A Study to Assess Safety, Tolerability, and Immunogenicity of V591 (COVID-19 Vaccine) in Healthy Participants (V591-001)

Study Overview
=================
Brief Summary
-----------------
The primary objective of this early Phase 1/2 study is to identify the V591 dose that achieves the target immune response in humans based on preclinical or early clinical data.

Detailed Description
-----------------
This study was terminated and modifications to the dosing regimens and clinical/laboratory procedures were implemented for trial discontinuation according to Protocol Amendment 04. Per protocol, certain panels were never enrolled and/or the second dose of study intervention was not administered.

Official Title
-----------------
A Phase 1/Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate the Safety, Tolerability and Immunogenicity of V591 (COVID-19 Vaccine) in Healthy Younger and Older Participants

Conditions
-----------------
Coronavirus Disease (COVID-19)

Intervention / Treatment
-----------------
* Biological: V591
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is in overall good health based on medical history, physical examination, electrocardiogram (ECG) and vital sign (VS) measurements performed prior to randomization. Is in overall good health based on laboratory safety tests obtained at the screening visit. Has a body mass index (BMI) <30 kg/m2 inclusive. On this basis a rounded BMI of 29.9 is acceptable to satisfy the inclusion criteria. BMI = weight (kg)/height (m)2. Has been practicing social distancing for at least two weeks prior to planned Day 1 vaccination and has no close contacts with known active severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in that time period. Sentinel trial participants ONLY (Panel A, Panel B, and the first 5 participants of Panel E): Seronegative for SARS-COV-2. Is male or female, from 18 years to 55 years of age (inclusive) (Parts 1 and 2A) or >55 years of age (Part 2B), at the time of providing documented informed consent. Male participants are eligible to participate if they agree to refrain from donating sperm during the intervention period and for at least 6 months after the last dose of study intervention, be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR agree to use contraception unless confirmed to be azoospermic . Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, is not a woman of childbearing potential (WOCBP) or Is a WOCBP and using an acceptable contraceptive method or be abstinent from heterosexual intercourse as their preferred and usual lifestyle. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Refrain from donating oocyte during the intervention period and for at least 6 months after the last dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study, including for future biomedical research. Is willing to comply with the study restrictions, including social distancing between screening and randomization. Is willing to abstain from donating whole blood or blood derivatives, tissue or organ all along the study. Agrees to provide study personnel with a primary telephone number as well as an alternate means of contact, if available (such as an alternate telephone number or email) for follow-up purposes. Can read, understand, and complete the Vaccination Report Card. Exclusion Criteria Is currently actively infected with SARS-CoV-2 (confirmed by polymerase chain reaction;[PCR]). Has prior medical history of confirmed SARS-CoV-2 infection or known exposure to an individual with confirmed coronavirus disease 2019 (COVID-19) disease or SARS CoV-2 infection within the past 2 weeks. With the exception of the sentinel participants (Panel A, Panel B, and the first 5 participants of Panel E), study participants will not be screened for enrollment by SARS-CoV-2 serology, allowing those who may have had a prior asymptomatic SARS-CoV-2 infection to be enrolled. Has a history of severe adverse reactions to vaccine administration, including anaphylaxis and related symptoms, such as urticaria, respiratory difficulty, angioedema and abdominal pain to vaccines, or history of known or suspected allergic reaction likely to be exacerbated by any component of the COVID-19 vaccine. Is currently (or highly suspected to be) immunocompromised, including anticipating the need for systemic immunosuppressive treatment within the next 6 months or 12 months for 2-dose Day 1, Day 169 panels or has been diagnosed or highly suspected as having a congenital or acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), inflammatory bowel disease, or other autoimmune condition that could impact the immune response or the safety of the study vaccine. Has clinically significant thrombocytopenia or other coagulation disorder contraindicating intramuscular vaccination or repeated venipuncture. Has history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might expose the participant to risk by participating in the study, confound the results of the study or interfere with the participant's participation for the full duration of the study. Has a history or presence of clinically significant pulmonary disorders (e.g. chronic obstructive pulmonary disease [COPD], etc.), or asthma. Has a history of confirmed SARS-CoV-1 or Middle Eastern respiratory syndrome (MERS) Has a history of or current clinically significant medical condition that puts or may put a participant at increased risk for severe SARS-CoV-2 disease, such