Humoral Immune Responses to a Malaria Vaccine Candidate: Towards a Correlate of Vaccine-Induced Protection

Abstract

Introduction: Identifying immune correlates of protection is a priority for malaria vaccine research. A successful pediatric Phase 2 clinical trial in Mali of FMP2.1/AS02A, a recombinant apical membrane antigen 1 (AMA1)-based vaccine candidate, provided a source of serum samples from subjects who may have developed vaccine-induced, strain-specific protective immunity to clinical malaria illness. We studied IgG subclass and avidity patterns of antibodies to the malaria protein AMA1 in a subset of participants, with the objective of identifying immune responses that may be associated with protection against malaria. We hypothesized that the AMA1 vaccine candidate would induce production of cytophilic antibody subclasses IgG1 and IgG3, as well as overall IgG avidity maturation. Methods: Titers of IgG1, IgG2, IgG3, and IgG4, as well as avidity of antibodies to AMA1, were determined by ELISA for ten AMA1 vaccine recipients and ten control subjects who had been randomized to receive a rabies vaccine in this double-blind trial at days 0, 90, and 150 after the first of three vaccinations. To identify statistically significant differences between the groups, responses in vaccine recipients were evaluated longitudinally and compared with responses in control subjects. Results: IgG1, IgG2, IgG3, and IgG4 were induced more strongly in vaccine recipients than in control subjects. Additionally, vaccine recipients had higher ratios of cytophilic to non-cytophilic antibodies than control subjects. Avidity indices were not significantly different between the two groups at the three time points tested, and there were no significant differences in avidity between time points in either group. Conclusion: Contrary to our hypothesis, both cytophilic and non-cytophilic antibodies were induced by the FMP2.1/AS02A vaccine candidate and immunization did not appear to stimulate avidity maturation. Therefore, IgG1, IgG2, IgG3, and IgG4 titers are candidate variables for a humoral immune correlate of vaccine-induced protection. These results are among the first reports of the subclasses and avidity of antibodies produced in response to a malaria vaccine candidate with allele-specific protective efficacy.