Original Article

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in = African=20 Children

The RTS,S Clinical Trials Partnership

October 18, 2011 (10.1056/NEJMoa1102287)

=20 Comments open through October 24, 2011

Abstract

Background

An ongoing phase 3 study of the efficacy, safety, and = immunogenicity of=20 candidate malaria vaccine RTS,S/AS01 is being conducted in seven = African=20 countries.

Full Text of Background...

Methods

From March 2009 through January 2011, we enrolled 15,460 children = in two=20 age categories =E2=80=94 6 to 12 weeks of age and 5 to 17 months of = age =E2=80=94 for=20 vaccination with either RTS,S/AS01 or a non-malaria comparator = vaccine. The=20 primary end point of the analysis was vaccine efficacy against = clinical=20 malaria during the 12 months after vaccination in the first 6000 = children 5 to=20 17 months of age at enrollment who received all three doses of vaccine = according to protocol. After 250 children had an episode of severe = malaria, we=20 evaluated vaccine efficacy against severe malaria in both age = categories.

Full Text of Methods...

Results

In the 14 months after the first dose of vaccine, the incidence of = first=20 episodes of clinical malaria in the first 6000 children in the older = age=20 category was 0.32 episodes per person-year in the RTS,S/AS01 group and = 0.55=20 episodes per person-year in the control group, for an efficacy of = 50.4% (95%=20 confidence interval [CI], 45.8 to 54.6) in the intention-to-treat = population=20 and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. = Vaccine=20 efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in = the=20 intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the=20 per-protocol population. Vaccine efficacy against severe malaria in = the=20 combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the = per-protocol=20 population during an average follow-up of 11 months. Serious adverse = events=20 occurred with a similar frequency in the two study groups. Among = children in=20 the older age category, the rate of generalized convulsive seizures = after=20 RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to = 1.64).

Full Text of Results...

Conclusions

The RTS,S/AS01 vaccine provided protection against both clinical = and severe=20 malaria in African children. (Funded by GlaxoSmithKline Biologicals = and the=20 PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.)

Full Text of Discussion...

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Media in This Article

Figure 1Enrollment of First 6000 Children in Older Age = Category=20 (5=E2=80=9317 Months).

Figure 2Enrollment of All Children through May 31, 2011, = or=20 Receipt of Booster Dose.

Article

Each year, malaria occurs in approximately 225 million persons = worldwide,=20 and 781,000 persons, mostly African children, die from the = disease.1 During the past decade, the scale-up of=20 malaria-control interventions has resulted in considerable reductions = in=20 morbidity and mortality associated with malaria in parts of = Africa.2,3 However, malaria continues to pose a = major public=20 health threat. A malaria vaccine, deployed in combination with current = malaria-control tools, could play an important role in future control = and=20 eventual elimination of malaria in Africa.4

The RTS,S vaccine that targets the circumsporozoite protein and is = given=20 with an adjuvant system (AS01 or AS02) has consistently shown = protection=20 against Plasmodium falciparum malaria in children and infants = in=20 phase 2 trials.5-10 The vaccine had an acceptable = side-effect=20 profile and was immunogenic in children who were 6 weeks of age or = older. In=20 addition, the vaccine could be administered safely with other = childhood=20 vaccines8,11 and provided protection against severe = malaria.5 Here, we report the initial results of an = ongoing=20 phase 3 trial being conducted at 11 centers in 7 African countries = (Figure 1=20 in the Supplementary=20 Appendix, available with the full text of this article at=20 NEJM.org).

Methods

Study Design

Detailed methods are presented in the Supplementary=20 Appendix and have been reported previously.12-15 This randomized, controlled, = double-blind trial=20 was designed to evaluate vaccine efficacy, safety, reactogenicity, and = immunogenicity in children up to 32 months after the administration of = the=20 first dose of vaccine. The trial included two age categories: children = 6 to 12=20 weeks of age and those 5 to 17 months of age at enrollment. The trial = included=20 three study groups in each age category: children who received all = three doses=20 of the RTS,S/AS01 vaccine administered at 1-month intervals and who = were=20 scheduled to receive a booster dose 18 months after the third dose, = children=20 who received the RTS,S/AS01 primary vaccination series without a = booster, and=20 a control group who received a non-malaria comparator vaccine. This = first=20 analysis combines the first two groups (referred to as the RTS,S/AS01 = group)=20 and compares this group with the control group (Figure 2 in the Supplementary=20 Appendix). Children in the younger age category received the = RTS,S/AS01=20 vaccine along with routine childhood vaccinations beginning at 6 weeks = of=20 age.

