Safety, Tolerability, and Immunogenicity of the Human Cytomegalovirus Vaccine (V160) in Healthy Adults (V160-001)

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and immunogenicity of various doses, formulations, and routes of administration of Human Cytomegalovirus (HCMV) vaccine V160 administered in a 3-dose regimen in healthy adults. The initial treatment arm of HCMV seropositive participants will receive V160 Low Dose without adjuvant by intramuscular injection. Escalation of the V160 dose, inclusion of adjuvant, administration by intradermal injection, and vaccination of HCMV seronegative participants will be performed only after review of safety data of previous treatment arms. The purpose of the study is to identify vaccine formulations associated with optimal safety profile and HCMV-specific immune response for evaluation in subsequent clinical studies of V160.

Official Title
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A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Immunogenicity of the Human Cytomegalovirus Vaccine (V160) in Healthy Adults

Conditions
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Cytomegalovirus Infections

Intervention / Treatment
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* Biological: V160 Low Dose IM
* Biological: V160 Medium Dose IM
* Biological: V160 High Dose IM
* Biological: V160 Medium Dose plus Merck Aluminum Phosphate Adjuvant (MAPA) 225 µg /dose IM
* Biological: V160 High Dose plus MAPA 225 µg /dose IM
* Biological: V160 Maximum Dose IM
* Other: Placebo IM
* Biological: V160 Medium Dose ID
* Other: Placebo ID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy based on medical history and physical examination Serologically confirmed to be HCMV seronegative or HCMV seropositive Agrees to avoid unusual, unaccustomed strenuous, vigorous physical exercise/activity from 72 hours before through 72 hours after each dose of study vaccine Body weight ≥110 lbs (50 kg) and body mass index (BMI) of 19 to 32 kg/m^2 If of reproductive potential, agrees to the following during the study and for 4 weeks after the last dose of study vaccine: 1) practice abstinence from heterosexual activity, or 2) use or have their partner use 2 allowable methods of birth control during heterosexual activity Exclusion Criteria: Has previously received any cytomegalovirus vaccine Has history of allergic reaction or anaphylactic reaction to any vaccine component that required medical intervention Has history of any severe allergic reaction that required medical intervention Is pregnant or breastfeeding or expecting to conceive from 2 weeks before the study through 1 month after the last dose of study vaccine Plans to donate eggs or sperm from study start through 1 month after the last dose of study drug Has impairment of immunologic function including, but not limited to autoimmune disease, splenectomy, or human immunodeficiency virus acquired immunodeficiency syndrome (HIV/AIDS) Received systemic corticosteroids for ≥14 consecutive days and has not completed treatment within 30 days of study start Received immunosuppressive therapy including, but not limited to rapamycin and equivalents, tacrolimus, FK-506, fujimycin, or other therapies used for solid organ/cell transplant, radiation therapy, immunosuppressive/cytotoxic chemotherapy, or other therapy known to interfere with the immune response within 1 year of study start Has a condition in which repeated venipuncture or injections pose more than minimal risk, such as hemophilia, thrombocytopenia or other severe coagulation disorders, or significantly impaired venous access Has a condition that requires active medical intervention or monitoring such as diabetes mellitus, autoimmune disease, or a clinically significant chronic medical condition that is considered progressive Has history within the past 5 years or current drug or alcohol abuse Has major psychiatric illness Is legally or mentally incapacitated Has participated in another clinical study in the past 4 weeks, or plans during the present study to participate in a treatment-based study or a study in which an invasive procedure is performed Has received valganciclovir, ganciclovir, valacyclovir, foscarnet, or cidofovir from 4 weeks prior to 1 month following each V160 vaccination

