A double-blind, individual randomised trial will be undertaken in 6000 children under the age of five years living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether the malaria vaccine RTS,S/AS01 is (a) as effective as SMC with SP + AQ in preventing clinical malaria (b) provides additional, useful protection when given together with SMC. The primary trial end-point will be the incidence of clinical episodes of malaria detected by passive case detection.

The RTS,S/AS01 malaria vaccine is a recombinant protein vaccine in which the fusion protein RTS (containing parts of the circumsporozoite protein (CSP) of Plasmodium falciparum fused to hepatitis B surface antigen (HBsAg)) is co-expressed in yeast together with free HBsAg (S) to form a virus like particle (RTS,S); it is given with the powerful adjuvant AS01. RTS,S/AS01 induces a strong antibody response to the P. falciparum CSP and high titres of anti-CSP antibody are associated with protection. Following a long process of development, a phase 3 study of RTS,S/AS01 conducted in 15,439 children in 7 countries in Africa showed that three doses of RTS,S/AS01 given with a one month interval between doses, followed by a fourth dose 18 months post dose 3, gave 36.5 % [95% CI 31,41%] protection against clinical attacks of malaria when given to young children aged 5-17 months who were followed for 48 months; efficacy was less when given to infants at the age of 6-12 weeks. RTS,S/AS01 provides a high level of protection during the first three months after vaccination, modelled to be about 70% in the phase 3 trial, a level of initial efficacy similar to that observed in an earlier phase 2 trial in Gambian adults. However, efficacy wanes progressively over the following months. A subsequent dose given 18 months after the primary series restores some but not all of the efficacy seen immediately after the primary series. In July 2015, the European Medicines Agency reviewed efficacy and safety data on RTS.S/AS01 and concluded that the risk benefit balance favoured the vaccine and gave a positive opinion on its use in children aged 6 weeks to 17 months. The World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) committee reviewed the vaccine's efficacy and safety in October 2015 and made a number of recommendations on its further evaluation. These included the pilot implementation of RTS,S/AS01 in children aged 5-17 months in 3-5 settings with moderate-to-high malaria transmission intensity, with a preference for areas where SMC is not being delivered, and evaluation of alternative approaches to deployment of the vaccine. Recent evidence from challenge studies conducted in American adult volunteers suggests that a higher level of protection can be obtained when the third dose of the priming schedule is reduced to one fifth of the usual amount and delayed until approximately 6 months post dose 2, and when a reduced dose is used for boosting. In these studies, a vaccine efficacy of 86% was achieved three weeks following priming and 90% efficacy following boosting with a fractional dose. This encouraging result is now being followed in further studies.

SMC involves monthly administration of an antimalarial drug or drug combination in a full therapeutic course to children on three of four occasions during the period of highest risk of malaria infection. Studies undertaken in several countries in West Africa, including Burkina Faso and Mali, have shown that SMC with sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) is highly effective in areas where the transmission of malaria is markedly seasonal, reducing the incidence of severe and uncomplicated malaria by up to 80%. SMC with a combination of SP and AQ is safe, with no serious drug related adverse event being reported after administration of over 800,000 courses in Senegal. Recent studies have defined the areas where SMC would be an appropriate intervention based on the seasonality and incidence of malaria. These include most of the Sahel and sub-Sahel, population approximately 200 million, and possibly other areas in southern and eastern Africa. A Technical Expert Group of the WHO reviewed all the available evidence on the efficacy and safety of SMC in May 2011 and recommended SMC with SP+AQ in areas of the Sahel and sub-Sahel with highly seasonal transmission. This recommendation was endorsed by the WHO Malaria Policy Advisory Committee (MPAC) in February 2012. Most countries in the Sahel and sub-Sahel region have incorporated SMC, along with other malaria control interventions in their strategic malaria control plan and the implementation of SMC at scale is in progress in many countries in this region through the UNITAID supported SMC ACCESS programme and the support of other major donor organisations. Preliminary evaluation suggests that SMC is providing about 50% protection against clinical malaria when delivered through a national programme (http://www.malariaconsortium.org/pages/access-smc.htm).

SMC is effective but its delivery is demanding on the recipient and provider, requiring four contacts each malaria transmission season if anti-malarials are given to mothers to administer at home and 12 contacts if directly observed treatment is employed. In addition, SMC is threatened by the emergence of resistance to SP and AQ and there are currently no other combinations of licensed antimalarials that could be used to replace them. It is likely to be 5-10 years before novel antimalarials under development could be deployed for SMC. In contrast to SMC, seasonal vaccination with RTS,S/AS01 would require only one visit each transmission season after priming. RTS,S/AS01 may be a little less effective than SMC during the malaria transmission season but this may be balanced by provision of protection during the dry season, when some malaria transmission still occurs and when SMC would provide no benefit. There is, therefore, a need for a comparative study of these two interventions. In some areas where SMC is currently being deployed, and other malaria control interventions such as long-lasting insecticide treated nets used widely, the incidence of malaria in young children remains high (0.4 episodes per year in children under the age of five years in SMC recipients in Burkina Faso). Thus, determining whether RTS,S/AS01 would provide added, useful protection to SMC in such situations is also important. It might also be able to protect some children who, because of side effects, are unable or unwilling to take SMC.

Although the European Medicines Agency has given a positive opinion on RTS,S/AS01, it is not yet certain how this partially effective malaria vaccine can be used most effectively. Three, large-scale pilot implementation studies are being planned by WHO but it is unlikely that, following WHO recommendations, any of these will be conducted in a country where SMC is being delivered. The WHO recommendations on RTS,S/AS01 indicate the need for research on alternative approaches to the delivery of this vaccine. Exploration of the potential of the vaccine to prevent seasonal malaria, taking advantage of its high but rapidly waning efficacy, meets this recommendation and is, therefore, timely.

Inclusion Criteria:

• The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial
• The child is 5 - 17 months of age at the time of first vaccination
• A parent or legally recognised guardian provides informed consent for the child to join the trial

Exclusion Criteria:

• The child is a transient resident in the study area
• The child is in care
• The age of the child is outside the stipulated range
• The child has a history of an adverse reaction to SP or AQ
• The child has a serious underlying illness, including known HIV infection, unless this is well controlled by treatment, or severe malnutrition (weight for age or mid arm circumference Z scores < 3 SD)
• The child is known to have an immune deficiency disease or is receiving an immunosuppressive drug
• The child has previously received a malaria vaccine.
• The child is enrolled in another malaria intervention trial
• The parents or guardians do not provide informed consent

Data will be made available through the LSHTM Data Compass system

Serious adverse event data were collected over a 3 year period, from 1st April 2017 to 31st March 2020.

The number of participants at risk for other (non-serious) adverse events is zero because non-serious adverse events were not collected or assessed as part of this study.