AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities, or the maturation of memory B cell clones that produce broadly cross-reactive antibodies, is unknown. In this study, we longitudinally analyzed immune responses in healthy adults following two dose vaccination with either a virus-like particle COVID-19 vaccine alone (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or an mRNA vaccination (mRNA-1273). Immunization with CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies, antigen specific CD4+ T cell and memory B cell responses relative to immunization with CoVLP. The frequency of antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with the frequency of antigen-specific memory B cells at 6 months, while this was not observed within the mRNA-1273 group. Memory B cell responses induced by CoVLP+AS03 evolved over 6 months, evidenced by accumulation of somatic hypermutations in immunoglobulin V-genes and enhanced neutralization breadth of monoclonal antibodies against SARS-CoV-2 Omicron variants and SARS-CoV. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months, and clonal tracing of memory B cells revealed an increase in neutralization breadth. These results show that AS03 can enhance the antigenic breadth of B cell memory at a clonal level and induce progressive maturation of the B cell response.