The findings will help to inform which populations are likely to benefit most from the vaccine candidate. They also have important implications for the design of future clinical trials of this and other vaccine candidates and highlight the importance of long-term follow-up studies for assessing vaccine efficacy.
The study involved 447 children in Kilifi, Kenya, who had been part of an earlier phase II trial to assess the safety and efficacy of the vaccine candidate. Of the 447 children, 320 completed four years of follow-up. The analysis, which was published today in the 'New England Journal of Medicine', was designed to look at how well the vaccine candidate protects against malaria over time.
Initial results from larger ongoing phase III studies showed that the candidate RTS,S vaccine reduced malaria over 12 months of follow-up by approximately half in young children and one-third in infants. The new findings on long-term follow-up of an earlier phase II study reveal that the vaccine efficacy dropped from 43.6 per cent protection against malaria in the first year to zero by the fourth year after vaccination.
The study's senior author, Dr Phillip Bejon (Research Fellow at the KEMRI-Wellcome Trust Research Programme and the Centre for Tropical Medicine, University of Oxford), said: "Despite the falling efficacy over time, there is still a clear benefit to the vaccine candidate. Many of the children will experience multiple episodes of clinical malaria infection, but overall we found that 65 cases of malaria were averted over the four-year period for every 100 children vaccinated. We now need to look at whether offering a vaccine booster can sustain efficacy for longer."
The study also shows that relative vaccine efficacy declines with increasing exposure to malaria, from 45.1 per cent among children with below-average exposure to malaria to 15.9 per cent among children with above-average exposure to malaria. The relative efficacy describes the number of cases of malaria that were avoided by vaccination as a percentage of the total number of cases in that group: because there were many more cases of malaria at higher exposure, the cases averted per 100 children vaccinated actually increased from 62 at below-average exposure to 78 at above-average exposure.
The study's lead author, Dr Ally Olotu, a Wellcome Trust PhD student at the KEMRI-Wellcome Trust Research Programme and Oxford University, explains: "We need to consider whether relative efficacy or absolute number of cases averted is the more informative measure. In any case, these are important findings that will help to inform which populations are likely to benefit most from the vaccine.
"The ongoing phase III study will provide further insights to the vaccine's efficacy in different settings of malaria exposure and includes an assessment of a booster dose to sustain efficacy over time."
Malaria remains an important cause of illness and death among children in sub-Saharan Africa, and there is currently no vaccine that offers complete protection against the disease. RTS,S is the most advanced candidate malaria vaccine and entered phase III clinical trials in Africa in 2009. The vaccine candidate seems to be well tolerated and has an acceptable safety profile, but it remains unclear which sub-groups of children might benefit most and what the duration of efficacy is.
Jimmy Whitworth, Head of International Activities at the Wellcome Trust, said: "This study indicates the durability of protection of a single initial course of this vaccine against malaria, and the variability of protection at different levels of exposure to malaria. These are key pieces of information required for us to understand how best to use this vaccine and the regimes of boosters that will be required to provide optimum protection."
Latest figures estimate that there are 1.44 billion people living in regions of stable malaria transmission worldwide. Most deaths occur among children living in Africa, where a child dies from malaria every minute.
Olotu A et al. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure(opens in a new tab). NEJM 2013 (epub ahead of print).
The paediatric clinical development of RTS,S in Africa began in 2001 through a public-private partnership between the PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK). The vaccine was first formulated in laboratories at GSK Biologicals' headquarters in Belgium in the late 1980s as part of a collaboration with the US Walter Reed Army Institute of Research. Following the rollout of phase II clinical trials in Mozambique in 2002, African research centres in four additional countries and collaborating institutions joined the partnership in 2005.
The extension study to the phase II trial was funded by the Wellcome Trust and MVI.
The multi-centre phase III trial, initiated in 2009, involves 15 460 children across 11 centres in seven African countries. It is designed to determine the length of the vaccine candidate's protection and evaluate the vaccine's efficacy and safety in different parts of Africa, where intensity of malaria transmission may differ. This study is funded by MVI.
RTS,S is designed to trigger the immune system to defend against the Plasmodium falciparum malaria parasite as soon as it enters the human host's bloodstream and/or when the parasite infects liver cells. This prevents the parasite from infecting the liver or maturing and multiplying in the liver and from re-entering the bloodstream, where the host would begin to show symptoms of infection.
To stimulate an immune response to the malaria parasite, RTS,S contains the critical circumsporozoite (CS) protein, the surface protein that helps the parasite invade human liver cells, fused to the protein found in GSK Bio's hepatitis B vaccine. On its own ,RTS,S does not stimulate a strong immune response. To improve the immune response, RTS,S has been given with GSK's proprietary adjuvant system in the phase II and III trials.
Data from the earlier phase II trial and ongoing phase III trial have confirmed that the RTS,S vaccine candidate appears to be well tolerated and has an acceptable safety profile. There was no increase in overall reporting of serious adverse events between the infants vaccinated with RTS,S and those who received a comparator vaccine. The observed side-effects were similar to those seen to comparator vaccines, primarily a small localised reaction at the site of injection.
Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school.
From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.
A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.
The KEMRI-Wellcome Trust Programme(opens in a new tab) is internationally renowned for its research tackling malaria and other important diseases in Kenya. Safeguarding the health of young children in Africa and their families is the primary motivation of the Programme's research. In Kilifi, the Programme is embedded within Kilifi District Hospital, building its research programmes around local medical infrastructure and contributing to healthcare delivery.
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.