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
Phase: PHASE3
Conditions: 18-42 Year Old Healthy Vaccinia-naïve Subjects
Sponsor: Bavarian Nordic

Clinical Trial Protocol
 
 
  
  
 
 
Bavarian Nordic 
Page 1 of 1 
 
FY12-19, HP-12-19, POX-MVA-006 
 
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 
 
Clinical Trial Protocol Edition 8  
29 September 2016 
NCT 01913353 
 
 

Clinical Trial Protocol 
Doc. No. 92000007 
FY12-19, HP-12-19, POX-MVA-006 
Edition 8 
 
Bavarian Nordic 
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FY12-19, HP-12-19, POX-MVA-006 
 
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 
 
Clinical Trial Protocol Edition 8  
29 September 2016 
 
 
 

Clinical Trial Protocol 
FYI2-19, HP-12-19, POX-MVA-006 
1 
General Information 
Doc. No. 92000007 
Edition 8 
1.1 
Principal Investigator Signature Page 
Herewith I agree that I have read and fully understand this protocol: 
29-Sep-20 16 
A randomized, open-label Phase Ill non-inferiority trial to compare indicators of efficacy for 
MVA BN® smallpox vaccine to ACAM2000® in 18-42 year old healthy vaccinia-naiVe subjects 
This protocol describes all the information necessary to conduct the trial. I agree that I will 
conduct the trial according to the instructions given within this protocol. FUithermore, T agree that 
I will conduct this trial according to rnternational Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP), the 2013 version ofthe Declaration ofHelsinki, the Belmont Report, as well as applicable 
local legal and regulatory requirements in the respective countries. I agree that all information 
revealed in this protocol is handled strictly confidentially. 
Additionally, I will permit trial related monitoring, audits, Institutional Review Board (IRB)/ 
Independent Ethics Committee (JEC) review and regulatory inspections, providing direct access 
to source data/documents. 
Principal 
Investigator 
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Clinical Trial Protocol 
FY12-19, HP-12-19, POX-MVA-006 
1.2 Sponsor Signature Page 
By signing the protocol: 
Doc. No. 92000007 
Edition 8 
29-Sep-2016 
A randomized, open-label Phase III non-inferiority trial to compare indicators of efficacy for 
MY A BN® smallpox vaccine to ACAM2000® in 18-42 year old healthy vaccinia-nai·ve subjects 
The undersigned parties agree that the protocol was written according to international ethical and 
scientific quality standards (ICH GCP), in compliance with the 2013 version of the Declaration of 
Helsinki, the Belmont Report, and applicable local legal and regulatory requirements in the 
respective countries. 
Coordinating 
Author 
Medical 
Monitor 
Manager QC 
Development 
Biostatistician 
GCP/GYP 
Compliance 
Management 
Sr. VP Clinical 
Development 
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(b) (1) (A)

C!inial Trial Plolocol 
FY12·19. HP-12·19, POX-MVA-006 
1.2 Sponsor Sign• ture l'ngo 
By signiJlg lhe prQU)col: 
Doc. No. 92000001 
Editioi'IS 
29-Scp-2016 
A randomized, opcn~labc:l Phase Ill non-inferiority trial to compare indicators ofeftkacy ror 
MVA BNCI smaJlpox vaccine ro ACAM2000'1 in 1842 year old haJlhy vaccinia-naive subjects 
The: undersigned parties aarcc lhA( lhe pt'O(OCOI was written .c:oonhn& 10 interrutional ethical and 
scicnlifle quality $lll1danls (ICII GCP), in compliance" ilb lbe 2013 vcnioo of the Dedlr.llion of 
l~rlsinki, the Belmont Report. and applicable k>caiJegal and rcgulalOry requin:ments in the 
respective countries.. 
Coordinating 
Aulllor 
Medical 
Monhor 
ManagerQC 
Development 
Aios:tati.stician 
GCP{()VP 
Compliance 
Management 
Sr. VP Clinical 
Development 
Bavarian Nord'ic 
RC'Seriaed Business Plop • t 1 
Page 3 or201 
(b) (1) (A)

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1.3 Responsibilities 
Trial Number 
 
FY12-19, HP-12-19, POX-MVA-006 
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. 
Principal Investigator 
 
  
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
Sub-Investigator 
 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
Sub-Investigator 
 
 
 
 
 
 
 
Phone 
 
 
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E-mail 
 
  
Clinical Trial Coordinator 
 
 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
Clinical Trial Coordinator 
 
 
 
 
  
 
 
Phone 
 
 
Email 
 
 
Clinical Trial Coordinator 
 
 
 
 
  
  
  
 
Phone 
 
 
Email 
 
 
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Sponsor and Product Supply 
MVA-BN® 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
Project Leader 
 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
Medical Monitor 
 
 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
Research Monitor 
 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
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Collaborator 
 
 
 
 
 
 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
Trial Statistician 
 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
CRO 
 
 
 
 
  
Phone 
 
 
Fax 
 
 
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Local Laboratory (Safety) 
 
 
 
 
  
 
E-mail 
 
 
Laboratory (Immunology 
Assays) 
 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
Centralized ECG 
Assessment 
 
 
 
 
Phone 
 
 
E-mail 
 
 
Centralized Randomization 
 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
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Centralized Imaging of 
‘takes’ 
 
 
 
  
  
 
Phone 
 
 
E-mail 
 
 
DSMB Chair Member 
 
 
 
 
 
Phone 
 
 
E-mail 
 
 
Independent Take Review 
Committee (ITRC) Chair 
Member 
 
 
 
 
 
 
 
Phone 
 
 
Fax 
 
 
E-mail 
 
 
 
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Table of Contents 
1 
General Information ........................................................................................ 2 
1.1 Principal Investigator Signature Page ............................................................ 2 
1.2 Sponsor Signature Page ................................................................................... 3 
1.3 Responsibilities .................................................................................................. 4 
Table of Contents .................................................................................................... 10 
List of Tables ........................................................................................................... 16 
List of Figures ......................................................................................................... 16 
List of Abbreviations .............................................................................................. 17 
Definitions ............................................................................................................... 20 
1.4 Protocol Synopsis ............................................................................................ 22 
1.5 Trial Procedure Schedule............................................................................... 32 
2 
Background Information and Scientific Rationale ..................................... 38 
2.1 Introduction ..................................................................................................... 38 
2.2 First Generation Smallpox Vaccines ............................................................. 38 
2.3 Second Generation Smallpox Vaccines......................................................... 39 
2.4 Origin and Characteristics of MVA-BN® ..................................................... 40 
2.5 Summary of Nonclinical Studies with MVA-BN® ....................................... 41 
2.6 Clinical Profile of MVA-BN® ......................................................................... 42 
2.6.1 
Safety Overview of MVA-BN® ................................................................... 42 
2.6.2 
Immunogenicity Overview of MVA-BN® .................................................. 49 
2.7 Rationale .......................................................................................................... 50 
2.8 Trial Population .............................................................................................. 52 
2.9 Risk/Benefit Assessment ................................................................................. 53 
2.9.1 
Potential Risks ............................................................................................. 53 
2.9.2 
Benefits ......................................................................................................... 54 
3 
Objectives ........................................................................................................ 54 

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3.1 Co-Primary Objectives ................................................................................... 54 
3.2 Secondary Objectives ..................................................................................... 54 
4 
Trial Design ..................................................................................................... 55 
4.1 Experimental Design ...................................................................................... 55 
4.2 Description of Trial Procedures .................................................................... 55 
4.2.1 
Screening Phase ........................................................................................... 55 
4.2.2 
Active Trial Phase ....................................................................................... 57 
4.2.3 
Follow Up Phase .......................................................................................... 67 
4.2.4 
Unscheduled Visits ...................................................................................... 68 
4.2.5 
Withdrawal from Further Trial Vaccinations (Group 1) ....................... 68 
4.2.6 
Premature Discontinuation ........................................................................ 70 
4.3 Trial Duration ................................................................................................. 71 
4.4 Data Safety Monitoring Board ...................................................................... 71 
4.5 Trial Halting Rules ......................................................................................... 71 
5 
Selection of Subjects ....................................................................................... 72 
5.1 Recruitment Procedure .................................................................................. 72 
5.2 Inclusion Criteria ............................................................................................ 73 
5.3 Exclusion Criteria ........................................................................................... 74 
6 
Investigational Product (MVA-BN®) and Comparator (ACAM2000®) ... 77 
6.1 MVA-BN® ........................................................................................................ 77 
6.1.1 
Production, Packaging and Labeling ........................................................ 77 
6.1.2 
Shipment, Storage and Handling ............................................................... 77 
6.1.3 
Preparation, Administration and Dosage ................................................. 77 
6.1.4 
Accountability and Disposal ....................................................................... 78 
6.2 ACAM2000® .................................................................................................... 78 
6.2.1 
Accountability and Disposal ....................................................................... 78 
6.2.2 
Treatment of Adverse Events after ACAM2000® Vaccination ............... 79 
7 
Assessment of Immunogenicity and Efficacy .............................................. 79 

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7.1 Humoral Immune Response .......................................................................... 79 
7.1.1 
PRNT ............................................................................................................ 80 
7.1.2 
ELISA ........................................................................................................... 80 
7.2 Future Use of Lab Specimen .......................................................................... 80 
7.3 Measurement of the Take .............................................................................. 81 
7.4 Assessment of ACAM2000® Vaccination Site .............................................. 81 
7.5 Independent Take Review Committee .......................................................... 82 
8 
Safety and Reactogenicity .............................................................................. 82 
8.1 Definitions ........................................................................................................ 83 
8.1.1 
Medical History ........................................................................................... 83 
8.1.2 
Baseline Signs and Symptoms .................................................................... 83 
8.1.3 
Adverse Events ............................................................................................ 83 
8.1.3.1 
Unsolicited Adverse Events .......................................................................83 
8.1.3.2 
Solicited Adverse Events ............................................................................83 
8.1.3.3 
Adverse Event of Special Interest .............................................................84 
8.1.3.4 
Serious Adverse Events ..............................................................................84 
8.2 Assessment ....................................................................................................... 85 
8.2.1 
Relevant Medical History ........................................................................... 85 
8.2.2 
Prior and Concomitant Medications ......................................................... 85 
8.2.3 
Physical Examination .................................................................................. 85 
8.2.4 
Vital Signs .................................................................................................... 86 
8.2.5 
Unsolicited Adverse Events ........................................................................ 86 
8.2.6 
Solicited Adverse Events ............................................................................. 89 
8.2.6.1 
Solicited Local Adverse Events .................................................................89 
8.2.6.2 
Solicited General Adverse Events .............................................................90 
8.2.7 
Cardiac Assessment ..................................................................................... 91 
8.2.8 
Safety Laboratory Measurements ............................................................. 94 
8.2.9 
Pregnancy ..................................................................................................... 94 

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8.3 Reporting ......................................................................................................... 95 
8.3.1 
Reporting of Serious Adverse Events ........................................................ 95 
8.3.2 
Reporting of Adverse Event of Special Interests ...................................... 98 
8.3.3 
Reporting of Pregnancy .............................................................................. 99 
8.3.4 
Health Recordkeeping Requirements for Investigational New Drug 
Products ........................................................................................................ 99 
9 
Statistical Considerations .............................................................................. 99 
9.1 Randomization Procedure ............................................................................. 99 
9.2 Co-Primary Trial Hypotheses ....................................................................... 99 
9.2.1 
Immunogenicity Hypothesis ....................................................................... 99 
9.2.2 
Efficacy Hypothesis ................................................................................... 100 
9.3 Endpoints ....................................................................................................... 101 
9.3.1 
Co-Primary Endpoints .............................................................................. 101 
9.3.2 
Secondary Endpoints ................................................................................ 101 
9.4 Sample Size Calculation ............................................................................... 103 
9.5 Trial Cohorts/Datasets to be Evaluated...................................................... 104 
9.6 Biometrical Evaluation ................................................................................. 104 
10 
Ethical Aspects .............................................................................................. 105 
10.1 Ethical and Legal Regulations ..................................................................... 105 
10.2 Good Clinical Practice .................................................................................. 105 
10.3 Approval by an IEC/IRB ............................................................................. 106 
10.4 Confidentiality and Data Protection ........................................................... 107 
11 
Informed Consent ......................................................................................... 108 
12 
Case Report Forms and Retention of Records .......................................... 109 
12.1 Case Report Forms ....................................................................................... 109 
12.2 Retention of Records .................................................................................... 110 
12.3 Monitoring of the Trial ................................................................................ 110 
13 
USAMRIID Relevant Administrative Procedures .................................... 111 

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13.1 Protocol Modifications ................................................................................. 111 
13.2 Exceptions ...................................................................................................... 111 
13.3 Protocol Deviation Procedures .................................................................... 111 
13.4 Compensation ................................................................................................ 111 
13.5 Medical Care for Research-Related Injuries ............................................. 112 
13.6 Problems or Questions ................................................................................. 112 
14 
Audits and Inspections ................................................................................. 112 
15 
Responsibilities of the Principal Investigator ............................................ 112 
16 
References ..................................................................................................... 114 
17 
Appendices .................................................................................................... 118 
17.1 Appendix I: Toxicity Scale for Laboratory Values ................................... 118 
17.2 Appendix II: DoD Clinical Guidelines for Post-Smallpox Vaccine 
Associated Myopericarditis, Vaccine Healthcare Centers Network ........ 121 
17.3 Appendix III: Case Definitions Acute Myocarditis / Pericarditis ............ 127 
17.3.1 Case Definition for Acute Myocarditis .................................................... 127 
17.3.2 Case Definition for Acute Pericarditis .................................................... 128 
17.4 Appendix IV: US Health Affairs Memorandum Update of Clinical 
Policy for the Department of Defense Smallpox Vaccination Program .. 129 
17.5 Appendix IVa: Attachment 1 to US Health Affairs Memorandum 
‘Medication Guide ACAM2000®’ ............................................................... 145 
17.6 Appendix IVb: Attachment 2 to US Health Affairs Memorandum 
‘Smallpox Trifold Brochure’ ....................................................................... 152 
17.7 Appendix IVc: Attachment 3 to US Health Affairs Memorandum 
‘ACAM2000® Prescribing Information’ .................................................... 155 
17.8 Appendix IVd: Attachment 4 to US Health Affairs Memorandum 
‘Chronological Record of Medical Care and Symptom Diary after 
Smallpox Vaccination’.................................................................................. 167 
17.9 Appendix IVe: Attachment 5 to US Health Affairs Memorandum 
‘Smallpox Vaccine in Pregnancy Registry, Information Paper’ .............. 174 

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17.10 
Appendix IVf: Attachment 6 to US Health Affairs Memorandum 
‘Vaccination Response Interpretation’ ....................................................... 177 
17.11 
Appendix IVg: Attachment 7 to US Health Affairs 
Memorandum ‘Policy for Smallpox Vaccine and Persons with 
Cardiac Conditions’ ...................................................................................... 179 
17.12 
Appendix IVh: Attachment 8 to US Health Affairs 
Memorandum ‘Establishment of Case Management Guidelines for 
Smallpox Vaccine Associated Myopericarditis’ ........................................ 182 
17.13 
Appendix IVi: Attachment 9 to US Health Affairs Memorandum 
‘Information Paper Vaccinia Immune Globulin Intravenous 
(Human) (VIGIV)’ ........................................................................................ 185 
17.14 
Appendix IVj: Attachment 10 to US Health Affairs 
Memorandum ‘Precision in ICD9 Coding of Medical Encounters’ ........ 188 
17.15 
Appendix V: CDC Fact Sheet ‘Medical Management of 
Smallpox (Vaccinia) Vaccine Adverse Reactions: Vaccinia Immune 
Globulin and Cidofovir’ ............................................................................... 191 
17.16 
Appendix VI: Interpretation Support for Assessment of 
Screening ECGs ............................................................................................ 195 
17.17 
Appendix VII: Volunteer Registry Data Sheet  (USAMRDC 60-
R) 197 
17.18 
Appendix VIII: Roles and Responsibilities ........................................ 200 
17.19 
Appendix IX: Amendment 8 to Clinical Trial Protocol Edition 
7.0 dated 01-Jun-2016 ................................................................................... 204 
17.19.1 Rationale ..................................................................................................... 205 
17.19.2 Changes ...................................................................................................... 205 
 
 

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List of Tables 
Table 1 
Suspected Adverse Drug Reactions Reported in Completed Clinical 
Trials* ..................................................................................................................... 43 
Table 2 
Serious Suspected ADRs (SAEs Assessed by the Investigator to be at 
Least Possibly Related to MVA-BN®) .................................................................. 46 
Table 3 
Grading of General Symptoms from the Subject’s Memory Aid ...................... 90 
Table 4  
Toxicity Scale for Serum Chemistry .................................................................. 119 
Table 5  
Toxicity Scale for Hematology ............................................................................ 120 
 
 
List of Figures 
Figure 1:  
Algorithm for Assessment of Cardiac Events ...................................................... 93 
Figure 2 
Algorithm for Reporting of SAEs ......................................................................... 97 
Figure 3 
Algorithm for Reporting of AESIs ....................................................................... 98 
 
 
 

