Until the introduction of effective vaccines in the early 1800s, poxviruses historically caused serious disease in humans. The last documented case occurred in 1977 in Somalia. The World Health Assembly declared that smallpox had been eradicated as of 1980. Before that time the virus had killed millions of people. Starting in 1977, the number of laboratories holding stocks of the variola virus was being reduced until all known stocks were consolidated at only two World Health Organization (WHO) collaborating centers: the Centers for Disease Control and Prevention in Atlanta, Ga., and the VECTOR labs in Kotsovo, Russia. Although outlawed by the Biological Weapons Convention in 1972, the potential existence of unregistered stocks of smallpox virus that can be used for bioterrorism or biological warfare is a source of concern. All vaccination programs against smallpox were discontinued after eradication of the disease. Thus, virtually all children and many adults are now fully susceptible to smallpox. There is only a limited stock of vaccine available, not all of which has been confirmed to be properly stored or monitored for potency (5
). Currently, there is also no established effective treatment. A smallpox outbreak occurring today in a highly mobile and susceptible population would likely spread widely before effective measures could be taken. Therefore, if smallpox were used in an act of terrorism or warfare, it could result in a real catastrophe (12
In 1994 destruction of all stocks of variola virus was recommended by a WHO expert committee on orthopoxvirus infections. In May of 1999, the WHO's 191 member states voted to delay destruction of the variola virus stocks until 2002 at the latest. A WHO advisory committee on variola virus research defined in December 1999 the following areas in which research should be conducted before the end of 2002: sequencing more completely the DNA of the smallpox virus, devising tests to detect the virus in humans, and developing drugs to treat human smallpox infections should they reappear (press release WHO/77, 10 December 1999).
Human monkeypox causes a systemic exanthem which resembles smallpox. It occurs sporadically in parts of western and central Africa. The disease is transmitted from animals (the probable reservoir being squirrels) to humans by physical contact. Also, secondary spread from human to human by aerosol is possible (11
). Between February 1996 and October 1997 an outbreak of monkeypox occurred in the province Kasai Oriental in the Democratic Republic of Congo (1
). It would also be important to have an effective treatment for monkeypox.
The use of recombinant vaccinia virus (rVV) expressing immunoreactive epitopes from the pathogen (or tumors) as immunoprophylaxis holds promise. However, generalized VV infection may occur in immuncompromised patients, particularly those infected with human immunodeficiency virus type 1 (10
). In such cases an effective antipoxvirus drug may be beneficial.
Several compounds have been shown to inhibit the in vitro replication of VV (9
). Of these, some demonstrated activity in the mouse tail lesion model. These include 3-deazaneplanocin A, ribavirin, cytosine arabinoside, and 5-iodo-2′-deoxyuridine. Only one drug, methisazone (Marboran; 1-methylisatin-3-thiosemicarbazone), has ever been used and reported to show prophylactic efficacy against smallpox (2
). We have reported on the potent anti-VV activity of the acyclic nucleoside phosphonate analog cidofovir in both immunocompetent and immunodeficient mice (16
). Recently, our findings were corroborated by the observation that cidofovir also protects mice from a lethal aerosolized or intranasal cowpoxvirus challenge (4
Here we report the potent efficacy of the diacetyl ester prodrug (H961) of the N-7-substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (S2242) in protecting mice against VV infections. Two infection models were used: (i) a model in which the virus is injected intravenously in immunocompetent mice and (ii) a model in which the virus is injected intraperitoneally in SCID mice. The NMRI mouse model allows the monitoring of pox lesion development on the tail in a nonlethal infection; the SCID mouse model allows the determination of protective effects on virus-induced mortality. Compound S2242 is a potent and selective inhibitor of the replication of herpesviruses (human cytomegalovirus, thymidine kinase-inducing and thymidine kinase-deficient strains of herpes simplex virus, and varicella-zoster virus) (17
). VV is, like variola virus, an orthopoxvirus; it has been used as a smallpox vaccine for the past 200 years, and there are no known natural hosts for this virus.