A comparative trial of seasonal vaccination with the malaria vaccine RTS,S/AS01, seasonal malaria chemoprevention and the two interventions combined

There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2015 there were still 438 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment: new tools and approaches are needed. In the African Sahel and sub-Sahel, the risk of malaria is concentrated in the few months of the rainy season, although some transmission continues during the rest of the year. The seasonality of malaria in this part of Africa has allowed the development of a control measure called seasonal malaria chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarials sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season, a regimen which is very demanding on health care givers and recipient children. The malaria vaccine RTS,S/AS01 has been in development for over 20 years. A recent trial conducted in 15,439 children showed that when three doses of the vaccine were given to children aged 5-17 months, followed by a fourth dose a year later, the vaccine provided 37% protection against clinical attacks of malaria over a period of 4 years, and a similar level of protection against severe malaria. The vaccine caused febrile convulsions in about 1% of children and there was a small, unexplained, increase in the incidence of meningitis in vaccine recipients. These findings were reviewed by the European Medicine Agency in July 2015 and, based on the balance of benefits and risks, the Agency gave the vaccine a positive opinion. WHO has subsequently recommended that several large pilot implementation studies should be done before the vaccine is deployed more widely and that alternative approaches to its delivery should be explored. A characteristic feature of the vaccine is that it produces high levels of protection in the first few months after vaccination but that this subsequently wanes. Vaccine efficacy of 86% (26/30 subjects protected) was obtained in a recent trial in USA military volunteers challenged shortly after three doses of vaccine had been given, the last dose at a lower concentration than usual. The aim of this study is to take advantage of the high initial efficacy of RTS,S/AS01 to investigate its potential to provide protection to children exposed to malaria for just a few months each year. A three arm trial is proposed which will compare (a) administration of three doses of RTS,S/AS01 to young children followed by a fourth and a fifth dose at the beginning of two subsequent malaria transmission season (b) administration of SMC with SP + AQ as recommended by WHO (c) the combination of these two interventions. The main objectives of the trial will be to determine whether RTS,S/AS01 provides a similar level of protection to that of SMC and is equally cost effective as SMC but is easier to administer and whether combination of the two interventions provides an added, cost effective benefit. The trial will be conducted in 6,000 children (2,000 in each arm) in Hounde, Burkina Faso and Bougouni, Mali where a trial of adding the antibiotic azithromycin to the anti-malaria treatment regimen used for SMC is currently under way and due to finish at the end of 2016. The study team and many of the techniques needed for the new trial are, therefore, in place. The main end-point of the new trial will be the incidence of episodes of clinical malaria severe enough to warrant treatment. Other end-points will be the incidence of severe malaria, hospital admissions with malaria and anaemia. The safety of the two interventions will be monitored, with a focus on meningitis. The costs of the two approaches and of the combination will be measured and the preference of the local populations for each intervention will be determined.