A Non-inferiority Trial to Compare MVA-BN® Smallpox Vaccine to ACAM2000®

• Sponsor: Bavarian Nordic (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01913353
• Collaborator: US Army Medical Research Institute of Infectious Diseases (U.S. Fed)
• Enrollment: 440
• Location: 1
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site Per Month: 15.1

Study Details

Study Description

Brief Summary

To demonstrate the efficacy of MVA-BN® in terms of vaccinia-specific Plaque Reduction Neutralization Test (PRNT) antibody response and by showing that vaccination prior to administration of ACAM2000® results in an attenuated take.

Condition or Disease	Intervention/Treatment	Phase
18-42 Year Old Healthy Vaccinia-naïve Subjects	Biological: MVA BN®; Biological: ACAM2000®	Phase 3

Detailed Description

To demonstrate the efficacy of MVA-BN® by assessing non-inferiority of MVA-BN® compared to ACAM2000® in terms of vaccinia-specific Plaque Reduction Neutralization Test (PRNT) antibody response at the Peak Visits (Day 42 for Group 1 and Day 28 for Group 2) and by showing that vaccination with MVA-BN® prior to administration of ACAM2000® results in an attenuation of take.

Study Design

• Study Type: Interventional
• Actual Enrollment: 440 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Open-label Phase III Non-inferiority Trial to Compare Indicators of Efficacy for MVA-BN® Smallpox Vaccine to ACAM2000® in 18-42 Year Old Healthy Vaccinia-naïve Subjects
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 Two vaccinations; MVA BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA BN® vaccination (Day 56).	Biological: MVA BN®; 0.5 ml MVA BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection; Other Names: IMVAMUNE IMVANEX ; Biological: ACAM2000®; 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Active Comparator: Group 2 A single vaccination of ACAM2000® will be administered at Day 0.	Biological: ACAM2000®; 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.

Outcome Measures

Primary Outcome Measures

1. Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at the Peak Visits [Day 42 for Group 1 and Day 28 for Group 2]

   GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of 1.

2. Maximum Lesion Area (MLA) in mm2 After Scarification With ACAM2000® [Day 6-8, 13-15 after 3rd Vaccination for Group 1 and Day 6-8, 13-15 after 1st vaccination for Group 2]

   The MLA was defined as the maximum of two measurements: the lesion area measured on Day 6-8 (after scarification) or the lesion area measured on Day 13-15 (after scarification). This was measured using the SilhouetteConnect camera system, and confirmed by the Independent Take Review Committee (ITRC).

Secondary Outcome Measures

1. Investigator-measured Maximum Lesion Diameter (MLD) in mm After Scarification With ACAM2000 [Day 6-8 and Day 13-15 after ACAM2000 scarification]

   The MLD was defined as the largest major diameter measured across the lesion on Day 6-8 (after scarification) or Day 13-15 (after scarification)

2. Investigator-measured Lesion Diameter in mm at Day 6-8 After Scarification With ACAM2000 [Day 6-8 after ACAM2000 scarification]

   The lesion diameter at Day 6-8 was defined as the major lesion diameter measured on Day 6-8 (after scarification)

3. Investigator-measured Lesion Diameter in mm at Day 13-15 After Scarification With ACAM2000 [Day 13-15 after ACAM2000 scarification]

   The lesion diameter at Day 13-15 was defined as the major lesion diameter measured on Day 13-15 (after scarification)

4. Individual Take as Classified by a Blinded Independent Take Review Committee (ITRC) [Day 6-8 visit following ACAM2000 vaccination]

   Take was assessed as either full, partial, or absent take by the ITRC based on Day 6-8 evaluations following ACAM2000 vaccination using subject profiles that contained supportive data up to Day 14 following ACAM2000 vaccination (in accordance with the ITRC Charter).

5. Lesion Area in mm2 at Day 6-8 After Scarification With ACAM2000 [Day 6-8 after ACAM2000 scarification]

   Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC.

6. Lesion Area in mm2 at Day 13-15 After Scarification With ACAM2000 [Day 13-15 after ACAM2000 scarification]

   Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC.

