Wide range of smallpox research efforts cited in WHO decision to retain virus stocks

Feb 15, 2002 (CIDRAP News) – A report that paved the way for the World Health Organization's (WHO's) recent recommendation to keep intact the two known collections of smallpox virus cites a wide range of ongoing research on smallpox, including genome sequencing, molecular diagnostic techniques, antiviral drugs, and new vaccines.

The report by the WHO Advisory Committee on Variola Virus Research says that the genomes of ten smallpox virus strains have been fully sequenced and that more than 140 potential antiviral compounds have shown activity against pox viruses. It also notes the recently reported successful efforts to infect monkeys with smallpox, a disease previously known only in humans.

The WHO Executive Board decided Jan 17 that the stocks of smallpox virus held by the United States and Russia should be kept for the time being so that research can continue in case the disease reappears. Smallpox was eradicated in the late 1970s, and since then the WHO has scheduled and then postponed destruction of the remaining virus collections several times. Before the January decision, the collections were scheduled to be destroyed by the end of this year.

US Secretary of Health and Human Services Tommy G. Thompson announced in mid-November that the United States would keep its virus collection until adequate medical tools are available to counter possible future outbreaks. At a meeting early in December, the WHO advisory committee recommended keeping the stocks, and the WHO Executive Board endorsed this recommendation in January. The board took no formal vote but accepted the recommendation unanimously after some debate, according to Iain Simpson, a press spokesman at WHO headquarters in Geneva, Switzerland.

Several national officials who were observing the meeting but are not currently on the 32-member executive board favored destruction of the virus, Simpson told CIDRAP news via e-mail. He also said several countries wanted the board to set another specific date for destruction of the virus, but this was not done. The board's decision does not have to be formally affirmed by the World Health Assembly at its annual meeting in May, but the matter could come up for debate if a country proposes a resolution relating to it, Simpson said.

The report of the advisory committee's December meeting states, "The committee agreed that, despite the considerable progress that had been made in investigating variola virus, significant components of this research, most notably the refinement and use of an animal model developed in 2001 and the development of antiviral drugs, were unlikely to be completed by the end of 2002. Further, during extensive discussion of the potential availability of an animal model, additional research was identified that would necessitate access to live variola virus stocks after the expected 2002 destruction date."

The committee was "informed of the successful infection of cynomolgus monkeys with two different variola virus strains by intravenous, or intravenous plus aerosol, routes," the report says. "The disease induced shared several pathological features with human smallpox but the course of disease is much faster and the dose of virus needed to cause intravenous infection is particularly high." This apparently refers to research done by Peter B. Jahrling of the US Army Research Institute of Infectious Diseases; the report does not mention specific researchers or laboratories. Jahrling's success in infecting monkeys with fatal smallpox was first reported in the mass media in January.

The committee report says, "Additional studies are needed to improve and validate this animal model, but this would need work extending beyond 2002. The monkey model has the potential to be used as an assay in prophylactic or therapeutic studies with live variola virus and could also provide access to good diagnostic reagents." Other "surrogate animal models" of smallpox are also being studied, including monkeypox virus in monkeys and cowpox virus in rodents.

Regarding development of drugs to treat smallpox, the report says most studies so far have focused on cidofovir, which is active against cowpox in mice and monkeypox in monkeys. Cidofovir could be used in the United States as an investigational new drug to treat reactions to smallpox immunization or as treatment if the disease resurfaced, the document states.

Concerning the more than 140 other compounds with activity against pox viruses, the committee said, "The finding that some of these compounds have selective activity, inhibiting one or more orthopoxviruses but not necessarily variola virus, supports the premise that access to live variola virus is necessary for the effective screening of additional lead compounds."

In the realm of molecular diagnostics, the report says that several recently developed methods promise to provide "very sensitive detection of variola virus DNA." The most promising methods include "polymerase chain reaction (PCR) of restriction fragment length polymorphisms, multiplex PCR and real-time PCR with fluorigenic probes." Some of these were used to diagnose definitively a recent laboratory-acquired infection with a nonvariola orthopoxvirus.

The committee said investigators have made "significant progress" in molecular diagnostics, but there is room for improvement in the sensitivity of the tests. The group said an ultimate goal might be the development of a hand-held device for detecting variola virus DNA and diagnosing infection.

On the genomic side, the report says that the complete genomes of seven more variola virus strains have recently been sequenced, bringing the number of full-length genome sequences to 10. Given the considerable amount of genetic information now available on the virus, the committee agreed that "further sequencing of the more variable genomic termini" should take priority over the sequencing of additional complete genomes. This could help in the forensic work of tracing viral strains in case of a deliberate release of the virus, the panel said.

The report also calls for more research on smallpox vaccines, since the existing live vaccinia vaccine is considered risky for immunocompromised people, the elderly, pregnant women, and children with eczema. Attenuated recombinant forms of the vaccinia virus are among approaches that have shown promise, the report says, adding that access to live variola virus is necessary for testing of new vaccines.

In other comments, the report notes that review of virus strains in the two known collections is continuing. The Centers for Disease Control and Prevention holds 451 isolates gathered from various countries when smallpox was endemic, the document says. Reports given at the meeting focused on 50 Russian-held strains that are not found in the American collection.

Following the recommendation of WHO Director-General Gro Harlem Brundtland, the executive board instructed the advisory committee to report again on the progress of research 2 to 3 years from now, according to Simpson.

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