Avid binding by B cells to the Plasmodium circumsporozoite protein repeat suppresses responses to protective subdominant epitopes

Summary Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSPRepeat) can protect against malaria. However, it has also been suggested that the CSPRepeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSPRepeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSPRepeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSPRepeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination.
Graphical abstract
Highlights • The repeat domain is immunodominant within the circumsporozoite protein • High avidity responses by repeat-specific B cells inhibit subdominant responses • The number of naive B cell precursors does not predict immunodominance hierarchies • Vaccination with repeat-truncated circumsporozoite proteins induces robust protection
Chatterjee et al. show that avid B cell responses to repeating epitopes can suppress B cell responses to other regions of the same protein, driving immunodominance hierarchies. In the context of malaria vaccination, circumsporozoite-based immunogens carrying truncated repeat regions stimulated more diverse antibody responses and induced robust protection.