7. Relationship to Vaccine of Any Serious Adverse Event (SAE) [Within 38 weeks for Group 1 and 30 weeks for Group 2]

   Presentation of SAEs by relationship to study vaccine

8. Intensity of Any Serious Adverse Event (SAE) [Within 38 weeks for Group 1 and 30 weeks for Group 2]

   Presentation of SAEs by intensity

9. Incidence of Any Cardiac Sign or Symptom Indicating a Case of Myo-/Pericarditis, i.e. Adverse Events of Special Interest (AESIs) [Within 38 weeks for Group 1 and 30 weeks for Group 2]

   In this clinical trial, an AESI was defined as any cardiac sign or symptom developed since the first vaccination, any ECG changes determined to be clinically significant, or any cardiac enzyme results of Troponin I ≥ 2 x ULN.

10. Related Grade >=3 Adverse Events [within 29 days after vaccination]

    Incidence of any Grade 3 or 4 adverse events (AEs) possibly, probably, or definitely related to the vaccine. Pooled solicited (general only) and unsolicited AEs.

11. Relationship to Vaccine of Any Non-serious AEs [within 29 days after vaccination]

    Presentation of non-serious AEs by relationship to study vaccine

12. Intensity of Any Non-serious AEs [within 29 days after vaccination]

    Presentation of non-serious AEs by intensity

13. Solicited General AEs [within 15 days after vaccination]

    Occurrence, intensity and relationship of solicited general AEs (body temperature [fever], headache, myalgia [muscle pain], chills, nausea, fatigue, malaise)

14. Incidence of Lymphadenopathy [within 29 days after vaccination]

    Incidence of events of Lymphadenopathy. Pooled solicited and unsolicited events.

15. Solicited Local AEs: Intensity [within 15 days after vaccination]

    Incidence of solicited local AEs (pain, redness [erythema], swelling, induration, itching [pruritus])

16. Major Lesion Size, Major Erythema, and Major Induration Diameter [Within 15 days after scarification with ACAM2000]

    Daily measurement of major lesion size, major erythema, and major induration diameter (mm) based on physical appearance of vaccination site as documented in the memory aid. If the shape of the lesion, erythema [excludes lymphangitis], and induration observed was not round but rather asymmetrical, then the largest [or major] cross-sectional measurement was recorded.

17. GMTs at the Peak Visits and Individual Peak Measured by Vaccinia-specific ELISA [within 8 weeks (for both groups)]

    Peak Visit was defined as Day 42 for Group 1 and Day 28 for Group 2. Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1.

18. GMTs at the Individual Peak Measured by Vaccinia-specific PRNT [within 8 weeks (for both groups)]

    Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1.

19. GMTs as Measured by Vaccinia-specific ELISA [within 12 weeks]

    GMT based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'.

20. GMTs as Measured by Vaccinia-specific PRNT [within 12 weeks]

    GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'.

21. PRNT Seroconversion Rates at Peak Visits [Group 1 at Week 6; Group 2 at Week 4]

    Seroconversion rate based on PRNT. Seroconversion is defined as the appearance of antibody titers "greater than or equal" 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.

22. ELISA Seroconversion Rates at Peak Visits [Group 1 at Week 6; Group 2 at Week 4]

    Seroconversion rate based on ELISA. Seroconversion is defined as the appearance of antibody titers "greater than or equal" 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 42 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy male and female subjects, 18-42 years of age

2. The subject has read, signed and dated the Informed Consent, 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 procedure

3. Acceptable medical history by screening evaluation and physical examination

4. BMI greater or eaqual than 18.5 and smaller than 35

5. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening and a negative urine or serum pregnancy test within 24 hours prior to each vaccination

6. WOCBP must have used an acceptable method of contraception for 28 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 surgically sterilized. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products)

7. Human Immunodeficiency Virus (HIV) antibody negative, hepatitis B surface antigen negative and negative antibody test to hepatitis C virus

8. White blood cells greater or eaqual than 2500/mm3 and smaller than 11,000/mm3

9. Hemoglobin within normal limits

10. Platelets greater or eaqual than lower normal limits

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

12. Adequate hepatic function in the absence of other evidence of significant liver disease defined as:

• Total bilirubin greater than 1.5 x Upper Limit Normal (ULN)

• Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) greater than 1.5 x ULN

• Alkaline Phosphatase (Alk Phos) greater than 1.5 x ULN

1. Troponin I smaller than 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, atrioventricular node block, QTc or PR prolongation, premature atrial contractions or other atrial arrhythmia, sustained ventricular arrhythmia, two premature ventricular contractions in a row, ST elevation consistent with ischemia

Exclusion Criteria:

1. Pregnant or breast-feeding women

2. Typical vaccinia scar

3. Known or suspected history of smallpox vaccination defined as visible vaccination scar or documentation of smallpox vaccination or as reported by the subject

4. History of vaccination with any poxvirus-based vaccine

5. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject

6. History of or active immunodeficiency or immunosuppression caused by acquired or congenital diseases or caused by ongoing treatments such as chronic (greater than 14 days) high-dose corticosteroids (smaller than 5 mg prednisone [or equivalent] per day applied systemically, i.e. parenterally or orally), chronic or planned treatment with steroid eye drops or ointment at time of enrollment or radiation, or immunosuppressive drugs; low-dose corticosteroid topical products and nasal sprays used sporadically, i.e. pro re nata (according to circumstances) are permissible

7. Having had radiation or X-ray treatment (not routine X-rays) within the last 3 months

8. Post organ and bone-marrow transplant subjects whether or not receiving chronic immunosuppressive therapy

9. Eye surgery within 4 weeks prior to trial vaccination

10. History of or active autoimmune disease. Persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded

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

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

13. History of keloid formation

14. History or clinical manifestation of severe hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders

15. 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

16. Chest pain (that is diagnosed as cardiac related) or trouble breathing on exertion

17. Ten 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

18. 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

19. Clinically significant psychological disorder not adequately controlled by medical treatment

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

21. History of anaphylaxis or any severe allergic reaction or serious adverse reaction to a vaccine

22. Eczema of any degree or history of eczema

23. People with active atopic dermatitis (AD) [characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings] or with a history of AD

24. People with chronic exfoliative skin disorders/conditions

25. People with active current Varicella zoster, Herpes zoster, impetigo, uncontrolled acne, Darier's disease or any acute skin disorders of large magnitude, e.g., laceration requiring sutures

26. People with a tattoo that covers the vaccination injection area (preventing assessment of the area and interfering with a vaccination site photograph)

27. Having received any vaccinations or planned vaccinations with a live vaccine within 28 days prior to or after trial vaccination

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

29. 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 trial conclusion

30. Use of any investigational or non-registered drug or vaccine other than the trial vaccines within 28 days preceding the first dose of the trial vaccine or planned administration of such a drug /vaccine during the trial period

31. Blood donation for the duration of the trial

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

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

34. Known household contacts with, or occupational exposure (other than minimal contact) to any of the following:

• Pregnant women

• Children <12 months of age

• People with eczema or a history of eczema

• People with active AD or history of AD

• People with chronic exfoliative skin disorders/conditions

• People with active Varicella zoster, Herpes zoster, impetigo, uncontrolled acne, Darier's disease or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn with areas greater than 2×2 cm

• People with active or recent immunodeficiency disease or use of immunosuppressive medications, for example: have or take medication for HIV, AIDS, leukemia, lymphoma, or chronic liver problem, have or take medication for Crohn's disease, lupus, arthritis, or other immune disease; have had radiation or X-ray treatment (not routine X-rays) within the last 3 months; have ever had a bone-marrow or organ transplant (or take medication for that ); or have another problem that requires steroids, prednisone or a cancer drug for treatment

• People having had eye surgery within the last 4 weeks

1. Known allergy to MVA-BN® vaccine or any of its constituents, e.g. tris(hydroxymethyl)-amino methane, including known allergy to egg or aminoglycoside (gentamycin)

2. Known allergies to ACAM2000® and its diluents including polymyxin B sulfate, neomycin sulfate, and phenol

3. Known allergies to vaccinia immunoglobulin (VIG) including thimerosal or previous allergic reaction to immunoglobulins

4. Known allergies to cidofovir, sulfa drugs, or probenecid

5. Trial personnel

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brian Allgood Army Community Hospital	Seoul		Korea, Republic of

Sponsors and Collaborators

• Bavarian Nordic
• US Army Medical Research Institute of Infectious Diseases

Investigators

• Principal Investigator: Phillip R Pittman, MD, MPH, US Army Medical Research Institute of Infectious Diseases

Study Documents (Full-Text)

• Statistical Analysis Plan: Edition 8 - Mar 21, 2016
• Study Protocol - Sep 29, 2016
• Statistical Analysis Plan: Edition 8, Amendment 1 - Oct 11, 2017

More Information

Publications

None provided.

