A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

Abstract

BackgroundThe RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria.MethodsUsing data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.ResultsVaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.ConclusionsVaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.

The public health impact of malaria vaccine RTS,S in malaria endemic Africa: country-specific predictions using 18 month follow-up Phase III data and simulation models

“…The analysis suggests that the efficacy in preventing infections decays exponentially with a half-life of decay of around 1 year (Table 2), which is much faster than was previously thought but is in line with published data of IgM serum concentrations [8]. The public health impact will depend on not just the half-life, but also the functional form of efficacy decay.…”

“…The effects of improvements in coverage for 6–9 month vaccination, small increases (C) or decreases in initial efficacy (D), are small, while increases in the half-life of the vaccine effect are substantial (E) especially if accompanied by an increase in initial efficacy (G). If initial efficacy is decreased, and half-life increased to give a profile similar to that estimated from Phase II data [8], the effect is a small improvement in each of the measures of public health impact, but the uncertainty bounds overlap with those for the reference scenarios. The impacts of other country-specific assumptions have been quantified in a simple sensitivity analysis on country levels of transmission exposure, access to effective treatment and reduced coverage of vaccination (Additional file 1: Table SM1 and Additional file 2: Figures S12-S13).…”

“…RTS,S has been shown to be efficacious and safe [1], but as antibody titres to CSP wane so does protection against successful infection of the liver [8], and observed efficacy against clinical disease decays relatively rapidly in the trial [1]. Repeated malaria infections induce natural, but not complete, immunity in the host to many stages of the parasite life cycle, predominantly to the blood stage causing clinical disease.…”

Application of Radiation Technology: A Novel Vaccine Approach to Induce Protective Immunity against Malaria Infection

“…This finding led to the cloning of P. falciparum CSP and the formulation of several CSP-based sub-unit vaccines designed to induce protective antibodies [121,122]. Although efficacy was low, subsequent development of CSP using a particle-based approach has led to the currently most advanced malaria sub-unit vaccine, RTS, S/AS01, that elicits 30% protection in young children [123] primarily mediated by anti-CSP antibodies and CD4 + T cells [124,125]. The partial efficacy of these first generation subunit vaccines suggests that a better understanding of RAS-induced protective mechanisms may provide a rationale to develop alternative or improved subunit strategies using newly discovered antigens or more potently inducing cell-mediated immunity.…”

Malaria Vaccine Development: Recent Advances alongside the Barriers

“…This vaccine candidate is a novel chimeric protein integrating the amino (N-) and carboxy (C-) repeat regions of CSP and a condensed repeat region of the immunologically different parasitic strains VK210 (type 1) and the VK247 (type 2) [31]. Antibodies induced to the P. falciparum CSP have been shown to provide protection against all strains [32,33]. In contrary, the repeat region of P. vivax CSP shows sequence heterogeneity indicating that a vaccine based on a single strain may not be fully protective against all strains of P. vivax [34], as a result two P. vivax strains were used in this candidate.…”