The association between naturally acquired IgG subclass specific antibodies to the PfRH5 invasion complex and protection from Plasmodium falciparum malaria

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.

Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes

“…Our analysis confirms previous studies showing that naturally acquired antibodies to PfRh5 and PfRipr are significantly associated with protection from malaria in longitudinal cohort studies of children exposed to P. falciparum (Chiu et al, ; Richards et al, ; Tran et al, ; Weaver et al, ). In contrast, no association with protection was found with antibodies to CyRPA nor to the binary Rh5/CyRPA complex.…”

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…A similar result was observed in children from Papua New Guinea (64), suggesting qualitative aspects of the vaccine-induced response may differ to those induced by natural exposure. Overall, the relevance of antibody isotype, affinity, and avidity to in vivo protection in humans against the P. falciparum merozoite remain debated, although the study in Papua New Guinea associated the IgG3 response against RH5 with reduced risk of malaria (64).…”

IgG subclass responses to excreted-secreted antigens of Plasmodium falciparum in a low-transmission malaria area of the Peruvian Amazon

“…Cytophilic subclasses of IgG (IgG1 and IgG3) have been considered the most important antibodies in the development of immunity to malaria, as these subclasses are capable of mediating the activation of leukocytes via their binding to FcγRI and FcγRIII. Together, the predominance of these subclasses is associated with lower risks of malaria-related complications in malaria-endemic areas [ 12 – 18 ].…”