A Clinical Trial of a Prophylactic Plasmid DNA Vaccine for COVID-19 [Covigenix VAX-001] in Adults

This study is a Phase I/II clinical study in healthy adults designed to assess the safety, tolerability, and immunogenicity of receiving 2 IM injections of Covigenix VAX-001/-1b, 28 days apart. Covigenix VAX-001/-1b is a plasmid DNA vaccine that expresses key antigenic determinants from SARS-CoV-2 and uses Entos Pharmaceuticals' Fusogenix PLV platform. The phase I part of this study was completed in Canada. The phase II part of the study will be completed in Burkina Faso, Senegal and South Africa.

Phase I portion of the study: Study design: ENTVAX01-101 is a phase I/II, placebo-controlled, randomized, observer-blind, dose ranging clinical trial in males and non-pregnant females, 18 years and older, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, tolerability, and immunogenicity of Covigenix VAX-001 manufactured by Entos Pharmaceuticals. Covigenix VAX-001 is a novel plasmid DNA-based vaccine that encodes for the full-length Spike protein from SARS-CoV-2 (VAX-001 encapsulated in a proprietary Fusogenix Proteo-Lipid Vehicle (PLV)). Enrollment for the phase I portion of the study will occur at one Canadian site. Thirty-six participants will be enrolled in a staggered manner into one cohort an 3 groups (0.100 mg \& 0.250 mg vs. placebo) in stage I. Participants will receive an intramuscular (IM) injection (0.5 milliliter \[mL\]) on Days 0 and 14 in the deltoid muscle of alternating arms and will be followed through 12 months post booster vaccination (Day 379). Follow-up visits will occur at Days 7, 14, 17, 21, 28, 42, 196, and 379. The primary objective is to evaluate the safety of a 2-dose vaccination schedule of the Covigenix VAX-001 vaccine, given 14 days apart. The secondary objectives are to evaluate the humoral immune response as measured by Immunoglobulin G (IgG) ELISA to the SARS-CoV-2 S protein and by pseudo-viral neutralization assay to pseudo-virion following a 2-dose vaccination schedule of Covigenix VAX-001. Clinical safety data will be collected at the Day 0 of the study and at defined intervals (Dose 1: Days 7, 14; Dose 2: Days: 21, 42). Clinical safety lab testing • Hematology \& Biochemistry: Immunogenicity testing: * ELISA and pseudo-viral neutralization tests * % of responders or individuals who seroconvert (with 95% CI): develop immune response defined as a 4-fold or greater rise. * Geometric mean concentration/geometric mean titers (with 95% CI) and pre-/post-vaccination ratios (geometric mean ratios) provide absolute values and increase in antibody titers at defined time points after each vaccination. * Reverse cumulative distribution (RCD) curves display percentage of participants versus antibody levels. The following immunogenicity tests will be performed as exploratory objectives: * SARS-CoV-2 neutralization antibody responses at Days 0, 7, 14, 21, 28, 42, 196, and 379. * Antigen-specific B\&T cell interferon (IFN)-γ cell responses measured by ELISPOT up to Day 379. * Antigen-specific T cell responses measured by flow cytometry up to Day 379 * Antigen-specific T cell responses including cluster of differentiation (CD)4+ and CD8+ cytotoxic T lymphocytes (CTLs), through ICS up to Day 379 * Whole blood immunophenotyping (B and T cell repertoire (BCR and TCR) as measured by high throughput sequencing of lymphocyte antigen receptor genes, SCS, and RNAseq to identify all genes regulated by the vaccine) up to Day 379 Sample size: 36 participants, 24 test subjects and 12 placebo controls; Study plan: Table 1. Study groups and treatments Arm Intervention 1. Experimental: Low dose (0.100mg), 18-\<55 years, 2 doses Biological: Covigenix VAX-001, 0.5 mL IM injection 2. Experimental: High dose (0.250mg), 18-\<55 years, 2 doses Biological: Covigenix VAX-001, 0.5 mL IM injection 3. Placebo Comparator: Placebo, 18-\<55 years Other: Placebo, 0.5 mL IM injection Enrollment plan: Enrollment plan: Study participants will be enrolled in a staged manner at each dosage level (Low and High), as described below: First, three participants of the cohort will be randomized (2:1; Groups 1 and 3) to the low dose of Covigenix VAX-001 or placebo, a minimum of one hour apart. Once three participants have received treatment there will be a 72-hour waiting period, and if no holding rule is met then the remaining participants from Group 1 and 3 will