The coprimary end points of the trial =E2=80=94 vaccine efficacy = against clinical=20 malaria after 12 months of follow-up in each age category =E2=80=94 = have been=20 completed for the first 6000 children enrolled in the older age = category.=20 Vaccine efficacy against severe malaria will be reported after 12 = months of=20 follow-up of the first 6000 children enrolled in each age category.=20 Accordingly, vaccine efficacy against both clinical and severe malaria = in the=20 older age category is presented here, and findings regarding efficacy = will be=20 presented for the younger age category in approximately 1 year, after = the=20 first 6000 children in that age category have completed 12 months of=20 follow-up. A secondary analysis of vaccine efficacy against severe = malaria in=20 the pooled age categories was planned to take place when at least one = severe=20 malaria episode had occurred in at least 250 children. This milestone = was=20 reached on May 31, 2011. Vaccine efficacy against severe disease in = the pooled=20 age categories is restricted to data obtained up to this date. Data = for=20 children who received a booster dose of vaccine before May 31, 2011, = were=20 censored at the time of booster vaccination.

The trial protocol,=20 which is available at NEJM.org, was approved by the ethical review = board and=20 national regulatory authority at each study center and partner = institution.=20 Written informed consent was obtained from the children's parents or = guardians=20 (Table 1 in the Supplementary=20 Appendix). The trial was undertaken in accordance with the = provisions of=20 the Good Clinical Practice Guidelines.16

Randomization and=20 Vaccination

From March 2009 through January 2011, we randomly assigned 15,460 = children=20 to one of the three original study groups in a 1:1:1 ratio. Comparator = vaccines were rabies vaccine (VeroRab, Sanofi-Pasteur) for children 5 = to 17=20 months of age at enrollment and meningococcal serogroup C conjugate = vaccine=20 (Menjugate, Novartis) for children 6 to 12 weeks of age at enrollment. = All=20 vaccines were administered intramuscularly.

Surveillance for=20 Clinical and Severe Malaria

Passive surveillance for malaria was undertaken from the time of = the=20 administration of the first dose of vaccine until the end of the = study.=20 Participants were encouraged to seek care at a health facility within = the=20 study area for any illness, and transportation was facilitated. All=20 participants who presented to a study facility with a reported or = measured=20 fever during the previous 24 hours were evaluated for malaria (for = details,=20 see the Supplementary=20 Appendix).

The primary efficacy end point for this analysis was the incidence = of=20 clinical malaria, which was defined as an illness in a child who was = brought=20 to a study facility with a temperature of 37.5=C2=B0C or more and = P.=20 falciparum asexual parasitemia (>5000 parasites per cubic = millimeter)=20 or a case of malaria meeting the primary case definition of severe=20 malaria.12 Different parasite thresholds were used = for=20 secondary case definitions (Table=20 1Table 1Efficacy of the RTS,S/AS01 Vaccine against = Clinical=20 Malaria in Children Enrolled at 5 to 17 Months of Age. = and Table=20 2Table 2Efficacy of the RTS,S/AS01 Vaccine against = Severe Malaria=20 in Children Enrolled at 5 to 17 Months of Age and in Pooled Age=20 Categories., and Table 2 in the Supplementary=20 Appendix). Participants who were hospitalized were evaluated for = severe=20 malaria on the basis of a protocol-defined algorithm (Table 3 in the = Supplementary=20 Appendix).12

Safety Surveillance

Data regarding serious adverse events were collected throughout the = trial=20 by passive surveillance. Seizures that occurred within 7 days after=20 vaccination were analyzed according to Brighton Collaboration = guidelines.17 Verbal autopsies were conducted on = deaths that=20 occurred outside study facilities.18 Information was collected on all = unsolicited=20 reports of adverse events that occurred within 30 days after = vaccination and=20 on reactogenicity within 7 days after vaccination among the first 200 = children=20 in the older age category at each study center (Table 4 in the Supplementary=20 Appendix).

Immunogenicity

Anti=E2=80=93circumsporozoite antibody titers were measured by = means of=20 enzyme-linked immunosorbent assay19 in the first 200 children in the older = age=20 category at each study center at enrollment and 1 month after the=20 administration of the third dose of a study vaccine. The threshold for = a=20 positive titer was 0.5 EU per milliliter.

