Malaria Vaccine Safety and Immunogenicity Study in Healthy Adults
Condition: Malaria Vaccine
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2

Summary: 
      Targeted malaria elimination (TME), which comprises appropriate case management by village
      health workers, vector control and mass drug administration, is currently being implemented
      through pilot projects in selected villages in the Greater Mekong Subregion (GMS) and the
      scale-up of the intervention to the regional level are underway. Based on mathematical
      modelling, extending the post-TME parasitaemia-free period in the majority of villagers for
      as short as 200 days will substantially increase the chances of achieving the interruption of
      malaria transmission. Immunogenicity of RTS,S is greater in older children, and the short
      term malaria protective effect is stronger than the overall effect assessed over 1-2 years.
      Addition of mass RTS,S/AS01E vaccination to the TME arsenal could provide this much needed
      additional protection.

      Currently there are no safety and immunogenicity data for the use of RTS,S/AS01 in Asian
      populations. This trial will generate the required data for the use of this vaccine in Asian
      populations. For integration with the current TME activities, which provide mass drug
      administrations at months M0, M1, and M2, it would be most efficient and practical to provide
      the vaccine at the same intervals. To address a two round intervention (M0, M2) where a three
      round intervention is not feasible, one study arm will look at the immune response generated
      by only two doses of vaccine and antimalarial medications. Recent evidence suggests that a
      vaccination schedule which includes a fractional dose of RTS,S/AS01 (1/5th of the standard
      dose) could be similarly or more protective than a schedule with three standard full doses,
      while requiring less vaccine and resources. The trial therefore includes study arms which
      will assess the safety and immunogenicity of fractional dose schedules.

      Each participant will be randomized into one of the following study arms in a ratio of
      20:20:30:30:30:30:30, as follows:

        -  RTS,S/AS01B Fractional dose group (Group 1)

        -  Double RTS,S /AS01E Fractional dose group (Group 2)

        -  RTS,S/AS01E Standard dose group (Group 3)

        -  RTS,S/AS01E + DHA-PIP+PQ Standard dose group (Group 4)

        -  RTS,S/AS01E Fractional dose group (Group 5)

        -  RTS,S/AS01E + DHA-PIP+PQ Fractional dose group (Group 6)

        -  RTS,S/AS01E + DHA-PIP+PQ Fractional two-dose group (Group 7)
    

Detailed description: 
      This is a randomized, open-label, single centre, Phase 2 trial of RTS,S/AS01 in healthy Thai
      adults.

      Screening and eligibility assessment (Screening visit)

      All potential volunteers will have a screening visit, which may take place up to 30 days
      prior to enrolment. Once informed consent is given, a screening number will be assigned in
      sequential order. Screening numbers will be issued consecutively (e.g. A-01, A-02, A-03…).

      Enrolment, baseline assessment, regimen allocation, and first vaccination (Month 0 / Day 0
      visit; Baseline visit) All inclusion and exclusion criteria will be checked before enrolment
      in the study. Physical examination will be performed. Any new medical issues or symptoms that
      have arisen will be assessed. Blood will be collected for baseline parasite microscopy,
      haemoglobin and biochemistry. Participants with parasitaemia or anaemia will be treated
      according to national guidelines. Blood will be collected and stored for measurement of
      antibodies against P. falciparum circumsporozoite (anti-CS antibody) until shipment to the
      reference laboratory. Urine will be collected from women of child-bearing age for immediate
      pregnancy test.

      If all inclusion criteria are fulfilled and none of the exclusion criteria apply, the patient
      will be enrolled into the study and a CRF specific to each participant completed. Regimen
      allocation and administration of the vaccine(s) will be on Day 0. The randomization lists
      will be prepared by MORU.

