Promising trials of malaria vaccine in East Africa lead to calls for Phase 3 development

Experts are recommending that a malaria vaccine progress to Phase 3 trials following the successful trial of the RTS, S/AS01E malaria vaccine among 5-17 month old children in Korogwe, Tanzania and coastal Kenya, which is reported today in the New England Journal of Medicine (NEJM).

In a separate paper, which also appears in the online journal today, the findings are presented of the first co-administration of the RTS, S/AS02 malaria vaccine through the WHO Expanded Program on Immunization (EPI) in infants living in an area of perennial transmission in Tanzania.

The RTS,S vaccine was invented, developed and manufactured by GlaxoSmithKline Biologicals, an active partner and the sponsor of the trials. Funding and technical support for the studies was provided by the PATH Malaria Vaccine Initiative (MVI) through a grant provided by the Bill & Melinda Gates Foundation.

Malaria persists as a major public health problem, and new tools for control of the disease are needed to facilitate the current renewed commitment for its control or elimination.

The first paper reports on the findings of a double-blind randomized trial of a novel formulation of the malaria candidate vaccine (RTS/S/AS01E, which was invented, developed and manufactured by GSK Biologicals) conducted in Tanzania and Kenya by a team of international experts. 894 children aged between 5 and 17 months, a target population for vaccine licensure, were treated and followed up between 4.5 and 10 months.

A team from the London School of Hygiene & Tropical Medicine (LSHTM) including Lorenz von Seidlein, Reader in Clinical Epidemiology, Chris Drakeley, Senior Lecturer, clinical trials manager Jayne Gould, and Eleanor Riley, Professor of Immunology, all in the Department of Infectious Diseases, led the work in Korogwe, Tanzania in collaboration with Dr John Lusingu and colleagues from the Tanzanian National Institute for Medical Research. Dr Philip Bejon of the Kenya Medical Research Institute (KEMRI) Wellcome Collaborative Research Programme and the Centre for Tropical Medicine, University of Oxford, led similar efforts in Kilifi, Kenya.

Among the 835 children who were vaccinated according to protocol, estimated vaccine efficacy against clinical malaria was 53%. A strong immune response was detected, and the vaccine was safe. There were fewer serious adverse events among the RTS,S/AS01E vaccine recipients.

Based on the findings, the authors recommend a multi-centre Phase 3 trial of the RTS, S vaccine which will lead to an application for licensure if these findings are confirmed.

In a second paper, a team including David Schellenberg, Professor of Malaria & International Health at LSHTM, reports that a slightly different formulation of the vaccine candidate, which is being developed for delivery through the EPI, has a promising safety profile and does not react adversely with other antigens being administered as part of the immunization programme. The vaccine also showed a reduction in the incidence of malaria infection by 65%, a welcome but unexpected finding given that this was primarily designed as a safety and immunogenicity trial with only 340 infants enrolled.

Chris Drakeley comments: 'These two important papers add to the data on RTS,S, making a strong case for moving forward to large-scale vaccination in phase 3 trials. The formulation of RTS,S with the ASO1E adjuvant has improved vaccine efficacy considerably. Testing the vaccine in a broad range of epidemiological settings will show if it is suitable for inclusion in routine vaccination programmes throughout sub-Saharan Africa'.

Professor Riley recommends further investigation: 'In numerous trials, in different countries with differing levels of malaria risk, this vaccine has consistently protected young children against malaria infection and against clinical episodes of malaria, and the new ASO1E vaccine formulation has significantly enhanced the potency of the vaccine. However, we still don't have a clear idea of how the vaccine works and we don't yet have a laboratory test that will identify which vaccine recipients are fully protected. Detailed immunological investigations of vaccine recipients and controls are now required to obtain a better understanding of the protective immune mechanisms that are induced and to obtain immunological correlates of protection'.

Professor Schellenberg comments: 'I'm delighted to have been able to support my colleagues at the Ifakara Health Institute in the conduct of this important study. It's the first time the vaccine has been given alongside routine vaccinations and we're really pleased to see that it was well tolerated, stimulated a detectable immune response and protected against malaria infection. The scene is now set for a larger-scale evaluation of the effect of this vaccine in a range of settings'.

Professor Sir Andrew Haines, Director of the London School of Hygiene & Tropical Medicine, concludes: 'The two malaria vaccine trials published in the New England Journal of Medicine this week demonstrate that substantial progress is being made in research to address one of the major global public health challenges – falciparum malaria. Both trials show promising efficacy of the candidate vaccines. One trial specifically looks at whether the vaccine in question can be co-administered with standard childhood vaccines delivered through the Expanded Programme and concludes that it does not appear to reduce the responses to these other vaccines. These results suggest that the way is now open to undertaking large scale Phase III trials in malaria endemic areas. I am delighted that Staff of the London School of Hygiene and Tropical Medicine have contributed substantially to this important research'.