Abstract
Coronaviruses are a diverse family of viruses that crossed over into humans at least seven times, precipitating mild to catastrophic outcomes. The severe acute respiratory syndrome coronavirus 2 pandemic renewed efforts to identify strains with zoonotic potential and to develop pan-coronavirus vaccines. The analysis of 2181 coronavirus genomes (from 102 host species) confirmed the limited sequence conservation across genera (alpha-, beta-, delta-, and gammacoronavirus) and proteins. A phylogenetically informed pan-coronavirus vaccine was not feasible because of high genetic heterogeneity across genera. We focused on betacoronaviruses and identified nonhuman-infecting receptor binding domain (RBD) sequences that were more genetically similar to human coronaviruses than expected given their phylogenetic divergence. These human-like RBDs defined three phylogenetic clusters. A vaccine candidate based on a representative sequence for each cluster covers the diversity estimated to protect against existing and future human-infecting betacoronaviruses. Our findings emphasize the potential value of conceptualizing prophylaxis against zoonoses in terms of genetic, rather than species, diversity.