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List of Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
ACV 
Assay Cut-off Value 
AD 
Atopic Dermatitis 
ADR 
Adverse Drug Reaction 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
Alk Phos 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BARDA 
Biomedical Advanced Research and Development Authority 
BMI 
Body Mass Index 
BN 
Bavarian Nordic 
CDC 
Centers for Disease Control and Prevention 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CrCl 
Creatinine Clearance 
CRA 
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
CRO 
Contract Research Organization 
CTP 
Clinical Trial Protocol 
DHA 
Defense Health Agency (formerly MILVAX) 
DMID 
Division of Microbiology and Infectious Diseases 
DS 
Drug Safety 
DSMB 
Data Safety Monitoring Board 
DoD 
United States Department of Defense 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
HBsAg 
Hepatitis B Virus Surface Antigen 
HCG 
Human Choriogonadotropin 
HCV 
Hepatitis C Virus 
HDL 
High-density Lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 

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HQ USAMRMC 
Headquarters US Army Medical Research and Materiel Command 
ICD 
Informed Consent Document 
ICH 
International Conference of Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITRC 
Independent Take Review Committee 
LDL 
Low-density Lipoprotein 
LLN 
Lower Limit of Normal 
LV 
Left Ventricular 
MedDRA 
Medical Dictionary for Regulatory Activities 
MILVAX 
Military Vaccine Agency 
MMWR 
Morbidity and Mortality Weekly Report 
MLA 
Maximum Lesion Area 
MLD 
Maximum Lesion Diameter 
MP 
Medical Product 
MPXV 
Monkeypox Virus 
MVA 
Modified Vaccinia Ankara Strain 
MVA-BN 
Modified Vaccinia Ankara – Bavarian Nordic 
NHP 
Non-human Primates 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NYCBH 
New York City Board of Health 
ODM 
Operational Data Modeling 
OHU&E 
Office of Human Use and Ethics 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PPS 
Per Protocol Set 
PRNT 
Plaque Reduction Neutralization Test 
PV 
Pharmacovigilance 
RA 
Regulatory Affairs 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
SCR 
Screening Visit 
SD 
Standard Deviation 
SIN 
Subject Identification Number 
SOP 
Standard Operating Procedure 
TCID50 
Tissue Culture Infectious Dose 50% 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USAMRIID 
United States Army Medical Research Institute of Infectious Diseases 
USAMRMC 
United States Army Medical Research and Materiel Command 

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V 
Visit 
VACV 
Vaccinia Virus 
VAERS 
Vaccine Adverse Event Reporting System 
VHC 
Vaccine Healthcare Centers (in USA) 
VIG 
Vaccinia Immunoglobulin 
VRBPAC 
Vaccines and Related Biological Products Advisory Committee 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 
 

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Definitions 
Full Take: 
A full take is a successful primary take according to Vaccinia (Smallpox) Vaccine 
Recommendations of the Advisory Committee on Immunization Practices (ACIP) (Morbidity and 
Mortality Weekly Report [MMWR] June 22, 2001). 
Formation of a major cutaneous reaction at the ACAM2000® vaccination site:  
• 
The inoculation site becomes reddened and pruritic 3 to 4 days after vaccination. 
• 
A vesicle surrounded by a red areola then forms, which becomes umbilicated (collapsed 
center) and then pustular by days 7 to 11 after vaccination. 
• 
The pustule begins to dry; the redness subsides; and the lesion becomes crusted between 
the second and third week, the scab falls off, leaving a permanent scar that at first is pink in color 
but eventually becomes flesh colored. 
Absent Take: 
An absent take is considered to be the absence of a cutaneous reaction i.e. consistent with a full 
or partial take, at the ACAM2000® vaccination site. 
Attenuation: 
After revaccination, skin reactions at the ACAM2000® vaccination site are often less pronounced 
and there is more rapid progression and healing than those after primary vaccination. For the 
purposes of this Clinical Trial Protocol (CTP), attenuation is considered to be when the takes 
observed in Group 1 subjects (MVA-BN® recipients vaccinated with ACAM2000®) are 
determined to be diminished full takes based on the median of the individual measured parameter 
of Maximum Lesion Areas in Group 1 subjects, in comparison to the median of Maximum 
Lesion Areas of takes in Group 2 subjects (ACAM2000® recipients).  
Maximum Lesion Area: 
The Maximum Lesion Area (MLA) is 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). If one of the lesion areas is missing, then the MLA will not be calculated. 
Lesion: 
Lesion measurements (area and diameter) referred to in this CTP will include signs (after 
scarification) of pustule, vesicle, pus, ulcer or scab but will not include extended symptoms of 
induration or erythema. 
Peak Visit: 
For the purposes of this CTP, the Peak Visit is the visit with the highest expected antibody titers. 

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For MVA-BN® the peak responses are considered to be at Day 42 after the first MVA-BN® 
vaccination (as described in the MVA-BN® Investigator’s Brochure) when the subject has 
received two (2) MVA-BN® vaccinations according to the standard vaccination schedule. For 
ACAM2000® the peak responses are considered to be at Day 28 post vaccination (Group 2) in 
order to be in alignment with published data for conventional smallpox vaccines reaching a peak 
four weeks post vaccination (Frey, 2003; Belshe, 2004; Kennedy, 2004, Frey, 2007), which is 
also in full agreement with the data published for ACAM2000® (ACAM2000 Vaccines and 
Related Biological Products Advisory Committee [VRBPAC] Briefing Document, April 2007). 
 

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1.4 Protocol Synopsis 
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. 
 
  
 
  
Clinical phase 
 Phase III 
 
  
 
  
Sponsor 
 Bavarian Nordic A/S 
Hejreskovvej 10A, 3490 Kvistgård, Denmark 
 
  
 
  
Principal 
Investigator 
 
 
 
  
 
  
Vaccination dose, 
schedule and 
administration route  
 One 0.5 ml standard dose Modified Vaccinia Ankara – Bavarian 
Nordic (MVA-BN®) liquid-frozen vaccine contains a nominal titer of 
1x108 tissue culture infectious dose 50% (TCID50) MVA-BN®. 
MVA-BN® vaccine will be administered as a subcutaneous (s.c.) 
injection preferably in the non-dominant upper arm. 
 
As per the prescribing information: One dose of reconstituted 
ACAM2000® vaccine consists of 2.5-12.5x105 plaque forming units of 
live vaccinia virus (VACV). A droplet (0.0025 ml) vaccine is picked 
up with a bifurcated needle and is administered by the percutaneous 
route (scarification) using 15 jabs of that bifurcated needle. 
 
Group 1: 
Two vaccinations each of 0.5 ml MVA-BN® vaccine will be 
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). 
 
Group 2: 
A single vaccination of ACAM2000® vaccine will be administered at 
Day 0. 
 
  
 
  
Trial duration 
 Up to 22 weeks for Group 1 and up to 14 weeks for Group 2, plus 
(b) (1) (A)

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follow-up (FU), (remote correspondence e.g. a phone call or email) 
6 months after the last vaccination. If the remote correspondence 
reveals a medical need or any underlying condition that requires further 
examinations, the subject will be called in for a physical visit. 
 
  
Trial Population 
 Volunteers from military personnel only. 
 
  
 
  
Sample size 
 Up to 750 subjects may be screened to be able to vaccinate 440 eligible 
vaccinia-naïve subjects (220 per group) in order to achieve at least 175 
subjects per group in the Per Protocol Set (PPS). 
 
  
 
  
Co-Primary 
objectives 
 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 in terms of MLA. 
 
  
 
  
Secondary objectives  To assess non-inferiority of MVA-BN® compared to ACAM2000® in 
terms of vaccinia-specific Enzyme-linked Immunosorbent Assay 
(ELISA) antibody response at the Peak Visits. 
 
To assess seroconversion rates of MVA-BN® compared to 
ACAM2000® at the Peak Visits. 
 
To assess immune response dynamics in terms of antibody responses. 
 
To assess the effect on the ACAM2000® vaccination take following 
MVA-BN® priming.  
 
To assess and compare safety and reactogenicity of vaccinations with 
MVA-BN and ACAM2000® given alone or ACAM2000® given after 
MVA-BN® priming. 
 
  
 
  
Co-Primary 
endpoints 
 PRNT GMT at the Peak Visits 
 
Maximum Lesion Area (MLA) in mm² after scarification with 
ACAM2000® 

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Secondary endpoints 
 Immunogenicity 
 
GMTs at the Peak Visits and individual peak measured by vaccinia-
specific ELISA. 
 
GMTs at the individual peak measured by vaccinia-specific PRNT. 
 
GMTs at all antibody blood sample time points measured by vaccinia-
specific PRNT and vaccinia-specific ELISA. 
 
PRNT seroconversion rates at Peak Visits defined as the percentage of 
initially seronegative subjects with appearance of antibody titers equal 
or greater than the Assay Cut-off Value (ACV) in a vaccinia-specific 
PRNT. 
 
ELISA seroconversion rates at Peak Visits defined as the percentage of 
initially seronegative subjects with appearance of antibody titers equal 
or greater than the ACV in a vaccinia-specific ELISA. 
 
Efficacy  
 
Investigator assessed Maximum Lesion Diameter (MLD) in mm after 
scarification with ACAM2000® 
 
Investigator assessed Lesion diameter in mm at Day 6-8 after 
scarification with ACAM2000® 
 
Investigator assessed Lesion diameter in mm at Day 13-15 after 
scarification with ACAM2000® 
 
The individual take will be classified as either full or partial or absent 
take by a blinded ITRC. 
 
Lesion area in mm² at day 6-8 after scarification with ACAM2000® 
 
Lesion area in mm² at day 13-15 after scarification with ACAM2000® 
 
(The correct measurement of the lesion area will be confirmed by a 
blinded ITRC). 
 

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Safety and Reactogenicity 
 
Occurrence, relationship to vaccine and intensity of any Serious 
Adverse Event (SAE). 
 
Occurrence of any cardiac sign or symptom indicating a case of myo-
/pericarditis, i.e. Adverse Events of Special Interest (AESIs). 
 
Occurrence of any Grade 3 or 4 Adverse Events (AEs) possibly, 
probably or definitely related to vaccine within 28 days after each 
vaccination. 
 
Occurrence, relationship to vaccine and intensity of any non-serious 
AEs within 28 days after each vaccination. 
 
Occurrence of solicited general AEs (body temperature, headache, 
myalgia, chills, nausea, fatigue, malaise, swollen lymph nodes), within 
15 days after each vaccination (days 0-14): Intensity, duration and 
relationship to vaccination. 
 
Occurrence of solicited local AEs (pain, redness (erythema), swelling, 
induration, itching (pruritus), and vaccination site appearance 
(normal/healed, red spot, bump, reddish blister, whitish blister, scab, 
ulcer/crater, warmth, swollen >3in, red streaks, drainage) (within 15 
days after each vaccination (days 0-14): Intensity and duration.  
 
Daily measurement of lesion size, erythema and induration based on 
physical appearance of vaccination site as documented in the memory 
aid. 
 
• 
major lesion diameter (mm) each day  
 
• 
major erythema diameter (mm) each day  
 
• 
major induration diameter (mm) each day  
 
If the shape of the lesion, erythema (excludes lymphangitis) and 
induration observed is not round but rather asymmetrical then the 
largest (or major) cross-sectional measurement would be recorded. 
 
  
 
  
Trial design 
 Open label, randomized, blinded immune analysis 

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Group 1: 
220 vaccinia-naïve subjects receiving two (2) standard doses of MVA-
BN®, s.c., 4 weeks apart followed by one dose of ACAM2000® via 
scarification 4 weeks after the second MVA-BN® vaccination. 
 
Group 2: 
220 vaccinia-naïve subjects receiving one (1) dose of ACAM2000® via 
scarification. 
 
  
 
  
Inclusion criteria 
 1. 
Healthy male and female subjects, 18-42 years of age at date of 
informed consent signature 
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. 
Body Mass Index (BMI) ≥ 18.5 and < 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 28 days after the last vaccination. A 
woman is considered of childbearing potential unless post-
menopausal (defined as ≥ 12 months without a menstrual period) 
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 ≥ 2,500/mm3 and < 11,000/mm3 
9. 
Hemoglobin within normal limits 
10. 
Platelets ≥ lower normal limits 
11. 
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 

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creatinine in mg/dl x 72) = CrCl (ml/min) 
○ For women: multiply the result by 0.85 = CrCl (ml/min) 
12. 
Adequate hepatic function in the absence of other evidence of 
significant liver disease defined as: 
• 
Total bilirubin ≤ 1.5 x Upper Limit Normal (ULN) 
• 
Alanine Aminotransferase (ALT), Aspartate Aminotransferase 
(AST) ≤ 1.5 x ULN 
• 
Alkaline Phosphatase (Alk Phos) ≤ 1.5 x ULN 
13. 
Troponin I < 2 x ULN 
14. 
Electrocardiogram (ECG) without clinically significant findings, 
e.g. without atrioventricular or intraventricular conditions or 
blocks such as incomplete/complete left or complete right bundle 
branch block, second or third degree atrioventricular block, two 
premature ventricular contractions in a row, ST elevation 
consistent with ischemia, atrial or ventricular arrhythmia 
• 
QTc prolongations > 500 ms which do not require clinical 
intervention should be discussed with the Medical Monitor 
before vaccination  
• 
Following conditions can be included, if they do not require 
clinical intervention: 
○ First degree atrioventricular block, PR interval prolongation, 
premature atrial contractions, occasional premature 
ventricular contractions, sinus bradycardia, right or left axis 
deviation, non-specific ST and T wave changes. 
 
Further guidance is provided in Appendix VI. 
 
 
 
 
  
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 (> 14 days) high-dose corticosteroids 
(e.g. > 5 mg prednisone [or equivalent] per day administered 
systemically, i.e. parenterally or orally), chronic or planned 
treatment with steroid eye drops or ointment at time of screening 

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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. 
Recent surgery (including dental or eye) within 4 weeks prior to 
trial vaccination  
10. 
History of or active autoimmune disease. Persons with vitiligo or 
hypothyroid 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, significant 
arrhythmia with or without corrective/ablative surgery, 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, e.g. using the 
National Heart, Lung and Blood Institute’s Risk Assessment 
Tool: http://cvdrisk.nhlbi.nih.gov/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) 

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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, recent tattoos or 
skin piercing (until it is healed, but not at least 4 weeks prior to 
trial vaccination), 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 (except trial 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)  
33. 
Temperature ≥ 100.4°F (38.0°C)  
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 

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○ People with active or recent immunodeficiency disease or 
use of immunosuppressive medications, for example: have or 
take medication for HIV, Acquired Immune Deficiency 
Syndrome (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 
35. 
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) 
36. 
Known allergies to ACAM2000® and its diluents including 
polymyxin B sulfate, neomycin sulfate, and phenol 
37. 
Known allergies to vaccinia immunoglobulin (VIG) including 
thimerosal or previous allergic reaction to immunoglobulins 
38. 
Known allergies to cidofovir, sulfa drugs, Tecovirimat (ST246) 
or probenecid 
39. 
Trial personnel 
 
  
 
  
Statistical 
considerations 
 The following statistical considerations were applied for the trial with 
GMTs measured by PRNT as co-primary endpoint for non-inferiority 
testing (assuming have a log-normal distribution): 
 
Using PRNT titers on the log10 scale: 
 
Delta=0.301  
Sigma=0.866 
Alpha=0.05 
N=175 (per group) 
Power=90.0% 
 
With GMTs measured by PRNT as a co-primary endpoint, a sample 
size of 175 subjects per group provides a power of 90%. 
 
To account for dropouts from the PPS,  440 subjects will be vaccinated 
(220 subjects per group). 
 
The efficacy co-primary analysis is based on the ratio of the median of 

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the MLA of subjects in Group 1 divided by the median in Group 2 after 
scarification with ACAM2000®. 
 
This is tested using a one-sided 97.5% Hodges-Lehmann confidence 
interval of 1 minus the ratio in medians of the MLA. If the lower 
confidence limit of the ratio is greater than a pre-specified percentage 
(λ = 40%) then the co-primary endpoint will have been met. 
 
Calculations based on the POX-MVA-002 data show that this sample 
size will give sufficient power (>90% power).  
 
The overall power for meeting both primary endpoints is therefore 
greater than 80% (since 0.9 × 0.9 > 0.8). 
 
