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

Conditions

Monkeypox

Keywords

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

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.

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.

Frey SE, Baden LR, El Sahly HM, Davey RT, Rebolledo PA, Diemert DJ, Little SJ, Creech CB, Oikonomopoulou Z, Sherman AC, Whitaker JA, Rouphael NG, Desrosiers A, Martin TCS, Rolsma SL, Hoet B, Watanabe A, Jaunarajs A, Moss B, Tomashek KM, Lerner A, Beigel JH, DMID 22-0020 Study Group.

2025-11-29

10.1016/j.vaccine.2025.127959

Interventions

BIOLOGICALJYNNEOS

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 50 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at Day 43	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

Measure	Time frame	Description
Individual Peak GMT Through Day 365	Day 1 through Day 365	Blood was collected at baseline and multiple timepoints post vaccination for evaluation in a vaccinia virus Western Reserve PRNT assay. For each participant, the highest assessment post vaccination was determined as their peak response. For each arm, the geometric mean of peak responses was determined.
Vaccinia Virus Specific PRNT GMT at Study Day 1, 15, 29, 43, 57, 90, 181, and 365	Day 1 through Day 365	Blood was collected at baseline and multiple timepoints post vaccination for evaluation in a vaccinia virus Western Reserve PRNT assay. Geometric means were determined for each timepoint.
Vaccinia Virus Specific PRNT Half-life (t ½)	Day 43 through Day 365	Half-life, defined as the time from expected peak response (Day 43) to 50% maximal response, was estimated using the first participant visit with titer results less than or equal to half the titer results at Day 43.
Number of Participants Reporting Solicited Systemic AEs Through 14 Days After Each Study Vaccination	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).
Number of Participants Reporting Solicited Local AEs Through 14 Days After Each Study Vaccination	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).
Number of Participants Reporting Unsolicited Related and Unrelated Adverse Events (AEs) Through 28 Days After Each Vaccination	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).
Number of Participants Reporting Related and Unrelated Medically Attended Adverse Events (MAAEs)	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.
Number of Participants Reporting Related and Unrelated Serious Adverse Events (SAEs)	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.
Number of Participants Who Withdrew or Discontinued Vaccination	Day 1 through Day 365	Participants could voluntarily withdraw their consent for study participation for any reason at any time. Primary reason for withdrawal was recorded and early termination visits were attempted. Participants who received the first vaccination could choose to discontinue receipt of study vaccine for any reason and could choose to remain in the study (i.e., not withdraw from study). In addition, a participant could be discontinued from receipt of the second vaccination. Discontinuation from vaccination did not mean automatic withdrawal from the study, and participants were monitored for safety and immunogenicity if the participant consented.

Countries

United States

Participant flow

Recruitment details

Participants were healthy, non-pregnant, non-breastfeeding adults 18 to 50 years old recruited from the communities at large surrounding 8 clinical sites throughout the U.S. The enrollment period occurred between 09SEP2022 and 12OCT2022.

Participants by arm

Arm	Count
2 x 10^7 ID MVA-BN 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.	75
1 x 10^7 ID MVA-BN 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.	78
1 x 10^8 SC MVA-BN 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.	76
Total	229

