A single line often inverts meaning once you see what it
answers, so neighbouring messages are always shown.
-
Nov. 21 - 30, 2011 - Spent hours on the phone trying to address the ADAP waiting list since we (HHS/PEPFAR) felt that if the POTUS announces a scale-up of treatment for PEPFAR, then the logical question is what are we doing about the ADAP waiting list? Tom Frieden suggested that we engage the drug companies. Since I know Jim Rooney from Gilead, I made the initial contact which led to many phone calls involving Jim and people from Gilead; people from HHS - me, Tom Frieden, Mat Wakefield (HRSA), Sally Howard (chief-of-staff to Sebelius), Dora Hughes as well as people from NASTAD and Welvista. Important issues is the Gilead agreed to greatly lower their prices for people on ADAP waiting list Dec.1, 2011 - World AIDS Day (WAD). A very special day. The White House has decided that the venue for the POTUS statement on WAD would be George Washington University in a program sponsored by One and RED, Bono's organizations. Sanjay Gupta was the MC. We had Presidents Bush and Clinton by live video conference and President Obama delivered the speech that Eric Goosby, Tom Frieden and I and others wrote for him. As expected, he went with Option #2 (see above - Nov. 8, 2011). In addition, he included an additional $15 million (for Clinics) + $35 million (for States) = $50 million for ADAP total. Again, Tom Frieden and HHS people (see above) have been working on the "domestic option" for the past couple of weeks to offset criticism that we were paying attention to global, but not domestic AIDS. Following the POTUS speech, there was a panel moderated by Sanjay consisting of Bono, Alecia Keys, Kay Warren, Rep. Barbara Lee, Sen. Marco Rubio and a few others. I was told a few days prior that Sanjay would turn to me with a question sometime during the program. Right after Pres. Clinton's live video speech, Sanjay said that you cannot have a discussion about HIV/AIDS without including Tony Fauci (who is in the audience) and his perspective on the science and he turned to me to speak. I spoke for a few minutes about the fact that the scientific data were overwhelming (circumcision; treatment as prevention, etc.) and the task now was to implement the science. The statement was similar to what I had said at the IAS meeting in Rome in July. Right after my comment, Bono said that he must tell a funny story and he proceeded to describe the night when he came to my house for dinner to discuss what we could do to push the global AIDS agenda. He was cute. He said that his friend Bobby Schriver told him that the only person that could break the logjam on Global AIDS programs was Tony Fauci. He finished by calling me a "proper hero". A YouTube record of this statement by Bono is available for Dec. 1. Also, I had a chance to say a few words to Pres. Obama as he was "working the line" following his speech. He congratulated me for the great work that we were doing and that he has been hearing about. All in all, a really good day!! Of note, Gregg Gonsalves wrote a scathing letter to Raj Shah (that went viral on the internet) scolding him for obstructing the treatment as prevention initiative (see above discussions re: Raj). Unclear to me how Gregg found out about all of this. Dec. 2,, 2011 - Finishing off WAD activities, went to Harvard on a beautiful crisp clear December day and participated in the AIDS@30 International Symposium. I gave the keynote "Perspective" on vaccines and participated in a panel Chaired by Bruce Walker and consisting of Bob Gallo, Nelson Michael, Jerry Sadoff, and Julie McElrath. Flew up to Boston with Eric Goosby and flew back to DC with Nelson Michael. All good. Dec. 2 thru 21, 2011 - Significant issues regarding dual use research. Check press from Dec. 20-21, 2011. Briefly, NIAID funded 2 studies - subcontract via CEIRS (Centers of Excellence for Influenza Research and Surveillance) to Erasmus University in Netherlands (Ron Fouchier) and grant to Yoshi Kawaoka at Wisconsin to study feasibility and mechanism of getting the highly lethal (60%), but poorly transmissible H5N1 (bird flu) that has been smothering in SE Asia since 1997 to become transmissible and maintain lethality in a mammal model (ferret). Rationale for the study was to determine - Can it happen (in mammals) since many people reasonably assume that it cannot since it has not done this in nature despite being around in chickens and rarely in humans since 1994? Also, if it does become transmissible by point mutations followed by passaging in ferrets (the experimental methodology), then what is the signature of it so that health officials in the