A Two-dose Primary Vaccination Study of a Tetravalent Dengue Virus Purified Inactivated Vaccine vs. Placebo in Healthy Adults

Study Overview
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Brief Summary
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The study is designed to afford a safety and immunogenicity assessment of three Tetravalent Dengue Virus-Purified Inactivated Vaccine(TDENV-PIV) vaccine candidates.

Detailed Description
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The study is designed to afford a safety and immunogenicity assessment of three Tetravalent Dengue Virus-Purified Inactivated Vaccine(TDENV-PIV) vaccine candidates, each formulated with a different adjuvant: either aluminum hydroxide, AS01E or AS03B (adjuvants used in Glaxo Smith Kline (GSK) Biologicals' hepatitis B candidate vaccine, malaria candidate vaccine and pandemic flu vaccine, respectively). Each vaccine candidate will contain 1 µg of purified virus antigen per each of the four DENV types. Additionally, the study will evaluate an alum adjuvanted TDENV-PIV vaccine candidate containing 4 µg of purified virus antigen per each of the four DENV types. The control group will receive a saline placebo. All experimental vaccinations will be administered according to a 2-dose schedule, 28 days apart.

Official Title
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A Phase I, Randomized, Placebo-Controlled, Observer-blind, Two-dose (0-28 Day Schedule) Primary Vaccination Study of Walter Reed Army Institute of Research (WRAIR) Tetravalent Dengue Virus Purified Inactivated Vaccine (TDENV-PIV) in Healthy Adults in a Non-Endemic Region

