E-DRUG: NEJM on malaria vaccine for African children
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[The article is very long and detailed. Methods and discussion are provided here.
The full text is available free at
http://www.nejm.org/doi/full/10.1056/NEJMoa1102287 ]
First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children
Authors: The RTS,S Clinical Trials Partnership
October 18, 2011 (10.1056/NEJMoa1102287)
Comments open through October 24, 2011
Each year, malaria occurs in approximately 225 million persons worldwide, and 781,000 persons, mostly African children, die from the disease.1 During the past decade, the scale-up of malaria-control interventions has resulted in considerable reductions in morbidity and mortality associated with malaria in parts of Africa.2,3 However, malaria continues to pose a major public health threat. A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa.4
The RTS,S vaccine that targets the circumsporozoite protein and is given with an adjuvant system (AS01 or AS02) has consistently shown protection against Plasmodium falciparum malaria in children and infants in phase 2 trials.5-10 The vaccine had an acceptable side-effect profile and was immunogenic in children who were 6 weeks of age or older. In addition, the vaccine could be administered safely with other childhood vaccines8,11 and provided protection against severe malaria.5 Here, we report the initial results of an ongoing phase 3 trial being conducted at 11 centers in 7 African countries (Figure 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
METHODS
Study Design
Detailed methods are presented in the Supplementary Appendix and have been reported previously.12-15 This randomized, controlled, double-blind trial was designed to evaluate vaccine efficacy, safety, reactogenicity, and immunogenicity in children up to 32 months after the administration of the first dose of vaccine. The trial included two age categories: children 6 to 12 weeks of age and those 5 to 17 months of age at enrollment. The trial included three study groups in each age category: children who received all three doses of the RTS,S/AS01 vaccine administered at 1-month intervals and who were scheduled to receive a booster dose 18 months after the third dose, children who received the RTS,S/AS01 primary vaccination series without a booster, and a control group who received a non-malaria comparator vaccine. This first analysis combines the first two groups (referred to as the RTS,S/AS01 group) and compares this group with the control group (Figure 2 in the Supplementary Appendix). Children in the younger age category received the RTS,S/AS01 vaccine along with routine childhood vaccinations beginning at 6 weeks of age.
The coprimary end points of the trial — vaccine efficacy against clinical malaria after 12 months of follow-up in each age category — have been completed for the first 6000 children enrolled in the older age category. Vaccine efficacy against severe malaria will be reported after 12 months of follow-up of the first 6000 children enrolled in each age category. Accordingly, vaccine efficacy against both clinical and severe malaria in the older age category is presented here, and findings regarding efficacy will be presented for the younger age category in approximately 1 year, after the first 6000 children in that age category have completed 12 months of follow-up. A secondary analysis of vaccine efficacy against severe malaria in the pooled age categories was planned to take place when at least one severe malaria episode had occurred in at least 250 children. This milestone was reached on May 31, 2011. Vaccine efficacy against severe disease in the pooled age categories is restricted to data obtained up to this date. Data for children who received a booster dose of vaccine before May 31, 2011, were censored at the time of booster vaccination.
The trial protocol, which is available at NEJM.org, was approved by the ethical review board and national regulatory authority at each study center and partner institution. Written informed consent was obtained from the children's parents or guardians (Table 1 in the Supplementary Appendix). The trial was undertaken in accordance with the provisions of the Good Clinical Practice Guidelines.16
DISCUSSION
The RTS,S/AS01 candidate malaria vaccine reduced clinical episodes of malaria and severe malaria by approximately half during the 12 months after vaccination in children 5 to 17 months of age. These findings are robust, with narrow confidence limits and similar results in the per-protocol and intention-to-treat populations and in the adjusted and unadjusted analyses. 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 children 5 to 17 months of age was lower at the end of the 12-month surveillance period than shortly after vaccination. The body of data from phase 2 studies of RTS,S/AS01 suggests a persistence in vaccine efficacy. However, varying study designs and statistical methods have led to different interpretations of the dynamics of efficacy over time, with some studies suggesting persistent protection and others suggesting waning protection.7,21-25 Decreasing protection over time could reflect waning immunity, acquisition of natural immunity in the control group, or heterogeneity of exposure.26 Further follow-up and evaluation of the effect of a booster dose will provide a better understanding of the relative contribution of these factors.
