A single line often inverts meaning once you see what it
answers, so neighbouring messages are always shown.
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Feb. 14, 2012 - Approved at the last minute (literally) that I can go to Geneva and was granted an Export Control License for me, Barbara Jasny (representing Bruce Alberts of Science), Paul Keim (Chair, NSABB), and Yoshi Kawaoka (author of Nature article)
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Feb. 16-17, 2012 - Geneva - Astounding!! During Ron's presentation of the data, I asked the "transforming" question that exposed the confusion that has been propagated regarding the study. It relates to the uncoupling of the issue of aerosol transmission from deadly pathogenesis. Bottom line is that the aerosol-transmitted virus when transmitted to uninfected ferret, not only does not kill them, it does not even cause significant disease. At worst, some mild flu like sxs. See below for my detailed description of the data gathered from the papers, the Geneva presentation together with discussions during the Geneva meeting including a dinner at Keiji's home with Ron, AB Osterhaus, Keiji Fukuda, and Yoshi on the evening of Feb. 15 (more on that later) as well as extensive discussion by phone with Ron after I returned to USA on Feb. 19 and 20, 2012. Recommendation (consensus) of the WHO-convened group was to 1) respect the PIP agreement; 2) extend the voluntary pause ("moratorium") on H5N1 transmissibility/pathogenicity research; 3) Delay publication of the 2 manuscripts until the safety and security issues of such research could be solidified for others. General agreement that the experiments of Yoshi and Ron were carried with safety and security that met or exceeded the guidelines; 4) After meeting conditions in #3, then publish the manuscripts in full; 5) discussion that the publishing of redacted manuscripts with mechanism for vetting and distributing to those with a need to know was completely impractical. This point was fortified by the almost unbelievable and counterintuitive requirements of Export Control Licenses. There was a unanimous recommendation for everything except the recommendation to publish. Nancy Cox did not comment, but Paul Keim and I stood by the recommendations of the NSABB. In the roll-out after the meeting in Geneva, Keiji at first messed up and said that everything was "unanimous consensus", which is an Science) oxymoron. Christ Feig is a former CNN producer and old friend of mine and is the communications director for WHO. I noticed the slip-up and she got Keiji to correct while still on the TV press conference. Emails were going back and forth from me to HHS (Bill Hall) to some of the NSS people when he made this mistake, but everyone calmed down after he corrected it. I was in the unusual position of officially sticking with the NSABB recommendation while being the one who actually led the WHO discussion to come to this point. The smart reporters like Jon Cohen and Helen Branswell picked this up and were sympathetic. The decision was written up on the front page of the NY Times by Denise Grady on Sunday. It was interesting how she quoted me with an articulate explanation of why the WHO group came to this decision at the same time that she mentioned that I stuck by the NSABB recommendations. Anyone with insight could figure out what I did. Of note, Paul Keim did not realize that the aerosol-transmitted H5N1 did not make the animals ill, much less kill them!!! There was a media storm after the decision was announced. See below for summary of meeting: Sunday, February 19, 2012 Summary of discussion at the WHO Geneva Meeting on Feb. 16-17, 2012 plus additional discussion with Ron Fouchier and Yoshi Kawaoka. Anthony S. Fauci, M.D. Fouchier Experiments (Science) and related information: Fouchier worked with a high pathogenicity (HP) H5N1 influenza virus obtained from a patient in Indonesia (A/Indonesia/5/05). He had been working for 4 to 5 years on trying to study the transmissibility of H5N1 for the purposes of determining the molecular aspects of increased transmissibility. His attempts at developing an H5N1 with increased transmissibility in a mammalian model have failed up to now. Recently, he used the already existing literature to identify the mutations that have been reported to be associated with the emergence of previous pandemics (1918 H1N1, 1957 H2N2, 1968 H3N2, 2009 H1N1 and other non-pandemic outbreaks, e.g. 1977 H1N1). He analyzed these and determined the 3 mutations that statistically seemed to be associated most closely with emergence of pathogenic pandemic viruses. Again, these mutations have already been reported in many published papers. With regard to the "technique" of passaging in ferrets, there are many papers that have appeared in the literature for decades (since the 1930s) describing the ferret passage technique to increase transmissibility. This is similar to passage techniques widely used to adapt a virus to a particular species. It has been done in mice, monkeys, etc. Usually (not always), when viruses are passaged in a particular species, as they gain transmissibility, i.e. species-specific adaptation, they develop decreased pathogenicity, i.e. attenuation. Fouchier took these 3 mutations and inserted them into a wild type (WT) HPH5N1 (see above). This technique is