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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
Full text linkA 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.; 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.; 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
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
Full text linkThe 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.; 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.; 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.; 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.; GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative
A phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants.
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The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.)
Number of cases of clinical malaria (secondary case definition) averted per 1,000 participants vaccinated during an 18-mo follow-up period (per-protocol population).
No full text<p>Clinical malaria secondary case definition: illness in a child brought to a study facility with a measured temperature of ≥37.5°C or reported fever within the last 24 h and <i>P. falciparum</i> asexual parasitemia at a density of >0 parasites/mm<sup>3</sup>. This definition was used for this analysis because during routine clinical practice these children would normally receive a full course of anti-malarial treatment.</p
CONSORT diagram of children aged 5–17 mo at enrollment and followed until 18 mo post-vaccination.
No full text<p><sup>a</sup>One 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. <sup>b</sup>The 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.</p
Graphical representation of anti-CS geometric mean titers, vaccine efficacy, and malaria incidence (per-protocol population).
No full text<p>Upper left panel: VE against clinical malaria versus malaria incidence (per-protocol population); lower left panel: anti-CS response versus malaria incidence (per-protocol population); lower right panel: anti-CS response versus VE against clinical malaria (per-protocol population). Blue diamonds (infants 6–12 wk) and red squares (children 5–17 mo) represent the study sites. VE (percent) is VE against all episodes of clinical malaria meeting the primary case definition over 18 mo after dose 3. Anti-CS antibody GMT (EU/ml) was measured at 1 mo after dose 3 in the first 200 participants enrolled at each site. Incidence (<i>n</i>/total [n/T]: episodes per person-year at risk) is the incidence of clinical malaria (primary case definition) in the control group in the corresponding age category over 18 mo after dose 3.</p
Cases of clinical malaria (secondary case definition) averted during an 18-mo follow-up period in infants 6–12 wk of age at enrollment, by study site, ordered by increasing malaria incidence at each site (intention-to-treat population).
No full text<p>Clinical malaria secondary case definition: illness in a child brought to a study facility with a measured temperature of ≥37.5°C or reported fever within the last 24 h and <i>P. falciparum</i> asexual parasitemia at a density of >0 parasites/mm<sup>3</sup>. This definition was used for this analysis because during routine clinical practice these children would normally receive a full course of anti-malarial treatment. 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/mm<sup>3</sup> (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.</p
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 (per-protocol population).
No full text<p>Interaction <i>p-</i>value = 0.0006. 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/mm<sup>3</sup> (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 <i>P. falciparum</i> asexual parasitemia at a density of >5,000 parasites/mm<sup>3</sup> or a case of malaria meeting the primary case definition of severe malaria.</p
Vaccine efficacy against all episodes of clinical and severe malaria in infants aged 6–12 wk at enrollment.
No full text1<p>Event rate for clinical malaria; affected rate (percent) for severe malaria and hospitalization.</p>2<p>For clinical malaria: <i>p</i>-value from negative binomial regression. For severe malaria, malaria hospitalization, and all-cause hospitalization: <i>p</i>-value from two-sided Fisher's exact test.</p>3<p>Clinical malaria primary case definition: illness in a child brought to a study facility with a measured temperature of ≥37.5°C and <i>P. falciparum</i> asexual parasitemia at a density of >5,000 parasites/mm<sup>3</sup> or a case of malaria meeting the primary case definition of severe malaria.</p>4<p>Clinical malaria secondary case definition: illness in a child brought to a study facility with a measured temperature of ≥37.5°C or reported fever within the last 24 h and <i>P. falciparum</i> asexual parasitemia at a density of >0 parasites/mm<sup>3</sup>.</p>5<p>Severe malaria primary case definition: <i>P. falciparum</i> asexual parasitemia at a density of >5,000 parasites/mm<sup>3</sup> with one or more markers of disease severity and without diagnosis of a coexisting illness. 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 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.</p>6<p>Malaria hospitalization case definition: a medical hospitalization with confirmed <i>P. falciparum</i> asexual parasitemia at a density of >5,000 parasites/mm<sup>3</sup>.</p>7<p>All-cause hospitalization primary case definition: a medical hospitalization of any cause, excluding planned admissions for medical investigation/care or elective surgery and admissions for trauma.</p
Cases of clinical malaria (secondary case definition) averted during an 18-mo follow-up period in children 5–17 mo of age at enrollment, by study site, ordered by increasing malaria incidence at each site (intention-to-treat population).
No full text<p>Clinical malaria secondary case definition: illness in a child brought to a study facility with a measured temperature of ≥37.5°C or reported fever within the last 24 h and <i>P. falciparum</i> asexual parasitemia at a density of >0 parasites/mm<sup>3</sup>. This definition was used for this analysis because during routine clinical practice these children would normally receive a full course of anti-malarial treatment. 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/mm<sup>3</sup> (i.e., clinical malaria secondary case definition), measured in control infants 6–12 wk of age at enrollment during 12 mo of follow-up.</p
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