Abstract
Declaration of smallpox eradication by the WHO in 1980 led to discontinuation of the worldwide vaccination campaign. The increasing percentage of unvaccinated individuals, the existence of its causative infectious agent variola virus (VARV), and the recent synthetic achievements increase the threat of intentional or accidental release and reemergence of smallpox. Control of smallpox would require an emergency vaccination campaign, as no other protective measure has been approved to achieve eradication and ensure worldwide protection. Experimental data in surrogate animal models support the assumption, based on anecdotal, uncontrolled historical data, that vaccination up to 4 days postexposure confers effective protection. The long incubation period, and the uncertainty of the exposure status in the surrounding population, call for the development and evaluation of safe and effective methods enabling extension of the therapeutic window, and to reduce the disease manifestations and vaccine adverse reactions. To achieve these goals, we need to evaluate the efficacy of novel and already licensed vaccines as a sole treatment, or in conjunction with immune modulators and antiviral drugs. In this review, we address the available data, recent achievements, and open questions.
Highlights
Appearance Unexposed Asymptomatic +1Unknown +2 Exposed Symptomatic −4 Vaccinia Immune Globulin (VIG) Antiviral Drug
Lister/Elstree, New York City Board of Health (NYCBH), EM-63, and Tian-Tan were predominantly used during the smallpox eradication campaign, because of their higher safety record compared to other vaccines, such as Vaccinia virus (VACV) Copenhagen or Bern [1]
Non-human primates develop severe disease with disseminated lesions and death, following respiratory infections, yet a rather high dose of Monkeypox virus (MPXV) is usually needed to produce acute severe systemic disease [96,97,98]. This potential disadvantage of the non-human primate model and the inherent complexities of working with Non-Human Primates (NHPs) led to the development of MPXV models in small animal species, including prairie dogs, squirrels, African dormice, Gambian rats, and selected mouse strains with attenuated immune response [17,99,100,101,102,103,104]
Summary
Smallpox was a human pandemic disease caused by variola virus (VARV), a virus species within the genus Orthopoxvirus of the poxvirus family. Following a worldwide vaccination campaign launched by the World Health Organization (WHO), the naturally occurring smallpox has been eradicated [1,2]. The strict limitations in VARV research, and the fact that VARV infects and cause smallpox disease only in humans, limits our knowledge about the molecular mechanisms of smallpox pathogenesis, potentially complicating the development and approval of new effective antivirals and vaccines. Combining available data on the disease, countermeasures efficacies, challenge strains, animal models, correlates of immunity and experimental protection data, allows to recommend therapeutic approaches to control future outbreaks
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