widely used in molecular virology. He then passaged the virus 10 times in ferrets. "Passaged" means inserting the virus into the nose of the animal, getting the animal to get infected, then taking virus from the nasal passages of the infected animal and inserting it into the nasal passage of the next animal in the sequence, and so on. The endpoint that is aimed at is to get a virus that is then able to be transmitted by aerosol (i.e. not relying on direct insertion into the nasal passage). Since ferrets sneeze when they are infected, one determines "aerosol transmission" by housing an infected ferret in a cage next to a separate cage of an uninfected ferret that is constructed such that an aerosol can get from one cage to the other due to "holes" in the barriers between cages. The virus resulting from the passaging was able to be transmitted by aerosol and was a "quasi-species", i.e. it contained different "versions" of the mutated virus. The viruses that were transmitted by aerosol were then sequenced and all of these viruses had 5 mutations in common: the 3 mutations that were inserted by reverse genetics and 2 additional ones. In addition, the viruses had 4 to 7 variable mutations (this latter sequencing information was not ready for reporting in the original manuscript). This virus isolate was used in the pathogenesis studies reported in the manuscript. It was the isolate with the minimal number of mutations (9 mutations - 5 common mutations + 4 variable mutations). After submission of the manuscript the authors took a wild-type H5N1 clone and inserted this minimal number of mutations to develop a virus that was transmissible without the need for passage. The pathogenesis studies with this cloned virus were identical to those of the isolate reported in the manuscript (see below). It is EXTREMELY IMPORTANT to point out that the animals that got infected by aerosolized virus described above did not die nor did they get sick. They were followed for 14 days. A few got minor flu-like symptoms, all recovered, they then were sacrificed since logistically the author could not house them indefinitely. Thus, the "engineered" virus that was made transmissible, did not kill or make the animals sick when exposed in the manner that flu in transmitted in humans. PATHOGENICITY. The classic way that influenza virus pathogenicity is established (welldescribed in the literature) for the ferret model is by direct insertion of the virus into the nasal cavity and/or directly into the trachea. Fouchier did both nasal and tracheal insertion of the viruses. In the nasal insertion studies, 106 (1 million) infectious doses of virus is inserted into the nose. This is a dose that far exceeds a dose that one gets through aerosolized virus (i.e. sneezing). When this dose of the pandemic 2009 H1N1 virus (not considered a particularly pathogenic virus, particularly in people who have been exposed to H1N1 over years by infection or vaccination - children who are naïve to this virus have had more problems) is inserted into the ferret, the animals develop flu-like symptoms but do not die. When HPH5N1 is inserted the animals essentially all get neurovirulence, they recover, none die. When the modified (aerosoltransmitted) H5N1 virus is inserted, there is some neurovirulence, but actually less neurovirulence than with the wild typeH5N1. Again, all recover and none die. In the tracheal insertion studies, 106 virus is inserted directly into the trachea. Again, this is a dose and a situation that would be extremely difficult, if not impossible, to achieve by aerosolized transmission. In these experiments, when this amount of wild type (unmodified) HPH5N1 is inserted into the trachea, all animals die on day 3. Similarly, when the modified H5N1 is inserted, all animals die on day 3. However, and importantly, when 2009H1N1 that was shown to be a mild pathogenicity virus was inserted under the same conditions, it killed some, but not all the animals. Although, this was a qualitative and not a quantitative study, it strongly suggests that in this model, the modified H5N1 is not dramatically different from the 2009 H1N1 in pathogenicity. Also, it should be pointed out that in the ferret model, 2009 H1N1 is much more transmissible (100% transmission on day one) than is the modified H5N1. Specifically, transmission with the modified H5N1 does not occur until day 3 to 4 and even then it is only 75% transmissible. This suggests that the R0 may be less than 1. This is important with regard to concerns over the potential catastrophic effects of lab accident and the known conditions that are needed for the start of an epidemic/pandemic. In this regard, there should be serious discussion of how pandemics occur. Nancy Cox can elaborate. Ferrets are naïve to influenza virus, i.e. they have no pre-existing immunity. Humans do have pre-existing immunity to influenza viruses due to repeated exposures (except in young children) and/or vaccinations. It is EXTREMELY IMPORTANT to point out that if you vaccinate the ferrets with seasonal H1N1, they are not protected against death from tracheal insertion of high dose (106 infectious doses) modified or wild type H5N1. Fouchier did not test the effect on transmission yet (moratorium). However, if you pre-infect ferrets with seasonal H1N1, let them recover and then insert high dose H5N1 