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Randomised controlled trial
The RTS,S/AS01 vaccine continues to show modest protection against malaria in African infants and children
  1. Philip J Rosenthal
  1. Department of Medicine, University of California, San Francisco, California, USA
  1. Correspondence to : Dr Philip J Rosenthal, Department of Medicine, University of California, San Francisco, CA 94143, USA; philip.rosenthal{at}ucsf.edu

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Context

Malaria remains one of the greatest infectious burdens in the world.1 The RTS,S vaccine results from decades of research showing that human responses to the Plasmodium falciparum circumsporozoite protein can protect against malaria.2 Vaccine developments benefitted from adjuvant optimisation, with AS01 chosen for recent trials. RTS,S has been extensively studied in African children recently, with vaccine efficacy approximately 25–50% against both symptomatic and severe malaria, but efficacy lower in infants than in children and waning over time after immunisation.3–5 This report provides final follow-up data for a large phase III trial conducted at 11 sites in sub-Saharan Africa. It offers new insights into the long-term efficacy of RTS,S and the value of a booster dose to extend efficacy.

Methods

In this phase III double-blind trial, 6537 infants (aged 6–12 weeks) and 8922 children (aged 5–17 months) were enrolled at 11 centres in seven countries, from 2009 to 2011. Participants were randomly assigned to three arms: three monthly doses of RTS,S; three monthly doses plus a booster dose at month 20; no RTS,S. Primary outcomes were symptomatic and severe malaria, identified through passive case detection. Initial results of the trial were reported earlier (3–5); this paper provides a final analysis after extended follow-up. Vaccine efficacy for prevention of symptomatic malaria was analysed by negative binomial regression and for prevention of severe malaria by relative risk reduction.

Findings

Infants were followed for a median of 38 months and children for a median of 48 months after the initial dose. Vaccine efficacy against symptomatic malaria in infants was 25.9% in those receiving RTS,S including a booster dose and 18.3% in those receiving RTS,S without the booster dose; efficacy in children was 36.3% in those receiving RTS,S including a booster dose and 28.3% in those receiving RTS,S without the booster dose. Efficacy against severe malaria in infants was 17.3% in those receiving RTS,S including a booster dose and 10.3% in those receiving RTS,S without the booster dose; efficacy in children was 32.2% in those receiving RTS,S including a booster dose and 1.1% in those receiving RTS,S without the booster dose.

Differences between vaccine and control arms were statistically significant, except against severe malaria in infants with either vaccine regimen or in children receiving the non-boosted vaccine. The number of cases of malaria averted was 983 and 558 in infants receiving boosted and non-boosted vaccine and 1774 and 1363 in children receiving boosted and non-boosted vaccine, respectively. Frequencies of serious adverse events were balanced between treatment arms, except that meningitis was more common in children who received RTS,S.

Commentary

Results from the final analysis of the phase III trial were consistent with those seen in earlier trials and earlier analysis of this trial. RTS,S has offered modest protection against both symptomatic and severe malaria, and efficacy has waned as follow-up has been extended. This analysis showed that a booster dose 20 months after the initial vaccine dose improved efficacy in infants as well as in children. These findings highlight the promise, as well as the challenges, of the RTS,S vaccine.

The promise lies in the potential to add to ongoing efforts to better control malaria in high transmission areas. However, challenges include: efficacy much lower than that of vaccines for other diseases; decreased efficacy in infants compared to that in children; a vaccine schedule that is not consistent with the current WHO Expanded Program on Immunisation schedule, especially if one or more boosters are utilised; uncertainty about which populations will receive the greatest benefit from the vaccine.

Additional vaccine development efforts are ongoing, but RTS,S is the only vaccine for which approval can be expected in the near future. Approval from the European Medicines Agency was received in July 2015, and WHO evaluation is anticipated. The partial efficacy of RTS,S highlights the critical importance of maintaining other malaria control measures even after the vaccine is implemented. These measures include control of mosquito vectors with insecticide impregnated bed nets and indoor residual spraying of insecticides, providing prompt therapy for malaria with artemisinin-based combination therapies and utilising antimalarial drugs for chemoprevention in high-risk groups.1

Implications for practice

The RTS,S vaccine should help to control malaria, especially in high transmission areas. However, the vaccine is not fully protective and if it becomes available it will be important for policymakers to maintain other effective malaria control measures regardless of the level of implementation of the vaccine.

References

View Abstract

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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