Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: further results from a phase IIb trial in Mozambican children

Abstract

Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.

Methodology/principal findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029) over the double-blind phase and of 9.0% (-30.6-36.6; p = 0.609) during the single-blind phase.

Conclusions/significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.

Trial registration: ClinicalTrials.gov NCT00197041.

Conflict of interest statement

Competing Interests: MVI supports the development and testing of a number of malaria vaccines, including some that can be regarded as competitors. AL, ML, WRB* and JC are currently employed by GSK Biologicals or *were employed at the time the study was conducted. AL, WRB and JC hold shares in GlaxoSmithKline. JC and WRB are inventors on patents relating to malaria vaccines. None of the other authors in this paper have declared a conflict of interest.

Figures

Figure 1. Kaplan-Meier survival curves for the cumulative proportion with at least one episode of clinical malaria during the double-blind and single-blind phases in cohort 2 respectively (ATP cohort).

Figure 2. Kaplan-Meier survival curves for the cumulative proportion with at least one episode of clinical malaria during the double-blind and single-blind phases in cohort 2 respectively (ATP cohort).

Figure 3. Study design.