Protocol Synopsis

SYNOPSIS OF PROTOCOL NUMBER INV-DEN-104 A randomized, Phase 1b study to investigate the safety and TITLE immunogenicity of various schedules of a tetravalent chimeric dengue vaccine in healthy adult volunteers between the ages of 18 45 years SPONSOR Inviragen Inc. CLINICAL PHASE Phase 1b IND NUMBER (IF APPLICABLE) 14292 DENVax (tetravalent dengue vaccine containing four live, attenuated INVESTIGATIONAL PRODUCT dengue virus strains, DENVax-1, DENVax-2, DENVax-3 and DENVax-4) Active vaccination for protection against dengue fever caused by a INDICATION dengue virus. Primary: To compare the safety and tolerability of different dose schedules of SC administered chimeric tetravalent dengue vaccine in healthy adults To compare the immunogenicity of different dose schedules of the vaccine against all four dengue serotypes in healthy adults Secondary:
OBJECTIVES

To measure viremia due to each of the four dengue vaccine components after each vaccination To evaluate the immune response induced by DENVax in a population with no previous exposure to dengue To assess the levels of neutralizing antibodies against each of the four dengue serotypes after each immunization

Screening and enrollment for primary immunization (ages 18-45 years) will commence after receipt of approvals for study conduct. It is estimated that 9-12 months will be required to enroll and complete all subjects in the study. Seventy two patients will be enrolled and randomized in 3 different dose schedules as follows:
STUDY DESIGN

Group 1 will receive active vaccine on Days 0 and 90 and placebo on Day 0 (N=24) Group 2 will receive two doses of active vaccine on Day 0 (one dose on each arm), and placebo on Day 90 (N=24) Group 3 will receive two doses of active vaccine on Day 0 (one dose on each arm), and active vaccine on Day 90 (N=24)

Blood samples will be obtained for safety labs on Days 0, 7, 14, 90, 97 and 104 and measurement of viremia at baseline (during the screening period or on Day 0), and then on Days 7, 9, 11, 14, 17, 21, 90, 97, and 104. Blood samples for measurement of dengue neutralizing antibodies in serum will be obtained at baseline (during the screening period or on

Day 0), then on Days 30, 90 and 120. A detailed schedule of events can be found in Section 4. The entire duration for each individual subjects participation will be approximately 5 months including recruitment and collection of data for primary outcomes (through Day 120). 4 4 5 5 Group 1, 2 and 3 -- 2 x 10 , 5 x 10 , 1 x 10 and 3 x 10 PFU of DENVax1, DENVax-2, DENVax-3 and DENVax-4, respectively Subcutaneous (SC) injection in the deltoid region Day 0 (one in each arm) and Day 90

DOSE LEVEL(S) ROUTE OF ADMINISTRATION DOSING REGIMEN

Group/Schedule 1
TREATMENT GROUPS

N 24 24 24

2 3

Day 0, Arm 1 Active Vaccine Active Vaccine Active Vaccine

Day 0, Arm 2 Placebo Active Vaccine Active Vaccine

Day 90 Active Vaccine Placebo Active Vaccine

NUMBER OF SUBJECTS TARGET POPULATION

72 Healthy male and female subjects aged 18 to 45 years inclusive. 1. Male or female at least 18 years and 45 years old at time of screening 2. In good health as determined by medical history, physical examination including height and weight 3. Normal clinical safety laboratory examinations (Na, K, Glucose, BUN, creatinine, ALT, AST, total bilirubin, WBC, neutrophil count, hemoglobin, platelets, PT, PTT, and urinalysis (by dipstick)). Normal ranges for safety laboratory tests will be according to those used in the laboratory performing the safety laboratory tests. For AST and ALT, the applicable cut-offs for determination are less than 1.5 times the upper limits, as there is no clinical significance associated with results with mild elevations above the upper limits of normal. Of note, subjects with mildly abnormal laboratory results may be enrolled after review and written approval of the medical monitor. 4. Weight: Body Mass Index (BMI) 32 5. Blood tests negative for antibodies to HIV-1, Hepatitis C, and Hepatitis B surface antigen 6. Females who are not surgically sterile or post-menopausal must have a negative urine pregnancy test result during screening and a negative urine pregnancy test immediately prior to vaccination and be willing to use oral, implantable, transdermal or injectable contraceptives or another reliable means of contraception approved by the Investigator (intrauterine device, female condom, diaphragm with spermicidal foam, cervical cap, use of condom by the sexual partner or a sterile sexual partner, or abstinence) from screening until Day 120

