The Johns Hopkins University, Center for Civilian Biodefense Strategies
D.A. Henderson, M.D., M.P.H.
Unofficial memo for the record
6-9 December, 1999
Note: The official record of the meeting will be made available at this web site as soon as it is available
WHO Advisory Committee on Variola Virus Research
Dr. Isao Arita, Japan*
Dr. Kalyan Banerjee, India
Dr. Robert Drillien, France
Dr. Mariano Esteban, Spain
Dr. Frank Fenner, Australia
Dr. Hans Gelderblom, Germany
Dr. Peter Greenaway, U.K. (Rapporteur)
Dr. James Hughes, U.S.A.
Dr. Grant McFadden, Canada*
Dr. Andre Plantinga, Netherlands (Chairman)
Prof. Lev Sandakhchiev, Russia
Dr. Hermann Schatzmayr, Brazil
Dr. R. Smoeck, Belgium
Prof. Muyembe Tamfum, Congo
Prof. Prasert Thongcharoen, Thailand
Dr. M.H. Wahdan, Egypt
*Unable to attend the meeting
Advisers to the Committee
Dr. Antonio Alcami, U.K.
Dr. Brian Mahy, U.S.A.
Dr. D.A. Henderson, U.S.A.
Dr. Michael Merchlinsky, U.S.A.
Dr. John Huggins, U.S.A.
Dr. Bernard Moss, U.S.A.
Dr. Lauren Iacono-Connors, U.S.A.
Prof. S. Shechelkunov, Russia
Dr. Peter Jahrling, U.S.A.
Dr. Geoffrey Smith, U.K.
Dr. Kenneth Bernard, U.S.A.
Dr. James Meegan, U.S.A.
Dr. Inger Damon, U.S.A.
Dr. Geoffrey Schild, U.K.
Dr. Gerald Epstein, U.S.A.
Drs. Lindsay Martinez, David Heymann, Riccardo Wittek, Ray Arthur, Cathy Roth and Mr. Tom Topping.
The 52nd World Health Assembly requested the Director General to appoint a group of experts to establish what research, if any, must be carried out to reach global consensus on the timing for the destruction of existing variola virus stocks. This Committee was requested to advise WHO on all actions to be taken with respect to variola; to develop a research plan for priority work on the virus; to devise a mechanism for reporting of research results to the world health community; to outline an inspection schedule to confirm the strict containment of existing stocks; and to assure a safe and secure research environment for work. The Committee was asked to report to the Executive Board in May 2000.
The Assembly also reaffirmed the decision of previous Assemblies that the remaining stocks of variola virus should be destroyed and authorized retention of the virus "up to not later than 2002 and subject to annual review".
The Committee was requested, if at all possible, to reach consensus conclusions on all of its recommendations. If irreconcilable differences persisted, the Committee was instructed to provide a report setting forth opposing views. Despite a range of expressed views on several subjects, the Committee, after due deliberation, succeeded in approving consensus recommendations on all topics.
Overall Conclusion of the Committee Regarding Research
The Committee concluded that further limited research on variola virus could be justified but members emphasized that this should, under no circumstances, go beyond the end of 2002. The possible retention of virus beyond 2002 for several different studies, including the pathogenesis of smallpox, was proposed by one member but this, ultimately, was rejected by the Committee.
DNA Sequence Information
Complete sequence information is available for three strains (two Asian variola major strains and alastrim) and partial information for five others (two African variola major strains, one variola minor strain and two classic laboratory strains -- Butler and Harvey). However, it was argued that gaining more sequence information on more strains might facilitate the targeted design of new drugs and better probes for diagnosis and detection.
The Committee agreed that it would be useful to determine the full-length genome sequences for an African variola major strain (Congo 70) and a variola minor strain (Somalia 77) and to prepare additional clone libraries of selected strains. The Committee was assured that there would be no difficulty in completing the required work well before 2002. The Committee requested that a specific work program with milestones be prepared.
The Need for Novel Diagnostic Tests
A full-range of PCR primers has been prepared and validated with scab specimens by Dr. Esposito at CDC. Incorporation of these into state-of-the-art hand held equipment for the diagnosis of a range of pathogens was said by U.S. investigators to be no more than a year away. Such devices would use stable reagents and be capable of being used by individuals with minimal training. It was said that large-scale manufacture of these instruments would reduce costs to a range suitable for public health use.
