Dose Ranging Trial to Assess Safety and Immunogenicity of V590 (COVID-19 Vaccine) in Healthy Adults (V590-001)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of V590 versus placebo and to assess the immunogenicity of V590 on Day 28. The primary hypothesis is that at least one well-tolerated dose of V590 increases the geometric mean titers (GMTs) of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike serum neutralizing antibody, as measured by plaque reduction neutralization test (PRNT), compared to placebo.

Detailed Description
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This study was terminated and study objectives, endpoints, and procedures were modified accordingly via Protocol Amendment 03. Analysis included the intervention doses (V590 5.00 x 10^5 plaque forming units [pfu], V590 2.4 x 10^6 pfu, V590 1.15 x 10^7 pfu, V590 5.55 x 10^7 pfu or placebo) as specified in the protocol.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate the Safety and Immunogenicity of V590 in Healthy Adults

Conditions
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Coronavirus Disease (COVID-19)

Intervention / Treatment
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* Biological: V590
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is in overall good health based on medical history, physical examination, and vital sign (VS) measurements performed prior to randomization, as assessed by the investigator. 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 (after rounding to the nearest whole number). Parts 1 and 2 (Panels A-H) only: Has negative testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on both antibody and reverse transcription polymerase chain reaction (RT-PCR), at screening and upon start of domiciling. Part 3 (Panel I) only: Has positive serology (antibody) testing for SARS-CoV-2, also with negative SARS CoV-2 RT-PCR testing at screening and upon start of domiciling, and without symptoms of respiratory infection for at minimum 3 weeks preceding screening. Has been practicing social distancing for at least two weeks prior to planned start of domiciling and has had no close contacts with known active SARS-CoV-2 infection in that time period. Is male or female, from 18 years to 54 years of age inclusive (Parts 1 and 3 [Panels A-D, I]) or ≥ 55 years of age (Part 2 [Panels E-H]) at the time of signing the informed consent. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 2 months after administration 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 (vasectomized or secondary to medical cause). A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP), or is a WOCBP and using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle. A WOCBP must have a negative highly sensitive pregnancy test before the first dose of study intervention. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. Exclusion Criteria: Has a known hypersensitivity to any component of V590 or placebo. Has any known or suspected active clinically significant autoimmune disease or immunosuppressive condition, acquired or congenital, as determined by medical history and/or physical examination. Has 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 of ongoing liver disease or, at the time of screening, has any one of the following: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × Upper Limit of Normal (ULN), alkaline phosphatase and direct bilirubin > ULN (total bilirubin may be up to 2 × ULN as long as direct bilirubin is equal to or below the ULN), or prothrombin time (PT) international normalized ratio (INR) > 1.25. Has a history of asthma or allergic asthma that required systemic corticosteroids in the previous year. Has a history of Guillain-Barré syndrome. Has a history of diabetes mellitus, requiring medication at the time of assessment, OR has a hemoglobin A1c ≥ 6.5. Has a history of any medical condition that would put the participant at risk for severe SARS-CoV-2 disease as judged by the investigator. Has any ongoing, symptomatic, acute or chronic illness requiring medical or surgical care or any condition that is immunosuppressive. Is mentally or legally incapacitated, has significant emotional problems at the time of 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 cancer (malignancy). Participant has an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m^2. Has a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to a vaccine or prescription or non-prescription drugs or food as judged by the investigator. Is positive for hepatitis B surface antigen, 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 negative 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. A WOCBP who has a positive urine or serum pregnancy test before vaccination. A WOCBP who is breastfeeding. Has any unstable chronic medical condition, including one that has resulted in change in therapy (medication or other) in the 30 days prior to randomization or hospitalization in the previous year or might be predicted to result in hospitalization in the year after enrollment. Has received or is expected to receive any SARS-CoV-2 vaccine or other coronavirus vaccine during the study (except V590), is using investigational agents for prophylaxis of SARS-CoV-2 or is taking any systemic antiviral medications. Has received any intra-articular steroid injections within the 3 months prior to study vaccination or is expected to require intra-articular steroid injection during the study. Is receiving immunosuppressive therapy or has received immunosuppressive therapy within 6 months of enrollment. Has received a blood transfusion or blood products, including immunoglobulin, in the 3 months before anticipated study vaccination. Is expected to be receiving or is currently receiving antipyretic or analgesic medication on a daily or every other day basis from randomization through Day 7 Has ever participated in an investigational study of a SARS-CoV-2 vaccine, a coronavirus vaccine, or an antiviral or other biologic product intended for the treatment of COVID-19. Has participated in another vaccine study within 3 months prior to screening or has participated in an investigational study within 4 weeks prior to the screening visit. Has ever received a vaccine based on vesicular stomatitis virus (VSV). Has a Fridericia's corrected time from Q wave to T wave (QTcF) interval >470 msec (male) or >480 msec (female), has a history of risk factors for Torsades de Pointes, or has uncorrected hypokalemia or hypomagnesemia. Is under the age of legal consent. Is smoking or vaping and/or has a history of chronic smoking or vaping within approximately six months prior to planned vaccination. Does not agree to follow the alcohol restrictions 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. Is a regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year. 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 an occupation with high risk of exposure to SARS-CoV-2 (e.g., health care worker with direct patient contact, emergency response personnel).

