walter?
DR. ROYAL: Yes, I'm back.
DR. STEPHENS: All right.
DR. ROYAL: I guess my mute was on. I agree with the comments with respect to the Fujian strain. Again, I'm forced to cast my vote for retaining the A/Panama.
DR. STEPHENS: Dr. Manley? Is she on the line?
DR. MANLEY: I am. I would vote to retain the A/Panama.
DR. STEPHENS: Dr. Goldberg?
DR. GOLDBERG: I vote to retain the A/Panama. However, I do believe that we have to make plans for a strain change and do everything that Dr. Palese is suggesting, and my other colleagues.
DR. STEPHENS: Dr. Overturf?
DR. OVERTURF: I would also vote to retain the A/Panama --
(Line feedback.)
DR. STEPHENS: Okay. Well, that was fun.
(Laughter.)
DR. STEPHENS: Gary?
DR. OVERTURF: I would also vote to retain A/Panama-like agents. But I think that it's really very clear that we are going to have to plan contingencies, which may include certifying other cell lines for culture to produce other strains. Because that may be necessary, because I think we're going to have to change this next year.
DR. STEPHENS: Dr. Karron?
DR. KARRON: I vote very reluctantly to retain the A/Panama and would like to ask in future meetings that we hear updates about ability to isolate appropriate A/Fujian-like viruses, so that hopefully we're not in this position next year.
DR. STEPHENS: Dr. Parsonnet?
DR. PARSONNET: I agree with the last comment and also would love to hear updates. So I vote for Panama, but I 'd also love to hear updates about our ability to explore other tissue culture systems for growing viruses in the future.
DR. STEPHENS: Dr. Fisher?
DR. FISHER: Well, because there are an increasing number of cases of new variant H3N2 viruses causing flu, I feel uncomfortable voting for inclusion of an A/Panama-like virus, when what may really be needed is an A/Fujian-like virus.
So I'm going to abstain and urge that the public be informed that next year's flu vaccine may not be protective against an emerging strain.
DR. STEPHENS: Okay. Dr. Diaz?
DR. DIAZ: I'm still here. I would prefer that we move to an A/Fujian-like strain. However, it seems from a regulatory standpoint and from a practical standpoint, in terms of manufacturing, we somewhat have our hands tied.
So I would agree that we need to maintain the A/Panama strain in next year's vaccine.
OPERATOR: Excuse me -- has joined.
DR. DIAZ: I would also give the same urgency to looking at manufacturing processes in particular and new strain lines -- or new cell lines to be able to be used. I don't think this will be the last time that we will be faced with this issue.
DR. STEPHENS: Okay. Rich Whitley? Is he still on the line?
DR. WHITLEY: I'm here, Dave. I don't think -- obviously, practically, we have to maintain A/Panama, but I want to reiterate what Peter said. And that is, if we're not prepared to have Fujian-like strains incorporated into next year's vaccine, we're making a mistake, number one.
And I'd like to make one other point. And Nancy alluded to it earlier in this conference call. And this is, this issue of encephalopathy in children can't be swept under the carpet. And we need to know more about that as quickly as possible.
We need to know whether it's in vaccinated individuals or non-vaccinated individuals, and we need to know the strain type, not that it's just globally associated with all three.
We know what happened in Japan. We know what's happening in Japan. And if this is a potential cofactor in immunization, we'd be making a mistake not to know more.
DR. STEPHENS: Thank you. Anyone that I've missed?
DR. SACHS: Dr. Decker needs to state his opinion for the record, please.
DR. STEPHENS: Okay. Mike?
DR. DECKER: My opinion is that the ideal strain would be a Fujian, but neither regulatory nor industrial circumstances permit us to pursue that this year. And I'm confident by the time we have to pursue it next year, we'll have appropriate isolates.
Meanwhile, I think the public health is best served by proceeding with the A/Panama because it gives adequate cross-protection. Not ideal, but adequate.
And widely immunizing the population with an adequate vaccine will better serve the public health than immunizing them with a somewhat better vaccine only a fraction of the same population.
DR. SACHS: Dr. Stephens, the next vote is yours.
DR. STEPHENS: Okay. Well, I share the majority's of the committee's reluctance about accepting A/Panama, but I really don't think we have a choice at this point. I certainly would like to see a change, if we could do that, to A/Fujian, but that's currently not possible.
I would like to continue to have this, as has been suggested by others, as a topic for -- in our future meetings.
I would also urge continued consideration of the supplemental idea. And although it has not been that successful in the past, it certainly is something that as we get strains that do grow in eggs, that it's something that we may want to continue to consider.
DR. SACHS: This is Jody Sachs. I'd like to just sum up the vote, if I may. It looks like 17 have voted to retain and keep the Panama --
DR. MIDTHUN: Can you speak up?
DR. SACHS: Sure. This is Dr. Sachs. I'd like to sum up the results. It looks like 17 have voted to retain the current strain. And it looks like two have abstained and one has stated that they would like a new strain, the Fujian-like strain replacing the old strain.
DR. STEPHENS: Okay. Other -- any additional comments at this point?
DR. KATZ: I have a question, David. This is Sam Katz. At the last meeting, in answer to a question that I submitted, someone said that there was a vaccine licensed in Holland that was prepared in tissue culture and not in eggs. Can Nancy or Roland or anyone tell us more about that? I think it was a vero cell.
DR. LEVANDOWSKI: This is Roland Levandowski. There are two vaccines that are registered in some country, at least one country in Europe. I don't believe that they're widely registered at this point.
The two companies that have registration for a tissue culture vaccine or what used to be called -- are they have an MDCK tissue culture vaccine that they have in registration. The other vaccine is from Baxter Healthcare. Their vaccine is produced in vero cells.
So there are those two tissue culture vaccine products that may be available there.
You should know that those companies are also dependent upon egg isolates. The regulatory authorities in Europe, under the current conditions with the tissue cultures that are used, laboratories for collecting viruses are still recommending that an egg isolate be used for that manufacturing, until issues related to getting availability of appropriate tissue cultures for isolation can be worked out.
DR. KATZ: Thank you very much.
DR. MEYERS: The tissue culture derived vaccine in Canada, I believe.
DR. LEVANDOWSKI: This is Roland again. There are companies that have products in development in a number of places. And you are correct that the company that used to be called Biochempharma -- I guess it's now Shire -- are developing a tissue culture vaccine and has published about their vaccine. That one, too, was an MDCK vaccine that was being developed. But it's not in use anyplace and it's not in use in Canada, as far as I know.
DR. MEYERS: And just one other thing, Sam, was that at the APIP meeting, I believe somebody from Baxter and that's -- that it was their intention to enter the U.S. marketplace.
DR. KATZ: Thanks.
DR. STEPHENS: Okay. If there are no further comments, Jody, any comments about future meetings?
DR. SACHS: Yes, I'd like -- to remind everybody that the next meeting is scheduled for May 8th and 9th. And I'll shortly have additional information regarding that meeting that I'll send out to everybody. But I just wanted to say please save the May 8th, 2003 date, because that is the next date coming up. Thank you.
DR. STEPHENS: Jody, are you implying that May 9th may not be used, or did you know?
DR. SACHS: Yes. I am implying that May 9th may not be used. Officially, I'd like to wait another week or so, but I'd like you to save the May 8th and reserve that date. And shortly, I'll be sending you details on the next meeting.
Thank you and thank you all for participating. I appreciate your calling in and participation.
DR. STEPHENS: Thank you very much.
(Whereupon, the meeting in the above-entitled matter was adjourned at 12:05 p.m.)
