Seasonal Malaria Vaccination (RTS,S/AS01) and Seasonal Malaria Chemoprevention (SP/AQ) Extension Study
Condition: Malaria,Falciparum; Child, Only
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Tetanus/diphtheria toxoids; SMC with SP+AQ; RTS,S/AS01; SMC placebo
Intervention type(s): Biological; Drug; Biological; Drug
Intervention description(s): One dose of tetanus/diphtheria toxoids vaccine (June) in year 1 and year 2.; Year 1 and 2 (2020/21) Four cycles of SMC (SP+AQ) (July, August, September, October). One cycle of SMC consisting of sulphadoxine - pyrimethamine (SP) 500mg/25 mg, and amodiaquine (AQ) 150mg on day 1, and AQ 150mg on days 2 and 3.; One booster dose of RTSS/AS01 (June) in year 1 and 2.; Year 1 and 2 (2020/21) Four cycles of SMC placebo (July, August, September, October)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Malaria; Seasonal vaccination; Seasonal chemoprevention