Trial to Evaluate the Immunogenicity of Dose Reduction Strategies of the MVA-BN Monkeypox Vaccine

Study Overview
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Brief Summary
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This study is a Phase 2 randomized, open-label, non-placebo controlled, multi-site clinical trial that will evaluate two intradermal (ID) regimens for Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine compared to the standard subcutaneous (SC) regimen in healthy, vaccinia-naïve adults 18 to 50 years of age, inclusive. At least 210 participants will be enrolled and randomized to one of three study arms. The two dose sparing strategies include one-fifth (2 x 10^7) and one-tenth (1 x 10^7) of the standard dose of MVA-BN administered ID on Day 1 and 29 (Arm 1 and 2, respectively). The comparator arm (Arm 3) will be the 2-dose standard (1 x 10^8) MVA-BN SC regimen. The study will enroll a 1:1:1 randomization allocation. Participants will not be stratified by clinical trial site, demographic characteristics or human immunodeficiency virus (HIV) infection status; however, these data will be collected during screening and enrollment. Each participant may be screened either in a separate visit in the 7 days prior to Day 1 or on Day 1. The primary hypothesis involves a two-step hierarchical process. The study will first test non-inferiority of the 2 x 10^7 ID regimen relative to 1 x 10^8 SC (standard dose regimen). If the 2 x 10^7 ID regimen is non-inferior to the standard dose regimen, hypothesis testing will proceed to test non-inferiority of the 1 x 10^7 ID regimen relative to the standard dose regimen. The primary objectives are: 1) to determine if peak humoral immune responses following an ID regimen of 2 x 10^7 50% Tissue Culture Infectious Dose (TCID50) MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC; 2) to determine if peak humoral immune responses following an ID regimen of 1 x 10^7 TCID50 MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC.

Detailed Description
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This study is a Phase 2 randomized, open-label, non-placebo controlled, multi-site clinical trial that will evaluate two intradermal (ID) regimens for Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine compared to the standard subcutaneous (SC) regimen. This study will enroll healthy, non-pregnant, non-breastfeeding adults 18 to 50 years old inclusive. Participants with stable medical conditions and well-controlled human immunodeficiency virus (HIV) infection can participate. At least 210 participants will be enrolled and randomized to one of three study arms. The two dose sparing strategies include one-fifth (2 x 10^7) and one-tenth (1 x 10^7) of the standard dose of MVA-BN administered ID on Day 1 and 29 (Arm 1 and 2, respectively). The comparator arm (Arm 3) will be the 2-dose standard (1 x 10^8) MVA-BN SC regimen. The study will enroll a 1:1:1 randomization allocation. Participants will not be stratified by clinical trial site, demographic characteristics or HIV infection status; however, these data will be collected during screening and enrollment. Each participant may be screened either in a separate visit in the 7 days prior to Day 1 or on Day 1. The primary hypothesis involves a two-step hierarchical process. The study will first test non-inferiority of the 2 x 10^7 ID regimen relative to 1 x 10^8 SC (standard dose regimen). If the 2 x 10^7 ID regimen is non-inferior to the standard dose regimen, hypothesis testing will proceed to test non-inferiority of the 1 x 10^7 ID regimen relative to the standard dose regimen. The primary objectives are: 1) to determine if peak humoral immune responses following an ID regimen of 2 x 10^7 50% Tissue Culture Infectious Dose (TCID50) MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC; 2) to determine if peak humoral immune responses following an ID regimen of 1 x 10^7 TCID50 MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC. The secondary objectives are: 1) to determine if individual peak humoral immune responses following each ID regimen are non-inferior to the licensed regimen administered SC; 2) to evaluate humoral immune responses of each ID regimen (separately) compared to licensed SC regimen each study day; 3) to evaluate the kinetics of the humoral immune responses of each ID regimen (separately) compared to licensed SC regimen through Day 365; 4) To compare relative safety among study arms as assessed by systemic and local reactogenicity for 14 days after each vaccination, unsolicited adverse events for 28 days after each vaccination, and serious adverse events (SAE) and medically attended events (MAAE) from Day 1 through Day 57, and related SAE/MAAEs through Day 181.

Official Title
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A Phase 2 Randomized, Open-Label, Multisite Trial to Evaluate the Immunogenicity of Dose Reduction Strategies of the MVA-BN Vaccine

