Safety, Tolerability and Immunogenicinity of a Coronavirus-Like Particle COVID-19 Vaccine in Adults Aged 18-55 Years.

Study Overview
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Brief Summary
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The study will be a randomized, partially-blinded, prime-boost, staggered dose-escalation Phase 1 study intended to assess the safety, tolerability, and immunogenicity of the Coronavirus-Like Particle COVID-19 Vaccine at three dose levels (3.75 µg, 7.5 µg, and 15 µg VLP) unadjuvanted or adjuvanted with either CpG 1018 or AS03 in healthy adults 18 to 55 years of age, who have been tested for the absence of SARS-CoV-2 antibodies. At each dose level, the vaccine will initially be administered to a small number of subjects. Vaccinations of the first 6 subjects at the lowest dose level will be staggered so that each vaccination must be performed at least 30 minutes apart. Vaccination of the remaining subjects at the same dose level and the next higher vaccine dose level will be administered with approval of the Independent Data Monitoring Committee (IDMC). The same process will be followed for the second vaccine administration. All subjects will be followed for a period of 12 months after the second administration of the vaccine for safety and immunogenicity testing at the end of the follow-up period.

Official Title
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A Randomized, Partially-Blinded, Dose-Ranging Phase 1 Study to Assess the Safety, Tolerability, and Immunogenicity of a Recombinant Coronavirus-Like Particle COVID 19 Vaccine in Adults 18-55 Years of Age

Conditions
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SARS-CoV 2

Intervention / Treatment
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* Biological: Intramuscular Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following inclusion criteria at the Screening (Visit 1) and/or Vaccination (Visit 2) visits to be eligible for participation in this study; no protocol waivers are allowed. All Investigator assessment-based judgements must be carefully and fully documented in the source documents: Subjects must have read, understood, and signed the informed consent form (ICF) prior to participating in the study; subjects must also complete study-related procedures and communicate with the study staff at visits and by phone during the study; At the Screening visit (Visit 1), male and female subjects must be 18 to 55 (has not yet had his/her 56th birthday) years of age, inclusive; At Screening (Visit 1) and Vaccination (Visit 2), subject must have a body mass index (BMI) of ≥ 18.5 and < 25 kg/m2; Subjects are considered by the Investigator to be reliable and likely to cooperate with the assessment procedures and be available for the duration of the study; Subjects must be healthy (no clinically significant health concerns) as determined by medical history, physical examination, vital signs, and clinical laboratory tests. Investigator discretion will be permitted with this inclusion criterion; Female subjects of childbearing potential must have a negative serum pregnancy test result at Screening (Visit 1) and a negative urine pregnancy test result at Vaccination (Visit 2 and Visit 4). Non-childbearing females are defined as: Surgically-sterile (defined as bilateral tubal ligation, hysterectomy or bilateral oophorectomy performed more than one month prior to the first study vaccination); or Post-menopausal (absence of menses for 12 consecutive months and age consistent with natural cessation of ovulation); Female subjects of childbearing potential must use an effective method of contraception for one month prior to vaccination (Visit 2) and agree to continue employing highly effective birth control measures for at least one month after the last administration of the investigational product (or in the case of early termination, she must not plan to become pregnant for at least one month after her last study vaccination). The following relationship or methods of contraception are considered to be highly effective: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral; Intravaginal; Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral; Injectable; Implantable; Intra-uterine device with or without hormonal release; Vasectomised partner, provided that this partner is the sole sexual partner of the study participant and that the vasectomised partner has received a medical assessment of the surgical success; Credible self-reported history of heterosexual vaginal intercourse abstinence prior to and for at least one month after the last administration of the investigational product ; Female partner. Exclusion Criteria: Subjects who meet any of the following criteria at the Screening (Visit 1) and/or Vaccination (Visit 2) visits will not be eligible for participation in this study; no protocol waivers are allowed. All Investigator assessment-based judgements must be thoroughly documented in the source documents: Clinically significant acute or chronic pulmonary (including but not limited to chronic obstructive pulmonary disease or asthma), cardiovascular (including but not limited to arterial hypertension, coronary