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

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.

Conflict of interest statement

The trial was sponsored by GlaxoSmithKline Biologicals SA (GSK), the vaccine developer and manufacturer, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative (MVI). All centers declare receiving a grant from MVI for running the trial. Author travel and accommodation related to this trial were financed by MVI. GlaxoSmithKline Biologicals SA received a grant from MVI to run the trial. MVI received a grant from the Bill & Melinda Gates Foundation to run this trial and to compensate MVI authors for trial-related travel. Additional conflicts of interest are as follows: JJA and PAl declare that their institutions received grant from the Catalan government and from the International Agency for Development and Cooperation. NA, CO, and KO declare that their institutions received a grant from the Malaria Clinical Trial Alliance. PB, SD, BG, CK, PL, CMai, GMwam, BO, and LO declare that their institution has received grants from MVI for other malaria studies. KM declares that his institution received a grant from the Wellcome Trust and that he received support from USAID and the Bill & Melinda Gates Foundation to participate in a scientific advisory group on malaria. MML declares that she received non-financial support from the WHO and the Biomérieux Foundation. PN declares that she received financial support from GSK to present the results of the study at ASTMH congress in 2012. LO declares that he received support from GSK to carry out clinical and epidemiological studies. JSa has received (for the Center) some GlaxoSmithKline group of companies' consultancy fees for other studies. MTa is a board member of the Optimus Foundation, and his institution is reimbursed for his activities on the scientific advisory board of the Novartis Institute for Tropical Diseases. He also has received for his institution other grants from MVI and from the Bill & Melinda Gates Foundation, and travel reimbursements from MVI and Sanaria corp. All GSK Vaccines authors are, or were at the time of the study, employed by the GlaxoSmithKline group of companies. JC now works as an independent consultant for GSK Vaccines. WRB, JC, EJ, DLa, OOA, JV, AL, and MLi have shares/stock options in the GlaxoSmithKline group of companies. JC and WRB declare that they are named inventors on patents for which the rights have been assigned to GlaxoSmithKline group of companies. DK, DLe, and BS are employees at PATH-MVI. DSc is employed by the London School of Hygiene & Tropical Medicine, and his consultancy activities for MVI are funded as a grant to the LSHTM by MVI. DK holds stock or stock options from Merck, Sharpe & Dome.

Figures

Figure 1. Study sites and malaria endemicity.

Adapted from Hay et al. . The location of each participating study site is shown on this previously published map showing the spatial distribution of P. falciparum (Pf) malaria endemicity. The data are the model-based geostatistical point estimates of the annual mean P. falciparum parasite rate (PR) age-standardized for 2–10 y for 2007 within the stable spatial limits of P. falciparum malaria transmission, displayed as a continuum of yellow to red from 0%–100% (see map legend). The rest of the land area was defined as unstable risk (medium grey) or no risk (light grey). Nanoro, Burkina Faso, has highly seasonal malaria transmission.

Figure 2. 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.

Figure 3. CONSORT diagram of infants aged 6–12 wk at enrollment followed until 18 mo post-vaccination.

aScreening data had not been reported before the database freeze for the analysis published in 2011 for 22 infants in the 6–12-wk age category, and these participants were not included in the 2011 CONSORT chart. bOne infant enrolled in the 6–12-wk age category who was reported to have received three doses of study vaccine (RTS,S/AS01 or comparator vaccine) was included in the per-protocol analyses reported previously, but was subsequently found to have received only the first dose of study vaccine. cTwo infants enrolled in the 6–12-wk age category who had been reported as “attending Visit 16 (12 months post dose-3)” in the 2012 CONSORT chart are reported as “migrated/lost to follow-up” in this CONSORT chart. In addition, one infant who was reported as “migrated/lost to follow-up” in the 2012 CONSORT chart has been recorded as “consent withdrawal” in this CONSORT chart .

Figure 4. 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).

Interaction p-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/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.

Figure 5. 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.

Figure 6. 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).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. This definition was used for this analysis because during routine clinical practice these children would normally receive a full course of anti-malarial treatment.

Figure 7. Number of cases of severe malaria (secondary case definition) averted per 1,000 participants vaccinated during an 18-mo follow-up period (per-protocol 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.

Figure 8. Number of cases of clinical malaria (secondary case definition) averted per 1,000 participants vaccinated during a 20-mo follow-up period (intention-to-treat population).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. This definition was used for this analysis because during routine clinical practice these children would normally receive a full course of anti-malarial treatment.

Figure 9. 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.

Figure 10. Number of 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 (per-protocol population).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. 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/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. A deviation pertaining to study vaccine exposure to temperatures outside recommended ranges resulted in the exclusion from the per-protocol population of all children 5–17 mo old enrolled in Manhiça, Mozambique, therefore no data are presented in this age category for Manhiça (asterisk).

Figure 11. 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).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. 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/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.

Figure 12. Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in infants 6–12 wk of age at enrollment, ordered by increasing malaria incidence at each study site (per-protocol population).

Interaction p-value = 0.1682. 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.

Figure 13. Vaccine efficacy against all episodes of clinical malaria (primary case definition) during an 18-mo follow-up period after dose 3 in infants 6–12 wk of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat population).

Interaction p-value = 0.1143. 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.

Figure 14. 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 (per-protocol population).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. 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/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.

Figure 15. 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).

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 P. falciparum asexual parasitemia at a density of >0 parasites/mm3. 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/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.

Figure 16. 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.

Figure 17. 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 (intention-to-treat 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.

Figure 18. Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in infants 6–12 wk 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.

Figure 19. Anti-CS antibody geometric mean titers (EU/ml) in RTS,S/AS01 recipients 1 mo after dose 3 in infants 6–12 wk of age at enrollment, ordered by increasing malaria incidence at each study site (intention-to-treat 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.

Figure 20. Graphical representation of anti-CS geometric mean titers, vaccine efficacy, and malaria incidence (per-protocol population).

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 (n/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.