Does the SARS-CoV-2 spike really have an Achilles heel?

The continued emergence of SARS-CoV-2 variants and waning vaccine immunity are some of the factors that drive the continuing search for more effective treatment and prevention options for COVID-19. In this issue of the JCI, Changrob, et al. describe an anti-SARS-CoV-2 spike antibody, isolated from a patient, that targets a vulnerable site on the spike protein receptor binding domain when it adopts a configuration called the “up” conformation. This antibody cross-neutralized all variants studied, including recent Omicron subvariants, and was protective against multiple variants in a hamster model. These results are of interest when considering the next generation of prophylactic and therapeutic antibodies for COVID-19, but they may also shape future approaches to vaccination against SARS-CoV-2.