Safety and Immunogenicity of the Malaria Vaccine, R21/MatrixM, in Healthy Thai Adults
Condition: Malaria,Falciparum
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 2

Summary: 
      Malaria remains one of the leading causes of morbidity and mortality worldwide. Plasmodium
      falciparum is a complex pathogen with numerous immune evasion mechanisms which has added
      layers of complexity to the development of safe and protective vaccines. There remains an
      urgent need to identify and develop more protective and more affordable vaccine candidates
      that could achieve the World Health Organization (WHO) goal of 75% efficacy against clinical
      malaria.

      R21 is a novel pre-erythrocytic candidate malaria vaccine. R21 includes Hepatitis B surface
      antigen (HBsAg) fused to the C-terminus and central repeats of the circumsporozoite protein
      of P. falciparum (CSP), which self-assemble into virus-like particles in yeast. R21 lacks the
      excess HBsAg found and comprises only fusion protein moieties.

      R21/MatrixM (MM) had a favourable safety profile and was well tolerated. The majority of
      adverse events were mild, with the most common event being fever. None of the serious adverse
      events were attributed to the vaccine. At one year, vaccine efficacy remained high, at 77%.
      Participants vaccinated with R21/MM showed high titres of malaria-specific anti-
      Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost
      doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to
      peak titres after the primary series of vaccinations after a fourth dose administered one
      year later.

      Currently, there are no safety and immunogenicity data for the use of R21/MatrixM in Asian
      populations. This trial will generate the required data for the use of this vaccine in Asia.
      For integration with the current targeted malaria elimination (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.

      In summary: The investigators propose to conduct a safety and immunogenicity trial of
      R21/MatrixM in Thai adults. The major aims of this study are to 1) assess the safety and
      immunogenicity of R21/MatrixM in Thai adults 2) confirm that the co-administration of
      antimalarial drugs with the malaria vaccine R21/MatrixM does not reduce the immunogenicity of
      the vaccine and 3) assess the absorption and pharmacokinetics of antimalarial drugs
      piperaquine, and a single low dose of primaquine (SLDPQ) when co-administered with
      R21/MatrixM.

      This is a randomized, open label, single centre, Phase 2 study. 120 healthy non-pregnant Thai
      adults, aged 18-55 years, inclusive, will be recruited.

      Each participant will be randomized into one of the following study arms in a ratio of 5:5:2,
      as follows:

        1. R21/MatrixM + Dihydroartimisinin (DHA)-Piperaquine (PIP)+ primaquine (PQ) (Group 1,
           n=50) will receive R21/MatrixM + 3 doses DHA-PIP+PQ at Month 0, Month 1 and Month 2

        2. R21/MatrixM only (Group 2, n=50) will receive R21/MatrixM standard dose at Month 0,
           Month 1 and Month 2

        3. DHA-PIP+PQ only (Group 3, n=20) will receive 3 doses DHA-PIP+PQ at Month 0, Month 1 and
           Month 2
    

Detailed description: 
      This is a randomized, open label, single centre, Phase 2 study.

      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. R21-001, R21-002, R21-003, …)

      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 P. falciparum testing,
      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-circumsporozoite antibody) until
      shipment to the reference laboratory. Urine will be collected from women of child-bearing age
      for immediate pregnancy test.

      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 P. falciparum testing, haemoglobin and
      biochemistry. Blood will be collected and stored for measurement of antibodies against P.
      falciparum circumsporozoite (anti-circumsporozoite 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 case record form (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 Mahidol-Oxford Tropical Medicine Research Unit
      (MORU).

      Randomization numbers will be generated in blocks, for the 3 study arms in a ratio of 5:5:2,
      as follows:

        -  R21/MatrixM + DHA-PIP+PQ (Group 1)

        -  R21/MatrixM alone (Group 2)

        -  DHA-PIP+PQ alone (Group 3)

      Study participants will be assigned the next available randomization number on the list, and
      thus will be randomly allocated to Group 1, 2, or 3. This is an open-label study.
      Participants and clinical investigators will not be blinded to group allocation.

      Subjects will then be vaccinated by intramuscular (IM) needle injection into the deltoid
      region of the arm. Subjects in Groups 1 and 3 will also receive anti-malarial medications.

