Dysfunctional memory B cell responses to the protective repeat region of the <i>Plasmodium</i> circumsporozoite protein are associated with waning humoral immunity

Malaria vaccines provide waning protection from disease that is correlated with the production of antibodies to the repeat region of the liver-stage circumsporozoite protein (CSP). CSP-based vaccines display limited durability in malaria-naïve individuals yet are even less effective in malaria-experienced individuals, suggesting the generation of non-optimal humoral immunity in response to both infection and vaccination. To address this hypothesis, we performed a cross-species, comprehensive analysis of B cell responses to CSP after <i>Plasmodium</i> infection or immunization, focusing our analysis on the repeat and C-terminus domains included in malaria subunit vaccines. Herein we demonstrate that while multiple factors may impinge on strong, lasting protective CSP-specific immunity, two forces predominantly impact proper memory B cell differentiation; a) inhibition of germinal center formation by infection and b) skewed B cell differentiation due to the repetitive nature of the protective region of the CSP protein.