Identification of human T-cell cytomegalovirus epitopes and their conservation across the herpes virus family 2310276

Abstract

Abstract Introduction Cytomegalovirus (CMV) is a leading cause of congenital birth defects and has a substantial clinical impact on a significant proportion of the U.S. population. To date, no approved vaccines are available to prevent congenital CMV infection in humans. Our study aimed to delineate specific immunogenic regions within each ORF through peptide deconvolution. Methods In a cohort of 27 CMV-positive donors, we examined T-cell memory responses across a set of 31 open reading frames (ORFs). We synthesized 15-mer peptides to prepare specific pools and megapools (MP) to detect T-cell responses and epitope identification. CD4 and CD8 T-cell responses were detected by activation-induced cell marker (AIM) assay. Results Our study established recognition of a set of CMV potential vaccine candidates for human CD4 and CD8 T-cell responses. Our results showed vigorous poly-antigenic responses of CMV ORFs varying in their CD4+ and CD8+ reactivity. A total of 552 different epitopes (458 CD4 epitopes and 94 CD8 epitopes) were identified. Of those, 66 CD4 epitopes and 36 CD8 epitopes were recognized in 3 or more donors. Correlation between regions containing CD4 and CD8 epitopes indicates that immunogens targeting both CD4 and CD8 responses can be designed. Antigen and epitope sequences are well conserved in human CMV strains (HCMV), but poorly conserved in other beta herpesviruses. The overall CD4/CD8 activity is correlated to IgG titers that are specific to pre- and post-fusion glycoprotein (gB). We have selected epitopes from ORFs associated with significant positive associations with IgG titers. Our proposed vaccine construct contained murine epitopes to assess for immunogenicity in mice for T-cells and antibody response enhancement. Conclusion Our study identified of a set of CMV regions eliciting human CD4/CD8 memory responses and IgG responses derived from a wide breadth of different antigenic targets. These regions could be combined to elicit robust humoral and T-cell responses targeting human CMV. Funding Source Advanced Research Projects Agency for Health (ARPA-H) Topic Categories Vaccines and Immunotherapy (VAC)