Laboratory and = Radiologic=20 Procedures

Laboratory and radiologic procedures are described in the Supplementary=20 Appendix and have been reported previously.13

Study Oversight

The trial was sponsored by GlaxoSmithKline Biologicals (GSK), the = vaccine=20 developer and manufacturer, and funded by both GSK and the Program for = Appropriate Technology in Health (PATH) Malaria Vaccine Initiative, = which=20 received a grant from the Bill and Melinda Gates Foundation. All study = centers=20 received study grants from the Malaria Vaccine Initiative, which also = provided=20 funding for authors' travel and accommodations related to this trial. = All the=20 authors reviewed all manuscript drafts, approved the final version of = the=20 manuscript, and made the decision to submit it for publication. The = Clinical=20 Trials Partnership Committee and Writing Group vouch for the = completeness and=20 accuracy of the data presented and for the fidelity of this report to = the=20 trial protocol.

Statistical Analysis

Statistical methods have been described previously.15 We used Cox regression models (1 minus = the hazard=20 ratio) to evaluate vaccine efficacy against the first or only episode = of=20 clinical malaria in the older age category, using the study center as = a=20 stratification factor that allowed for differential baseline hazards. = The=20 proportionality of hazards was evaluated by Schoenfeld residuals and = models,=20 including time-varying covariates. Secondary analyses included = evaluations of=20 other clinical case definitions and multiple episodes of clinical = malaria by=20 means of negative binomial regression. Vaccine efficacy against severe = malaria, which was defined as 1 minus the risk ratio, is expressed as = a=20 percent and is presented with Fisher's exact P values. All end points = are=20 presented with 95% confidence intervals except for the primary = efficacy end=20 point, which is presented with 97.5% confidence intervals.

Primary analyses of vaccine efficacy were based on the per-protocol = population, which included all participants who received three doses = of a=20 study vaccine and who contributed to efficacy surveillance, starting = 14 days=20 after the administration of the third dose of a study vaccine. The=20 intention-to-treat population included all participants who received = at least=20 one dose of a study vaccine.

Data were censored for the first 6000 children in the older age = category 14=20 months after the administration of the first dose of vaccine or at the = date of=20 emigration, withdrawal of consent, or death. For analysis of the = pooled age=20 categories, the time at risk ended on May 31, 2011, when a booster = dose was=20 given, or at the date of withdrawal of consent or death. Estimates of = vaccine=20 efficacy according to study site and according to the incidence of = clinical or=20 severe malaria in the younger age category are not yet available, = owing to=20 insufficient statistical power and follow-up time, but will be = analyzed at a=20 later time.

Adverse events were coded from clinician-assigned diagnoses for = serious=20 adverse events using the preferred terms of the Medical Dictionary = for=20 Regulatory Activities.20 All adverse events are presented = according to age=20 category in the intention-to-treat population. Diagnoses for serious = adverse=20 events are based on all available clinical evidence and are not bound = by=20 stringent laboratory or diagnostic criteria. Therefore, they should = not be=20 used to infer vaccine efficacy. A formal analysis of vaccine efficacy = against=20 coexisting illnesses is planned for the end of the study.

To preserve blinding, analyses were conducted by external = statisticians=20 using SAS software, version 9.2 (SAS Institute).

Results

Study Population

The first 6000 children 5 to 17 months of age at enrollment were = included=20 in the primary analysis of vaccine efficacy during the 12 months after = the=20 administration of the third dose of vaccine. Of these children, 4296 = (71.6%)=20 were included in the per-protocol analysis (Figure=20 1Figure 1Enrollment of First 6000 Children in Older Age = Category=20 (5=E2=80=9317 Months).). (The number of children who = participated=20 according to study center is shown in Table 5 in the Supplementary=20 Appendix.) A survey undertaken 14 months after the administration = of the=20 first dose of a study vaccine showed that approximately 75% of = children in the=20 two study groups were using bed nets (Table 6 in the Supplementary=20 Appendix). At one center, enrollment was delayed, and no children = from=20 that center were among the first 6000 enrolled. At another center, = study=20 vaccines were exposed to temperatures outside the recommended storage = range,=20 leading to the exclusion of 870 children from the per-protocol = analysis. The=20 first 200 participants from each center contributed to the analysis of = reactogenicity and immunogenicity.

In total, 15,460 participants were enrolled, including 6537 infants = 6 to 12=20 weeks of age and 8923 children 5 to 17 months of age at the time of = the first=20 vaccination (Figure=20 2Figure 2Enrollment of All Children through May 31, 2011, = or=20 Receipt of Booster Dose.). The mean follow-up times were = 9=20 months in the younger age category and 18 months in the older age = category=20 after the administration of the first dose of a study vaccine (Table 7 = in the=20 Supplementary=20 Appendix). Baseline demographic characteristics were similar in = the two=20 study groups (Table 8 in the Supplementary=20 Appendix).

