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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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Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population).Interaction p-value = 0.8100. The size of each blue square reflects the relative number of participants enrolled at 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. VE is VE against all episodes of clinical malaria meeting the primary case definition, unadjusted for covariates. Clinical malaria primary case definition: illness in a child brought to a study facility with a temperature of ≥37.5°C and P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 or a case of malaria meeting the primary case definition of severe malaria.
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pmed-1001685-g005: Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population).Interaction p-value = 0.8100. The size of each blue square reflects the relative number of participants enrolled at 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. VE is VE against all episodes of clinical malaria meeting the primary case definition, unadjusted for covariates. Clinical malaria primary case definition: illness in a child brought to a study facility with a temperature of ≥37.5°C and P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 or a case of malaria meeting the primary case definition of severe malaria.

Mentions: The incidence of all episodes of clinical malaria meeting the primary case definition during the 18 mo of follow-up in the per-protocol population was 0.69/person-year in the RTS,S/AS01 group and 1.17/person-year in the control group, resulting in a VE of 46% (95% CI 42% to 50%), with overall estimates of VE consistent across case definitions and with the ITT analysis (ITT, VE = 45% [95% CI 41% to 49%]) (Tables 1 and S5; Figures 4, 5, and S3). Significant heterogeneity in VE was seen across sites, with VE ranging from 40% to 77% (interaction test, p<0.001; VE, p<0.01 at all sites). VE in the ITT population ranged across sites from 41% to 70%. Analysis of site-specific VE in the per-protocol population did not suggest that this heterogeneity was driven by variations in transmission intensity (interaction between study group and transmission intensity, p = 0.66). Lower VE was associated with moderate anemia at baseline (p = 0.04) (Table S6). VE varied over time, being highest close to vaccination (Schoenfeld residuals p<0.001) (Figure S4), but it persisted throughout the observation period. The reduction in the incidence of clinical malaria by 6-mo periods was 68% (95% CI 64% to 72%) during months 1–6, 41% (95% CI 36% to 46%) during months 7–12, and 26% (95% CI 19% to 33%) during months 13–18 after vaccine dose 3. Corresponding values in the ITT population were 60% (95% CI 56% to 64%), 41% (95% CI 36% to 46%), and 28% (95% CI 21% to 35%) (Figures S5 and S6). VE against clinical malaria and severe malaria during the first 12 mo of follow-up is presented in Figure S8 and Table S15. VE against prevalent parasitemia, 18 mo after vaccination, was 31% (95% CI 17% to 42%) (ITT, VE = 29% [95% CI 15% to 40%]) (Table S7). VE was 36% (95% CI 15% to 51%) against severe malaria (ITT, VE against severe malaria = 34% [95% CI 15% to 48%]), 42% (95% CI 29% to 52%) against malaria hospitalization (ITT, VE against malaria hospitalization = 41% [95% CI 30% to 50%]), and 19% (95% CI 9% to 28%) against all-cause hospitalization (ITT, VE against all-cause hospitalization = 19% [95% CI 11% to 27%]) (Table 1). The incidence of severe malaria by 6-mo periods is shown in Figure S5.


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)

Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population).Interaction p-value = 0.8100. The size of each blue square reflects the relative number of participants enrolled at 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. VE is VE against all episodes of clinical malaria meeting the primary case definition, unadjusted for covariates. Clinical malaria primary case definition: illness in a child brought to a study facility with a temperature of ≥37.5°C and P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 or a case of malaria meeting the primary case definition of severe malaria.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4114488&req=5

pmed-1001685-g005: Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in children 5–17 mo of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population).Interaction p-value = 0.8100. The size of each blue square reflects the relative number of participants enrolled at 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. VE is VE against all episodes of clinical malaria meeting the primary case definition, unadjusted for covariates. Clinical malaria primary case definition: illness in a child brought to a study facility with a temperature of ≥37.5°C and P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 or a case of malaria meeting the primary case definition of severe malaria.
Mentions: The incidence of all episodes of clinical malaria meeting the primary case definition during the 18 mo of follow-up in the per-protocol population was 0.69/person-year in the RTS,S/AS01 group and 1.17/person-year in the control group, resulting in a VE of 46% (95% CI 42% to 50%), with overall estimates of VE consistent across case definitions and with the ITT analysis (ITT, VE = 45% [95% CI 41% to 49%]) (Tables 1 and S5; Figures 4, 5, and S3). Significant heterogeneity in VE was seen across sites, with VE ranging from 40% to 77% (interaction test, p<0.001; VE, p<0.01 at all sites). VE in the ITT population ranged across sites from 41% to 70%. Analysis of site-specific VE in the per-protocol population did not suggest that this heterogeneity was driven by variations in transmission intensity (interaction between study group and transmission intensity, p = 0.66). Lower VE was associated with moderate anemia at baseline (p = 0.04) (Table S6). VE varied over time, being highest close to vaccination (Schoenfeld residuals p<0.001) (Figure S4), but it persisted throughout the observation period. The reduction in the incidence of clinical malaria by 6-mo periods was 68% (95% CI 64% to 72%) during months 1–6, 41% (95% CI 36% to 46%) during months 7–12, and 26% (95% CI 19% to 33%) during months 13–18 after vaccine dose 3. Corresponding values in the ITT population were 60% (95% CI 56% to 64%), 41% (95% CI 36% to 46%), and 28% (95% CI 21% to 35%) (Figures S5 and S6). VE against clinical malaria and severe malaria during the first 12 mo of follow-up is presented in Figure S8 and Table S15. VE against prevalent parasitemia, 18 mo after vaccination, was 31% (95% CI 17% to 42%) (ITT, VE = 29% [95% CI 15% to 40%]) (Table S7). VE was 36% (95% CI 15% to 51%) against severe malaria (ITT, VE against severe malaria = 34% [95% CI 15% to 48%]), 42% (95% CI 29% to 52%) against malaria hospitalization (ITT, VE against malaria hospitalization = 41% [95% CI 30% to 50%]), and 19% (95% CI 9% to 28%) against all-cause hospitalization (ITT, VE against all-cause hospitalization = 19% [95% CI 11% to 27%]) (Table 1). The incidence of severe malaria by 6-mo periods is shown in Figure S5.

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