MICA: Seasonal vaccination with the RTS,S/AS01 malaria vaccine given with or without seasonal malaria chemoprevention (SMC): an extension study.

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There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2018 there were still 405 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment of malaria. 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 an effective control measure called Seasonal Malaria Chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarial drugs sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season. RTS,S/AS01E is the most advanced malaria vaccine. A trial conducted in seven countries in Africa in 2009-2014 in 15,439 children showed that when three doses of the RTS,S/AS01E vaccine were given to children aged 5-17 month, 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. Based on the balance of risks and benefits from these findings, the European Medicine Agency gave the vaccine a positive opinion in July 2015. However, WHO's SAGE committee recommended the conduct of three, large pilot studies prior to widespread introduction of the vaccine and these are now underway in approximately 750.000 children in Ghana, Kenya and Malawi. A characteristic feature of the RTS,S/AS01E vaccine is that it produces a high level of protection in the first few months after vaccination but that this subsequently wanes. This property of the vaccine suggest that it might be especially useful in areas where malaria transmission is concentrated in just a few months each year if given as an annual,seasonal vaccine in a manner comparable to seasonal influenza vaccination.To investigate the potential of RTS,S/AS01E as a seasonal vaccine, a trial was started in 2017 in Burkina Faso and Mali to compare the protective efficacy against clinical episodes of malaria of (a) administration of three doses of RTS,S/AS01 to young children followed by a second and third booser dose at the beginning of two subsequent malaria transmission seasons (b) administration of SMC with SP + AQ as recommended by WHO and (c) the combination of these two interventions. 5920 children were enrolled in the trial in 2017 and they have now been followed for nearly three years with recording of the incidence of episodes of uncomplicated and severe malaria throughout this period. This phase of the trial will finish in June 2020. Meanwhile, at the request of the Bill and Melinda Gates Foundation, an independent statistician has undertaken a preliminary analysis of the information collected until the end of November 2019. Based on the results of this review, the Foundation has recommended that the trial should continue, including all three groups, until the study children reach the age of five years, the age beyond which SMC is no longer recommended in most countries. This recommendation has been endorsed by the trial's Data Safety Monitoring Board. During the two years of the extension period, the same series of observations will be made in study children to those undertaken during the first phase of the trial including the incidence of uncomplicated and severe clinical malaria, anaemia and impaired nutrition. The costs of implementing seasonal vaccination and SMC will be measured and the preference of the local populations for each intervention will be determined.