Vaccine=20 Efficacy against Clinical and Severe Malaria in the Older Age = Category

During 12 months of follow-up in the first 6000 children in the = older age=20 category, the incidence of the first or only episode of clinical = malaria=20 meeting the primary case definition was 0.44 per person-year in the = RTS,S/AS01=20 group and 0.83 per person-year in the control group, resulting in a = vaccine=20 efficacy of 55.8% (97.5% confidence interval [CI], 50.6 to 60.4) (Figure=20 3Figure 3Cumulative Incidence of First or Only Episodes = of Clinical=20 Malaria (Primary Case Definition) in the Older Age = Category.).=20 Evaluation of the proportionality of the hazard assumption showed that = vaccine=20 efficacy was not constant over time (P<0.001 by Schoenfeld = residuals)=20 (Table 9 in the Supplementary=20 Appendix), with vaccine efficacy higher at the beginning than at = the end=20 of the follow-up period. Vaccine efficacy against all clinical malaria = episodes was 55.1% (95% CI, 50.5 to 59.3), and estimates were = consistent=20 across all case definitions and in both adjusted and = intention-to-treat=20 analyses (Table=20 1).

At least one episode of severe malaria that met the primary case = definition=20 occurred in 57 of 2830 children (2.0%) in the RTS,S/AS01 group and in = 56 of=20 1466 children (3.8%) in the control group, for a vaccine efficacy of = 47.3%=20 (95% CI, 22.4 to 64.2) (Table=20 2).

Vaccine=20 Efficacy against Severe Malaria in the Pooled Age Categories

Among children in the combined age categories, at least one episode = of=20 severe malaria that met the primary case definition occurred in 149 of = 8597=20 children (1.7%) in the RTS,S/AS01 group and in 116 of 4364 children = (2.7%) in=20 the control group (Table=20 2). The average durations of follow-up were 16 months after the=20 administration of the third dose of a study vaccine (range, 0 to 22 = months) in=20 the older age category and 7 months (range, 0 to 15 months) in the = younger age=20 category. Vaccine efficacy against severe malaria in the pooled age = categories=20 was 34.8% (95% CI, 16.2 to 49.2). Vaccine efficacy was similar for the = secondary case definition and in the intention-to-treat population. = (The=20 clinical features of children with severe malaria are provided in = Table 10 in=20 the Supplementary=20 Appendix.)

Serious Adverse Events

In the older age category, serious adverse events were reported in = 1048 of=20 5949 children (17.6%; 95% CI, 16.7 to 18.6) in the RTS,S/AS01 group = and in 642=20 of 2974 children (21.6%; 95% CI, 20.1 to 23.1) in the control group = (Table=20 3Table 3Serious Adverse Events after the First Dose of a = Study=20 Vaccine in the Intention-to-Treat Population, According to Age=20 Category.). In the younger age category, the = corresponding rates=20 were 569 of 4358 children (13.1%; 95% CI, 12.1 to 14.1) in the = RTS,S/AS01=20 group and in 293 of 2179 children (13.4%; 95% CI, 12.0 to 15.0) in the = control=20 group (Table=20 3).

Similar proportions of children died in each study group. In the = older age=20 category, 56 of 5949 children (0.9%; 95% CI, 0.7 to 1.2) died in the=20 RTS,S/AS01 group and 28 of 2974 children (0.9%; 95% CI, 0.6 to 1.4) in = the=20 control group; in the younger age category, 49 of 4358 children (1.1%; = 95% CI,=20 0.8 to 1.5) died in the RTS,S/AS01 group and 18 of 2179 children = (0.8%; 95%=20 CI, 0.5 to 1.3) in the control group. Of the 151 children who died, 78 = (52%)=20 died in the hospital after a thorough medical assessment was made; 9% = of=20 deaths occurred at a health facility before completion of a full = medical=20 assessment, and 39% occurred in the community. Causes of death were = similar in=20 the two groups (Table 11 in the Supplementary=20 Appendix). Ten children died with a diagnosis of malaria, which = was=20 confirmed on blood smear in 7 children.