Conditions
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Monkeypox

Intervention / Treatment
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* Biological: JYNNEOS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals 18 - 50 years of age inclusive at the time of consent. Able to read the written informed consent, states willingness to comply with all study procedures, and is anticipated to be available for all study visits. Agreement to adhere to Lifestyle Considerations during the study. Females of reproductive potential who have sexual intercourse with males must agree to use highly effective contraception for at least 1 month prior to signing ICF and through Day 57. In good general health as evidenced by medical history, physical examination, and clinical judgement of the investigator to be in stable state of health. *Participants with pre-existing stable chronic medical conditions defined as conditions not requiring significant change in therapy or hospitalization for worsening disease in the 4 weeks prior to enrollment can be included at the discretion of the investigator. This includes stable, well-controlled HIV positive individuals. If HIV infected individual, they must be on suppressive Antiretroviral therapy (ART) for at least 6 months, report a cluster of differentiation 4 (CD4) count of greater than 350 cells/uL and no Acquired Immune Deficiency Syndrome (AIDS)-defining illness in the last year. Exclusion Criteria: Ever received a licensed or an investigational smallpox or monkeypox vaccine. *This includes Dryvax, Acam2000, LC 16 m8, Modified Vaccinia Ankara (MVA)-based vaccine candidate or licensed vaccines, and Jynneos, Imvamune or Imvanex). Any history of monkeypox, cowpox, or vaccinia infection. Close contact of anyone known to have monkeypox in the 3 weeks prior to signing Informed Consent Form (ICF). Immunocompromised as determined by the investigator. Recent or current use of any immunosuppressing medications in the 4 weeks prior to signing ICF. **Topical, ophthalmic, inhaled, intranasal and intraarticular corticosteroids are acceptable, but receipt of >/= 20 mg/day of prednisone or equivalent for >/= 14 consecutive days in the 4 weeks prior to signing ICF is exclusionary. Pregnant or breast feeding. Received or plans to receive a live vaccine in the 4 weeks prior to signing ICF and 4 weeks after each vaccination. Received or plans to receive any other vaccine in the 2 weeks prior to signing ICF through Day 43. Received experimental therapeutic agent or vaccine in the 3 months prior to signing ICF. Has known allergy or history of anaphylaxis or other serious adverse reaction to a vaccine or vaccine products. ***This includes individuals with history of severe allergic reaction to gentamicin, ciprofloxacin, chicken or egg protein. Has tattoos, scars, or other marks which would, in the opinion of the investigator, interfere with assessment of the vaccination site. Has any medical disease or condition that, in the opinion of the participating site Principal Investigator (PI) or appropriate sub-investigator, precludes study participation. This includes acute, subacute, intermittent, or chronic medical disease or condition that would place the participant at an unacceptable risk of injury, render the participant unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the participant's successful completion of this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>0.1 mL of 2 x 10^7 (50% Tissue Culture Infectious Dose (TCID50) JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)) administered intradermally on Days 1 and 29. N=70 | Biological: JYNNEOS<br>* JYNNEOS is FDA-approved and licensed as a smallpox and monkeypox vaccine in the United States. JYNNEOS is a live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus. Each 0.5 mL dose is formulated to contain 0.5 x 10^8 to 3.95 x 10^8 infectious units of MVA-BN live virus in 10 mM Tris (tromethamine), 140 mM sodium chloride at pH 7.7. Subcutaneous is administered in the deltoid region, intradermal is administered in the volar aspect (inner side) of the forearm.<br>|
| Experimental: Arm 2<br>0.05 mL of 1 x 10^7 (50% Tissue Culture Infectious Dose (TCID50) JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)) administered intradermally on Days 1 and 29. N=70 | Biological: JYNNEOS<br>* JYNNEOS is FDA-approved and licensed as a smallpox and monkeypox vaccine in the United States. JYNNEOS is a live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus. Each 0.5 mL dose is formulated to contain 0.5 x 10^8 to 3.95 x 10^8 infectious units of MVA-BN live virus in 10 mM Tris (tromethamine), 140 mM sodium chloride at pH 7.7. Subcutaneous is administered in the deltoid region, intradermal is administered in the volar aspect (inner side) of the forearm.<br>|
| Active Comparator: Arm 3<br>0.5 mL of 1 x 10^8 (50% Tissue Culture Infectious Dose (TCID50) JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)) administered subcutaneously on Days 1 and 29. N=70 | Biological: JYNNEOS<br>* JYNNEOS is FDA-approved and licensed as a smallpox and monkeypox vaccine in the United States. JYNNEOS is a live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus. Each 0.5 mL dose is formulated to contain 0.5 x 10^8 to 3.95 x 10^8 infectious units of MVA-BN live virus in 10 mM Tris (tromethamine), 140 mM sodium chloride at pH 7.7. Subcutaneous is administered in the deltoid region, intradermal is administered in the volar aspect (inner side) of the forearm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Vaccinia virus specific plaque reduction neutralizing antibody (PRNT) Geometric Mean Titers (GMT) | To determine if peak humoral immune responses following an ID regimen of 1 x 10^7 TCID50 MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC | Day 1 through Day 43 | 
| Change from baseline Vaccinia virus specific plaque reduction neutralizing antibody (PRNT) Geometric Mean Titers (GMT) | To determine if peak humoral immune responses following an ID regimen of 2 x 10^7 TCID50 MVA-BN are non-inferior to the licensed regimen of 1 x 10^8 MVA-BN administered SC | Day 1 through Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in peak Geometric Mean Titers (GMT) |  | Day 1 through Day 365 | 
| Change from baseline in Vaccinia virus specific plaque reduction neutralizing antibody (PRNT) Geometric Mean Titers (GMT) |  | Day 1, 15, 29, 43, 57, 90, 181 365 | 
| Frequency of withdrawals or discontinuation of vaccination | Frequency in each study arm | Day 1 through Day 181 | 
| Occurrence of Medically Attended Events (MAAE) | Frequency and relatedness in each study arm | Day 1 through Day 181 | 
| Occurrence of serious Adverse Events (SAE) | Frequency and relatedness in each study arm | Day 1 through Day 181 | 
| Occurrence of solicited Adverse Events (AE) | Frequency, severity, and relatedness of solicited systemic and local Adverse Events for 14 days after each vaccination | Day 1 through Day 43 | 
| Occurrence of unsolicited Adverse Events (AE) | Frequency, severity, and relatedness of unsolicited Adverse Events for 28 days after each vaccination; in each study arm | Day 1 through Day 57 | 
| Vaccinia virus specific plaque reduction neutralizing antibody (PRNT) half-life (t ½) |  | Day 1 through Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose Reduction, Immunogenicity, JYNNEOS, Monkeypox, MVA-BN, Open-Label, Randomized, Vaccine