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.

A chemokine-fusion vaccine targeting immature dendritic cells elicits elevated antibody responses to malaria sporozoites in infant macaques

“…These human antibody isotypes are important in mediating antibody-dependent cellular cytotoxicity and complement dependent killing, as are the mouse IgG2b and 2c isotypes elicited by AddaVax, but not alum, in the current study. Of note, Kurtovic et al 45 , 46 found that complement fixing capability of sera from immunized infant and child recipients of the RTS,S vaccine declined rapidly after immunization and this decline paralleled the decline both in IgG complement fixing isotypes and protection against severe disease. While this finding suggests further justification for the use of the AddaVax adjuvant in subsequent vaccine trials, Potocnjak et al .…”

Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine

“…Nanoparticle-induced complement activation is generally perceived as undesirable when nanoparticles administered systemically lead to complement-mediated infusion reactions (27,90). While uncontrolled complement activation can induce inflammatory and life-threatening consequences, controlled complement activation by nanoparticles may be beneficial for vaccination strategies (91)(92)(93). Opsonization of pathogens by complement proteins facilitates their uptake by antigen presenting cells via complement receptors CD21 and CD33 (94).…”

A Chemokine-Fusion Vaccine Targeting Immature Dendritic Cells Elicits Elevated Antibody Responses to Malaria Sporozoites in Infant Macaques

“…Of note, Kurtovic et al . 45,46 found that complement fixing capability of sera from immunized infant and child recipients of the RTS,S vaccine declined rapidly after immunization and this decline paralleled the decline both in IgG complement fixing isotypes and protection against severe disease. While this finding suggests further justification for the use of the AddaVax adjuvant in subsequent vaccine trials, Potocnjak et al .…”