Safety and Immunogenicity of the Malaria Vaccine, R21/MatrixM, in Healthy Thai Adults
- Conditions
- Malaria,Falciparum
- Interventions
- Biological: R21/Matrix-M vaccinationDrug: DHA-PIPDrug: PQ
- Registration Number
- NCT05252845
- Lead Sponsor
- University of Oxford
- Brief 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 127
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description R21/Matrix-M + DHA-PIP+PQ R21/Matrix-M vaccination The R21/Matrix-M vaccine (IM injection) + co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine R21/Matrix-M + DHA-PIP+PQ DHA-PIP The R21/Matrix-M vaccine (IM injection) + co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine R21/Matrix-M + DHA-PIP+PQ PQ The R21/Matrix-M vaccine (IM injection) + co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine R21/Matrix-M only R21/Matrix-M vaccination The R21/Matrix-M vaccine (IM injection) only DHA-PIP+PQ only DHA-PIP Co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine DHA-PIP+PQ only PQ Co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine
- Primary Outcome Measures
Name Time Method Occurrence of adverse events (AEs), according to the Medical Dictionary for Regulatory Activities (MedRA) classification. From the date of the first vaccination to 29 days after the last vaccination Occurrence of serious adverse events (SAEs), according to the MedRA classification. During the whole study period, i.e. during a 6-month follow-up period from the receipt of first vaccination
- Secondary Outcome Measures
Name Time Method For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody) Six months after the first dose (at Study Month 6) For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody)circumsporozoite (anti-circumsporoziote antibody) One month after the first dose (at Study Month 1) Exploratory immunology endpoints including but not limited to cellular immunity Six months after the first dose (at Study Month 6) For Arms 1 and 3, piperaquine levels following the administration of the antimalarials with or without vaccine On day 0, 1, 2, and 7 of study month 0, 1, and 2
Trial Locations
- Locations (1)
Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University
🇹🇭Bangkok, Thailand