Definition of epitopes and antigens recognized by vaccinia specific immune responses: Their conservation in variola virus sequences, and use as a model system to study complex pathogens

In the last few years, a wealth of information has become available relating to the targets of vaccinia virus (VACV)-specific CD4⁺ T cell, CD8⁺ T cell and antibody responses. Due to the large size of its genome, encoding more than 200 different proteins, VACV represents a useful model system to study immunity to complex pathogens. Our data demonstrate that both cellular and humoral responses target a large number of antigens and epitopes. This broad spectrum of targets is detected in both mice and humans. CD4⁺ T cell responses target late and structural antigens, while CD8⁺ T cells preferentially recognize early antigens. While both CD4⁺ and CD8⁺ T cell responses target different types of antigens, the antigens recognized by T_H cells are highly correlated with those recognized by antibody responses. We further show that protein abundance and antibody recognition can be used to predict antigens recognized by CD4⁺ T cell responses, while early expression at the mRNA level predicts antigens targeted by CD8⁺ T cells. Finally, we find that the vast majority of VACV epitopes are conserved in variola virus (VARV), thus suggesting that the epitopes defined herein also have relevance for the efficacy of VACV as a smallpox vaccine.