be vaccinated. Similarly, once 7-day safety data are available on a minimum of 75% (n=14) of participants in Groups 1/3, 1) participants of the cohort will be randomized (2:1; groups 2 and 3) to the high dose of Covigenix VAX-001 or placebo. After review of day 42 data (Day 28 post second dose) on participants in Groups 1/3 (Low dose), it will be decided whether this group will be enrolled in the Ph II of the study. Infection during the study: During the observation period of the study, if fever and respiratory symptoms with cough develop in a participant, he/she should immediately follow local procedures for care of suspected COVID-19 illness and contact the study team. The participant's nasopharyngeal and throat swab/sputum will be collected and tested for SARS-CoV-2 at a designated provincial testing center. If a COVID-19 infection is found during the study, a case investigation will be undertaken. Careful monitoring for vaccine-related enhanced disease will be undertaken in conjunction with the participant's primary physician. In addition to the real-time PCR testing for SARS-CoV-2, the collected nasopharyngeal swab/sputum will be tested for other respiratory pathogens. Participants testing positive for SARS CoV 2 between IP Dose 1 and Dose 2 will not receive Dose 2, but will be followed for safety. Study duration: 13 months Study Design for the phase II portion of the study: For the Phase II part, enrollment will occur at sites globally. Approximately 500 participants will be enrolled into 1 of 5 groups (approximately 100 per group) as safety data emerge from the Phase I portion . Participants will receive an IM injection (0.5 mL) on Days 0 and 14 in the deltoid muscle of alternating arms and will be followed through 12 months post Dose 2. Follow-up visits will occur at Days 14, 28, 42, 196, and 379. The total duration for an individual participant in the Phase II part will be approximately 13 months. Study arms are: 1. Experimental: Low dose (0.100mg), 18 years and older, 2 doses active Biological: Covigenix VAX-001, 0.5 mL IM injection 2. Experimental: Low dose (0.100mg), 18 years and older, 1 dose active, 1 dose placebo Biological: Covigenix VAX-001, 0.5 mL IM injection 3. Experimental: High dose (0.250mg), 18 years and older, 2 doses active Biological: Covigenix VAX-001, 0.5 mL IM injection 4. Experimental: High dose (0.250mg), 18 years and older, 1 dose active, 1 dose placebo Biological: Covigenix VAX-001, 0.5 mL IM injection 5. Placebo Comparator: Placebo, 18 years and older Other: Placebo, 0.5 mL IM injection Clinical safety lab testing • Hematology \& Biochemistry: Immunogenicity testing: * ELISA and pseudo-viral neutralization tests * % of responders or individuals who seroconvert (with 95% CI): develop immune response defined as a 4-fold or greater rise. * Geometric mean concentration/geometric mean titers (with 95% CI) and pre-/post-vaccination ratios (geometric mean ratios) provide absolute values and increase in antibody titers at defined time points after each vaccination. The following immunogenicity tests will be performed as exploratory objectives: * SARS-CoV-2 neutralization antibody responses at Days 0,14, and 28. * Antigen-specific T cell responses including cluster of differentiation (CD)4+ and CD8+ cytotoxic T lymphocytes (CTLs), through ICS up to Day 379 Phase II The Phase II part will be initiated following DSMC recommendation based on 42-day reviews of each group (complete or partial group) in Phase I Canada part and the enrollment and DSMC recommendations from the Phase II Lead-in groups in South Africa, Burkina Faso, and Senegal. Recruitment will be staggered by group as summarized in Table 5 of the protocol. The Phase II part will consist of a randomized, observer-blinded, multi-center, dose ranging clinical study in males and nonpregnant females, 18 years and older who meet all eligibility criteria. Approximately 500 participants will be enrolled into 1 of 4 cohorts: low dose 0.100 mg as 1 or 2 dose schedule and high dose 0.250 mg as 1 or 2 dose schedules. Participants will receive an IM injection (0.5 mL) on Days 0 and 28 in the deltoid muscle of alternating arms and will be followed through 12 months post Dose 2 (Table 5). Follow-up visits will occur at Days 28, 42, 56, 118, 210, and 393. Enrollment in the phase II part of the study will be carried out globally in Burkina Faso, Senegal and South Africa.