The Safety and Immunogenicity of a DNA-based Vaccine (COVIGEN) in Healthy Volunteers

Study Overview
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Brief Summary
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In this trial, we are evaluating the safety and tolerability of a new investigational DNA vaccine to protect against SARS CoV-2 virus, called COVIGEN, that is developed by a company called BioNet-Asia. A device will be used to inject the vaccine that does not require the use of a needle (needle-free injection made by a company called Pharmajet). For delivery into the skin (intradermally) a device called Tropis will be used, and for delivery into the muscle (intramuscularly) a device called Stratis will be used. This is a 2 part study In Part A vaccine naive participants will be given 2 vaccinations, either two active vaccines or two placebo vaccines on Day 1 and Day 29. COVIGEN C19 vaccine will be used in Part A In Part B participants who have previously received a 2-dose primary COVID vaccine schedule will be given a booster dose of active vaccine. COVIGEN C20 vaccine will be used in Part B. Participants in part A and B will be followed up using a combination of on-site and telephone visits for assessment of safety and immunogenicity for 12 months from 1st vaccination.

Detailed Description
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Part A Vaccine Naïve participants: The study comprises three dose groups (0.8 mg COVIGEN, administered ID, 2 mg COVIGEN, administered IM and 4 mg COVIGEN, administered IM) with 50 participants in each group. Each group of 50 participants comprises two sub-groups: 25 young adults and 25 older adults. Within each group and within each sub-group, participants will be randomised 4:1 to receive COVIGEN or placebo in a double-blind fashion. Participants will receive 2 study vaccinations, 28 days apart (Day 1 and Day 29). Each dose will be divided into 2 injections, with each injection being administered using a needle free injection system into the upper arm (left and right) at each visit. The study will utilise a sequential dose-escalating design with a 48-hour observation period required for sentinel participants prior to the decision to dose escalate. Enrolment of the remainder of each age cohort will commence at least 48 hours after the last of the sentinel participants has received a vaccine. A Safety Review Committee (SRC) will supervise enrolment and monitoring of participant safety throughout the trial Part B: Vaccine booster participants: The study comprises a single dose group (1.0mg COVIGEN, administered ID) to 50 participants in total, comprising 25 participants who have received a primary course of 2 doses of Pfizer BioNTech vaccine and 25 participants who have received a primary course of 2 doses of Astra Zeneca vaccine. The dose will be divided into 2 injections, with each injection being administered using a needle free injection system into the upper arm (left and right) at each visit. Participants will be followed up using a combination of on-site and telephone visits for assessment of safety and immunogenicity for 12 months from 1st vaccination.

Official Title
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A Phase I, Double-blind, Dose-ranging, Randomised, Placebo-controlled Trial to Study the Safety and Immunogenicity of a DNA-based Vaccine Against COVID-19 (COVIGEN) in Healthy Participants Aged 18 to 75 Years Old

Conditions
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SARS-CoV2 COVID-19

Intervention / Treatment
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* Biological: COVIGEN C19 0.8 mg ID or Placebo ID
* Biological: COVIGEN C19 2.0 mg IM or Placebo IM
* Biological: COVIGEN C19 4.0 mg IM or Placebo IM
* Biological: COVIGEN C20 1.0mg vaccine ID