The Committee agreed that validation studies could be conducted using live variola virus if necessary. Such studies were expected to be able to be completed within the next year or so. The Committee requested that a specific work program with milestones be prepared.
The Need for Antiviral Drugs
It was generally acknowledged that an antiviral drug to treat clinical disease could be useful if available. Its utility, however, would inevitably be limited given the proven high level of efficacy and low cost of existing vaccines. Because of these considerations, use of the vaccine would be preferred where ever possible. It was also recognized that the costs of developing and producing an anti-viral drug would be considerable and that distributing it in quantity to required populations would be difficult. It was noted that the validation processes required for licensure of such a product could be lengthy.
The Committee believed that a better strategy would be to develop an anti-vaccinia drug to deal with possible complications of vaccinial infections.
Although there was some discussion about the utility of a broad-based drug development program using such as interferons, chemokines and fusion inhibitors, it was recognized that this could lead to a very protracted program which was not warranted if work were required beyond 2002. Accordingly, it was agreed that the drug development program would focus on already identified candidate compounds such as cidofovir.
The Committee requested that benchmarks be developed against which progress could be monitored by independent observers.
The Need for Monoclonal Antibodies
Hyperimmune vaccinia immune globulin (VIG) has been used in the past for treatment of vaccinial complications and, in outbreaks, to provide protection to those who might have been exposed to smallpox but who are not able to be vaccinated. Given that clinical recovery from infection is dependent on developing an adequate cell mediated immune response, it is uncertain as to how effective VIG really is. Moreover, supplies are now in very short supply.
The Committee agreed that monoclonal antibodies might be of value for diagnostic purposes, less likely for therapeutic ones. It agreed that it would be appropriate for a time-limited monoclonal antibody production program to be established.
The Need for Novel Smallpox Vaccines
Clearly needed is a modern tissue culture propagated vaccine product that could replace the traditional vaccine which has been produced on the skin of calves, sheep or water buffaloes. This could be accomplished by adapting current strains to tissue culture and validating their immunogenic and reactogenic properties with the established strains. This validation would not require use of variola virus.
A new vaccine that would be safer, but similarly efficacious, would require special manipulation of the virus genome and would ultimately require use of variola virus for validation purposes. Given the time and costs involved in developing such a vaccine and the fact that it could never be field tested prior to use, it was difficult to justify a substantial effort in this field.
The Committee, in brief, recommended that priority be given to development of a new tissue cell culture vaccine. Work with other strains that would require access to variola virus stocks was not warranted.
Need for a Non-Human Primate or other Animal Model for Smallpox Infection
Proponents argued for the development of animal models (primates, transgenic mice or suckling mice) for variola virus infection that could be used for the development of drugs, vaccines or diagnostics. Others expressed doubts that a model could be developed that produced data which could be directly correlated with human infections. Researchers indicated that an evaluation of such models could be completed within the next two years and could be useful for the assessment of drugs now under study.
The Committee agreed to a limited exploration of the susceptibility of non-human primates and other species to defined variola viruses whose genomic sequences are known or are likely to be determined. The Committee requested a time-limited work plan defining species, variola virus strain(s) to be used and inoculation route. It was understood that the research program would have to be greatly accelerated in order to complete the studies in time for destruction of variola virus by 31 December 2002.
The Need for Basic Research
Some members argued for an open-ended program of basic research using live variola viruses. Others believed that this should have low priority as it would require the unlikely development of an animal model and would require the use of scarce, high-security laboratories. Note was made of the fact that surrogate orthopoxvirus infections in various mammalian species have been successfully and productively used for years in documenting the pathobiology of the orthopoxviruses.
The Committee had no objection to a basic research program being conducted in parallel with other studies. However, it believed this should be of a time-limited nature with specific benchmarks and defined end points. It should not extend beyond 2002.
Back to Smallpox Virus Destruction Page
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Meeting of the WHO Variola Research Committee
Research Agenda Utilizing Variola Virus:
A Public Health Perspective
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Its Impact on Virus Destruction
Deliberations Regarding the Destruction of Smallpox Virus: A Historical Review, 1980-1998
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