Bivalent mRNA COVID vaccines elicit predominantly cross-reactive CD4⁺ T cell clonotypes

Bivalent COVID vaccines containing mRNA for ancestral and Omicron BA.5 spike proteins do not induce stronger T cell responses to Omicron BA.5 spike proteins than monovalent vaccines that contain only ancestral spike mRNA. The reasons for this finding have not been elucidated. Here, we show that healthy donors (HDs) and people living with HIV (PLWH) on antiretroviral therapy mostly target T cell epitopes that are not affected by BA.5 mutations. We use the functional expansion of specific T cells (FEST) assay to determine the percentage of CD4⁺ T cells that cross-recognize both spike proteins and those that are monoreactive for each protein. We show a predominance of cross-reactive CD4⁺ T cells; less than 10% percent of spike-specific CD4⁺ T cell receptors were BA.5 monoreactive in most HDs and PLWH. Our data suggest that the current bivalent vaccines do not induce robust BA.5-monoreactive T cell responses.