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

Abstract

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.

Figure 1. Trial profile for participants aged 5–17 months

Participants’ flow in the study in those enrolled in the 5–17 months age category. ITT=intention to treat. *For 70 children, the screening data had not been reported before the database freeze of the previous analyses and these participants were not included in the CONSORT charts published previously. †During monitoring, one participant was found to have been enrolled twice at two different clinics under two different participant numbers. This participant was excluded from the per-protocol analyses. Because of the removal of one participant number from the database, the total number of participants enrolled into the study changed from 15 460 (8923 in the 5–17 months age group), as reported in previous analyses, to 15 459 participants (8922 in the 5–17 months age group) in the final analyses reported here. ‡2867 children in the with booster group, 2887 in the without booster group, and 2905 in the control group received doses 1 and 2.

Figure 2. Trial profile for participants aged 6–12 weeks

Participants’ flow in the study in those enrolled in the 6–12 weeks age category. ITT=intention to treat. *For 118 infants, the screening data had not been reported before the database freeze of the previous analyses and these participants were not included in the CONSORT charts published previously. †2115 children in the with booster group, 2119 in the without booster group, and 2134 in the control group received doses 1 and 2. ‡For some participants, consent to the extension occurred before visit 34. One participant consented to the extension but died before visit 34. This participant is considered as enrolled into the extension and the reason for not undertaking visit 38 is recorded as died.

Figure 3. Vaccine efficacy against clinical and severe malaria by study site in the 5–17 months age category

VE against all episodes of clinical malaria (primary case definition) in (A) the R3C group and (B) the R3R group from month 0 to study end; and VE against severe malaria (primary case definition) in (C) the R3C group and (D) the R3R group from month 0 to study end. Study sites are ordered from lowest (Kilifi) to highest (Siaya) incidence of clinical malaria (secondary case definition) measured in control infants 6–12 weeks of age at enrolment during 12 months of follow-up. p_interaction not calculated for (C) or (D). Analyses were by modified intention to treat. Bars are 95% CIs. The size of each square is proportional to the number of participants enrolled at each study site. The following numbers of children aged 5–17 months were enrolled by site for all three groups (R3R, R3C, and C3C) together: 600 in Kilifi, 912 in Korogwe, 1002 in Manhiça, 704 in Lambaréné, 903 in Bagamoyo, 800 in Lilongwe, 600 in Agogo, 1000 in Kombewa, 1002 in Kintampo, 600 in Nanoro, and 799 in Siaya. R3C=RTS,S/AS01 primary schedule without booster. C3C=control group. R3R=RTS,S/AS01 primary schedule with booster. VE=vaccine efficacy.

Figure 4. Cases of clinical and severe malaria averted at each site during 48 months of follow-up in the 5–17 months age category

Analyses were by modified intention to treat. Data are ordered by increasing malaria incidence at each study site. Cases averted of (A) clinical malaria (secondary case definition) and (B) severe malaria (secondary case definition) between month 0 and study end. The secondary case definition of severe malaria was used for this analysis because, during routine clinical practice, these children would normally receive a full course of antimalarial treatment. R3C=RTS,S/AS01 primary schedule without booster. R3R=RTS,S/AS01 primary schedule with booster.

Figure 5. Vaccine efficacy against clinical and severe malaria by study site in the 6–12 weeks age category

VE against all episodes of clinical malaria (primary case definition) in (A) the R3C group and (B) the R3R group from month 0 to study end; and VE against severe malaria (primary case definition) in (C) the R3C group and (D) the R3R group from month 0 to study end. Study sites are ordered from lowest (Kilifi) to highest (Siaya) modified incidence of clinical malaria (secondary case definition) measured in control infants 6–12 weeks of age at enrolment during 12 months of follow-up. Analyses were by modified intention to treat. Bars are 95% CIs. The size of each square is proportional to the number of participants enrolled at each study site. The following numbers of infants aged 6–12 weeks were enrolled by site for all three groups (R3R, R3C, and C3C) together: 304 in Kilifi, 593 in Korogwe, 635 in Manhiça, 226 in Lambaréné, 802 in Bagamoyo, 826 in Lilongwe, 688 in Agogo, 631 in Kombewa, 331 in Kintampo, 681 in Nanoro, and 820 in Siaya. C3C=control group. R3C=RTS,S/AS01 primary schedule without booster. R3R=RTS,S/AS01 primary schedule with booster. VE=vaccine efficacy.

Figure 6. Cases of clinical and severe malaria averted at each site during 38 months of follow-up in the 6–12 weeks age category

Analyses were by modified intention to treat. Data are ordered by increasing malaria incidence at each study site. Cases averted of (A) clinical malaria (secondary case definition) and (B) severe malaria (secondary case definition) between month 0 and study end. The secondary case definition of severe malaria was used for this analysis because, during routine clinical practice, these children would normally receive a full course of antimalarial treatment. R3C=RTS,S/AS01 primary schedule without booster. R3R=RTS,S/AS01 primary schedule with booster.