Humoral epitope dominance and immune imprinting by <scp>SARS</scp> ‐ <scp>CoV</scp> ‐1 and <scp>SARS</scp> ‐ <scp>CoV</scp> ‐2 vaccines

Long-lasting protective immunity against sarbecoviruses is hampered by the dominance of elicited antibodies to variable parts of the Spike protein, allowing ongoing viral escape and evolution. We investigated Modified Vaccinia Ankara (MVA) vaccine candidates expressing the SARS-CoV-1 or SARS-CoV-2 Spike for their ability to induce antibodies targeting different epitopes on the SARS-CoV-2 Receptor Binding Domain (RBD), including those with wide variant conservation. We also explored the capacity of these different Spike proteins to induce broad cross-reactive or cross-neutralizing B cells against multiple variants. This revealed that the SARS-CoV-1 Spike induced distinct patterns of epitope dominance compared to the traditional SARS-CoV-2 Spike antigens. Following immune imprinting by previous exposure to ancestral SARS-CoV-2 Spike, the epitope dominance patterns induced by SARS-CoV-1 and SARS-CoV-2 vaccines still differed, with most of the germinal center response consisting of de novo recruited B cells. In addition to the de novo response, B cells with germline cross-reactivity to both antigens further increased their binding toward the most recently immunized antigen. Interestingly, we found that, while SARS-CoV-2 vaccinated animals were extremely capable of mounting an antigen-specific germinal center and plasmablast response to a booster immunization with SARS-CoV-1, SARS-CoV-2 boosters were less capable of inducing SARS-CoV-2 specific B cells following prior SARS-CoV-1 vaccination. These findings have broad implications for the implementation of vaccine strategies against emerging coronavirus variants and potential future coronavirus spillover events. The implications stemming from a fundamental directionality of immune imprinting and epitope dominance may have wider implications for noncoronavirus antigens.