Abstract

BACKGROUND: RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. METHODS: We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcgamma-receptors (FcRgammas) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). RESULTS: RTS,S vaccination induced CSP-specific IgG with FcgammaRIIa and FcgammaRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcgammaR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. CONCLUSIONS: Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.

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