Targets of complement-fixing antibodies in protective immunity against malaria in children

Reiling, Linda; Boyle, Michelle J.; White, Michael; Wilson, Danny W.; Feng, Gaoqian; Weaver, Rupert; Opi, D. Herbert; Persson, Kristina; Richards, Jack S.; Siba, Peter; Fowkes, Freya J. I.; Takashima, Eizo; Tsuboi, Takafumi; Müeller, Ivo; Beeson, James G.

doi:10.1038/s41467-019-08528-z

Cited by 86 publications

(125 citation statements)

References 57 publications

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“…6,46,47,[78][79][80] In a recent development, it has been shown that antibody-mediated complement fixation on merozoites via the classical pathway and the subsequent formation of the membrane attack complex is more strongly associated with immunity against malaria than is GIA activity. 81 The absence of an appreciable GIA or IIA activity as observed in our study is, therefore, not unexpected and does not afford a qualified assessment of the potential clinical efficacy of full-length MSP1 against malaria.…”

Section: Discussioncontrasting

confidence: 54%

Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

et al. 2020

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A vaccine remains a priority in the global fight against malaria. Here, we report on a single-center, randomized, double-blind, placebo and adjuvant-controlled, dose escalation phase 1a safety and immunogenicity clinical trial of full-length Plasmodium falciparum merozoite surface protein 1 (MSP1) in combination with GLA-SE adjuvant. Thirty-two healthy volunteers were vaccinated at least three times with MSP1 plus adjuvant, adjuvant alone, or placebo (24:4:4) to evaluate the safety and immunogenicity. MSP1 was safe, well tolerated and immunogenic, with all vaccinees sero-converting independent of the dose. The MSP1-specific IgG and IgM titers persisted above levels found in malaria semi-immune humans for at least 6 months after the last immunization. The antibodies were variant-and strain-transcending and stimulated respiratory activity in granulocytes. Furthermore, full-length MSP1 induced memory T-cells. Our findings encourage challenge studies as the next step to evaluate the efficacy of full-length MSP1 as a vaccine candidate against falciparum malaria (EudraCT

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Section: Discussioncontrasting

confidence: 54%

Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

et al. 2020

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“…An invasion-blocking experiment will be required to test this possibility. It is also possible that RBP2-P1 antibodies provide clinical protection through a different mechanism, such as complement fixation (29).…”

Section: Discussionmentioning

confidence: 99%

The Blood Stage Antigen RBP2-P1 of Plasmodium vivax Binds Reticulocytes and Is a Target of Naturally Acquired Immunity

et al. 2020

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The interactions between Plasmodium parasites and human erythrocytes are prime targets of blood stage malaria vaccine development. The reticulocyte binding protein 2-P1 (RBP2-P1) of Plasmodium vivax, a member of the reticulocyte binding protein family, has recently been shown to be highly antigenic in several settings endemic for malaria. Yet, its functional characteristics and the relevance of its antibody response in human malaria have not been examined. In this study, the potential function of RBP2-P1 as an invasion ligand of P. vivax was evaluated. The protein was found to be expressed in schizonts, be localized at the apical end of the merozoite, and preferentially bind reticulocytes over normocytes. Human antibodies to this protein also exhibit erythrocyte binding inhibition at physiologically relevant concentrations. Furthermore, RBP2-P1 antibodies are associated with lower parasitemia and tend to be higher in asymptomatic carriers than in patients. This study provides evidence supporting a role of RBP2-P1 as an invasion ligand and its consideration as a vaccine target.

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“…Natural host immunity is critically reliant upon the complement system to protect and eliminate infections from a number of microorganisms 71 and viruses; the classical complement initiation pathway has been demonstrated to contribute to antiviral activity and protection against West Nile virus, 72 Zika, 73 influenza, 74 vaccinia virus, 75 cytomegalovirus, 76 respiratory syncytial virus, 77 and human immunodeficiency virus 78,79 . In addition, classical complement has been implicated in host defense against the pathogenic bacteria Salmonella , 71 Gonorrhea , 80 as well as against parasites 81‐83 . However, genetic variation affecting antigen identity and character can dramatically influence the susceptibility of a virus or pathogen to classical complement neutralization or lysis, even in the instance of closely related viruses 84 .…”

Section: Role In Infectious Disease: From Elimination To Evasion To Ementioning

confidence: 99%

Antibody‐mediated complement activation in pathology and protection

Goldberg

Ackerman

2020

Immunol Cell Biol

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Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/ epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.

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Targets of complement-fixing antibodies in protective immunity against malaria in children

Cited by 86 publications

References 57 publications

Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

The Blood Stage Antigen RBP2-P1 of Plasmodium vivax Binds Reticulocytes and Is a Target of Naturally Acquired Immunity

Antibody‐mediated complement activation in pathology and protection

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