Combination HTNV and PUUV DNA Vaccine

Study Overview
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Brief Summary
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To evaluate the safety and reactogenicity of the hantaan virus (HTNV), puumala virus (PUUV), and combination HTNV/PUUV DNA vaccine candidates delivered to healthy adults

Detailed Description
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The development of DNA (deoxyribonucleic acid) vaccines, such as those to be utilized in this study, is based on the observation that antigen-encoding DNA plasmids can induce both cellular and humoral immune responses against various viral and bacterial pathogens. DNA vaccines are perceived as having a number of potential advantages over other types of vaccines. For example, DNA vaccines are easily constructed by recombinant technology; easily and inexpensively manufactured as a well-characterized molecule [DNA plasmid]; and at boost, not eliminated by prior immune response to the carrier or vector. Furthermore, as nonliving vaccines, they cannot lead to infection. The object of DNA vaccination is to deliver DNA into the nuclei of cells capable of presenting the encoded antigen to immune reactive cells that can elicit an immune response. The study will enroll 6 randomized groups of 12 subjects each, for a total of 72 subjects. This approach will ensure at least 60 subjects complete all vaccinations at around 10 subjects per group, taking possible attrition into account. Subjects will receive one dose of vaccine on each of Days 0, 28, and 56 either intramuscularly or intradermally by electroporation and will be followed until Day 220.

Official Title
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A Phase 1, Randomized Trial to Assess the Safety, Reactogenicity, and Immunogenicity of a Combination HTNV and PUUV DNA Vaccine Candidate Administered by Electroporation

Conditions
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Hantaan Virus Disease, Puumala Virus

