Safety of and Immune Response to a West Nile Virus Vaccine (WN/DEN4-3'delta30) in Healthy Adults

Study Overview
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Brief Summary
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West Nile (WN) virus infection is an emerging disease; WN infection may lead to paralysis, coma, and death. The purpose of this study is to test the safety of and immune response to a WN vaccine in healthy adults. The vaccine is based on a live attenuated vaccine developed against dengue virus.

Detailed Description
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WN is widely distributed in Africa and Europe, where it is usually associated with mild illness. In the United States, WN is considered a public health threat because severe illness caused by WN infection has caused paralysis, coma, and death, especially in the elderly. This study will evaluate the safety and immunogenicity of a live attenuated chimeric virus, WN/DEN4-3'delta30, which is derived from the DEN4 dengue virus and wild-type WN serotypes. This study will last 180 days. Participants in Cohort 1 will be randomly assigned to receive the lowest dose of WN/DEN4-3'delta30 or placebo at study entry. Cohort 2 will begin only after safety review of all participants in Cohort 1. Participants in Cohort 2 will receive a higher dose of WN/DEN4-3'delta30 or placebo. Cohort 3 will begin only after safety review of all participants in Cohort 2. Participants in Cohort 3 will receive the highest dose of WN/DEN4-3'delta30 or placebo. Immediately after receiving their injections, participants will be observed for 30 minutes for immediate adverse reactions. After vaccination, participants will be asked to monitor their temperatures every day for 16 days and on Day 19. Study visits will occur every other day after vaccination until Day 16, followed by 5 additional visits at selected days through Day 180. Blood collection and a targeted physical exam will occur at each study visit. Some participants will be asked to undergo a skin biopsy or additional blood collection at selected visits.

Official Title
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Phase 1 Study of the Safety and Immunogenicity of West Nile/Dengue-4 3'delta30 Chimeric Virus Vaccine (WN/DEN4-3'delta30), a Live Attenuated Vaccine for West Nile Encephalitis

Conditions
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West Nile Fever Encephalitis

Intervention / Treatment
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* Biological: WN/DEN4-3'delta30
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to be followed for the duration of the study Willing to use acceptable methods of contraception Good general health Exclusion Criteria: Clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease Behavioral, cognitive, or psychiatric disease that, in the opinion of the investigator, affects the ability of the volunteer to understand and cooperate with the study Hematologic disease History of migraine headaches History of encephalitis Alcohol or drug abuse within 12 months prior to study entry History of severe allergic reaction or anaphylaxis Emergency room visit or hospitalization for severe asthma within 6 months prior to study entry HIV-1 infected Hepatitis C virus infected Hepatitis B surface antigen positive Known immunodeficiency syndrome Use of corticosteroids or immunosuppressive drugs within 30 days of study entry. Participants who have used topical or nasal corticosteroids are not excluded. Live vaccine within 4 weeks prior to study entry Killed vaccine within 2 weeks prior to study entry Blood products within 6 months prior to study entry Participation in another investigational vaccine or drug trial within 60 days of starting this study, or while participating in this study Previously received a licensed or experimental yellow fever, tick-borne encephalitis, or dengue vaccine Surgical removal of spleen History of West Nile encephalitis History of dengue virus infection or other flavivirus infection (e.g., yellow fever virus, St. Louis encephalitis, West Nile virus) Other condition that, in the opinion of the investigator, would affect the participant's participation in the study Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>One subcutaneous vaccination with WN/DEN4-3'delta30 vaccine (10^3 PFU dose) into the deltoid region of either arm. | Biological: WN/DEN4-3'delta30<br>* Live attenuated WN/DEN4-3'delta30 vaccine (one of three doses)<br>|
| Experimental: 2<br>One subcutaneous vaccination with WN/DEN4-3'delta30 vaccine (10^4 PFU dose) into the deltoid region of either arm. This arm may enroll after the results from Arm 1 are analyzed. | Biological: WN/DEN4-3'delta30<br>* Live attenuated WN/DEN4-3'delta30 vaccine (one of three doses)<br>|
| Experimental: 3<br>One subcutaneous vaccination with WN/DEN4-3'delta30 vaccine (10^5 PFU dose) into the deltoid region of either arm. This arm may enroll after the results from Arm 2 are analyzed. | Biological: WN/DEN4-3'delta30<br>* Live attenuated WN/DEN4-3'delta30 vaccine (one of three doses)<br>|
| Placebo Comparator: 4<br>One subcutaneous vaccination with placebo vaccine into the deltoid region of either arm. | Biological: Placebo<br>* Placebo for WN/DEN4-3'delta30 vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of vaccine-related adverse effects, graded by severity, for each dose |  | Throughout study | 
| Immunogenicity of vaccine against WN virus |  | Throughout study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the durability of the antibody response |  | At Day 180 | 
| To assess the frequency, quantity, and duration of viremia in each dose cohort studied |  | Throughout study | 
| To assess the immunogenicity of the WN/DEN4-3'delta30 vaccine against WN wild-type virus |  | Throughout study | 
| To compare the T cell medicated immune response against West Nile virus of those volunteers infected with the WN/DEN4-3'delta30 vaccine virus with that of uninfected volunteers and placebo recipients |  | At study completion | 
| To evaluate the immunopathological mechanism of vaccine-associated rash in those volunteers who are willing to undergo skin biopsy |  | Throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue Virus, Chimeric Virus Vaccine, West Nile Virus