Safety and Immunogenicity of a First-in-Human Mosquito Saliva Peptide Vaccine

Study Overview
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Brief Summary
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Background: Mosquitos carry diseases that cause major health problems and death worldwide. The AGS-v vaccine targets proteins in mosquito saliva. This may help prevent many mosquito-borne diseases. It might also reduce the lifespan of the mosquito that bites the vaccinated person. Objective: To see if the AGS-v vaccine is safe in humans and how it affects the immune system. Eligibility: Healthy adults ages 18-50 Design: Participants will be screened another study. Participants will be randomly assigned to get either the vaccine with a booster vaccine, the vaccine without the booster, or a placebo. These are given through a needle in the upper arm. Participants will have visits that include medical history, physical exam, and blood and urine tests: Baseline: They will get the vaccine and be monitored for 2 hours. Follow-up visits 1 and 2 weeks after baseline. Visit 3 weeks after baseline: They will get the booster and be monitored for 2 hours. Follow-up visits 1 and 2 weeks after booster visit. Visit 3-5 weeks after booster visit: This includes mosquito feeding. Mosquitos grown in the lab will be allowed to bite the arm. Blood will be drawn 4 times in the 3 hours after the feeding. Phone follow-up a few days after the mosquito feeding. After the feeding visit, 5 follow-up visits about every 2 months Participants will keep a symptom diary for 7 days after each vaccine. They will record their temperature. They will measure any redness around the injection site. They will document and if possible photograph any mosquito bites they get.

Detailed Description
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Mosquito-borne diseases continue to cause significant morbidity and mortality worldwide despite on-going control efforts. In 2015, there were >200 million cases of malaria worldwide, causing nearly half a million deaths, with most of the deaths occurring among children under the age of 5 years. Mosquitos also transmit arboviruses, including dengue, yellow fever, West Nile virus, chikungunya, Rift Valley fever, Japanese encephalitis, and Zika virus. The current new outbreak of Zika virus in Central and South America, as well as the Caribbean, serves as a reminder of how quickly these viruses can spread and how difficult they can be to control. In this protocol we plan to perform a Phase I study of a novel universal mosquito-borne disease vaccine. Through modulation of the immune system after a mosquito feeding, this vaccine targets the vector saliva and may provide prophylaxis against multiple arboviral and protozoal diseases. In addition the vaccine potentially leads to a reduced mosquito lifespan after feeding therefore also reducing transmission of these diseases. In this protocol we hope to demonstrate the safety of this vaccine similar to SEEK s other peptide based vaccines Flu-v and HIV-v that have been found to have very good safety profiles in previous Phase I trials. We also hope to demonstrate immunomodulation after a controlled clean Aedes aegypti mosquito feeding to demonstrate proof of concept efficacy of the vaccine. With the current rise of Zika in the Americas and the threat of local mosquito transmission in the U.S. and the rest of the world, a successful universal mosquito-borne disease vaccine offers the benefit of targeting this emerging disease as well as the many established infections such as dengue and malaria that make dealing with this newly emerging epidemic a challenge.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study in Healthy Volunteers to Evaluate the Safety and Immunogenicity of AGS-v, a Universal Mosquito-Borne Disease Vaccine

Conditions
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Mosquito-Borne Disease

Intervention / Treatment
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* Biological: AGS-v
* Biological: AGS-v + adjuvant
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Healthy women and men who are greater than or equal to 18 and less than or equal to 50 years of age. Willingness to complete all study visits and comply with all study requirements. A male subject is eligible for the study if he agrees to practicing abstinence or using a condom with spermicide plus an acceptable form of contraception (see inclusion criteria 4) being used by any female partner from 4 weeks before study start to 12 weeks after the second vaccine administration. A female participant is eligible for this study if she is not pregnant or breast feeding and 1 of the following: Of non-child bearing potential (i.e., women who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses in greater than or equal to 1 year). Of childbearing potential but agrees to practice effective contraception or abstinence for 4 weeks prior to study initiation through 12 weeks after the second vaccine administration. Acceptable methods of contraception include a male partner who is sterile and is the sole sexual partner of the female participant or a male partner who uses a condom with spermicide plus 1 or more of the following: 1) implants of levonorgestrel; 2) injectable progestogen; 3) an intrauterine device with a documented failure rate of <1%; 4) oral contraceptives; and 5) double barrier method including diaphragm. Willing to have samples stored for future research (including genetic research). Agrees to abstain from alcohol intake for 24 hours prior to each study visit. Agrees to not donate blood or blood products throughout the study. EXCLUSION CRITERIA: Participant has any underlying or current medical condition, which, in the opinion of the Investigator, would interfere with the participation in the study. Individual with body mass index (BMI) less than or equal to 18 and greater than or equal to 40. Participants who have a clinically significant (as determined by the PI) baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table. Receipt of blood or blood products (including immunoglobulins) within 3 months prior to enrollment. Receipt of any unlicensed drug within 3 months or 5.5 half-lives (whichever is greater) prior to enrollment. Receipt of any unlicensed vaccine within 6 months prior to enrollment. Self-reported or known history of alcoholism or drug abuse within 6 months prior to enrollment, or positive urine/serum test for drugs of abuse at screening Self-reported or known history of psychiatric or psychological issues that require treatment and are deemed by the PI to be a contraindication to protocol participation. History of a previous severe allergic reaction with generalized urticaria, angioedema, anaphylaxis or anaphylactoid reaction. Any condition or event that, in the judgment of the PI, is a contraindication to protocol participation or impairs the volunteer's ability to give informed consent. Has a known allergy to any of the components of the vaccine. Has a history of severe immunization reaction. Has a severe allergic reaction to mosquito bites

