Safety, Tolerability, and Immunogenicity of Trivalent Coronavirus Vaccine Candidate VBI-2901a

VBI-2901a is an investigational vaccine candidate that uses enveloped virus-like particles (eVLPs) to express the spike proteins of three coronaviruses: SARS-CoV-2 (the virus that causes COVID-19 disease), SARS-CoV-1 and MERS-CoV. The trivalent vaccine candidate is designed to induce neutralizing antibody and cell-mediated immune responses against the spike protein of the original strain of SARS-CoV-2, SARS-CoV-2 variants (such as Beta, Delta and Omicron) and other related coronaviruses that could emerge in the future.

The Phase 1 study will be an open-label comparison of two intramuscular doses of VBI-2901a at 5 µg or 10 µg per dose or one dose of VBI-2901a at 10 µg per dose in adults 18 to 64 years of age who had previously received two or more vaccinations with licensed COVID-19 vaccines. The purpose of the study is to test the safety of VBI-2901a and to know more about its ability to boost immune response against SARS-CoV-2 (the virus that causes COVID-19 disease) and two other related coronaviruses SARS-CoV-1 and MERS-CoV.

VBI-2901a is an investigational trivalent COVID-19 vaccine candidate that comprises enveloped virus-like particles (eVLPs) expressing the spike proteins of the beta-coronaviruses SARS-CoV-2, SARS-CoV-1 and MERS-CoV. The study will enroll participants 18 to 64 years of age who have previously received two or more vaccinations with a licensed COVID-19 vaccine(s) and will test two intramuscular doses of VBI-2901a containing 5 µg or 10 µg of spike protein and one dose of VBI-2901a containing 10 µg of spike protein. VBI-2901a eVLPs are formulated with 0.33 mg of aluminum phosphate (alum) adjuvant per dose. VBI-2901a is designed to induce neutralizing antibody and cell-mediated immune responses against multiple coronavirus respiratory disease strains and variants of SARS-CoV-2.

This is a randomized, open-label Phase 1 study. The study will enroll adults, aged 18 to 64 years, who are healthy or in stable health; had previously received two or more vaccinations with a licensed COVID-19 vaccine(s) with the final dose administered a minimum of 6 months (24 weeks) prior to enrollment; have a negative PCR or rapid antigen SARS-CoV-2 test at screening; and have met all other eligibility criteria. Participants with a history of mild COVID-19 illness are eligible if they fully recovered a minimum of 6 months (24 weeks) prior to enrollment.

A total of 99 participants will be randomized at a 1:1:1 ratio to the following study groups:

Group G1: 33 participants to receive two doses of VBI-2901a at 5 µg per dose at Day 1 and Day 56.

Group G2: 33 participants to receive two doses of VBI-2901a at 10 µg per dose at Day 1 and Day 56.

Group G3: 33 participants to receive one dose of VBI-2901a at 10 µg per dose at Day 1.

The total study duration for each vaccinated subject is 48 weeks (336 days) after administration of the first dose of study vaccine. During the study, the participant will make 9 visits to the study site, including the screening visit.

The objective of the study is to select the optimal dose level (5 µg or 10 µg) and number of doses (1 or 2 doses) of trivalent coronavirus vaccine candidate VBI-2901a in individuals who had been vaccinated against COVID-19 previously. To achieve this objective, the study will evaluate outcomes including safety and tolerability as well as antibody and T cell immune responses against SARS-CoV-2 ancestral (Wuhan) strain, selected SARS-CoV-2 variants, SARS-CoV-1 and MERS-CoV.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female subject 18-64 years of age
2. Be willing and able to provide personally signed informed consent indicating understanding of the purpose, procedures required for the study and potential risks and benefits of the study, and be willing to participate in the study
3. Be healthy or in stable health. Participants with pre-existing, stable, well-controlled disease, defined as mild disease or medical condition not requiring medical therapy or not requiring a change in medical therapy due to worsening of disease during the 6 months before enrollment may be enrolled at the discretion of the investigator. Participants with history of asymptomatic SARS-CoV-2 infection who tested positive by PCR or rapid antigen test or participants with history of having signs and symptoms mild COVID-19 illness (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who did not have shortness of breath, dyspnea, or abnormal chest imaging are eligible for the study if they fully recovered a minimum of 6 months before enrollment.
4. Meets reproductive inclusion criteria

   1. Female participants

      Female participant is eligible if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:

      • is of childbearing potential and must have a negative pregnancy test prior to study vaccinations and agree to use an effective method of birth control as deemed appropriate by the investigator (e.g., hormonal contraceptive, barrier contraceptive with additional spermicide, or an intrauterine device) beginning \>30 days prior to the first study vaccine administration and continuing for a minimum of 30 days after the last dose of study vaccine.

