Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

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 Fcγ-receptors (FcRγs) 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 FcγRIIa and FcγRIII 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 FcγR 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.

Immunogenicity, Efficacy, and Safety of a Novel Synthetic Microparticle Pre-Erythrocytic Malaria Vaccine in Multiple Host Species

“…Pre-erythrocytic vaccines aim to prevent the development of the blood-stage parasites responsible for clinical disease by targeting both the extracellular sporozoite and the intracellular hepatic stages, both of which express circumsporozoite (CS) protein, which contains several epitopes (T1, B, and T*) that show promise as vaccine components [ 26 , 27 , 28 ]. Several pre-erythrocytic vaccine candidates are currently in various stages of preclinical and clinical development, including whole attenuated sporozoites [ 29 , 30 , 31 ] and subunit-based virus-like particles (VLP) [ 9 , 11 , 32 , 33 , 34 , 35 ]. The most advanced malaria subunit vaccine is RTS,S or Mosquirix™, which presents CS epitopes on hepatitis B surface antigen (HBsAg) virus-like particles and has been approved for use by European regulators [ 36 , 37 ].…”

“…These studies demonstrate the feasibility of CS subunit vaccines in eliciting protection in the target population, infants, and children <5 years of age, who suffer the majority of deaths due to P. falciparum infection. However, RTS,S-induced immune responses were suboptimal as sterile immunity was not obtained and recent follow-up studies indicate that protection wanes rapidly over time in areas of high transmission [ 10 , 11 , 32 , 38 ]. R21/Matrix-M, a second CS VLP based on HBsAg, has been shown to be more potent and perhaps more efficacious than RTS,S [ 34 , 35 ] and has recently been endorsed by the World Health Organization.…”

Fc-dependent functional activity of ChAdOx1-S and CoronaVac vaccine-induced antibodies to the SARS-CoV-2 spike protein

“…FcγR-binding assays were conducted to quantify antibody binding to FcγRI, FcγRIIa, and FcγRIII as previously described (38)(39)(40). Briefly, 384-well Spectra plates were coated with Ancestral, Delta, or Omicron S trimer at 0.5 µg/ml in PBS and incubated overnight at 4°C.…”

Antibody-Dependent Respiratory Burst against Plasmodium falciparum Merozoites in Individuals Living in an Area with Declining Malaria Transmission

“…In children, malaria antibodies and antibody-mediated functional activity generally decrease with the reduction in malaria transmission [ 19 , 20 , 21 ]. Even in the context of RTS, S vaccination, antibody magnitude, and antibody-mediated functional activity significantly reduce post-vaccination in children [ 22 , 23 ]. There is limited knowledge of the influence of changing malaria transmission on antibody magnitude in adults.…”