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGS-v<br>AGS-v (unadjuvanted) as a suspension in WFI (0.5mL) on Day 0 and on Day 21 | Biological: AGS-v<br>* AGS-v (unadjuvanted) as a suspension in WFI (0.5mL) on Day 0 and on Day 21<br>|
| Experimental: AGS-v with adjuvant<br>ISA-51-adjuvanted AGS-v emulsified in WFI (0.5mL)on Day 0 and on Day 21 | Biological: AGS-v + adjuvant<br>* ISA-51-adjuvanted AGS-v emulsified in WFI (0.5mL) on Day 0 and on Day 21<br>|
| Placebo Comparator: Placebo<br>WFI (0.5mL) on Day 0 and Day 21 | Other: Placebo<br>* WFI (0.5mL) on Day 0 and Day 21<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEs Grade 3 or Higher | Grade 3 or higher adverse events identified within 1 year after 2 vaccinations 21 days apart. | 1 year after vaccination (study duration) | 
| GM-CSF Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| IL-10 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| IL-1B Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| IL-2 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| IL-4 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| IL-5 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| Interferon-gamma Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| Number of Subjects With 1 or More Aes | Percent of people with an AE | 1 year after vaccination (study duration) | 
| Number of Subjects With 1 or More Grade 3 or Higher AE | Percent of people with a Grade 3 or higher AE | 1 year after vaccination (study duration) | 
| TNF-a Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 21 days after last vaccination | 
| Total AGS-v Specific Immunoglobulin | Total AGS-v specific immunoglobulin measured in serum 14 days after the first and/or second vaccination. | 21 days after last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GM-CSF Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| IL-10 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| IL-1B Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| IL-2 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| IL-4 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| IL-5 Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| Interferon-gamma Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| Number of Adults Developed From 100 Eggs | Measurement of changes to Aedes aegypti mosquito life cycle post feeding on blood from participants after vaccination | Day 42 Mosquito feeding | 
| Number of Eggs Laid | Measurement of changes to Aedes aegypti mosquito life cycle post feeding on blood from participants after vaccination | Day 42 Mosquito feeding | 
| Number of Pupae Hatched of 100 Eggs | Measurement of changes to Aedes aegypti mosquito life cycle post feeding on blood from participants after vaccination | Day 42 Mosquito feeding | 
| Percent of Eggs That Developed Into Pupae | Measurement of changes to Aedes aegypti mosquito life cycle post feeding on blood from participants after vaccination | Day 42 Mosquito feeding | 
| Percent of Pupae That Developed Into Adults | Measurement of changes to Aedes aegypti mosquito life cycle post feeding on blood from participants after vaccination | Day 42 Mosquito feeding | 
| TNF-a Cytokine Level as Measured by Luminex | Interferon-gamma and other cytokine markers of Th1 and Th2 response measured in vitro from PBMCs incubated with AGS-v antigens as indicators of Th1 vs. Th2 response | 60 days after Day 42 Mosquito Feeding | 
| Total AGS-v Specific Immunoglobulin | Total AGS-v specific immunoglobulin measured in serum after the first and/or second vaccination. | 60 days after Day 42 Mosquito Feeding | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mosquito-Borne Diseases, Universal Mosquito Vaccine, Mosquito Transmission, Vector Borne Viruses, Vaccine