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: 4 µg TDENV-PIV with Alum adjuvant
* Biological: 1 µg TDENV-PIV with AS03B1 adjuvant
* Other: Phosphate buffered saline
* Biological: 1 µg TDENV-PIV with Alum adjuvant
* Biological: 1 µg TDENV-PIV with AS01E1 adjuvant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits, etc.) A male or female between 18 and 39 years of age (inclusive) at the time of consent Written informed consent obtained from the subject Healthy subjects as established by medical history and clinical examination before entering into the study Female subjects of non-childbearing potential (non-childbearing potential is defined as having either a current tubal ligation at least three months prior to enrollment, hysterectomy, ovariectomy, or is post-menopause). See Definition of Terms for adequate contraception. Female subjects of childbearing potential may be enrolled in the study, if the subject has: Practiced adequate contraception for 30 days prior to vaccination, and A negative urine pregnancy test on the day of vaccination, and Agreed to continue adequate contraception until two months after completion of the vaccination series Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines/placebo during the period starting 30 days preceding the first dose of study vaccine/placebo and/or planned use during the study period Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 180 days prior to the first vaccine/placebo dose (for corticosteroids, this will mean prednisone ≥ 20 mg/day or equivalent; inhaled and topical steroids are allowed) Planned administration or administration of a vaccine/product not foreseen by the study protocol during the period starting 30 days prior to the first dose of vaccine/placebo until after the visit at Day 56 (if influenza activity warrants vaccination of healthy young adults, influenza vaccination will be encouraged and will not lead to study exclusion) Planned administration of any flavivirus vaccine for the entire study duration Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Family history of congenital or hereditary immunodeficiency History of, or current auto-immune disease History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or related to a study procedure Major congenital defects or serious chronic illness History of any neurological disorders or seizures Acute disease and/or fever (≥37.5°C/99.5°F oral body temperature) at the time of enrollment (a subject with a minor illness, i.e., mild diarrhea, mild upper respiratory infection, etc., without fever, may be enrolled at the discretion of the investigator) Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality,as determined by physical examination or laboratory screening tests Administration of immunoglobulins and/or any blood products during the period starting 90 days preceding the first dose of study vaccine/placebo or planned administration during the study period History of chronic alcohol consumption and/or drug abuse Pregnant or lactating female or female planning to become pregnant or planning to discontinue contraceptive precautions A planned move to a location that will prohibit participating in the trial until study end for the participant Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study. Subject seropositive for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV) Safety laboratory test results that are outside the acceptable values at screening. The following values are not acceptable: >110% upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, creatinine, serum urea nitrogen (SUN) and bilirubin (total and direct) <100% lower limit of normal (LLN) or > 120% ULN for hemoglobin, hematocrit and platelet count <75% LLN or >110% ULN for total white blood cell count (WBC) Note that all screening laboratory results must be either within normal limits (WNL) or no more than Grade l not clinically significant (NCS) (LLN=lower limit of normal; ULN= upper limit of normal, WNL= within normal limits, NCS= not clinically significant)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TDENV-PIV alum4<br>4 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: 4 µg TDENV-PIV with Alum adjuvant<br> <br> |
| Experimental: TDENV-PIV AS01E1<br>1 µg TDENV-PIV with AS01E1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: 1 µg TDENV-PIV with AS01E1 adjuvant<br> <br> |
| Experimental: TDENV-PIV AS03B1<br>1 µg TDENV-PIV with AS03B1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: 1 µg TDENV-PIV with AS03B1 adjuvant<br> <br> |
| Placebo Comparator: Placebo<br>Phosphate buffered saline; 0.5 mL intramuscular injection at 0 and 28 days | Other: Phosphate buffered saline<br> <br> |
| Experimental: TDENV-PIV alum1<br>1 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: 1 µg TDENV-PIV with Alum adjuvant<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Adverse Events Within the 28 Day Follow-up | Number of subjects with adverse events occurring within days 0-28 following vaccination | Days 0-28 | 
| Incidence of Any Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period. Total Vaccinated Cohort (TVC) | Overall incidence of any symptoms (solicited and unsolicited) reported during the 7-day (days 0-6) post vaccination period in TVC population | Days 0-6 post vaccination | 
| Incidence of General Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC) | Incidence of General Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period for TVC population. General symptoms are described as fatigue, gastrointestinal symptoms, headache, joint pain, muscle aches and increased temperature (oral). | Days 0-6 post vaccination | 
| Incidence of Local Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC) | Incidence of Local Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period in TVC population. Local symptoms are described as pain, redness and swelling. | Days 0-6 post vaccination | 
| Summary of Subjects With Serious Adverse Events | Summary of subjects with serious adverse events through out the study | days 0-392 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Laboratory Values Within and Outside the Normal Ranges and With Different Grade of Adverse Event From Screening to Day 56 Visit | The percentage of subjects with hematological and biochemical laboratory values within and outside the normal ranges and with different grade of AE were tabulated with exact 95% CI at baseline and at each specified timepoint. Safety laboratory assays were performed at a WRAIR-designated Clinical Laboratory Improvement Amendments-certified laboratory. All safety-related clinical laboratory values were reviewed and all abnormal values were assessed by the investigators as clinically significant or not, with respect to safety. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D35) = Post-dose 2, Day 35 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit | day 56 visit | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibody Titers Specific to Each DENV Type - According to Protocol Population (ATP) | Geometric Mean Titers (GMTs) of Neutralizing antibody titers specific to each DENV type were measured by a quantitative microneutralization assay with a titer giving 50% reduction in viral infection (MN50) at specified time points. MN50 is specific and sensitive for the detection of anti-DENV neutralizing antibodies. The cut-off for seropositivity was 1: 10 for neutralizing antibody titers measured by MN50 assay. MN50 assay was used to determine initial DENV antibody status of subjects for inclusion in the ATP cohort. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit | up to month 13 | 
| Number of Subject Showing Monovalent, Bivalent, Trivalent and Tetravalent Response for Neutralizing Antibodies - Total Vaccinated Cohort (TVC) | Number of subjects showing Monovalent, bivalent, trivalent and tetravalent response for neutralizing antibodies by Microneutralization Titer (giving 50% reduction in viral infection (MN50)) in the TVC population. PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit | up to month 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Dengue fever, Dengue Hemorrhagic Fever, Flavivirus