The findings come from a long-term follow-up of a phase II study of GlaxoSmithKline (GSK)’s malaria vaccine by Oxford University and KEMRI-Wellcome Trust Research Programme researchers based in Kenya.
The analysis, published 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 have shown that the candidate RTS,S vaccine reduced malaria by around a half in young children and one-third in infants over the next 12 months.
The new findings, which followed up an earlier but smaller phase II study for a longer period, reveal that the vaccine efficacy dropped from 43.6% protection against malaria in the first year to zero by the fourth year after vaccination.
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 RTS,S vaccine candidate. Of the 447 children, 320 completed four years of follow-up.
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.
Despite the falling efficacy over time, there is still a clear benefit to the vaccine candidate.
Dr Phillip Bejon
‘Despite the falling efficacy over time, there is still a clear benefit to the vaccine candidate,’ says the study’s senior author Dr Phillip Bejon of the KEMRI-Wellcome Trust Research Programme and the Centre for Tropical Medicine, University of Oxford. ‘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% among children with below-average exposure to malaria to 15.9% 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.’
GSK’s RTS,S vaccine is being developed jointly by GSK and the PATH Malaria Vaccine Initiative.
The extension study to the phase II trial was funded by the Wellcome Trust and the PATH Malaria Vaccine Initiative.