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V590 5.00x10^5 pfu (Panel A)<br>Participants in this 18 to 54-year-old SARS-CoV-2 seronegative cohort (Panel A) will receive a single dose of V590 5.00x10^5 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: V590 2.40x10^6 pfu (Panel B)<br>Participants in this 18 to 54-year-old SARS-CoV-2 seronegative cohort (Panel B) will receive a single dose of 2.40x10^6 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: V590 1.15x10^7 pfu (Panel C)<br>Participants in this 18 to 54-year-old SARS-CoV-2 seronegative cohort (Panel C) will receive a single dose of 1.15x10^7 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: V590 5.55x10^7 pfu (Panel D)<br>Participants in this 18 to 54-year-old SARS-CoV-2 seronegative cohort (Panel D) will receive a single dose of V590 5.55x10^7 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: Part 2: 5.00x10^5 pfu (Panel E)<br>Participants in this ≥ 55 years old SARS CoV-2 seronegative cohort (Panel E) will receive a single dose of V590 5.00x10^5 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: Part 2: 2.40x10^6 pfu (Panel F)<br>Participants in this ≥ 55 years old SARS-CoV-2 seronegative cohort (Panel F) will receive a single dose of 2.40x10^6 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: Part 2: 1.15x10^7 pfu (Panel G)<br>Participants in this ≥ 55 years old SARS-CoV-2 seronegative cohort (Panel G) will receive a single dose of V590 1.15x10^7 pfu or placebo on Day 1 | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: Part 2: 5.55x10^7 pfu (Panel H)<br>Participants in this ≥ 55 years old SARS-CoV-2 seronegative cohort (Panel H) will receive a single dose of V590 5.55x10^7 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|
| Experimental: Part 3: 5.55x10^7 pfu (Panel I)<br>Participants in this 18 to 54-year-old SARS-CoV-2 seropositive cohort (Panel I) will receive a single dose of V590 5.55x10^7 pfu or placebo on Day 1. | Biological: V590<br>* Single dose of V590 administered via intramuscular (IM) injection with dosage levels of 5.00x10^5 pfu/mL (Panels A, E), 2.40x10^6 pfu/mL (Panels B,F), 1.15x10^7 pfu/mL (Panels C, G), 5.55x10^7 pfu/mL (Panels D, H, I).<br>Other: Placebo<br>* Placebo administered via IM injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least 1 Solicited Injection Site Adverse Event | An adverse event (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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Solicited injection site AEs (injection site redness/erythema, pain, swelling) were assessed. | Up to 5 days post-vaccination | 
| Percentage of Participants With at Least 1 Solicited Systemic 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Solicited systemic AEs (joint stiffness/arthralgia, tiredness/fatigue, headache, joint swelling, muscle pain/myalgia, nausea, oral disorder, and rash) were assessed. | Up to 28 days post-vaccination | 
| Percentage of Participants With at Least 1 Unsolicited 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Participants with reported unsolicited AEs were assessed. | Up to  28 days post-vaccination | 
| Percentage of Participants With at Least 1 Medically Attended Adverse Event | A medically attended adverse event (MAAE) is an AE 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. Any MAAE was assessed. | Up to 28 days post-vaccination | 
| Percentage of Participants With at Least 1 Serious Adverse Event | A serious adverse event (SAE) is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other important medical event. Any SAE was assessed. Active monitoring of SAEs occurred through Day 28 but were collected per protocol till study completion/termination or  90 days post-vaccination. | Active monitoring through Day 28 post-vaccination (Up to a maximum of  90 days post-vaccination) | 