• Responsible Party: Bavarian Nordic
• ClinicalTrials.gov Identifier: NCT01913353
• Other Study ID Numbers: POX-MVA-006
• First Posted: Aug 1, 2013
• Last Update Posted: Dec 5, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Vaccinia; Smallpox

Study Results

Participant Flow

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA BN® vaccination (Day 56). MVA BN®: 0.5 ml MVA BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Period Title: Overall Study
STARTED	221	219
COMPLETED	189	204
NOT COMPLETED	32	15

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Total
Arm/Group Description	Two vaccinations; MVA BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA BN® vaccination (Day 56). MVA BN®: 0.5 ml MVA BN® with a nominal titre of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	Total of all reporting groups
Overall Participants	220	213	433
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.5 (4.77)	23.4 (4.58)	23.5 (4.67)
Sex: Female, Male (Count of Participants)
Female	39 17.7%	29 13.6%	68 15.7%
Male	181 82.3%	184 86.4%	365 84.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	54 24.5%	40 18.8%	94 21.7%
Not Hispanic or Latino	166 75.5%	173 81.2%	339 78.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	8 3.6%	6 2.8%	14 3.2%
Asian	14 6.4%	12 5.6%	26 6%
Native Hawaiian or Other Pacific Islander	5 2.3%	3 1.4%	8 1.8%
Black or African American	48 21.8%	40 18.8%	88 20.3%
White	126 57.3%	136 63.8%	262 60.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	19 8.6%	16 7.5%	35 8.1%
Region of Enrollment (participants) [Number]
South Korea	220 100%	213 100%	433 100%

Outcome Measures

1. Primary Outcome

Title	Plaque Reduction Neutralization Test (PRNT) Geometric Mean Titer (GMT) at the Peak Visits
Description	GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of 1.
Time Frame	Day 42 for Group 1 and Day 28 for Group 2

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Geometric Mean (95% Confidence Interval) [Titer]	153.5	79.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin to show that Group 1 (after 2 doses of MVA-BN) is non-inferior to Group 2 (after 1 dose of ACAM2000) in terms of PRNT GMTs at the respective peak visit (Week 6 in Group 1 / Week 4 in Group 2) was predefined as '1/2 (i.e. 0.5)' for the GMT ratio (Group 1 / Group 2).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio (Group 1 / Group 2)
	Estimated Value	1.935
	Confidence Interval	(2-Sided) 95%; 1.562 to 2.397
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Lesion Area (MLA) in mm2 After Scarification With ACAM2000®
Description	The MLA was defined as the maximum of two measurements: the lesion area measured on Day 6-8 (after scarification) or the lesion area measured on Day 13-15 (after scarification). This was measured using the SilhouetteConnect camera system, and confirmed by the Independent Take Review Committee (ITRC).
Time Frame	Day 6-8, 13-15 after 3rd Vaccination for Group 1 and Day 6-8, 13-15 after 1st vaccination for Group 2

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm2]	0.0	76.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Superiority
	Comments	Predefined threshold of clinical relevance for the area attenuation ratio (AAR): 40%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area attenuation ratio (AAR)
	Estimated Value	97.9
	Confidence Interval	(2-Sided) 95%; 96.6 to 98.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The AAR, i.e. the reduction in MLA [1 - MLA ratio (Group 1/Group 2)] after scarification was to be significantly above 40%. The MLA ratio and the corresponding 95% CI were based on the Hodges-Lehmann estimate of the shift for log-transformed MLAs.

