Study of the Transmission-Blocking Vaccine Pfs230D1-EPA/Matrix-M Against Malaria in Adults in Mali

Study Overview
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Brief Summary
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Background: Researchers are trying to develop a vaccine that will safely reduce the spread of malaria in the community by preventing mosquitos from carrying malaria from person to person. Objective: To assess in African adults the safety of and immune response to the administration of Pfs230D1-EPA/Matrix-M vaccine as compared to the rabies vaccine control. Eligibility: Healthy adults (18 to 50 years of age) who reside in Sotuba and surrounding villages in Mali Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Malaria comprehension exam Participants will be randomly assigned to get either the experimental vaccine or the approved rabies vaccine. They will not know which they are getting. Participants will get 3 doses of the study or comparator vaccine via injection in the upper arm. This occurs at the first visit, 1 month, and 2 months later. Participants will have up to 23 scheduled visits over 14 to 16 months. Each visit includes a physical exam, and blood will be collected at most visits. Participants will be followed up to 1 year after the final vaccination. If participants develop an injection site rash or reaction, photographs may be taken of the site.

Detailed Description
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A vaccine to interrupt malaria transmission (VIMT), targeting disruption of parasite transmission through both human and mosquito, would be a valuable additional resource in the fight to eliminate this disease. Transmission-blocking vaccines (TBVs) induce anti-sporogonic antibodies that disrupt parasite transmission to the mosquito, thereby halting transmission to another human host. Malaria-exposed populations acquire antibody against Pfs230, a parasite protein expressed by gametocytes in the human stage of P. falciparum and a surface antigen of gametes and zygotes in the mosquito stage, which suggests that a Pfs230-based vaccine may be boosted by natural malaria infection. Pfs230D1 has become one of the leading transmission-blocking antigens for consideration as a licensed TBV to be used either alone or in combination with other transmission-blocking antigens. Clinical trials with this antigen adjuvanted with either Alhydrogel or AS01 have provided very encouraging results. This is a Phase 1, dose-escalating, randomized, double-blind, comparator-controlled study to assess the safety, tolerability, immunogenicity and transmission-blocking activity (TBA) of a 3 dose regimen of Pfs230D1-EPA/Matrix-M versus rabies vaccine in healthy adults. This will be a first-in-human assessment of Pfs230D1-EPA/Matrix-M and will be conducted as a dose-escalation trial. Participants will be randomized to 1 of the study arms to receive 1 of 3 dose levels of Pfs230D1-EPA/Matrix-M or a standard dose of comparator rabies vaccine administered as an intramuscular injection at 3 timepoints. For the 3 Pfs230D1-EPA/Matrix-M antigen dosages, we will start with a Pilot Group of 5 subjects in each Pfs230D1-EPA/Matrix-M arm and the rabies vaccine control arm. For the Pilot Group, the different dosage administrations are separated by approximately 2 weeks. Safety outcomes will include the frequency of systemic and local adverse events and serious adverse events. Immunogenicity outcomes will be antibody responses measured by ELISA against Pfs230D1. Functional activity will be assessed by standard membrane feeding assays.

Official Title
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Phase 1, Dose-Escalating, Double-Blind, Randomized, Comparator-Controlled Trial of the Safety, Tolerability, and Immunogenicity of the Transmission-Blocking Vaccine Pfs230D1-EPA/Matrix-M™ Against Plasmodium Falciparum in Adults in Mali

