A Phase II Trial to Compare a Liquid-frozen and a Freeze-dried Formulation of IMVAMUNE (MVA-BN®) Smallpox Vaccine in Vaccinia-naïve Healthy Subjects

• Sponsor: Bavarian Nordic (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01668537
• Collaborator: (none)
• Enrollment: 651
• Locations: 3
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 217
• Patients Per Site Per Month: 14.5

Study Details

Study Description

Brief Summary

A randomized, double-blind, multicenter Phase II trial to compare the immunogenicity and safety of a liquid-frozen and a freeze-dried formulation of IMVAMUNE (MVA-BN®) smallpox vaccine in vaccinia-naïve healthy subjects

Condition or Disease	Intervention/Treatment	Phase
Smallpox	Biological: LF formulation of IMVAMUNE®; Biological: FD formulation of IMVAMUNE®	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 651 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-blind, Multicenter Phase II Trial to Compare the Immunogenicity and Safety of a Liquid-frozen and a Freeze-dried Formulation of IMVAMUNE® (MVA-BN®) Smallpox Vaccine in Vaccinia-naïve Healthy Subjects
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 LF formulation of IMVAMUNE® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart	Biological: LF formulation of IMVAMUNE®
Experimental: Group 2 FD formulation of IMVAMUNE® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart	Biological: FD formulation of IMVAMUNE®

Outcome Measures

Primary Outcome Measures

1. ELISA GMT [Week 6]

   Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Titers below the detection limit are included with a value of '1'

Secondary Outcome Measures

1. Number of Participants With Serious Adverse Events [up to 32 weeks]

   Occurrence, relationship to the trial vaccine and intensity of any Serious Adverse Event (SAE).

2. Number of Participants With Adverse Events of Special Interest (AESI) [up to 32 weeks]

   Occurrence, relationship to the trial vaccine and intensity of any Adverse Event of Special Interest (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzyme troponin I elevated above 2 x the Upper Limit of Normal

3. Number of Participants With Related Grade >=3 Adverse Events [within 29 days after vaccination]

   Occurrence of any Grade >=3 Adverse Events related to the trial vaccine.

4. Number of Participants With Unsolicited Adverse Events [within 29 days after vaccination]

   Occurrence, relationship to the trial vaccine and intensity of unsolicited treatment-emergent AEs (TEAEs).

5. Number of Participants With Solicited Local Averse Events [8 days after any vaccination]

   Occurrence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).

6. Number of Participants With Solicited General Adverse Events [within 8 days after any vaccination]

   Occurrence, intensity and relationship to the trial vaccines of solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and chills) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).

7. ELISA GMTs [within 8 weeks]

   Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.

8. PRNT GMT [Week 6]

   Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Titers below the detection limit are included with a value of '1'

9. PRNT GMTs [within 8 weeks]

   Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.

10. Percentage of Participants With Seroconversion by ELISA [Week 6]

    Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.

11. Percentage of Participants With Seroconversion by ELISA [within 8 weeks]

    Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.

12. Percentage of Participants With Seroconversion by PRNT [Week 6]

    Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.

13. Percentage of Participants With Seroconversion by PRNT [within 8 weeks]

    Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.

14. ELISPOT Magnitudes of Response [within 8 weeks]

    Magnitudes of response of IFNγ producing T-cells measured by vaccinica-specific ELISPOT. Spot Forming Units below the detection limit are included as a value of '1'.

15. Percentage of Participants With Response by ELISPOT [within 8 weeks]

    Response rates regarding IFNγ producing T-cells measured by vaccinia-specific ELISPOT. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.

16. Percentage of Responders by ELISPOT [within 8 weeks]

    Responder rate measured by vaccinia specific ELISPOT. A participant was defined as a responder to the vaccine determined by ELISPOT if the participant had at least 1 post-baseline visit determined to be a response. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.