      OR

      • is not of childbearing potential, defined as postmenopausal (a minimum of 12 months with no menses without an alternative medical cause) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy).
   2. Male participants

   Male participant is eligible to participate if he agrees to the following requirements from the time of first study vaccination until at least 30 days after the last dose of study vaccine:
   * Be abstinent from heterosexual intercourse with a female of childbearing potential OR
   * Must agree to use a male condom. In addition to male condom use, an effective method of contraception may be considered in female partners of male participants AND
   * Must refrain from sperm donation
5. Have previously received 2 or more doses of a licensed COVID-19 vaccine(s) with the last dose administered a minimum of 6 months (24 weeks) prior to enrollment. Participants vaccinated with any of the vaccines approved by Health Canada for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 18 years of age and older are eligible for the study. This includes the following COVID-19 vaccines: Moderna Spikevax®, Pfizer-BioNTech Comirnaty®, AstraZeneca Vaxzevria®, Janssen Jcovden® (Johnson \& Johnson), Novavax Nuvaxovid® and Medicago Covifenz®. Participants who received one or more doses of VBI-2902a, VBI-2905a or any other COVID-19 vaccines that are either investigational or not approved by Health Canada are not eligible for the study.

Exclusion Criteria:

1. History of COVID-19 illness of moderate or greater severity, defined as one of the following:

   1. Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level.
   2. Severe COVID-19 illness: Individuals who have SpO2 \<94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) \<300 mm Hg, a respiratory rate \>30 breaths/min, or lung infiltrates \>50%.
   3. Critical COVID-19 illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.
2. Participants with a known history of SARS-CoV-1 or MERS infection.
3. Positive SARS-CoV-2 PCR or rapid antigen test at screening.
4. Participant with a history of an underlying clinically significant acute or chronic medical condition or physical examination findings for which, in the opinion of the investigator, participation in the study would not be in the best interest of the participant (e.g., could compromise participant's wellbeing) or that could prevent, limit, or confound the protocol-specified assessments.
5. Individuals with medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
6. History of cancer requiring chemotherapy or radiation within 5 years
7. Lack of participant's capacity (mental, social, behavioral), in the investigator's judgement, to provide informed consent for participation in the study.
8. Known or suspected impairment of immunological function, including but not limited to autoimmune diseases:

   1. autoimmune diseases (e.g. multiple sclerosis, type 1 diabetes, myasthenia gravis, Crohn's disease and other inflammatory bowel diseases, celiac disease, systemic lupus erythematosus, scleroderma, including diffuse systemic form and CREST syndrome, systemic sclerosis, dermatomyositis polymyositis, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis - including Hashimoto thyroiditis, Grave's or Basedow's disease, immune thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune hepatitis, psoriasis, vitiligo, vasculitis, Guillain- Barré syndrome, transverse myelitis, Addison's disease, Bell's palsy and alopecia areata);
   2. secondary immunodeficiency disorders (e.g., Acquired Immunodeficiency Syndrome caused by Human Immunodeficiency Virus infection (HIV/AIDS), solid organ transplant, splenectomy);
   3. primary immunodeficiency disorders (e.g., common variable immune deficiency (CVID), defective phagocytic cell function and neutropenia syndromes, complement deficiency).
9. History of allergic reactions or anaphylactic reaction to any vaccine component.
10. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). Negative result of Anti-HIV, Anti-HCV and HBsAg testing at screening is required for eligibility.
11. Pregnant or breastfeeding or plans to conceive from 2 weeks before the study until the end of study.
12. Clinically significant abnormal physical examination, vital signs, or clinically significant abnormal values for hematology, serum chemistry or urinalysis at screening as determined by the investigator.
13. Any laboratory test abnormality that would be considered of Grade 1 severity or above (as per FDA grading guidelines) and is considered as clinically significant by the investigator. Grade 2 severity or above is exclusionary, regardless of clinical assessment.
14. Receipt of blood products or immunoglobulin within 90 days prior to enrollment or likely to require blood products during the study period.
15. Chronic administration (defined as more than 14 days in total) of immune-suppressive or other immune-modifying drug within 6 months prior to enrollment (for corticosteroids, this is defined as prednisone ≥20 mg/day or equivalent). Inhaled and topical steroids are allowed.
16. Immunization with attenuated vaccines (e.g., shingles) within 4 weeks prior to enrollment.
17. Immunization with inactivated vaccines (e.g., influenza) within 2 weeks prior to enrollment.
18. Participation in another clinical study within 30 days prior to enrollment. Participants who received one or more doses of VBI-2902a or VBI-2905a or other investigational COVID-19 vaccines are not eligible for the study.
19. Any skin abnormality or tattoo that would limit post-vaccination injection site assessment.
20. Family members of study site personnel.