Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial

Abstract

Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.

Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.

Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5-54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1-61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.

Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.

Funding: PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.

Figure 1

Consort diagram (total vaccinated cohort) “Other” includes children missing vaccinations because of hospital admission, with contraindications to further vaccination, medical conditions not permitted by the protocol, and with no concomitant vaccination documentation. ITT=intention to treat.

Figure 2

Kaplan-Meier curves showing the cumulative proportion of clinical falciparum malaria, by follow-up period (per-protocol cohort) Clinical falciparum malaria defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Kilifi and Korogwe cohorts over 12 months of follow-up; p=0·0005 (A). Kilifi cohort only over 15 months of follow-up; p=0·0018 (B).

Figure 3

Anti-circumsporozoite antibody titres in individuals who received RTS,S/AS01E (per-protocol cohort)

Figure 4

Kaplan-Meier curves showing the cumulative proportion of clinical falciparum malaria, by anti-circumsporozoite antibody tertiles Clinical falciparum malaria defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Individuals who received RTS,S/AS01E, by tertile of anti-circumsporozoite antibody titres measured 1 month after dose three (A). Individuals who received RTS,S/AS01E, by tertile of anti-circumsporozoite antibody titres measured 6·5–10 months after dose one (B). GMT=geometric mean titre.

Figure 5

Anti-circumsporozoite antibody titres and efficacy The modelled relation between anti-circumsporozoite antibody titres and efficacy is shown for a cumulative normal distribution, fit by maximising the log likelihood estimate. 5th and 95th percentiles calculated by bootstrap.