3. Secondary Outcome

Title	Investigator-measured Maximum Lesion Diameter (MLD) in mm After Scarification With ACAM2000
Description	The MLD was defined as the largest major diameter measured across the lesion on Day 6-8 (after scarification) or Day 13-15 (after scarification)
Time Frame	Day 6-8 and Day 13-15 after ACAM2000 scarification

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm]	0.0	11.0

4. Secondary Outcome

Title	Investigator-measured Lesion Diameter in mm at Day 6-8 After Scarification With ACAM2000
Description	The lesion diameter at Day 6-8 was defined as the major lesion diameter measured on Day 6-8 (after scarification)
Time Frame	Day 6-8 after ACAM2000 scarification

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm]	0.0	8.0

5. Secondary Outcome

Title	Investigator-measured Lesion Diameter in mm at Day 13-15 After Scarification With ACAM2000
Description	The lesion diameter at Day 13-15 was defined as the major lesion diameter measured on Day 13-15 (after scarification)
Time Frame	Day 13-15 after ACAM2000 scarification

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm]	0.0	10.0

6. Secondary Outcome

Title	Individual Take as Classified by a Blinded Independent Take Review Committee (ITRC)
Description	Take was assessed as either full, partial, or absent take by the ITRC based on Day 6-8 evaluations following ACAM2000 vaccination using subject profiles that contained supportive data up to Day 14 following ACAM2000 vaccination (in accordance with the ITRC Charter).
Time Frame	Day 6-8 visit following ACAM2000 vaccination

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Full Take	23.0	92.5
Partial Take	23.0	4.3
Absent Take	53.9	1.9
Missing	0	1.2

7. Secondary Outcome

Title	Lesion Area in mm2 at Day 6-8 After Scarification With ACAM2000
Description	Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC.
Time Frame	Day 6-8 after ACAM2000 scarification

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm2]	0.0	37.0

8. Secondary Outcome

Title	Lesion Area in mm2 at Day 13-15 After Scarification With ACAM2000
Description	Lesion area was measured by the Investigator using the SilhouetteConnect camera system and confirmed by the blinded ITRC.
Time Frame	Day 13-15 after ACAM2000 scarification

Outcome Measure Data

Analysis Population Description

Per-protocol Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	165	161
Median (95% Confidence Interval) [mm2]	0.0	75.0

9. Secondary Outcome

Title	Relationship to Vaccine of Any Serious Adverse Event (SAE)
Description	Presentation of SAEs by relationship to study vaccine
Time Frame	Within 38 weeks for Group 1 and 30 weeks for Group 2

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	220	213
Unrelated/None	4	2
Unlikely	1	1
Possible	0	0
Probable	0	0
Definite	0	0

10. Secondary Outcome

Title	Intensity of Any Serious Adverse Event (SAE)
Description	Presentation of SAEs by intensity
Time Frame	Within 38 weeks for Group 1 and 30 weeks for Group 2

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	220	213
Mild: routine daily activity not impaired	0 0%	0 0%
Moderate: routine daily activity impaired	0 0%	0 0%
Severe: prevents routine daily activities	1 0.5%	1 0.5%
Life threatening	4 1.8%	2 0.9%

11. Secondary Outcome

Title	Incidence of Any Cardiac Sign or Symptom Indicating a Case of Myo-/Pericarditis, i.e. Adverse Events of Special Interest (AESIs)
Description	In this clinical trial, an AESI was defined as any cardiac sign or symptom developed since the first vaccination, any ECG changes determined to be clinically significant, or any cardiac enzyme results of Troponin I ≥ 2 x ULN.
Time Frame	Within 38 weeks for Group 1 and 30 weeks for Group 2

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after second dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	220	208	196	213
Count of Participants [Participants]	2 0.9%	2 0.9%	3 0.7%	4 NaN

12. Secondary Outcome

Title	Related Grade >=3 Adverse Events
Description	Incidence of any Grade 3 or 4 adverse events (AEs) possibly, probably, or definitely related to the vaccine. Pooled solicited (general only) and unsolicited AEs.
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	220	208	196	213
Count of Participants [Participants]	3 1.4%	2 0.9%	3 0.7%	22 NaN

13. Secondary Outcome

Title	Relationship to Vaccine of Any Non-serious AEs
Description	Presentation of non-serious AEs by relationship to study vaccine
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	220	208	196	213
Unrelated/None	94	67	110	102
Unlikely	24	19	29	23
Possible	27	15	18	30
Probable	5	1	0	6
Definite	107	56	9	34

14. Secondary Outcome

Title	Intensity of Any Non-serious AEs
Description	Presentation of non-serious AEs by intensity
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	220	208	196	213
Mild	233	141	143	163
Moderate	20	16	18	25
Severe	4	1	5	7