Vaccine efficacy against severe malaria in the pooled age categories showed a lower estimate than was seen in the first 6000 children in the older age category who were followed for 12 months (Table 2). Although the confidence limits on these estimates overlap, we have considered reasons that might explain the differing estimates. Immunity against severe malaria may have waned beyond the 12-month follow-up period in the older age category. Alternatively, vaccine efficacy may have been lower in the younger age category for a number of possible reasons. However, the latter 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 estimates should be answered by continuation of follow-up of children in the trial. In 1 year, we will report vaccine efficacy against clinical and severe malaria in the younger age category, and at study end, we will report the duration of efficacy in each age category.
Despite the relatively high vaccine efficacy against severe malaria, we did not observe a reduction in the rate of death from malaria or from any cause in the RTS,S/AS01 group. Malaria-specific mortality was very low in the trial, representing only 10 of the 151 reported deaths (6.6%). Seven of these deaths were confirmed to have been caused by malaria on blood smears. Since the rate of death from malaria was low, we would not expect to be able to detect a reduction in the rate of death from any cause unless RTS,S/AS01 also provided protection against coexisting illnesses and the associated deaths. We attribute the very low malaria-specific mortality in this trial to the high level of access to high-quality care provided at study facilities. The low malaria-specific mortality is unlikely to be due to misclassification of moderate malaria as severe malaria. Children who were classified as having severe malaria had objective clinical markers of severe disease, and nearly half had two or more markers. Approximately 3% of children with clinical malaria and 35% of those who were hospitalized with malaria were classified as having severe malaria, consistent with reported estimates.27 At the end of the study, a formal analysis of vaccine efficacy against death will be conducted.
In the older age category, RTS,S/AS01 was more reactogenic than rabies vaccine in terms both of systemic and local effects. However, few reactions were severe. Generalized convulsive seizures in the 7 days after RTS,S/AS01 vaccination occurred at a rate of approximately 1 per 1000 vaccine doses, a higher rate than that seen with the comparator rabies vaccine. All cases were associated with a history of fever, and all children recovered from the acute event. The increase in the rate of meningitis in the RTS,S/AS01 group is being monitored. Additional data from ongoing follow-up will clarify the relationship with the study intervention. However, the lack of a temporal association with vaccination and low biologic plausibility suggest that these events are unlikely to be related to the vaccine.
The trial was conducted with rigorous standardization among centers and provided a high standard of clinical care.12 Participants from one center were excluded from the per-protocol analyses because vaccines at that center were exposed to temperatures outside the recommended range. However, participants at this center were included in the intention-to-treat analyses, with similar results to those in the per-protocol analyses.
Our initial results show that the RTS,S/AS01 vaccine reduced malaria by half in children 5 to 17 months of age during the 12 months after vaccination and that the vaccine has the potential to have an important effect on the burden of malaria in young African children. Additional information on vaccine efficacy among young infants and the duration of protection will be critical to determining how this vaccine could be used most effectively to control malaria.
Supported by GlaxoSmithKline Biologicals (GSK) and the PATH Malaria Vaccine Initiative, which received a grant from the Bill and Melinda Gates Foundation.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article (10.1056/NEJMoa1102287) was published on October 18, 2011, at NEJM.org.
SOURCE INFORMATION
Address reprint requests to Ms. Kelsey Mertes at PATH Malaria Vaccine Initiative, Communications and Advocacy Unit, 455 Massachusetts Ave. NW, Suite 1000, Washington, DC 20001-2621, or at kmertes@path.org.
The authors are listed in the Appendix. All the authors assume responsibility for the overall content and integrity of the article.
Information provided by
Dr Valeria Frighi
University Dept. of Psychiatry
Neurosciences Building
Warneford Hospital
Oxford
OX3 7JX
UK
Valeria Frighi <valeria.frighi@psych.ox.ac.uk>