field could do better surveillance and also design better diagnostics, therapies and possibly vaccine. Both papers (with slight differences found that relatively few mutations (~5) followed by serial passage in ferrets led to virus that had better transmissibility and kept virulence. Kawaoka paper showed increased transmissibility but not maintenance of virulence, while Fouchier paper showed both. Papers submitted to Nature (Kawaoka) and Science (Fouchier). Program staff (NIAID), Fouchier and editors asked (because of possibility of dual use) the NSABB to examine the results and advise if it was OK to publish. Kawaoka was asked by NIAID to do the same. To everyone's surprise, the NSABB recommended that the papers be published with the conclusions, but with redaction of the key results, mutations and methodologies. I believe that this was group think and "cover your ass". Decision was to do this and provide a link in the paper whereby people (health officials, legitimate scientists, PHARMA, etc) who have a need to know can have access to the data. This was a precedent setting recommendation that was virtually impossible to ignore even though I disagreed with it since the complexity of influenza adaptability is extremely complex and it is unlikely that terrorists could replicate this work largely because it is unlikely that if that this model just simply predicts that it will maintain these characteristics if taken from ferret to human. Furthermore and more importantly, since the data had already been presented (by Fouchier) at an international meeting in Malta and the papers were reviewed by several reviewers and known by many, the data are already "out their" and would be virtually impossible to "restrict" the access to the full papers by a "vetting" mechanism of people who "apply" for the unredacted papers. Journal editors were disappointed (Bruce Alberts - Science and Phil Campbell - Nature) as were many flu scientists. However, we heard the usual hysteria from people like Ebert and Ingelsby who complained that the experiments should never have been done in the first place. Also, Mike Osterholm who is a member of the NSABB was practically hysterical that the NSABB recommendations should go out right away so that he could "answer all of the press calls" that he was getting. In reality, the only press that was agitating was - you guessed it - Laurie Garrett. Of note, Mike Osterholm is the Head of the CIERS group that subcontracted through the Mount Sinai group to Fouchier to conduct these experiments. Osterholm now (incredibly) says that he never thought that this situation would arise when he knew about the contract and actually was given updates through the CIERS on the actual data. Yet, he is the loudest one saying we should now lock down all experiments and treat this like BSL-4. Problem here is that as I predicted, the White House is now involved and they want the USG to examine all research that is ongoing and that is proposed for its dual use potential and to put restrictions on it if it has such potential. What they do not understand it that in the "discovery of science" you cannot always predict what will be dual use and the danger is that scientific work and importantly the normal open discourse of science will suffer because some uninformed people who live for "intrigue" are acting out their own agenda. More later. Dec.22, 2011 to Jan. 7, 2012 - Situation has escalated with wall-towall conference calls with HHS and a variety of WH folks about what to do. Major issues are that Bruce Alberts and Phil Campbell are willing to publish a redacted version of the papers in Science and Nature, respectively; however, they insist that the USG have in place a link or some mechanism that they can publish with the redacted versions of the paper that would allow legitimate scientists and Public Health officials to have access to the entire manuscript. I found out through painful probing that recommendations from NSABB guidelines USG policy should have been in place years ago to deal with the upstream (prior to the start of experiments) and downstream (progress reports and communication of results) issues of Dual Use Research of Concern (DURC). Problem is that the recommendations of the NSABB as to the "7 deadly sins" of DURC never got "clearance" from the multiple agencies to which NSABB officially reports (DoD, DHS, DoS, DoJ, intelligence community) in order for it to get the Public Comment in the Federal Register to give the scientific community the opportunity to weigh in on the feasibility of controlling or not such research at the same time a preserving the fundamental basis of open scientific discourse. I