into their trachea, this fully protects against disease and no ferrets die. This strongly suggests that pre-existing immunity due to prior infection with seasonal influenza A protects against serious disease with this modified virus (heterosubtypic immunity). This could be a possible explanation for why so few people get infected with H5N1 in the wild. Yoshi Kawaoka Experiments (Nature). The studies of this investigator are very similar to those of Fouchier except that Kawaoka took the HA from the HPH5N1 and did random mutations from which he selected those that enhanced transmissibility when this HA was reassorted with the 2009 H1N1to make a hybrid of the H5N1 and the 2009 H1N1. This is something that we are concerned could happen in the wild. He then did similar passages as described above. Kawaoka's results differed from the Fouchier study in that although his virus was transmissible, it was not any more pathogenic than the 2009 H1N1 influenza. EPIDEMIOLOGICAL DATA: With regard to the importance of these data for the real and present danger of the evolution of H5N1 in the wild, as well as for the impact on surveillance, Kawaoka and Fouchier have done some epidemiological "mapping" of their modified virus with what is going on in the wild. Viruses were studied that were obtained from chickens in Japan, Mongolia, Nepal, and Egypt as well as viruses from people infected with H5N1 in Egypt. Some of the mutations that Fouchier and Kawaoka described involving the PB2 gene (627 K) and the receptor binding genes (HA) were present in 100% of the H5N1 viruses that infected humans and only in 30% of the chicken viruses. This suggests that the viruses that accumulate the mutations in question are the ones that transmit from chickens to humans. In addition, many of the viruses circulating in chickens are only 2 to 3 mutations away from the mutations described by Fouchier in their modified viruses. People will argue that knowing mutations cannot help predict or alert public health officials to what will emerge as a pandemic. They state that since viruses have several routes to get to where they want to go, i.e. to be able to be transmitted, the studies in question should not even have been performed. However, historically, after pandemic viruses emerge and infect people and then you go back and trace what was evolving in birds, or (more importantly) in mammals you see a pattern where you could have actually traced and connected the dots pointing to the emergence of a pandemic. This was clearly the case where the pandemic 2009 H1N1 virus was evolving in pigs for at least 10 years and was "working its way" towards human transmissibility. If there had been better surveillance in both pigs and humans as to what was evolving, then as Tom Frieden has said, we could have had a major head-start on the 2009 H1N1 virus. What the Fouchier and Kawaoka viruses tell us is that the virus in the wild is creeping towards a virus that they have shown is capable of transmission in mammals, presumably including humans. Whether the virus ultimately uses that precise pathway or those precise mutations is not clear, but clearly these studies are critical to understand the process of evolution and adaptability of viruses that are a real threat of working their way to transmissibility in humans. Not making these data freely available to scientists only slows down the necessary work and the incentive to get more scientists involved, and does not really provide a serious terrorist with any additional advantage since these techniques have been widely available for years. An uninformed terrorist would not be able to do this. An informed virologist-terrorist just needs to go to PubMed to easily figure out what was done and how it was done. Not publishing the work may do more harm than good by discouraging legitimate scientists from getting involved. Clearly, there needs to be assurance of biosafety and biosecurity in the laboratories that work with transmissibility of H5N1. The laboratories in question (Fouchier and Kawaoka) have met or exceeded our standards for these types of studies. Redacted versus Unredacted: The impracticality of redacted versus unredacted manuscripts was clear to everyone at the Geneva meeting and the likelihood of the unredacted manuscripts ultimately reaching the internet were important factors in the consensus at WHO to publish in full after a pause to assure biosafety and biosecurity and to have a better articulation of the benefits of the research as described above. The way forward. People are making incendiary statements without really having discussed with the investigators the precise details of the experiments as described above. The interaction of the NSABB with the investigators (Fouchier and Kawaoka) was on a relatively brief conference call. Much additional information that was available during the intensive 2 day discussion in Geneva was not available to the NSABB. My recommendation is to reassemble the working group of the NSABB for a face-to-face meeting with the investigators, security people, international public health people (similar to the WHO meeting) and a larger number of influenza experts with hands on expertise in such studies. Post- Geneva: Have spent the past few days explaining the above summary to HHS, White House NSS X 2. Could not comment too much to the press.
