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

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30 Scopus citations

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
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09894-4
State	Published - 1 Dec 2019

Bibliographical note

Funding Information:
We are grateful for assistance with Ebola reagents from Sean Elias, Catherine Cherry, and Geneviève Labbé; for permission to use the hIgG1Δnab Fc region, advice and access to unpublished data from Mike Clark and Kathryn Armour; and for assistance with contracts from Fay Nugent and Carly Banner. The study was supported in part by the University Challenge Seed Fund (Oxford University Innovation); A.D.D. is supported by the Wellcome Trust [grant 201477/Z/16/Z] and is a Jenner Investigator; the GIA work was supported by the United States Agency for International Development (USAID) and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; DGWA held a UK Medical Research Council (MRC) iCASE PhD Studentship [MR/K017632/1]; and S.J.D. is a Jenner Investigator; a Lister Institute Research Prize Fellow and a Wellcome Trust Senior Fellow [106917/Z/15/Z]. Z.A.Z. and G.J.W. were supported by the Wellcome Trust grant 206194. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

Publisher Copyright:
© 2019, The Author(s).

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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), [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.",

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

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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 - Diouf, Ababacar

AU - Zenonos, Zenon A.

AU - Ventocilla, Julio A.

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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.

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AU - Long, Carole A.

AU - Royal, Joseph M.

AU - Draper, Simon J.

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

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