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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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Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population).The blue squares reflect the number of participants in the per-protocol population with a valid assay result available 1 mo after dose 3 in each study site. The horizontal bars show the lower limit (LL) and upper limit (UL) of the 95% confidence interval. Study sites are ordered from lowest (Kilifi) to highest (Siaya) incidence of clinical malaria, defined as a measured or reported fever within previous 24 h and parasite density >0 parasites/mm3 (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.
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pmed-1001685-g016: Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population).The blue squares reflect the number of participants in the per-protocol population with a valid assay result available 1 mo after dose 3 in each study site. The horizontal bars show the lower limit (LL) and upper limit (UL) of the 95% confidence interval. Study sites are ordered from lowest (Kilifi) to highest (Siaya) incidence of clinical malaria, defined as a measured or reported fever within previous 24 h and parasite density >0 parasites/mm3 (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.

Mentions: In children, post-vaccination anti-CS antibody geometric mean titer (GMT) varied from 348 to 787 EU/ml across sites in the per-protocol population (Figures 16 and 17; Table S16), but post-vaccination titers did not explain the differences in level of protection (p = 0.24) (Table S11). Previous hepatitis B vaccination was not associated with a higher post-vaccination anti-CS antibody response (p = 0.73; Table S12). However, younger age at the time of vaccination (5–11 mo versus 12–17 mo) and living in a higher transmission setting were associated significantly with higher post-vaccination anti-CS responses (p<0.001 and p<0.001, respectively) (Table S12). Young infants had a lower post-vaccination anti-CS antibody GMT than children (anti-CS antibody GMT range across sites: 117 to 335 EU/ml, per-protocol population), and, in contrast to what was observed in children, higher anti-CS antibody titers were associated with lower malaria incidence (p<0.001) (Figures 18 and 19; Tables S11 and S16). Younger age (6 wk versus 7–12 wk) and the presence of anti-CS antibodies prior to vaccination were associated with a lower post-vaccination anti-CS antibody response (p = 0.003 and p<0.001, respectively) (Tables S12 and S13). A graphic depiction of the relationships between anti-CS antibody GMT, malaria incidence, and VE is shown in Figure 20.


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)

Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population).The blue squares reflect the number of participants in the per-protocol population with a valid assay result available 1 mo after dose 3 in each study site. The horizontal bars show the lower limit (LL) and upper limit (UL) of the 95% confidence interval. Study sites are ordered from lowest (Kilifi) to highest (Siaya) incidence of clinical malaria, defined as a measured or reported fever within previous 24 h and parasite density >0 parasites/mm3 (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4114488&req=5

pmed-1001685-g016: Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population).The blue squares reflect the number of participants in the per-protocol population with a valid assay result available 1 mo after dose 3 in each study site. The horizontal bars show the lower limit (LL) and upper limit (UL) of the 95% confidence interval. Study sites are ordered from lowest (Kilifi) to highest (Siaya) incidence of clinical malaria, defined as a measured or reported fever within previous 24 h and parasite density >0 parasites/mm3 (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.
Mentions: In children, post-vaccination anti-CS antibody geometric mean titer (GMT) varied from 348 to 787 EU/ml across sites in the per-protocol population (Figures 16 and 17; Table S16), but post-vaccination titers did not explain the differences in level of protection (p = 0.24) (Table S11). Previous hepatitis B vaccination was not associated with a higher post-vaccination anti-CS antibody response (p = 0.73; Table S12). However, younger age at the time of vaccination (5–11 mo versus 12–17 mo) and living in a higher transmission setting were associated significantly with higher post-vaccination anti-CS responses (p<0.001 and p<0.001, respectively) (Table S12). Young infants had a lower post-vaccination anti-CS antibody GMT than children (anti-CS antibody GMT range across sites: 117 to 335 EU/ml, per-protocol population), and, in contrast to what was observed in children, higher anti-CS antibody titers were associated with lower malaria incidence (p<0.001) (Figures 18 and 19; Tables S11 and S16). Younger age (6 wk versus 7–12 wk) and the presence of anti-CS antibodies prior to vaccination were associated with a lower post-vaccination anti-CS antibody response (p = 0.003 and p<0.001, respectively) (Tables S12 and S13). A graphic depiction of the relationships between anti-CS antibody GMT, malaria incidence, and VE is shown in Figure 20.

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