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Feb. 21-24, 2012 - had conversations and e-mail exchanges with Ron Fouchier trying to work out that he re-submit a manuscript and that the NSABB reconvene to review with the new data and the clarifications from Geneva. Also, spoke with Journal editors to try and get them to agree (which they did) to hold off on publication, but agree to quickly consider a revised manuscript. Of note, during the Feb. 22 Situation Room meeting, I outted Kris Beardsley as a "leak" to the NSABB. Paul Keim had asked how things were going right after we returned from Geneva (see e-mails on file). I told him that I was about to brief the WH on Feb. 22. He said good luck and that he already had spoken to Kris Beardsley. I did not return e-mail, but I was astounded. She is NSS!!!. Now it became clear that the NSABB people were directly trying to get to and agitate the WH through Kris and also with Mike Osterholm getting to Rick Weiss, the Press person for John Holdrin at OSTP. Rick is a former Washington Post reporter. I believe that Paul Keim is OK, but it is incredible that Kris Beardsley and Rick Weiss are doing this. In order to make sure that Kris would not undermine my presentation to Heidi and the NSS, I started my explanation (see summary above) by saying that I know that Paul Keim has briefed Kris about part of this a day or so ago, but I will give a little more information since I spoke with Ron after the WHO meeting and Paul did not. Kris almost fell through her chair and Heidi gave her a very mean look followed by a statement that we have only one point of contact with NSABB and that is Fauci. Clearly Heidi not only was not briefed by Kris, she had no idea and was extremely pissed that Kris had spoken about this with Paul. Paul is advisory to HHS and NIH and NOT to the White House. BTW, I have been completely wearing myself down by this getting virtually no sleep and doing 1000 things at a time that are very heavy, i.e. White House stuff, Press misinterpretation. Mike Osterholm acting in his usually hysterical manner, Laurie Garret getting it wrong as usual. OF GREAT IMPORTANCE: How is it possible that everyone got it wrong? Why did not anyone ever ask the "Fauci question" that I asked in Geneva of Ron. This includes the reviewers of the papers, the entire NSABB including the Chairman Paul Keim, the outside influenza expert called to advise the NSABB (Rob Webster), the editors of the Journal. After I briefed him, Bruce almost comically stated. "You know, I knew there was something funny here when I read the paper and found that after aerosol transmission, blood samples were taken from the ferrets for 12 days. If the ferrets all died in 3 days, did they take samples from dead animals?" Clearly his own editorial staff did not pick it up. There is plenty of blame to go around. Clearly Ron did not say in the manuscript that the aerosol-transmitted animals died, but he never said in the manuscript that they did not die. Clearly he was doing what many scientists do, i.e. play up their own data to make it seem exciting. Yet, he knew that the media were clearly getting it wrong. He will say that he was never given the chance to explain this to the NSABB and his only comments to the press that they clearly misunderstood were before the NSABB and he did not realize that they misunderstood. However, after the decision of the NSABB, he still spoke to the press, yet never made it explicit what really happened. He could claim that at that point he could not discuss the data since it was confidential and the press could not ask the specific question sine they did not see the data. It is clear to me that a lot of people are embarrassed for not asking the Fauci question and as human nature goes, people are running for cover and/or looking to blame someone. Ron is in danger of getting thrown under the bus when the press finds out that he never clarified things. As an example, ABS World News on Saturday PM, Feb 18 had a piece showing all aerosol-infected animals dying schematically on the screen with the ever-present Laurie Garret commenting that "This virus just should not be allowed to exist". See Important e-mails below: Thursday, Feb. 24, 2012 11:26 AM Ron: In follow-up of our previous conversations, it is important for you to revise and expand your manuscript to include the important new data that were presented in