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Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites.

- PLoS Med. (2014)

Bottom Line: Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).VE waned over time in both age categories (Schoenfeld residuals p<0.001).Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.

View Article: PubMed Central - PubMed

ABSTRACT

Background: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.

Methods and findings: 6,537 infants aged 6-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from -1 to 49, respectively; corresponding ranges among infants were -10 to 1,402 and -13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.

Conclusions: RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.

Trial registration: www.ClinicalTrials.gov NCT00866619 Please see later in the article for the Editors' Summary.

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Related in: MedlinePlus

CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.aOne child enrolled in the 5–17-mo age category who was reported previously to have received three doses of study vaccine, and was included in the per-protocol analyses reported previously, had received only the first and second doses of study vaccine. bThe date of birth of three children who were included in the per-protocol analysis reported previously was corrected, and these children were identified as “out of age range” when they received the first dose of study vaccine. These three children were excluded from the per-protocol analyses reported here. CW, consent withdrawal.
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pmed-1001685-g002: CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.aOne child enrolled in the 5–17-mo age category who was reported previously to have received three doses of study vaccine, and was included in the per-protocol analyses reported previously, had received only the first and second doses of study vaccine. bThe date of birth of three children who were included in the per-protocol analysis reported previously was corrected, and these children were identified as “out of age range” when they received the first dose of study vaccine. These three children were excluded from the per-protocol analyses reported here. CW, consent withdrawal.

Mentions: Overall, 8,923 children and 6,537 young infants were enrolled. All randomized children and young infants were included in the ITT population, while 6,885 (77%) children and 6,003 (92%) young infants were included in the per-protocol population (Figures 2 and 3; Table S3). Baseline characteristics were similar in the two study groups but differed by site. ITN use was 78% in children and 86% in young infants (Figure S2, ITT). Malaria incidence in young infants in the control group, an approximation of the force of infection, ranged across sites from 0.03 to 4.27 episodes per infant per year (Table S4, per protocol).


Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites.

- PLoS Med. (2014)

CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.aOne child enrolled in the 5–17-mo age category who was reported previously to have received three doses of study vaccine, and was included in the per-protocol analyses reported previously, had received only the first and second doses of study vaccine. bThe date of birth of three children who were included in the per-protocol analysis reported previously was corrected, and these children were identified as “out of age range” when they received the first dose of study vaccine. These three children were excluded from the per-protocol analyses reported here. CW, consent withdrawal.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4114488&req=5

pmed-1001685-g002: CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.aOne child enrolled in the 5–17-mo age category who was reported previously to have received three doses of study vaccine, and was included in the per-protocol analyses reported previously, had received only the first and second doses of study vaccine. bThe date of birth of three children who were included in the per-protocol analysis reported previously was corrected, and these children were identified as “out of age range” when they received the first dose of study vaccine. These three children were excluded from the per-protocol analyses reported here. CW, consent withdrawal.
Mentions: Overall, 8,923 children and 6,537 young infants were enrolled. All randomized children and young infants were included in the ITT population, while 6,885 (77%) children and 6,003 (92%) young infants were included in the per-protocol population (Figures 2 and 3; Table S3). Baseline characteristics were similar in the two study groups but differed by site. ITN use was 78% in children and 86% in young infants (Figure S2, ITT). Malaria incidence in young infants in the control group, an approximation of the force of infection, ranged across sites from 0.03 to 4.27 episodes per infant per year (Table S4, per protocol).

Bottom Line: Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).VE waned over time in both age categories (Schoenfeld residuals p<0.001).Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.

View Article: PubMed Central - PubMed

ABSTRACT

Background: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.

Methods and findings: 6,537 infants aged 6-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from -1 to 49, respectively; corresponding ranges among infants were -10 to 1,402 and -13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.

Conclusions: RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.

Trial registration: www.ClinicalTrials.gov NCT00866619 Please see later in the article for the Editors' Summary.

Show MeSH
Related in: MedlinePlus