A Study to Test Experimental Blood Stage Malaria Vaccine in Burkina Faso.

Study Overview
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Brief Summary
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This is a Phase IIb randomised controlled trial of the safety, immunogenicity and efficacy of the blood-stage malaria vaccine candidates RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in infants aged 5-17 months in Burkina Faso

Detailed Description
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During the initial recruitment to Groups 1 and 2, participants will be randomised 1:2 to receive vaccination with the rabies control vaccination or RH5.1/Matrix-M. During recruitment to Groups 3, 4 and 5, participants will be randomised 1:2:2 to receive vaccination with rabies control vaccination, RH5.1/Matrix-M or RH5.2-VLP/Matrix-M Efficacy of vaccination will be assessed by comparing the incidence of malaria cases in the pooled control groups (Groups 1 and 3) to the incidence of malaria in each investigational vaccine group (Groups 2,4 and 5). There are three study vaccines: the IMP, 10μg RH5.1 adjuvanted with Matrix-M; 5μg RH5.2-VLP and Rabies Vaccine. Participants will receive the first vaccination of RH5.1 10μg with 50μg Matrix-M (Groups 2 and 4) or RH5.2 5μg with 50μg Matrix-M (Group 5). After approximately 4 weeks, a second dose will be administered, followed by a third and final vaccination approximately 4 weeks later (Groups 3-5) or approximately 4 months later (Groups 1-2). Second and third vaccinations will be administered at the same dose of both vaccine and adjuvant as at the initial vaccination and will be given within the window period of 5 months. Volunteers will be followed for 12 months from final vaccination.

Official Title
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A Phase IIb Randomised Controlled Trial of the Safety, Immunogenicity and Efficacy of the Blood-stage Malaria Vaccine Candidates RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in Infants Aged 5-17 Months in Burkina Faso.

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Biological: Rabies vaccine
* Biological: RH5.1 10μg adjuvated with 50μg Matrix-M
* Biological: RH5.2 5μg adjuvated with 50μg Matrix-M


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infant aged 5-17 months at the time of first study vaccination Parent/guardian provides signed/thumb-printed informed consent Infant and parent/guardian resident in the study area villages and anticipated to be available for vaccination and follow-up for 12 months following last dose of vaccination. Exclusion Criteria: Clinically significant congenital abnormalities as judged by the PI or other delegated individual. Clinically significant skin disorder (psoriasis, contact dermatitis etc.), cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurological illness as judged by the PI or other delegated individual. Weight-for-age Z score of less than -3 or other clinical signs of malnutrition. History of allergic reaction, significant IgE-mediated event, or anaphylaxis to immunization. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines. Sickle cell disease. Clinically significant laboratory abnormality as judged by the study clinician. Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate. Receipt of any vaccine in the 7 days preceding enrolment, or planned receipt of any other vaccine within 7 days following each study vaccination. History of vaccination with another malaria vaccine. Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period. Known maternal HIV infection (no testing will be done by the study team). Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (for corticosteroids, this will mean prednisone, or equivalent, ≥0.5 mg/kg/day; inhaled and topical steroids are allowed). Any significant disease, disorder or situation which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

