Looking back at smallpox.
Smallpox apparently arose through transfer of variola virus to humans from another animal species. By causing a brief infection that required close contact for transmission and engendered solid immunity, the agent was always vulnerable to simple isolation measures. The high replicative fidelity of the viral DNA polymerase limited variola's ability to adapt to humans and preserved orthopoxviral antigenic cross-reactivity, so that vaccinia vaccination protected against smallpox. Host-derived genes encoding immunomodulatory proteins helped shelter viral replication from innate immune responses. Examination of clinical variants suggests that severity of illness was usually determined by host responses during the incubation period. Control of viral replication was aided by early postexposure vaccination and might be strengthened by additional immunological interventions. Massive inflammatory responses were responsible for major features of illness. Some patients with high levels of circulating virus developed hemorrhagic disease resembling septic shock. Continued study of virus-host interactions is needed to defend against genetically modified agents.