Mark Buller and so called US develops lethal new viruses

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1. 2003-10-30 13:09 Pamela Mclinnes open
   Embedded: unnamed Tony: Background on Mark Buller presentation in Geneva re so-called US development of lethal new viruses In 2000, Australian investigators, while pursuing a contraceptive development program for controlling mice, serendipitously discovered that by engineering ectromelia (mousepox) to include mouse IL-4, the new virus was more virulent and could evade normally protective vaccination (Dryvax). These data were published (Jackson RJ, et al. J Virol. 2001 Feb;75(3):1205-10. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox.) The data created some disturbance in the poxvirus research community, in the national security community and in the press because of the possible implications for engineering a smallpox virus with human IL-4. Given that the data were in the public domain and the study design was not optimal from a virologic perspective, it was felt to be both important and appropriate to verify these data and to explore ways to control this new virulent virus, utilizing either a vaccine or a therapeutic. Under Contract NO1-Al-15436, Dr. Mark Buller of St. Louis University implemented a study in mice utilizing a mouse pox virus engineered with mouse IL-4. (Carole sent you the attached e-mail 7/16/2002 informing you of progress on the study.) The MOUSE part of each component is critical and adds two levels of safety. Both the virus and the IL-4 used were mouse species specific. This study confirmed the Australian findings and Dr. Buller has presented these data in several forums including the International Poxvirus Meeting held in Lake Placid in summer 2002, and down at DHHS. Shift to Geneva. Last week a meeting organized by Acambis was held in Geneva. DA was prominently involved in the meeting and honored at a dinner. Larry Kerr (DHS) , Bernie Moss, Peter Jahrling, Jim Meegan, Mark Challberg were among other meeting attendees. Mark Buller had been assigned the topic of "The Potential Use of Genetic Engineering to Enhance Orthopoxviruses as Bioweapons". Jim Meegan reports that in the first half of Mark's talk, he discussed hypothetical scenaria and tried to show that these would not add to the general body of knowledge in a meaningful way; e.g. engineering monkey pox. In the second half of his talk, he presented his data that confirmed the Australian findings with engineered ectromelia. The only new data presented were partial protection against the engineered virus with antivirals (cidofovir). He acknowledged funding of the work from NIAID. At the end of his talk, Buller said that in partnership with Jahrling, he was going to create a cowpox virus mouse IL-4 construct and a vaccinia virus mouse IL-4 construct for testing of antivirals in the mouse system. Following his talk, Jim Meegan immediately jumped up and stressed that the Australian data were already published, that it was important to confirm them, that safety issues had been fully considered and embraced in the design of the experiment, and no aspect of the study had been covert. The next individual to comment from the audience (US person, unknown name) expressed relief that Dr. Meegan had clarified those issues because that eased his concerns re the experiment and the data and the chance that we were "giving terrorists a recipe for a bioweapon." At the end of the session, Dr. Meegan instructed Dr. Buller not to initiate work on the cowpox virus mouse IL-4 or vaccinia virus mouse IL-4 construct experiment without discussion and express permission if NIAID money was proposed for use. The reason for his concern obviously was that one of the two safety barriers (cowpox and vaccinia can infect humans) would not be in place for such an experiment. Dr. Buller yesterday sent an e-mail to Dr. Meegan asking for clarification on this. Dr. Meegan has not yet responded. However, within the last 24 hours we have discovered that Barney Graham has already created and tested a vaccinia virus mouse IL-4 construct. (There is some similar work published almost a decade ago.) We hear that this virus was also more
2. 2003-10-30 13:51 Robin Gruber
   Summary: * Yes, NIAID is funding Dr. Mark Buller's research under a contract. * Dr. Buller's experiments have been limited to validating the already published Australian data. + Dr. Buller research to date has been on engineered ectromelia, which does not infect humans. Jim Meegan has instructed Dr. Buller not to begin any research on cowpox or vaccinia without express permission from NIAID. * I am awaiting a summary of Barney Graham's research (due by 4:00 today) From: "Kerr, Lawrence D." EEE @0sp.c0p.gov> E (@bhs.gov, "Fauci, Anthony (NIH/NIAID)" <AFAUCI@niaid.nih.gov>, (@bhs.gov, "Bernard, Kenneth" (@who.eop.gov>, "Tavel, Jorge" (@ovp.eop.gov>, "Dale, Shana L." (@ostp.eop.gov> Ce: "Green, Terry M. (NIH/NIAID)" EE onic .nih.gov>, "Harrington, Kathryn M." I@ostp.eop.gov> Subject: FW: New Scientist: US develops lethal new viruses Date: Thu, 30 Oct 2003 08:53:48 -0500 Importance: Normal Good morning, Dr. Marburger and General Gordon met this morning to discuss this news release. I had been over the scientific presentation that Mark Buller gave in Geneva with Dr. Marburger so he knows that the news article doesn't reflect the true nature of the science and the development of countermeasures (anti-IL-4 mAb) that Mark has worked on. None-the-less there are some serious concerns that this raises and they have asked that we solicit Dr. Fauci's and HHS's