Baseline characteristics

Characteristic	1 x 10^8 SC MVA-BN	Total	1 x 10^7 ID MVA-BN	2 x 10^7 ID MVA-BN
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	76 Participants	229 Participants	78 Participants	75 Participants
Age, Continuous	32.7 years STANDARD_DEVIATION 9.1	32.2 years STANDARD_DEVIATION 8.9	31.6 years STANDARD_DEVIATION 8.9	32.2 years STANDARD_DEVIATION 8.9
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants	47 Participants	15 Participants	10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	54 Participants	182 Participants	63 Participants	65 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
HIV Status HIV Negative	73 Participants	221 Participants	75 Participants	73 Participants
HIV Status HIV Positive	3 Participants	8 Participants	3 Participants	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	7 Participants	27 Participants	9 Participants	11 Participants
Race (NIH/OMB) Black or African American	14 Participants	38 Participants	13 Participants	11 Participants
Race (NIH/OMB) More than one race	4 Participants	10 Participants	4 Participants	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	5 Participants	1 Participants	1 Participants
Race (NIH/OMB) White	47 Participants	148 Participants	51 Participants	50 Participants
Region of Enrollment United States	76 participants	229 participants	78 participants	75 participants
Sex: Female, Male Female	37 Participants	112 Participants	42 Participants	33 Participants
Sex: Female, Male Male	39 Participants	117 Participants	36 Participants	42 Participants
Sex/Gender, Customized Cisgender Man	36 Participants	112 Participants	36 Participants	40 Participants
Sex/Gender, Customized Cisgender Woman	37 Participants	107 Participants	41 Participants	29 Participants
Sex/Gender, Customized Decline to state	1 Participants	1 Participants	0 Participants	0 Participants
Sex/Gender, Customized Gender Non-binary	1 Participants	5 Participants	1 Participants	3 Participants
Sex/Gender, Customized Gender Non-conforming	1 Participants	1 Participants	0 Participants	0 Participants
Sex/Gender, Customized Genderqueer	0 Participants	1 Participants	0 Participants	1 Participants
Sex/Gender, Customized Other	0 Participants	0 Participants	0 Participants	0 Participants
Sex/Gender, Customized Transgender Man/Trans Man	0 Participants	1 Participants	0 Participants	1 Participants
Sex/Gender, Customized Transgender Woman/Trans Woman	0 Participants	1 Participants	0 Participants	1 Participants
Sexual Identity Asexual	1 Participants	4 Participants	1 Participants	2 Participants
Sexual Identity Bisexual	6 Participants	27 Participants	8 Participants	13 Participants
Sexual Identity Decline to state	1 Participants	1 Participants	0 Participants	0 Participants
Sexual Identity Heterosexual or straight	48 Participants	148 Participants	54 Participants	46 Participants
Sexual Identity Lesbian or gay	19 Participants	40 Participants	10 Participants	11 Participants
Sexual Identity Other	0 Participants	0 Participants	0 Participants	0 Participants
Sexual Identity Pansexual	0 Participants	3 Participants	2 Participants	1 Participants
Sexual Identity Queer	1 Participants	6 Participants	3 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 75	0 / 78	0 / 76
other Total, other adverse events	75 / 75	78 / 78	75 / 76
serious Total, serious adverse events	0 / 75	1 / 78	1 / 76

Outcome results

Primary

Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at 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.

Time frame: Day 43

Population: The modified intent-to-treat (mITT) population includes all participants who received at least one dose of vaccine and contributed both pre- and at least one post-vaccination venous blood sample for immunogenicity testing for which valid results were reported. Participants are analyzed according to the study product that they received.

Arm	Measure	Value (GEOMETRIC_MEAN)
2 x 10^7 ID MVA-BN	Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at Day 43	203.2 titer
1 x 10^7 ID MVA-BN	Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at Day 43	113.2 titer
1 x 10^8 SC MVA-BN	Vaccinia Virus Specific Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at Day 43	288.9 titer

Comparison: The selection of the noninferiority (NI) margin was based on the pivotal Phase 3 trial by Pittman et al., in 2019 comparing one dose of ACAM2000 and the now licensed 2-dose standard MVA-BN regimen, which provided an estimated relative (peak) immune response of approximately 2-times higher for MVA-BN. An NI margin of 0.5 corresponds to an immune response of the lower-dose MVA-BN at least as high as what would be expected for ACAM2000.p-value: 0.04595% CI: [0.5, 1]t-test, 2 sided

Comparison: The selection of the noninferiority (NI) margin was based on the pivotal Phase 3 trial by Pittman et al., in 2019 comparing one dose of ACAM2000 and the now licensed 2-dose standard MVA-BN regimen, which provided an estimated relative (peak) immune response of approximately 2-times higher for MVA-BN. An NI margin of 0.5 corresponds to an immune response of the lower-dose MVA-BN at least as high as what would be expected for ACAM2000.p-value: 0.16295% CI: [0.3, 0.6]t-test, 2 sided

Secondary

Individual Peak GMT Through Day 365

Blood was collected at baseline and multiple timepoints post vaccination for evaluation in a vaccinia virus Western Reserve PRNT assay. For each participant, the highest assessment post vaccination was determined as their peak response. For each arm, the geometric mean of peak responses was determined.

Time frame: Day 1 through Day 365

Population: The modified intent-to-treat (mITT) population includes all participants who received at least one dose of vaccine and contributed both pre- and at least one post-vaccination venous blood sample for immunogenicity testing for which valid results were reported. Participants are analyzed according to the study product that they received.

Arm	Measure	Value (GEOMETRIC_MEAN)
2 x 10^7 ID MVA-BN	Individual Peak GMT Through Day 365	215.8 Titer
1 x 10^7 ID MVA-BN	Individual Peak GMT Through Day 365	127.0 Titer
1 x 10^8 SC MVA-BN	Individual Peak GMT Through Day 365	312.0 Titer

Secondary

Number of Participants Reporting Related and Unrelated Medically Attended Adverse Events (MAAEs)

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.

Time frame: Day 1 through Day 181