ABSTRACT
Targeted synthetic vaccines have the potential to transform our response to viral outbreaks; yet the design of these vaccines requires a comprehensive knowledge of viral immunogens, including T-cell epitopes. Having previously mapped the SARS-CoV-2 HLA-I landscape, here we report viral peptides that are naturally processed and loaded onto HLA-II complexes in infected cells. We identified over 500 unique viral peptides from canonical proteins, as well as from overlapping internal open reading frames (ORFs), revealing, for the first time, the contribution of internal ORFs to the HLA-II peptide repertoire. Most HLA-II peptides co-localized with the known CD4+ T cell epitopes in COVID-19 patients. We also observed that two reported immunodominant regions in the SARS-CoV-2 membrane protein are formed at the level of HLA-II presentation. Overall, our analyses show that HLA-I and HLA-II pathways target distinct viral proteins, with the structural proteins accounting for most of the HLA-II peptidome and non-structural and non-canonical proteins accounting for the majority of the HLA-I peptidome. These findings highlight the need for a vaccine design that incorporates multiple viral elements harboring CD4+ and CD8+ T cell epitopes to maximize the vaccine effectiveness.
Competing Interest Statement
S.W.-G., D-Y.C, S.S., K.R.C, N.H., S.A.C., J.G.A., M.S., and P.C.S. are named co-inventors on a patent application related to this work filed by The Broad Institute that is being made available in accordance with the COVID-19 technology licensing framework to maximize access to university innovations. N.H. is a founder of Neon Therapeutics, Inc. (now BioNTech US), was a member of its scientific advisory board, and holds shares. N.H. is also an advisor for IFM Therapeutics. S.A.C is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer and PrognomIQ. J.G.A. is a past employee of Neon Therapeutics, Inc. (now BioNTech US). P.C.S. is a co-founder of and consultant to Sherlock Biosciences and Delve Biosciences and a board member of Danaher Corporation and holds equity in the companies. The remaining authors declare no competing interests.