Intervention / Treatment
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* Combination Product: Hantann virus vaccine (HTNV) - Using TriGrid Delivery System (TDS) for Intradermal Delivery (ID)
* Combination Product: Hantann virus vaccine (HTNV) - Using TriGrid Delivery System (TDS) for Intramuscular Delivery (IM)
* Combination Product: Puumala virus vaccine (PUUV) - Using the TriGrid Delivery System (TDS) for Intradermal Delivery (ID)
* Combination Product: Puumala virus vaccine (PUUV) - Using the TriGrid Delivery System (TDS) for Intramuscular Delivery (IM)
* Combination Product: Hantaan/Puumala (HTNV/PUUV) virus vaccines - Using the TriGrid Delivery System (TDS) for Intradermal Delivery (ID)
* Combination Product: Hantaan/Puumala (HTNV/PUUV virus vaccines - Using the TriGrid Delivery System (TDS) for Intramusular Delivery (IM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or nonpregnant, nonlactating female, ages 18-49 (inclusive) at time of screening Have demonstrated adequate comprehension of the protocol by achieving a score of at least 80% correct on a short multiple-choice quiz. Individuals who fail to achieve a passing score on the initial quiz will be given the opportunity to retest after a review of the protocol information. Individuals who fail the quiz for the second time will not be enrolled. Have provided written informed consent before screening Subject is in good health as determined by past medical history, medication use, and abbreviated physical examination Good health is defined by the absence of any medical condition described in the exclusion criteria in a subject with a normal abbreviated physical examination including vital signs. If the subject has another current, ongoing medical condition, the condition cannot meet any of the following criteria: (1) first diagnosed within 3 months of enrollment, (2) is worsening in terms of clinical outcome in last 6 months, or (3) involves need for medication that may pose a risk to subject's safety or impede assessment of adverse events or immunogenicity if they participate in the study. An abbreviated physical examination differs from a complete physical examination in that it does not include a genitourinary and rectal examination. Available and able to participate for all study visits and procedures Sexually active men and women of childbearing potential must agree to use an effective method of contraception from 30 days prior to the first study vaccination until 6 months after the last study vaccination. A sexually active man is defined as one whose partner is a woman of childbearing potential (see definition below) and has not had a vasectomy performed > 1 year prior to screening. They must agree not to father a child until 6 months after the last vaccination. These subjects must agree to use a barrier method of birth control (eg, either condom with spermicidal foam/gel/film/cream or partner usage of occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository). Women of childbearing potential are defined as those who have not been sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, or successful Essure® placement (permanent, non-surgical, non-hormonal sterilization) with history of documented radiological confirmation test at least 90 days after the procedure and are still menstruating or < 1 year of the last menses if perimenopausal. For this study, an effective contraceptive method is defined as one that results in a failure rate of less than 1% per year when it is used consistently and correctly (see the Manual of Procedures [MOP] for a list of acceptable methods). Female subjects agree to not donate eggs (ova, oocytes), and male subjects agree to not donate sperm from the start of screening until at least 6 months after the last vaccination. Negative hantavirus PsVNA test result at screening Exclusion Criteria: History of prior infection with any hantavirus virus or prior participation in an HTNV, PUUV, or Andes virus vaccine trial. Has plans to travel to an area with endemic Hantaan, Puumala, Seoul, and Dobrava virus transmission during the study. NOTE: Refer to the MOP for information on areas with endemic Hantaan, Puumala, Seoul, and Dobrava virus transmission History of severe local or systemic reactions to any vaccine or vaccine products or a history of severe allergic reactions. This includes a known allergy to an aminoglycoside (eg, gentamicin, tobramycin, neomycin, and streptomycin). Is currently participating in or plans to participate in another study involving any investigational product (eg, vaccine, drug, or biologics) or a study that involves blood drawing, and/or an invasive procedure. An invasive procedure includes endoscopy, bronchoscopy, or procedure requiring administration of IV contrast or removal of tissue. Receipt or planned receipt of any live vaccination, experimental or otherwise, within the period 30 days prior to or after each vaccination and receipt or planned receipt of an inactivated vaccination, experimental or otherwise, within the period of 14 days prior to or after each vaccination. Individuals, who based on clinical assessment by the investigator, have insufficient muscle mass to accommodate the 1 inch/25 mm penetration depth or have a skinfold thickness at eligible injection sites (deltoid region) that exceeds 40 mm. Individuals in whom the ability to observe local reactions at the eligible injection sites (deltoid region) is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art. Presence of any surgical or traumatic metal implants at the injection site (medial deltoid muscles or overlying skin). Screening laboratory results that are outside of the normal range (exceptions listed below) within 56 days prior to enrollment Hemoglobin > 11.0 g/dL for women; > 12.9 g/dL for men CBC (WBC and platelet) with differential either within institutional normal