Geneva. In addition (and this is critical), you need to make exceptionally clear the differences between the transmission studies and the pathogenicity studies, i.e. the response that you gave to me when I asked that direct question in Geneva whether there was any illness or death in the animals that had been infected by aerosol with the engineered highly pathogenic H5N1. You responded that some of these animals developed flu-like symptoms, all recovered, none got seriously ill and none died. This seems to be the key point about which many people were and are confused. It would be very important to make this exceptionally clear in the manuscript. There are also other important data that we discussed that would be important to include in a revised manuscript. I believe that the best course of action would be to resubmit this revised manuscript to the NSABB so that they have the opportunity to have all of the data that we discussed in Geneva in front of them as well as to directly question you in person in order to clarify any important points. Amy Patterson will request that the NSABB meet and review this manuscript. As I had mentioned to you, Francis Collins and I have spoken to Bruce Alberts about the importance of your having enough journal space to add the new data and a broader discussion of the issues. In our initial conversations with him, he seemed amenable to this approach. Obviously, we cannot know for sure what the journal decision will be. Francis and I will be speaking to Bruce again today (I hope) and we will bring this up to him. However, the important issue is that the NSABB have the opportunity to see the expanded manuscript as described above. I would be happy to discuss this further with you. Please give my office a call at your convenience at (301) 496-2263. I am not available between 12:00 and 12:30 PM and 3:30 - 4:00 PM Washington time. Best regards, Tony Anthony S. Fauci, MD Director National Institute of Allergy and Infectious Diseases Building 31, Room 7A-03 31 Center Drive, MSC 2520 National Institutes of Health Bethesda, MD 20892-2520 Phone: (301) 496-2263 FAX: (301) 496-4409 E-mail: afauci@niaid.nih.gov ______________________________________________ Tuesday, Feb. 21, 2012 to Paul Keim Paul: Line-up and tasks sound good to me. We should strategize by phone on how to handle discussion of the WHO meeting. I have a meeting at the White House tomorrow to brief the security people on the WHO meeting and the outcome of those discussions may impact our decision on how to handle this. We should talk after that. Best regards, Tony Tuesday, Feb. 21, 2012 from Paul Keim referencing Kris bearsdley Good luck with the meeting. I've prepping Kris today on the issues. Paul Keim, PhD TGen/NAU On Feb 21, 2012, at 5:41 PM, "Fauci, Anthony (NIH/NIAID) [E]" <AFAUCI@niaid.nih.gov> wrote: Paul: Line-up and tasks sound good to me. We should strategize by phone on how to handle discussion of the WHO meeting. I have a meeting at the White House tomorrow to brief the security people on the WHO meeting and the outcome of those discussions may impact our decision on how to handle this. We should talk after that. Best regards, Tony
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Feb. 22, 2012 - Briefed the NSS in the Situation Room with Heidi Avery leading (I had precontacted her explaining that I had to do the briefing and she agreed), Laura Holgate and Brian Kamoi from NSS, Kris Beardsley (more of her later), Francis Collins, Amy Patterson, Nancy Ann De Parle, Bill Shultz (HHS OGC), Bill Corr (Deputy HHS Sec.).
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2012-02-23 00:00
Anthony S. Fauci
Feb. 23, 2012 - Finally, a pleasant evening. Attended reception at the Jefferson Hotel for the Global Health Corps (GHC) created and led by Barbara Bush, George W's daughter. Great reception. It was a fund raiser for the fellows of the GHC. Laura Bush was there and she and Barbara during the speeches called me out for praise for all that I have done for AIDS research. All the GHC fellows were so happy to meet me since they had been hearing about me for years and now were meeting me. I met Marvin Bush, George's brother. The usual crew was there - Mark Dybul (host), Eric Goosby, Stephen Hadley former National Security advisor to GWB. Many other luminaries. The Ambassador for Woman's issues of DoS mentioned in her speech how much Sec. Clinton admired me.
