Smallpox, caused by the Variola virus, was a devastating infectious disease. It was highly contagious and lethal, killing up to 30% of those infected and often leaving survivors with disfiguring scars or blindness. Responsible for an estimated 300 million deaths in the 20th century alone, its successful elimination stands as the only time a human disease has been globally eradicated. This monumental achievement shifts the meaning of prevention from protecting populations against a circulating virus to protecting the world against its potential re-emergence.
The Global Strategy for Eradication
The World Health Organization (WHO) launched its Intensified Eradication Program in 1967, initially relying on mass vaccination. Logistical challenges soon required a more targeted approach, pivoting the strategy to “ring vaccination.” This method focused on rapidly identifying new cases through active surveillance. Once a case was found, the infected individual was isolated, and public health teams created a protective “ring” of immunity by vaccinating all known contacts and their contacts. This strategy was efficient because the virus lacks an animal reservoir and requires direct, prolonged person-to-person contact. This surveillance and containment model led to the last naturally occurring case in 1977, and the disease was declared officially eradicated in 1980.
The Smallpox Vaccine: Mechanism and Efficacy
The smallpox vaccine, derived from the Vaccinia virus (a related but less harmful orthopoxvirus), underpinned the eradication campaign. This live-virus preparation works by inducing cross-immunity, meaning the immune response generated against Vaccinia protects against the deadly Variola virus. The vaccine stimulates both B-cell antibody production and T-cell responses, providing robust and long-lasting defense.
The vaccine was administered using a specialized instrument called a bifurcated needle, a small, two-pronged metal tool. The technique involved rapidly pricking the skin’s surface multiple times, ensuring the live virus was introduced and leading to a localized infection called a “take,” which confirmed successful vaccination. While highly effective, first and second-generation vaccines carried risks due to the use of a live, replicating virus. Side effects included localized reactions and, in rare cases, serious complications such as generalized vaccinia or post-vaccinial encephalitis, particularly in immunocompromised individuals. This safety profile has driven the development of newer, safer third-generation vaccines, such as MVA-BN (JYNNEOS), which are non-replicating.
Current Biosecurity Measures and Stockpiles
In the post-eradication era, prevention has shifted entirely to biosecurity and preparedness against accidental or intentional re-emergence. The only two officially recognized repositories for the live Variola virus are at the Centers for Disease Control and Prevention (CDC) in the U.S. and the Vector Institute in Russia. These stocks are kept under stringent protocols within maximum-containment Biosafety Level 4 (BSL-4) laboratories. Routine public vaccination ceased decades ago, leaving the majority of the global population susceptible. Today, vaccination is limited to specific groups facing elevated occupational risk, such as laboratory researchers and certain military personnel.
Global readiness is maintained through substantial vaccine and therapeutic stockpiles. The U.S. Strategic National Stockpile (SNS) holds millions of doses, including the replicating ACAM2000 and the non-replicating JYNNEOS vaccine. The WHO also maintains a Smallpox Vaccine Emergency Stockpile (SVES) for rapid, coordinated international response. Additionally, modern medical countermeasures, such as the antiviral drugs tecovirimat (TPOXX) and brincidofovir (Tembexa), are stockpiled to treat smallpox infection should an event occur.