 

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1.5 Trial Procedure Schedule 
Trial Procedure Schedule – Group 1 
Visit (V) 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Remote FU 
Day / V +… d 
-70- -1 
0 
V1 
+6-8 
V1 
+13-15 
V1 
+27-29 
V4 
+6-8 
V4 
+13-15 
V1 
+55-57 
V7 
+6-8 
V7 
+13-15 
V7 
+27-29 
Last Vaccination 
+182-210 
Week 
-10- -1 
0 
1 
2 
4 
5 
6 
8 
9 
10 
12 
34-38 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion / exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Check vaccination history and 
absence of vaccination scar 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam1 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical exam1 
 
X 
(X) 
X 
X 
(X) 
X 
X 
(X) 
X 
X 
(X) 
Evaluation of vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Recording of Baseline signs and 
symptoms 
X 
X 
 
 
 
 
 
 
 
 
 
 
Check cardiac risk factors 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG2 
X 
 
 
X 
 
 
(X) 
 
 
X 
 
 
Questions on cardiac signs and 
symptoms 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Review of prior/concomitant 
medications 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
(X) 
Counseling3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Examination of vaccination site 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Photo of vaccination site 
 
 
 
 
 
 
 
 
X 
X 
 
 
Bandage application / change4 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Assessment of axillary and 
supraclavicular lymphadenopathy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SAE/AE/AESI recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 

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Trial Procedure Schedule – Group 1 continued 
Visit (V) 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Remote FU 
Day / V +… d 
-70- -1 
0 
V1 
+6-8 
V1 
+13-15 
V1 
+27-29 
V4 
+6-8 
V4 
+13-15 
V1 
+55-57 
V7 
+6-8 
V7 
+13-15 
V7 
+27-29 
Last 
Vaccination 
+182-210 
Week 
-10- -1 
0 
1 
2 
4 
5 
6 
8 
9 
10 
12 
34-38 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Vaccine administration 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Subject Observation (at least 30 
minutes) 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Handout of memory aid6 
 
X 
 
 
X 
 
 
X 
 
X7 
 
 
Review of memory aid 
 
 
X 
X 
 
X 
X 
 
X 
X 
X7 
 
Collection of memory aid6 
 
 
 
X 
 
 
X 
 
 
X 
X7 
 
Labs 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test8 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Safety lab2 
(CBC with differential, total bilirubin, 
Alk Phos, AST, ALT, creatinine, 
sodium, potassium and calcium) 
X 
 
 
X 
 
 
X 
 
 
X 
 
(X) 
Total, HDL and LDL cholesterol 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology (HBsAg / Anti-
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
Troponin I testing2 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Blood draw for antibody analysis 
 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
Blood volume 
 
 
 
 
 
 
 
 
 
 
 
 
Blood volume drawn per visit (ml)9 
22 
21 
16 
26 
21 
 
26 
21 
 
10 
21 
(10) 
Cumulative blood volume drawn (ml)9 
22 
43 
59 
85 
106 
 
132 
153 
 
163 
184 
(194) 
 
 

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( ) Only indicated in case of medical need or any underlying condition that requires further examinations. 
1 For more information on the physical examinations, please refer to Section 8.2.3 
2 Additional safety measures can be taken at any other trial visits or at unscheduled visits, if clinically indicated. 
3 Counseling on avoidance of pregnancy and HIV infection and specifically after the ACAM2000® vaccination counseling on the avoidance of contact 
 spread. At Visit 10 counseling for avoidance of pregnancy is not required. 
4 After ACAM2000® administration subjects should change their own dressings as instructed by the administering clinic (leave the bandage on for the 1st 
 48 hours, then change every day or when bandage becomes wet) using the Care Kits provided by site staff until the vaccination site scab falls off, as this 
 will keep the vaccination site intact and will minimize softening. Salves or ointments must not be applied to the vaccination site. Measurements of the 
 vaccination site are to be taken until bandage not required.  
5 Follow-up on ongoing AEs, AESIs, SAEs and recording of new SAEs/AESIs. 
6 The memory aid should be completed daily for 15 days (day of vaccination and the following 14 days). If symptoms persist at 14 days post vaccination, 
 temperature/symptom should be recorded until resolution or Visit 10. 
7 If lesion at vaccination site has not healed at Day 14, measurements of lesion size, erythema and induration should be recorded on a memory aid 
 extension each day until healed or Visit 10.   
8 WOCBP only. At Screening Visit, a serum test must be performed. At all other visits, either a serum or urine pregnancy test will be performed.  
9 Approximate volumes of single blood draws: Safety lab including all tests: 22 ml at SCR (incl. serum for pregnancy test) and 10 ml at regular visits, 5 
ml  
for serum pregnancy test and 16 ml for antibody analysis. 
 
 

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Trial Procedure Schedule – Group 2 
Visit (V) 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
Remote FU 
Day / V +… d 
-70- -1 
0 
V1 
+6-8 
V1 
+13-15 
V1 
+27-29 
V1 
+41-43 
V1 
+55-57 
Last Vaccination 
+182-210 
Week 
-10- -1 
0 
1 
2 
4 
6 
8 
26-30 
Procedures 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Check inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
Check vaccination history and absence of 
vaccination scar 
X 
 
 
 
 
 
 
 
Complete physical exam1 
X 
 
 
 
 
 
 
 
Targeted physical exam1 
 
X 
(X) 
X 
X 
 
 
(X) 
Evaluation of vital signs 
X 
X 
X 
X 
X 
 
 
(X) 
Recording of Baseline signs and symptoms 
X 
X 
 
 
 
 
 
 
Check cardiac risk factors 
X 
 
 
 
 
 
 
 
ECG2 
X 
 
 
X 
 
 
 
 
Questions on cardiac signs and symptoms 
 
X 
 
X 
X 
 
 
 
Review of prior/concomitant medications 
X 
X 
 
X 
X 
 
 
(X) 
Counseling3 
X 
X 
X 
X 
X 
 
 
 
Examination of vaccination site 
 
X 
X 
X 
X 
 
 
 
Photo of vaccination site 
 
 
X 
X 
 
 
 
 
Bandage application / change4 
 
X 
X 
X 
X 
 
 
 
Assessment of axillary and supraclavicular 
lymphadenopathy 
 
X 
X 
X 
X 
 
 
 
SAE/AE/AESI recording 
 
X 
X 
X 
X 
 
 
X5 
 
 
 

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Trial Procedure Schedule – Group 2 continued 
Visit (V) 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
Remote FU 
Day / V +… d 
-70- -1 
0 
V1 
+6-8 
V1 
+13-15 
V1 
+27-29 
V1 
+41-43 
V1 
+55-57 
Last Vaccination 
+182-210 
Week 
-10- -1 
0 
1 
2 
4 
6 
8 
26-30 
Vaccination 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Vaccine administration 
 
X 
 
 
 
 
 
 
Subject Observation (at least 30 minutes) 
 
X 
 
 
 
 
 
 
Handout of memory aid6 
 
X 
 
X7 
 
 
 
 
Review of memory aid 
 
 
X 
X 
X7 
 
 
 
Collection of memory aid6 
 
 
 
X 
X7 
 
 
 
Labs 
 
 
 
 
 
 
 
 
Pregnancy test8 
X 
X 
 
 
X 
 
 
 
Safety lab2 
(CBC with differential, total bilirubin, Alk 
Phos, AST, ALT, creatinine, sodium, 
potassium and calcium) 
X 
 
 
X 
 
 
 
(X) 
Total, HDL and LDL cholesterol 
X 
 
 
 
 
 
 
 
Hepatitis serology (HBsAg / Anti-HCV) 
X 
 
 
 
 
 
 
 
HIV 
X 
 
 
 
 
 
 
 
Troponin I testing2 
X 
 
 
X 
 
 
 
 
Blood draw for antibody analysis 
 
X 
X 
X 
X 
X 
X 
 
Blood volume 
 
 
 
 
 
 
 
 
Blood volume drawn per visit (ml)9 
22 
21 
16 
26 
21 
16 
16 
(10) 
Cumulative blood volume drawn (ml)9 
22 
43 
59 
85 
106 
122 
138 
(148) 
 
 

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( ) Only indicated in case of medical need or any underlying condition that requires further examinations. 
1 For more information on the physical examinations, please refer to Section 8.2.3. 
2 Additional safety measures can be taken at any other trial visits or at unscheduled visits, if clinically indicated. 
3 Counseling on avoidance of pregnancy and HIV infection and specifically after the ACAM2000® vaccination counseling on the avoidance of contact 
 spread. At Visit 4 counseling for avoidance of pregnancy is not required. 
4 After ACAM2000® administration subjects should change their own dressings as instructed by the administering clinic (leave the bandage on for the 1st 
 48 hours, then change every day or when bandage becomes wet) using the Care Kits provided by site staff until the vaccination site scab falls off, as this 
 will keep the vaccination site intact and will minimize softening. Salves or ointments must not be applied to the vaccination site. Measurements of the 
 vaccination site are to be taken until bandage not required.  
5 Follow-up on ongoing AEs, AESIs, SAEs and recording of new SAEs/AESIs. 
6 The memory aid should be completed daily for 15 days (day of vaccination and the following 14 days). If symptoms persist 14 days post vaccination, 
 temperature/symptom should be recorded until resolution or Visit 4. 
7 If lesion at vaccination site has not healed at Day 14, measurements of lesion size, erythema and induration should be recorded on a memory aid 
 extension each day until healed or Visit 4.  
8 WOCBP only. At Screening Visit, a serum test must be performed. At all other visits, either a serum or urine pregnancy test will be performed.  
9 Approximate volumes of single blood draws: Safety lab including all tests: 22 ml at SCR (incl. serum for pregnancy test) and 10 ml at regular visits, 5 
ml  
for serum pregnancy test and 16 ml for antibody analysis. 
 

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2 Background Information and Scientific Rationale 
2.1 Introduction  
Despite the fact that the World Health Organization (WHO) officially declared successful global 
eradication of smallpox in 1980, the existence of variola stockpiles and the threat of bioterrorism 
demands to maintain immunity to smallpox through vaccination. After the events of September 
11th, 2001, concern over the use of bioweapons as agents of terrorism increased (McCurdy, 
2004). As mass vaccination programs halted more than 30 years ago, it is estimated that the 
majority of the world population has no existing immunity to smallpox, and as such, the release 
of this highly contagious virus would have devastating effects. As a consequence, there is an 
urgent need for a safe and efficacious vaccine to protect the public against smallpox.  
Bavarian Nordic A/S (BN), an international biopharmaceutical company, is developing a 
proprietary strain of Modified Vaccinia Ankara (MVA [MVA BN®, trade name IMVAMUNE® 
outside the European Union {EU} invented name IMVANEX® in the EU]) for use as a vaccine 
protecting against smallpox infection. For IMVANEX® a marketing authorization under 
exceptional circumstances was granted in July 2013. BN filed a New Drug Submission with 
Health Canada in 2011 under the invented name IMVAMUNE®. A marketing authorization for 
IMVAMUNE® was granted in November 2013. 
2.2 First Generation Smallpox Vaccines 
The original smallpox vaccines were based on a number of different VACV strains, e.g. Lister-
Elstree recommended by the WHO and used primarily in Europe or the New York City Board of 
Health (NYCBH, Dryvax®) strain used in the United States of America (USA). While these 
proved to be highly effective immunizing agents making the eradication of smallpox possible, 
they also showed considerable side effects. Besides local reactions with scab development and 
scarring, general symptoms observed frequently after smallpox vaccination have been pyrexia, 
weakness, muscular pain, headache, swelling and soreness of local lymph nodes and rashes. 
Apart from less dramatic and transient side effects like erythematous or urticarial rashes, severe 
and potentially fatal cutaneous complications of VACV vaccination include eczema vaccinatum 
and progressive vaccinia. Most feared are complications of the central nervous system, especially 
post-vaccinal encephalitis, which lead to death in 15-25% of cases and in 25% to neurologic 
sequelae (Goldstein, 1975; Lane, 1969; Lane, 1970). Even though some countries such as the 
USA excluded high-risk individuals from vaccination, an average of seven persons a year still 
died from complications due to smallpox vaccination during the eradication campaign 
(McElwain, 1972). 
Traditionally, successful vaccination with a smallpox vaccine was assessed based on the 
formation of a vesicle (“take”) at the inoculation site seven to nine days after vaccination. Recent 

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clinical trials using Dryvax® confirmed a success rate by vesicle formation in vaccinia-naïve 
volunteers of 95 to 99% (Frey, 2002; ACAM2000 VRBPAC Briefing Document, 2007). 
In an individual previously exposed to a smallpox vaccine, successful revaccination is confirmed 
when a pustular lesion is present or an area of definite induration or congestion surrounding a 
central lesion (i.e. scab or ulcer) is observed upon examination 6-8 days after revaccination 
(MMWR, June 22, 2001). However, revaccination may lead to skin reactions that are less 
pronounced with more rapid progression and healing than those after primary vaccination or a 
lesion may even be absent (Frey, 2003). Still, these individuals are considered to be fully 
protected, i.e. the occurrence of a partial take or the absence of a take in previously vaccinated 
individuals does not require any additional vaccination (ACAM2000 prescribing information, 
Appendix IVc; Section 17.7). In an earlier clinical trial comparing MVA-BN® and Dryvax®, 
priming with MVA-BN® either prevented take development or resulted in a diminished take 
coupled with an accelerated healing time following scarification with Dryvax® (Frey, 2007). The 
attenuation of the take following vaccination due either to a prior vaccination and/or infection 
with Variola virus has historically been a measure of a protection against smallpox (Fenner, 
1988). 
2.3 Second Generation Smallpox Vaccines 
Second generation smallpox vaccines are derived from first generation VACV strains by plaque 
purification and manufactured in cell cultures according to current Good Manufacturing Practice 
standards (Monath, 2004). Vaccination of individuals with these vaccines is performed in the 
same way as with first generation smallpox vaccines, namely by intradermal administration 
(scarification) of a single dose. 
ACAM2000® is based on the Dryvax® NYCBH strain (Monath, 2004). In preparation of a 
Biologics License Application at the US Food and Drug Administration (FDA), two pivotal 
Phase III clinical trials were conducted enrolling either vaccinia-naïve or vaccinia-experienced 
populations. The trials were designed to compare the safety, tolerability and efficacy of 
ACAM2000® to Dryvax®. In total, the ratio of individuals in these trials receiving ACAM2000® 
and Dryvax® was 3:1 (ACAM2000 VRBPAC Briefing Document, 2007). 
Safety information available from these trials suggests that the non-serious adverse reactions 
were typical for vaccines administered by injection or scarification. The majority (99% and 97% 
respectively) of subjects experienced at least one treatment-emergent AE after vaccination. The 
AEs most commonly reported fell into four distinct categories: reactions at the vaccination site, 
lymphadenitis, constitutional “flu-like” symptoms and minor gastrointestinal symptoms. Of 
special interest, however, were a total of 10 serious cases of myo-/pericarditis that were reported 
within the ACAM2000® development program. In a vaccinia-naïve population of 1,675 subjects, 
these events occurred in seven subjects treated with ACAM2000® (5.73 events per thousand 
vaccinations) and in three subjects having received Dryvax® (10.38 events per thousand 
vaccinations) for a combined calculated incidence of 5.97 cases of myo-/pericarditis per thousand 

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vaccinations (95% confidence interval of 2.87 to 10.95 cases per thousand). These figures 
represent quite a high rate of potentially life-threatening serious AE following vaccination with a 
prophylactic vaccine. 
Vaccine efficacy data were collected to demonstrate non-inferiority compared to Dryvax® based 
on the efficacy parameters of major cutaneous reaction (“take”) rates and neutralizing antibody 
titers by PRNT in both trials. Enrolling vaccinia-naïve subjects in one of the two trials, non-
inferiority against Dryvax® could be shown for take rates, but not for antibody titers. On the 
contrary, for the trial population of vaccinia-experienced subjects enrolled in the second Phase III 
trial, non-inferiority against Dryvax® could be determined for neutralizing antibody titers, but not 
for take rates. Taken together, two of the four targeted efficacy measures were met in these trials. 
Based on the safety and efficacy data collected in these pivotal Phase III trials, the FDA approved 
ACAM2000® in September 2007 for use in vaccinia-naïve, as well as vaccinia-experienced 
healthy populations, issuing a black box warning on the prescribing information (Appendix IVc; 
Section 17.7) for the special risks of this conventional second generation smallpox vaccine. In 
Section 2.4 of the prescribing information entitled “Instructions for Interpreting Vaccination 
Response”, it states that formation of a major cutaneous reaction at day 6 to 8 is evidence of a 
successful take and acquisition of protective immunity. It additionally states that prior 
vaccination may modify the cutaneous response upon revaccination such that the absence of a 
cutaneous response does not necessarily indicate vaccination failure. 
2.4 Origin and Characteristics of MVA-BN® 
VACV is considered the best known member of the poxvirus family and the prototype live viral 
smallpox vaccine. VACV replicates in the cytoplasm of the host cell, its deoxyribonucleic acid 
does not integrate into the host cell genome and it is non-oncogenic. 
Modified Vaccinia Ankara (MVA) was derived from the serial passage of Chorioallantois 
Vaccinia Ankara, a VACV strain used during the smallpox eradication program. During this 
passaging, MVA suffered a multitude of mutations within its genome, including six major 
deletions, resulting in the loss of 15% (31kbp) of original genetic information (Antoine, 1998). 
The deletions affected a number of virulence and host range genes (Antoine, 1998; Rosel, 1986; 
Meyer, 1991) and as a consequence, MVA exhibits a severely restricted host range in most 
mammalian cell types (Sutter, 1992; Carroll, 1997; Blanchard, 1998; Drexler, 1998). Although 
MVA exhibits a strongly attenuated replication in these cell types, its genes are efficiently 
transcribed with the block in viral replication being at the level of virus assembly and egress 
(Sutter, 1992; Carroll, 1997). 
MVA-BN® has been derived from MVA-572 and is a highly attenuated, purified live vaccine 
produced under serum-free conditions in chicken embryo fibroblast cells. In contrast to the first 
and second generation smallpox vaccines MVA-BN® is not administered by scarification. The 
standard route and schedule of MVA-BN® are two subcutaneous injections administered four 

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weeks apart. Since MVA-BN® is non-replicating in human cells (Mayr, 1975) and is 
administered via the subcutaneous route, it does not form vesicles (“takes”). 
For further details on MVA-BN®, please refer to the relevant sections in the Investigator's 
Brochure. 
2.5 Summary of Nonclinical Studies with MVA-BN® 
An extensive nonclinical development program has demonstrated the safety, efficacy and bio-
equivalence of MVA-BN® compared to other traditional smallpox vaccines. 
The studies conducted demonstrated the superior attenuation profile of MVA-BN® compared to 
conventional smallpox vaccines (e.g. ACAM2000®, Dryvax®) as well as to other MVA strains. In 
contrast to other strains, MVA-BN® does not replicate in any of the human cell lines tested 
(Chaplin, 2002) and is not lethal for severely immune compromised animals (Suter, 2009). 
Repeated administrations (s.c. or intra-muscular) of MVA-BN® at doses up to 4.9x108 TCID50 
resulted in injection site irritations and some lymphoid changes; however, these effects were 
minimal and reversible and are therefore not considered to be dose-limiting. 
Three developmental toxicity studies in rats and rabbits demonstrated that none of the tested 
doses of MVA-BN® (1x107 TCID50 or 1x108 TCID50) were teratogenic or caused intrauterine 
toxicity to the fetuses. In a peri- and postnatal study in rats MVA-BN® did not have any effect on 
the dams or the intrauterine development of the embryos. Furthermore, it did not have any effect 
on the lactating females or their developing offspring.  
Non-clinical studies on immunogenicity and efficacy demonstrated that MVA-BN® smallpox 
vaccine induces a comparable immune response (antibody and T cells) as conventional smallpox 
vaccines (ACAM2000®, Dryvax® and Elstree) in both mice and non-human primates (NHP) 
(Stittelaar, 2005). A linear correlation between vaccine dose and antibody responses (total and 
neutralizing antibodies) induced by MVA-BN® could be demonstrated in mice and NHP (and in 
human subjects). This correlation translated into a vaccine dose related protection of NHP from 
lethal challenge with monkeypox virus (MPXV), indicating that antibodies are good predictive 
correlates for protection, reasonably likely to predict clinical efficacy. Indeed, the correlation of 
the fit between PRNT titers (induced by MVA-BN®) and the probability of survival from a lethal 
MPXV challenge was 0.9992, demonstrating a highly significant correlation between neutralizing 
antibodies and protection (p = 0.00076). Similarly, the correlation of the fit between ELISA titers 
(induced by MVA-BN®) and the probability of survival from a lethal MPXV challenge was 
0.9966, demonstrating a highly significant correlation between total antibodies and protection (p 
= 0.00336). 
For more detailed information on preclinical data please refer to the respective sections of the 
Investigator's Brochure. 

