A Randomized, Open Label, Single Centre, Phase 2 Trial of the Malaria Vaccine, R21/Matrix-M, to Assess Safety and Immunogenicity of the Vaccine in Thai Adults

MAL22001

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

2023-01-04

2023-06-08

2023-09-18

Completed

Early phase I

127

Inclusion Criteria The participant is eligible to enter the study if all of the following apply: 1. Participant is a healthy adult, aged 18 to 55 years (inclusive), of Thai origin. 2. Participant is willing and able to give informed consent to participate in the trial 3. Able, in the investigator's opinion, and willing to comply with the study requirements and follow-up. 4. Women of childbearing potential: must agree to practice continuous, effective contraception for the duration of the trial, and have a negative pregnancy test before each vaccination. (Costs for contraceptives will be reimbursed by the trial.) Exclusion criteria The following criteria should be checked at the time of study entry. If ANY exclusion criterion applies, the subject must not be included in the study: 1. Pregnancy or breastfeeding, or planned pregnancy during the course of the study. 2. Presence of any medical condition (physical or mental) which, may place the participant at undue risk or interfere with the results of the study\*. Including: serious cardiac, renal, hepatic or neurological disease, severe malnutrition 3. Any confirmed or suspected immunosuppressive or immunodeficient condition. Including: history of splenectomy, human immunodeficiency virus (HIV) infection 4. Chronic administration (\>14 days in total) of immunosuppressants or other immune-modifying drugs within six months of enrollment. Including: oral corticosteroids equivalent to prednisone \> 20 mg/day (a) 5. History of an autoimmune disease 6. Hepatitis B surface antigen (HBsAg) detected in serum. 7. Screening electrocardiogram (ECG) demonstrating a QTc interval ≥ 450 ms 8. Seropositivity for hepatitis C virus (antibodies to HCV) at screening (b) 9. Finding on safety laboratory values as defined below: * AST \> 2 x upper normal limit * ALT \> 2 x upper normal limit * Anaemia (Hb \< 10 g/dL), * Platelets \< 100,000 * Total bilirubin \> 2 x upper normal limit 10. Abnormalities of examination or investigations at screening. Including: hepatomegaly, right upper quadrant abdominal pain or tenderness, abnormal blood tests (as defined in the protocol which are not listed above) 11. Positive malaria parasitaemia at screening or baseline (Month 0, Day 0). 12. Receipt or planned receipt of an investigational medical product or participation in an interventional clinical trial during the study period 13. Contraindications to the use of artemisinins, piperaquine or primaquine\*. Including: use of medications with known potential interactions, prior allergic reactions to one or more components of the drug regimen. 14. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (e.g. egg products) 15. History of clinically significant contact dermatitis. 16. Contraindication to intramuscular (IM) injection\* 17. Administration of a vaccine not included in the study protocol within 30 days of a study vaccine (c). 18. History of anaphylaxis post-vaccination. 19. Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period. * subject to the investigator's judgement Exceptions: a Inhaled and topical steroids. b Participation in hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study c The following vaccinations may be administered more than 7 days before or after a study vaccination: polio, diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Bacillus Calmette-Guérin (BCG vaccine), measles, influenza, pneumococcal disease, COVID-19 or yellow fever

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'PREVENTION', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 127, 'type': 'ACTUAL'}}

2023-10-27