INCLUSION CRITERIA

7. Willing and able to give written informed consent to participate or have informed consent form signed by the parent(s) 8. Willing and able to communicate with the Investigator and understand the requirements of the study 9. Access to a fixed or mobile telephone 1. Any condition which would limit the subjects ability to complete the study in the opinion of the Investigator 2. Clinically significant ECG findings (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two PVC's in a row, or ST elevation consistent with ischemia) 3. Febrile illness (temperature 38C or 100.4F) or moderate or severe acute illness or infection within three days before vaccination 4. History of any significant dermatologic disease in the last 6 months, particularly with a maculopapular or petechial rash. However, if a subject had a self-limited candida infection that was cured, then the subject can be enrolled if there is no evidence of an infection for at least 3 weeks prior to the date of dosing. If the subject has acne limited to the face and is not on any medications concurrently and has not been on any medications for this condition for at least 3 months, then the subject can be enrolled 5. History of diabetes mellitus
EXCLUSION CRITERIA

6. History of thymic pathology, thymectomy, myasthenia or any immunodeficiency 7. History of recurring headaches or migraines (more frequent than once per week) or on prescription medication for treatment of recurring headaches or migraines 8. Hypersensitivity to any vaccine 9. Receipt of any vaccine in the 4 weeks preceding the first vaccination 10. Planned receipt of any vaccine in the 4 weeks following each of the vaccinations in this study 11. Known

history of Japanese Encephalitis Virus (JEV) and/or Yellow Fever (YF)

12. Previous vaccination (in a clinical trial or with an approved product) against flaviviruses including dengue, yellow fever (YF) and Japanese Encephalitis (JE) 13. Seropositivity to dengue or West Nile (WN) virus 14. Known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or

radiation therapy within the preceding 6 months 15. Use within the previous 6 months of systemic corticosteroids therapy (at a dose of at least 0.5 mg/kg/day). Topical prednisone is not permitted if currently in use or within the last 3 months. Note, inhaled prednisone (or equivalent) is allowed 16. Use of any non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen or antihistamines for the 3 days immediately prior to each vaccination 17. Use of any prescription or over the counter medications (besides those specifically mentioned above or those required for medical management of concurrent diseases) 7 days before the first vaccination (Day 0) 18. Positive urine screen for cocaine, amphetamines, opiates, or cannabinoids 19. Known history of alcohol abuse 20. Receipt of any other investigational product or participation in any other clinical trial in the month before the first dose(s) (Day 0) until 30 days after the dose on day 90 21. Receipt of blood products or immunoglobulins 8 weeks before the first dose(s) (Day 0) or planned use up to and including 30 days after the dose on day 90 22. Donation of blood 6 weeks before the first dose(s) (Day 0) until 30 days after the dose on day 90 23. Females who are pregnant or lactating

PROPOSED START DATE STUDY SITE(S) STUDY DURATION COMPARATOR DOSE/ROUTE/REGIMEN ASSESSMENTS OF: SAFETY

Q4 2011 Approximately 1-2 sites in the United States Each subject will participate in the study for approximately five months. Total study duration will be approximately 1 year, including screening and dosing of all groups. Placebo (phosphate buffered saline) Frequency and severity of adverse events, including local and systemic; solicited and unsolicited. Safety outcome measures include evaluations of local and systemic reactogenicity and adverse events (all subjects) and measurement of routine hematology and chemistry parameters

IMMUNOGENICITY

Neutralizing antibody titers against each of the four dengue serotypes Seroconversion rates (SCR) for all four dengue serotypes. Seroconversion rate is defined as number of subjects with PRNT 50 titer 10 or, if the titer on Day 0 is greater than 10, a four-fold rise in antibody titer must be observed

VIREMIA

PROCEDURES

STATISTICAL ANALYSES

Incidence, duration, and titer of viremia for each of the four dengue vaccine components after the prime and boost vaccinations Prior to enrollment, each subject will be screened for eligibility in the study. Screening will occur up to 35 days prior to dosing. Once enrolled, subjects will be dosed subcutaneously on three occasions (Day 0/0/90) with either DENVax or placebo. Blood samples will be taken at regular intervals for assessment of neutralizing antibodies (all subjects) and viremia against all four dengue serotypes. Subjects will complete diaries for 14 days after each vaccination, to record oral temperature (using provided thermometers) and any symptoms experienced after vaccination. Any adverse events occurring during the study will be recorded. This study is an exploratory trial to assess the safety, tolerability and immunogenicity of vaccination with a new schedule of tetravalent dengue vaccine in healthy adults. Therefore, this study is not powered to detect any differences in potential safety and immunogenicity data between the treatment groups. Exploratory analyses of final data will be conducted as deemed appropriate. Where appropriate, a two-tailed p-value of 0.05 or less will be regarded as statistically significant. Continuous variables will be summarized using descriptive statistics (e.g., N, mean, SD, min, median, max) and categorical variables will be summarized using counts and percentages.