Naturally processed HLA class I-restricted epitopes inform targets of protective CD8+ T cell-mediated immunity (113.11)

Abstract

Abstract Rational design of CD8+ T cell (TCD8)-based vaccines requires knowledge of the immunogenic and protective epitopes presented during infection, information which is currently lacking. Using the clinically successful smallpox vaccine as a model, ~200 novel naturally processed vaccinia viral peptides presented by HLA-A*0201 and -B*0702 molecules were identified and characterized. Humans showed a variegated response to these determinants, reminiscent of the hierarchic response seen in HLA class I transgenic mice. Importantly, multiple TCD8 epitopes were commonly recognized by humans and mice and identified potential targets for protective TCD8-mediated immunity. After acute infection, both dominant and subdominant TCD8 specificities exhibited all of the immunologic features necessary for protection. However, early and efficient presentation of immune determinants during infection ensured protective responses, regardless of dominance, such that subunit vaccination targeting subdominant or recessive TCD8 specificities conferred protection against lethal poxvirus challenge. Hence, an in-depth knowledge of naturally processed T cell epitopes coupled with the identification of TCD8-based targets that protect from lethal poxviral infection are essential for rational vaccine design.