believe that Amy Patterson should have shown some greater strength of leadership to make sure that this process moved along, when in fact it just froze. The NSABB sent in their recommendations in 2007 (NSABB started in 2004) that should have become guidelines USG Policy that ultimately could guide the local institutional Biosafety Committees (IBCs) to monitor this at the local level. Irony is that now the papers have been reviewed, the Fouchier paper was presented in an international meeting in Malta and multiple people have seen the data. BTW, Fouchier has been acting like a jerk in his cavalier attitude about disseminating the results. Now NSABB and the journals above all want a mechanism is a few days (to coincide with the publication dates of the papers (Jan. - Feb. 2012) that they have not been able to do in 4-5 years. All of the demagogues have weighed in. People thinking that the world is not in danger of a terrorist making a "killer virus" that spreads easily. What is at stake is the proper balance of doing microbial research that has DU potential with security issues. Of, note, I wrote an opinion piece in the Dec. 31, 2011 issue of the Washington Post on the value of the science. The security people do not understand the scientific enterprise, although I can understand their concerns. This whole thing has destroyed my Christmas Holidays. It still is not over. Divergent opinions in the scientific community ranging from 1) this work should never have been done in the first place (Ebright; Ian Lipkin) to 2) we should not restrict publication of any of the data and should just let it out (Racaniello; Peter Palese) to 3) we should publish only redacted version (which is ridiculous since the data are out already) to 4) we should destroy the virus (D.A. Henderson). Please note that the complexities of species adaptability to virus transmission and lethality is so complex that just because multiple induced mutations followed by passaging in ferrets of 1 strain of H5N1 does not mean that this virus would do the same in humans or that anyone else could replicate the experiment. Of great importance is the fact the Fouchier found out (but DID NOT submit it with his paper to Science - he wants to put it into a second paper)that if you take these 5 mutations and go back and put them into the wild-type H5N1, you do not get increased transmissibility, which proves my point (and that of Jeff Taubenberger) that transmissibility is a multi-genic process that is strongly "context-dependent". In other words, just knowing these 5 mutations may have little impact on someone's ability or not to repeat these experiments. Let me be clear, I believe that we need to now once and for all get the process going of a SOP for evaluating dual use research of concern (DURC) before the experiments are performed to evaluate the risk/benefit of even doing the experiments and to periodically look at the data to determine whether the data should be shared (presented or published) before one presents it or submits it to a journal. I think that there was major multifaceted failure here of NSABB covering their asses with the recommendation; researchers wanting attention for their work; failure of Amy Patterson's shop to get their job done over years; panic and hubris on the part of USG agencies who know nothing about science. I can go on and on. The problem that we are facing now is that we (USG) is being put in an untenable position of be involved in and associated with restricted (or as some say "censoring") scientific information when it is already out there. The process sets a bad precedent and it evokes all kinds of conspiracy theories and makes us look foolish. My choice at this point would be to admit that it is too late in the process - we should publish the unredacted papers and make this an "Asilomar moment" to make sure that we are not in this position again. Of note, on Jan. 7, 2012 a NY Times (written by Phil Boffey - unsigned - I know because he called me about it) came out with an inappropriately alarmist editorial entitled "Engineered Doomsday" calling into question the rationale for the research and asking for lock down of virus in BSL-4 and ultimate destruction of virus. He got most of his information from Ian Lipkin (my good friend) who feels strongly about this and was nice enough to tell me that he was going to do this. This editorial has only inflamed the hysteria and posturing.
-
Jan. 15, 2012 - I still believe that there is no reason for the Journals insisting that the papers (redacted) need to be published by end of Jan/early Feb. Why not wait until this mess in openly discussed in an "Asilomar-like" setting.