17. Correlation ELISA vs PRNT Titers [within 8 weeks]

    Pearson Correlation Coefficient between the ELISA titers and the PRNT titers at weeks 4, 6 and 8 based on the log10 transformed titer values

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria

1. Male and female subjects, 18-55 years of age

2. The subject has read, signed and dated informed consent form, having been advised of the risks and benefits of the trial in a language understood by the subject and prior to performance of any trial specific procedures and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form

3. Body Mass Index (BMI) ≥ 18.5 and < 35

4. Women of childbearing potential (WOCBP) must have used an acceptable method of contraception for 30 days prior to the first vaccination, must agree to use an acceptable method of contraception during the trial, and must avoid becoming pregnant for at least 28 days after the last vaccination. A woman is considered of childbearing potential unless post-menopausal or with a history of hysterectomy. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products)

5. WOCBP must have a negative serum pregnancy test at screening (SCR) and a negative urine pregnancy test within 24 hours prior to each vaccination

6. White blood cells ≥ 2500/mm3 and < ULN

7. Absolute neutrophil count (ANC) within normal limits

8. Hemoglobin within normal limits

9. Platelets within normal limits

10. Adequate renal function defined as a calculated Creatinine Clearance (CrCl) > 60 ml/min as estimated by the Cockcroft-Gault equation:

• For men: (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dl x 72) = CrCl (ml/min)

• For women: multiply the result by 0.85 = CrCl (ml/min)

1. Adequate hepatic function defined as:

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) in the absence of other evidence of significant liver disease

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase < 1.5 x ULN

1. Troponin I < 2 x ULN

2. Electrocardiogram (ECG) without clinically significant findings, e.g. any kind of atrioventricular or intraventricular conditions or blocks such as complete left or right bundle branch block, AV node block, QTc or PR prolongation, premature atrial contractions or other atrial arrhythmia, sustained ventricular arrhythmia, two premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia

Exclusion criteria

1. Typical vaccinia scar

2. Known or suspected history of smallpox vaccination

3. History of vaccination with any poxvirus-based vaccine

4. US Military service before 1991 or after January 2003

5. Pregnant or breast-feeding women

6. Uncontrolled serious infection, i.e. not responding to antimicrobial therapy

7. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject or would limit the subject's ability to complete the trial in the opinion of the investigator

8. History of or active autoimmune disease, persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded

9. Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, moderate to severe kidney impairment

10. History of malignancy, other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure. Subjects with history of skin cancer must not be vaccinated at the previous tumor site

11. History or clinical manifestation of clinically significant and severe hematological, pulmonary, central nervous, cardiovascular or gastrointestinal disorders

12. Clinically significant mental disorder not adequately controlled by medical treatment

13. History of coronary heart disease, myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor

14. History of an immediate family member (father, mother, brother, or sister) who has had onset of ischemic heart disease before the age of 50 years

15. Twenty percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's Risk Assessment Tool: http://hin.nhlbi.nih.gov/atpiii/calculator.asp NOTE: This criterion applies only to subjects 20 years of age and older

16. Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse (within the past 6 months)

17. Known allergy to IMVAMUNE® vaccine and its constituents, e.g. tris(hydroxymethyl)-amino methane, including known allergy to egg or aminoglycoside (gentamycin)

18. History of anaphylaxis or severe allergic reaction to any vaccine

19. Acute disease (illness with or without a fever) at the time of enrollment

20. Body Temperature ≥ 100.4°F (38.0°C) at the time of enrollment

21. Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior or after trial vaccination

22. Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior or after trial vaccination

23. Chronic systemic administration (defined as more than 14 days) of > 5 mg prednisone (or equivalent)/day or any other immune-modifying drugs during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5)

24. Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy

25. Administration or planned administration of immunoglobulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at last physical trial visit (Visit 5)

26. Use of any investigational or non-registered drug or vaccine other than the trial vaccine within 30 days preceding the first dose of the trial vaccine or planned administration of such a drug during the trial period (with the day of the FU call being considered the last day of the trial period).

27. Trial personnel

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Miami Research Associates	South Miami	Florida	United States	33143
2	PRA	Lenexa	Kansas	United States	66219
3	University of Kentucky	Lexington	Kentucky	United States	40536

Sponsors and Collaborators

• Bavarian Nordic

Investigators

• Principal Investigator: Richard N Greenberg, MD, University of Kentucky

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bavarian Nordic
• ClinicalTrials.gov Identifier: NCT01668537
• Other Study ID Numbers: POX-MVA-027
• First Posted: Aug 20, 2012
• Last Update Posted: Oct 12, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Vaccinia; Smallpox

Study Results

Participant Flow

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen (LF) formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, subcutaneous (s.c.), 4 weeks apart LF formulation of MVA-BN®	Freeze Dried (FD) formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Period Title: Overall Study
STARTED	327	324
COMPLETED	305	314
NOT COMPLETED	22	10