opinion on this work and the proper response (if any) that we should be prepared to give. Coincidently, Mark Buller just called and we had a good talk. He is quite upset with the tone of the article. I made a couple of requests to him- First, that he contact St. Louis University's public relations department and fill them in on his scientific work. Kathryn I offered your contact information should they want to talk to someone here. Secondly, I ask him to review some talking points and Q&As for me. I am preparing a non-scientific version of his observations, balanced with the work he has done to develop prophylactic countermeasures. I am working on Q&As for Mark McClellan should they be needed. I will share all of this with you as they are prepared and ask for your comments. Mark is sending me his ppt from Geneva (I only have the handouts currently). More to come.... Larry US develops lethal new viruses 19:00 29 October 03 Exclusive from New Scientist Print Edition. Ascientist funded by the US government has deliberately created an extremely deadly form of mousepox, a relative of the smallpox virus, through genetic engineering. The new virus kills all mice even if they have been given antiviral drugs as well as a vaccine that would normally protect them. The work has not stopped there. The cowpox virus, which infects a range of animals including humans, has been genetically altered in a similar way. The new virus, which is about to be tested on animals, should be lethal only to mice, Mark Buller of the University of St Louis told New Scientist. He says his work is necessary to explore what bioterrorists might do. But the research brings closer the prospect of pox viruses that cause only mild infections in humans being turned into diseases lethal even to people who have been vaccinated. And vaccines are currently our main defence against smallpox and its relatives, such as the monkeypox that reached the US this year. Some researchers think the latest research is risky and unnecessary. "I have great concern about doing this in a pox virus that can cross species," said lan Ramshaw of the Australian National University in Canberra on being told of Buller's work. Ramshaw was a member of the team that accidentally discovered how to make mousepox more deadly (New Scientist, 13 January 2001). But the modified mousepox his team created was not as deadly as Buller's. No rebound Since then, Ramshaw told New Scientist, his team has also created more deadly forms of mousepox, and has used the same method to engineer a more deadly rabbitpox virus. But this research revealed that the modified pox viruses are not contagious, he says. That is good news in the sense that these viruses could not cause ecological havoc by wiping out mouse or rabbit populations around the world if they escaped from a lab. However, this discovery also means some bioterrorists might be more tempted to use the same trick to modify a pox virus that infects humans. Such a disease, like anthrax, would infect only those directly exposed to it. It would not spread around the world and rebound on the attackers. But there is no guarantee that other pox viruses modified in a similar way would also be non-contagious. Ramshaw's team made its initial discovery while developing contraceptive vaccines for sterilising mice and rabbits without killing them. The researchers modified the mousepox virus by adding a gene for a natural immunosuppressant called IL-4, expecting this would boost antibody production. Instead, the modified mousepox virus was far more lethal, killing 60 per cent of vaccinated mice. The addition of IL-4 seems to switch off a key part of the immune system called the cell-mediated response. Maximised production Now Buller has engineered a mousepox strain that kills 100 per cent of vaccinated mice, even when they were also treated with the antiviral drug cidofovir. A monoclonal antibody that mops up IL-4 did save some, however. His team "optimised" the virus by placing the IL-4 gene in a different part of the viral genome and adding a promoter sequence to maximise production of the IL-4 protein, he told a biosecurity conference in Geneva last week. Buller has also constructed a cowpox virus containing the mouse IL-4 gene, which is about to be tested on mice at the US Army Medical Research Institute of Infectious Diseases at Fort Detrick, Maryland. Cowpox infects people, but Buller says the IL-4 protein is species-specific and would not affect the human immune system. The experiments are being done at the second-highest level of biological containment. Ramshaw says there is no reason to do the cowpox experiments, as his group's work on rabbits has already shown the method works for other pox viruses. While viruses containing mouse IL-4 should not be lethal to humans, recombinant viruses can have unexpected effects, he says. "You'd hope the combination remains mouse-specific." Why his group's engineered viruses are not contagious is a mystery, he says. It is not, for instance, because the host dies faster than usual, taking the virus with it. But his findings could explain why pox viruses containing IL-4 have never evolved naturally, even though the viruses frequently pick up genes that affect their host's immunity. Despite the concerns, work on lethal new pox viruses seems likely to continue in the US. When members of the audience in Geneva questioned the need for such experiments, an American voice in the back boomed out: "Nine-eleven". There were murmurs of agreement. Debora MacKenzie, Geneva

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