London School of Hygiene & Tropical Medicine

News that the RTS,S vaccine has been found in trials to halve the risk of malaria in children attracted headlines around the world recently. In this analysis, Dr Colin Sutherland, Reader in Parasitology at the School, takes a closer look at what the results mean and asks where we do we go from here?

Analysis - what did they find?

A publication in the New England Journal of Medicine presented preliminary results from a large, ongoing Phase III trial of the malaria vaccine RTS,S/AS01. The project is currently led and funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative, and has enjoyed sustained support from the Bill and Melinda Gates Foundation. An impressive consortium of African research institutions with North America and European partners, including LSHTM, are carrying out the study in Burkina Faso, Gabon, Ghana, Kenya, Mozambique, Malawi and Tanzania. 15,460 children under 18 months of age are participating.

So, if the trial is not yet complete, why is there a fuss right now? A preliminary estimate of vaccine efficacy has been derived from analysis of the first 6,000 of 5 months age or older, and found evidence of vaccine-induced protection against clinical malaria over the first 12 months in children receiving three doses of RTS,S, compared to the control group which received a course of rabies vaccine. If all 6,000 children are included in this analysis, over 2,000 had at least one episode of documented malaria illness and the efficacy of the vaccine is estimated to be 50.4%; this estimate rises to 55.8% if the analysis included only those 4,296 children who were treated exactly “per protocol”. Thus the study authors reasonably conclude that the vaccine prevented half of the malaria attacks in the 5 – 17 month age-group, and highlighted a pleasing reduction of over 40% in severe malaria cases in the older children, and a reduction of about 35% across both age groups.

The burden of malaria in Africa

Many staff and students at LSHTM have witnessed first-hand the impact of malaria on African communities. One morning in 2000, while conducting a clinical trial at Farafenni, in The Gambia, I was examining a blood film down my microscope. A local man walked quietly into the laboratory and handed me a small, wrapped bundle –the body of his small child, who had probably died during the night. All we could do was provide transport to the local hospital to confirm the death, and assist with transport back to his village some kilometres away. The death of this child might have been prevented if effective antimalarial drugs were available in that village, but ensuring universal access to such treatment in poor rural areas is a huge challenge. Effective infant vaccination against malaria, were it available, would go a long way to preventing these unnecessary child deaths. Whereas vaccine roll-out is of course a challenge in itself, the success of the Extended Programme of Immunisation demonstrates that good coverage can be achieved. RTS,S has been developed with delivery as part of the EPI a likely strategy, and as such could be rapidly added to existing vaccination efforts, should the purchase costs be affordable to African governments. A vaccine able to prevent about half of all episodes of malaria illness, and likely to be delivered efficiently through the EPI is likely to be a very beneficial public health intervention for African children.

Key conclusions – what does it mean for malaria in Africa?

So is the excitement we have seen recently warranted? My answer would be a carefully qualified “yes”. It has to be “yes” because no malaria vaccine has ever progressed to Phase III before, as all bar RTS,S have been defeated by the (necessary) stringency of Phase I and II testing. It has to be “yes” because a 50% reduction of malaria illness (and 30-40% fewer severe cases) in children in Africa means many thousands of malaria deaths prevented each year, many more kids surviving to attend school, and surviving other infections usually worsened by having malaria at the same time. It means healthier, happier kids achieving more and progressing further through the education system, and as adults contributing successfully to the social and economic well-being of their countries. Yet this “yes” must be qualified, because these are only preliminary results, and there is so much more we need to know. Analysis of efficacy in the younger age group will not be available for some time, and important analysis of safety data across all sites for the full duration of follow-up is required before the licensing of this vaccine could proceed.

Where do we go from here?

The developers of the RTS,S vaccine should be congratulated and encouraged but it’s not the end of the story – it’s just the start. It will take a couple of years for the final Phase III evaluation to be published, and as the full trial results are digested and considered, a timetable for eventual licensing of this vaccine may emerge. Yet there is so much more we could hope for from a vaccine against malaria: a formulation that protects adults; a vaccine for vivax malaria, not to mention P. ovale sp and P. malariae; high efficacy (>90%) so that travellers may be adequately protected during short periods of exposure; a vaccine formulation suitable for use in pregnancy to protect mother and foetus. The results this week prove beyond reasonable doubt that a malaria vaccine is possible. RTS,S may well turn out to be the first malaria vaccine to be deployed; in that case we should all hope it isn’t the last.