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Feb. 25, 2012 - Went to a (now commonplace for me) dinner at Café Milano hosted by Catherine and Wayne Reynolds in honor of Gov. Jerry brown (D-CA) and his wife Anne. Brown in DC for Governor's Convention. Sat next to Anne and got major insight into the Gov. He was known as Governor "Moonbeam" in the 70s during the hippy years when he dated Linda Ronstadt. However, he is an amazing person in that he just tells the truth without an obvious ideology. Anne told me that Pres. Obama completely shuns even other Democrats such as Democratic Governors. Obama has never once asked Jerry for any advice about anything. It was a lively evening talking about the Republican Primaries and the ridiculousness of it with Romney vs Paul vs Gingrich vs Santorum. Other usual notables at dinner. Chris and Kathleen Matthews, Supreme Court Justice Anthony Kennedy. I sat next to his wife Mary who is extremely conservative and not too bright (scary), Also there was Bob Barnett and his wife. NPR Nina Totenberg and husband David, Peter Agre, etc.
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Feb. 27, 2012 - Briefed the senior, but sub-Interagency Policy Committee on the Geneva meeting. Chaired by Laura Holgate from NSS (National Security Staff). Also present were Brian Kamoi (NSS - he has lost about 90 lbs. and looks great); Sally Howard (Chief-of-Staff to Sec. Sebelius); Kevin..... from Commerce; a bunch of representatives from the various US Government departments. Tom Countryman from State Department is really a jerk, pompous and uninformed. I alleviated the anxieties of the group regarding the studies by clarifying the difference between transmission and virulence in the Fouchier study. I strongly suggest that we reconvene the NSABB to allow them to see the new data and hear the clarification of the old data.
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Feb. 28, 2012 - Ron Fouchier flew in from Rotterdam to be on a panel tomorrow AM (Feb. 29) organized by American Society of Microbiology (ASM) to discuss this issue. Invited Ron over my house for dinner (rigatoni and sausage with tomato sauce) with Cliff Lane and Hugh Auchincloss to discuss the approach for tomorrow. Ron related to me that the NSABB never gave him a chance to explain his experiments and that he met them via teleconference. Clearly they were hostile to him and when his interview was over, Mike Osterholm started speaking before Ron signed off and Mike said (without knowing that Ron was still on the line) that Ron was a "liar". Ron stayed on the line in secret and described what sounded like a major ad hominem to Ron. After intense discussion with me before and during the dinner, Ron Finally got it that he has to be very clear tomorrow that the ferrets who got infected by aerosol transmission did not get very ill (flu-like sxs at worst), all recovered and NONE died. Only animals who got 1 million infectious doses of H5N1 directly inserted into the trachea died. It is clear that everyone NSABB, all the pundits who commented (Laurie Garret, Tom Ingelsby, Richard Ebright, D.A. Henderson, etc.) and the press thought that after aerosol transmission, the ferrets died. We had long discussions about future experiments and upcoming issues. Later in the dinner, Bruce Alberts (Editor of Science) flew in from San Francisco, called my cell phone to let me know he arrived, and I invited him over for the remainder of the dinner.
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Feb. 29, 2012 - ASM panel at 7:15 to 8:15 at Omni-Shoreham in D.C. Standing room only, fed live on Website with many reporters tuned in. Paul Keim chaired panel that included Ron Fouchier, me, Bruce Alberts, and Mike Osterholm. Everything was clarified and most people asked the question that I have been asking all along - how could this pervasive misunderstanding have occurred. It was clear, but no one wanted to embarrass anyone, that the NSABB missed this major point. March 1 and 2, 2012 - Much press coverage going on trying to decide what went wrong. Jon Cohen from Science is coming close to figuring it out. However, when he asked several members of NSABB to answer some questions, it become clear that they are being defensive and saying that it is the mere fact of making the virus "transmissible" that prompted them to recommend against publication, even if it was not clear that the aerosol-transmitted virus did not kill the ferrets. We are going to reconvene the NSABB ASAP to review the revised manuscripts from Ron and Yoshi to that they can see the additional and clarified data. I am afraid that they will not change their minds because they need to save face that they actually dropped the ball badly. I believe that Mike Osterholm and to some extent David Relman aggressively persuaded the others to vote not to publish. HOWEVER, I believe if the other members of NSABB knew that the aerosol transmission did not result in death of the ferrets, they would not have been convinced by the histrionics of Mike who told the press that this was equivalent to "thermonuclear war" if this virus gets out.