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Biological: Pfs230D1-EPA/Matrix-M Vaccine
* Biological: Verorab Rabies Vaccine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: All of the following criteria must be fulfilled for a volunteer to participate in this trial: Age: > 18 years old and < 50 years old. Available for the duration of the trial. Known resident or long-term resident (more than 1 year) of Sotuba, Mali or surrounding villages. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. In good general health and without clinically significant medical history in the opinion of the investigator. Females of childbearing potential must be willing to use reliable contraception from 21 days prior to Study Day 0 and until 1 month after the last vaccination. A reliable method of birth control includes one of the following: Confirmed pharmacologic contraceptives (parenteral) delivery. Intrauterine or implantable device. EXCEPTIONS to required pregnancy prevention includes the following: Postmenopausal state: defined as no menses for 12 months without an alternative medical cause. Surgical sterilization. Willing to have blood samples stored for future research. EXCLUSION CRITERIA: An individual will be excluded from participating in this trial if any one of the following criteria is fulfilled: Pregnant, as determined by a positive urine or serum beta human choriogonadotropin (β hCG) test (if female). NOTE: Pregnancy is also a criterion for discontinuation of any further vaccine dosing. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and comply with the study protocol at a level appropriate for the subject's age. Hemoglobin, white blood cell (WBC), absolute neutrophil count, or platelet levels outside the local laboratory-defined limits of normal. (Subjects may be included at the investigator's discretion for not clinically significant values outside of normal range and ≤ Grade 2.) Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Subjects may be included at the investigator's discretion for not clinically significant values outside of normal range and ≤ Grade 2.) Infected with HIV. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies. History of receiving any investigational product within the past 30 days. Current or planned participation in an investigational vaccine study until the time period of the last required study visit under this protocol. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months. History of a severe allergic reaction or anaphylaxis. Known: Severe asthma, defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past 2 years, or that has required the use of oral or parenteral corticosteroids at any time during the past 2 years. Autoimmune or antibody-mediated disease including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, or autoimmune thrombocytopenia. Immunodeficiency syndrome. Seizure disorder (exception: history of simple febrile seizures). Asplenia or functional asplenia. Use of chronic (≥14 days) oral or intravenous (IV) corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of Study Day 0. Allergy to latex or neomycin. Receipt of: Live vaccine within 4 weeks prior to enrollment or a killed vaccine within 2 weeks prior to enrollment. Immunoglobulins and/or blood products within the past 6 months. Investigational malaria vaccine in the last 2 years. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1a (Pilot Group)<br>(n=5) to receive 12.5 µg Pfs230D1-EPA/25 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Experimental: 1b (Pilot Group)<br>(n=5) to receive 20 µg Pfs230D1-EPA/50 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Experimental: 1c (Pilot Group)<br>(n=5) to receive 40 µg Pfs230D1-EPA/50 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Active Comparator: 1d (Pilot Group)<br>(n=4) to receive rabies vaccine (standard dose) on D1, D29, D57 | Biological: Verorab Rabies Vaccine<br>* Verorab Rabies Vaccine is a purified inactivated rabies vaccine (Wistar rabies PM/WI 38 1503-3M strain) prepared on Vero cells. It is supplied as a powder and solvent for suspension for injection in a prefilled syringe. Before reconstitution, the powder is a white and homogeneous pellet. The solvent is a limpid solution.<br>|
| Experimental: 2a (Main Group)<br>(n=15) to receive 12.5 µg Pfs230D1-EPA/25 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Experimental: 2b (Main Group)<br>(n=15) to receive 20 µg Pfs230D1-EPA/50 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Experimental: 2c (Main Group)<br>(n=15) to receive 40 µg Pfs230D1-EPA/50 µg Matrix-M on D1, D29, D57 | Biological: Pfs230D1-EPA/Matrix-M Vaccine<br>* Each single-use vial of Pfs230D1M-EPA contains 160 µg/mL of conjugated Pfs230D1M and 124 µg/mL or 143 µg/mL of conjugated EPA in 4 mM phosphate-buffered saline (PBS), in a volume of 0.5 mL. Each vial of Matrix-M1 contains saponin content of 0.375 mg/mL in PBS, at a pH of 7.2, in a final volume of 0.75 mL. Components will be combined in volumes defined in the protocol at point of use.<br>|
| Active Comparator: 2d (Main Group)<br>(n=16) to receive rabies vaccine (standard dose) on D1, D29, D57 | Biological: Verorab Rabies Vaccine<br>* Verorab Rabies Vaccine is a purified inactivated rabies vaccine (Wistar rabies PM/WI 38 1503-3M strain) prepared on Vero cells. It is supplied as a powder and solvent for suspension for injection in a prefilled syringe. Before reconstitution, the powder is a white and homogeneous pellet. The solvent is a limpid solution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of local and systemic adverse events (AEs) and serious adverse events (SAEs) to assess the safety of the study drug |  | 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of humoral immune response as measured by ELISA titer response to Pfs230D1M after third immunization |  | 6 months post 3rd vaccination | 
| Duration of humoral immune response as measured by ELISA titer response to Pfs230D1M after third immunization |  | 6 months post 3rd vaccination | 
| Level of functional antibody response to Pfs230D1M as measured by standard membrane feeding assay |  | 6 months post 3rd vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Reactogenicity, Antibody, Mosquito, Vaccine