At least one serious adverse event that was considered to be = related to a=20 study vaccine occurred in 11 children in the older age category: 10 of = 5949=20 children in the RTS,S/AS01 group reported 12 events (7 seizures, 3 = episodes of=20 pyrexia, 1 episode of myositis, and 1 injection-site reaction) and 1 = of 2974=20 children in the control group reported 1 event (seizure). In the = younger age=20 category, serious adverse events that were considered to be related to = a study=20 vaccine occurred in 6 children: 3 of 4358 children in the RTS,S/AS01 = group=20 reported 3 events (1 injection-site reaction, 1 episode of pyrexia, = and 1=20 episode of febrile convulsion), and 3 of 2179 children in the control = group=20 reported 3 events (2 episodes of pyrexia and 1 episode of = anaphylaxis). All=20 children who had seizures that were deemed to be related to a study = vaccine=20 recovered from the acute event; epilepsy subsequently developed in 1=20 child.

Meningitis was reported more frequently in the RTS,S/AS01 group = than in the=20 control group, with 11 of 5949 children versus 1 of 2974 children in = the older=20 age category and 8 of 4358 children versus 1 of 2179 children in the = younger=20 age category, for a relative risk of 5.5 (95% CI, 0.7 to 42.6) in the = older=20 age category and 4.0 (95% CI, 0.5, 32.0) in the younger age category.=20 Laboratory diagnosis of meningitis, indicated by culture or elevated=20 white-cell count in cerebrospinal fluid, was made in half these cases. = There=20 was no apparent temporal relationship to vaccination or clustering = according=20 to center.

Seizure = within 7 Days=20 after Vaccination

In the older age category, the incidence of generalized convulsive = seizure=20 within 7 days after vaccination (according to the Brighton = Collaboration=20 diagnostic certainty level of 1 to 3) was 1.04 per 1000 doses in the=20 RTS,S/AS01 group (95% CI, 0.62 to 1.64) and 0.57 per 1000 doses in the = control=20 group receiving rabies vaccine (95% CI, 0.19 to 1.34), for a risk = ratio of 1.8=20 (95% CI, 0.6 to 4.9). All seizures occurred in children with a history = of=20 fever; 23 occurred within 7 days after vaccination, and of those, 12 = of 18=20 seizures occurred within 3 days after vaccination in the RTS,S/AS01 = group and=20 2 of 5 seizures in the control group. In the younger age category, the = incidence of generalized convulsive seizures within 7 days after = vaccination=20 was 0.16 per 1000 doses in the RTS,S/AS01 group (95% CI, 0.02 to 0.57) = and=20 0.47 per 1000 doses in the control group receiving meningococcal = vaccine (95%=20 CI, 0.10 to 1.37), for a risk ratio of 0.3 (95% CI, 0.1 to = 2.0).

Adverse Events

Unsolicited reports of adverse events that occurred within 30 days = after=20 each vaccination were reported with similar frequency in the two study = groups=20 (Table 12 in the Supplementary=20 Appendix). (The frequencies of solicited reports of symptoms in = the=20 intention-to-treat population are shown in Table 13 and Figure 3 in = the Supplementary=20 Appendix.) The most frequently reported symptoms were pain and = fever.=20 Overall, RTS,S/AS01 vaccine was more reactogenic than was rabies = vaccine, but=20 grade 3 symptoms occurred infrequently.

Immunogenicity

The geometric mean titer of anti=E2=80=93circumsporozoite antibody = at enrollment=20 was low in the two study groups and remained low in the control group = (Table=20 14 and Figure 4 in the Supplementary=20 Appendix). One month after the administration of the third dose of = a study=20 vaccine, 99.9% of children in the RTS,S/AS01 group were positive for=20 anti=E2=80=93circumsporozoite antibodies, with a geometric mean titer = of 621 EU per=20 milliliter (95% CI, 592 to 652).

Discussion

The RTS,S/AS01 candidate malaria vaccine reduced clinical episodes = of=20 malaria and severe malaria by approximately half during the 12 months = after=20 vaccination in children 5 to 17 months of age. These findings are = robust, with=20 narrow confidence limits and similar results in the per-protocol and=20 intention-to-treat populations and in the adjusted and unadjusted = analyses.=20 These efficacy results are consistent with those from phase 2 = trials.5,6

The level of protection provided by the RTS,S/AS01 vaccine to the = 6000=20 children 5 to 17 months of age was lower at the end of the 12-month=20 surveillance period than shortly after vaccination. The body of data = from=20 phase 2 studies of RTS,S/AS01 suggests a persistence in vaccine = efficacy.=20 However, varying study designs and statistical methods have led to = different=20 interpretations of the dynamics of efficacy over time, with some = studies=20 suggesting persistent protection and others suggesting waning = protection.7,21-25 Decreasing protection over time = could reflect=20 waning immunity, acquisition of natural immunity in the control group, = or=20 heterogeneity of exposure.26 Further follow-up and evaluation of the = effect of=20 a booster dose will provide a better understanding of the relative=20 contribution of these factors.

