Safety, Tolerability, and Immunogenicity of the COVID-19 Vaccine Candidates VBI-2902a and VBI-2905a

Study Overview
=================
Brief Summary
-----------------
VBI-2902a and VBI-2905a are investigational vaccine candidates that use enveloped virus-like particle (eVLP) expression of a modified version of the SARS-CoV-2 spike (S) glycoprotein and are designed to induce neutralizing antibody and cell-mediated immune responses against the SARS-CoV-2 spike protein. VBI-2902a expresses the spike protein of SARS-CoV-2 Wuhan isolate (the first virus variant isolated in 2019 in Wuhan, China), while VBI-2905a expresses the spike protein of SARS-CoV-2 variant Beta (B.1.351 variant, first isolated in 2020 in South Africa). The Phase 1a portion of this study tests one- and two-dose regimens of VBI- 2902a with 5 μg S protein content and aluminum phosphate (alum) adjuvant or placebo delivered by intramuscular (IM) injection. The Phase 1b portion of the study tests a one-dose regimen of VBI-2905a with 5 μg S protein content and alum adjuvant or placebo delivered by IM injection in participants previously vaccinated with an authorized mRNA COVID-19 vaccine.

Detailed Description
-----------------
Phase 1a: The primary objective is to evaluate the safety and tolerability of VBI-2902a containing 5 μg of S protein in one- or two-dose regimens in healthy adults of 18-54 years of age. The secondary objective is to evaluate the immunogenicity of VBI-2902a containing 5 μg of S protein in one- or two-dose regimens in healthy adults 18-54 years of age. Group G1 - 20 participants will receive VBI-2902a at a dose of 5 μg of S protein at Day 1 and placebo at Day 28. Group G2 - 20 participants will receive VBI-2902a at a dose of 5 μg of S protein at Days 1 and 28. Group G3 - 20 participants will receive placebo at Days 1 and 28. An Independent Data Safety Monitoring Board (DSMB) will review blinded safety data (reactogenicity, adverse events (AEs) and safety laboratory assessments) at Day 7 after the first vaccination. The second vaccination will only be given if the DSMB confirms that Day 7 safety is acceptable and that stopping rules were not met. The DSMB will further review blinded post-vaccination safety through Day 35, 7 days after the second vaccination and through Day 56, 28 days after the second vaccination. The study will be unblinded following DSMB review of safety data collected through Day 56. Study participants will continue with study visits as planned up to 12 months of follow up after the first dose of study vaccine. Phase 1b: The primary objective is to evaluate the safety and tolerability of a one-dose regimen of VBI-2905a at a 5 μg dose level of S protein in healthy adults (age 18-54 years) who had been previously vaccinated with mRNA vaccines. The secondary objective is to evaluate the immunogenicity of a one-dose regimen of VBI-2905a at a 5 μg dose level of S protein in healthy adults (age 18-54 years) who had been previously vaccinated with mRNA vaccines. A total of 54 healthy adults, age 18-54 years, with no history of clinical or laboratory diagnosis of SARS-CoV- 2 infection or COVID-19 illness, will be enrolled in the Phase 1b part of the study. All participants in Phase 1b will have been previously vaccinated with an authorized mRNA COVID-19 vaccine, including the second dose administered at least 4 months prior to enrollment, will be randomized at a 1:1 ratio to receive, in a blinded fashion, one dose of VBI-2905a or placebo: Group G4 - 27 participants will receive VBI-2905a at a dose of 5 μg of S protein at Day 1 Group G5 - 27 participants will receive placebo at Day 1 The DSMB will review blinded post-vaccination safety data 7 days after each vaccination (reactogenicity, AEs and safety laboratory assessments). In Phase 1b, the DSMB will review blinded Day 7 safety data after the first 10 participants in groups G4 and G5 have received the first dose. Only after the DSMB confirms that safety is acceptable and that stopping rules were not met will the enrollment in the respective study groups continue to its completion.

Official Title
-----------------
A Phase 1a/1b, Randomized, Observer-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of the COVID-19 (SARS-CoV-2) Vaccine Candidates VBI-2902a and VBI-2905a in Healthy Adults

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Biological: VBI-2902a
* Biological: Placebo
* Biological: VBI-2905a