-
Jan. 16 - 21, 2012 - Major development pushed by my decision to be much more proactive in this process. Too many people were posturing and playing the "sound bite game" - Richard Ebright (who is a complete asshole), Mike Osterholm (with whom I am becoming progressively more disillusioned with due to his hysteria) and other well-meaning people who just like to comment, like D.A. Henderson. I never liked the fact that the journals (Science and Nature) were on a fast track to publish when we still did not know how we were going to develop a system to get the unredacted manuscripts only to "those who had a legitimate scientific need to know". We were getting significant pressure from the White House via HHS to make sure that there are no surprises with other such projects appearing. In addition, additional data were leaking out from Ron Fouchier's group having WH/HHS asking whether we should be shutting off their funding. I became concerned over the possibility that outside (non-scientific) influences would force us to set a bad precedent and stop funding these flu projects. Therefore, I took the bull by the horns and contacted Fouchier and strongly suggested that he and the flu scientists call a moratorium (60 days) on all work dealing with increased transmissibility and/or virulence of highly pathogenic H5N1 virus. At first, Fouchier was reluctant to do so since he felt that this would be an admission that what he did was dangerous and that he was backing down. He totally disagrees with the NSABB recommendations. In addition, I felt and told this to many in the press that we need to get more international involvement in this situation with WHO playing a major role. I felt that people were concerned that this was too much of a USA-centric situation and the USG was driving things that affect many others outside of USA. I agree. Therefore I agitated and accomplished that WHO (Keiji Fukuda) should hold a meeting in Geneva to add an international component to this situation. Importantly, on Wednesday, Feb. 18 I called Ron Fouchier in his home in Rotterdam (actually I e-mailed him and asked him to call me) at 4:30 PM DC time - 10:30 PM Rotterdam time. I strongly suggested that he call a moratorium on this work and encourage his flu colleagues to also do so. He was not totally convinced and said that he would consult with the others tomorrow (Feb. 19) AM and get back to me. I emphasized that it is likely if he does not do it voluntarily that forces beyond our control (i.e. the security people) would force us to defund the work. The next morning he called me and said that they had agreed to call a moratorium for 60 days and see what the Geneva meeting brings. Furthermore, Francis Collins and I called Bruce Alberts (Science) and Phil Campbell (Nature) and convinced them to delay the publication until at least March. Fouchier came out with a press statement on Feb 20 and Francis Collins and I came out with an NIH statement the same day applauding their decision. This was a good example of my having to take the bull by the horns since things were not going in the right direction. Now we wait to see what happens. There was wide coverage in the press about this "breakthrough" in negotiations with big stories in Washington Post, NY Times, Wall Street Journal, etc.
-
Jan. 23, 2012 - Went to Situation Room in the White House at 3:15 PM. Cold, very damp, gray day. Purpose to discuss the H5N1 situation and brief the National Security Staff (NSS) about my upcoming trip to the Geneva meeting scheduled for Feb. 16-17, 2012. Present at the meeting: John Brennan (Chief, NSS), Heidi Avery (Deputy Chief), Francis Collins, Amy Patterson, Bill Corr (Deputy Secretary-HHS), Sally Howard (Chief-of-Staff to Sebelius), Bill Shultz (OGC-HHS). NSS concern was what we would agree to or not at the Geneva meeting. I tried to explain that the information was already out there and multiple papers have already described the methodology. I explained that what I wanted to get out of the meeting was a transparency to others about what we are trying to do in order to get away from this USA-centric perception. Of note, after the meeting, Heidi sent an email to Bill Corr saying that there are certain "redlines" that we should not give in to at the meeting. I fear that she is not fully getting what I want to accomplish at the meeting. Also, of note, she mentioned in her e-mail that she does not want total unbridled availability of the information in the papers (her "redline") even though she knows that certain USG scientists do not agree with her. I am certain that she is referring to me.
-
2012-02-03 00:00
Anthony S. Fauci
Feb. 3, 2012 - Super Bowl night. Ravens beat 49ers 34-31. Nonetheless spent the evening at a dinner and panel discussion at the Fairmont Hotel (24th and M Street, N.W.), Colonnade Room. Occasion was a pre-Summit dinner for the Global Women's Cancer Summit to take place the following week. Panel discussion between David Rubenstein (Carlyle group) and Wolf Blitzer (CNN) with Mark Dybul contributing. Sat a dinner table with David Rubenstein (who is still trying to get me to work for him at Carlyle because he thinks that I am "...the smartest person in the world"), Laura Bush, Wolf Blitzer, Agnes Binagwaho (Minister of Health of Rwanda), Nancy Brinker, Mark Dybul, Julie Gerberding. Great discussion about transforming events in global health. Chatted with Laura about President George W. who recently had back surgery as well as about President George H.W. who is slowly recovering from bronchitis hospitalization.
-
Feb. 11, 2012 - The past couple of weeks have been intensively involved in discussion about the H5N1 issue. Extraordinary "legal" issues come up about what can and cannot be discussed in public. I pushed for and it will happen next week for a WHO meeting to make all of this more transparent and international. The issue is what can and cannot be discussed at this meeting. There are 2 options to allow discussion at the meeting: 1) an "export control license" from the Dept. of Commerce that restricts discussion to the people listed on the license, i.e. all the attendees at the meeting or; 2) An advisory opinion from the dept. of Commerce saying that the information is intended to be published by the journals and therefore the expert control requirement does not exist. Some subterfuge has gone on with HHS in getting the journals to say that they have every intention of publishing the papers without restrictions (which is not true) just so that they can get an advisory opinion. The problem is that since Commerce grants both the export control (which assumes restriction) as well as advisory opinion (which assumes open publication without restriction) you cannot have it both ways. Bottom line is that based on the journals declaring that they intend to publish an advisory opinion will be granted. I expressed my concern that this was not entirely honest, but it went ahead anyway. This is something that I do not control. I leave for Geneva on Feb. 14 for a meeting on Feb. 16-17, 2012.