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2.6 Clinical Profile of MVA-BN® 
To date, 19 clinical trials (13 sponsored by BN, thereof eight (9) under Investigational New Drug 
(IND) 11596; one (1) under Investigational New Drug (IND) 15316, six (6) sponsored by the 
Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and 
Infectious Diseases (NIAID), National Institutes of Health (NIH) under IND 11229 evaluating 
the safety and immunogenicity of MVA-BN® have been completed. Currently two (2) clinical 
trials are ongoing (sponsored by BN) under IND 11596.. As of July 31, 2016, 7,542 subjects have 
been vaccinated with MVA-BN® in the completed clinical trials, including risk groups with 
contraindications to conventional smallpox vaccines, such as HIV infected patients and patients 
with AD. 
2.6.1 Safety Overview of MVA-BN® 
In all completed and ongoing clinical trials, vaccinations with MVA-BN® have shown to be 
generally safe and well tolerated. No cases of death, assessed as being even possibly related, have 
been reported for a subject in a clinical trial using MVA-BN®. 
Serious Suspected Adverse Drug Reactions 
A total of seven (7 out of 7,758 vaccinated subjects = 0.09 %) serious suspected Adverse Drug 
Reactions (ADRs) have been reported for MVA-BN® so far (see Table 2). All of them have been 
thoroughly reviewed by BN and the trial specific Data Safety Monitoring Board (DSMB), who 
concluded that the continued use of MVA-BN® in a clinical setting presented no special risks to 
the subjects. In the NIH sponsored trial POX-MVA-036, the Safety Monitoring Committee 
(SMC) had put the trial on a temporary hold and had requested further information,  following the 
receipt of a possibly related SAE of throat tightness and further hypersensitivity symptoms (see 
Table 2) along with three further non-serious cases of rashes/hives (two of which were reported 
as possibly related). BN assessed reactions as “possibly related” for which no medical cause or 
medical etiology is known to date and thus a relationship to the vaccine cannot be ruled out 
technically. No pattern regarding serious suspected ADRs could be detected. This trial had 
resumed recruiting in January 2014, after a review of all available safety and quality data by the 
SMC. 
Adverse Drug Reactions 
Suspected ADRs were reported in completed clinical trials (see Table 1): 

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Table 1 
Suspected Adverse Drug Reactions Reported in Completed Clinical Trials* 
MedDRA System 
Organ Class 
Very 
common  
(≥ 1/10) 
Common  
 
(≥ 1/100 to < 1/10) 
Uncommon  
 
(≥ 1/1,000 to 
< 1/100) 
Rare 
 
(≥ 1/10,000 to 
< 1/1,000) 
Infections and 
Infestations 
- 
- 
Nasopharyngitis 
Upper respiratory tract 
infection 
Sinusitis 
Conjunctivitis 
Influenza 
Gastroenteritis 
Oral Herpes 
Viral Infection 
Blood and Lymphatic 
System Disorders 
- 
- 
Lymphadenopathy 
 
- 
Metabolism and 
Nutrition Disorders 
- 
Appetite disorder 
- 
- 
Psychiatric Disorders 
- 
- 
Sleep disorder 
- 
Nervous System 
Disorders 
Headache 
- 
Dizziness 
Paraesthesia 
 
Migraine 
Dysgeusia 
Peripheral sensory 
neuropathy 
Somnolence 
Ear and Labyrinth 
Disorders 
- 
- 
- 
Vertigo 
Ear pain 
Cardiac Disorders 
- 
- 
- 
Tachycardia 
Respiratory, Thoracic 
and Mediastinal 
Disorders 
- 
- 
Pharyngolaryngeal 
pain 
Rhinitis 
Cough 
- 
Gastrointestinal 
Disorders 
Nausea 
- 
Diarrhoea 
Vomiting 
Dry mouth 
Abdominal Pain 
Aphthous stomatitis 
Skin and 
Subcutaneous Tissue 
Disorders 
- 
- 
Rash 
Pruritus 
Dermatitis 
Urticaria 
 
Skin discolouration 
Ecchymosis 
Hyperhidrosis 
Night sweats 
Subcutaneous Nodule 
Angioedema 
Musculoskeletal and 
Connective Tissue 
Disorders 
Myalgia 
Arthralgia 
Pain in extremity 
 
Musculoskeletal 
stiffness 
Back pain 
Neck pain 
Muscle spasms 
 Musculoskeletal pain 
Muscular weakness  
General Disorders and 
Administration Site 
Conditions 
Injection 
site pain 
Injection 
site 
erythema 
Injection 
site swelling 
Injection 
Injection site oedema 
Injection site 
discolouration 
Injection site nodule 
Injection site 
haematoma 
Chills 
Malaise 
Injection site warmth  
Injection site 
haemorrhage 
Injection site irritation 
Injection site rash 
Underarm swelling 
Flushing 
Chest pain 
Injection site 
exfoliation  
Injection site 
inflammation 
Injection site 
paraesthesia 
Injection site reaction 
Injection site dryness 

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MedDRA System 
Organ Class 
Very 
common  
(≥ 1/10) 
Common  
 
(≥ 1/100 to < 1/10) 
Uncommon  
 
(≥ 1/1,000 to 
< 1/100) 
Rare 
 
(≥ 1/10,000 to 
< 1/1,000) 
site 
induration 
Injection 
site pruritus  
Fatigue 
Axillary pain 
 
 
Injection site vesicles 
Oedema peripheral 
Injection site 
anesthesia 
Injection site 
movement impairment 
Injection site papule 
Asthenia 
Influenza like illness 
 
Investigations 
- 
Body temperature 
increased 
Pyrexia 
Troponin I increased  
Hepatic enzyme 
increased 
White blood cell count 
decreased 
Mean platelet volume 
decreased 
 
White blood cell count 
increased 
Injury, Poisoning and 
Procedural 
Complications 
- 
- 
 
- 
 
Contusion 
 
* POX-MVA-001, -002, -004, -005, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, HIV-
NEF-004 and HIV-POL-002; 7 subjects in POX-MVA-009 received Dryvax® either on the same day or within 
7 days after MVA-BN® administration and were therefore not included to avoid a potential bias in the adverse 
event reporting.   
Looking only at the events that were reported by at least 1% of the subjects, the majority of 
ADRs represented local vaccination site reactions as well as common systemic reactions typical 
for modern injectable vaccines and were classified as being mild to moderate. Overall, the ADRs 
reported to date following multiple administrations with MVA-BN® in healthy or various special 
populations, be it vaccinia-experienced or vaccinia-naïve, are comparable in frequency and have 
not identified any particular safety risks for the vaccine. 
The current Investigator’s Brochure provides more details on frequencies of suspected ADRs 
according to System of Organ Class and Preferred Term reported in completed clinical trials and 
a comparison of suspected ADRs reported by ≥1% of immunocompromised subjects vaccinated 
with MVA-BN®. 
Cardiac Signs and Symptoms 
Based on earlier observations with first and second generation smallpox vaccines (see 
Sections 2.2 and 2.3), particular attention has been placed on monitoring for cardiac signs and 
symptoms in all recent smallpox vaccine clinical trials.  

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Ongoing evaluation of health outcomes among Armed Forces personnel indicates individuals 
vaccinated with conventional smallpox vaccine are at higher risk for myocarditis and/or 
pericarditis than those not vaccinated. Suspected cases of myocarditis and/or pericarditis have 
been observed in healthy adult primary vaccinees at an approximate rate of 5.73 per 1,000 
receiving ACAM2000®. This finding includes cases of acute symptomatic or asymptomatic 
myocarditis or pericarditis or both. 
Despite close cardiac monitoring, no confirmed cases of myo-/pericarditis have been observed in 
any completed MVA-BN® trials. In a recently completed Phase III trial, a case of chest pain in a 
32-year-old female subject was observed. This chest pain was described as worse when lying 
down and improving when sitting in an upright position, thereby meeting the case definition of a 
‘possible case of acute pericarditis’ according to the criteria stated in the trial protocol. All 
cardiologist examinations, including repeated ECGs, troponin testing and echocardiography 
showed normal results, not confirming a pericarditis. Physical examination did not show 
auscultatory signs of a pericardial rub. The subject was in a good physical condition, including 
exercise tolerability. In summary, the sponsor assessment in this case was concluded as unlikely 
related, as it remained unclear whether a diagnosis of pericarditis can be finally confirmed in this 
subject considering the diagnosis of ‘possible acute pericarditis’ was purely based on the clinical 
observation (chest pain being worse when lying down). As possible alternative risk factor, viral 
serology examinations for this subject revealed a positive titer for Coxsackie B virus in temporal 
relation to the reported chest pain in this subject, which may be considered as contributory factor 
for the medical condition. 
 

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Table 2 
Serious Suspected ADRs (SAEs Assessed by the Investigator to be at Least Possibly Related to MVA-BN®) 
Trial 
Age/ 
Gender 
Days After 
Vaccination 
Event 
Outcome 
Underlying Diseases/ 
Circumstances 
Investigator 
Assessment  
BN Opinion 
POX-MVA-
005 
30/Male 
70 days after 
2nd vaccinatio
n 
Sarcoidosis 
Stable and 
asymptomatic 
Urinary tract infection with 
Chlamydia trachomatis at time 
of first symptoms (arthralgia) 
Possibly 
related 
Possibly 
related 
POX-MVA-
005 
31/Female 
26 months 
after 
2nd vaccinatio
n 
Crohn’s 
disease 
Stable and 
asymptomatic 
under therapy  
Abnormal  lab results (elevated 
alkaline phosphatase, absolute 
neutrophils and platelet counts) 
at screening for 2-year follow-
up study POX-MVA-023 
(excluded) 
Possibly 
related 
Possibly 
related  
POX-MVA-
008 
28/Female 
8 days after 
2nd vaccinatio
n 
Transitory 
ocular 
muscle 
paresis 
Resolved without 
sequelae 
No relevant medical history  
Probably 
related 
Possibly 
related 
POX-MVA-
010 
30/Female 
133 days after 
2nd vaccinatio
n 
Congestive 
heart failure 
due to 
cardiomyopa
thy 
Stable under 
cardiac 
medications 
Surgery for ventricular septal 
defect as child. HIV infection. 
Concomitant (denied, therefore 
previously unknown to BN) 
participation in a Growth-
Hormone Releasing Hormone 
study; event also assessed as 
possibly related to Growth-
Hormone Releasing Hormone 
Possibly 
related 
Unlikely 
related 
POX-MVA-
011 
39/Female 
1 day after 
2nd vaccinatio
n 
Simple 
pneumonia 
and pleurisy 
Resolved without 
sequelae 
HIV infection (CD4 count four 
weeks prior to second 
vaccination was 299 cells/µl). 
History of chronic obstructive 
pulmonary disease. Acute 
sinusitis and nasal congestion 
due to swimmer’s ear which 
triggered hospital admittance.  
Possibly 
related 
Unlikely 
related 

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Trial 
Age/ 
Gender 
Days After 
Vaccination 
Event 
Outcome 
Underlying Diseases/ 
Circumstances 
Investigator 
Assessment  
BN Opinion 
POX-MVA-
036 
27/Female 
0 days after 
2nd vaccinatio
n 
Throat 
tightness and 
other 
hypersensitiv
ity symptoms 
such as 
hives, 
pruritus, 
tender 
vaccination 
site, swollen 
axilla, 
angioedema 
of forearms 
Resolved without 
sequelae 
The subject received her 
second dose of MVA-BN® 21 
days after the first dose and 
after 2 hours developed 
symptoms such as skin 
reactions and throat tightness 
which was responsive to 
epinephrine treatment. She had 
no wheezing and was not 
hypotensive. Symptoms 
subsided after several days 
under prednisone and 
diphenhydramine treatment. 
She has a family history of 
allergies and a medical history 
of shingles. She has received 
multiple vaccines before but 
never had previous hives or 
other problems with vaccines. 
 
Possibly 
related 
Possibly 
related 
POX-MVA-
036 
30/Male 
117 days after 
1st 
vaccination 
Non ST 
segment 
elevation 
myocardial 
infarction 
Resolved without 
sequelae 
Positive family history for 
cardiovascular diseases (both 
grandfathers had myocardial 
infarctions in their 50ies, father 
had blood clots), as well as 
overweight with a BMI above 
33. A few days before event 
onset, subject returned from a 
trip to India with diarrhoea and 
was started on ciprofloxacine 
treatment (which per US 
prescribing information is 
associated with angina pectoris 
Possibly 
related 
Unlikely 
related 

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Trial 
Age/ 
Gender 
Days After 
Vaccination 
Event 
Outcome 
Underlying Diseases/ 
Circumstances 
Investigator 
Assessment  
BN Opinion 
and myocardial infarction). He 
showed chest pain and 
increased troponin I, but no ST 
segment changes in the ECG 
and no coronary artery disease 
in cardiac catheterization. A 
post-infectious myocarditis 
(published case reports exist 
for campylobacter, shigella, 
salmonella) was considered as 
alternative etiology for the 
reported event. 
 