15. Secondary Outcome

Title	Solicited General AEs
Description	Occurrence, intensity and relationship of solicited general AEs (body temperature [fever], headache, myalgia [muscle pain], chills, nausea, fatigue, malaise)
Time Frame	within 15 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	208	193	187	200
Pyrexia, Grade 1, Related	0 0%	0 0%	0 0%	1 NaN
Pyrexia, Grade 2, Related	2 0.9%	0 0%	1 0.2%	1 NaN
Pyrexia, Grade 3, Related	0 0%	1 0.5%	0 0%	1 NaN
Headache, Grade 1, Related	25 11.4%	11 5.2%	17 3.9%	38 NaN
Headache, Grade 2, Related	6 2.7%	3 1.4%	7 1.6%	21 NaN
Headache, Grade 3, Related	1 0.5%	2 0.9%	1 0.2%	9 NaN
Myalgia, Grade 1, Related	28 12.7%	13 6.1%	15 3.5%	44 NaN
Myalgia, Grade 2, Related	5 2.3%	5 2.3%	2 0.5%	21 NaN
Myalgia, Grade 3, Related	0 0%	1 0.5%	0 0%	7 NaN
Chills, Grade 1, Related	1 0.5%	0 0%	8 1.8%	19 NaN
Chills, Grade 2, Related	0 0%	2 0.9%	2 0.5%	12 NaN
Chills, Grade 3, Related	1 0.5%	0 0%	0 0%	2 NaN
Nausea, Grade 1, Related	7 3.2%	4 1.9%	6 1.4%	21 NaN
Nausea, Grade 2, Related	0 0%	2 0.9%	4 0.9%	12 NaN
Nausea, Grade 3, Related	1 0.5%	0 0%	1 0.2%	6 NaN
Fatigue, Grade 1, Related	29 13.2%	14 6.6%	21 4.8%	45 NaN
Fatigue, Grade 2, Related	7 3.2%	2 0.9%	7 1.6%	30 NaN
Fatigue, Grade 3, Related	1 0.5%	1 0.5%	1 0.2%	8 NaN
Malaise, Grade 1, Related	16 7.3%	6 2.8%	12 2.8%	30 NaN
Malaise, Grade 2, Related	5 2.3%	2 0.9%	8 1.8%	25 NaN
Malaise, Grade 3, Related	2 0.9%	1 0.5%	2 0.5%	10 NaN

16. Secondary Outcome

Title	Incidence of Lymphadenopathy
Description	Incidence of events of Lymphadenopathy. Pooled solicited and unsolicited events.
Time Frame	within 29 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	220	208	196	213
Count of Participants [Participants]	24 10.9%	15 7%	17 3.9%	109 NaN

17. Secondary Outcome

Title	Solicited Local AEs: Intensity
Description	Incidence of solicited local AEs (pain, redness [erythema], swelling, induration, itching [pruritus])
Time Frame	within 15 days after vaccination

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1, Period 1	Group 1, Period 2	Group 1, Period 3	Group 2
Arm/Group Description	after 1st dose of MVA-BN	after 2nd dose of MVA-BN	after ACAM2000	ACAM2000
Measure Participants	208	193	187	200
Injection Site Pain, Grade 1	72 32.7%	49 23%	21 4.8%	58 NaN
Injection Site Pain, Grade 2	21 9.5%	22 10.3%	6 1.4%	44 NaN
Injection Site Pain, Grade 3	4 1.8%	0 0%	1 0.2%	33 NaN
Injection Site Erythema, Grade 1	44 20%	40 18.8%	106 24.5%	105 NaN
Injection Site Erythema, Grade 2	9 4.1%	10 4.7%	9 2.1%	81 NaN
Injection Site Erythema, Grade 3	0 0%	0 0%	0 0%	5 NaN
Injection Site Swelling, Grade 1	14 6.4%	16 7.5%	46 10.6%	120 NaN
Injection Site Swelling, Grade 2	5 2.3%	6 2.8%	0 0%	17 NaN
Injection Site Swelling, Grade 3	0 0%	0 0%	0 0%	1 NaN
Injection Site Induration, Grade 1	23 10.5%	11 5.2%	44 10.2%	125 NaN
Injection Site Induration, Grade 2	1 0.5%	2 0.9%	1 0.2%	7 NaN
Injection Site Induration, Grade 3	0 0%	0 0%	0 0%	0 NaN
Injection Site Pruritus, Grade 1	24 10.9%	19 8.9%	99 22.9%	101 NaN
Injection Site Pruritus, Grade 2	3 1.4%	1 0.5%	11 2.5%	60 NaN
Injection Site Pruritus, Grade 3	2 0.9%	0 0%	1 0.2%	18 NaN