artery disease, or congestive heart failure), renal, metabolic (including but not limited to type 2 diabetes), or other somatic (medical) or neuropsychiatric illness within 3 months prior to Screening (Visit 1), excessive alcohol use or drug abuse, as determined by medical history, physical examination, vital signs, and clinical laboratory tests. Investigator discretion is permitted with this exclusion criterion and must be carefully and fully documented in the source documents; Any unexplained clinical syndrome (including, but not limited to, chronic fatigue syndrome, Raynaud's syndrome, unexplained pain syndromes such as fibromyalgia, etc.); Acute disease defined as presence of any moderate or severe acute illness with or without a fever within 48 hours prior to Vaccination (Visit 2); Prior exposure to SARS-CoV-2 as determined by detection of IgM or IgG antibodies against SARS-CoV-2 at Screening (Visit 1) and Vaccination (Visit 2); Any confirmed or suspected current immunosuppressive condition or immunodeficiency, including cancer, human immunodeficiency virus (HIV), hepatitis B or C infection (subjects with a history of cured hepatitis B or C infection without any signs of immunodeficiency at present time are allowed). Investigator discretion is permitted with this exclusion criterion; Current autoimmune disease (such as rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis). Investigator discretion is permitted with this exclusion criterion, and subjects may be eligible to participate with appropriate written justification in the source document (i.e. subjects with a history of autoimmune disease who are disease-free without treatment for three years or more, or on stable thyroid replacement therapy, mild psoriasis [i.e. a small number of minor plaques requiring no systemic treatment], etc.); Administration of any medication or treatment that may alter the vaccine immune responses, such as: Systemic glucocorticoids within one month prior to Vaccination (Visit 2). Inhaled, nasal, dermal, intraarticular, ophthalmic and other topical glucocorticoids are permitted; Cytotoxic, antineoplastic, or immunosuppressant drugs - within 36 months prior to Vaccination (Visit 2); Any immunoglobulin preparations or blood products, blood transfusion - within 6 months prior to Vaccination (Visit 2); Administration of any vaccine within 30 days prior to Vaccination (Visit 2); planned administration of any vaccine during the study (up to blood sampling on Day 42 of the study). Immunization on an emergency basis during the study will be evaluated on case-by-case basis by the Investigator; Administration of any other SARS-CoV-2 / COVID-19, or other experimental coronavirus vaccine at any time prior to or during the study; Known current or previous laboratory-confirmed SARS-CoV-1 or SARS-CoV-2 / COVID 19 infection as documented by a positive PCR test or positive serological test; Subjects at high risk of contracting SARS-CoV-2/COVID-19 infection, including but not limited to the individuals with known close contact of anyone with laboratory-confirmed SARS-CoV-2 / COVID-19 infection within 2 weeks prior to vaccine administration, those who traveled outside Canada for any duration within 30 days before the study vaccination, healthcare workers in acute care hospitals, rehabilitation hospitals, mental health hospitals, long term care facilities, emergency departments, and others who through their work must come into close face-to-face contact with their clients or patients (including, but not limited to, physiotherapists, dentists, hair dressers/barbers, etc.); Use of any investigational or non-registered product within 30 days or 5 half-lives, whichever is longer, prior to Vaccination (Visit 2) or planned use during the study period; Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at injection site that may interfere with injection site reaction rating. Investigator discretion will be permitted with this exclusion criterion; Use of any prescription medication on a regular basis for more than 30 continuous days within the last 3 months, with the following exceptions: Medications listed among the methods of contraception in inclusion criterion 7; Subjects on stable thyroid replacement therapy, as noted in exclusion criterion 6. Use of any prescription antiviral drugs with the intention of COVID-19 prophylaxis, including those that are thought to be effective for prevention of COVID-19 but have not been licensed for this indication, within one month prior to Vaccination (Visit 2); Use of prophylactic medications (e.g. antihistamines [H1 receptor antagonists], nonsteroidal anti-inflammatory drugs [NSAIDs], systemic and topical glucocorticoids, non-opioid and opioid analgesics) within 24 hours prior to the Vaccination (Visit 2) to prevent or pre-empt symptoms due to vaccination; History of allergy to any of the constituents of the Coronavirus-Like Particle COVID-19 Vaccine, vaccine adjuvants, or tobacco; History of anaphylactic allergic reactions to plants or plant components (including fruits and nuts); Currently smoke more than 10 cigarettes per month or any use of vaping products; Subjects with a history of Guillain-Barré Syndrome; Any female subject who has a positive or doubtful pregnancy test result prior to vaccination or who is lactating; Subjects identified as an Investigator or employee of the Investigator or clinical site with direct involvement in the proposed study, or identified as an immediate family member (i.e. parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study, or any employees of Medicago.