 

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2.6.2 Immunogenicity Overview of MVA-BN® 
In three Phase I and II dose finding trials MVA-BN® was tested for safety and immunogenicity 
among healthy volunteers (Vollmar, 2006; Frey, 2007; Von Krempelhuber, 2010; Zitzmann-
Roth, 2015). Across these trials a linear dose relationship was observed between the vaccine 
doses for both ELISA and PRNT titers. Maximum ELISA seroconversion rates and peak titers 
were reached two weeks after the second vaccination, with 100% seroconversion after the second 
dose for all dose groups receiving at least 2x107 TCID50 of MVA-BN® or higher. Statistical 
analysis indicated lower doses to be inferior to a nominal titer of 1x108 TCID50 tested throughout 
all dose ranging studies. This highest dose tested achieved ELISA seroconversion rates between 
81 and 100% already after the first dose. For the PRNT, the same trend was observed with 71-
96% seroconversion rates two weeks after the second MVA-BN® administration in all groups 
receiving the highest dose. 
The early onset of seroconversion and the higher titers of total and neutralizing antibodies 
combined with an excellent safety profile qualified the highest dose as the most suitable human 
dose. Therefore, based on the results of these dose ranging studies, coupled with the animal 
immunogenicity and efficacy studies, the final optimal (standard) dose and schedule for the 
general population was decided to be two doses of MVA-BN® with a nominal titer of 1x108 
TCID50 administered (s.c.) four weeks apart. 
Although antibody responses measured by ELISA in HIV infected subjects tend to be lower 
compared to GMT in healthy (Greenberg, 2013; Overton, 2015) and AD subjects four weeks 
after the first and second vaccinations with MVA-BN®, GMTs measured by PRNT were 
comparable in HIV infected compared to healthy and AD populations (von Sonnenburg, 2014; 
Greenberg, 2015). The ability of the second MVA-BN® vaccination to significantly boost the 
immune response in immunocompromised populations to high titer levels is as robust as in the 
healthy population. 
In NIH sponsored trials POX-MVA-002 (DMID 02-017; Frey, 2007) and POX-MVA-009 
(DMID 06-0012, Frey, 2013) the immune responses induced by MVA-BN® were compared to 
Dryvax®. In total 97.8% of subjects vaccinated with a single administration of the standard dose 
of MVA-BN®  seroconverted by ELISA either at Day 14 or Day 28 post vaccination (29/29 in 
POX-MVA-002 and 61/63 in POX-MVA-009). 100% of subjects in the Dryvax® group had 
seroconverted 28 days after scarification (13/13 and 8/8 respectively). A second vaccination with 
MVA-BN® significantly increased the titers measured two weeks later so that the GMTs two 
weeks after the second vaccination with MVA-BN® were comparable to those four weeks after a 
single vaccination with Dryvax®. Furthermore, the majority of study participants (n=54) received 
MVA-BN® prior to challenge (vaccination) with Dryvax®. In these subjects, MVA-BN® priming 
(even at lower doses, i.e. 2x107 TCID50) resulted in a significant reduction of viral replication at 
the site of Dryvax® inoculation and either prevented take development or resulted in a diminished 
take coupled with an accelerated healing time; factors which are associated with people 
previously vaccinated with traditional smallpox vaccines or infected with variola virus. Partial 

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attenuation of primary takes in some vaccinia-experienced individuals receiving vaccination has 
also been well documented in previous studies (Stickl, 1974; Cherry, 1977; McIntosh, 1977; 
Orr, 2004). 
Analysis of sera derived from MVA-BN® vaccinees compared to sera from Dryvax® recipients 
demonstrated that subjects vaccinated with MVA-BN® had a significantly higher in vitro Variola 
virus neutralization capacity (titer) compared to subjects vaccinated with Dryvax® 
(Damon, 2009). This result supports a comparable efficacy afforded by MVA-BN® and 
conventional smallpox vaccines against smallpox in people. 
In addition, MVA-BN® and Dryvax® induced similar levels of T cell immunity with most 
subjects having detectable T cell responses 26-30 days following vaccinations. Data on cellular 
immune responses, analyzed in various trials using intracellular cytokine staining for detection of 
vaccinia-specific Interferon -γ producing CD4+/CD8+ T cells showed a strong dose-dependency. 
In vaccinia-experienced subjects, MVA-BN® was able to stimulate the memory T and B cell 
responses induced by a previous smallpox vaccination with conventional vaccines.  
Additional detailed information on the clinical development of MVA-BN® is provided in the 
Investigator's Brochure. 
2.7 Rationale 
The efficacy of MVA-BN® cannot be demonstrated in traditional pivotal human Phase III 
efficacy trials since Variola challenge studies in humans are unethical and the world-wide 
eradication of smallpox makes field trials impossible. During the global smallpox vaccination 
campaigns, the development of a major cutaneous reaction following scarification (pock or 
"take") was used as a surrogate parameter of clinical efficacy, i.e. protection against smallpox 
following vaccination was reported upon the formation of a vaccinia take, which occurred one 
week post vaccination with a traditional smallpox vaccine (Fenner, 1988). This is also confirmed 
by the ACAM2000® prescribing information that states "formation of a major cutaneous reaction 
by day 6-8 is evidence of a successful 'take' and acquisition of protective immunity" and the take 
rate was used as surrogate parameter for approval of this vaccine. 
Since MVA-BN® does not induce a take due to its high attenuation, inability to replicate in 
humans and route of administration, demonstration of the protective efficacy of MVA-BN® needs 
to be built on alternative strategies. This phase III trial therefore aims to demonstrate efficacy of 
MVA-BN® by comparing indicators of efficacy to the US licensed smallpox vaccine 
ACAM2000®. The first important component of BN’s strategy to demonstrate efficacy of MVA-
BN® in this Phase III trial is to compare the neutralizing antibody response induced by MVA-
BN® to that of the conventional, US licensed smallpox vaccine ACAM2000®. Immunogenicity 
results obtained in preclinical studies have demonstrated that MVA-BN® induces equivalent 
immune responses (total antibodies, neutralizing antibodies and T cells) and efficacy in mice and 
NHP (Stittelaar, 2005) when compared to conventional smallpox vaccines, such as ACAM2000® 

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and Dryvax®. Furthermore, a linear correlation between vaccine dose and antibody responses 
(total and neutralizing antibodies) induced by MVA-BN® could be demonstrated in mice and 
NHP (and in human subjects). This correlation translated into a vaccine dose related protection of 
NHP from lethal challenge with MPXV, indicating that antibodies are good predictive correlates 
for protection, reasonably likely to predict clinical efficacy. 
A NIH / DMID sponsored Phase I trial (POX-MVA-002 / DMID 02-017; Frey, 2007) allowed for 
a direct comparison of immune responses induced by either MVA-BN® or Dryvax® alone and 
results demonstrated that the peak and long-term immune responses (ELISA and PRNT) induced 
by MVA-BN® were comparable to those induced by Dryvax® in healthy vaccinia-naïve subjects. 
Furthermore, a retrospective study demonstrated the non-inferiority of total (ELISA) and 
neutralizing antibodies (PRNT) induced in healthy vaccinia-naïve subjects after vaccination with 
MVA-BN® drawn from three (3) BN clinical studies (POX-MVA-005, POX-MVA-008 and 
POX-MVA-011) compared to responses obtained from five (5) NIH / DMID sponsored studies 
with Dryvax®/Wetvax (Aventis Pasteur Smallpox Vaccine [APSV]). All sera were analyzed 
using the same validated ELISA and PRNT assays, allowing a retrospective comparison of 
immune responses induced by MVA-BN® and the two first generation smallpox vaccines 
(Bavarian Nordic Scientific Report; Sept 2011). 
In conclusion, 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) was selected to demonstrate the efficacy of 
MVA-BN®. 
However, only very few subjects have seroconverted by Day 8 post vaccination with Dryvax® 
(Frey, 2003; Kennedy, 2004). Therefore, protection afforded by traditional smallpox vaccines 
would appear to occur in the absence of detectable antibodies. Therefore the second component 
of the strategy to demonstrate the protective efficacy of MVA-BN® is to evaluate in subjects 
immunized with MVA-BN® the absence and/or the attenuation of the take after subsequent 
scarification with ACAM2000®. This absence and/or the attenuation of the take has historically 
been associated with pre-existing immunity against smallpox infections, acquired either by 
previous vaccination(s) using conventional smallpox vaccines or a prior smallpox infection 
(Fenner, 1988). A significant reduction of the lesion size in vaccinia-experienced subjects 
following re-vaccination with traditional smallpox vaccines was also shown in controlled clinical 
trials. Vaccinia-experienced participants presented with significantly smaller skin lesions 
(Frey, 2003) or a reduced mean diameter of the peak lesion size (Parrino, 2007) after vaccination 
with Dryvax® compared to the full take observed in vaccinia-naïve individuals. In the above 
mentioned Phase I trial (POX-MVA-002 / DMID 02 017), MVA-BN® (even at lower doses, i.e. 
2x107 TCID50/ml) given prior to vaccination with Dryvax® reduced viral replication at the site of 
Dryvax® inoculation, resulting in a significantly diminished skin response (i.e. take), as well as 
an accelerated healing time, suggesting that immune responses induced by MVA-BN® were 
protective against vaccinia replication. Taken together, this experience strongly suggests that 

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attenuation of the take in MVA-BN® recipients following vaccination with ACAM2000® can be 
considered to indicate induction of a strong vaccinia-specific immunity. 
Therefore, the co-primary objective of the present trial is to demonstrate the efficacy of MVA-
BN® by showing that vaccination with MVA-BN® prior to scarification with ACAM2000® 
results in an attenuation of take. In the clinical trial POX-MVA-002 a reduction of average lesion 
area was observed in pre-vaccinated subjects and noted as being clinically relevant (Frey, 2003). 
There is a high subject to subject variability in the timing and level of attenuation observed, and 
the calculation of whether a subject has an attenuation of take therefore needs be considered as a 
defined concept that is calculated per subject for the period following scarification with 
ACAM2000®. 
The present trial will therefore define attenuation as when the takes observed in Group 1 subjects 
(MVA-BN® recipients vaccinated with ACAM2000®) are determined to be diminished full takes 
based on the median of the individual measured parameter of Maximum Lesion Areas in Group 1 
subjects, in comparison to the median of Maximum Lesion Areas of takes in Group 2 subjects 
(ACAM2000® recipients). 
Since these two components are considered important indicators of the protective efficacy of 
MVA-BN®, both will be co-primary endpoints of the present trial, i.e. to assess the non-
inferiority of MVA-BN® compared to ACAM2000® based on the neutralizing antibody GMT 28 
days after an ACAM2000® vaccination and on the neutralizing antibody GMT 42 days after the 
first MVA-BN® vaccination measured using a validated PRNT and to demonstrate the efficacy of 
MVA-BN® by showing that vaccination with MVA-BN® prior to scarification with ACAM2000® 
results in an attenuation of take. The day 28 time point was selected in order to be in alignment 
with published data for conventional smallpox vaccines reaching a peak four weeks post 
vaccination (Frey, 2003; Belshe, 2004; Kennedy, 2004; Frey, 2007), which is also in full 
agreement with the data published for ACAM2000® (ACAM2000 VRBPAC Briefing Document, 
2007). The clinical trials conducted for MVA-BN® to date consistently show that the peak 
responses are observed at Day 42 after the first MVA-BN® vaccination (Investigator Brochure). 
Further secondary objectives of the trial include a comparison of safety and reactogenicity of 
MVA-BN® and ACAM2000® vaccinations and the effect on the ACAM2000® vaccination take 
following MVA-BN® priming. 
It is planned to have at least 175 healthy vaccinia-naïve subjects per group (assigned to the PPS) 
vaccinated with either MVA-BN® and ACAM2000® or ACAM2000® alone. 
2.8 Trial Population 
Male and female United States military personnel aged 18 to 42 years, who meet all the inclusion 
criteria and none of the exclusion criteria. 

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2.9 Risk/Benefit Assessment 
2.9.1 Potential Risks 
Blood drawing may cause local discomfort or bleeding under the skin from needle sticks, 
resulting in a localized hematoma that generally resolves within 1 to 2 weeks. A rare 
complication may be localized infection at the phlebotomy site or thrombophlebitis (swelling of a 
vein caused by a blood clot). This would be treated as medically indicated. Some subjects may 
feel lightheaded, queasy, or nauseated; have chills; develop a fast heartbeat; and/or faint during 
blood collection. These symptoms can be resolved by having the subject lie down and/or by 
stopping the procedure. To minimize risks, only qualified personnel will draw blood. 
Preclinical data with MVA- BN® in rats and rabbits have revealed no special hazards for humans 
based on conventional studies of safety. 
Based on the present clinical experience with MVA-BN® and MVA-based vaccines, adverse 
reactions to MVA- BN® in this trial setting are expected to be comparable to adverse reactions 
previously reported for MVA-BN® and/or those typically seen with other modern vaccines. Main 
risks involve the development of local reactions at the vaccination site, e.g. erythema, pain, 
swelling and induration. 
As with all injected vaccines, there is a risk of an allergic reaction or an anaphylactic event. 
Clinical trial site staff will watch subjects for at least 30 minutes after each vaccination and in 
case a severe allergic reaction should occur, appropriate medical treatment and supervision will 
be readily available. 
Serious complications that may follow either primary ACAM2000® vaccination or revaccination 
include: myocarditis and/or pericarditis, encephalitis, encephalomyelitis, encephalopathy, 
progressive vaccinia (vaccinia necrosum), generalized vaccinia, severe vaccinial skin infections, 
erythema multiforme major (including Stevens-Johnson syndrome), eczema vaccinatum and 
blindness (ocular vaccinia), and fetal death in pregnant women. For risks associated with 
ACAM2000® please see the prescribing information (Appendix IVc; Section 17.7) and the 
medication guide (Appendix IVa; Section 17.5). 
MVA-BN® is replication incompetent in human cells and consequently has a favorable safety and 
tolerability profile. It is essentially impossible that MVA-BN® could induce the severe side 
effects listed above associated with replication competent vaccinia viruses. Apart from the 
favorable safety profile with regard to severe reactions, the available clinical experience with 
MVA-BN® shows that it is in general well tolerated, for example with regard to local reactions. 

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2.9.2 Benefits 
Based on the current immunogenicity and efficacy data collected for MVA-BN® and 
ACAM2000® in preclinical and clinical studies, trial participants are expected to acquire 
protection against smallpox infection. Subjects will contribute significantly to the development of 
a safer smallpox vaccine, which is a benefit for society in view of a potential threat following 
deliberate release of smallpox virus. 
Future analysis of the samples collected will not directly benefit the subject. BN may learn more 
about immune response to smallpox disease: prevention, treatment, or cure. 
3 Objectives 
3.1 Co-Primary Objectives 
To demonstrate the efficacy of MVA-BN® by assessing non-inferiority of MVA-BN® compared 
to ACAM2000® in terms of vaccinia-specific 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 
scarification with ACAM2000® results in an attenuation of take in terms of MLA. 
3.2 Secondary Objectives 
To assess non-inferiority of MVA-BN® compared to ACAM2000® in terms of vaccinia-specific 
ELISA antibody response at the Peak Visits. 
To assess seroconversion rates of MVA-BN® compared to ACAM2000® at the Peak Visits. 
To assess immune response dynamics in terms of antibody responses. 
To assess the effect on the ACAM2000® vaccination take following MVA-BN® priming.  
To assess and compare safety and reactogenicity of vaccinations with MVA-BN® and 
ACAM2000®given alone or ACAM2000®given after MVA-BN® priming. 

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4 Trial Design 
4.1 Experimental Design 
This trial is a randomized, open-label Phase III non-inferiority trial to demonstrate efficacy for 
MVA-BN® compared to ACAM2000® in 18 to 42 year old healthy, vaccinia-naïve subjects. 
Group 1 
MVA-BN®, two standard doses s.c., 4 weeks apart followed by one dose of ACAM2000® via 
scarification 4 weeks after the second MVA-BN® vaccination. 
Group 2 
ACAM2000®, one dose via scarification, in accordance with US military smallpox vaccine 
program. 
Subjects in Group 1 will participate in eleven physical trial visits, nine blood draws and one 
remote follow-up visit. Subjects in Group 2 will participate in seven physical trial visits, seven 
blood draws and one remote follow-up visit. For the schedule of the trial visits and the 
description of trial procedures, please refer to the trial procedure schedule and the following 
protocol sections. 
4.2 Description of Trial Procedures 
The trial procedures will be conducted according to the trial procedure schedule and as described 
in this CTP. Visits should be scheduled within the given time intervals. All blood tests are non-
fasting. 
4.2.1 Screening Phase 
Screening Visit (SCR, Day -70 to -1) 
The informed consent must be reviewed with and signed and dated by the subject prior to the 
initiation of any evaluations or procedures required by the protocol. All subjects must be 
thoroughly informed of all aspects of the trial (e.g. trial procedure schedule, required evaluations 
and procedures, risks and benefits) as described in the informed consent document. 
After informed consent has been signed, subjects will enter a screening period of up to ten weeks 
before the first vaccination. 
An extensive screening assessment will be performed during the screening period. 

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Screening Visit (Days -70 to -1) 
The following tasks will be performed: 
• 
Subject to read, sign and date Informed Consent Document (ICD) 
• 
Check inclusion/exclusion criteria (which incorporates the criteria from the US 
Department of Defense [DoD] Smallpox Vaccine Screening Forms) 
• 
Obtain medical/surgical history 
• 
Check vaccination history and absence of smallpox vaccine scar 
• 
Complete physical examination / vital signs (temperature, pulse, respiratory rate and 
blood pressure, including auscultation of heart and lungs and measurement of body 
weight and height and examination of axillary and supraclavicular lymph nodes) 
• 
Evaluation of vital signs, BMI calculation and calculation for creatinine clearance  
• 
Recording of baseline signs and symptoms 
• 
Check cardiac risk factors, including immediate family (father, mother, brother or sister) 
risk factors, total cholesterol, high-density and low-density lipoprotein (HDL, LDL) and 
calculation of individual cardiac risk factor 
• 
Perform baseline ECG 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread (specifically after ACAM2000® vaccination), 
HIV infection, and pregnancy: Review of acceptable contraceptive methods and recent 
menstrual history with WOCBP.  
• 
Blood draw (22 ml) for safety laboratory (CBC with differential, total bilirubin, Alk Phos, 
AST, ALT, creatinine, sodium, potassium and calcium) including total, HDL and LDL 
cholesterol, hepatitis serology (HBsAg, Anti-HCV), HIV, troponin I and serum 
pregnancy test  
If a subject is screened and cannot be vaccinated because of a certain transient condition (e.g. 
abnormal lab value due to an acute condition or a missing lab evaluation due to mishandling of 
the sample), then the subject can be re-screened on one further occasion only and the respective 
tests should be repeated as a "partial" re-screening rather than a “full” re-screening. The re-
screening visit must be within the 70 day window started by the first Screening Visit and the 
window -70 to 1 day before 1st vaccination must not be exceeded. A “partial” re-screening visit is 
indicated by completing only the respective re-screening sections of the Case Report Form 
(CRF). 

