Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies

Abstract

Summary The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria.

Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models

“…Moreover, one anti-PfRH5 mAb without neutralising activity potentiated the activities of other inhibitory antibodies indirectly, by slowing down the invasion time of merozoites and thereby increasing the time window for inhibitory antibodies to act. 23 The PfCyRPA vaccine-induced parasite-binding IgG antibodies, confirming that virosomes presented the lipidated recombinant PfCyRPA protein in its native conformation to the immune system. After having established that vaccine-induced antibodies bound to the endogenous PfCyRPA protein expressed in the invasive stage of the parasite blood-stage cycle, we conducted in vitro GIAs with blood-stage parasites cultured in human red blood cells.…”

Protective Immunity in Mice Immunized With P. vivax MSP119-Based Formulations and Challenged With P. berghei Expressing PvMSP119

“…The presence of the antigen during infection likely induces B cell affinity maturation in the germinal centers, and after 10 days of challenge, the secretion of antibodies with higher affinity starts to mediate parasite control. The gain in inhibitory activity may also be related to the recent observation that non-inhibitory monoclonal antibodies (mAbs) to the P. falciparum Reticulocyte binding protein homolog 5 (PfRh5) reduces the speed of merozoite invasion, increasing the time merozoites are target to invasion blocking antibodies and consequently increasing the invasion inhibition activity of inhibitory mAbs to PfRh5 (39). It is possible that, likewise, the presence of high titers of specific anti-PvMSP1 19 in vaccinated mice facilitate the invasion blocking activity of antibodies to other parasite antigens that are raised in the course of infection.…”

A high affinity human monoclonal antibody against Pfs230 binds multiple parasite stages and blocks oocyst formation in mosquitoes

“…Malaria eradication is a global priority and will require innovative strategies that, in addition to preventing or controlling human infection, might block parasite transmission through mosquitoes. Sequences of matched heavy and light chain variable regions from single human B cells have been used to identify antibodies generated in response to infection or vaccination and inform vaccinology [4][5][6][7] . In this study, we apply this approach to examine human antibodies elicited in response to a transmission blocking vaccine (TBV), that used a Pfs230 fragment as antigen.…”