Dysfunctional memory B cell responses to the protective repeat region of the Plasmodium 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 Plasmodium 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.