Avid binding by B cells to thePlasmodiumcircumsporozoite protein repeat suppresses responses to protective subdominant epitopes

Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSP Repeat ) can confer protection against malaria. However, it has also been suggested that this repeat domain exists as a decoy that distracts the immune system from mounting protective responses targeting other domains of CSP. Here we show that B cell responses to the repeat domain are indeed ∼10 fold higher than responses to the N- and C-terminal regions of CSP after sporozoite immunization. We investigated the role of the number of CSP Repeat -specific naïve precursor B cells and high avidity binding by B cells in driving the immunodominance of the CSP Repeat . Using adoptive transfer of germline precursors specific for the CSP Repeat , we found that increasing precursor number did indeed increase the responses to the repeat region, but not to the detriment of responses to other epitopes. To investigate the role of avid binding by B cells to the CSP Repeat in driving immunodominance we generated CSP9: a truncated CSP molecule with just 9 NANP repeats. Compared to near full length CSP molecules, CSP9 induced lower BCR signalling in CSP Repeat -specific cells and induced stronger responses to non-repeat epitopes. Finally, we found mice immunized with CSP9 molecules were strongly protected against mosquito bite challenge. Collectively these data demonstrate that the CSP Repeat does function as an immunodominant decoy and that truncated CSP molecules may be a promising avenue for future malaria vaccines. Significance Statement Malaria kills approximately 420,000 individuals each year(1). Our best vaccine, RTS,S/AS01 is based on the circumsporozoite protein that coasts the surface of the parasite. However, this vaccine is only partially protective. Here we show that responses to a repeat region in the circumsporozoite dominate the immune response. However, immunizing with a circumsporozoite protein with a shortened repeat region induces a more diverse immune response, which could be an avenue to make better malaria vaccines.