Design of a pan-betacoronavirus vaccine candidate through a phylogenetically informed approach

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 coro-navirus 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 iden-tified 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.

Automated summary

Coronaviruses have caused various outcomes in humans through multiple crossovers, and efforts to find vaccines for zoonotic potential have been renewed. The analysis of coronavirus genomes showed limited sequence conservation across genera and proteins, making a pan-coronavirus vaccine unfeasible. However, focusing on betacoronaviruses, human-like receptor binding domain (RBD) sequences were identified, which could be used to develop a vaccine covering the diversity of future human-infecting betacoronaviruses. This highlights the importance of considering genetic diversity in prophylaxis against zoonoses rather than species diversity.