Improved VSV-Ebola-GP booster vaccination approach promotes antibody affinity maturation and durable anti-Ebola immunity in humans

Short-term boosting of the currently licensed rVSV∆G-ZEBOV-GP vaccine does not generate lasting antibody respones to Ebola virus (EBOV), prompting interest in strategies that elicit more durable immunity. Here, we elucidated the longitudinal humoral immune repertoire over 3 years following prime and boost rVSV∆G-ZEBOV-GP vaccinations administered 18 months apart in healthy adults compared to participants randomized to no boost. This delayed booster vaccination induced long-lasting EBOV-neutralizing antibodies that persisted up to 36 month at levels similar to peak titers after a single dose. Phage display libraries, expressing linear and conformational epitopes of EBOV glycoprotein (GP), demonstrated a highly diverse and durable antibody epitope repertoire following prime boost vaccination. Delayed booster vaccination recalled memory B cells, promoted anti-GP IgG class switching and induced antibodies specific to GP with Fcγ receptor interaction and functional antibody-dependent cellular cytotoxicity and phagocytosis. The 18-month interval led to 13-fold higher antibody affinity maturation than a single dose, maintained up to 36 months. Overall, delayed rVSV∆G-ZEBOV-GP booster vaccination promoted a diverse, stronger, durable, predominant IgG, highly affinity-matured antibody response to GP.