Baseline Characteristics

Arm/Group Title	LF Formulation	FD Formulation	Total
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®	Total of all reporting groups
Overall Participants	327	324	651
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.8 (6.36)	27.6 (6.21)	27.7 (6.28)
Sex: Female, Male (Count of Participants)
Female	178 54.4%	170 52.5%	348 53.5%
Male	149 45.6%	154 47.5%	303 46.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	95 29.1%	95 29.3%	190 29.2%
Not Hispanic or Latino	232 70.9%	229 70.7%	461 70.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.3%	1 0.2%
Asian	4 1.2%	1 0.3%	5 0.8%
Native Hawaiian or Other Pacific Islander	1 0.3%	1 0.3%	2 0.3%
Black or African American	78 23.9%	67 20.7%	145 22.3%
White	239 73.1%	247 76.2%	486 74.7%
More than one race	5 1.5%	5 1.5%	10 1.5%
Unknown or Not Reported	0 0%	2 0.6%	2 0.3%
Region of Enrollment (participants) [Number]
United States	327 100%	324 100%	651 100%

Outcome Measures

1. Primary Outcome

Title	ELISA GMT
Description	Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Titers below the detection limit are included with a value of '1'
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Geometric Mean (95% Confidence Interval) [Titer]	875.1	1099.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LF Formulation, FD Formulation
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin to show that the FD formulation is non-inferior to the LF formulation in terms of ELISA GMTs at the peak visit (Week 6) was predefined as '1.5' for the GMT ratio (LF/FD). Non-inferiority is demonstrated if the upper 95% CI of the GMT ratio (LF/FD) is entirely below 1.5
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (LF/FD)
	Estimated Value	0.796
	Confidence Interval	(2-Sided) 95%; 0.707 to 0.896
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Serious Adverse Events
Description	Occurrence, relationship to the trial vaccine and intensity of any Serious Adverse Event (SAE).
Time Frame	up to 32 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	327	324
SAE	5 1.5%	2 0.6%
SAE related to vaccine	0 0%	0 0%
SAE Grade >=3	3 0.9%	1 0.3%

3. Secondary Outcome

Title	Number of Participants With Adverse Events of Special Interest (AESI)
Description	Occurrence, relationship to the trial vaccine and intensity of any Adverse Event of Special Interest (AESI). AESIs were defined as any cardiac symptoms and ECG changes determined to be clinically significant or cardiac enzyme troponin I elevated above 2 x the Upper Limit of Normal
Time Frame	up to 32 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	327	324
AESI	1 0.3%	4 1.2%
Drug-related AESI	0 0%	0 0%
AESI Grade >=3	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants With Related Grade >=3 Adverse Events
Description	Occurrence of any Grade >=3 Adverse Events related to the trial vaccine.
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	327	324
Count of Participants [Participants]	0 0%	1 0.3%

5. Secondary Outcome

Title	Number of Participants With Unsolicited Adverse Events
Description	Occurrence, relationship to the trial vaccine and intensity of unsolicited treatment-emergent AEs (TEAEs).
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	327	324
TEAE	313 95.7%	310 95.7%
Drug-Related TEAE	207 63.3%	207 63.9%
TEAE Grade >=3	6 1.8%	5 1.5%
Drug-Related TEAE Grade >=3	0 0%	1 0.3%

6. Secondary Outcome

Title	Number of Participants With Solicited Local Averse Events
Description	Occurrence and intensity of solicited local AEs (redness, swelling, induration, pruritus and pain) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).
Time Frame	8 days after any vaccination

Outcome Measure Data

Analysis Population Description

Subjects of the Full Analysis Set with at least one completed diary card

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	322	321
Injection site pain : All	274 83.8%	290 89.5%
Injection site pain : Grade >=2	138 42.2%	167 51.5%
Injection site pain : Grade =3	22 6.7%	35 10.8%
Injection site erythema : All	247 75.5%	255 78.7%
Injection site erythema : Grade >=2	140 42.8%	181 55.9%
Injection site erythema : Grade =3	16 4.9%	47 14.5%
Injection site swelling : All	210 64.2%	223 68.8%
Injection site swelling : Grade >=2	94 28.7%	125 38.6%
Injection site swelling : Grade =3	10 3.1%	23 7.1%
Injection site induration : All	211 64.5%	213 65.7%
Injection site induration : Grade >=2	73 22.3%	96 29.6%
Injection site induration : Grade =3	5 1.5%	6 1.9%
Injection site pruritus : All	177 54.1%	189 58.3%
Injection site pruritus : Grade >=2	38 11.6%	47 14.5%
Injection site pruritus : Grade =3	7 2.1%	11 3.4%