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCMV seropositive (+) V160 Low Dose Intramuscular (IM)<br>Participants seropositive for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Low Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV seronegative (-) V160 Low Dose IM<br>Participants seronegative for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Low Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV+ V160 Medium Dose IM<br>Participants seropositive for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Medium Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV- V160 Medium Dose IM<br>Participants seronegative for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Medium Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV+ V160 High Dose IM<br>Participants seropositive for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 High Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV- V160 Medium Dose plus MAPA 225 µg IM<br>Participants seronegative for HCMV at Baseline will receive vaccination with V160 plus MAPA adjuvant by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Medium Dose plus Merck Aluminum Phosphate Adjuvant (MAPA) 225 µg /dose IM<br>* V160 plus MAPA administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV- V160 High Dose IM<br>Participants seronegative for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 High Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV+ V160 High Dose plus MAPA 225 µg IM<br>Participants seropositive for HCMV at Baseline will receive vaccination with V160 plus MAPA adjuvant by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 High Dose plus MAPA 225 µg /dose IM<br>* V160 plus MAPA administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV+ V160 Maximum Dose IM<br>Participants seropositive for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Maximum Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV- V160 High Dose plus MAPA 225 µg IM<br>Participants seronegative for HCMV at Baseline will receive vaccination with V160 plus MAPA adjuvant by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 High Dose plus MAPA 225 µg /dose IM<br>* V160 plus MAPA administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV- V160 Maximum Dose IM<br>Participants seronegative for HCMV at Baseline will receive V160 vaccination by IM injection on Day 1, Month 1, and Month 6 | Biological: V160 Maximum Dose IM<br>* V160 administered as a 0.75 mL intramuscular injection<br>|
| Placebo Comparator: HCMV+ Placebo IM<br>Participants seropositive for HCMV at Baseline will receive placebo by IM injection on Day 1, Month 1, and Month 6 | Other: Placebo IM<br>* Placebo administered as a 0.75 mL intramuscular injection<br>|
| Placebo Comparator: HCMV- Placebo IM<br>Participants seronegative for HCMV at Baseline will receive placebo by IM injection on Day 1, Month 1, and Month 6 | Other: Placebo IM<br>* Placebo administered as a 0.75 mL intramuscular injection<br>|
| Experimental: HCMV+ V160 Medium Dose Intradermal (ID)<br>Participants seropositive for HCMV at Baseline will receive V160 vaccination by ID injection on Day 1, Month 1, and Month 6 | Biological: V160 Medium Dose ID<br>* V160 administered as a 0.1 mL intradermal injection<br>|
| Experimental: HCMV- V160 Medium Dose ID<br>Participants seronegative for HCMV at Baseline will receive V160 vaccination by ID injection on Day 1, Month 1, and Month 6 | Biological: V160 Medium Dose ID<br>* V160 administered as a 0.1 mL intradermal injection<br>|
| Placebo Comparator: HCMV+ Placebo ID<br>Participants seropositive for HCMV at Baseline will receive placebo by ID injection on Day 1, Month 1, and Month 6 | Other: Placebo ID<br>* Placebo administered as a 0.1 mL intradermal injection<br>|
| Placebo Comparator: HCMV- Placebo ID<br>Participants seronegative for HCMV at Baseline will receive placebo by ID injection on Day 1, Month 1, and Month 6 | Other: Placebo ID<br>* Placebo administered as a 0.1 mL intradermal injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Adverse Event (AE) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to 2 weeks after vaccination on Day 1, Month 1 and Month 6 (up to Day 15, Week 6 and Week 26) | 
| Percentage of Participants With an Injection-site AE | Injection-site AEs are defined as redness, swelling, and pain/tenderness. | Up to 2 weeks after vaccination on Day 1, Month 1 and Month 6 (up to Day 15, Week 6 and Week 26) | 
| Percentage of Participants With a Systemic AE | A Systemic AE includes, but is not exclusive of, the following AEs: fatigue, myalgia, headache and joint pain | Up to 2 weeks after vaccination on Day 1, Month 1 and Month 6 (up to Day 15, Week 6 and Week 26) | 
| Percentage of Participants With a Serious Adverse Event (SAE) | A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event | Up to 2 weeks after vaccination on Day 1, Month 1 and Month 6 (up to Day 15, Week 6 and Week 26) | 
| Percentage of Participants With a Serious Vaccine-Related Adverse Event | A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event. A serious vaccine-related adverse event was determined by the investigator to be related to the vaccine. | Up to 2 weeks after vaccination on Day 1, Month 1 and Month 6 (up to Day 15, Week 6 and Week 26) | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to Month 6 | 
| Percentage of Participants With Events of Clinical Interest (ECI) | An event of clinical interest (ECI) is identified as any overdose, elevated liver values meeting threshold criteria (aspartate aminotransferase or alanine aminotransferase ≥3x upper limit of normal (ULN); total bilirubin ≥2x ULN, and, at the same time, alkaline phosphatase <2xULN). Additionally, confirmed, diagnosed autoimmune conditions are considered ECIs. | Up to 18 months | 
| Geometric Mean Titer of HCMV-specific Neutralizing Antibody After Vaccination 3 | Serum samples for measuring neutralizing antibodies using the Merck Neutralizing Antibody (NAb) assay were collected at month 7. The LiCor-based near-infrared dye (NIRDye) In-Cell Western (ICW) HCMV microneutralization assay was used to detect and quantify anti-HCMV neutralizing antibodies. The primary hypothesis was that for HCMV-seronegative participants, at least 1 of the vaccination groups receiving V160 formulated with or without adjuvant would exhibit higher HCMV-specific neutralizing antibody titers than the placebo group. | Month 7 (1 month after vaccination 3 at Month 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Count of Peripheral Blood Mononuclear Cells Secreting Interferon-Gamma | In order to evaluate the cellular immune response to the vaccine(s), the HCMV enzyme-linked immunospot (ELISPOT) assay was used to detect interferon gamma (IFN-γ) secreting HCMV-specific cells from peripheral blood mononuclear cells (PBMCs). Results are expressed as the frequency of spot forming cells (SFCs) per million PBMCs (SFC/10^6 PBMCs). Results are presented for the following HCMV proteins: pp65, Immediate early Protein 1 (IE1), Immediate early Protein 2 (IE2), Glycoprotein B (gB), and also for purified HCMV virion stock. | Month 7 (1 month after vaccination 3 at Month 6) | 
| Geometric Mean Concentration of Interferon-Gamma After Stimulation of Whole Blood Sample With Pooled HCMV Antigen Peptides | In response to HCMV-specific stimulation of whole blood specimens the whole Blood Cytokine Stimulation (WBStim) assay was used to detect the secretion of interferon gamma (IFN -γ) by an ELISA assay. Results are presented for the following HCMV proteins: pp65, IE1, and gB. | Month 7 (1 month after vaccination 3 at Month 6) | 
| Geometric Mean Titer of HCMV-specific Neutralizing Antibody After Vaccinations 1 and 2 | Serum samples for measuring neutralizing antibodies using the Merck NAb assay were collected at months 1 and 2. The LiCor-based near-infrared dye (NIRDye) In-Cell Western (ICW) HCMV microneutralization assay was used to detect and quantify anti-HCMV neutralizing antibodies. Values below the lower limit of titer are represented by NA. | Month 1 and 2 (one month after vaccination 1 [Day 1] and vaccination 2 [Month 1]) |