Phase 2a Immunogenicity Study of Hantaan/Puumala Virus DNA Vaccine for Prevention of Hemorrhagic Fever

Study Overview
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Brief Summary
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The purpose of this study is to compare the immune responses of two different doses (1.0 mg and 2.0 mg) and two different dosing schedules (two doses or three doses) of a mixed Hantaan virus (HTNV) and Puumala virus (PUUV) DNA vaccine in healthy participants. To maintain a blind, participants in the two-dose group will receive one dose of normal saline placebo. All of the groups will also receive a booster dose 6 months after first vaccination. The results will help to determine which dose and vaccination schedule will be best to move forward in the vaccine development process.

Detailed Description
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The study will enroll 4 randomized groups of 30 subjects each for a total of 120 subjects. These groups will be split so that 60 individuals receive the 1.0 mg dose and the other 60 receive the 2.0 mg dose. Every subject will receive a total of 3 injections on Days 0, 28, and 56. Half of each of these groups (n = 30) will receive 2 vaccine injections at Days 0 and 56 (normal saline placebo on Day 28) while the other half will receive 3 vaccine injections at Days 0, 28, and 56. All subjects will receive a booster dose at Day 168 to help assess immunogenicity with this booster dose. All doses will be administered with the TDS-IM device. All subjects will be followed until at least Day 252 (a 12 month follow-up visit may be requested). Subjects will complete post-injection memory aids for 7 days after each injection. There will also be up to 12 alternates enrolled and used to replace any original subject who fails to complete all 3 scheduled primary injections and Day 70 follow-up visit.

Official Title
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A Phase 2a Double-Blind, Dose-optimizing Study to Evaluate the Immunogenicity of Hantaan/Puumala Virus DNA Vaccine Administered to Healthy Adult Volunteers by Electroporation for Prevention of Hemorrhagic Fever With Renal Syndrome

Conditions
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Hemorrhagic Fever With Renal Syndrome

Intervention / Treatment
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* Biological: HTNV/PUUV DNA vaccine
* Biological: Placebo
* Device: TriGrid Delivery System (TDS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or non-pregnant, non-lactating female, ages 18-49 (inclusive) at the time of screening Have provided written informed consent before screening Free of clinically significant health problems, as determined by pertinent medical history and clinical examination prior to entry into the study Available and able to participate for all study visits and procedures Females, if sexually active, are known to be at least one year post-menopausal (defined as no menses for 12 consecutive months), or willing to use an effective method of contraception (eg, hormonal contraception, diaphragm, cervical cap, intrauterine device, condom, anatomical sterility [self or partner]) from the date of screening until at least 3 months after the last injection Negative hantavirus pseudovirion neutralization assay (PsVNA) test result at screening Exclusion Criteria: History or serologic evidence of prior infection with any hantavirus virus, or prior participation in a HTNV or PUUV vaccine trial History of severe local or systemic reactions to any vaccination or a history of severe allergic reactions Ongoing participation in another clinical trial Receipt or planned receipt of any vaccination, experimental or otherwise within the period 30 days prior to the first injection through the period 60 days after Study Day 168 (booster dose; approximately 9 month period in total), with the exception of emergency use vaccinations as needed Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue for all eligible injection sites (deltoid region) exceeds 40 mm Individuals in whom the ability to observe possible local reactions at the eligible injections sites (deltoid region) is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, or hepatic or renal functional abnormality as determined by the investigator based on medical history, physical exam, electrocardiogram (ECG), and/or laboratory screening test Pregnant or lactating female, or female who intends to become pregnant during the study period Administration of immunoglobulins and/or any blood products within the 120 days preceding study entry or planned administration during the study period Any serologic evidence of hepatitis B or C infection Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection Administration of chronic (defined as more than 14 days) immunosuppressants or other immune modifying drugs within 6 months of study entry For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day Intranasal and topical steroids are allowed Any chronic or active neurologic disorder, including seizures and epilepsy, excluding a single febrile seizure as a child Syncopal episode within 12 months of screening Suspected or known current alcohol and/or illicit drug abuse Unwilling to allow storage and use of blood for future hantavirus-related research Any other significant finding that in the opinion of the investigator would increase the risk of the individual having an adverse outcome from participating in this study