7. Secondary Outcome

Title	Number of Participants With Solicited General Adverse Events
Description	Occurrence, intensity and relationship to the trial vaccines of solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and chills) during the 8-day period (day of vaccination and the following 7 days) after any vaccination. Events were graded by intensity (1 = mild, 2 = moderate, 3 = severe).
Time Frame	within 8 days after any vaccination

Outcome Measure Data

Analysis Population Description

Subjects of the Full Analysis Set with at least one completed diary card

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	322	321
Body Temperature increased : All	23 7%	33 10.2%
Body Temperature increased : Grade >=2	7 2.1%	8 2.5%
Body Temperature increased : Grade =3	3 0.9%	2 0.6%
Body Temperature increased : Related	22 6.7%	30 9.3%
Body Temperature increased : Related Grade =3	3 0.9%	2 0.6%
Headache : All	125 38.2%	112 34.6%
Headache : Grade >=2	37 11.3%	27 8.3%
Headache : Grade =3	8 2.4%	7 2.2%
Headache : Related	110 33.6%	94 29%
Headache : Related Grade =3	6 1.8%	6 1.9%
Myalgia : All	68 20.8%	59 18.2%
Myalgia : Grade >=2	24 7.3%	18 5.6%
Myalgia : Grade =3	1 0.3%	5 1.5%
Myalgia : Related	59 18%	47 14.5%
Myalgia : Related Grade =3	1 0.3%	3 0.9%
Chills : All	38 11.6%	35 10.8%
Chills : Grade >=2	14 4.3%	10 3.1%
Chills : Grade =3	2 0.6%	5 1.5%
Chills : Related	34 10.4%	33 10.2%
Chills : Related Grade =3	2 0.6%	4 1.2%
Nausea : All	57 17.4%	51 15.7%
Nausea : Grade >=2	19 5.8%	18 5.6%
Nausea : Grade =3	4 1.2%	2 0.6%
Nausea : Related	53 16.2%	44 13.6%
Nausea : Related Grade =3	4 1.2%	2 0.6%
Fatigue : All	113 34.6%	102 31.5%
Fatigue : Grade >=2	39 11.9%	39 12%
Fatigue : Grade =3	15 4.6%	9 2.8%
Fatigue : Related	106 32.4%	95 29.3%
Fatigue : Related Grade =3	14 4.3%	9 2.8%

8. Secondary Outcome

Title	ELISA GMTs
Description	Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Week 0	1.1	1.1
Week 2	56.0	90.4
Week 4	89.6	131.3
Week 6	875.1	1099.6
Week 8	546.4	689.0

9. Secondary Outcome

Title	PRNT GMT
Description	Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Titers below the detection limit are included with a value of '1'
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Geometric Mean (95% Confidence Interval) [Titer]	81.8	101.2

10. Secondary Outcome

Title	PRNT GMTs
Description	Geometric Mean Titers (GMT) at all immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). For the calculation of GMTs all measurements are included as they provide meaningful information even if below the detection limit (DL). Disregarding these measurements would highly bias the reported GMTs. We imputed values <DL as a value of '1' and the GMT and corresponding 95% confidence intervals were calculated.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Week 0	1.1	1.0
Week 2	7.1	10.4
Week 4	9.3	12.5
Week 6	81.8	101.2
Week 8	59.7	76.1

11. Secondary Outcome

Title	Percentage of Participants With Seroconversion by ELISA
Description	Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Number [percentage of subjects]	100.0	100.0

12. Secondary Outcome

Title	Percentage of Participants With Seroconversion by ELISA
Description	Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Week 2	83.5	91.5
Week 4	91.9	97.0
Week 6	100.0	100.0
Week 8	100.0	100.0

13. Secondary Outcome

Title	Percentage of Participants With Seroconversion by PRNT
Description	Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Number [percentage of subjects]	99.0	100.0

14. Secondary Outcome

Title	Percentage of Participants With Seroconversion by PRNT
Description	Seroconversion rates at all post-baseline immunogenicity sampling time points based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (2) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set. Number Analyzed refers to the number of participants with measurements at the respective sampling time point.

