A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

New England Journal of Medicine
December 13, 2012  Vol. 367 No. 24
http://content.nejm.org/current.shtml

Original Articles
A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants
The RTS,S Clinical Trials Partnership

Abstract
Background
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.

Methods
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.

Results
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).

Conclusions
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.)

Editorials
Malaria Vaccine Trials — Beyond Efficacy End Points
J.P. Daily

Extract [First 100 words]

Plasmodium falciparum infection, malaria, continues to cause more than 1 million childhood deaths each year.1 In addition, millions of nonlethal infections affect communities on an economic basis and inhibit children from reaching their full developmental potential.2 The creation of an effective vaccine has been a long-sought, elusive goal.

The first results of the phase 3 trial of the candidate malaria vaccine RTS,S/AS01, which is being conducted in seven African countries, were reported for children 5 to 17 months of age at enrollment, with a vaccine efficacy of 56% against all clinical malaria infections and 47% against severe malaria during a . . .