| Geometric Mean Titers for Serum Neutralizing Antibodies as Measured by Plaque Reduction Neutralization Test | Serum samples were collected and the presence of serum neutralization antibodies (SNAs) were assessed using plaque reduction neutralization test (PRNT). Geometric mean titers (GMTs) and 95% confidence intervals (CIs), GMT ratios and 90% CIs, and p-values are estimated from a longitudinal data analysis (LDA) model and are provided in accordance with the statistical analysis plan. | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers for SNAs as Measured by PRNT- 7 Days | Serum samples were collected and analyzed on a subset of participants but assays were not conducted on all samples that were collected. Due to the early termination of the study, testing was prioritized for the key samples and timepoints that would provide the required safety and immunogenicity data to support programmatic decision-making and subsequent clinical studies. Blank cells indicate that data were not generated and no data were available. The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | 7 days post-vaccination | 
| Geometric Mean Titers for SNAs as Measured by PRNT- 14 Days | Serum samples were collected for all participants and the presence of SNAs was assessed using PRNT. The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | 14 days post vaccination | 
| Geometric Mean Titers for Total Anti-Spike Immunoglobulin G Antibodies as Measured by Enzyme-Linked Immunosorbent Assay | Serum samples were collected and the total anti-spike immunoglobulin G (IgG) antibodies were assessed using enzyme-linked immunosorbent assay (ELISA). The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | 7, 14, and 28 days post vaccination | 
| Number of Participants With Vaccine Viremia as Measured by Reverse Transcription-Polymerase Chain Reaction | Positive viremia was defined as detectable reverse transcription polymerase chain reaction (RT-PCR) results greater than or equal to the lower limit of detection (≥ LLOD); results were deemed quantifiable if the result was greater than or equal to the lower limit of quantification (≥ LLOQ). The number of participants who have a positive V590 RT-PCR result greater than or equal to the lowest limit of detection (≥LLOD) were assessed. | 1, 2, 3, 4, 5, 6, 7, 14 and 28 days post-vaccination | 
| Number of Participants With Viral Shedding in Saliva as Measured by RT-PCR | The number of participants with viral shedding detected by RT-PCR in saliva specimens was assessed. Only Day 7 samples were assayed for all participants. Day 14 and 28 samples for a participant were assayed if the Day 7 result was positive (≥LLOD). Due to the early termination of the study, testing was prioritized for the key samples and timepoints that would provide the required safety and immunogenicity data to support programmatic decision-making and subsequent clinical studies. Blank cells indicate data were not generated and no data were available. Additional sample testing is not possible because the viral shedding assay is not qualified for samples that have been stored for this length of time. | 1, 2, 3, 4, 5, 6, 7, 14, and 28 days post-vaccination | 
| Number of Participants With Viral Shedding in Urine as Measured by RT-PCR | The number of participants with viral shedding detected by RT-PCR in urine specimens was assessed. Due to the early termination of the study, testing was prioritized for the key samples and timepoints that would provide the required safety and immunogenicity data to support programmatic decision-making and subsequent clinical studies. Only Day 7 samples were assayed for all participants. Day 14 and 28 samples for a participant were assayed if the Day 7 result was positive (≥LLOD). Blank cells indicate data were not generated and no data were available. | 1, 2, 3, 4, 5, 6, 7, 14, and 28 days post-vaccination | 
| Number of Participants With Viral Shedding in Stool (If Assayed) as Measured by RT-PCR | The study was terminated and V590 stool samples for viral shedding (considered optional per protocol) were not assayed. Due to the early termination of the study, testing was prioritized for the key samples and timepoints that would provide the required safety and immunogenicity data to support programmatic decision-making and subsequent clinical studies. Blank cells indicate that data were not generated and no data were available. | 2-4, 5-7 days post-vaccination |