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 major histocompatibility complex (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 33-mer 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.