Complement in malaria immunity and vaccines

Abstract

Developing efficacious vaccines for human malaria caused by Plasmodium falciparum is a major global health priority, although this has proven to be immensely challenging over the decades. One major hindrance is the incomplete understanding of specific immune responses that confer protection against disease and/or infection. While antibodies to play a crucial role in malaria immunity, the functional mechanisms of these antibodies remain unclear as most research has primarily focused on the direct inhibitory or neutralizing activity of antibodies. Recently, there is a growing body of evidence that antibodies can also mediate effector functions through activating the complement system against multiple developmental stages of the parasite life cycle. These antibody-complement interactions can have detrimental consequences to parasite function and viability, and have been significantly associated with protection against clinical malaria in naturally acquired immunity, and emerging findings suggest these mechanisms could contribute to vaccine-induced immunity. In order to develop highly efficacious vaccines, strategies are needed that prioritize the induction of antibodies with enhanced functional activity, including the ability to activate complement. Here we review the role of complement in acquired immunity to malaria, and provide insights into how this knowledge could be used to harness complement in malaria vaccine development.

Keywords: antibodies; complement; immunity; malaria; vaccines.

Figure 1

Plasmodium life cycle and opportunities for antibody‐complement attack. Plasmodium spp. has a complex life cycle within the human host, whereby several developmental stages of the parasite are known to be susceptible to antibody recognition, and subsequently complement fixation and activation. These include sporozoites, merozoites, parasitized red blood cells (pRBCs) and sexual‐stage parasites (gametocytes/gametes). Figure adapted from Beeson et al, 20192 (Copyright © 2019 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science)

Figure 2

Complement activation pathways. The complement system can be activated by three distinct pathways termed the classical, mannose‐binding lectin and alternative pathways. Complement activation via any pathway leads to formation of C3 convertase, which cleaves C3 into the active C3a and C3b fragments. Subsequently, the C5 convertase molecule is generated, which cleaves C5 into the activate C5a and C5b fragments. C5b, together with C6, C7, C8 and multiple C9 monomers create the membrane attack complex (MAC) that deposits in the target cell membrane and causes cell lysis. Several complement proteins mediate anti‐malarial immunity, including: (1) C1q enhances antibody‐mediated neutralization of sporozoites and merozoites, (2) C3b can mediate opsonic phagocytosis and is a potential anti‐malarial immune mechanism, (3) C5a is pro‐inflammatory, and (4) MAC formation can lyse sporozoites, merozoites and gametes

Figure 3

Naturally acquired human antibodies can fix and activate complement against P. falciparum sporozoites and merozoites, and are associated with protection. A, Sporozoites and merozoites were treated with immune antibodies from malaria‐exposed populations, and tested for sporozoite traversal of hepatocytes (HC‐04 cell line) or merozoite invasion of red blood cells in the presence of active (NHS) or inactive (HIS) human complement. Traversal/invasion inhibition by antibodies was greatly enhanced by active complement compared to inactive complement (mean and range is shown). Data were originally presented in Kurtovic et al, 2018 and Boyle et al, 2015.7, 38 B, Natural acquisition of C1q fixing antibodies to sporozoite and merozoite surface antigens (CSP and MSP2, respectively) among children and adults resident in Kenya, n = 64 (percentage positive is shown). Data were originally presented in Kurtovic et al, 2018.7 C, High levels of C1q fixing antibodies (compared to low levels of C1q fixing antibodies) to selected merozoite antigens are significantly associated with protection against clinical malaria in a longitudinal cohort study of Papua New Guinean children, n = 206 (adjusted hazard ratio is shown). Data were originally presented in Reiling et al, 201965

Figure 4

The RTS,S malaria vaccine induces complement fixing antibodies that rapidly wane over time. Children resident in Mozambique were vaccinated with RTS,S, and antibody responses were evaluated 30 d after the third and final vaccine dose (month 3) and at later time‐points, n = 30. Decay of (A) functional anti‐CSP antibodies that fix C1q, and the decay of (B) anti‐CSP antibodies of the IgG1 and IgG3 subclass (median and 95% CI of the median is shown). Data were originally presented in Kurtovic et al, 2019132