TY - JOUR
T1 - A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
AU - Douglas, Alexander D.
AU - Baldeviano, G. Christian
AU - Jin, Jing
AU - Miura, Kazutoyo
AU - Diouf, Ababacar
AU - Zenonos, Zenon A.
AU - Ventocilla, Julio A.
AU - Silk, Sarah E.
AU - Marshall, Jennifer M.
AU - Alanine, Daniel G.W.
AU - Wang, Chuan
AU - Edwards, Nick J.
AU - Leiva, Karina P.
AU - Gomez-Puerta, Luis A.
AU - Lucas, Carmen M.
AU - Wright, Gavin J.
AU - Long, Carole A.
AU - Royal, Joseph M.
AU - Draper, Simon J.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064950649&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-09894-4
DO - 10.1038/s41467-019-09894-4
M3 - Artículo
C2 - 31028254
AN - SCOPUS:85064950649
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1953
ER -