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If a subject could not be vaccinated due to other circumstances (e.g. intermediate closure of the 
trial group because of an interim safety analysis) and the 70 day period is over, a “full” re-
screening assessment including re-consenting, physical examination, lab examination, ECG must 
be performed. The clock then re-starts at the re-screening visit with Day -70 before 1st 
vaccination. A “full” re-screening visit is indicated by completing all re-screening CRF pages. 
4.2.2 Active Trial Phase 
After successfully passing the screening evaluations, the eligible subjects will enter the active 
trial phase starting with Visit 1. At Visit 1 subjects will be assigned randomly to one of the two 
treatment groups (Groups 1 or 2) after re-confirmation of subject’s eligibility. The active trial 
phase will continue until Visit 10 for Group 1 subjects and until Visit 4 for Group 2 subjects.  
The procedures performed at the active trial phase visits are listed below. Blood draws and all 
other examinations listed above the vaccination procedure must always be performed prior to 
vaccination. 
At Visit 1 / Day 0, subjects in Group 1 will receive the first of two s.c. vaccinations with one 
standard dose of MVA-BN® preferably in the non-dominant upper arm (deltoid region). Subjects 
in Group 2 will receive a single vaccination with ACAM2000®. One dose of reconstituted 
ACAM2000® vaccine consists of 2.5-12.5x105 plaque forming units of live VACV. A droplet 
(0.0025 ml) vaccine is picked up with a bifurcated needle and is administered by the 
percutaneous route (scarification) using 15 jabs of the bifurcated needle. Following vaccination 
subjects will be kept under close observation for at least 30 minutes, with appropriate medical 
treatment readily available in case of a rare anaphylactic reaction following the administration of 
the vaccine. Only appropriately trained and qualified medical personnel according to DoD 
guidelines will administer the ACAM2000® vaccination. The DoD Smallpox Vaccination 
Training curriculum is an online course for Military Healthcare Personnel and can be found under 
the weblink: http://www.vaccines.mil/default.aspx?cnt=ImzU/SmallpoxTraining. ACAM2000® 
will be administered in the appropriate designated military site clinic and will be the 
responsibility of the administering military site clinic. 
Further information on the ACAM2000® product can be found in Appendix IVc; Section 17.7: 
ACAM2000® Prescribing Information. Information on the medical management of adverse 
reactions after ACAM2000® vaccination can be found in Appendix V; Section 17.15: Medical 
Management of Smallpox (Vaccinia) Vaccine Adverse Reactions: Vaccinia Immune Globulin 
and Cidofovir. 
Subjects receiving MVA-BN® may have the vaccination site covered with a BAND-AID® or 
equivalent as needed. Subjects receiving ACAM2000®  will have the vaccination site covered 
with a semi-permeable bandage provided in a Care Kit (the contents of which will be defined in 
agreement with the trial site staff and will be the same for all ACAM2000®  vaccinated subjects). 
The vaccination site must be kept covered for 30 days and/or until the site is healed. The vaccinee 

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should change the bandage as instructed by the administering clinic (leave the bandage on for the 
1st 48 hours, then change every day or when bandage becomes wet) until the vaccination site scab 
falls off as this will keep the vaccination site intact and will minimize softening. Salves or 
ointments must not be applied to the vaccination site.  
Any AEs that occur during or after vaccination will be recorded. All subjects will be asked to 
record, on a subject memory aid, daily maximum temperatures and solicited AEs for 15 days, 
beginning with the day of vaccination and report them to the research staff. If solicited AEs 
persist after 14 days post vaccination, daily symptoms and temperatures will continue to be 
measured each day until resolved or Visit 10 (Group 1) or Visit 4 (Group 2) respectively. 
Visit 1 (Day 0) 
Tasks to be performed prior to randomization and vaccination: 
• 
Re-check inclusion/exclusion criteria 
• 
Check of safety laboratory results obtained at Screening Visit 
• 
Targeted physical examination, including auscultation of heart and lungs, see 
Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Recording of baseline signs and symptoms 
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Assessment of axillary and supraclavicular lymphadenopathy, see Section 8.2.3 for more 
details 
• 
Examination of the possible deltoid vaccination sites 
• 
Counseling on avoidance of contact spread (specifically after ACAM2000® vaccination), 
HIV infection and pregnancy 
• 
Urine or serum pregnancy test (5 ml, if applicable) 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
Blood draws and all other tasks mentioned above must always be performed prior to 
vaccination. If the subject is still eligible for participation in this trial, the subject will be 
randomized. The following tasks will be performed after randomization: 
• 
Vaccination: 
Group 1: administration of one (1) dose of MVA-BN® 
  
 
Group 2: administration of one (1) dose of ACAM2000® 
• 
Subject observation by clinical trial site staff for at least 30 minutes after vaccination 

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Visit 1 (Day 0) 
• 
Examination of the vaccination site and/or the area around the bandage for skin reactions 
(approximately 30 minutes after vaccination) 
• 
Recording of immediate AEs/SAEs/AESIs 
• 
Handout of memory aid, ruler and thermometer 
• 
Bandage application and handout of clinical trial specific Care Kits to Group 2 subjects 
only 
• 
After ACAM2000® scarification subjects should change their own bandage as instructed 
by the administering clinic (leave the bandage on for the 1st 48 hours, then change every 
day or when bandage becomes wet) using the clinical trial specific Care Kits provided by 
site staff 
Temporary deferral of vaccination: If an acute illness is present at the time scheduled for the 
vaccination, the subject may be vaccinated at a later date within the foreseen time window. The 
vaccine can be administered to persons with a minor illness such as diarrhea, mild upper 
respiratory infection, or any other mild condition with or without low-grade febrile illness, i.e. 
oral temperature < 100.4°F (< 38.0°C). 

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Visit 2 (Visit 1 + 6-8 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs (if clinically 
indicated); see Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Counseling on avoidance of contact spread (specifically after ACAM2000® vaccination), 
HIV infection and pregnancy 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Examination of vaccination site 
• 
Recording of AEs/SAEs/AESIs 
• 
Review of memory aid 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
Group 2 only: 
• 
Photo of vaccination site 
• 
Bandage application/change 

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Visit 3 (Visit 1 + 13-15 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Perform ECG  
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread (specifically after ACAM2000® vaccination), 
HIV infection and pregnancy 
• 
Examination of the vaccination site 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Collection of the memory aid and review with subject 
• 
Blood draw for safety laboratory (CBC with differential, total bilirubin, Alk Phos, AST, 
ALT, creatinine, sodium, potassium and calcium, 10 ml) including troponin I testing 
• 
Blood draw (serum collection) for antibody analysis (16 ml)  
• 
If vaccination site has not yet fully healed then a memory aid extension would be handed 
out 
Group 2 only: 
• 
Photo of vaccination site 
• 
Bandage application/change 

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Visit 4 (Visit 1 + 27-29 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread (specifically after ACAM2000® vaccination), 
HIV infection and pregnancy. Group 2: Counseling for avoidance of pregnancy not 
required. 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Examination of vaccination site 
• 
Urine or serum pregnancy test (5 ml, if applicable) 
• 
Recording of AEs/SAEs/AESIs 
• 
Blood draw (serum collection) for antibody analysis (16 ml)  
• 
If a memory aid extension had been provided at Visit 3 then a review of the memory aid 
extension should be conducted and the memory aid collected 
Group 1: 
Tasks mentioned above must always be performed or repeated prior to vaccination 
• 
Second administration of one (1) dose of MVA-BN® 
• 
Subject observation by clinical trial site staff for at least 30 minutes after vaccination 
• 
Handout of memory aid 
• 
Recording of immediate AEs/SAEs/AESIs 
Temporary deferral of vaccination: If an acute illness is present at the time scheduled for the 
vaccination, the subject may be vaccinated at a later date within the foreseen time window. The 
vaccine can be administered to persons with a minor illness such as diarrhea, mild upper 
respiratory infection, or any other mild condition with or without low-grade febrile illness, i.e. 
oral temperature < 100.4°F (< 38.0°C). 

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Visit 4 (Visit 1 + 27-29 days) 
Group 2: 
• 
If vaccination site has not yet fully healed then another memory aid extension would be 
handed out.  
• 
Bandage application/change 
 
All subsequent visits are relevant for Group 1 subjects only. 
Visit 5 (Group 1: Visit 4 + 6-8 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs (if clinically 
indicated); see Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Counseling on avoidance of HIV infection and pregnancy 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Examination of vaccination site 
• 
Review of memory aid 
 
Visit 6 (Group 1: Visit 4 + 13-15 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Perform ECG (if clinically indicated) 
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 

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Visit 6 (Group 1: Visit 4 + 13-15 days) 
• 
Counseling on avoidance of HIV infection and pregnancy 
• 
Examination of the vaccination site 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Collection of the memory aid handed out at Visit 4 and review with subject 
• 
Recording of AEs/SAEs/AESIs 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
• 
Blood draw for safety laboratory (CBC with differential, total bilirubin, Alk Phos, AST, 
ALT, creatinine, sodium, potassium and calcium, 10 ml) 
 
Visit 7 (Visit 1 + 55-57 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread, HIV infection and pregnancy 
• 
Examination of vaccination site 
• 
Assessment of axillary and supraclavicular lymphadenopathy, see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Urine or serum pregnancy test (5 ml, if applicable) 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
• 
Check of safety laboratory results obtained at Visit 6 
 
Tasks mentioned above must always be performed prior to vaccination.  
• 
Administration of one dose of ACAM2000® 

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Visit 7 (Visit 1 + 55-57 days) 
 
The following tasks will be performed (or repeated) after vaccination: 
• 
Subject observation by clinical trial site staff for at least 30 minutes after vaccination 
• 
Handout of memory aid 
• 
Recording of immediate AEs/SAEs/AESIs 
• 
Examination of the vaccination site and/or the area around the bandage for skin reactions 
(approximately 30 minutes after vaccination) 
• 
Bandage application and handout of clinical trial specific Care Kits 
Temporary deferral of vaccination: If an acute illness is present at the time scheduled for the 
vaccination, the subject may be vaccinated at a later date within the foreseen time window. The 
vaccine can be administered to persons with a minor illness such as diarrhea, mild upper 
respiratory infection, or any other mild condition with or without low-grade febrile illness, i.e. 
oral temperature < 100.4°F (< 38.0°C). 
 
Visit 8 (Visit 7 + 6-8 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs (if clinically 
indicated); see Section 8.2.3 for more details 
• 
Evaluation of vital signs 
• 
Counseling on avoidance of contact spread, HIV infection and pregnancy 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Examination of vaccination site 
• 
Photo of vaccination site 
• 
Bandage application/change 
• 
Review of memory aid 
 

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Visit 9 (Visit 7 + 13-15 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details  
• 
Evaluation of vital signs 
• 
Perform ECG  
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread, HIV infection and pregnancy 
• 
Examination of the vaccination site 
• 
Photo of vaccination site 
• 
Bandage application/change  
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Collection of the memory aid handed out at Visit 7 and review with subject 
• 
If vaccination site has not yet fully healed then a memory aid extension would be handed 
out 
• 
Blood draw for safety laboratory (CBC with differential, total bilirubin, Alk Phos, AST, 
ALT, creatinine, sodium, potassium and calcium, 10ml) including troponin I testing 
 
Visit 10 (Visit 7 + 27-29 days) 
The following tasks will be performed 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details  
• 
Questions on cardiac signs and symptoms 
• 
Review of prior/concomitant medications 
• 
Counseling on avoidance of contact spread and HIV infection  

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Visit 10 (Visit 7 + 27-29 days) 
• 
Examination of the vaccination site 
• 
Bandage application/change 
• 
Assessment of axillary and supraclavicular lymphadenopathy; see Section 8.2.3 for more 
details 
• 
Recording of AEs/SAEs/AESIs 
• 
Urine or serum pregnancy test (5 ml, if applicable) 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
• 
If a memory aid extension had been provided at Visit 9 then a review of memory aid 
extension should be conducted and the memory aid collected 
4.2.3 Follow Up Phase 
Visit 5 (Group 2: Visit 1 + 41-43 days) 
The following tasks will be performed 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
 
Visit 6 (Group 2: Visit 1 + 55-57 days) 
The following tasks will be performed 
• 
Blood draw (serum collection) for antibody analysis (16 ml) 
 
To monitor long-term safety, the clinical trial site will contact the subjects by remote 
correspondence (e.g. telephone or email) 6 months after the last trial vaccination to inquire 
whether SAEs and/or AESIs might have occurred since the last trial visit. In cases where a 
serious condition is detected, the trial subject will be asked to return for a physical examination 
and further work-up at the clinical trial site or (specifically in the case of deployed military 
subjects) at another medical unit as agreed upon by the Principal Investigator (PI). 

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Remote FU (Last vaccination + 182 – 210 days) 
The following tasks will be performed: 
• 
FU on ongoing AEs, AESIs, SAEs and recording of new SAEs/AESIs 
In case a physical visit is deemed necessary, the following should be performed: 
• 
Targeted physical examination, including auscultation of heart and lungs; see 
Section 8.2.3 for more details 
• 
Review of prior / concomitant medications, (if related to an ongoing AE, AESIs, SAEs 
and new SAEs/AESIs)  
• 
Blood draw (10 ml) for safety laboratory (CBC with differential, total bilirubin, Alk Phos, 
AST, ALT, creatinine, sodium, potassium and calcium, if clinically indicated) 
• 
Other safety evaluation, if clinically indicated 
 
4.2.4 Unscheduled Visits 
If clinically indicated, additional visits may be necessary between scheduled visits. Unscheduled 
visits may be performed to repeat laboratory testing or physical exams due to a new development. 
Unscheduled visits may occur when subjects request assistance with or experience problems with 
bandage changes after ACAM2000® vaccination. In cases where the vaccination site has not fully 
healed at Visit 4 in Group 2 subjects and at Visit 10 in Group 1 subjects, then the subject would 
be asked to provide date that scab fell off. Examinations, performed at unscheduled visits will be 
documented in the source documents as well as on the respective CRF pages for unscheduled 
visits. 
4.2.5 Withdrawal from Further Trial Vaccinations (Group 1) 
The decision not to administer further trial vaccinations can be made by the PI as well as by the 
subject. 
Criteria: 
For Group 1 subjects the following criteria should be checked prior to administration of the 
second MVA-BN® vaccination at Visit 4 and the ACAM2000® vaccination at Visit 7. 
If any are applicable, the subject should not receive any of these vaccinations: 

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• 
Any clinically significant cardiac sign and symptom. 
The detection of cardiac events indicative for cases of myo-/pericarditis are collected as 
AESI, defined as: 
o Any cardiac sign or symptom (e.g. chest pain, shortness of breath etc.) developed since 
the first vaccination  
o ECG abnormalities determined to be clinically significant by the investigating 
physician 
o Cardiac enzyme troponin I ≥ 2 x ULN (≥ Grade 2 according to the toxicity scale 
provided in Appendix I; Section 17.1) 
Case definitions for acute myocarditis and pericarditis, as published by the Center of Disease 
Control and Prevention (CDC) (MMWR, May 30, 2003) are provided in Appendix III; 
Section 17.3, in order to: 
o help Investigators to recognize possible events of acute myocarditis and/or pericarditis 
and 
o distinguish from unspecific and isolated ECG abnormalities without or with unclear 
clinical significance.  
• 
An AE that, in the opinion of the investigator, makes it unsafe for the subject to receive any 
further trial vaccination. In this case, the appropriate measures will be taken 
• 
Anaphylactic reaction following the administration of any vaccine(s) 
• 
Start of chronic administration (defined as more than 14 days) of > 5 mg prednisone (or 
equivalent) per day or any other immune-modifying drugs 
• 
Administration of immunoglobulins and/or any blood products 
• 
Clinical need for concomitant or ancillary therapy not permitted in the trial 
• 
Use of any investigational or non-registered drug or vaccine other than the trial vaccine 
• 
Any condition which contradicts administration of any further trial vaccination in the 
opinion of the investigator 
• 
Pregnancy 
• 
Subject refuses to receive any further vaccination 
 

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Procedure: 
If the subject is withdrawn from further trial vaccinations the reason for this decision should be 
recorded. The procedures below should be followed: 
If withdrawn after the 1st MVA-BN® vaccination 
• 
All visits up to Visit 4 must be performed according to the trial procedure schedule. 
• 
Visit 5 to Visit 10 will not be performed. 
• 
The remote FU Visit has to be performed 182 to 210 days after Visit 1. 
 
If withdrawn after the 2nd MVA-BN® vaccination 
• 
All visits up to Visit 7 must be performed according to the trial procedure schedule 
• 
Visit 8 to Visit 10 will not be performed 
• 
The remote FU Visit has to be performed 182 to 210 days after Visit 4 
 
4.2.6 Premature Discontinuation 
The trial may be discontinued prematurely for a subject at any time. The decision to discontinue a 
subject prematurely can be made by the PI as well as by the subject. Reasons may include, but 
are not limited to, the following: 
Criteria: 
• 
Subject’s request to discontinue prematurely 
• 
Subject unwilling or unable to comply with trial requirements 
• 
Any reason that, in the opinion of the investigator, precludes the subject’s further 
participation in the trial 
Procedure: 
If a subject discontinues prematurely, the reason for this decision should be recorded. If the 
subject is unable or not willing to attend all planned visits, every attempt should be made to 
perform at least a concluding safety visit. For WOCBP a pregnancy test should be performed 
during this safety visit. If the subject is not willing to undergo any further trial procedure 
(withdrawal of consent), "withdrawal of consent" needs to be documented in writing as reason for 
premature discontinuation. 