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine (3.75 µg) unadjuvanted<br>• Group 1: 3.75 µg of the Coronavirus-Like Particle COVID-19 Vaccine | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (3.75 µg) adjuvanted with CpG 1018<br>• Group 2: 3.75 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with CpG 1018 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (3.75 µg) adjuvanted with AS03<br>• Group 3: 3.75 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with AS03 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (7.5 µg) unadjuvanted<br>• Group 4: 7.5 µg of the Coronavirus-Like Particle COVID-19 Vaccine unadjuvanted | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (7.5 µg) adjuvanted with CpG 1018<br>• Group 5: 7.5 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with CpG 1018 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (7.5 µg) adjuvanted with AS03<br>• Group 6: 7.5 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with AS03 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (15 µg) unadjuvanted<br>• Group 7: 15 µg of the Coronavirus-Like Particle COVID-19 Vaccine unadjuvanted | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (15 µg) adjuvanted with CpG 1018<br>• Group 8: 15 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with CpG 1018 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|
| Experimental: Vaccine (15 µg) adjuvanted with AS03<br>• Group 9: 15 µg of the Coronavirus-Like Particle COVID-19 Vaccine adjuvanted with AS03 | Biological: Intramuscular Vaccine<br>* Subjects will receive two intramuscular (IM) injections 21 days apart (Day 0 and Day 21), into the deltoid region of the alternating arm (each arm will be injected once), with their assigned vaccine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immediate adverse event (AEs) | Percentage, intensity, and relationship to vaccination of immediate adverse events (AEs) | 30 minutes | 
| Solicited local and systemic adverse events (AEs) | Percentage, intensity, and relationship to vaccination of solicited local and systemic adverse events (AEs) following each vaccination | 7 days | 
| Unsolicited adverse events (AEs) | Percentage, intensity, and relationship of unsolicited adverse events (AEs) following each vaccine administration | 21 days | 
| Serious adverse events (SAEs), adverse events (AEs) leading to withdrawal, adverse event of special interest (AESI) (including vaccine-enhanced disease) and deaths | Occurrences of serious adverse events (SAEs), adverse events (AEs) leading to withdrawal, adverse event of special interest (AESIs) (including vaccine-enhanced disease (VED)), and deaths following each vaccine administration | 21 days | 
| Safety labs | Number and percentage of subjects with normal and abnormal clinically significant urine, haematological and biochemical values prior to and 3 days following each vaccination. | 3 days | 
| Neutralizing antibody (Nab assay) response | Nab response induced by the vaccine against the SARS-CoV-2 virus | 21 days | 
| Specific Th1 cell-mediated immunity (CMI) response | Cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus after each vaccination, as measured by Interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot) | 21 days | 
| Specific Th2 cell-mediated immunity (CMI) response | Cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus after each vaccination, as measured by Interleukin-4 (IL-4) ELISpot | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse events (SAEs), adverse events (AEs) leading to withdrawal, adverse event of special interest (AESI) (including vaccine-enhanced disease) and deaths | Occurrences of serious adverse events (SAEs), adverse events (AEs) leading to withdrawal, adverse event of special interest (AESIs) (including vaccine-enhanced disease (VED)), and deaths from 22 days after the last vaccination up to the end of the study | Day 42 to 386 | 
| Specific antibody response induced by the vaccine against the SARS-CoV-2 virus measured by total IgG and/or IgM levels | Specific antibody response induced by the vaccine against the SARS-CoV-2 virus, as measured by total IgG and/or IgM levels | Day 21, 42, 201 and 386 | 
| Neutralizing antibody (Nab assay) response induced by the treatment groups against the SARS-CoV-2 virus | Neutralizing antibody (Nab assay) response induced by the treatment groups against the SARS-CoV-2 virus | Day 201 and 386 | 
| Specific Th1 cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus | Specific Th1 cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus measured by IFN- γ ELISpot | Day 201 and 386 | 
| Specific Th2 cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus | Specific Th2 cell-mediated immunity (CMI) response induced by the vaccine against the SARS-CoV-2 virus measured by IL-4 ELISpot. | Days 201 and 386 |