Protection from Smallpox: Beyond Immune Biomarkers

Since the eradication of smallpox, immunological studies of smallpox vaccine (vaccinia virus) have provided great gains in understanding immunology as well as depecting smallpox vaccine-derived immune responses. Despite this wealth of knowledge, two confounding problems remain. First, that surviving smallpox provides an individual with lifelong protective immunity, whereas vaccination may not, and second, that specific molecular correlates of protection against smallpox remain vague. Historical literature on smallpox and contemporary studies of other human infections with orthopoxviruses, such as monkeypox, indicate that vaccination may lower disease risks, but it does not provide complete protection against infection in all individuals. Factors impacting protective immunity include longevity of immunologic memory post-vaccination, challenge dose and differences in the challenge viruses, as well as route of exposure. This article discusses historical information regarding smallpox attack rates during outbreaks and contemporary views on aspects of vaccines and naturally occurring orthopoxvirus outbreaks as related to vaccine-derived immunity.