as conditions associated with increased risk of severe illness from COVID-19, cancer, chronic kidney disease, COPD, immunocompromised state (weakened immune system) from solid organ transplant, obesity (BMI of 30 or higher), serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies, sickle cell disease, Type 2 diabetes mellitus, asthma, cerebrovascular disease, cystic fibrosis, hypertension or high blood pressure, an immunocompromised state (weakened immune system), neurologic conditions, such as dementia, liver disease, pregnancy, pulmonary fibrosis (having damaged or scarred lung tissues), smoking, thalassemia (a type of blood disorder), or Type 1 diabetes mellitus. Part 2B ONLY: Older adult participants having mild, well controlled hypertension as is widely characteristic of aging are allowed if their medication regimens have not substantively changed for the past 6 months, hypertension has not led to hospitalization or currently increased rate of clinic visits over the past year, and hypertension has not been confirmed as putting subjects at increased risk of severe illness from COVID-19 by the CDC (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html). Is mentally or legally incapacitated, has significant emotional problems at the time of pre-study (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. Has a history of any clinically significant major neurological disorders or seizures (including Guillain-Barré syndrome), with the exception of febrile seizures during childhood. Has a history of cancer (malignancy) Has a known or suspected history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic allergic reaction) to prescription or non-prescription drugs or food. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies or human immunodeficiency virus (HIV)-1 or 2 antibodies. Individuals with antibodies to hepatitis C may be enrolled if hepatitis C viral load is undetectable and there is no evidence of or history of liver disease. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pre-study (screening) visit. Has received immunosuppressive drugs (like e.g. systemic corticosteroids, excluding topical preparations and inhalers) within 3 months prior to the first vaccination or 6 months for chemotherapies. *Has received vaccination within 4 weeks prior to first vaccination or is planning to receive a licensed vaccine 4 weeks before or after each study vaccination (e.g. Inactivated influenza vaccine). *Has received measles-containing vaccine within 3 months prior to the first vaccination. Has received a blood transfusion or blood products, including immunoglobulin, starting from 3 months before the first study vaccination or is scheduled to receive a blood transfusion or blood product through study completion. Autologous blood transfusions are not considered an exclusion criterion. Is unable to meet the concomitant medication restrictions Is using antiviral medications or any investigational agents for prophylaxis of SARSCoV-2 within 4 weeks prior to the first vaccination. Has ever participated in an investigational study of a SARS-CoV-2 vaccine, or an antiviral or other biologic product intended for the treatment of COVID-19. Is currently participating in any study of a vaccine or investigational medicinal product (IMP) or has recently completed participation in another study of a vaccine or IMP and received a vaccine within 3 months prior to screening or an IMP within 4 weeks (or 5 half-lives of the IMP, whichever is longer) prior to the pre-study (screening) visit. The window will be derived from the date of the last study intervention (e.g., receiving a vaccine or IMP) in the previous study to the date of the pre-study (screening) visit for this study. In addition, a participant cannot participate in another investigational trial up to the post-trial visit of this study (approximately 12 months after the last study vaccination). Has glycated hemoglobin (A1C) ≥ 6.5% at screening. Has a history of alcohol, cocaine, or opioid abuse during the previous 3 years. Participants who currently smoke or used nicotine or nicotine-containing products (e.g. nicotine patch) within last 3 months. Former smokers that have less than a 10 pack-year history of smoking and have not smoked in the last 12 months are eligible to be enrolled. Has a tattoo, scar or other physical finding at the area of the vaccination site that would interfere with intramuscular injection or a local tolerability assessment. Presents any concern by the investigator regarding safe participation in the study or for any other reason the investigator considers the participant inappropriate for participation in the study. Lives in a nursing home or long-term care facility. Is currently working in occupations with high risk of exposure to SARS-CoV-2 (e.g., health care worker with direct patient contact, emergency response personnel), or, at the investigator's discretion to be at increased risk to acquire SARS-CoV-2 for any other reason. Individuals who are living and/or working with severely immunocompromised people, pregnant women, lactating women, children under 12 months old, or any other individual that, in the judgment of the investigator, might be at increased risk. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigatively involved with this study. if the participant meets these exclusion criteria, the Day 1 Visit may be rescheduled for a time when these criteria are not met.

