MSP3-CRM-Vac4All/ Alhydrogel® Vaccine

Study Overview
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Brief Summary
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Two-arm, randomized, double-blinded and controlled clinical trial to first assess the safety and tolerability of the vaccine in a Phase 1b trial and proceed to assess its efficacy against clinical malaria in young children living in highly seasonal malaria areas of Mali

Detailed Description
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This study is designed to be executed in two steps to achieve the primary efficacy objective: The first step is a Phase 1b safety study, involving injections in a small safety subgroup for each dose before age-de-escalation into the younger age group and then proceeding to the second step of dosing the corresponding injection in the larger Phase 2b efficacy cohort. Vaccination of the Phase 2b cohort will require an acceptable reactogenicity data over the first week following the corresponding vaccination of the older and younger age groups in the Phase 1 subgroup. The study DSMB will be charged with this review and ensuring that vaccination proceeds only if the reactogenicity profile meet study go criteria (Table 1). The objectives of each phase are: Phase 1b: The primary objective is to assess the safety and tolerability of the vaccine for each injection. The secondary objective is to evaluate the immune response to the vaccine and safety for up to 12 months after the first dose. Phase 2b: The primary objective is to assess the efficacy in young children* against clinical malaria** during one transmission season. The timeline for the primary analysis assessment is from 14 days to 6 months after Dose 3. Should the primary analysis data demonstrate that the vaccine gives good efficacy, a boost vaccination will be programmed to be administered to willing subjects before the start of the subsequent transmission season. The study protocol will be amended with the precise details in this event.

Official Title
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A Phase 1b/2b Double Blind, Randomized, Controlled Study of the Safety, Immunogenicity, and Efficacy of Malaria Vaccine Candidate MSP3-CRM-Vac4All/ Alhydrogel® in Young Children in Mali

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Biological: MSP3-CRM-Vac4All/ Alhydrogel®
* Biological: Anti-Rabies Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 12-59 months years old Healthy by medical history, physical examination and laboratory investigation Signed/thumb printed informed Consent by guardian/parent Resident in the study area villages during the whole trial period Exclusion Criteria: Symptoms, physical signs of disease that could interfere with the interpretation of the trial results or compromising the health of the participants Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior recruitment. (For corticosteroids, this will mean prednisone, or equivalent, more or equal to 0.5 mg/kg/day. Inhaled and topical steroids are allowed.) Cannot be followed for any social, psychological or geographical reasons. Use of any investigational drug or vaccine other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use up to 30 days after the third dose. Suspected or known hypersensitivity to any of the vaccine components or to previous vaccine. Clinically significant laboratory abnormalities on screened blood samples. Planned administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of vaccine. An exception, is the receipt of an childhood immunization program or licensed vaccine (measles, oral polio, Hib, meningococcal and combined diphtheria/pertussis/tetanus vaccines) which may be given before or after vaccination*. Evidence of chronic or active hepatitis B or C infection Presence of chronic illness that, in the judgment of the investigator, would interfere with the study outcomes or pose a threat to the participant's health. Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period History of surgical splenectomy. Moderate or severe malnutrition at screening based on clinical judgement. o (Weight-for-age Z score of less than -3 or other clinical signs of malnutrition). Previous participation to a malaria vaccine trial Known history of HIV infection

