Impaired innate, humoral, and cellular immunity despite a take in smallpox vaccine recipients

Smallpox vaccine is highly effective, inducing protective immunity to smallpox and diseases caused by related orthopoxviruses. Smallpox vaccine efficacy was historically defined by the appearance of a lesion or "take" at the vaccine site, which leaves behind a characteristic scar. Both the take and scar are readily recognizable and were used during the eradication effort to indicate successful vaccination and to categorize individuals as "protected." However, the development of a typical vaccine take may not equate to the successful development of a robust, protective immune response. In this report, we examined two large (>1000) cohorts of recipients of either Dryvax^® or ACAM2000 using a testing and replication study design and identified subgroups of individuals who had documented vaccine takes, but who failed to develop robust neutralizing antibody titers. Examination of these individuals revealed that they had suboptimal cellular immune responses as well. Further testing indicated these low responders had a diminished innate antiviral gene expression pattern (IFNA1, CXCL10, CXCL11, OASL) upon in vitro stimulation with vaccinia virus, perhaps indicative of a dysregulated innate response. Our results suggest that poor activation of innate antiviral pathways may result in suboptimal immune responses to the smallpox vaccine. These genes and pathways may serve as suitable targets for adjuvants in new attenuated smallpox vaccines and/or effective antiviral therapy targets against poxvirus infections.