Trial of Yellow Fever Inactivated Vaccine

Randomized, Double Blind, Controlled Phase I Trial of the Safety, Tolerability,and Immunogenicity of Graded Doses of XRX-001 Yellow Fever 17D, Inactivated Vaccine, Alum Adsorbed in Healthy Adults.

The Phase 1 trial is a single-center, randomized, double blind, placebo-controlled, dose-ranging out-patient study designed to provide the first clinical data on the safety, tolerability and immunogenicity of XRX-001 inactivated yellow fever vaccine in 60 healthy male and female volunteers, 18-49 years of age. Subjects will receive two inoculations of one of two dose levels of XRX-001 vaccine. A control group will receive placebo.

Safety will be determined by the incidence and severity of adverse events in each treatment group and in the combined cohorts in the double blind treatment period up to 42 days post-vaccination. Subjects will also be followed-up at 3, 6 and 12 months to determine severe adverse events (SAEs) and changes in health status.

Efficacy will be assessed by neutralizing antibody response to the vaccine. The co-primary immunogenicity endpoints will be the dose-response analysis of seroconversion rates (fourfold or greater increase in neutralizing antibody titer between baseline and Day 42) and of the 50% plaque reduction neutralization test (PRNT50) geometric mean titers (GMT) at Day 42.

Secondary immunogenicity endpoints will include:

1. The seroconversion rates and GMT neutralizing antibody titers for all dose groups combined on Days 21 and 42.
2. The reverse cumulative distribution curve of antibody titers on Days 21 and 42 for each dose group and for all dose groups combined
3. The duration of antibody titers displaying the seroconversion rate and GMT across all time-points to Month 12, by treatment group and for both dose groups combined.

Inclusion Criteria:

• All aspects of the protocol explained and written informed consent obtained from the subject;
• Aged 18 to 49 years, inclusive;
• In good general health, without significant medical history, physical examination findings, or abnormal laboratory results; and
• Subject must be available for the study duration, including all planned follow-up visits.
• For female subjects of child bearing potential: Negative serum pregnancy tests at Day -7 to -1, and negative urine pregnancy tests prior to vaccination on Days 0, in conjunction with a menstrual and contraceptive history indicating a low probability of pregnancy in the opinion of the physician. Females of childbearing potential will be required to be correctly using an efficacious hormonal method of contraception or intrauterine device for at least 1 month before randomization and during the on-study phase to Day 42. Barrier methods of contraception will not be considered acceptable for study entry. Female subjects of child-bearing potential will acknowledge by signing their informed consent that contraception will be correctly practised during the specified periods and will specify the method used. Female subjects unable to become pregnant must have this documented (e.g. tubal ligation, hysterectomy or postmenopausal [at least one year since last menstrual period]).

Exclusion Criteria:

• History of travel to South America or SubSaharan Africa;
• History of active duty military service;
• History of vaccination against yellow fever, tick-borne encephalitis (TBE), or Japanese encephalitis;
• Went to primary (grade) school in Austria, Germany, Japan, South Korea, India, Thailand, Nepal, Vietnam, or Taiwan (where TBE vaccination is practiced)
• History of dengue fever;
• Known or suspected immunodeficiency disorder, including leukemia, lymphoma, generalized malignancy, or treatment with immunosuppressive medications, including corticosteroids, alkylating agents, antimetabolites, or radiation therapy. Low dose steroids (≤ 10 mg prednisone or equivalent, topical or intra-articular/bursal/tendon/epidural injections of corticosteroids) do not constitute a reason for exclusion;
• History of an autoimmune disorder, including systemic lupus, rheumatoid arthritis, scleroderma, other collagen vascular disease, multiple sclerosis, etc. Psoriasis limited to cutaneous manifestations is not an exclusion criterion;
• Prior history of anaphylaxis to foods, hymenoptera stings, vaccines or drugs;
• Transfusion of blood or treatment with any blood product, including intramuscular or intravenous serum globulin within 3 months of the Screening Visit or anticipated up to Study Day 42;
• Administration of another vaccine within 30 days preceding the screening visit or anticipated up to Day 42 (these subjects may be rescheduled for vaccination at a later date);
• Participation in another clinical trial within 60 days of the screening visit;
• Positive serum or urine pregnancy test prior to vaccination (women of child-bearing potential or lactation or intended pregnancy during study period);
• Abnormalities on laboratory assessment (i.e. meeting the criteria defined for a mild, moderate or severe adverse event in Appendix 1, a1A);
• Seropositive to HIV or HCV or positive for HBsAg;
• Physical examination indicating any clinically significant medical condition;
• Body temperature >38.1°C (100.6°F) or acute illness within 3 days prior to vaccination (subject may be rescheduled);
• Intention to travel out of the area prior to the study visit on Day 42;
• History of excessive alcohol consumption, drug abuse, significant psychiatric illness; and
• Intention to increase normal exercise routine, participate in contact sports or strenuous weight lifting or to initiate vigorous exercise from Screening until after Day 42.