      The study participants will be observed closely for at least 30 minutes following the
      administration of each study vaccine, with appropriate medical treatment readily available in
      case of an anaphylactic reaction.

      Subsequent vaccination visits (Month 1 / Day 0 and Month 2 / Day 0 visits)

      Physical examination will be performed. Any new medical issues or symptoms that have arisen
      will be assessed. Blood will be collected for P. falciparum testing. 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-circumsporozoite) 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.

      Follow up assessments

      Follow-up assessments (visits not involving vaccination) will be done at month 3 and month 6
      after the first vaccination.

      Blood tests

      Blood will be drawn at the time points indicated in the schedule of procedures and the
      following laboratory assays performed:

      At screening:

        -  Haematology: haemoglobin (Hb), leukocytes (white blood cells [WBC]) and platelets (PLT).

        -  Biochemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST) and
           creatinine (CREA).

        -  Diagnostic serology: HBsAg, HCV antibodies, HIV antibodies (Counselling will be given
           prior to testing blood for these blood-borne viruses)

        -  P. falciparum testing

      At M0, D0: P. falciparum testing, Haematology: Hb, WBC, PLT, Biochemistry: ALT, AST, CREA,
      anti-circumsporozoite antibody; Pharmacokinetics (piperaquine and primaquine drug levels will
      be assessed if additional data are required) At M0, D1: Pharmacokinetics (piperaquine and
      primaquine drug levels) At M0, D2: Pharmacokinetics (piperaquine drug levels) At M0, D7:
      Haematology: Hb, WBC, PLT; Biochemistry: ALT, AST, CREA; Pharmacokinetics (piperaquine drug
      levels) At M1, D0: P. falciparum testing, anti-circumsporozoite antibody; Pharmacokinetics
      (piperaquine drug levels) At M1, D1: Pharmacokinetics (piperaquine and primaquine drug
      levels) At M1, D2: Pharmacokinetics (piperaquine drug levels) At M1, D7: Haematology: Hb,
      WBC, PLT; Biochemistry: ALT, AST, CREA; Pharmacokinetics (piperaquine drug levels) At M2, D0:
      P. falciparum testing, anti-circumsporozoite antibody; Pharmacokinetics (piperaquine drug
      levels) At M2, D1: Pharmacokinetics (piperaquine and primaquine drug levels) At M2, D2:
      Pharmacokinetics (piperaquine drug levels) At M2, D7: Haematology: Hb, WBC, PLT;
      Biochemistry: ALT, AST, CREA; Pharmacokinetics (piperaquine drug levels) At M3: P. falciparum
      testing, Haematology: Hb, WBC, PLT; Biochemistry: ALT, AST, CREA; anti-circumsporozoite
      antibody At M6: P. falciparum testing, anti-circumsporozoite antibody
    

Intervention name(s): R21/Matrix-M vaccination; DHA-PIP; PQ
Intervention type(s): Biological; Drug; Drug
Intervention description(s): R21/Matrix-M is the standard formulation of the vaccine (Once prepared, a standard dose of R21/Matrix-M contains approximately 5 µg of R21 antigen, in 0.5 mL of liquid adjuvant containing 50 µg MatrixM). The reconstituted vaccine will be administered by slow IM injection on Day 0 at Study Months 0, 1 and 2.; Dihydroartemisinin/piperaquine tablets for adult patients each contain 40 mg dihydroartemisinin and 320 mg piperaquine with a therapeutic dose range between 2-10 mg/kg/day dihydroartemisinin and 16-26 mg/kg/dose piperaquine. Participants will receive three rounds of antimalarial drugs - each round starting on the day of vaccination (Day 0) at Study Months 0, 1 and 2. Each round consists of three daily doses of co-formulated dihydroartemisinin/piperaquine on Day 0, 1, and 2.; Each participant will receive a single low dose primaquine on the day of vaccination (Day 0) at Month 0, Month 1, and Month 2. One single low dose primaquine of approximately 0.25 mg/kg will be administered.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Malaria vaccine; Immunogenicity of the malaria vaccine; Immunologic response to malaria vaccine