The live smallpox vaccine was a historical first and highly effective vaccine. However, along with high immunogenicity, the vaccinia virus (VACV) caused serious side effects in vaccinees, sometimes with lethal outcomes. Therefore, after global eradication of smallpox, VACV vaccination was stopped. For this reason, most of the human population worldwide lacks specific immunity against not only smallpox, but also other zoonotic orthopoxviruses. Outbreaks of diseases caused by these viruses have increasingly occurred in humans on different continents. However, use of the classical live VACV vaccine for prevention against these diseases is unacceptable because of potential serious side effects, especially in individuals with suppressed immunity or immunodeficiency (e.g., HIV-infected patients). Therefore, highly attenuated VACV variants that preserve their immunogenicity are needed. This review discusses current ideas about the development of a humoral and cellular immune response to orthopoxvirus infection/vaccination and describes genetic engineering approaches that could be utilized to generate safe and highly immunogenic live VACV vaccines.

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The last case of natural smallpox was recorded in October, 1977. It took humanity almost 20 years to achieve that feat after the World Health Organization had approved the global smallpox eradication program. Vaccination against smallpox was abolished, and, during the past 40 years, the human population has managed to lose immunity not only to smallpox, but to other zoonotic orthopoxvirus infections as well. As a result, multiple outbreaks of orthopoxvirus infections in humans in several continents have been reported over the past decades. The threat of smallpox reemergence as a result of evolutionary transformations of these zoonotic orthopoxviruses exists. Modern techniques for the diagnostics, prevention, and therapy of smallpox and other orthopoxvirus infections are being developed today.

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