18. Secondary Outcome

Title	Major Lesion Size, Major Erythema, and Major Induration Diameter
Description	Daily measurement of major lesion size, major erythema, and major induration diameter (mm) based on physical appearance of vaccination site as documented in the memory aid. If the shape of the lesion, erythema [excludes lymphangitis], and induration observed was not round but rather asymmetrical, then the largest [or major] cross-sectional measurement was recorded.
Time Frame	Within 15 days after scarification with ACAM2000

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	220	213
Maximum Lesion Diameter	5.0	11.5
Maximum Erythema	6.0	26.0
Maximum Induration	5.0	15.0

19. Secondary Outcome

Title	GMTs at the Peak Visits and Individual Peak Measured by Vaccinia-specific ELISA
Description	Peak Visit was defined as Day 42 for Group 1 and Day 28 for Group 2. Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1.
Time Frame	within 8 weeks (for both groups)

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Peak Visit	1076.9	194.6
Individual Peak	1105.2	214.0

20. Secondary Outcome

Title	GMTs at the Individual Peak Measured by Vaccinia-specific PRNT
Description	Individual Peak was the maximum titer per subject from Visit 1 to Visit 7 (Week 8) in Group 1 and maximum titer from Visit 1 to Visit 6 (Week 8) in Group 2. Titers below the detection limit are included with a value of 1.
Time Frame	within 8 weeks (for both groups)

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Geometric Mean (95% Confidence Interval) [Titer]	201.5	117.8

21. Secondary Outcome

Title	GMTs as Measured by Vaccinia-specific ELISA
Description	GMT based on vaccinia-specific ELISA. Titers below the detection limit are included with a value of '1'.
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Week 0	1.2	1.2
Week 1	1.6	1.2
Week 2	104.9	21.9
Week 4	129.8	194.6
Week 6	1076.9	149.2
Week 8	671.9	113.7
Week 12	550.5	NA

22. Secondary Outcome

Title	GMTs as Measured by Vaccinia-specific PRNT
Description	GMT based on vaccinia-specific PRNT. Titers below the detection limit are included with a value of '1'.
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Week 0	1.0	1.0
Week 1	1.1	1.0
Week 2	16.2	16.2
Week 4	16.9	79.3
Week 6	153.5	64.7
Week 8	118.2	67.1
Week 12	96.5	NA

23. Secondary Outcome

Title	PRNT Seroconversion Rates at Peak Visits
Description	Seroconversion rate based on PRNT. Seroconversion is defined as the appearance of antibody titers "greater than or equal" 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	Group 1 at Week 6; Group 2 at Week 4

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Number (95% Confidence Interval) [percentage of subjects]	100.0	97.3

24. Secondary Outcome

Title	ELISA Seroconversion Rates at Peak Visits
Description	Seroconversion rate based on ELISA. Seroconversion is defined as the appearance of antibody titers "greater than or equal" 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	Group 1 at Week 6; Group 2 at Week 4

Outcome Measure Data

Analysis Population Description

Per-protocol Set for Immunogenicity

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Two vaccinations; MVA-BN ®; administered 4 weeks apart (Day 0 and Day 28) followed by a single vaccination of ACAM2000® vaccine 4 weeks after the second MVA-BN® vaccination (Day 56). MVA-BN®: 0.5 ml MVA-BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.	A single vaccination of ACAM2000® will be administered at Day 0. ACAM2000®: 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Measure Participants	185	186
Number (95% Confidence Interval) [percentage of subjects]	100	96.8

