The Johns Hopkins University, Center for Civilian Biodefense Strategies

Deliberations Regarding the Destruction of Smallpox Virus: A Historical Review, 1980-1998

D.A. Henderson, M.D., M.P.H.
Working paper - meeting of a Committee of the Institute of Medicine
20 November, 1998

Following the 1980 declaration that smallpox had been eradicated, WHO established a Committee on Orthopoxvirus Infections under Dr. Frank Fenner's chairmanship, to advise on steps to be taken in the post-eradication era and to monitor them. The Committee continued to meet every 4 years since that time, its next meeting being scheduled for January 1999. The question of retention of smallpox virus along with the conditions for retention was one of the most important of its agenda items. The virologists on the Committee initially included, in addition to Dr. Fenner, Dr. Keith Dumbell (UK), Dr. Svetlana Marennikova (USSR), Dr. James Nakano and Joseph McCormick (USA) and Dr. T. Kitamura (Japan). Later, Dr. Brian Mahy was to represent the USA and Drs. K.Barnerjee (India) and P.J.Greenaway (UK) were added to the group.

Throughout its deliberations, the Committee had to deal with two strongly held, contrary points of view. Some scientists and many countries, especially those that were most recently endemic, greatly feared the reintroduction of smallpox and argued passionately for taking all possible steps to avert this. They advocated early destruction of all known stocks of the virus. It was recognized that this provided no absolute guarantee that some stocks of virus might not be covertly retained. However, it was generally thought that an international agreement to destroy known stocks of virus would diminish to some extent the likelihood of the virus being released. On the other side, certain scientists, expressing concern about the destruction of a species and the inevitable loss of genetic information, argued for its retention. Not surprisingly, participants in the various discussions found themselves in broad agreement in perceiving merit in both points of view. Efforts to reconcile the two incompatible policies was a challenge for the WHO Committee as well as for others who deliberated the policies. Fortunately for your IOM Committee, this is not a challenge with which it will have to cope since, by its charter, it will be assessing only the scientific merits of retention of the virus.

The WHO Orthopoxvirus Committee recommended, as first steps, that a program be launched to restrict the virus to the fewest possible laboratories -- specifically two ( the Centers for Disease Control, Atlanta, and the Institute for Virus Preparations, Moscow)-, to assure through independent inspection that the virus was handled under approved BSL4 conditions; and to inventory the isolates held in each institution. Subsequently, it recommended that cloned fragment libraries of selected strains be prepared and, later, it recommended that selected prototypical strains be sequenced. Meanwhile, detailed field studies in Zaire (1981-86) of naturally occurring monkeypox revealed that this disease, caused by a closely related orthopoxvirus, was a zoonotic infection that only incidentally infected humans. Clinically, it closely resembled variola major infections in Zaire and bore the same case-fatality rate but with a sharply decreased propensity for spread.

In 1986 and again in 1990, the WHO Committee affirmed the desirability of destroying variola virus when satisfactory progress had been made with the sequencing, mapping and cloning. The destruction of monkeypox virus strains was not contemplated. In fact, retention of these strains offered the possibility of their subsequent use in experimental studies pertaining to the pathogenicity of variola/monkeypox and in surrogate monkeypox infections in monkeys to evaluate candidate antiviral agents and vaccines. The alternative use of monkeypox virus assumes special importance, of course, because of the fact that variola virus infection being a uniquely human infection, cannot itself be studied in laboratory animals and such studies with variola virus as might be performed in the U.S. would have to be conducted in one of two overtaxed SSL4 laboratories at CDC in Atlanta.

The WHO Committee decided that before making a final decision with regard to virus destruction, it would consult more widely with the scientific community. In August 1993, a special round table discussion was arranged to take place in Glasgow at the International Congress on Virology and alternative views regarding virus destruction were published in companion articles in Science. That same year, several professional bodies were solicited as to their views. During 1993, a decision to destroy the virus was endorsed by the Council of the American Society of Microbiology, the Executive Board of the International Union of Microbiological Societies, the Board of Scientific Counselors of the National Center for Infectious Diseases of the CDC, the Board of Directors of the American Type Culture Collection and the Russian Academy of Medical Sciences.

In 1994, the WHO Orthopoxvirus Committee met to review the views which it had received and the progress that had been made in mapping, cloning and sequencing of strains. After a full review, the Committee voted unanimously to recommend that the virus be destroyed, all but two members recommending June 1996 as a target date. The others recommended a delay until June 1999. The Committee decided to recommend to the Executive Board of the World Health Assembly that a resolution be endorsed and forwarded for action to the World Health Assembly calling for the destruction of all known stocks of variola virus in June 1996.

The question as to what position the USA should take at the Executive Board was discussed in a series of intragovernmental meetings. Finally, in a 22 December conference call, senior government staff along with selected advisers addressed the then current arguments which mitigated against virus destruction. The participants (see below) expressed unanimous agreement on the following points:

  1. "That there would be scientific value in retaining existing smallpox stocks"

  2. "That the current viral stocks would not be required for diagnosis of the disease if it were to reemerge in the future, regardless of the source of reemergence"

  3. "That the current viral stocks would not be required to develop more effective or safer smallpox vaccines in the future"

  4. "That future national security requirements are unknown; however, defensive scientific research against a diagnosed but unidentified threat would be predicated on recovering or obtaining an isolate of the specific virus or its genome (not the strains currently held)".

