Implementation of RTS,S/AS01 Malaria Vaccine — The Need for Further Evidence

Sunday, 10th of July 2016

Implementation of RTS,S/AS01 Malaria Vaccine — The Need for Further Evidence

John Clemens, M.D., and Vasee Moorthy, B.M., B.Ch., Ph.D.

N Engl J Med 2016; 374:2596-2597June 30, 2016DOI: 10.1056/NEJMe1606007

In 2015, an estimated 438,000 people died from malaria.1 The overwhelming majority of these deaths occurred in young African children who were infected with Plasmodium falciparum. An effective vaccine would represent an important additional tool in the control of malaria. The most advanced of the current candidates against P. falciparum is RTS,S/AS01, a recombinant vaccine against the pre-erythrocytic stage of the parasite in which regions of P. falciparum circumsporozoite protein are fused to hepatitis B surface antigen.2 This vaccine was developed by a public–private partnership, with support from the Bill and Melinda Gates Foundation, and investigators have completed a randomized, double-blind, phase 3 trial involving 15,459 infants and young children in seven countries in sub-Saharan Africa.3

In this trial, children 5 to 17 months of age and infants 6 to 12 weeks of age were randomly assigned to receive three doses of the malaria vaccine or a comparator vaccine, administered intramuscularly at 1-month intervals, with or without a fourth dose given 20 months after the first; participants were followed by means of passive surveillance. There were several salient findings over the 4-year follow-up in the modified intention-to-treat analyses of the group of children who were assigned to receive the first dose at 5 to 17 months of age and received at least one dose. Overall protection against all malaria episodes by the malaria vaccine was 28% (95% confidence interval [CI], 23 to 33) in the three-dose group and 36% (95% CI, 32 to 41) in the four-dose group. The malaria vaccine efficacy declined over time and became negligible after 32 months of follow-up among participants in the three-dose group; the vaccine efficacy declined more slowly in the four-dose group than in the three-dose group and remained low but significant at the end of follow-up.

The magnitude of vaccine protection against severe malaria was 1% (95% CI, −23 to 21) in the three-dose group and 32% (95% CI, 14 to 47) in the four-doses group and waned rapidly to nil levels at 20 months after the first dose in each cohort. Among infants who were assigned to receive the first dose at 6 to 12 weeks of age, the vaccine efficacy of either the three-dose or the four-dose regimen against all malaria episodes was lower than the efficacy in the 5-to-17-month group overall and during the initial 32 months of follow-up. Finally, among children who were assigned to receive a first dose at 5 to 17 months of age, those who received the RTS,S/AS01 vaccine had a higher risk of febrile convulsions than those who received the control vaccine; they also had potential safety signals for cerebral malaria and meningitis.

Models that used these data projected a significant preventive effect of the two malaria-vaccine regimens on clinical caseload and mortality, as well as a favorable cost-effectiveness profile, in the 5-to-17-month group across geographic areas with a wide range of intensities of malaria transmission.4 In addition, a review by the European Medicines Agency indicated an acceptable vaccine quality and risk–benefit ratio.5 In view of the poor performance of the two dosing regimens in the 6-to-12-week age group and the three-dose regimen in the 5-to-17-month age group, the World Health Organization (WHO) gave support only to the four-dose regimen in the 5-to-17-month age group. However, because of residual questions about programmatic feasibility, preventive effect, and safety, the WHO recommended that more evidence be generated in pilot implementation studies in three to five sub-Saharan countries with moderate-to-high levels of malaria transmission.6,7

In this issue of the Journal, investigators from Kilifi, Kenya, one of the sites in the phase 3 trial, report on the extended follow-up of an earlier, phase 2, randomized, double-blind trial of a three-dose regimen of RTS,S/AS01 in 447 children who were 5 to 17 months of age at the receipt of the first dose.8 Earlier analyses of this trial showed a decline of vaccine efficacy against all malaria episodes, from 44% (95% CI, 16 to 62) in the first year to nil in the fourth year of follow-up, with lower levels of efficacy among children residing in areas with higher levels of malaria transmission.9 The investigators now report that during the fifth through seventh years of surveillance, there was an apparent negative rebound in vaccine efficacy, which is attributable to negative values for efficacy among children with higher-than-average exposure to malaria. As compared with the earlier article, which reported that 65 cases of malaria were averted by vaccination per 100 vaccinated children, the extended follow-up analysis estimated only 32 cases averted per 100 vaccinated children, including an excess of approximately 14 cases per 100 vaccinated children in the high-exposure cohort.

The interpretation of these findings requires caution, in view of the high attrition of the original cohort over time and the emergence of these findings in the context of many analyses, with the attendant risk of increased type I error. In addition, the trial evaluated only a three-dose regimen, which has not been recommended by the WHO, and the field site for the trial had substantially lower rates of malaria transmission than many of the sites in the phase 3 trial. Fortunately, three other sites participating in the phase 3 trial are extending surveillance beyond the fourth year and include cohorts receiving either a three-dose or four-dose regimen; these sites will provide an important resource to test and better understand the findings of this trial. To maximize the usefulness and ensure the validity of these additional trials, it will be critical that the analyses be done conjointly, with the use of common a priori analytic plans and definitions. In the meantime, it would be unwise to postpone the planning of the WHO-recommended pilot implementation studies, which will be designed to yield data of importance to decisions regarding the deployment of this vaccine.

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

The views expressed in this article are those of the authors and should not be taken to be the policy or position of the World Health Organization.

Source Information

From iccdr,b, Dhaka, Bangladesh (J.C.); the University of California Los Angeles Fielding School of Public Health, Los Angeles (J.C.); and the World Health Organization, Geneva (V.M.).

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Full Text

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