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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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Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during a 20-mo follow-up period (intention-to-treat population).Severe malaria secondary case definition: P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 with one or more markers of disease severity, including cases in which a coexisting illness was present or could not be ruled out. Markers of severe disease were prostration, respiratory distress, a Blantyre coma score of ≤2 (on a scale of 0 to 5, with higher scores indicating a higher level of consciousness), two or more observed or reported seizures, hypoglycemia, acidosis, elevated lactate level, or a hemoglobin level of <5 g/dl. Coexisting illnesses were defined as radiographically proven pneumonia, meningitis established by analysis of cerebrospinal fluid, bacteremia, or gastroenteritis with severe dehydration.
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pmed-1001685-g009: Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during a 20-mo follow-up period (intention-to-treat population).Severe malaria secondary case definition: P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 with one or more markers of disease severity, including cases in which a coexisting illness was present or could not be ruled out. Markers of severe disease were prostration, respiratory distress, a Blantyre coma score of ≤2 (on a scale of 0 to 5, with higher scores indicating a higher level of consciousness), two or more observed or reported seizures, hypoglycemia, acidosis, elevated lactate level, or a hemoglobin level of <5 g/dl. Coexisting illnesses were defined as radiographically proven pneumonia, meningitis established by analysis of cerebrospinal fluid, bacteremia, or gastroenteritis with severe dehydration.

Mentions: The number of cases of clinical malaria averted per 1,000 young infants vaccinated with RTS,S/AS01 in the ITT population ranged across sites from −10 to 1,402 (average for the 11 study sites: 449), and the number of severe malaria cases averted ranged from −13 to 37 (average across all sites: 6) during the 18-mo follow-up period (Figures 6–9, 14, and 15; Table S8). One hundred seventeen young infants (1.8%) died during the 20-mo observation period, 83/4,358 (1.9%) infants in the RTS,S/AS01 group and 34/2,179 (1.6%) in the control group. VE was not demonstrated against all-cause mortality, malaria mortality, hospitalized pneumonia, septicemia, or prevalent anemia, nor was there a detectable effect on nutritional status or growth (Tables S7, S9, and S10).


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)

Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during a 20-mo follow-up period (intention-to-treat population).Severe malaria secondary case definition: P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 with one or more markers of disease severity, including cases in which a coexisting illness was present or could not be ruled out. Markers of severe disease were prostration, respiratory distress, a Blantyre coma score of ≤2 (on a scale of 0 to 5, with higher scores indicating a higher level of consciousness), two or more observed or reported seizures, hypoglycemia, acidosis, elevated lactate level, or a hemoglobin level of <5 g/dl. Coexisting illnesses were defined as radiographically proven pneumonia, meningitis established by analysis of cerebrospinal fluid, bacteremia, or gastroenteritis with severe dehydration.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4114488&req=5

pmed-1001685-g009: Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during a 20-mo follow-up period (intention-to-treat population).Severe malaria secondary case definition: P. falciparum asexual parasitemia at a density of >5,000 parasites/mm3 with one or more markers of disease severity, including cases in which a coexisting illness was present or could not be ruled out. Markers of severe disease were prostration, respiratory distress, a Blantyre coma score of ≤2 (on a scale of 0 to 5, with higher scores indicating a higher level of consciousness), two or more observed or reported seizures, hypoglycemia, acidosis, elevated lactate level, or a hemoglobin level of <5 g/dl. Coexisting illnesses were defined as radiographically proven pneumonia, meningitis established by analysis of cerebrospinal fluid, bacteremia, or gastroenteritis with severe dehydration.
Mentions: The number of cases of clinical malaria averted per 1,000 young infants vaccinated with RTS,S/AS01 in the ITT population ranged across sites from −10 to 1,402 (average for the 11 study sites: 449), and the number of severe malaria cases averted ranged from −13 to 37 (average across all sites: 6) during the 18-mo follow-up period (Figures 6–9, 14, and 15; Table S8). One hundred seventeen young infants (1.8%) died during the 20-mo observation period, 83/4,358 (1.9%) infants in the RTS,S/AS01 group and 34/2,179 (1.6%) in the control group. VE was not demonstrated against all-cause mortality, malaria mortality, hospitalized pneumonia, septicemia, or prevalent anemia, nor was there a detectable effect on nutritional status or growth (Tables S7, S9, and S10).

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