HOGVAX: Exploiting epitope overlaps to maximize population coverage in vaccine design with application to SARS-CoV-2.

The efficacy of epitope vaccines depends on the included epitopes as well as the probability that the selected epitopes are presented by the major histocompatibility complex (MHC) proteins of a vaccinated individual. Designing vaccines that effectively immunize a high proportion of the population is challenging because of high MHC polymorphism, diverging MHC-peptide binding affinities, and physical constraints on epitope vaccine constructs. Here, we present HOGVAX, a combinatorial optimization approach for epitope vaccine design. To optimize population coverage within the constraint of limited vaccine construct space, HOGVAX employs a hierarchical overlap graph (HOG) to identify and exploit overlaps between selected peptides and explicitly models the structure of linkage disequilibrium in the MHC. In a SARS-CoV-2 case study, we demonstrate that HOGVAX-designed vaccines contain substantially more epitopes than vaccines built from concatenated peptides and predict vaccine efficacy in over 98% of the population with high numbers of presented peptides in vaccinated individuals.