Elsevier

The Lancet

Volume 386, Issue 9988, 4–10 July 2015, Pages 31-45
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(15)60721-8Get rights and content

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.

Introduction

Substantial progress has been made in malaria control during the past decade, but the burden of malaria in Africa remains high.1 A malaria vaccine could be an important complement to existing control measures and could help reduce morbidity and mortality in children.

RTS,S/AS01 is a recombinant protein candidate malaria vaccine that targets the circumsporozoite protein of Plasmodium falciparum, expressed by the malaria parasite at the pre-erythrocytic stage, in which part of the circumsporozoite sequence is coexpressed with fused and free hepatitis B surface antigen2, 3 and formulated with the AS01 adjuvant. Previous studies have established the ability of RTS,S/AS01 to provide protective immunity.4, 5, 6

We undertook a phase 3, double-blind (observer-blind), individually randomised, controlled trial to assess the efficacy and safety of RTS,S/AS01. Study results up to 18 months of follow-up have been reported previously.7, 8, 9 The coprimary endpoints of efficacy to clinical malaria over the first 12 months after dose 3 were 55·8% (97·5% CI 50·6–60·4) in children aged 5–17 months and 31·3% (23·6–38·3) in infants aged 6–12 weeks.7, 8, 9 Protection against clinical and severe malaria was noted in both children and young infants during the first 12 months after vaccination, but protection waned over time in both age categories.9 Herein, we report the efficacy, immunogenicity, and safety of RTS,S/AS01 and the number of cases averted by the use of the vaccine in children and young infants followed up to the end of the trial, including findings in those who received a booster dose of vaccine.

Research in context

Evidence before this study

We did a systematic literature search between Dec 18, 2014, and Feb 20, 2015, of randomised controlled trials of RTS,S malaria vaccine on PubMed, the Cochrane Library, and other relevant data sources for the period 1984 to Jan 31, 2015. We searched PubMed using the Medical Subject Headings (MeSH) terms “RTS,S-AS01B vaccine”[All Fields] OR “RTS,S-AS01E vaccine”[All Fields] OR “RTS,S-AS02A vaccine”[All Fields] OR “RTS,S-AS02D vaccine”[All Fields] OR “RTS,S/AS01”[All Fields] OR “RTS,S/AS02”[All Fields] AND “clinical trial”[Publication Type] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields] AND “humans”[MeSH Terms]. For the Cochrane Library and other data sources, we used the following key search terms: “RTS,S”, “malaria vaccines”, AND “clinical trials”. The 60 manuscripts identified included five that reported the results of randomised controlled trials with long-term safety or efficacy follow-up or booster dose, two pooled analyses, and two systematic reviews.

Added value of this study

This study provided additional information on the safety and long-term efficacy of RTS,S/AS01 in a large population of children across different malaria transmission settings. Additionally, the study showed how booster vaccination extended the period of protection provided by the vaccine.

Implications of all available evidence

The RTS,S malaria vaccine candidate has consistently shown protection against clinical malaria episodes in different age groups across different transmission settings. Vaccine efficacy has been shown with or without concurrent Expanded Program on Immunization vaccination. The vaccine has consistently shown a good safety profile, although a meningitis safety signal reported among older children will need further follow-up. The results of the present study show the potential public health benefit of the RTS,S vaccine as an additional means for malaria control whilst the next generation of malaria vaccines are being developed.

Section snippets

Study design and participants

We undertook this phase 3, double-blind, observer-blind, individually randomised controlled trial between March 27, 2009, and Jan 31, 2014, at 11 centres in seven countries in sub-Saharan Africa that are situated in areas with different intensities of malaria transmission (appendix p 18). Trial methods have been reported previously,7, 8, 9, 10 and are described in the appendix (pp 4–13). We initially designed this trial to assess vaccine efficacy (VE), safety, and immunogenicity during 32

Results

8922 children and 6537 young infants were enrolled and included in the modified ITT analyses; of these, 6918 (78%) children and 5997 (92%) young infants were included in the per-protocol analyses (Figure 1, Figure 2). The median follow-up after dose 1 in the 6–12 weeks age group was 37·8 months (IQR 34·3–41·0) in R3R, 37·7 months (34·1–41·1) in R3C, and 37·8 months (34·1–41·1) in C3C (median overall 37·7 months, (IQR 34·1–41·1; modified ITT). The median follow-up after dose 1 in the 5–17 months

Discussion

The decrease in efficacy of RTS,S/AS01 against clinical and severe malaria over time since vaccination, which was reported previously,9 continued during the extended follow-up period in both children and infants who did not receive a booster dose of vaccine. Nevertheless, VE against clinical malaria during the full follow-up period in the absence of a booster dose were about 28% in children and 18% in young infants, which resulted in a substantial reduction in the number of cases of clinical

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