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Abstract
Understanding the targets and mechanisms of human immunity to malaria is important for advancing the development of highly efficacious vaccines and serological tools for malaria surveillance. The PfRH5 and PfRipr proteins form a complex on the surface of P. falciparum merozoites that is essential for invasion of erythrocytes and are vaccine candidates. We determined IgG subclass responses to these proteins among malaria-exposed individuals in Papua New Guinea and their association with protection from malaria in a longitudinal cohort of children. Cytophilic subclasses, IgG1 and IgG3, were predominant with limited IgG2 and IgG4, and IgG subclass-specific responses were higher in older children and those with active infection. High IgG3 to PfRH5 and PfRipr were significantly and strongly associated with reduced risk of malaria after adjusting for potential confounding factors, whereas associations for IgG1 responses were generally weaker and not statistically significant. Results further indicated that malaria exposure leads to the co-acquisition of IgG1 and IgG3 to PfRH5 and PfRipr, as well as to other PfRH invasion ligands, PfRH2 and PfRH4. These findings suggest that IgG3 responses to PfRH5 and PfRipr may play a significant role in mediating naturally-acquired immunity and support their potential as vaccine candidates and their use as antibody biomarkers of immunity.
Highlights
Stage antigens have been shown to be an important part of this protective immune response[3,4,8,10–15]
Individuals naturally exposed to P. falciparum in malaria endemic regions of Africa and Papua New Guinea have been shown to develop anti-PfRH5 antibodies[5,26,27], and antibodies to PfRH5 were associated with protection from symptomatic malaria in malaria-endemic regions of Papua New Guinea[5], and Mali[27]
In this study we found that cytophilic antibodies IgG1 and IgG3 were the predominant subclass responses to PfRH5 and PfRipr, which are present as an invasion complex on the merozoite surface
Summary
Stage antigens have been shown to be an important part of this protective immune response[3,4,8,10–15]. While all five members of this family play important roles in merozoite invasion, only PfRH5 appears essential to blood stage replication of P. falciparum in vitro[13,19–21]. The PfRH5 protein is located in the rhoptries, but is secreted onto the surface of merozoites prior to RBC invasion[13]. PfRH5 forms a complex on the merozoite surface with PfRipr (P. falciparum PfRH5 interacting protein)[22] and CyRPA (Cysteine-rich protective antigen)[23,24]. Affinity-purified antibodies to PfRH5 from naturally-exposed individuals were shown to inhibit P. falciparum growth in vitro[26,27]. These findings suggest that PfRH5 complex is an important target of immunity. The aims of the present study were to define the nature of IgG subclass responses to PfRH5 and PfRipr, and determine the associations between subclass-specific responses and the prospective risk of malaria. We aimed to assess the potential influence of host age and P. falciparum infection on acquisition of these antibodies and their relationship to the acquisition of antibodies to other PfRH invasion ligands
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