FMP2.1/AS02A: Rabies Vaccine Malaria-Experienced Adults in Bandiagara, Mali

Study Overview
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Brief Summary
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Malaria is a disease that affects many people in Africa and in Mali. It is caused by germs that are spread by mosquito bites. This study will look at the safety, effectiveness, and best dose of an experimental malaria vaccine in people who are regularly exposed to malaria. Study participants will be 60 adults, 18-55 years old, who live in Bandiagara, Mali. Volunteers will get either 3 full doses of the experimental malaria vaccine, 3 half doses of the malaria vaccine, or a rabies vaccine that has been approved in Mali. (Rabies is an infection of the brain that usually causes death, and can be caught from being bitten by infected dogs or bats.) The 3 vaccinations will be given by injection into the upper arm 30 days apart. Volunteers will be enrolled in the study for approximately 12 months after the first vaccination. Volunteers will have 14 blood samples collected during the study for testing to make sure that the vaccine is not harmful and to measure the effect of the vaccine.

Detailed Description
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The primary objective of this study is to evaluate the safety and reactogenicity of two dose levels of WRAIR's AMA1 malaria antigen (FMP2.1) adjuvanted in GlaxoSmithKline Biologicals' AS02A compared to rabies vaccine in malaria-experienced Malian adults aged 18-55 years inclusive. Secondary objectives are to: (1) measure the magnitude and duration of antibody response to FMP2.1; (2) measure cellular immune responses to FMP2.1 at baseline and after immunization; (3) measure the inhibition of parasite growth by the in vitro GIA; and (4) determine the specificity of the antibodies to diverse AMA1 genotypes in addition to 3D7, by measuring by ELISA, and GIA on parasites with typed AMA1. A double-blind controlled dose escalation trial will allow assessment of vaccine safety in each of three groups, one group each to receive medium and full dose levels of the experimental vaccine, and one group to receive the comparator vaccine. Thirty adults will be randomized to receive the medium dose level of FMP2.1 (n=20) or rabies vaccine (n=10) and thirty to receive the full dose level of FMP2.1 (n=20) or rabies vaccine (n=10). The division of the rabies group into two groups of ten is done to maintain blinding at each immunization time point, and all participants who receive the rabies vaccine will be analyzed as a single group. The sample size of the groups, however, will not allow detection of anything other than very large differences in the occurrence of adverse events among the three groups. The advantage of double blinding is to remove the potential for investigator and participant prejudgment about the effects of the vaccines in the reporting of adverse events.

Official Title
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Double Blind Randomized, Controlled Phase 1 Dose Escalation Trial to Evaluate the Safety and Immunogenicity of the WRAIR AMA1 Malaria Antigen (FMP2.1) Adjuvanted in GSK's AS02A Versus Rabies Vaccine in Malaria-experienced Adults in Bandiagara, Mali

Conditions
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Malaria, Plasmodium Falciparum Malaria

Intervention / Treatment
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* Biological: FMP2.1/AS02A
* Biological: Rabies vaccine (RabAvert)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male or non-pregnant female aged 18-55 years inclusive at the time of screening For women, willingness not to become pregnant until 1 month after the last immunization (pre-menopausal female participants will be referred to the local family planning clinic in Bandiagara, which offers several means of contraception that are approved and recommended by the Malian Ministry of Health) Separate written informed consent obtained from the participant before screening and study start, respectively Available and willing to participate in follow-up for the duration of study (12 months) Exclusion Criteria: Previous vaccination with any investigational vaccine or with any rabies vaccine Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first study immunization, or planned use up to 30 days after the third immunization Chronic administration (defined as more than 14 days) of immuno-suppressants or other immune-modifying drugs within six months prior to the first immunization. This will include any dose level of oral steroids or inhaled steroids, but not topical steroids Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before the first study immunization with the exception of tetanus toxoid Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection Any confirmed or suspected autoimmune disease History of allergic reactions or anaphylaxis to immunizations or to any vaccine component History of serious allergic reactions to any substance, requiring hospitalization or emergent medical care History of allergy to tetracycline, doxycycline, nickel, Imidazole, chicken eggs, processed bovine gelatin, chicken protein, neomycin, or amphotericin B History of splenectomy Serum ALT >/=43 IU/L Serum creatinine level >113 µmol /L for males and 70 µmol /L for females Hgb <11 g/dL for males and <10 g/dL for females WBC <4.0 x 1000/cubic mm or >13 x 1000/cubic mm Absolute lymphocyte count </=1.4 x 1000 /µl Thrombocytopenia < 108,000/µl More than trace protein, more than trace hemoglobin or positive glucose in urine Administration of immunoglobulins and/or any blood products within the three months preceding the first study immunization or planned administration during the study period Suspected or known current alcohol or illicit drug abuse Pregnancy or positive urine beta-HCG on the day of or prior to immunization Breastfeeding Simultaneous participation in any other interventional clinical trial Acute or chronic pulmonary, cardiovascular, hepatic, renal or neurological condition, or any other findings that in the opinion of the Principal Investigator (PI) may increase the risk of participating in the study Other condition that in the opinion of the PI would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Cohort 1: 25ug FMP2.1 / AS02A<br>20 subject to receive 25ug of FMP2.1 vaccine in 0.25mL of GSK Biologicals' adjuvant AS02A | Biological: FMP2.1/AS02A<br>* FMP2.1 in GSK Biologicals' AS02A<br>|
| Experimental: Cohort 2: 50ug FMP2.1 / AS02A<br>20 subjects to receive 50ug of FMP2.1 vaccine in 0.5mL of GSK Biologicals' adjuvant AS02A | Biological: FMP2.1/AS02A<br>* FMP2.1 in GSK Biologicals' AS02A<br>|
| Active Comparator: Cohorts 1 and 2: Rabies vaccine (RabAvert)<br>20 subjects to receive Rabies vaccine (RabAvert). 10 subjects from Cohort 1 and 10 subjects from Cohort 2 Rabies vaccine (RabAvert): RabAvert Rabies vaccine | Biological: FMP2.1/AS02A<br>* FMP2.1 in GSK Biologicals' AS02A<br>Biological: Rabies vaccine (RabAvert)<br>* RabAvert Rabies vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Reactogenicity (SAEs and AEs) | The primary objective was to evaluate the safety and reactogenicity of 2 dose levels of WRAIR's AMA1 malaria antigen (FMP2.1) adjuvanted in GlaxoSmithKline Biologicals' (GSK) AS02A compared to rabies vaccine in malaria-experienced Malian adults aged 18-55 years inclusive. Solicated AEs were recorded for the 7 day surveillance period after each vaccination. Unsolicited AEs were recorded for 30 days after each vaccination. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody Response to FMP2.1 Over Time | Measurement of anti-AMA1 antibody titers over time | 90 Days | 
| Anti-AMA1 Log Antibody Titers Over Time | Summary of Anti-AMA1 Log Antibody titers on days 0, 14, 30, 44, 60, 74 and 90 | 90 Days | 
| Geometric Mean Antibody Titers Over Time | Measurement of geometric mean antibody titers on days 0, 14, 30, 44, 60, 74 and 90 | 90 Days | 
| Subjects With 2- and 4-fold Increases in Anti-FMP2.1 Antibody Levels Over Time | Proportion of Subjects with 2- and 4-fold increases in Anti-FMP2.1 Antibody levels on days 14, 30, 44, 60, 74 and 90 | 90 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium falciparum Malaria, Mali, adjuvant