Vaccine efficacy against severe malaria in the pooled age = categories showed=20 a lower estimate than was seen in the first 6000 children in the older = age=20 category who were followed for 12 months (Table=20 2). Although the confidence limits on these estimates overlap, we = have=20 considered reasons that might explain the differing estimates. = Immunity=20 against severe malaria may have waned beyond the 12-month follow-up = period in=20 the older age category. Alternatively, vaccine efficacy may have been = lower in=20 the younger age category for a number of possible reasons. However, = the latter=20 supposition is not supported by phase 2 data, which have shown similar = efficacy against clinical malaria in younger and older children.6,7 The questions raised by these different = efficacy=20 estimates should be answered by continuation of follow-up of children = in the=20 trial. In 1 year, we will report vaccine efficacy against clinical and = severe=20 malaria in the younger age category, and at study end, we will report = the=20 duration of efficacy in each age category.

Despite the relatively high vaccine efficacy against severe = malaria, we did=20 not observe a reduction in the rate of death from malaria or from any = cause in=20 the RTS,S/AS01 group. Malaria-specific mortality was very low in the = trial,=20 representing only 10 of the 151 reported deaths (6.6%). Seven of these = deaths=20 were confirmed to have been caused by malaria on blood smears. Since = the rate=20 of death from malaria was low, we would not expect to be able to = detect a=20 reduction in the rate of death from any cause unless RTS,S/AS01 also = provided=20 protection against coexisting illnesses and the associated deaths. We=20 attribute the very low malaria-specific mortality in this trial to the = high=20 level of access to high-quality care provided at study facilities. The = low=20 malaria-specific mortality is unlikely to be due to misclassification = of=20 moderate malaria as severe malaria. Children who were classified as = having=20 severe malaria had objective clinical markers of severe disease, and = nearly=20 half had two or more markers. Approximately 3% of children with = clinical=20 malaria and 35% of those who were hospitalized with malaria were = classified as=20 having severe malaria, consistent with reported estimates.27 At the end of the study, a formal = analysis of=20 vaccine efficacy against death will be conducted.

In the older age category, RTS,S/AS01 was more reactogenic than = rabies=20 vaccine in terms both of systemic and local effects. However, few = reactions=20 were severe. Generalized convulsive seizures in the 7 days after = RTS,S/AS01=20 vaccination occurred at a rate of approximately 1 per 1000 vaccine = doses, a=20 higher rate than that seen with the comparator rabies vaccine. All = cases were=20 associated with a history of fever, and all children recovered from = the acute=20 event. The increase in the rate of meningitis in the RTS,S/AS01 group = is being=20 monitored. Additional data from ongoing follow-up will clarify the=20 relationship with the study intervention. However, the lack of a = temporal=20 association with vaccination and low biologic plausibility suggest = that these=20 events are unlikely to be related to the vaccine.

The trial was conducted with rigorous standardization among centers = and=20 provided a high standard of clinical care.12 Participants from one center were = excluded from=20 the per-protocol analyses because vaccines at that center were exposed = to=20 temperatures outside the recommended range. However, participants at = this=20 center were included in the intention-to-treat analyses, with similar = results=20 to those in the per-protocol analyses.

Our initial results show that the RTS,S/AS01 vaccine reduced = malaria by=20 half in children 5 to 17 months of age during the 12 months after = vaccination=20 and that the vaccine has the potential to have an important effect on = the=20 burden of malaria in young African children. Additional information on = vaccine=20 efficacy among young infants and the duration of protection will be = critical=20 to determining how this vaccine could be used most effectively to = control=20 malaria.

Supported by GlaxoSmithKline Biologicals (GSK) and the PATH Malaria = Vaccine=20 Initiative, which received a grant from the Bill and Melinda Gates=20 Foundation.

Disclosure=20 forms provided by the authors are available with the full text of = this=20 article at NEJM.org.

This article (10.1056/NEJMoa1102287) was published on October 18, = 2011, at=20 NEJM.org.

Source Information

Address reprint requests to Ms. Kelsey Mertes at PATH Malaria = Vaccine=20 Initiative, Communications and Advocacy Unit, 455 Massachusetts Ave. = NW, Suite=20 1000, Washington, DC 20001-2621, or at kmertes@path.org.

