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

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): RABIPUR®; RTS,S/AS01; SMC with SP+AQ; SMC placebo
Intervention type(s): Biological; Biological; Drug; Drug
Intervention description(s): Year 1 (2017) Three doses of rabies vaccine (April, May, June) Year 2 and 3 (2018/19) One dose of Hepatitis A vaccine (June); Year 1 (2017) Three doses of RTSS/AS01 (April, May, June) Year 2 and 3 (2018/19) One booster dose of RTSS/AS01 (June); Year 1, 2 and 3(2017/18/19) Four cycles of SMC (SP+AQ) during the malaria transmission season One cycle of SMC for children above one year of age consisting of sulphadoxine - pyrimethamin (SP) 500mg/25 mg, and amodiaquine (AQ) 150mg on day 1, and AQ 150mg on days 2 and 3. Infants will receive half of these doses.; Year 1, 2 and 3(2017/18/19) Four cycles of SMC placebo during the malaria transmission season
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A double-blind, individually randomised trial to compare the incidence of clinical episodes of malaria across three study arms:
Seasonal vaccination with the malaria vaccine RTS,S/AS01
Seasonal malaria chemoprevention with SP/AQ
Combination of these two interventions
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Malaria; Seasonal vaccination; Seasonal chemoprevention