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 59 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test Vaccine<br>MSP3-CRM-Vac4All/ Alhydrogel® | Biological: MSP3-CRM-Vac4All/ Alhydrogel®<br>* 30 microgram MSP3-CRM-Vac4All protein extemporaneously formulated with Alhydrogel® adjuvant<br>|
| Active Comparator: Control Vaccine<br>Anti-rabies vaccine | Biological: Anti-Rabies Vaccine<br>* Control vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protective Efficacy against Clinical Malaria | To assess the efficacy of 30 µg MSP3-CRM-Vac4All/Alhydrogel® vaccine in children ages 12-60 months old, against clinical malaria occurring over one transmission season. The primary efficacy outcome is clinical malaria, with the primary case definition of clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 37.5ºC with P. falciparum parasitemia ≥5000/µL | The timeline for assessment will be from 14 days to 6 months after Dose 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy- different definitions of malaria fever and parasite thresholds on microscopy | To compare efficacy against clinical malaria for different case definitions using Fever thresholds that are higher than 37.5ºC, such as 38.5ºC and 39.5ºC History of fever instead of measured fever Different parasitemia by microscopy thresholds [any parasitemia, 1000, 10,000 and 20,000/µL] Efficacy outcomes clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 38.5ºC with P. falciparum parasitemia ≥5000/µL or ≥ 39.5ºC with P. falciparum parasitemia ≥5000/µL or clinical malaria episodes defined as history of fever with P. falciparum parasitemia of the following levels: any parasitemia, 1000, 10,000 and 20,000/µL clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 38.5ºC with or ≥ 39.5ºC with P. falciparum parasitemia of the following levels: any parasitemia, 1000, 10,000 and 20,000/µL | For 12 months after first vaccination | 
| Efficacy duration | To assess the efficacy of MSP3-CRM-Vac4All/Alhydrogel® in young children against clinical malaria occurring during the 12 months following dose 3. | For 12 months following the first vaccination | 
| Efficacy against first malaria episodes | To assess the efficacy of MSP3-CRM-Vac4All/Alhydrogel® in young children against first clinical malaria episodes occurring from over the 6 month period 14 days after 2nd and 3rd vaccination and up to the end of study follow-up (12 months after first vaccination). The efficacy outcome is first episode of clinical malaria, with the case definition of clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 37.5ºC with P. falciparum parasitemia ≥5000/µL | From 14 days post 2nd or 3rd vaccination to 6 months following and up to the end of study follow-up (12 months after first vaccination | 
| Efficacy (conditional boost) | To assess the efficacy of MSP3-CRM-Vac4All/Alhydrogel® in young children against clinical malaria occurring The efficacy outcome is clinical malaria, with the primary case definition of clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 37.5ºC with P. falciparum parasitemia ≥5000/µL | For the 6 months following boost vaccination | 
| Efficacy (conditional boost) | To assess the efficacy of MSP3-CRM-Vac4All/Alhydrogel® in young children against clinical malaria occurring. The efficacy outcome is clinical malaria, with the primary case definition of clinical malaria episodes defined as a febrile episode with an axillary temperature of ≥ 37.5ºC with P. falciparum parasitemia ≥5000/µL | For the 12 months following boost vaccination | 
| Number of adverse events | To assess the safety and reactogenicity of 3 doses of 30 µg MSP3-CRM-Vac4All/Alhydrogel® given at D0, D28 and D56 in healthy young children | During the month following each vaccination, and 6 months and 12 months after first vaccination. | 
| Number of adverse events for conditional boost vaccination | Safety and reactogenicity of boost vaccination doses of MSP3-CRM-Vac4All/Alhydrogel® in healthy young children | At one month, 6 month and 12 months following boost vaccination | 
| Immune response | To examine the duration of immune responses of a 3-dose regimen of during periods corresponding to that used for primary and other secondary efficacy endpoints as measured through a > 5-fold decrease of MSP3-specific serum IgG antibody titers after each vaccination in comparison to baseline levels (14 days post last dose) | From 14 days post last dose to up to a month after last dose, 6 months after last dose and 12 months after first dose | 
| Immune response | To determine immunogenicity in terms of the proportion with titres either more than 3SD above the median for negative controls (positive) or at least 50% of the positive controls (strongly positive) after dose 3. | A month after dose 3 | 
| Parasite densities | To measure effect on parasitemia by comparing parasite densities in malaria episodes occurring in vaccinees compared to control | From vaccination to up to 6 months after last dose and 12 months after first dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, malaria vaccine, vaccine efficacy