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Potential participants must fulfil all of the following inclusion criteria to be eligible to participate in the study: Willing and capable of providing written informed consent prior to the performance of any study-specific procedure. Male or female, ≥18.0 to ≤75. years of age, at the time of consent. The participant must be in good health, as established by pertinent medical history, physical examination and vital signs assessments performed at Screening. Body mass index (BMI) of 18 to 40 kg/m2, inclusive, at Screening. Women of childbearing potential must have a negative urine pregnancy test at Screening and pre-dose on Day 1, and must agree to remain sexually abstinent, use medically effective contraception (see Section 4.3.10), or have a partner who is sterile or same-sex, from Screening until at least 90 days after the 2nd vaccination (Part A) or the Booster (Part B). a. Females with natural amenorrhea for <2 years (without an alternative medical cause) and who are not surgically sterile, i.e. tubal ligation, bilateral oophorectomy, or complete hysterectomy will only be considered not to be of childbearing potential if they have a documented follicle-stimulating hormone (FSH) value in the postmenopausal range. Sexually active male participants who are considered sexually fertile must agree to use either a barrier method of contraception from the time of 1st vaccination until at least 90 days after the 2nd vaccination (Part A) or the Booster (Part B), or have a same sex partner, or have a partner who is permanently sterile or unable to become pregnant; Both male and female participants must agree to refrain from sperm and egg donation from the day of the 1st vaccination until at least 90 days after the 2nd vaccination (Part A) or the Booster (Part B).. Clinical safety laboratory evaluations at Screening must be toxicity Grade 0 or 1, or deemed not clinically significant by the Investigator. The participant must agree to refrain from donating blood or plasma during the study for non-study purposes. The participant must agree to have study samples retained for secondary research including exploratory analyses. The participant must be able to attend all scheduled visits and to understand and comply with planned study procedures, in the Investigator's judgement. Part B only: The participant must have completed a primary course (2 doses) of either Comirnaty (Pfizer BioNTech) or Astra Zeneca vaccine and ≥3 months (≥90 days) has elapsed since receipt of dose 2 in the primary course. EXCLUSION CRITERIA If any of the following exclusion criteria apply, the potential participant will not be permitted to participate in the study: Female participant who is breastfeeding or intends to become pregnant from Screening until at least 90 days after the 2nd vaccination (Part A) or at least 90 days after booster vaccination (Part B). History of any major (per Investigator's discretion) cardiovascular, renal, neurological, metabolic, gastrointestinal, hepato-biliary, uncontrolled hypertension and diabetes, clinically significant chronic pulmonary disease, asthma (with the exception of history of resolved childhood asthma), immunological and autoimmune diseases or any condition which, in the opinion of the Investigator, might interfere with the evaluation of the study objectives. Chronic use (more than 14 continuous days) of systemic corticosteroids within 30 days prior to Screening. Intra-articular, intra-bursal, or topical (skin or eyes) corticosteroids are permitted. History of any haematological malignancy or active neoplastic disease (excluding non-melanoma skin cancer that was successfully treated). Active is defined as having received treatment within the past 5 years. History of demyelinating disease or Guillain Barre syndrome. Eczema or other significant skin lesion, infection or tattoo at the site of vaccination (left or right upper arm). History of blood dyscrasia or significant disorder of coagulation that, in the opinion of the Investigator, contraindicates IM injection (Part A only). History of known or suspected hypersensitivity or any severe allergic reaction including anaphylaxis, generalised urticaria, angioedema, and other significant reaction to Kanamycin or any vaccine component,. Presence of active viral or bacterial infection, with or without fever (oral temperature ≥37.8 °C) at Screening or within 72 hours prior to each vaccination, if determined by the Investigator to be of clinical significance (enrolment [provided Screening period does not exceed 30 days] or dosing may be delayed for full recovery if acceptable to the Investigator). Positive serological test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody or HIV (Type 1 or 2) antibody at Screening. Known current or previous laboratory confirmed SARS-CoV-2 infection/COVID 19, or positive for SARS-CoV-2 infection, either by SARS CoV 2-specific IgG antibody (Part A only) or RT-PCR, at Screening. Suspected SARS-CoV-2 infection/COVID-19, including individuals who are required to self-isolate. Individuals currently working in occupations with high risk of exposure to SARS CoV-2, e.g. healthcare workers in direct care of COVID-19 patients, emergency responders or front-line workers. Receipt of any other SARS-CoV-2 or other experimental coronavirus vaccine at any time prior to the study or planned receipt of any other SARS-CoV-2 or other experimental vaccine within 57 days of receipt of the 1st study vaccination (Part A only). Receipt of any other experimental coronavirus vaccine at any time prior to the study or planned receipt of any other SARS-CoV-2 or other experimental vaccine within 29 days of receipt of the booster vaccination (Part B only). Participating in any other clinical study and have received any other investigational product (i.e. study vaccine, drug, biologic or device) within 30 days or 5 half-lives (whichever is longer) prior to Screening, or are taking part in a non medication study which, in the opinion of the Investigator, would interfere with the interpretation of the assessments