The authors are listed in the Appendix. All the authors assume=20 responsibility for the overall content and integrity of the=20 article.

Appendix

The authors are as follows: Albert Schweitzer Hospital, = Lambarene,=20 Gabon, and Institute of Tropical Medicine, University of = T=C3=BCbingen, T=C3=BCbingen,=20 Germany: Selidji Todagbe Agnandji, M.D., M.P.H., Bertrand Lell, = M.D.,=20 Solange Solmeheim Soulanoudjingar, M.D., Jos=C3=A9 Francisco = Fernandes, M.D.,=20 B=C3=A9atrice Peggy Abossolo, M.D., Cornelia Conzelmann, Barbara = Gaelle Nfono Ondo=20 Methogo, M.D., Yannick Doucka, Arnaud Flamen, M.D., Benjamin = Mordm=C3=BCller, M.D.,=20 Saadou Issifou, M.D., Ph.D., Peter Gottfried Kremsner, M.D.; Centro = de=20 Investiga=C3=A7=C3=A3o em Sa=C3=BAde de Manhi=C3=A7a, Manhi=C3=A7a, = Mozambique: Jahit Sacarlal,=20 M.D., M.P.H., Ph.D., Pedro Aide, M.D., Miguel Lanaspa, M.D., John J. = Aponte,=20 M.D., Ph.D., Arlindo Nhamuave, B.Sc., Diana Quelhas, Ph.D., Quique = Bassat,=20 M.D., Ph.D., Sofia Mandjate, B.Sc., Eus=C3=A9bio Macete, M.D., M.P.H., = Ph.D., Pedro=20 Alonso, M.D., Ph.D.; Ifakara Health Institute, Bagamoyo, = Tanzania:=20 Salim Abdulla, M.D., Ph.D., Nahya Salim, M.D., Omar Juma, M.D., = Mwanajaa=20 Shomari, B.Sc., Kafuruki Shubis, M.Sc., Francisca Machera, A.M.O., Ali = Said=20 Hamad, M.D., Rose Minja, C.O., Maxmillian Mpina, M.Sc., Ali Mtoro, = M.D., Alma=20 Sykes, M.D., Saumu Ahmed, M.D., Alwisa Martin Urassa, M.P.H., Ali = Mohammed=20 Ali, M.Sc., Grace Mwangoka, M.V.M., Marcel Tanner, Ph.D.; Institut = de=20 Recherche en Science de la Sant=C3=A9, Nanoro, Burkina Faso: = Halidou Tinto,=20 Pharm.D., Ph.D., Umberto D'Alessandro, M.D., Ph.D., Hermann Sorgho, = Ph.D.,=20 Innocent Valea, Pharm.D., Marc Christian Tahita, Pharm.D., William = Kabor=C3=A9,=20 M.D., Sayouba Ou=C3=A9draogo, M.Sc., Yara Sandrine, Pharm.D., Robert = Tinga=20 Guiguemd=C3=A9, M.D., Ph.D., Jean Bosco Ou=C3=A9draogo, M.D., Ph.D.; = KEMRI/CDC=20 Research and Public Health Collaboration, Kisumu, Kenya: Mary J. = Hamel,=20 M.D., D.T.M.&H., Simon Kariuki, Ph.D., Chris Odero, Dip.Clin.Med., = H.N.D.P.H., Martina Oneko, M.D., Kephas Otieno, H.N.D.M.L.T., Norbert = Awino,=20 P.Dip.P.M., Jackton Omoto, M.B., Ch.B., John Williamson, Sc.D., = Vincent=20 Muturi-Kioi, M.B., Ch.B., Kayla F. Laserson, Sc.D., Laurence Slutsker, = M.D.,=20 M.P.H.; KEMRI=E2=80=93Walter Reed Project, Kombewa, Kenya: = Walter Otieno, M.D.,=20 M.Med.,Ph.D., Lucas Otieno, M.D., M.P.H., Otsyula Nekoye, M.D., Stacey = Gondi,=20 M.A., Allan Otieno, M.D., Bernhards Ogutu, M.D., Ph.D., Ruth Wasuna, = B.Pharm.,=20 Victorine Owira, B.A., David Jones, M.D., M.P.H., Agnes Akoth Onyango, = R.N.;=20 KEMRI=E2=80=93Wellcome Trust Research Program, Kilifi, Kenya: = Patricia Njuguna,=20 M.B., Ch.B., Roma Chilengi, M.D., M.P.H., Pauline Akoo, M.B., Ch.B., = Christine=20 Kerubo, M.B., Ch.B., Jesse Gitaka, M.B., Ch.B., Charity Maingi, R.N., = M.P.H.,=20 Trudie Lang, Ph.D., Ally Olotu, M.B., Ch.B., Benjamin Tsofa, B.D.S., = M.Sc.,=20 Philip Bejon, M.B., B.S., D.T.M.