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

Study Overview
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Brief Summary
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This is a first time in humans (FTiH) study designed to assess the experimental TDENV-PIV vaccine in a predominantly dengue-primed adult population. The study is designed to afford a first time in humans (FTiH) safety and immunogenicity assessment of three TDENV-PIV vaccine candidates, each formulated with a different adjuvant: either aluminum hydroxide, AS01E or AS03B (adjuvants used in 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. There is a parallel FTiH study that is conducted in the United States in a dengue-naive population using the same investigational vaccines.

Official Title
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A Phase I, Randomized, Placebo-Controlled, Observer-blind, Two-dose (0-28 Day Schedule) Primary Vaccination Study of WRAIR Tetravalent Dengue Virus Purified Inactivated Vaccine (TDENV-PIV) in Healthy Adults in Puerto Rico

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: Biological/Vaccine: 4 µg TDENV-PIV with Alum adjuvant
* Biological: Biological/Vaccine: 1 µg TDENV-PIV with AS03B adjuvant
* Other: Phosphate buffered saline
* Biological: 1 µg TDENV-PIV with Alum adjuvant
* Biological: 1 µg TDENV-PIV with AS01E 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 20 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 Subject has lived in the Caribbean for more than 10 years 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). 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 Exclusion: 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) Previous or planned administration of any other flavivirus vaccine (approved or investigational) for the entire study duration Previous receipt of any investigational dengue virus vaccine 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 normal limits for their age, gender, and locality at screening.

Ages Eligible for Study
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Minimum Age: 20 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: Biological/Vaccine: 4 µg TDENV-PIV with Alum adjuvant<br> <br> |
| Experimental: TDENV-PIV AS03B<br>1 µg TDENV-PIV with AS03B adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: Biological/Vaccine: 1 µg TDENV-PIV with AS03B 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> |
| Experimental: TDENV-PIV AS01E<br>1 µg TDENV-PIV with AS01E adjuvant; 0.5 mL intramuscular injection at 0 and 28 days | Biological: 1 µg TDENV-PIV with AS01E adjuvant<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and reactogenicity of various TDENV-PIV formulations from Day 0 through 28 days after the second dose (Day 0 - Day 56) | Safety and Reactogenicity: Occurrence, intensity and relationship to vaccination of solicited local and general adverse events (AEs) during the 7-day follow-up period post each vaccination (Day 0-6) Occurrence, intensity and relationship to vaccination of unsolicited AEs during the 28-day follow-up period post each vaccination (Day 0-27) Hematological and biochemical levels at study visits on Days 0, 7, 28, 35 and 56 Occurrence of serious adverse events (SAEs) from Day 0 to Day 56 Occurrence of potential immune-mediated diseases (pIMDs) and medically attended AEs from Day 0 to Day 56 | Up to Day 56 | 
| Humoral immunogenicity to each of four DENV types of various TDENV-PIV formulations 28 days after the second dose (Day 56) | Humoral Immunogenicity: Neutralizing antibody titers specific to each DENV type at Day 56 Geometric mean titers (GMTs) of neutralizing antibody titers to each DENV type Rate of fold increases in neutralizing antibody from Day 0 for each DENV type Seropositivity rates for each DENV type Trivalent and tetravalent seropositivity rates | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of various TDENV-PIV formulations, from Day 0 to Month 13 (Visits 1-11) | Safety: Hematological and biochemical levels at study visits on Months 4, 7, 10 and Month 13 Occurrence of pIMDs and medically attended AEs from Day 0 to Month 13 Occurrence of any SAE from Day 0 to Month 13 | Up to month 13 | 
| Humoral immunogenicity to each of four DENV types of various TDENV-PIV formulations on Days 0, 7 and 28 and Months 7 and 13 | Humoral Immunogenicity: Geometric mean titers (GMTs) of neutralizing antibody titers to each DENV type Rate of fold increases in neutralizing antibody from Day 0 for each DENV type Seropositivity rates for each DENV type Trivalent and tetravalent seropositivity rates | Up to month 13 | 
| • To evaluate the safety of various TDENV-PIV formulations from Month 14 through the end of the study (Visit 15) | Occurrence of serious adverse events (SAEs) related to study procedures from Month 14 to end of study (Month 37-39) | Up to the end of study (Month 37-39) | 

 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