range or Grade 1 deviation from normal and deemed clinically insignificant Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 1.25x upper limit of normal (ULN) Serum creatinine ≤ ULN Subjects with autoimmune disorders or chronic inflammatory disorders with a potential autoimmune correlation. Receipt of immunoglobulins and/or any blood products within the 120 days preceding screening or planned administration during the study period Donation of blood to a blood bank within 56 days prior to screening and at any time during the study period. Subject seropositive for hepatitis B surface antigen (HBsAg) or hepatitis C antibodies (anti-HCV). Any confirmed or suspected immunosuppressive or immunodeficient condition, including HIV infection, or use of anticancer chemotherapy or radiation therapy (cytotoxic) in the 3 years prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Single Group Assignment
Interventional Model Description: 6 groups of 12 subjects each will receive varying vaccine dosages and vaccine canditdate combinations
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 0.6 mg HTNV - Intradermal (ID)<br>0.1 mL 6.0 mg/mL HTNV DNA + 0.1 mL 0.9% saline (ID) The HTNV and PUUV DNA vaccines will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Hantann virus vaccine (HTNV) - Using TriGrid Delivery System (TDS) for Intradermal Delivery (ID)<br>* The HTNV vaccine will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: HTNV vaccine using TDS ID;|
| Experimental: Group 2: 3.0 mg HTNV - Intramuscular (IM)<br>0.5 mL 6.0 mg/mL HTNV DNA + 0.5 mL 0.9% saline (IM) The HTNV and PUUV DNA vaccines will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Hantann virus vaccine (HTNV) - Using TriGrid Delivery System (TDS) for Intramuscular Delivery (IM)<br>* The HTNV vaccine will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: HTNV vaccine using TDS IM;|
| Experimental: Group 3: 0.6 mg PUUV - Intradermal (ID)<br>0.1 mL 6.0 mg/mL PUUV DNA + 0.1 mL 0.9% saline (ID) The HTNV and PUUV DNA vaccines will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Puumala virus vaccine (PUUV) - Using the TriGrid Delivery System (TDS) for Intradermal Delivery (ID)<br>* The PUUV vaccine will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: PUUV vaccine using TDS ID;|
| Experimental: Group 4: 3.0 mg PUUV - Intramuscular (IM)<br>0.5 mL 6.0 mg/mL PUUV DNA + 0.5 mL 0.9% saline (IM) The HTNV and PUUV DNA vaccines will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Puumala virus vaccine (PUUV) - Using the TriGrid Delivery System (TDS) for Intramuscular Delivery (IM)<br>* The PUUV DNA vaccine will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: PUUV vaccine using the TDS IM;|
| Experimental: Group 5: 1.2 mg HTNV/PUUV (0.6 mg each) - Intradermal (ID)<br>0.1 mL 6.0 mg/mL HTNV DNA + 0.1 mL 6.0 mg/mL PUUV DNA (ID) The HTNV and PUUV DNA vaccines will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Hantaan/Puumala (HTNV/PUUV) virus vaccines - Using the TriGrid Delivery System (TDS) for Intradermal Delivery (ID)<br>* The HTNV and PUUV vaccines will be administered using the ID TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: HTNV/PUUV vaccines using the TDS ID;|
| Experimental: Group 6: 6.0 mg HTNV/PUUV (3.0 mg each) - Intramuscular (IM)<br>0.5 mL 6.0 mg/mL HTNV DNA + 0.5 mL 6.0 mg/mL PUUV DNA (IM) The HTNV and PUUV DNA vaccines will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue. | Combination Product: Hantaan/Puumala (HTNV/PUUV virus vaccines - Using the TriGrid Delivery System (TDS) for Intramusular Delivery (IM)<br>* The HTNV and PUUV vaccines will be administered using the IM TriGrid™ Delivery System (TDS), which utilizes the in vivo application of electrical fields (electroportation) to enhance the intracellular delivery of agents of interest in a targeted region of tissue.<br>* Other names: HTNV/PUUV vaccines using the TDS IM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Adverse Events (AEs) to Evaluate Safety and Reactogenicity of the HTNV, PUUV DNA and Combination HTNV/PUUV DNA Vaccines | Summary of solicited local and systemic AEs occurring from the time of each injection through 14 days to evaluate the safety and reactogenicity of the HTNV, PUUV and combination HTNV/PUUV DNA vaccines | Days 0-14 after injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Experiencing Vaccine-related Unsolicited Adverse Events (AEs) | Subjects experiencing vaccine-related unsolicited AEs from the time of the first injection through 28 days following each injection | Days 0-28 after injection | 
| Subjects Experiencing Serious Adverse Events (SAEs) | Subjects experiencing SAEs from the time of the first injection through the final study visit | Day 0 - approx. 6 months post-last vaccination | 
| Subjects Experiencing Clinical Safety Laboratory Adverse Events (AEs) | Subject experiencing clinical safety laboratory AEs through 14 days following each vaccination | Days 0 - 14 after vaccination | 
| Proportion of Seropositive Subjects | Determination of seropositive subjects (defined as PsVNA50 ≥ 1:20) at each scheduled time point | Days 0, 28, 56, 84, 140 and 220 | 
| Final Overall Rate of Seroconversion Over all Scheduled Time Points | Determination of the final overall rate of serconversion over all scheduled time points to study completion for each study group. Seroconversion is defined as a post-vaccination HTNV- or PUUV-specific titer of ≥1:40, or a minimum four-fold rise compared to baseline titer, and all study volunteers will begin the study with a baseline titer <20 (ie, seronegative) | Days 0, 28, 56, 84, 140 and 220 | 
| Geometric Mean Titer (GMT) of the PsVNA50 | GMT of the PsVNA50 for HTNV- and PUUV-specific neutralizing antibodies at each schedule time point for each study group and over all time points for each study group | Days 0, 28, 56, 84, 140 and 220 |