Study of VMP001 and AS01B (Adjuvant Formulation) in Healthy Malaria-Naïve Adults

Phase 1/2a Open-label Dose Safety, Reactogenicity, Immunogenicity and Efficacy of the Candidate Plasmodium Vivax Malaria Protein 001 (VMP001) Administered Intramuscularly With GlaxoSmithKline (GSK) Biologicals' Adjuvant System AS01B in Healthy Malaria-Naïve Adults

This is a first-in-humans safety, immunogenicity and efficacy study with recombinant protein VMP001, a Plasmodium vivax circumsporozoite (CS) protein based vaccine. This open label study will be performed in malaria-naïve adults in the United States. Three doses of VMP001 formulated in AS01B (adjuvant system) will be given intramuscularly at different intervals followed by a challenge with P. vivax infected mosquitoes. Safety, immunogenicity and efficacy parameters will be studied.

This is a Phase 1/2a, non-randomized, open label, dose escalation study in healthy, malaria-naïve adults aged 18 to 55 years (inclusive). The vaccine will be administered with GlaxoSmithKline Biologicals' adjuvant system AS01B. This is a first-in-human study of VMP001; therefore the study design will incorporate a dose-escalation phase evaluating 15 µg, 30 µg, and 60 µg doses of VMP001 in 500 µL of AS01B. A total of 30 volunteers, divided into 3 groups (10 in each group), will receive 3 doses of the VMP001/AS01B vaccine. Group 1 will receive 15 µg of VMP001, Group 2 will receive 30 µg of VMP001, and Group 3 will receive 60 µg of VMP001 at each immunization. The dose of AS01B will be 500 µL for all groups. The first and second dose in each group will be separated by 28 days. The third dose in the three groups will be given at intervals scheduled to normalize the time to challenge between the last immunization and challenge. The second and third dose in Group 1 will be separated by 56 days, Group 2 by 42 days and Group 3 by 28 days. The challenge will occur 2 weeks following the third immunization. A group of 6-12 infectivity controls will begin participation in the study at the challenge stage. They will not receive any immunizations or placebos prior to challenge. All volunteers will receive a standard treatment regimen consisting of chloroquine and primaquine on the day that parasitemia is detected. Volunteers who do not become parasitemic will also begin the same treatment regimen on day 28 following the challenge (study day 126).

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> Safety and immunogenicity will be evaluated during the study through the final study visit 6 months after challenge (study day 280).

Inclusion Criteria:

• Subjects who meet all of the following criteria may participate in this study:
• Healthy adults (male or non-pregnant, non-lactating female) 18 to 55 years of age (inclusive) at the time of enrollment
• If the subject is female, she must be of non-childbearing potential (either surgically sterilized or one year post-menopausal) or, if of childbearing potential, she must be capable of preventing pregnancy, have a negative pregnancy test at the time of each vaccination, and must agree to continue such precautions until completion of the last study visit.
• Free of significant health problems as established by medical history, laboratory and clinical examination before entering the study
• Duffy positive phenotype (homozygous or heterozygous)
• Normal (non-deficient) Glucose 6-phosphate dehydrogenase (G6PD) phenotype (range: 4.6 to 13.5 units/gm hemoglobin)
• Volunteers must have low cardiac risk factors according to the NHANES I criteria and a non-significant electrocardiogram (EKG)
• Available to participate and reachable by phone for duration of study (approximately 9 months)
• No plans to travel to outside the Washington, District of Columbia (DC) area up until treatment course has been completed (post challenge)
• No plans to travel to a malaria endemic area during the course of the study
• Written informed consent must be obtained from the subject before screening procedures
• Volunteers must score at least 80% correct on a 10 or 14 question multiple-choice quiz (control and immunization groups, respectively) that assesses their understanding of this study
• If a subject is active duty military he or she must obtain approval from his or her supervisor per Walter Reed Army Institute of Research (WRAIR) Policy 06-15

Exclusion Criteria:

• Subjects meeting any of the following criteria will be excluded from the study:
• Any history of malaria infection
• History of travel to P. vivax endemic areas in the last three months, and travel to Republic of Korea or China in the last 18 months
• Any history of receiving malaria vaccine or any licensed vaccine within 7 days prior to first immunization
• History of receipt of malaria prophylaxis during the previous 2 months or the use of any drugs with significant anti-malarial activity during the study period one month prior to challenge (for control volunteers). Examples include tetracycline, doxycycline, clindamycin, azithromycin or sulfa drugs
• Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of study vaccine or planned use during the study period.
• Any history of allergic reaction or anaphylaxis to previous vaccination

Allergy to kanamycin, nickel, or imidazole

• Pregnant (positive β-HCG) or nursing at screening or plans to become pregnant or nurse from the time of enrollment until study completion.
• Allergy to antimalarial drugs or use of medications known to cause drug reactions with chloroquine and/or primaquine
• Significant (e.g. systemic) hypersensitivity reactions to mosquito bites (local hypersensitivity reactions at the site of mosquito bites are not an exclusion criterion)
• History of sickle cell disease
• History of psoriasis or porphyria
• History of splenectomy
• Any confirmed or suspected immunodeficiency, including HIV infection
• Administration of chronic (defined as more than 14 days) immunosuppressive drugs or other immune-modifying drugs within 6 months of immunization. For corticosteroids, this is defined as >20 mg/day prednisone or equivalent. -Inhaled and topical steroids are allowed
• A family history of congenital or hereditary immunodeficiency
• Acute or chronic, clinically significant, pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by history, physical examination, and laboratory evaluation
• History of diabetes or hypertension even if well controlled on medication
• An abnormal baseline screening electrocardiogram (EKG) suggestive of cardiac disease as determined by a clinical investigator
• Chronic or active neurologic disease including seizure disorder and chronic migraine headaches
• Any abnormal baseline laboratory screening tests: Alanine Aminotransferase (ALT) above normal range, -Creatinine above normal range, Hemoglobin out of normal range, Platelet count out of normal range, Total white blood cell count out of normal range
• Hepatomegaly, right upper quadrant abdominal pain or tenderness
• Seropositive for HIV or hepatitis C virus, or HBsAg positive
• Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or any planned administration during the study period
• Suspected or known current alcohol or drug abuse as determined from the medical history or by physical examination
• Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study