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4.3 Trial Duration 
The total duration of the trial for each subject including the screening period and remote FU will 
be up to 48 weeks. The duration of the trial as a whole is dependent on the recruitment period. 
4.4 Data Safety Monitoring Board 
The DSMB is an independent board that oversees the safety of subjects participating in the trial. 
The members of the DSMB are independent, i.e. not involved as investigators in any MVA-BN® 
trials and have no direct or indirect financial interests in BN or the Contract Research 
Organization (CRO) managing the trial. The primary responsibilities of the DSMB are to review 
periodically and to evaluate the accumulated trial data for participant safety, trial conduct and 
progress, and to make recommendations to BN and the PI(s) concerning the continuation, 
modification, or termination of the trial program. The DSMB considers trial specific data as well 
as relevant background knowledge about the disease, test agent, and subject population under 
trial. A separate charter describes in detail relevant operational procedures, communication 
pathways, roles and responsibilities of the DSMB. 
In case an event occurs which fulfils the trial halting criteria, the DSMB will review the event in 
a timely manner and give a recommendation to BN and the PI(s) to halt, resume or terminate the 
trial participation of the affected subject and/or the trial as a whole. 
4.5 Trial Halting Rules 
A temporary halting or termination for the trial as a whole can be decided by the DSMB in the 
event of an occurrence of  
• 
an SAE 
• 
an unexpected Grade 3 or higher systemic reaction or lab toxicity (Appendix I; 
Section 17.1) 
with an at least reasonable possibility of a causal relationship to the administration of MVA-BN®, 
i.e. the relationship cannot be ruled out. 
Suspected cases of illnesses such as progressive vaccinia, eczema vaccinatum, and severe 
generalized vaccinia or inadvertent inoculation or other SAE observed after smallpox vaccination 
with ACAM2000® should be reported immediately following standard of practice. VIG and 
Cidofovir are available from CDC for treatment of AEs among smallpox vaccine recipients and 
their contacts under IND protocols.  
Additionally, SAEs after ACAM2000® vaccination should be reported to the Vaccine Adverse 
Event Reporting System (VAERS). Reports can be submitted through a secure Internet-based 
system at https://vaers.hhs.gov/esub/step1. Printable VAERS forms are located online at 

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https://vaers.hhs.gov/resources/vaers_form.pdf, or postage-paid forms can be obtained by calling 
800 822 7967 (toll-free). Submission of VAERS reports by Internet is encouraged to expedite 
processing and data entry. Completed forms can be faxed to 877 721 0366 (toll-free) or mailed to 
P.O. Box 1100, Rockville, MD 20894-1100. Additional information related to VAERS reporting 
can be obtained by calling 800 822 7967 or by e-mail at info@vaers.org.  
These parameters are not all-inclusive. Other AEs could occur that would trigger a DSMB 
review. Any member of the DSMB, the PI and/or the BN Pharmacovigilance Officer could 
request a DSMB review based on any observation. 
If an event fulfilling the trial halting criteria reaches the investigator’s attention, the investigator 
has the responsibility to alert the responsible DS Department immediately (within 24 hours) and 
provide a comprehensive documentation of the event. Contact details of the responsible DS 
Department are provided in Section 8.3.1. 
5 Selection of Subjects 
The clinical trial site investigator or designee will keep a log of subjects screened for the trial 
according to the USAMRIID Standard Operating Procedure (SOP) 
 Clinical Trials 
Enrollment: Assignment of Subject Study Identification Numbers and Documentation of Subject 
Study Participation. 
5.1 Recruitment Procedure 
Subjects will be recruited from DoD personnel who are scheduled to receive their initial smallpox 
vaccination.  
Recruitment strategies, including IRB approved advertisements, will be evaluated by the 
Sponsor. Prospective volunteers will be briefed by trial personnel on the nature of the trial and 
will be provided the appropriate approved consent document describing all aspects of the 
research trial and procedures. Prospective volunteers will be provided the opportunity to discuss 
the trial with trial personnel. 
Up to 750 subjects may be screened in order to vaccinate 440 eligible healthy subjects (220 in 
each group) in order to obtain at least 175 subjects per group qualifying for the PPS. After 
signing the Informed Consent, subjects undergo screening procedures to check eligibility 
according to the inclusion/exclusion criteria (Section 1.4). In the event of a screening failure 
secondary to mild or limited acute illness or abnormal laboratory values, the subject may be re-
screened after resolution of the event. Re-screening may require only an additional blood draw or 
may require a full re-screening evaluation, depending on the circumstances of and the time 
interval from the initial screening failure as described in Section 4.2.1. 
 
(b) (1) (A)

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5.2 Inclusion Criteria 
1. 
Healthy male and female subjects, 18-42 years of age at date of informed consent signature 
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 ≥ 18.5 and < 35 
5. 
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 28 days after the last vaccination. A woman is 
considered of childbearing potential unless post-menopausal (defined as ≥ 12 months 
without a menstrual period) or surgically sterilized. (Acceptable contraception methods are 
restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or 
licensed hormonal products) 
7. 
HIV antibody negative, hepatitis B surface antigen negative and negative antibody test to 
hepatitis C virus 
8. 
White blood cells ≥ 2,500/mm3 and < 11,000/mm3 
9. 
Hemoglobin within normal limits 
10. 
Platelets ≥  lower normal limits 
11. 
Adequate renal function defined as a calculated 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) 
12. 
Adequate hepatic function in the absence of other evidence of significant liver disease 
defined as: 
• 
Total bilirubin ≤ 1.5 x ULN 
• 
ALT, AST ≤ 1.5 x ULN 
• 
Alk Phos ≤ 1.5 x ULN 
13. 
Troponin I < 2 x ULN 
14. 
Electrocardiogram (ECG) without clinically significant findings, e.g. without 
atrioventricular or intraventricular conditions or blocks such as incomplete/complete left or 

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complete right bundle branch block, second or third degree atrioventricular block, two 
premature ventricular contractions in a row, ST elevation consistent with ischemia, atrial or 
ventricular arrhythmia 
• 
QTc prolongations > 500 ms which do not require clinical intervention should be discussed 
with the Medical Monitor before vaccination  
• 
Following conditions can be included, if they do not require clinical intervention: 
o First degree atrioventricular block, PR interval prolongation, premature atrial 
contractions, occasional premature ventricular contractions, sinus bradycardia, right or 
left axis deviation, non-specific ST and T wave changes. 
Further guidance is provided in Appendix VI. 
5.3 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 (> 14 days) high-dose 
corticosteroids (> 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 screening or radiation, or immunosuppressive drugs; low-dose corticosteroid topical 
products and nasal sprays used sporadically, i.e. pro re nata 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. 
Recent surgery (including dental or eye) 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 

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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, 
significant arrhythmia with or without corrective/ablative surgery, 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, e.g. using the National Heart, Lung and Blood Institute’s Risk 
Assessment Tool: http://cvdrisk.nhlbi.nih.gov/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 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, recent tattoos or skin piercing (until it is healed, but not within 4 weeks 
prior to trial vaccination), 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 take assessment photograph) 
27. 
Having received any vaccinations or planned vaccinations with a live vaccine (except trial 
vaccine) within 28 days prior to or after trial vaccination 
28. 
Having received any vaccinations or planned vaccinations with a killed vaccine within 14 
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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)  
33. 
Temperature ≥ 100.4°F (38.0°C)  
34. 
Known household contacts with, or occupational exposure to (other than minimal contact) 
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 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 
35. 
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) 
36. 
Known allergies to ACAM2000® and its diluents including polymyxin B sulfate, neomycin 
sulfate, and phenol 
37. 
Known allergies to VIG including thimerosal or previous allergic reaction to 
immunoglobulins 
38. 
Known allergies to cidofovir, sulfa drugs, Tecovirimat (ST246) or probenecid 
39. 
Trial personnel 

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6 Investigational Product (MVA-BN®) and Comparator (ACAM2000®) 
6.1 MVA-BN® 
MVA-BN® is a highly attenuated live vaccinia virus. It will be provided as liquid-frozen aliquots 
in 2 ml glass vials. One dose of 0.5 ml vaccine has a nominal virus titer of 1x108 TCID50 MVA 
BN®. MVA-BN® will be given s.c. 
For further details please refer to current version of the Investigator’s Brochure. 
6.1.1 Production, Packaging and Labeling 
MVA-BN®: 
The MVA-BN® bulk drug substance is produced at Bavarian Nordic A/S and the MVA-BN® 
final drug product is formulated, filled and labeled at the contract manufacturer 
 
. 
Addresses: 
Bavarian Nordic A/S 
 
 
 
 
 
 
 
 
 
 
  
The packages and vials will be labelled with the US IND label. 
6.1.2 Shipment, Storage and Handling 
MVA-BN® will be shipped temperature controlled from the warehouse to the clinical trial site. 
The package is handed over to the personnel in charge of vaccine preparation, e.g. the 
pharmacist. After receipt of vaccine this personnel is responsible for proper storage. 
Liquid-frozen MVA-BN® must be stored at -4°F ± 9°F (-20°C ± 5°C) avoiding direct light. A 
vial should not be re-frozen once it has been thawed. Details on shipment, storage and handling 
are provided in BN’s SOP 
 entitled “Storage, Handling and Vaccination Procedures 
of Liquid Frozen MVA-BN® (IMVAMUNE®) and Recombinant MVA-based Vaccines in 
Clinical Trials”. 
6.1.3 Preparation, Administration and Dosage 
The preparation of the vaccine will be performed by authorized personnel only.  
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Details on vaccine preparation, administration and dosage of MVA-BN® is provided in BN’s 
SOP 
, entitled “Storage, Handling and Vaccination Procedures of Liquid Frozen 
MVA-BN® (IMVAMUNE®) and recombinant MVA-based vaccines in Clinical Trials”. 
6.1.4 Accountability and Disposal 
After receipt of MVA-BN®, the clinical trial site personnel have the responsibility for 
distribution, proper storage and vaccine accountability. Logs of receipt, temperature, 
maintenance, and disposal must be maintained by the responsible personnel in the trial regulatory 
file.  
Used and unused vials should be stored in a safe place and remain the property of BN. The 
personnel of the respective clinical trial site are responsible for ensuring adequate accountability 
of all used and unused MVA-BN®. This includes acknowledgement of receipt of each shipment 
of MVA-BN® (quantity and condition) and MVA-BN® accountability using an MVA-BN® 
inventory log. The MVA-BN® inventory log will document quantity of MVA-BN® received, 
quantity of MVA-BN® used for vaccination (including lot number, date dispensed, subject 
identification number and initials of the person dispensing MVA-BN®) and quantity of MVA-
BN® returned to BN or destroyed.  
Additionally, the quantity of MVA-BN® returned to BN or destroyed has to be documented on an 
MVA-BN® return/destruction form. In case destruction at the clinical trial site is agreed, material 
should be autoclaved or incinerated and discarded at the clinical trial site according to local 
regulations. 
Furthermore, used syringes should be autoclaved or incinerated and discarded at the clinical trial 
site according to local regulations. 
6.2 ACAM2000® 
For details regarding shipment/storage/handling and preparation/administration/dosage of 
ACAM2000® please refer to the ACAM2000® prescribing information (Appendix IVc; 
Section 17.7). The clinical trial site will follow local procedures in line with DoD guidance. 
6.2.1 Accountability and Disposal 
The military trial site personnel have the ultimate responsibility for distribution, proper storage, 
vaccine administration and vaccine accountability of ACAM2000®. ACAM2000® vaccine given 
under the auspices of the Defense Health Agency (DHA) and clinical trial site will follow local 
procedures in guidance with DoD guidelines. Logs of receipt, temperature, maintenance, and 
disposal are the responsibility of the site personnel following local procedures in line with DoD 
guidance. 
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6.2.2 Treatment of Adverse Events after ACAM2000® Vaccination 
A smallpox factsheet containing information for clinicians and public health professionals 
entitled: “Medical Management of Smallpox (Vaccinia) Vaccine Adverse Reactions: Vaccinia 
Immune Globulin and Cidovovir” can be found on the CDC website: 
http://www.bt.cdc.gov/agent/smallpox/vaccination/mgmt-adv-reactions.asp and is contained in 
Appendix V; Section 17.15: Medical Management of Smallpox (Vaccinia) Vaccine Adverse 
Reactions: Vaccinia Immune Globulin and Cidofovir of this CTP. 
The US Health Affairs policy memorandum (Appendix IV; Section 17.4) offers useful advice 
regarding the management of AEs after vaccination. These clinical guidelines are available at the 
DHA Web site at www.vaccines.mil. 
As stated in the US Health Affairs Memorandum issued by the US Assistant Secretary of Defense 
in April 2008, VIG is indicated for the treatment or modification of certain conditions induced by 
the smallpox vaccine. Consultation with a board certified infectious disease or allergy-
immunology specialist is required prior to administration. The VHC Network will provide and 
coordinate professional consultation services to optimize clinical use of VIG, and then maintain a 
registry of patients treated with VIG. Long-distance consultations will be arranged via the VHC 
Network’s Vaccine Clinical Call Center (
). An infectious disease or allergy 
immunologist, in consultation with the VHC, and CDC physician, authorizes release of VIG. VIG 
is requested directly from the CDC by calling the CDC Director’s Emergency Operation Center 
at (
) and request to speak with the Division of Bioterrorism Preparedness and 
Response on-call person. The CDC is the release authority for VIG. 
7 Assessment of Immunogenicity and Efficacy 
7.1 Humoral Immune Response 
Analysis of humoral immune response is planned to occur at Visit 1 (baseline measurement) 
through Visit 4 for both groups and additionally for the Group 1 subjects at Visit 6, Visit 7 and at 
Visit 10 and for Group 2 subjects at Visit 5 and 6. Baseline (i.e. Visit 1 [Week 0]), Visit 4 (Week 
4) and Visit 7 (week 8) blood samples will be drawn prior to any scheduled vaccination. 
The immune response measured at the Peak Visits by validated vaccinia-specific PRNT and 
vaccinia-specific ELISA will be used as the relevant immunologic response for the assessment of 
non-inferiority. 
Antibody responses to MVA-BN® and ACAM2000® will be measured using a vaccinia-specific 
PRNT and a vaccinia-specific ELISA which were established and validated at BN. Endpoint 
GMT titers will be done on all subjects, independent from their baseline immune status. The tests 
will be performed at BN, Martinsried, Germany. All immunological clinical analysis personnel 
will be blinded to subject randomization details. 
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The methods for collection, storage and handling of lab specimens for the immune analysis are 
specified in a separate manual which will be provided to the investigators before enrollment. 
Additionally, training will be provided on the procedures during the investigator meeting and/or 
at the initiation visit. The protocols for the analytical tests performed are detailed in the BN SOPs 
listed below in the assay sections. Copies of the SOPs (from BN and the CRO), effective at the 
time of trial conduct will be filed in the Trial Master File. 
7.1.1 PRNT 
The PRNT GMT is calculated by taking the antilogarithm of the mean of the log10 titer 
transformations. Antibody titers below the ACV will be given an arbitrary value of one for the 
purpose of calculation. 
The seroconversion rate is defined as the percentage of initially seronegative subjects with 
appearance of antibody titers ≥ the ACV in a vaccinia-specific PRNT using Vaccinia Virus 
Western Reserve as challenge virus. 
Details on the PRNT assay procedure can be found in SOP 
: “Human Plaque 
Reduction Neutralization Test Using Vaccinia Virus Western Reserve”. 
7.1.2 ELISA 
The ELISA GMT is calculated by taking the antilogarithm of the mean of the log10 titer 
transformations. Antibody titers below the ACV will be given an arbitrary value of one for the 
purpose of calculation. 
The seroconversion rate is defined as the percentage of initially seronegative subjects with 
appearance of antibody titers ≥ ACV in a vaccinia-specific ELISA using MVA as antigen. 
Details on the ELISA assay procedure can be found in SOP 
: “Automated ELISA for 
Detection of Vaccinia Specific Antibodies in Human Sera”. 
7.2 Future Use of Lab Specimen 
Serum specimens remaining after completion of all immunogenicity analysis for the trial are 
planned to be stored for future analysis supporting the licensure path of MVA-BN®. Future 
analyses would facilitate bridging trial data to animal immunogenicity data and/or to immune 
response data collected from subjects vaccinated with conventional smallpox vaccines.  
Subjects will be asked for consenting to future storage / use of samples and will be informed 
about data protection measures. Specimens will be stored in BN’s secured laboratory area or at an 
external storage facility in a coded, anonymized manner to ensure data protection. Genetic testing 
will not be performed. 
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7.3 Measurement of the Take 
A digital photograph will be taken of the vaccination site at the visits 6-8 days and 13-15 days 
after scarification with ACAM2000®.  
The system for capturing the digital photographs and measuring the area of the lesion is described 
in detail in the ITRC Charter. 
The ITRC will confirm the correct measurement of the lesion area by reviewing blinded subject 
profiles (as described in the ITRC Charter). Statistical calculations for attenuation of take will be 
based on the ITRC confirmed lesion areas. 
The healing will be confirmed by the investigator at the appropriate scheduled visit. 
7.4 Assessment of ACAM2000® Vaccination Site 
The vaccination site will be examined by the Investigator or designee on Day 0 (prior to 
vaccination), and Days 7, 14 and 28 post vaccination with ACAM2000®. The day 6-8 
examination (Visit 8 for Group 1 and Visit 2 for Group 2) is critical to the determination of a 
successful vaccination, and the day 13-15 examination (Visit 9 for Group 1 and Visit 3 for Group 
2) is critical to the determination of the co-primary endpoint and subjects should be strongly 
encouraged to return for these clinical visits on schedule. The examiner shall wear protective 
gloves during each examination.  
During the examination, the vaccination site will be examined and scored for the following 
parameters: 
• 
healing time (i.e. number of days until scab separates from the skin) 
• 
major lesion diameter (mm) 
• 
major erythema diameter (mm) 
• 
major induration diameter (mm). 
If the shape of the lesion, erythema and induration observed is not round but rather asymmetrical 
then the maximum cross-sectional measurement would be recorded. 
The type of lesion will also be noted (specifying papule, vesicle, pustule, ulcer, crust or scab). 
In the unlikely circumstance that there is more than one lesion, this fact will be noted in the CRF 
but the satellite lesions would not be measured. 
Individual take rates will be classified as either full, partial or absent take. The categorization will 
be in line with the World Health Organization (WHO) criteria for a “Major Reaction” as listed in 