&H., Ph.D., Norbert Peshu, M.B., = Ch.B.,=20 D.T.M.&H., Kevin Marsh, M.D., M.R.C.P., D.T.M.&H.; Kintampo = Health=20 Research Center, Kintampo, Ghana: Seth Owusu-Agyei, Ph.D., Kwaku = Poku=20 Asante, M.D., M.P.H., Kingsley Osei-Kwakye, M.D., M.P.H., Owusu = Boahen,=20 M.P.H., Samuel Ayamba, M.D., M.P.H., Kingsley Kayan, B.Sc., Ruth = Owusu-Ofori,=20 M.D., M.P.H., David Dosoo, M.Sc., Isaac Asante, M.B.A., George Adjei, = M.Sc.,=20 Evans Kwara, M.D., Daniel Chandramohan, M.D., Ph.D., Brian Greenwood, = M.D.;=20 National Institute for Medical Research, Korogwe, Tanzania: = John=20 Lusingu, M.D., Ph.D., Samwel Gesase, M.D., Anangisye Malabeja, M.D., = Omari=20 Abdul, M.D., Hassan Kilavo, B.Sc., Coline Mahende, M.Sc., Edwin = Liheluka,=20 B.A., Martha Lemnge, Ph.D., Thor Theander, M.D., D.D.Sc., Chris = Drakeley,=20 Ph.D.; School of Medical Sciences, Kumasi, Ghana: Daniel = Ansong, M.B.,=20 Ch.B., Tsiri Agbenyega, M.B., Ch.B., Ph.D., Samuel Adjei, M.B., Ch.B., = P.G.Dip., Harry Owusu Boateng, M.B., Ch.B., M.P.H., M.W.A.C.P., = Theresa=20 Rettig, M.D., John Bawa, M.B.A., Justice Sylverken, M.B., Ch.B., = Grad.Dip.,=20 M.W.A.C.P., David Sambian, Dip.Lab.Tech., Alex Agyekum, M.Phil., Larko = Owusu,=20 M.B., Ch.B., M.W.A.C.P.; University of North Carolina Project, = Lilongwe,=20 Malawi: Francis Martinson, M.B., Ch.B., M.P.H., Ph.D., Irving = Hoffman,=20 M.P.H., Tisungane Mvalo, M.B., B.S., Portia Kamthunzi, M.B., B.S., = Ruthendo=20 Nkomo, M.B., Ch.B., Albans Msika, Dip.Clin.Med., Allan Jumbe, P.G.D.,=20 H.M.G.M., N.M.T., Nelecy Chome, R.G.N., Dalitso Nyakuipa, = Dip.Med.Lab.Tech.,=20 Joseph Chintedza, Dip.Computer.Sc.; GlaxoSmithKline, Wavre, Belgium = (in=20 alphabetical order): W. Ripley Ballou, M.D., Myriam Bruls, M.Sc., = Joe=20 Cohen, Ph.D., Yolanda Guerra, M.D., Erik Jongert, Ph.D., Didier = Lapierre,=20 M.D., Amanda Leach, M.R.C.P.C.H., Marc Lievens, M.Sc., Opokua = Ofori-Anyinam,=20 Ph.D., Johan Vekemans, M.D., Ph.D.; and PATH Malaria Vaccine = Initiative,=20 Washington, D.C. (in alphabetical order): Terrell Carter, M.H.S., = Didier=20 Leboulleux, M.D., Christian Loucq, M.D., Afiya Radford, B.S., Barbara=20 Savarese, R.N., David Schellenberg, M.D., Marla Sillman, M.S., Preeti=20 Vansadia, M.H.S.

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<= /OL>

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The New England Journal of = Medicine

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in = African=20 Children

Background

Methods

Results

Conclusions

Media in This Article

Methods

Study Design

Randomization and=20 Vaccination

Surveillance for=20 Clinical and Severe Malaria

Safety Surveillance

Immunogenicity

Laboratory and = Radiologic=20 Procedures

Study Oversight

Statistical Analysis

Results

Study Population

Serious Adverse Events

Seizure = within 7 Days=20 after Vaccination

Adverse Events

Immunogenicity

Discussion

Source Information

Appendix

References

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