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: To be eligible for the study, each participant must satisfy all of the following criteria: Healthy female and male participants 18 -54 years of age. If female: 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 until the end of the study. OR is not of childbearing potential, defined as postmenopausal (12 months with no menses without an alternative medical cause) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy orhysterectomy). Phase 1b: previously received a full course (2 doses) of an authorized S protein mRNA COVID-19 vaccine (e.g. COVID-19 vaccines produced by Pfizer/BioNTech or Moderna) at least 4 months prior to enrollment. Sign an informed consent document indicating understanding of the purpose of and procedures required for the study and willingness to participate in the study. Exclusion Criteria Participants with any of the following criteria will be excluded: History of clinical or laboratory diagnosis of COVID-19 or SARS-CoV-2 infection. Phase 1b: Previous receipt of an experimental or authorized SARS-CoV-2 (COVID-19) vaccines other than an S-protein mRNA vaccine. Phase 1a: Previous receipt of an experimental or authorized SARS-CoV-2 (COVID-19) vaccine. Positive PCR or rapid antigen test for SARS-CoV-2 at screening. Individuals with chronic medical conditions, including any of the following: Diabetes mellitus Type 1 or Type 2 Chronic pulmonary disease (e.g., COPD or Asthma) Hypertension (e.g., SBP >140 mmHg or DBP >90 mmHg) Chronic kidney disease (e.g., GFR <60 mL/min/1.73 m2) Chronic liver disease Obesity (e.g., BMI >30 kg/m2) Any history of cancer requiring chemotherapy or radiation within 5years. Other 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. Lack of participant's capacity (mental, social, behavioral), in the investigator's judgement, to provide informed consent for participation in the study. Known or suspected impairment of immunological function, including but not limited to autoimmune diseases: autoimmune diseases (e.g. multiple sclerosis, type 1 diabetes, myasthenia gravis, Crohn 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); secondary immunodeficiency disorders (e.g., Acquired Immunodeficiency Syndrome caused by Human Immunodeficiency Virus infection (HIV/AIDS), solid organ transplant,splenectomy); primary immunodeficiency disorders (e.g., common variable immune deficiency (CVID), Defective phagocytic cell function and neutropenia syndromes, complement deficiency). History of allergic reactions or anaphylactic reaction to any vaccine component. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). Pregnant or breastfeeding or plans to conceive from 2 weeks before the study until the end of study. 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. 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. Has received blood products or immunoglobulin within 90 days of enrollment or is likely to require blood products during the study period. Chronic administration (defined as more than 14 days in total) of immune-suppressive or other immune-modifying drug within six months prior to the product dose (for corticosteroids, this is defined as prednisone ≥20 mg/day or equivalent). Inhaled and topical steroids are allowed. Immunization with attenuated vaccines (e.g., measles, mumps, and rubella vaccine) within 4 weeks prior to enrollment. Immunization with inactivated vaccines (e.g., influenza) within 2 weeks prior to enrolment. Participation in another clinical study within 30 days. Any skin abnormality or tattoo that would limit post-vaccination injection site assessment. Family members of study site personnel.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 54 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a, Group G1<br>20 participants age 18-54 will receive VBI-2902a at a dose of 5 μg of S protein at Day 1 and placebo at Day 28 | Biological: VBI-2902a<br>* VBI-2902a is an intramuscular injection of VBI-2902a investigational enveloped virus-like particle COVID-19 vaccine with aluminum phosphate adjuvant.<br>Biological: Placebo<br>* 0.9% sodium chloride<br>|
| Experimental: Phase 1a, Group G2<br>20 participants age 18-54 will receive VBI-2902a at a dose of 5 μg of S protein at Days 1 and 28 | Biological: VBI-2902a<br>* VBI-2902a is an intramuscular injection of VBI-2902a investigational enveloped virus-like particle COVID-19 vaccine with aluminum phosphate adjuvant.<br>|
| Placebo Comparator: Phase 1a, Group G3<br>20 participants age 18-54 will receive placebo at Days 1 and 28 | Biological: Placebo<br>* 0.9% sodium chloride<br>|
| Experimental: Phase 1b, Group G4<br>27 participants age 18-54 will receive VBI-2905a at a dose of 5 μg of S protein at Day 1 | Biological: VBI-2905a<br>* VBI-2905a is an intramuscular injection of VBI-2905a investigational enveloped virus-like particle COVID-19 vaccine with aluminum phosphate adjuvant.<br>|
| Placebo Comparator: Phase 1b, Group G5<br>27 participants age 18-54 will receive placebo at Day 1 | Biological: Placebo<br>* 0.9% sodium chloride<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate and severity of local and systemic solicited adverse events after each study vaccination |  | Through 7 days after each study vaccination | 
| Rate and severity of unsolicited adverse events after each study vaccination |  | Through 28 days after each study vaccination | 
| Rate and severity of medically attended adverse events after each study vaccination |  | Through 28 days after each study vaccination | 
| Rate of serious adverse events after each study vaccination |  | Through 28 days after each study vaccination | 
| Adverse events leading to discontinuation of study vaccination |  | Through study completion, approximately 1 year | 
| Adverse events leading to study discontinuation |  | Through study completion, an approximately 1 year | 
| Rate and severity of laboratory abnormalities (hematology, biochemistry, urinalysis) |  | Through 28 days after each study vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate and severity of unsolicited adverse events |  | Through study completion, approximately 1 year | 
| Rate and severity of medically-attended adverse events |  | Through study completion, approximately 1 year | 
| Rate and severity of serious adverse events |  | Through study completion, approximately 1 year | 
| Rate and severity of laboratory abnormalities (hematology, biochemistry, urinalysis) |  | Through study completion, approximately 1 year | 
| Geometric Mean Titer (GMT) and the geometric mean fold increase in serum antibody titer post-vaccination over baseline |  | Study Days 56 and 224 (Phase 1a) and 56 and 168 (Phase 1b) | 
| GMT and the geometric mean fold increase in serum antibody titer post-vaccination over baseline |  | Study Days 7, 28, 35, 56, 112, 224 and 336 (Phase 1a); Days 7, 14, 28, 56, 84, 168 and 336 (Phase 1b) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
enveloped virus-like particle (eVLP), SARS-CoV-2 spike, neutralizing antibody, cell-mediated immune responses