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Week 2	80.1	87.3
Week 4	84.8	91.5
Week 6	99.0	100.0
Week 8	100.0	99.7

15. Secondary Outcome

Title	ELISPOT Magnitudes of Response
Description	Magnitudes of response of IFNγ producing T-cells measured by vaccinica-specific ELISPOT. Spot Forming Units below the detection limit are included as a value of '1'.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

ELISPOT Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	101	94
Week 0	1.0	1.0
Week 2	393.0	581.5
Week 4	88.0	133.0
Week 6	235.0	315.0
Week 8	145.5	240.0

16. Secondary Outcome

Title	Percentage of Participants With Response by ELISPOT
Description	Response rates regarding IFNγ producing T-cells measured by vaccinia-specific ELISPOT. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

ELISPOT Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	101	94
Week 2	95.0	97.9
Week 4	66.0	80.2
Week 6	88.0	94.4
Week 8	84.0	92.3

17. Secondary Outcome

Title	Percentage of Responders by ELISPOT
Description	Responder rate measured by vaccinia specific ELISPOT. A participant was defined as a responder to the vaccine determined by ELISPOT if the participant had at least 1 post-baseline visit determined to be a response. A response to the vaccine was defined as either the appearance of a positive signal for participants without a positive signal at Baseline or an increase by a factor of at least 1.7 of the SFU/1 x 10E6 PBMC compared to the Baseline SFU/1 x 10E6 PBMC for participants with a positive signal at Baseline.
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

ELISPOT Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	101	94
Number [percentage of subjects]	100	100

18. Secondary Outcome

Title	Correlation ELISA vs PRNT Titers
Description	Pearson Correlation Coefficient between the ELISA titers and the PRNT titers at weeks 4, 6 and 8 based on the log10 transformed titer values
Time Frame	within 8 weeks

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis Set

Arm/Group Title	LF Formulation	FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®	Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
Measure Participants	297	306
Week 4	0.597	0.492
Week 6	0.646	0.553
Week 8	0.567	0.565

Adverse Events

Time Frame	32 weeks
Arm/Group Title	LF Formulation		FD Formulation
Arm/Group Description	Liquid Frozen formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart LF formulation of MVA-BN®		Freeze Dried formulation of MVA-BN® 2 doses of 1 x 10E8 TCID50, s.c., 4 weeks apart FD formulation of MVA-BN®
All Cause Mortality
	LF Formulation		FD Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/327 (0%)		0/324 (0%)
Serious Adverse Events
	LF Formulation		FD Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/327 (1.5%)		2/324 (0.6%)
Blood and lymphatic system disorders
Haemolytic Anaemia	1/327 (0.3%)	1	0/324 (0%)	0
Infections and infestations
Subcutaneous Abscess	0/327 (0%)	0	1/324 (0.3%)	1
Injury, poisoning and procedural complications
Limb Injury	1/327 (0.3%)	1	0/324 (0%)	0
Metabolism and nutrition disorders
Diabetic Ketoacidosis	1/327 (0.3%)	1	0/324 (0%)	0
Nervous system disorders
Presyncope	1/327 (0.3%)	1	0/324 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	1/327 (0.3%)	1	0/324 (0%)	0
Psychiatric disorders
Anxiety	0/327 (0%)	0	1/324 (0.3%)	1
Other (Not Including Serious) Adverse Events
	LF Formulation		FD Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	115/327 (35.2%)		114/324 (35.2%)
Gastrointestinal disorders
Vomiting	4/327 (1.2%)		4/324 (1.2%)
General disorders
Injection site induration	77/327 (23.5%)		74/324 (22.8%)
Injection site hemorrhage	2/327 (0.6%)		17/324 (5.2%)
Injection site pain	6/327 (1.8%)		7/324 (2.2%)
Injection site discoloration	5/327 (1.5%)		9/324 (2.8%)
Injection site hematoma	5/327 (1.5%)		5/324 (1.5%)
Fatigue	4/327 (1.2%)		0/324 (0%)
Infections and infestations
Upper respiratory tract infection	16/327 (4.9%)		19/324 (5.9%)
Viral upper respiratory tract infection	12/327 (3.7%)		8/324 (2.5%)
Nervous system disorders
Headache	8/327 (2.4%)		5/324 (1.5%)
Respiratory, thoracic and mediastinal disorders
Sinus congestion	6/327 (1.8%)		8/324 (2.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.