FMP2.1 Trial in Bandiagara, Mali

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.

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.

• Malaria
• Plasmodium Falciparum Malaria

• Biological: FMP2.1/AS02A
• Biological: Rabies vaccine

• Experimental: FMP2.1
  FMP2.1 vaccine
  Intervention: Biological: FMP2.1/AS02A
• Placebo Comparator: Rabies vaccine
  Rabies vaccine
  Intervention: Biological: Rabies vaccine

Inclusion Criteria:

1. A male or non-pregnant female aged 18-55 years inclusive at the time of screening
2. 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)
3. Separate written informed consent obtained from the participant before screening and study start, respectively
4. Available and willing to participate in follow-up for the duration of study (12 months)

Exclusion Criteria:

1. Previous vaccination with any investigational vaccine or with any rabies vaccine
2. 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
3. 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
4. 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
5. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection
6. Any confirmed or suspected autoimmune disease
7. History of allergic reactions or anaphylaxis to immunizations or to any vaccine component
8. History of serious allergic reactions to any substance, requiring hospitalization or emergent medical care
9. History of allergy to tetracycline, doxycycline, nickel, Imidazole, chicken eggs, processed bovine gelatin, chicken protein, neomycin, or amphotericin B
10. History of splenectomy
11. Serum ALT >/=43 IU/L
12. Serum creatinine level >113 µmol /L for males and 70 µmol /L for females
13. Hgb <11 g/dL for males and <10 g/dL for females
14. WBC <4.0 x 1000/cubic mm or >13 x 1000/cubic mm
15. Absolute lymphocyte count </=1.4 x 1000 /µl
16. Thrombocytopenia < 108,000/µl
17. More than trace protein, more than trace hemoglobin or positive glucose in urine
18. Administration of immunoglobulins and/or any blood products within the three months preceding the first study immunization or planned administration during the study period
19. Suspected or known current alcohol or illicit drug abuse
20. Pregnancy or positive urine beta-HCG on the day of or prior to immunization
21. Breastfeeding
22. Simultaneous participation in any other interventional clinical trial
23. 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
24. 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

• National Institute of Allergy and Infectious Diseases (NIAID)
• Walter Reed Army Institute of Research (WRAIR)
• GlaxoSmithKline
• University of Maryland