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      Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial

      research-article
      RTS,S Clinical Trials Partnership
      Lancet (London, England)
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          Summary

          Background

          The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.

          Methods

          From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619.

          Findings

          8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39–50) and young infants for 38 months (34–41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8–40·5) and 7396 occurred in the R3C group (28·3%, 23·3–32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, –23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9–31·5) and 5444 occurred in the R3C group (18·3%, 11·7–24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI –9·4 to 37·5) and 104 in the R3C group (10·3%, –17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387–2186) in the R3R group and 1363 per 1000 children (995–1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children.

          Interpretation

          RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.

          Funding

          GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.

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          Author and article information

          Journal
          2985213R
          5470
          Lancet
          Lancet
          Lancet (London, England)
          0140-6736
          1474-547X
          26 September 2017
          23 April 2015
          04 July 2015
          03 October 2017
          : 386
          : 9988
          : 31-45
          Author notes
          Correspondence to: Prof Brian M Greenwood, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK, brian.greenwood@ 123456lshtm.ac.uk
          Article
          PMC5626001 PMC5626001 5626001 ems74290
          10.1016/S0140-6736(15)60721-8
          5626001
          25913272
          32d839cc-0361-409d-a503-12bc4e4f3588
          History
          Categories
          Article

          Comments

          Malaria vaccine development collection topic 3) Vaccines in development:

          See https://www.scienceopen.com/collection/malariavaccine

           

          This report shows the final results of an efficacy and safety trial of the RTS,S/AS01 candidate malaria vaccine. The study followed the vaccinees for 18 months and also includes the results of the efficacy of a booster dose.

          2018-10-08 21:39 UTC
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