Safety and Immunogenicity of Recombinant Pichia Pastoris AMA1-DiCo Candidate Malaria Vaccine With GLA-SE and Alhydrogel ® as Adjuvant in Healthy Malaria Non-Exposed European and Malaria Exposed African Adults

Study Overview
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Brief Summary
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The primary objective is to evaluate the safety of 3 doses given at D0, W4, and W26 of 50 µg dosage of AMA1-DiCo adjuvanted either with GLA-SE or Alhydrogel® in healthy European adults not previously exposed to the parasite P.falciparum and in healthy African adults exposed to the parasite. The safety and the tolerability of the vaccine will be assessed on the rate of solicited and unsolicited events/reactions. The safety profile will include local and systemic reactions/events as well as the biological safety, based on a clinically significant change of the baseline value of the main biological criteria.

Detailed Description
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The project aims are : -To evaluate the safety of 50 µg AMA1-DiCo malaria vaccine candidate with GLA-SE and Alhydrogel® as adjuvant, in healthy European adults not previously exposed to the parasite Plasmodium falciparum and in healthy African adults exposed to the parasite. T-o assess the humoral immune response to the vaccine antigens by measuring the level of IgG in all volunteers. To assess the cellular immune response by measuring the T cell cytokines IL-5 and IFNγ production following in vitro stimulation with the vaccine antigens in all volunteers. Design : This trial is a staggered Phase Ia/Ib, Randomised, Double-blind, Multi-center Centre trial. Two different adjuvants will be assessed, Alhydrogel® and GLA-SE. One dosage of 50 µg/3 injections of AMA1-DiCo will be evaluated for each adjuvant. Sixty six (66) healthy volunteers will be included into the 2 following cohorts (A and B): Cohort A: 30 Non-exposed European Volunteers (France) Cohort B: 36 Malaria Exposed African Volunteers (Burkina Faso) The non-exposed European volunteers (cohort A) will be randomised in a 1:1 ratio into two groups of 15 volunteers per group. The malaria exposed African volunteers (cohort B) will be randomised in a 1:1 ratio, into two groups of 18 volunteers per group. European Volunteers: Cohort A (30): Group A1 (15): 50µg AMA1-DiCo + Alhydrogel® Group A2 (15): 50 µg AMA1-DiCo+ GLA-SE African Volunteers Cohort B (36) : Group B1 (18): 50 µg AMA1-DiCo + GLA-SE Group B2 (18): Placebo (isotonic saline solution) In order to start recruitment in cohort B (Africa), the safety will be evaluated on the data of all European volunteers until Day 7 after 1st immunisation of the last European volunteer Data will be presented to an Independent Data safety Monitoring Board (DSMB) that will be appointed for this trial

Official Title
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Safety and Immunogenicity of Recombinant Pichia Pastoris AMA1-DiCo Candidate Malaria Vaccine With GLA-SE and Alhydrogel ® as Adjuvant in Healthy Malaria Non-Exposed European and Malaria Exposed African Adults:a Staggered Phase Ia/Ib, Randomised, Double-blind, Multi-Centre Trial

Conditions
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Malaria, Falciparum

Intervention / Treatment
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* Biological: Group A1 : 50µg AMA1-DiCo + Alhydrogel
* Biological: Group A2 : 50 µg AMA1-DiCo+ GLA-SE
* Biological: Group B2 : Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 20 and < 45 years healthy female and male General good health based on history and clinical examination. Written informed consent obtained before any trial procedure. Female and male volunteers practicing contraception before and up to four (4) weeks after the third vaccination. Available to participate in follow-up for the duration of trial. Reachable by phone during the whole trial period. Volunteers should be affiliated to a social security regimen Exclusion Criteria: Positive pregnancy test Active breast feeding Previous participation in any malaria vaccine trial History of blood transfusion within the last 6 months Symptoms, physical signs or laboratory values suggestive of systemic disorders, including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric and other conditions, which could interfere with the interpretation of the trial results or compromise the health of the volunteers. Any clinically significant laboratory abnormalities on screened blood samples outside the normal range, as defined at the clinical trial site. Enrolment in any other clinical trial during the whole trial period Intake of chronic medication, especially immunosuppressive agents (steroids, immunomodulating or immunosuppressive drugs) during the thirteen weeks preceding the screening visit or during the trial period except topical steroid use including intranasal. Any confirmed or suspected immunosuppressive or immunodeficiency condition during the whole trial period Volunteers unable to be closely followed for social, geographic or psychological reasons. Previous history of drug or alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the trial. History of anaphylaxis or Known severe hypersensitivity to any of the vaccine components (adjuvant or antigen or excipient) Vaccination or gamma globulin: 4 weeks prior and after each vaccination if a vaccination is necessary during this period, the volunteer will be withdrawn from the study. Positive HIV, HBV (Ag HBS) and HCV tests. History of malaria or travel in malaria endemic areas within the past twenty-six weeks. Positive serology for malaria antigen PfAMA-1 Intention to travel to malaria endemic countries during the trial period. -

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMA1-DiCo + Alhydrogel<br>AMA1-DiCo: 50µg Alhydrogel® : 0.85 mg Al3+ per dose Route : Intramuscular Vaccination schedule : Do, W4, W26 | Biological: Group A1 : 50µg AMA1-DiCo + Alhydrogel<br> <br> |
| Experimental: AMA1-DiCo+ GLA-SE<br>Group A2 (15) : European volunteer : AMA1-DiCo + GLA-SE AMA1-DiCo: 50µg GLA-SE 2.5 µg GLA per dose Route : Intramuscular Vaccination schedule : Do, W4, W26 | Biological: Group A2 : 50 µg AMA1-DiCo+ GLA-SE<br> <br> |
| Experimental: AMA1-DiCo + GLA-SE<br>Group B1 (18) : African volunteer : AMA1-DiCo + GLA-SE AMA1-DiCo: 50µg GLA-SE 2.5 µg GLA per dose Route : Intramuscular Vaccination schedule : Do, W4, W26 | Biological: Group A2 : 50 µg AMA1-DiCo+ GLA-SE<br> <br> |
| Placebo Comparator: Placebo<br>Group B2 (18) : African volunteer : Placebo Placebo : isotonic saline solution Route : Intramuscular Vaccination schedule : Do, W4, W26 | Biological: Group B2 : Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse events | The safety profile will be assessed in all volunteers on the following criteria: Immediate reactogenicity (reactions within 60 minutes after each vaccination). Local and systemic reactogenicity measured from Day 0 to Week 2 after each vaccination. Any unsolicited adverse event between the first vaccination and four weeks after the third vaccination. Any SAE occurring from the inclusion throughout the trial. | Up to four weeks after the third vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The humoral and cellular responses | The humoral response to the vaccine antigens (DiCo1, DiCo2 and DiCo3) will be assessed by measuring the level of IgG by ELISA on samples obtained at screening visit Day 0, Week 4, 5, 8, 26, 27, 30 and 52. The cellular immune response will be assessed by measuring the T cell cytokine IL-5, and IFNg production by ELISpot following in vitro stimulation with the vaccine antigens on samples obtained at Day 0, Week 26, 30 and 52. | 6 months after the last vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria vaccine, phase 1,, AMA1-DiCO