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

Alexander D Douglas; G Christian Baldeviano; Jing Jin; Kazutoyo Miura; Ababacar Diouf; Zenon A Zenonos; Julio A Ventocilla; Sarah E Silk; Jennifer M Marshall; Daniel G W Alanine; Chuan Wang; Nick J Edwards; Karina P Leiva; Luis A Gomez-Puerta; Carmen M Lucas; Gavin J Wright; Carole A Long; Joseph M Royal; Simon J Draper

doi:10.1038/s41467-019-09894-4

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

Alexander D Douglas, G Christian Baldeviano, Jing Jin, Kazutoyo Miura, Ababacar Diouf, Zenon A Zenonos, Julio A Ventocilla, Sarah E Silk, Jennifer M Marshall, Daniel G W Alanine, Chuan Wang, Nick J Edwards, Karina P Leiva, Luis A Gomez-Puerta, Carmen M Lucas, Gavin J Wright, Carole A Long, Joseph M Royal, Simon J Draper

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	1953
Number of pages	8
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09894-4
Publication status	Published - 26 Apr 2019

Keywords

parasites and microbes
staffpaper

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10.1038/s41467-019-09894-4

s41467-019-09894-4
© The Author(s) 2019
Final published version, 864 KBLicence: CC BY

Cite this

Douglas, A. D., Baldeviano, G. C., Jin, J., Miura, K., Diouf, A., Zenonos, Z. A., Ventocilla, J. A., Silk, S. E., Marshall, J. M., Alanine, D. G. W., Wang, C., Edwards, N. J., Leiva, K. P., Gomez-Puerta, L. A., Lucas, C. M., Wright, G. J., Long, C. A., Royal, J. M., & Draper, S. J. (2019). A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates. Nature Communications, 10(1), Article 1953. https://doi.org/10.1038/s41467-019-09894-4

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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.",

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Douglas, AD, Baldeviano, GC, Jin, J, Miura, K, Diouf, A, Zenonos, ZA, Ventocilla, JA, Silk, SE, Marshall, JM, Alanine, DGW, Wang, C, Edwards, NJ, Leiva, KP, Gomez-Puerta, LA, Lucas, CM, Wright, GJ, Long, CA, Royal, JM & Draper, SJ 2019, 'A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates.', Nature Communications, vol. 10, no. 1, 1953. https://doi.org/10.1038/s41467-019-09894-4

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AU - Douglas, Alexander D

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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

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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.

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