Asymptomatic HLA-A^*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8 ⁺ T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes

Evidence from C57BL/6 mice suggests that CD8⁺ T cells, specific to the immunodominant HSV-1 glycoprotein B (gB) H-2^b- restricted epitope (gB_498-505), protect against ocular herpes infection and disease. However, the possible role of CD8⁺ T cells, specific to HLA-restricted gB epitopes, in protective immunity seen in HSV-1-seropositive asymptomatic (ASYMP) healthy individuals (who have never had clinical herpes) remains to be determined. In this study, we used multiple prediction algorithms to identify 10 potential HLA-A^*02:01-restricted CD8⁺ T cell epitopes from the HSV-1 gB amino acid sequence. Six of these epitopes exhibited high-affinity binding to HLA-A^*02:01 molecules. In 10 sequentially studied HLA-A^*02:01-positive, HSV-1-seropositive ASYMP individuals, the most frequent, robust, and polyfunctional CD8⁺ T cell responses, as assessed by a combination of tetramer, IFN-γ-ELISPOT, CFSE proliferation, CD107a/b cytotoxic degranulation, and multiplex cytokine assays, were directed mainly against epitopes gB _342-350 and gB_561-569. In contrast, in 10 HLA-A ^*02:01-positive, HSV-1-seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent clinical herpes disease) frequent, but less robust, CD8⁺ T cell responses were directed mainly against nonoverlapping epitopes (gB_183-191 and gB_441-449). ASYMP individuals had a significantly higher proportion of HSV-gB-specific CD8⁺ T cells expressing CD107a/b degranulation marker and producing effector cytokines IL-2, IFN-γ, and TNF-α than did SYMP individuals. Moreover, immunization of a novel herpes-susceptible HLA-A^*02:01 transgenic mouse model with ASYMP epitopes, but not with SYMP epitopes, induced strong CD8⁺ T cell-dependent protective immunity against ocular herpes infection and disease. These findings should guide the development of a safe and effective T cell-based herpes vaccine.