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

• ClinicalTrials.gov Identifier: NCT05512949
• Recruitment Status: Active, not recruiting
• First Posted: August 23, 2022
• Results First Posted: January 9, 2024
• Last Update Posted: January 9, 2024
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Monkeypox	Biological: JYNNEOS	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 229 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 2 Randomized, Open-Label, Multisite Trial to Evaluate the Immunogenicity of Dose Reduction Strategies of the MVA-BN Vaccine
• Actual Study Start Date: September 9, 2022
• Actual Primary Completion Date: December 1, 2022
• Estimated Study Completion Date: March 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1; 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; 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.
Experimental: Arm 2; 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; 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.
Active Comparator: Arm 3; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at Day 43 [ Time Frame: Day 43 ]
   Venous blood was collected at Study Day 43 and the serum was analyzed via the PRNT assay to determine if GMT of the intradermal regimen of 2 x 10^7 TCID50 MVA-BN and 1 x 10^7 TCID50 MVA- BN were non-inferior to that of the licensed regimen of 1 x 10^8 TCID50 MVA-BN administered subcutaneously.

Secondary Outcome Measures :

1. Individual Peak GMT Through Day 365 [ Time Frame: Day 1 through Day 365 ]
2. Vaccinia Virus Specific PRNT GMT at Study Day 1, 15, 29, 43, 57, 90, 181, and 365 [ Time Frame: Day 1 through Day 365 ]
3. Vaccinia Virus Specific PRNT Half-life (t ½) [ Time Frame: Day 1 through Day 365 ]
4. Number of Participants Reporting Solicited Systemic AEs Through 14 Days After Each Study Vaccination [ Time Frame: Day 1 through Day 43 ]
   Systemic AEs solicited on a memory aid provided to participants included fever, chills, nausea, headache, fatigue, change in appetite, myalgia, and arthralgia. Participants are considered reporting the systemic AE if they reported mild or greater severity at any time through 14 days after each study vaccination (Day 1 through Day 15 for Dose 1 and Day 29-43 for Dose 2).
5. Number of Participants Reporting Solicited Local AEs Through 14 Days After Each Study Vaccination [ Time Frame: Day 1 through Day 43 ]
   Local AEs solicited on a memory aid provided to participants included pain at injection site, erythema/redness, induration/swelling (functional grade based on interference with daily activity and any measure value greater than 2.5 cm) and pruritis at injection site. Participants are considered reporting the local AE if they reported mild or greater severity at any time through 14 days after each study vaccination (Day 1 through Day 15 for Dose 1 and Day 29 through 43 for Dose 2).
6. Number of Participants Reporting Unsolicited Related and Unrelated Adverse Events (AEs) Through 28 Days After Each Vaccination [ Time Frame: Day 1 through Day 57 ]
   Frequency of all unsolicited non-serious AEs from day of each study vaccination through 28 days after each vaccination (Day 1 through Day 29 for Dose 1 and Day 29 through Day 57 for Dose 2).
7. Number of Participants Reporting Related and Unrelated Medically Attended Adverse Events (MAAEs) [ Time Frame: Day 1 through Day 181 ]
   An MAAE is an unsolicited AE that results in unscheduled medical attention such as a hospitalization for less than 24 hours, an emergency room visit, or an otherwise unscheduled healthcare visit for any reason. All MAAEs were collected from Study Day 1 through Study Day 57, and all MAAEs deemed related to the vaccine were collected through Study Day 181.
8. Number of Participants Reporting Related and Unrelated Serious Adverse Events (SAEs) [ Time Frame: Day 1 through Day 181 ]
   SAEs included any untoward medical occurrence that resulted in death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. All SAEs were collected from Study Day 1 through Study Day 57, and all SAEs deemed related to the vaccine were collected through Study Day 181.
9. Number of Participants Who Withdrew or Discontinued Vaccination [ Time Frame: Day 1 through Day 365 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Individuals 18 - 50 years of age inclusive at the time of consent.
2. 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.
3. Agreement to adhere to Lifestyle Considerations during the study.
4. 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.

5. 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.

6. 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:

1. 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).

2. Any history of monkeypox, cowpox, or vaccinia infection.
3. Close contact of anyone known to have monkeypox in the 3 weeks prior to signing Informed Consent Form (ICF).
4. Immunocompromised as determined by the investigator.

5. 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.

6. Pregnant or breast feeding.
7. Received or plans to receive a live vaccine in the 4 weeks prior to signing ICF and 4 weeks after each vaccination.
8. Received or plans to receive any other vaccine in the 2 weeks prior to signing ICF through Day 43.
9. Received experimental therapeutic agent or vaccine in the 3 months prior to signing ICF.

10. 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.

11. Has tattoos, scars, or other marks which would, in the opinion of the investigator, interfere with assessment of the vaccination site.

12. 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.

Contacts and Locations

Locations

United States, California

University of California, San Diego (UCSD) - Antiviral Research Center (AVRC)

San Diego, California, United States, 92103-8208

United States, District of Columbia

George Washington University Medical Faculty Associates

Washington, District of Columbia, United States, 20037

United States, Georgia

The Hope Clinic of Emory University

Decatur, Georgia, United States, 30030

United States, Maryland

NIH Clinical Research Center, Investigational Drug Management and Research Section

Bethesda, Maryland, United States, 20892-1504

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115-6110

United States, Missouri

Saint Louis University Center for Vaccine Development

Saint Louis, Missouri, United States, 63104-1015

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37212

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030-3411

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] August 31, 2023

Statistical Analysis Plan  [PDF] October 20, 2023

Informed Consent Form  [PDF] September 12, 2022

More Information

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT05512949
• Other Study ID Numbers: 22-0020A
• First Posted: August 23, 2022
• Results First Posted: January 9, 2024
• Last Update Posted: January 9, 2024
• Last Verified: October 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Dose Reduction; Immunogenicity; JYNNEOS; Monkeypox; MVA-BN; Open-Label; Randomized; Vaccine

Additional relevant MeSH terms:

Mpox (monkeypox); Poxviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Smallpox and monkeypox vaccine modified vaccinia ankara-bavarian nordic; Antiviral Agents; Anti-Infective Agents