      Randomization numbers will be generated in blocks, for the 7 intervention arms in a ratio of
      20:20:30:30:30:30:30, as follows:

      Each participant will be randomized into one of the following study arms Group 1: RTS,S/AS01B
      Fractional dose group Month 0 and Month 1 will receive RTS,S/AS01B full dose Month 2 will
      receive RTS,S/AS01B fractional dose (1/5th dose)

      Group 2: RTS,S/AS01E Fractional dose group Month 0 and Month 1will receive a double dose of
      RTS,S/AS01E full dose Month 2 will receive a double dose of RTS,S/AS01E fractional dose
      (1/5th dose)

      Group 3: RTS,S/AS01E Full dose group Month 0, Month 1 and Month 2 will receive RTS,S/AS01E
      full dose

      Group 4: RTS,S/AS01E + DHA-PIP+PQ Full dose group Month 0, Month 1 and Month 2 will receive
      RTS,S/AS01E full dose + DHA-PIP+PQ

      Group 5: RTS,S/AS01E Fractional dose group Month 0 and Month 1 will receive RTS,S/AS01E full
      dose Month 2 will receive RTS,S/AS01E fractional dose (1/5th dose)

      Group 6: RTS,S/AS01E + DHA-PIP+PQ Fractional dose group Month 0 and Month 1 will receive
      RTS,S/AS01E full dose + DHA-PIP+PQ Month 2 will receive RTS,S/AS01E fractional dose (1/5th
      dose) + DHA-PIP+PQ

      Group 7: RTS,S/AS01E + DHA-PIP+PQ Fractional two-dose group Month 0 will receive RTS,S/AS01E
      full dose + DHA-PIP+PQ Month 2 will receive RTS,S/AS01E fractional dose (1/5th dose) +
      DHA-PIP+PQ

      RTS,S/AS01B = Standard dose RTS,S/AS01B: 50µg RTS,S + standard dose AS01B RTS,S/AS01E =
      Standard dose RTS,S/AS01E: 25µg RTS,S + standard dose AS01E DHA-PIP =
      Dihydroartemisinin/piperaquine PQ = Primaquine

      Study participants will be assigned the next available randomization number on the list, and
      thus will be randomly allocated to Group 1, 2, 3, 4, 5, 6 or 7.

      Subsequent vaccination visits (Month 1 / Day 0 and Month 2 / Day 0 visits) Subsequent
      vaccination visits will be done according to the schedule of procedures. Physical examination
      will be performed. Any new medical issues or symptoms that have arisen will be assessed.
      Blood will be collected for parasite microscopy, haemoglobin and biochemistry. Participants
      with parasitaemia or anaemia will be treated according to national guidelines. Blood will be
      collected and stored for measurement of antibodies against P. falciparum circumsporozoite
      (anti-CS antibody) until shipment to the reference laboratory. Urine will be collected from
      women of child-bearing age for immediate pregnancy test.

      Before vaccination, the on-going eligibility of the volunteer will be reviewed. All
      participants will attend the clinic for vaccination visits, will be observed closely for at
      least 30 minutes following the administration of each study vaccine, and will receive a paper
      diary card for recording solicited AEs, as described above. Information will be recorded in
      the CRF for subsequent vaccination visits.
    

Intervention name(s): RTS,S/AS01B Fractional dose; Double RTS,S/AS01E Fractional dose; RTS,S/AS01E Standard dose; RTS,S/AS01E + DHA-PIP+PQ Standard dose; RTS,S/AS01E Fractional dose; RTS,S/AS01E + DHA-PIP+PQ Fractional dose; RTS,S/AS01E + DHA-PIP+PQ Fractional two-dose
Intervention type(s): Biological; Biological; Biological; Biological; Biological; Biological; Biological
Intervention description(s): RTS,S/AS01B standard dose at Month 0 and Month 1 + RTS,S/AS01B fractional dose (1/5th dose) at Month 2.; A double dose of RTS,S/AS01E standard dose at Month 0 and Month 1 + a double dose of RTS,S/AS01E fractional dose (1/5th dose) at Month 2.; RTS,S/AS01E standard dose at Month 0, Month 1 and Month 2.; RTS,S/AS01E standard dose + DHA-PIP+PQ at Month 0, Month 1 and Month 2; RTS,S/AS01E standard dose at Month 0 and Month 1 + RTS,S/AS01E fractional dose (1/5th dose) at Month 2.; RTS,S/AS01E standard dose + DHA-PIP+PQ at Month 0 and Month 1 + RTS,S/AS01E fractional dose (1/5th dose) + DHA-PIP+PQ at Month 2.; RTS,S/AS01E standard dose + DHA-PIP+PQ at Month 0 + RTS,S/AS01E fractional dose (1/5th dose) + DHA-PIP+PQ at Month 2
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized 7 groups
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: safety; immunogenicity