PT  - JOURNAL ARTICLE
AU  - Kamalakannan Vijayan
AU  - Ramyavardhanee Chandrasekaran
AU  - Olesya Trakhimets
AU  - Samantha L. Brown
AU  - Nicholas Dambrauskas
AU  - Meghan Zuck
AU  - Ganesh Ram R. Visweswaran
AU  - Alexander Watson
AU  - Andrew Raappana
AU  - Sara Carbonetti
AU  - Laurel Kelnhofer-Millevolte
AU  - Elizabeth K.K. Glennon
AU  - Rachel Postiglione
AU  - D. Noah Sather
AU  - Alexis Kaushansky
TI  - Antibody interference by a non-neutralizing antibody abrogates humoral protection against <em>Plasmodium</em> liver stage
AID  - 10.1101/2020.09.15.298471
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.15.298471
4099  - http://biorxiv.org/content/early/2020/09/15/2020.09.15.298471.short
4100  - http://biorxiv.org/content/early/2020/09/15/2020.09.15.298471.full
AB  - Both subunit and attenuated whole sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naïve 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 2F6’s 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.Competing Interest StatementThe authors have declared no competing interest.