A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates

Nat Commun. 2019 Apr 26;10(1):1953. doi: 10.1038/s41467-019-09894-4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / therapeutic use
  • Antibodies, Protozoan / immunology
  • Humans
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism
  • Malaria Vaccines / therapeutic use
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / metabolism
  • Malaria, Falciparum / prevention & control*
  • Plasmodium falciparum / immunology
  • Plasmodium falciparum / pathogenicity
  • Primates

Substances

  • Antibodies, Neutralizing
  • Antibodies, Protozoan
  • Immunoglobulin G
  • Malaria Vaccines