Antibody interference by a non-neutralizing antibody abrogates humoral protection against Plasmodium yoelii liver stage

Both subunit and attenuated whole-sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naive westerners but less efficacy in malaria-exposed individuals in endemic areas. Here, we demonstrate proof of concept by using a rodent malaria model in which non-neutralizing antibodies (nNAbs) can directly interfere with protective anti-circumsporozoite protein (CSP) humoral responses. We characterize a monoclonal antibody, RAM1, against Plasmodium yoelii sporozoite major surface antigen CSP. Unlike the canonical PyCSP repeat domain binding and neutralizing antibody (NAb) 2F6, RAM1 does not inhibit sporozoite traversal or entry of hepatocytes in vitro or infection in vivo. Although 2F6 and RAM1 bind non-overlapping regions of the CSP-repeat domain, pre-treatment with RAM1 abrogates the capacity of NAb to block sporozoite traversal and invasion in vitro. Importantly, RAM1 reduces the efficacy of the polyclonal humoral response against PyCSP in vivo. Collectively, our data provide a proof of concept that nNAbs can alter the efficacy of malaria vaccination.