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Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria

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      Abstract

      BackgroundAn understanding of the mechanisms mediating protective immunity against malaria in humans is currently lacking, but critically important to advance the development of highly efficacious vaccines. Antibodies play a key role in acquired immunity, but the functional basis for their protective effect remains unclear. Furthermore, there is a strong need for immune correlates of protection against malaria to guide vaccine development.MethodsUsing a validated assay to measure opsonic phagocytosis of Plasmodium falciparum merozoites, we investigated the potential role of this functional activity in human immunity against clinical episodes of malaria in two independent cohorts (n = 109 and n = 287) experiencing differing levels of malaria transmission and evaluated its potential as a correlate of protection.ResultsAntibodies promoting opsonic phagocytosis of merozoites were cytophilic immunoglobulins (IgG1 and IgG3), induced monocyte activation and production of pro-inflammatory cytokines, and were directed against major merozoite surface proteins (MSPs). Consistent with protective immunity in humans, opsonizing antibodies were acquired with increasing age and malaria exposure, were boosted on re-infection, and levels were related to malaria transmission intensity. Opsonic phagocytosis was strongly associated with a reduced risk of clinical malaria in longitudinal studies in children with current or recent infections. In contrast, antibodies to the merozoite surface in standard immunoassays, or growth-inhibitory antibodies, were not significantly associated with protection. In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against malaria, highlighting its potential as a correlate of immunity. Furthermore, we demonstrate that human antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these antigen-specific responses and protection for the first time.ConclusionsOpsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. The opsonic phagocytosis assay appears to be a strong correlate of protection against malaria, a valuable biomarker of immunity, and provides a much-needed new tool for assessing responses to blood-stage malaria vaccines and measuring immunity in populations.

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            Author and article information

            Affiliations
            [1 ]KEMRI Centre for Geographic Medicine Research-Coast, Kilifi, Kenya
            [2 ]Centre for Biomedical Research, The Burnet Institute, 85 Commercial Road, 3004 Melbourne, Victoria, Australia
            [3 ]Australian Army Malaria Institute, Enoggera, Queensland, Australia
            [4 ]Department of Biochemistry, La Trobe University, Melbourne, Australia
            [5 ]Department of Microbiology, Monash University, Wellington Rd, Clayton, VIC 3800, Australia
            Contributors
            Journal
            BMC Med
            BMC Med
            BMC Medicine
            BioMed Central
            1741-7015
            2014
            1 July 2014
            : 12
            : 108
            24980799
            4098671
            1741-7015-12-108
            10.1186/1741-7015-12-108
            Copyright © 2014 Osier et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Research Article

            Medicine

            malaria, vaccines, immunity, phagocytosis, monocytes, merozoites, plasmodium falciparum

            Comments

            Malaria vaccine development collection topic 2) Plasmodium life-cycle and immunological responses.

            See: https://www.scienceopen.com/collection/malariavaccine

             

            Our understanding of the mechanisms mediating protective immunity against malaria is still incomplete. This is, however, critically important to advance the development of highly efficacious vaccines.

            This study by Osier and colleagues showing that opsonic phagocytosis of merozoites is an important mechanism contributing to protective immunity in humans represents a big step forward in our understanding of how antibodies mediate protection. In addition to contributing to the development of efficacious vaccines, this knowledge is also useful as a correlate of protective/effective immunity, which can be helpful to distinguish between immune and susceptible individuals.

            2018-10-03 18:27 UTC
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