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Douglas, Alexander D; Baldeviano, G Christian; Jin, Jing; Miura, Kazutoyo; Diouf, Ababacar; Zenonos, Zenon A; Ventocilla, Julio A; Silk, Sarah E; Marshall, Jennifer M; Alanine, Daniel G W; Wang, Chuan; Edwards, Nick J; Leiva, Karina P; Gomez-Puerta, Luis A; Lucas, Carmen M; Wright, Gavin J; Long, Carole A; Royal, Joseph M; Draper, Simon J
Nature communications, 04/2019, Volume: 10, Issue: 1Journal Article
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.
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