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

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.

SMC is recommended until the age of 5 years. Thus, if seasonal vaccination with RTS,S/AS01E, or another malaria vaccine with a high initial efficacy but a relatively short duration of protection, is to be considered as a potential supplement or replacement for SMC, it is important to determine the efficacy of annual, seasonal vaccination in primed children until they reach the age of five years. A preliminary analysis of the efficacy and safety data obtained from the ongoing RTS,S+SMC trial by an independent expert appointed by the Gates Foundation in January 2020, at a time when study children had reached the age of three or four years, recommended that the trial should continue with all three trial groups (SMC alone, RTS,S/AS01E alone and the combination) until study children reached the age of five years and this recommendation was endorsed by the trial's Data Safety and Monitoring Board. Therefore, it is proposed that the trial should be continued, with inclusion of all three groups of children, until they reach the age of five years.

Children in the SMC alone group will receive tetanus toxoid in June 2020 and 2021 together with four rounds of SMC (SP + AQ) in 2020 and 2021, those in the RTS,S/AS01E alone group will receive a booster dose of RTS,S/AS01E in June 2020 and 2021 together with four rounds of SMC placebo in 2020 and 2021 and those in the SMC + RTS,S/AS01E vaccine group will receive a booster dose of RTS,S/AS01E vaccine in June 2020 and 2021 together with four rounds of SMC (SP+AQ) in 2020 and 2021.The primary end-point for the extension study will remain the incidence of clinical episodes of malaria that are severe enough to require treatment at a health centre and which are accompanied by a positive blood film with a parasite density =>5000/microlitre. Secondary end-points will include episodes of severe malaria and the prevalence of malaria parasitaemia and anaemia. The cost of each intervention and its acceptability will be assessed.

The primary impact of this research will potentially be on the communities of the Sahel and sub-Sahel where malaria transmission is highly seasonal and where SMC is currently recommended by WHO. This area has a population of approximately 300 million, including about 40 million children under the age of five years of age who are still at high risk of malaria during the rainy season. If it can be shown that a booster dose of the RTS,S/AS01E malaria vaccine given at the beginning of the malaria transmission season is as effective at preventing malaria in young children as four courses of SMC, and this effect is sustained until the age of 5 years, this will substantially ease the burden on the families of recipient children who currently need to ensure that their child receives four rounds of SMC during each rainy season. In some programmes, SMC is delivered door-to-door but mothers must remain at home to await the uncertain time of arrival of the drug distributor. In other programmes, mothers are required to take their child to a central delivery point where they may have to wait for some time for anti-malarial drugs to be given. Only the first dose of SP and AQ is delivered by the health care worker and mothers must remember to administer the second and third doses of amodiaquine. Attending one mass vaccination campaign one a year would be easier and allow mothers or guardians to spend more time on other productive activities. If it can be shown that the addition of RTS,S/AS01E to SMC provides an added, cost effective benefit in the prevention of malaria this will help to reduce further the continuing burden of malaria in countries of the Sahel and sub-Sahel where malaria remains the main cause of death and hospital admissions in young children.

A second group of potential beneficiaries of the research are the national malaria control programmes of counties where SMC is currently recommended. Working in conjunction with national infant immunization programmes, delivery of RTS,S in early childhood and then as a seasonal booster dose may prove logistically easier, and potential cheaper, to deliver than the complex process of ordering, distributing and delivering the drugs needed for SMC.

A third potential beneficiary is WHO's Malaria Policy Advisory Committee as the results of the trial will assist this committee in its deliberations on how the RTS,S/AS01 vaccine and other malaria vaccines under development, which have high initial efficacy but provide only a period of protection can be deployed most effectively.

Finally, the trial will provide training and support for Burkinabe and Malian scientists and support staff employed by the project who will be able to contribute effectively to other trials in the future.