Seasonal Malaria Vaccination (RTS,S/AS01) and Seasonal Malaria Chemoprevention (SP/AQ) Extension Study

A double-blind, individual randomised trial will be undertaken in children under five years of age living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether administration of further doses of the malaria vaccine RTS,S/AS01 at the beginning of the malaria transmission until children reach the age of five years 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. This is a two year extension of the current RTS,S/AS01 + SMC trial to continue the trial until the study children reach the age of five years, the current age at which SMC is recommended until.

Although there has been substantial progress in malaria control in the past decade, this progress has stalled in many countries in sub-Saharan Africa, especially in countries of the Sahel and central Africa, despite widespread deployment of insecticide treated bednets, chemoprevention and improved access to treatment. Recognition of this new challenge has led WHO's Global Malaria Programme (GMP) to establish a new 'High Burden, High Impact' programme which focuses on 10 countries in Africa, including Burkina Faso and Mali, and India. In these countries, where current control and treatment measure are failing to bring malaria fully under control, new approaches to malaria control are needed.

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. One potential use for the RTS,S/AS01 vaccine is to use it to prevent seasonal malaria, taking advantage of its high but rapidly waning efficacy.

Across the African Sahel and sub-Sahel, where malaria transmission is very high and concentrated in a few months of the year, Seasonal Malaria Chemoprevention (SMC),a malaria control intervention in which children under the age of five years, the group most at risk, are given the antimalarials sulphadoxine pyrimethamine and amodiaquine (SP+AQ) at monthly intervals for four months during the peak malaria transmission season, has proved very effective. However, the delivery of SMC 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.

Thus, in 2017, a double-blind, individual randomised trial trial was started in Mali and Burkina Faso to investigate the beneficial effects of adding the RTS,S/AS01 malaria vaccine to SMC and to determine whether it might be possible to replace SMC with RTS,S/AS01. The RTS,S/AS01 + SMC trial, which is supported by the UK Global Clinical Trials Programme and PATH, recruited 5887 children aged 5-17 months in Burkina Faso and Mali who have been randomised to one of three trial groups (a) SMC + RTS,S/AS01 (b) RTS,S/AS01 + a SMC placebo or (c) SMC + a control vaccine. Study children have now been followed through three malaria transmission seasons and the first phase of the trial will finish in April 2020. This trial will now be extended for two years until the study children reach the age of five years, the current age at which SMC is recommended until.

Eligibility Criteria:
Inclusion Criteria:

* The child had been enrolled in the initial phase of the trial of seasonal vaccination with the RTS,S/AS01 vaccine
* A parent or legally recognised guardian provides informed consent for the child's inclusion in the extension study
* 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 under five years of age at the time of enrolment.

Exclusion Criteria:

* The child has had an allergic reaction to the study drugs or vaccines
* The child had febrile convulsions on more than one occasion following vaccination
* The child has developed a serious underlying illness such as severe malnutrition (weight for age or mid arm circumference Z scores \< 3 SD) which in view of the investigators might impair the response to vaccination
* The child has been enrolled in another malaria vaccine or other experimental malaria intervention study