Adverse Events

Time Frame	38 weeks for Group 1 and 30 weeks for Group 2
Arm/Group Title	Group 1, Period 1		Group 1, Period 2		Group 1, Period 3		Group 2
Arm/Group Description	after 1st dose of MVA-BN		after 2nd dose of MVA-BN		after ACAM2000		ACAM2000
All Cause Mortality
	Group 1, Period 1		Group 1, Period 2		Group 1, Period 3		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/220 (0%)		0/208 (0%)		0/196 (0%)		0/213 (0%)
Serious Adverse Events
	Group 1, Period 1		Group 1, Period 2		Group 1, Period 3		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/220 (0.9%)		0/208 (0%)		3/196 (1.5%)		3/213 (1.4%)
Gastrointestinal disorders
Haemorrhoids	0/220 (0%)	0	0/208 (0%)	0	0/196 (0%)	0	1/213 (0.5%)	1
Infections and infestations
Appendicitis	1/220 (0.5%)	1	0/208 (0%)	0	0/196 (0%)	0	0/213 (0%)	0
Peritonsillar Abscess	0/220 (0%)	0	0/208 (0%)	0	1/196 (0.5%)	1	0/213 (0%)	0
Injury, poisoning and procedural complications
Alcohol Poisoning	0/220 (0%)	0	0/208 (0%)	0	1/196 (0.5%)	1	0/213 (0%)	0
Road Traffic Accident	0/220 (0%)	0	0/208 (0%)	0	0/196 (0%)	0	1/213 (0.5%)	1
Tibia Fracture	1/220 (0.5%)	1	0/208 (0%)	0	0/196 (0%)	0	0/213 (0%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/220 (0%)	0	0/208 (0%)	0	0/196 (0%)	0	1/213 (0.5%)	1
Psychiatric disorders
Suicidal Ideation	0/220 (0%)	0	0/208 (0%)	0	1/196 (0.5%)	1	0/213 (0%)	0
Other (Not Including Serious) Adverse Events
	Group 1, Period 1		Group 1, Period 2		Group 1, Period 3		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/220 (43.2%)		63/208 (30.3%)		79/196 (40.3%)		88/213 (41.3%)
Blood and lymphatic system disorders
Lymphadenopathy	10/220 (4.5%)	11	6/208 (2.9%)	6	3/196 (1.5%)	3	23/213 (10.8%)	27
General disorders
Axillary Pain	0/220 (0%)	0	0/208 (0%)	0	0/196 (0%)	0	5/213 (2.3%)	5
Injection Site Erythema	30/220 (13.6%)	30	23/208 (11.1%)	23	1/196 (0.5%)	1	0/213 (0%)	0
Injection Site Nodule	32/220 (14.5%)	38	13/208 (6.3%)	13	1/196 (0.5%)	1	0/213 (0%)	0
Vaccination Site Erythema	10/220 (4.5%)	10	7/208 (3.4%)	7	2/196 (1%)	2	0/213 (0%)	0
Vaccination Site Nodule	11/220 (5%)	11	3/208 (1.4%)	3	0/196 (0%)	0	2/213 (0.9%)	2
Vaccination Site Warmth	13/220 (5.9%)	13	10/208 (4.8%)	10	1/196 (0.5%)	1	0/213 (0%)	0
Infections and infestations
Nasopharyngitis	7/220 (3.2%)	7	4/208 (1.9%)	4	6/196 (3.1%)	6	5/213 (2.3%)	5
Upper Respiratory Tract Infection	14/220 (6.4%)	14	14/208 (6.7%)	14	14/196 (7.1%)	14	14/213 (6.6%)	14
Injury, poisoning and procedural complications
Laceration	5/220 (2.3%)	5	1/208 (0.5%)	1	4/196 (2%)	4	1/213 (0.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	4/220 (1.8%)	5	4/208 (1.9%)	4	2/196 (1%)	2	6/213 (2.8%)	6
Back Pain	7/220 (3.2%)	7	0/208 (0%)	0	4/196 (2%)	4	1/213 (0.5%)	1
Nervous system disorders
Headache	4/220 (1.8%)	4	2/208 (1%)	2	6/196 (3.1%)	6	5/213 (2.3%)	5
Respiratory, thoracic and mediastinal disorders
Cough	0/220 (0%)	0	0/208 (0%)	0	4/196 (2%)	4	1/213 (0.5%)	1
Skin and subcutaneous tissue disorders
Dermatitis Contact	0/220 (0%)	0	0/208 (0%)	0	44/196 (22.4%)	44	49/213 (23%)	49

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.