-
Feb. 13, 2012 - You really cannot make this up if you tried. They (HHS, DoC, White House) have finally decided that we all need export control licenses to go to Geneva. The DoC and HHS are working feverishly to get them on time before we all (me, Nancy Cox, Paul Keim - representing NSABB) leave for Geneva. The entire process has been ludicrous with regard to the concern over security as well as the craziness of the laws related to export control licenses. Export control was originally designed as a multinational agreement to protect against the shipment of sensitive products such as computer chips, weapons, etc. to countries with whom we (USG) or other countries have a problem with. In this case (uniquely), the export control applies to shipping of information or even being in a room where information (sensitive) is shared. In this case, the information is the H5N1 unredacted manuscripts. I need an export control license (even though I am not taking anything with me) to go to Geneva and I must name on the license everyone who will be at the meeting. I cannot do this since the WHO will not release the names of the attendees until the day of the meeting and so DoC cannot put in for a license for me. OK, we get the names and then Tom Countryman from State has deep concern that we are even going to such a meeting to discuss potentially sensitive information. We calm him down and then the White House (John Brennan and Heidi Avery) do not want Fouchier to discuss the 9 mutations that are capable of giving the ferrets transmission/lethality without the requirement for passage among ferrets (more below on that). They only want him to discuss what is in the unredacted paper (5 mutations + passage). They (through Sally Howard of HHS) want me to call Ron Fouchier to ask him to not mention the 9 mutations and to restrict his discussion to the paper. The discovery of the non-passaged virus's ability with 9 mutations by reverse genetics to allow transmission/lethality is not contained in the paper. Now here I am (very uncomfortably) asking Ron to voluntarily withhold any information both during the question period and the discussion about the other 4 mutations that together with the original 5 make a wild type H5N1 transmissible/lethal in ferrets without the requirement of passage. Ron reluctantly agreed because he wants the meeting to occur and the White House said that the meeting will be nixed if we discuss the 9 mutations. Here is the irony of this all. The meeting was called by WHO to add "transparency" to the process and to preserve the PIP agreement so that the Indonesians and Vietnamese do not feel that we are withholding information from them and a White House condition for supporting the meeting and allowing me to go is that Ron "withholds" information if asked about the obvious questions that any virologist would ask, i.e. if you took a wild-type H5N1 (cloned) and only inserted the 5 mutations, would it transmit in ferrets - answer = no. Then what did you do? Ron would answer that the virus after 5 mutations (commonly known in the literature) + 12 passages obviously also accumulated other mutations besides the original 5 (3 + 2). Ron then did deep sequencing of the transmissible virus and by reverse genetics figured out that you needed the 5 + an additional 4 (now he says less than 4). This was not in the original manuscript (unredacted). White House does not understand that the 5 mutations + Passage = the unpassaged 9 mutations. They fixate about not mentioning the precise 9 mutations when anyone can just take any quasispecies and get a transmissible virus after many passages. You just need a virus and some ferrets. I again am very uncomfortable in asking Ron to hold back this information and told him that this would be his choice and he would have to play it by ear at the meeting, but he will try his best to be vague about the 9. Another ludicrous happening is that this export control issue must also get input from the iPC (interagency Policy Committee) which includes DoD. The night before I am leaving for Geneva (tomorrow on 5:47 PM flight) DoD says that they want to know when I am leaving since they are not sure that I can go since they want the WHO to disinvite the Chinese (where the disease is occurring) since we (USG) do not share restricted information with them. They fail to realize that Margaret Chan (Director General of WHO) is Chinese!!!!! You cannot make this up. DoD is examining this issue tonight and will let me know tomorrow if I can go to Geneva.
-
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)
-
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.