in this study. Received or plans to receive a live-attenuated vaccine within 4 weeks before or after each study vaccination. Received or plans to receive an inactivated vaccine within 2 weeks before or after each study vaccination (including influenza vaccines). Received immunoglobulins and/or any blood or blood products within 3 months before the 1st vaccination (Part A) or before the booster vaccination (Part B) or plans to receive any blood or blood products at any time during the study. Has a history of alcohol abuse, or other drug abuse assessed as a dependency problem by the Investigator within 6 months before the 1st vaccination (Part A) or before the booster vaccination (Part B). Has any psychiatric or cognitive disease that, in the opinion of the Investigator, may interfere with the participant's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Arm1 (COVIGEN (C19) 0.8 mg ID or Placebo ID)<br>Participants will be randomized to receive either COVIGEN C19 (0.8 mg) given by ID (n=40) or saline placebo (n=10), administered in a two dose regimen, 28 days apart. | Biological: COVIGEN C19 0.8 mg ID or Placebo ID<br>* 2 doses of COVIGEN C19 0.8 mg ID or Placebo ID will be given at Day 1 and Day 29.<br>|
| Experimental: Part A: Arm2 (COVIGEN (C19) 2.0 mg IM or Placebo IM)<br>Participants will be randomized to receive either COVIGEN C19 (2 mg) given by IM (n=40) or saline placebo (n=10), administered in a two dose regimen, 28 days apart. | Biological: COVIGEN C19 2.0 mg IM or Placebo IM<br>* 2 doses of COVIGEN C19 2.0 mg IM or Placebo IM will be given at Day 1 and Day 29.<br>|
| Experimental: Part A; Arm 3 (COVIGEN (C19) 4.0 mg IM or Placebo IM)<br>Participants will be randomized to receive either COVIGEN C19 (4 mg) given by IM (n=40) or saline placebo (n=10), administered in a two dose regimen, 28 days apart | Biological: COVIGEN C19 4.0 mg IM or Placebo IM<br>* 2 doses of COVIGEN C19 4.0 mg IM or Placebo IM will be given at Day 1 and Day 29.<br>|
| Experimental: Part B: Arm 1 (COVIGEN (C20) 1.0 mg ID) in BNT162b2 primed participants<br>Participants in Part B who have received a 2 dose primary course of Pfizer BNT162b2 vaccine will receive COVIGEN C20 (1mg) vaccine given by ID (n=25) | Biological: COVIGEN C20 1.0mg vaccine ID<br>* COVIGEN C20 1.0mg ID vaccine will be given at Day 1<br>|
| Experimental: Part B: Arm 2 (COVIGEN (C20) 1.0 mg ID) in ChAdOx1-S primed participants<br>Participants in Part B who have received a 2 dose primary course of Astra Zeneca ChAdOx1-S vaccine will receive COVIGEN C20 (1mg) vaccine given by ID (n=25) | Biological: COVIGEN C20 1.0mg vaccine ID<br>* COVIGEN C20 1.0mg ID vaccine will be given at Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of solicited local reactogenicity AEs | Percentage of participants with any local reaction (pain, swelling/induration, erythema/redness) for 7 days following each vaccination | Through 7 days after each vaccination (Day 1, 29 for Part A and Day 1 for Part B) | 
| Frequency of solicited systemic reactogenicity AEs | Percentage of participants with any systemic reaction (fever, fatigue, chills, myalgia, arthralgia, headache, nausea/vomiting and diarrhea) for 7 days following each vaccination | Through 7 days after each vaccination (Day 1, 29 for Part A and Day 1 for Part B) | 
| Frequency of any unsolicited AEs | Percentage of participants with unsolicited AEs up to Day 57 | Day 1 to Day 57 after the 1st vaccination (Part A) or from Day 1 to Day 29 after booster vaccination (Part B). | 
| Frequency of any serious adverse events (SAEs) | Percentage of participants with SAEs from Day 1 to 12 months after 1st vaccination | Day 1 to 12 months after 1st vaccination | 
| Frequency of any medically attended adverse events (MAAES) | Measured by MedDRA classification, severity score and relatedness. | From Day 1 to 12 months after the 1st vaccination | 
| Change in safety laboratory values from baseline | Number of participants with abnormal laboratory values (haematology, chemistry and urinalysis) by FDA toxicity scoring. | From Day1 to Day 36 in Part A and from Day 1 to Day 8 in Part B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GMTs for serum neutralizing antibody response | Level of neutralizing antibodies as measured by SARS-CoV-2 Neutralization assay | At day1, day 29 and day 57 (Part A) and Day 1, Day 8, Day 29 (Part B only); | 
| GMFR from baseline for serum neutralizing antibody response | Measured by SARS-CoV-2 Neutralization assay | At day 57 (Part A) or day 29 (Part B) | 
| Seroconversion rate for serum neutralizing antibody response | Defined as proportion of participants with a with a ≥4-fold rise | At day 57 compare to baseline for Part A and at day 29 compare to baseline for Part B | 
| GMTs for serum S1- and RBD-specific IgG antibody responses | SARS-CoV-2 anti-S1 and anti-RBD IgG antibody ELISAs | At day 1, day 29 and day 57 (Part A) and at Day 1, Day 8, Day 29; (Part B only) | 
| GMFR from baseline for serum S1- and RBD-specific IgG antibody responses | As measured by ELISA | At day 57 (Part A) and at day 29 (Part B) | 
| Seroconversion rate serum S1- and RBD-specific IgG antibody responses | Defined as the proportion of participants with a ≥ 4-fold rise | At day 57 compare to baseline for Part A and at day 29 compare to baseline for Part B | 
| Geometric means of T-cells (spot-forming cells) producing IFNγ, IL-2, or both for S protein specific IFN-γ and IL-2 T-cell responses | SARS-CoV-2 Spike Protein dual IFN-γ and IL-2 T-cell ELISpot (FluoroSpot) | At day 1, day 29, and day 57 (Part A) or at Day 1, Day 8, and Day 29 (Part B only) | 
| Fold rise of T-cells (spot-forming cells) producing IFNγ, IL-2, or both for S protein specific IFN-γ and IL-2 T-cell responses | SARS-CoV-2 Spike Protein dual IFN-γ and IL-2 T-cell ELISpot (FluoroSpot) | At day 57 compared to baseline for Part A and at day 29 compare to baseline for Part B | 
| Proportion of participants with significant T-cell responses for S protein specific IFN-γ and IL-2 T-cell responses | IL-2 T-cell ELISpot (FluoroSpot) | At day 57 for Part A and at day 29 for Part B |