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine + Placebo at 1.0 mg<br>1.0 mg HTNV/PUUV DNA vaccine IM-EP via TriGrid™ Delivery System (TDS) on Study Day 0, 56 and 168. 1.0 mg placebo administration on Study Day 28. | Biological: HTNV/PUUV DNA vaccine<br>* HTNV/PUUV DNA vaccine mixture, composed of pWRG/HTN-M(co) and pWRG/PUU-M(s2)<br>* Other names: Hantaan Virus/Puumala Virus DNA Vaccine;Biological: Placebo<br>* 0.9% sodium chloride<br>* Other names: Normal saline placebo;Device: TriGrid Delivery System (TDS)<br>* The TDS-IM is an integrated, fully automated clinical EP system designed for delivering DNA-based vaccines and therapies to target tissues, through temporary disruption of cellular membranes via electrical pulses<br>* Other names: TriGrid Delivery System for intramuscular delivery (TDS-IM);|
| Experimental: Vaccine at 1.0 mg<br>1.0 mg HTNV/PUUV DNA vaccine IM-EP via TriGrid™ Delivery System (TDS) on Study Day 0, 28, 56 and 168. | Biological: HTNV/PUUV DNA vaccine<br>* HTNV/PUUV DNA vaccine mixture, composed of pWRG/HTN-M(co) and pWRG/PUU-M(s2)<br>* Other names: Hantaan Virus/Puumala Virus DNA Vaccine;Device: TriGrid Delivery System (TDS)<br>* The TDS-IM is an integrated, fully automated clinical EP system designed for delivering DNA-based vaccines and therapies to target tissues, through temporary disruption of cellular membranes via electrical pulses<br>* Other names: TriGrid Delivery System for intramuscular delivery (TDS-IM);|
| Experimental: Vaccine + Placebo at 2.0 mg<br>2.0 mg HTNV/PUUV DNA vaccine IM-EP via TriGrid™ Delivery System (TDS) on Study Day 0, 56 and 168. 2.0 mg placebo administration on Study Day 28. | Biological: HTNV/PUUV DNA vaccine<br>* HTNV/PUUV DNA vaccine mixture, composed of pWRG/HTN-M(co) and pWRG/PUU-M(s2)<br>* Other names: Hantaan Virus/Puumala Virus DNA Vaccine;Biological: Placebo<br>* 0.9% sodium chloride<br>* Other names: Normal saline placebo;Device: TriGrid Delivery System (TDS)<br>* The TDS-IM is an integrated, fully automated clinical EP system designed for delivering DNA-based vaccines and therapies to target tissues, through temporary disruption of cellular membranes via electrical pulses<br>* Other names: TriGrid Delivery System for intramuscular delivery (TDS-IM);|
| Experimental: Vaccine at 2.0 mg<br>2.0 mg HTNV/PUUV DNA vaccine IM-EP via TriGrid™ Delivery System (TDS) on Study Day 0, 28, 56 and 168. | Biological: HTNV/PUUV DNA vaccine<br>* HTNV/PUUV DNA vaccine mixture, composed of pWRG/HTN-M(co) and pWRG/PUU-M(s2)<br>* Other names: Hantaan Virus/Puumala Virus DNA Vaccine;Device: TriGrid Delivery System (TDS)<br>* The TDS-IM is an integrated, fully automated clinical EP system designed for delivering DNA-based vaccines and therapies to target tissues, through temporary disruption of cellular membranes via electrical pulses<br>* Other names: TriGrid Delivery System for intramuscular delivery (TDS-IM);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Seroconversion of HTNV and PUUV Using PsVNA50 | The primary endpoint will be to determine the seroconversion rates of the vaccines. Seroconversion is defined as production of neutralizing antibody titers measured using a pseudovirion neutralization assay (PsVNA). A PsVNA50 titer ≥ 20 is considered positive. Sera were collected on Days 0, 28, 56, 84, 140, 168, 196, 252, 365 and evaluated for the presence of neutralizing antibodies using PsVNA50. Percentages for seroconversion are based on the number of subjects presenting non-missing data. | Study Days 0 to 365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Solicited Adverse Events (AEs) in Study Subjects | The nature, frequency, and severity of solicited adverse events (AE) occurring from the time of each injection through 14 days following the procedure. The total number of events counts all solicited adverse events for all subjects. Subjects may have more than one solicited adverse event per body system and preferred term. | The time of each injection through 14 days following the procedure | 
| Number of Participants With Seroconversion of HTNV and PUUV Using PsVNA80 | Seroconversion is defined as production of neutralizing antibody titers measured using a pseudovirion neutralization assay (PsVNA). Sera were collected on Days 0, 28, 56, 84, 140, 168, 196, 252, 365 and evaluated for the presence of neutralizing antibodies by using PsVNA80. Percentages for seroconversion are based on the number of subjects presenting non-missing data. | Study Days 0 to 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hantaan virus, Puumala virus, HFRS