(Participants included from DHHS, Drs. Varmus, Fauci, Henderson and Mahy; from USAMRIID, Drs. Jarling and McClean; from DOD, COLs Kadilac and Kerkorian; plus Drs. Lederberg, Shelokov, Monath and Zelicoff. A senior person from the NSC moderated.)

In preparation for the 1995 WHO Executive Board, an interagency group weighed the scientific arguments for retention of virus against the social-political arguments for its destruction and decided that U.S. delegates should support the recommendation to destroy the virus as of June 1996.

As it happened, the proposal before the 1995 Executive Board was preemptorily withdrawn without discussion on the grounds that there was no consensus on the issues and that it should be debated at a subsequent Executive Board meeting after further discussions had taken place.

In 1995, continuing disagreements within government as to the appropriate U.S. policy led to the appointment of a group, comprised of civilian advisers to DoD and DHHS, to reexamine the issues. This group, consisting of representatives of the Board of Scientific Counselors of the National Center for Infectious Diseases, CDC, and the Armed Forces Epidemiological Board met on 20-21 April 1995 and submitted a six page report. [Members included Drs. Gail Cassell, Harlan Halvarson, Philip Russell, Michael Ascher, James Chin and Martin Wolfe.] Key conclusions and recommendations were as follows:

Coincidentally, DHHS and DoD convened a meeting of their own on 20 April 1995 and decided to create a Joint Coordinating Group (JCG) to address critical scientific issues and to elaborate a research agenda which would involve collaboration between USAMR[ID, NIH and CDC. The Group and its terms of reference were approved by the NSC on 26 April and Dr. Henderson and LCOL Rausch were designated co-chairs.

The JCG identified three principal areas for research which embraced the issues raised by the advisory group. The first, dealing with antiviral substances, called for the evaluation in treatment of smallpox of antiviral agents which had been FDA approved for other purposes or were well along the path for approval. The enormous costs of drug development as well as the time involved dictated the need to restrict the screening to these drugs . A first step was to undertake a screening of these compounds in tissue cell cultures of smallpox and other orthopox viruses and then to proceed through animal models using appropriate surrogate orthopox viruses, recognizing that there is no satisfactory animal model for variola infection. A second research area was to ascertain the possible applicability of a model utilizing monkeypox virus infection in monkeys to measure the effect of antivirals and to assess the efficacy of vaccines. It was thought that if this model proved unsatisfactory, further consideration would have to be given to the possible development of genetically modified rodents or perhaps the use of immunosuppressed animals. A third research thrust was to develop simple, rapid laboratory methods to differentiate and identify the different orthopox viruses.

The JCG met every 4-6 weeks either in person or by conference call to discuss progress and options. By the end of November 1995, the studies which were programmed had been completed. The tissue culture screening of 10 compounds representing 5 classes of drugs had been completed and, based on the information obtained, further studies of promising agents had begun using mammalian models. Only limited funding was provided, however, and progress was slow. The monkeypox/monkey model was found to offer the requisite characteristics for a surrogate model. Monkeys exposed to an aerosol of monkeypox virus developed a rash illness resembling smallpox and virus was recovered from spleen and liver. After vaccination with both current and new cell-culture vaccines, they seroconverted and when later exposed to aerosol challenge, they were fully protected. For diagnosis, primer pairs were identified to amplify variola, vaccinia, monkeypox and cowpox viruses and these methods were validated using stored specimens from smallpox patients. Further work is in progress to further simplify and standardize techniques. On 15 December 1995, a final report on the results of the work was submitted through the respective responsible Assistant Secretaries to the NSC.

In only one research area did HHS and DoD offer significantly different positions relative to the retention of variola virus. DoD believed "that in order to continue research on antiviral therapeutics, variola virus would be necessary because no clear-cut surrogate virus model was identified to accurately predict the effects for all drug classes against variola." It pointed out that "two drugs in development and one drug approved for another indication have been identified as good candidates for smallpox therapy" and that "3-5 years of appropriately funded effort will be required to obtain all the information required for an FDA submission." HHS held that "reasonable surrogate viruses, vaccinia and monkeypox virus, have been identified which can be used for cell culture and preclinical animal studies." "They are not perfect surrogates as they are less sensitive to the drugs tested than variola" but "any drug that inhibits them should be even more potent against variola. Therefore, further studies with variola itself should not be necessary."

In January 1996, the USA, at the WHO Executive Board meeting, supported the decision to destroy the virus at the end of June 1996. However, as a result of further discussion and debate at the Board and at the World Health Assembly, the decision was made to defer destruction of the virus until June 1999 and then, only after a reaffirmation of the decision at the January 1999 Executive Board and the May 1999 World Health Assembly.

 

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