Abstract

BACKGROUND: RTS,S is the leading malaria vaccine candidate, but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, however, it is unclear how these protective antibodies function. METHODS: We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N=45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcgamma-receptors (FcgammaRs) that are expressed on immune cells, which promote various immunological functions. RESULTS: Our major findings were i) RTS,S-induced antibodies mediate Fc-dependent effector functions, ii) functional antibodies were generally highest after the second vaccine dose; iii) functional antibodies targeted multiple regions of CSP, iv) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (p<0.05); v) non-protected subjects had higher levels of anti-CSP IgM. CONCLUSIONS: Our data suggests a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.

Link to publisher’s web site

This work was funded by the National Health and Medical Research Council (NHMRC) of Australia (Program Grant and Project Grant to JGB; Project Grant to PMH and BDW; Senior Research Fellowship to JGB; Career Development Fellowship to FJIF), National Institutes of Health, the Military Infectious Disease Research Program (MIDRP, TA and EBL), Australian Government Research Training Program Scholarship to LK, Monash Postgraduate Publication Award to LK, and the Australian Society for Parasitology Network Researcher Exchange, Training and Travel award to LK. The Burnet Institute is supported by a Victorian State Government Operational Infrastructure Support grant, and the NHMRC Independent Research Institutes Infrastructure Support Scheme. JGB, FJIF, LK, MJB, JAC, and GF are supported by the Centre for Research Excellence in Malaria Elimination, which is funded by the NHMRC, Australia.