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Panel A<br>Participants in this 18 to 55 year old sentinel cohort will receive 2 doses (Day 1 and Day 57) of 1x10^5 50% tissue culture infectious dose (TCID50) V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel B<br>Participants in this 18 to 55 year old sentinel cohort will receive 2 doses (Days 1 and 57) of 1x10^6 TCID50 V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panels C, G<br>Participants in this 18 to 55 year old cohort (Panel C) or >55 year old cohort (Panel G) will receive 1 dose of 1x10^5 TCID50 V591 or placebo. | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panels D, H<br>Participants in this 18 to 55 year old cohort (Panel D) or >55 year old cohort (Panel H) will receive 1 dose of 1x10^6 TCID50 V591 or placebo. | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel E<br>Participants in this 18 to 55 year old cohort will receive 1 dose of 1x10^7 V591 or placebo. | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel F<br>Participants in this 18 to 55 year old cohort will receive 2 doses (Days 1 and 169) of V591 or placebo. Day 1 will be 1x10^4 TCID50 V591 or placebo and Day 169 will be 1x10^5 TCID50 V591 or placebo. | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel I<br>Participants in this >55 year old cohort will receive 2 doses (Days 1 and 57) of 1x10^5 TCID50 V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel J<br>Participants in this >55 year old cohort will receive 2 doses (Days 1 and 57) of 1x10^6 TCID50 V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel K<br>Participants in this >55 year old cohort will receive 2 doses (Days 1 and 169) of 1x10^5 TCID50 V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|
| Experimental: Panel L<br>Participants in this >55 year old cohort will receive 2 doses (Days 1 and 169) of 1x10^6 TCID50 V591 or placebo | Biological: V591<br>* 1 or 2 ascending doses of V591 will be administered via intramuscular (IM) injection.<br>Other: Placebo<br>* Placebo (0.9% sodium chloride) administered via IM injection.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One Solicited Injection Site Adverse Event (AE) After Any Study Intervention | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Injection site AEs of pain/tenderness, swelling, and redness/erythema were assessed. | Up to 5 days after any study intervention | 
| Percentage of Participants With at Least One Solicited Systemic AE After Any Study Intervention | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Systemic AEs of fever, muscle pain, joint pain, headache, fatigue, rash, or nausea were assessed. | Up to 14 days after any study intervention | 
| Percentage of Participants With at Least One Unsolicited Adverse Event After Any Study Intervention | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All unsolicited AEs were assessed. | Up to 28 days after any study intervention | 
| Percentage of Participants With at Least 1 Serious Adverse Event | An SAE is defined as any untoward medical occurrence that at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. | Up to 56 days after vaccination 1 and up to 122 days after vaccination 2 (up to 178 days) | 
| Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 57 days | 
| Percentage of Participants With at Least 1 Medically Attended Adverse Event (MAAE) | A MAAE is defined as an adverse event in which medical attention is received during an unscheduled, non-routine outpatient visit, such as an emergency room visit, office visit, or an urgent care visit with any medical personnel for any reason. | Up to 56 days after vaccination 1 and up to 122 days after vaccination 2 (up to 178 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers for Serum Neutralizing Antibodies (nAb) as Measured by Pseudo-virus Neutralization Assay (PNA) | Serum samples were collected and the titers of serum neutralization antibodies were assessed using PNA. Geometric mean titers were calculated using a constrained longitudinal data analysis (cLDA) method where the response vector consisted of the log transformed pre-vaccination and post-vaccination antibody titers. The point estimates were calculated by exponentiating the estimates of the mean of the natural log values; and the within-group 95% confidence intervals (CIs) were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | Days 1, 15, 29, 57, 71, and 85 | 
| Geometric Mean Concentration of Total Anti-Spike Immunoglobulin G (IgG) Antibodies as Measured by Enzyme-Linked Immunosorbent Assay (ELISA) | Serum samples were collected and the concentrations of total anti-spike IgG antibodies were assessed using ELISA. Geometric mean concentrations were calculated using a cLDA method where the response vector consisted of the log transformed pre-vaccination and post-vaccination antibody titers. The point estimates were calculated by exponentiating the estimates of the mean of the natural log values; and the within-group 95% confidence intervals (CIs) were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | Days 1, 15, 29, 57, 71, and 85 | 
| Geometric Mean Fold Rise (GMFR) for Serum nAb as Measured by PNA | Serum samples were collected and the titers of serum neutralization antibodies were assessed using PNA. Geometric mean titers were calculated using a cLDA method where the response vector consisted of the log transformed pre-vaccination and post-vaccination antibody titers. GMFR is defined as the geometric mean of the ratio of concentration at specified timepoints after vaccination divided by concentration at baseline (Day 1). | Days 1, 15, 29, 57, 71, and 85 | 
| Geometric Mean Fold Rise (GMFR) of Total Anti-Spike IgG Antibodies as Measured by ELISA | Serum samples were collected and the total anti-spike IgG antibodies assessed using ELISA. Geometric mean concentrations were calculated using a cLDA method where the response vector consisted of the log transformed pre-vaccination and post-vaccination antibody titers. GMFR is defined as the geometric mean of the ratio of concentration at specified timepoints after vaccination divided by concentration at baseline (Day 1). | Days 1, 15, 29, 57, 71, and 85 |