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

Abstract

Both subunit and attenuated whole sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naive westerners but exhibited less efficacy in malaria-exposed individuals in endemic areas. It has been hypothesized that preexisting immunity to malaria represents a significant roadblock to the development of a protective vaccine. Here, we demonstrate proof-of-concept that non-neutralizing antibodies (nNAb) can directly interfere with protective anti-PyCSP humoral responses. We developed and characterized a novel monoclonal antibody, RAM1, against the P. yoelii sporozoite major surface antigen, circumsporozoite protein (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. Though 2F6 and RAM1 bind non-overlapping regions of the CSP-repeat domain, pretreatment with RAM1 abrogated 2F6s capacity to block sporozoite traversal and invasion in vitro. Importantly, RAM1 reduced the efficacy of the polyclonal humoral response against CSP in vivo, paralleling the observed reduced efficacy of RTS,S in malaria-exposed populations. Taken together, our data demonstrate the interference of non-neutralizing antibodies with the efficacy of NAbs and may impact the efficacy of anti-CSP vaccines in malaria-exposed individuals.