Ages Eligible for Study
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Minimum Age: 5 Months
Maximum Age: 17 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1 (Control group)<br>n= 60. Age= 5-17 months Rabies Vaccine administered on Days 0, 28 and 152. | Biological: Rabies vaccine<br>* Vaccine<br>|
| Experimental: Group 2<br>n=120 Age= 5-17 months First vaccination of RH5.1 10μg with 50μg Matrix-M will be administered on day 0, followed by a second dose administered on Day 28, followed by a third and final dose at Day 152. | Biological: RH5.1 10μg adjuvated with 50μg Matrix-M<br>* Vaccine<br>|
| Placebo Comparator: Group 3 (Control Group)<br>n= 60. Age= 5-17 months Rabies Vaccine administered on Days 0, 28 and 56. | Biological: Rabies vaccine<br>* Vaccine<br>|
| Experimental: Group 4<br>n=120 Age= 5-17 months First vaccination of RH5.1 10μg with 50μg Matrix-M will be administered on day 0, followed by a second dose administered on Day 28, followed by a third and final dose at Day 56. | Biological: RH5.1 10μg adjuvated with 50μg Matrix-M<br>* Vaccine<br>|
| Experimental: Group 5<br>n=120 Age= 5-17 months First vaccination of RH5.2-VLP 5μg with 50μg Matrix-M will be administered on day 0, followed by a second dose administered on Day 28, followed by a third and final dose at Day 56. | Biological: RH5.2 5μg adjuvated with 50μg Matrix-M<br>* Vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the protective efficacy against clinical malaria of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area for 6 months after the last vaccination. | Time to first episode of clinical malaria (defined as the presence of axillary temperature higher than 37.5 degree celsius and P. Falciparum parasite density >5000 asexual forms/µL) | From 14 days after the third study vaccination until 6 months after the third study vaccination. | 
| To assess the safety and reactogenicity of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area. | Occurrence of solicited systemic reactogenicity signs and symptoms via clinic and home visits | The month following each vaccination and at 6 and 12 months after administration of the final dose of vaccine. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the humoral immunogenicity of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area. | The following measures will be assessed Serum ELISA response: 1. Quantitative antigen-specific IgG antibody levels (µg/mL readout) over time - analysis of peak responses and longevity; 2. Antigen-specific antibody subclass/isotype measurement; 3. Antigen-specific antibody avidity measurement; In vitro GIA against 3D7 clone P. falciparum parasites using purified total IgG and a single-cycle pLDH readout assay Purified IgG ELISA versus GIA titration Quality Analysis | Immunology blood samples will be collected at screening, day of vaccination (V) 1, 14 & 28 days post V2, day of V3, 14 days post V3, 2, 6 and 12 months post V3. | 
| To assess the protective efficacy against clinical malaria of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area for 3 months after the last vaccination. | Time to first episode of clinical malaria (defined as the presence of axillary temperature ≥37.5°C and P. falciparum parasite density >5000 asexual forms/µL). | From 14 days after the third study vaccination until 3 months after the third study vaccination | 
| To assess the protective efficacy against clinical malaria of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area | Occurrence of solicited local reactogenicity signs and symptoms via clinic and home visits | For 12 months after the last vaccination | 
| To assess the protective efficacy against asymptomatic P. falciparum infection of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area, by qPCR. | Efficacy tested by conducting qPCR analysis | At 6 and 12 months after administration of the final dose of vaccine. | 
| To assess the protective efficacy against asymptomatic P. falciparum infection against gametocytaemia of RH5.1 in Matrix-MTM and RH5.2-VLP in Matrix-MTM in 5-17 months old children living in a malaria-endemic area, by qPCR. | The proportion of participants in each study arm that show presence of parasite density >5000 asexual forms/µL as measured by quantitative reverse-transcriptase PCR PLUS presence of axillary temperature <37.5°C and absence of history of fever within the last 24 hours. The proportion of participants in each study arm that show presence of parasite density >0 asexual forms/µL as measured by quantitative reverse-transcriptase PCR PLUS presence of axillary temperature <37.5°C and absence of history of fever within the last 24 hours. | At 6 and 12 months post third study vaccination. | 
| To assess the protective efficacy against clinical malaria of RH5.1 in Matrix-M and RH5.2-VLP in Matrix-M in 5-17 months old children living in a malaria-endemic area for 12 months after the last vaccination. | Time to first episode of clinical malaria (defined as the presence of axillary temperature ≥37.5°C and P. falciparum parasite density >5000 asexual forms/µL). | From 14 days after the third study vaccination until 12 months after the third study vaccination | 
| To assess the protective efficacy against gametocytaemia of RH5.1 in Matrix-M and RH5.2-VLP in Matrix-M in 5-17 months old children living in a malaria-endemic area, by qPCR at 2 and 6 months after administration of the final dose of vaccine | The proportion of participants in each study arm that show presence of gametocytes >0 gametocytes/μL as measured by quantitative reverse-transcriptase PCR. | At 2 and 6 months post third study vaccination. | 
| Efficacy against incident severe anaemia and blood transfusion requirement | The proportion of participants in each study arm with documented Hb <5.0 g/dL identified at clinical presentation in association with P. falciparum asexual parasitaemia > 5000 parasites/µL. The proportion of participants in each study arm with documented Hb <5.0 g/dL identified at clinical presentation and requirement for a blood transfusion. | From 14 days after the third study vaccination until 6 months after the third study vaccination. |