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Smallpox is caused by Variola major, a double-stranded DNA virus belonging to the Poxviridae family. This virus carries genes encoding DNA-dependent RNA polymerase and other essential enzymes that enable replication entirely within the host cell cytoplasm, allowing it to evade some nuclear antiviral defenses.

Smallpox transmission occurs primarily through inhalation of virus-laden droplets or direct contact with infectious scabs. Upon inhalation, the virus targets mucosal surfaces of the respiratory tract, attaching to cell surface molecules on respiratory epithelial cells and triggering viral entry by endocytosis.

Smallpox lesions progress sequentially through distinct stages: flat red macules develop first, then progress to raised papules, followed by fluid-filled vesicles, and later pustules filled with pus. Eventually pustules crust over into scabs that fall off, often leaving deep, pitted pockmarks, especially on facial skin.

After viral replication in respiratory epithelial cells, newly formed viral particles are released and engulfed by macrophages, which transport them to nearby lymph nodes. The virus multiplies further before entering the bloodstream, causing viremia and systemic dissemination throughout the body, similar to mechanisms seen in viral meningitis.

Smallpox diagnosis relies primarily on clinical presentation, particularly the synchronous progression of skin lesions and exposure history. Laboratory confirmation is achieved through polymerase chain reaction (PCR) testing of lesion fluid, electron microscopy, or viral culture in biosafety level 4 facilities, with serological assays providing supportive evidence.

No specific antiviral treatment is universally approved for smallpox. However, antiviral agents such as tecovirimat (ST-246) have shown efficacy in inhibiting viral envelope formation, while cidofovir and brincidofovir demonstrate in vitro activity against poxviruses. Supportive care including hydration, fever management, and secondary infection control remains critical.

The vaccinia virus-based smallpox vaccine induces cross-protective immunity and is highly effective if administered before or within a few days of exposure. The vaccine uses a live, attenuated virus and historically prevented smallpox until routine vaccination ceased after eradication in 1980, though it remains part of biodefense stockpiles.