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Summary Here we propose a SARS-CoV-2 vaccine design concept based on identification of highly conserved regions of the viral genome and newly acquired adaptations, both predicted to generate epitopes presented on MHC class I and II across the vast majority of the population. We further prioritize genomic regions that generate highly dissimilar peptides from the human proteome, and are also predicted to produce B cell epitopes. We propose sixty-five 33mer peptide sequences, a subset of which can be tested using DNA or mRNA delivery strategies. These include peptides that are contained within evolutionarily divergent regions of the spike protein reported to increase infectivity through increased binding to the ACE2 receptor and within a newly evolved furin cleavage site thought to increase membrane fusion. Validation and implementation of this vaccine concept could specifically target specific vulnerabilities of SARS-CoV-2 and should engage a robust adaptive immune response in the vast majority of the population., Graphical Abstract, Highlights • Selecting optimal epitopes is essential for vaccine safety and efficacy • We report 65 vaccine peptides predicted to drive long-term immunity in most people • Epitopes contain domains conserved in 15 coronaviruses and newly evolved SARS2 regions • Epitopes can be used to generate B and/or T cell vaccines (RNA and DNA), Yarmarkovich et al. report SARS-CoV-2 peptides for use in multi-epitope vaccines. These peptides are predicted to activate CD4 and CD8 T cells, are highly dissimilar from the self-proteome, and are conserved across 15 related coronaviruses. Presented epitopes are expected to drive long-term immunity in the majority of the population.