Multivalency drives the neutralizing activity of antibodies against the Plasmodium falciparum circumsporozoite protein

The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal calorimetry and X-ray crystallography to analyze the binding of the Plasmodium-neutralizing 2A10 antibody to CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies and that this multivalent interaction drives the affinity of this antibody. Because the CSP protein can cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T-independent. However, by sequencing the BCRs of CSP-repeat specific cells we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Interestingly, the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response.