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the US Health Affairs Memorandum issued by the US Assistant Secretary of Defense in April 
2008 (Appendix IVf; Section 17.10), namely: 
A vesicular (blistery) or pustular (pus-filled) lesion or area of definite palpable induration or 
congestion surrounding a central lesion that might be a crust or an ulcer. 
After primary (first) vaccination, the vaccination site usually progresses as follows (and will be 
referred to as “full take” in the POX-MVA-006 CTP): 
• 
The inoculation site becomes reddened and pruritic 3 to 4 days after vaccination. 
• 
A vesicle surrounded by a red areola then forms, which becomes umbilicated (collapsed 
center) and then pustular by days 7 to 11 after vaccination. 
• 
The pustule begins to dry; the redness subsides; and the lesion becomes crusted between the 
second and third week, the scab falls off, leaving a permanent scar that at first is pink in 
color but eventually becomes flesh colored. 
7.5 Independent Take Review Committee 
BN has established the blinded ITRC consisting of 3 physicians experienced in scarification of 
replicating smallpox vaccines. The ITRC will assess the responses of subjects vaccinated with 
ACAM2000®. This committee will act independent of the DSMB. The purpose of having an 
ITRC to review subject profiles is to provide an independent determination of take responses and 
to assure a consistent evaluation of subject responses. A Charter describes the details of the 
committee’s requirements, organization and obligations. 
The ITRC’s determinations will be considered the source data for the analysis of the individual 
takes observed in the MVA-BN®-experienced ACAM2000® boosted subjects (Group 1) and the 
MVA-BN®-naïve ACAM2000® vaccinated subjects (Group 2). 
More information on the ITRC’s assessment criteria can be found in the ITRC Charter. 
8 Safety and Reactogenicity 
Taking into account the medical history of the subject, safety will be monitored by performing 
physical examinations including vital signs, routine laboratory measurements as well as by 
evaluating local and general solicited AEs and unsolicited AEs.  
Using replication-competent 1st and 2nd generation vaccinia-based smallpox vaccines during 
smallpox vaccination programs in the USA during the last years, cases of acute myocarditis and 
pericarditis were observed (Cassimatis, 2004). Therefore special cardiac monitoring assessments 
will be performed. 

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8.1 Definitions 
8.1.1 Medical History 
Symptoms present before or at the screening visit will be documented in the medical history. 
8.1.2 Baseline Signs and Symptoms 
Any new signs, symptoms or changes in health starting after ICD signed and before the first 
vaccination will be recorded in the "baseline signs and symptoms" section of the CRF and in the 
subject`s research record. Symptoms starting prior to ICD being signed will be documented in 
medical history. 
8.1.3 Adverse Events 
New signs, symptoms or changes in health starting after the first vaccination are documented in 
the AE section. AEs are recorded based on unsolicited and solicited questioning (Section 8.1.3.1 
and 8.1.3.2). 
8.1.3.1 Unsolicited Adverse Events 
Unsolicited AEs are defined as any untoward (undesirable) occurrence of a medical event in a 
clinical trial subject temporally associated with the administration of an Investigational Medicinal 
Product (IMP) or a medical product (MP) which does not necessarily have a causal relationship 
with this IMP/MP. Up to Visit 10 all AEs (e.g. feeling of ill-health, subjective symptoms and 
objective signs, intercurrent diseases, accidents, etc.) observed by the investigator and/or reported 
by the subject must be recorded in the CRF regardless of the assessment of causality in 
relationship with the IMP/MP.  
Abnormal laboratory values assessed as being clinically significant by the investigator are to be 
documented as AEs. In addition, abnormal laboratory values fulfilling the Grade 3 or Grade 4 
criterion according to the toxicity scale (Appendix I; Section 17.1) are to be documented as AE in 
the CRF, regardless of whether they are considered clinically relevant or not. Toxicity grade and 
seriousness of an AE will be assessed separately, i.e. a Grade 3 or Grade 4 AE will not 
automatically be regarded as serious. 
At every trial visit up to Visit 10 in Group 1 and up to Visit 4 in Group 2, the investigator will ask 
the subject if they have experienced any AEs since their last visit. All intercurrent diseases 
reported by the subject need to be recorded by the investigator in the appropriate page of the 
CRF. 
8.1.3.2 Solicited Adverse Events 
Within this CTP solicited AEs are defined as all symptoms specifically listed in the memory aid 
provided to the subjects following each vaccination. The subjects are requested to monitor and 
record local symptoms (i.e. pain, redness (erythema), swelling, induration, itching (pruritus) and 

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vaccination site appearance (normal/healed, red spot, bump, reddish blister, whitish blister, scab, 
ulcer/crater, warmth, swollen >3in, red streaks, drainage) as well as general symptoms (i.e. body 
temperature, headache, muscle pain (myalgia), chills, nausea, fatigue, malaise, swollen 
lymphnodes) in the memory aid daily for the day of vaccination and the following 14 days (days 
0-14, 15 day period). Any symptoms persisting beyond Day 14 post vaccination are recorded in a 
memory aid extension. The definition of AEs originates from the MVA-BN® Investigator’s 
Brochure and the ACAM2000® Prescribing Information (Appendix IVc; Section 17.7). 
8.1.3.3 Adverse Event of Special Interest 
An AESI is defined in this trial as: 
• 
Any cardiac sign or symptom developed since the first vaccination 
• 
ECG abnormalities determined to be clinically significant 
• 
Cardiac enzyme troponin I ≥ 2 x ULN (≥Grade 2; see toxicity scale, Appendix I; 
Section 17.1) 
8.1.3.4 Serious Adverse Events 
A SAE is any untoward medical occurrence or reaction that at any dose: 
• 
Results in death 
• 
Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death, if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
or is an otherwise important medical event, e.g. 
o leads to suspicion of transmission of an infectious agent 
o suggests lack of efficacy of the product 
o documents an overdose of the product 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. 

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Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
8.2 Assessment 
8.2.1 Relevant Medical History 
Relevant medical history will be documented at the Screening Visit and will focus particularly on 
any important diseases and in case of infections or tumors, the pathogen involved or the 
pathological diagnosis, if available. Special attention should be given to history of prior allergic 
reactions, especially to vaccines. 
In addition, smallpox vaccination history will be assessed (check for a smallpox vaccine scar and 
any documentation (written/oral) of previous smallpox vaccination, if available). 
8.2.2 Prior and Concomitant Medications 
All concomitant (ongoing) medications except homeopathic substances and dietary supplements 
must be recorded in the CRF and in the subject`s medical record including information about the 
indication, dosage regimen, and the onset and end of treatment. 
The following medications, taken within three months prior to screening, will also be recorded in 
the CRF: Vaccines, corticosteroids (via any route of administration), other immune-modulating 
drugs, immunoglobulins and/or any blood products, investigational drugs and depot preparations 
which are still active at the date of screening. 
8.2.3 Physical Examination 
Complete physical examination 
A complete physical examination will be performed at the Screening Visit. The examination 
includes a review of major organ systems as well as height and weight. The examination should 
be directed at finding evidence of any infections, tumors and lymphadenopathy. In addition, 
auscultation of the heart and lungs to check specifically for signs of any heart condition will be 
performed. 
Targeted physical examination 
A targeted physical examination, guided by any signs or symptoms previously identified or any 
new symptoms that the subject has experienced since the last visit, is conducted at visits 
according to the Trial Procedure Schedule during the active trial phase. In addition, auscultation 
of the heart and lungs will be performed.  
 

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A grading scale for lymphadenopathy would apply as follows: 
Grade 0 (normal finding): no palpable lymph nodes  
Grade 1 (mild): lymph nodes up to a diameter of 1 cm, ipsilateral or bilaterally enlarged lymph 
nodes, signs of tenderness 
Grade 2 (moderate): lymph node diameter greater than 1 cm, ipsilateral or bilaterally enlarged 
lymph nodes, pain, skin redness, warmth, limiting instrumental activities of daily living (ADL) 
(instrumental ADL refer to performing work related duties, routine physical training activities, 
etc.) 
Grade 3 (severe): lymph node(s) diameter exceeds 2 cm, severe pain, general symptoms like 
fever and sweating limiting self-care activities of daily living (self-care ADL refer to performing 
personal needs, and not bedridden). 
8.2.4 Vital Signs 
Vital signs will be measured at visits according to the Trial Procedure Schedule. Blood pressure, 
respiration rate and pulse rate will be taken after the subject has been sitting for at least two 
minutes. Body temperature will be measured orally. 
8.2.5 Unsolicited Adverse Events 
During every trial visit following screening, the investigator has to report any unsolicited AE 
experienced by the subject. 
All intercurrent diseases reported when the investigator actively inquiries from the subject will be 
documented in the source data and all required details (e.g. start and stop date, severity) will be 
assessed. Unsolicited AEs will be reported in the AE section of the CRF. 
AEs will be assessed and documented at all visits of the active trial phase and if ongoing after the 
active trial phase followed until resolution or until the remote FU visit at the latest. 
SAEs and AESIs will be assessed and documented at all trial visits, including the remote FU 
Visit. Ongoing AESIs and SAEs after first vaccination will be followed up until resolution or 
achievement of stable clinical conditions. 

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Assessment of Intensity  
For all unsolicited AEs not represented in the Toxicity Scale for Laboratory Values (Appendix I; 
Section 17.1), grading of the maximum intensity will be based on the following descriptions: 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and not 
interfering with activities of daily living. 
Grade 2 
An AE which is sufficiently discomforting to interfere with activities of daily living. 
Grade 3 
An AE which prevents activities of daily living. (Such an AE would, for example, 
prevent attendance at work and would necessitate the administration of corrective 
therapy.) 
Assessment of Causality 
The relationship between the occurrence of an AE and the IMP and the Comparator will be 
assessed using the categories presented below. For expedited reporting and all other purposes, the 
categories “none” and “unlikely” will represent no evidence or argument to suggest a causal 
relationship, while “possible”, “probable” and “definite” will be seen to convey that there is 
evidence or argument to suggest a causal relationship. Following worst case scenario all AEs 
without a causality assessment from the investigator will be classified as “possible”: 
 
 

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None 
• 
The time interval between the administration of the IMP or Comparator and 
the occurrence or worsening of the AE rules out a relationship, and/or 
• 
another cause is established and there is no evidence of a (concomitant) causal 
connection with or worsening caused by the IMP or Comparator. 
Unlikely 
• 
The time interval between administration of the IMP or Comparator and the 
occurrence or worsening of the AE makes a causal relationship unlikely, 
and/or 
• 
the known effects of the IMP, Comparator or substance class provide no 
indication of a (concomitant) causal connection with or worsening caused by 
the IMP or Comparator and there is another cause which serves as an adequate 
explanation, and/or 
• 
although the known effects of the IMP, Comparator or substance class make it 
possible to derive a plausible causal chain with regard to a (concomitant) 
causal connection or worsening; however, another cause is considerably more 
likely, and/or 
• 
another cause of the AE has been identified and a (concomitant) causal 
connection with or worsening caused by the IMP or Comparator is unlikely. 
Possible 
• 
A plausible causal chain with regard to a (concomitant) causal connection with 
/ worsening of the AE can be derived from the pharmacological properties of 
the IMP, Comparator or substance class. However, other approximately 
equally likely causes are known, or 
• 
although the pharmacological properties of the IMP, Comparator or substance 
class provide no indication of a (concomitant) causal connection with / 
worsening of the AE, there is no other known cause which provides an 
adequate explanation. 
Probable 
• 
The pharmacological properties of the IMP, Comparator or substance class, 
and/or 
• 
the course of the AE after discontinuation of the trial drug and possible 
subsequent re-exposure, and/or 
• 
specific findings (e.g. positive allergy test or antibodies against the IMP / 
Comparator / metabolites) suggest a (concomitant) causal connection with / 
worsening of the AE resulting from the IMP or Comparator; however another 
cause cannot completely be ruled out. 
Definite 
• 
The pharmacological properties of the IMP, Comparator or substance class 
and/or 
• 
the course of the AE after discontinuation of the IMP or Comparator and 
possible subsequent re-exposure, and/or 
• 
specific findings (e.g. positive allergy test or antibodies against the trial drug / 
metabolites) definitely indicate that there is a (concomitant) causal connection 
with / worsening of the AE resulting from the IMP or Comparator and there 
are no indications of other causes. 

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8.2.6 Solicited Adverse Events 
After each vaccination subjects receive a memory aid to record solicited local and general AEs 
most likely to occur on the day of vaccination and the following 14 days (days 0-14; 15 day 
period). 
All solicited symptoms observed after vaccination with details concerning the intensity and the 
course of the reaction should be documented there. The investigator or designee will collect this 
information during the following scheduled visits and transfer it to the CRF. Local and general 
reactions still ongoing after 14 days post vaccination will be measured or examined each day 
until resolution or Visit 10 (Group 1) or Visit 4 (Group 2) respectively. 
In case of severe and unexpected local and/or general reactions, the subject should be instructed 
to contact the trial physician outside of scheduled trial visits. 
8.2.6.1 Solicited Local Adverse Events 
The solicited local symptoms pain, redness (erythema), swelling, induration, itching (pruritus) 
and vaccination site appearance (normal/healed, red spot, bump, reddish blister, whitish blister, 
scab, ulcer/crater, warmth, swollen >3in, red streaks, drainage) are to be documented in the 
memory aid by the subject.  
To standardize procedures, uniform rulers will be handed out to all subjects for measurements of 
erythema, swelling and induration diameters, as will digital thermometers for oral measurements 
of body temperature. 
Assessment of Intensity 
Injection site erythema 
size measured in diameter 
Injection site swelling 
size measured in diameter 
Injection site induration 
size measured in diameter 
The maximum severity will be scored as follows: 
0 
= 
0 
1 
= 
< 30 mm 
2 
= 
≥ 30 – <100 mm 
3 
= 
≥ 100 mm 
Injection site pruritus: 
0 
= 
No symptoms 
1 
= 
Mild: routine daily activities not impaired  
2 
= 
Moderate: routine daily activities impaired 
3 
= 
Severe: prevents routine daily activities 

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Injection site pain: 
0 
= 
No pain 
1 
= 
Pain when touched 
2 
= 
Pain when moving the limb 
3 
= 
Spontaneously painful 
For red spot, bump, reddish blister, whitish blister, scabs, ulcers/craters, warmth, swollen > 3 in., 
red streaks or drainage the presence or absence of the symptom is captured in the memory aid. 
The injection site pruritus and injection site pain is rated by the subject in the memory aid. 
Assessment of Causality  
Solicited local AEs are defined as being related to the vaccine. 
8.2.6.2 Solicited General Adverse Events 
The solicited general symptoms body temperature, headache, myalgia, chills, nausea, fatigue, 
malaise, swollen lymph nodes, and are to be documented in the memory aid by the subject.  
Assessment of Intensity 
Subjects are asked to document the solicited general AEs in the memory aid as described in Table 
3 below. In the subject's memory aid, the grading of maximum symptom intensity is described in 
basic, easily understood language based on the following descriptions: 
Table 3 
Grading of General Symptoms from the Subject’s Memory Aid 
MedDRA coded Preferred Term 
General AEs 
Grade 
Maximum Severity 
Body temperature* 
0 
< 99.5°F (< 37.5°C) 
1 
≥  99.5 – <100.4°F ( ≥ 37.5 – < 38.0°C) 
2 
≥  100.4 – <102.2 F ( ≥ 38.0 – < 39.0°C) 
3 
≥  102.2 – <104°F ( ≥ 39.0 – < 40.0°C) 
4 
≥  104°F (≥ 40.0°C)  
Headache, Myalgia, Chills, Nausea,  
Fatigue, Malaise,  
0 
No symptoms 
1 
Mild: routine daily activities not impaired 
2 
Moderate: routine daily activities impaired 
3 
Severe: prevents routine daily activities 
Swollen lymph nodes 
Yes/No 
 
*Pyrexia is defined as oral temperature ≥ 100.4°F (≥ 38.0°C). 
Assessment of Causality  
Causal relationship between solicited general AEs and the vaccine will be assessed by the 
investigator using the same categories as for unsolicited AEs (see Section 8.2.5). 

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8.2.7 Cardiac Assessment 
To evaluate the cardiac profile of MVA-BN®, targeted physical exams including auscultation of 
the heart and lung will be performed (Section 8.2.3). Any kind of cardiac signs (i.e. discovered by 
the physician during examination of the subject) or symptom(s) (i.e. experienced and reported by 
the subject) detected during the trial such as but not limited to chest pain, dyspnea, arrhythmia or 
edema are recorded. 
ECG 
A standard 12-lead ECG will be taken at the Screening Visit, at Visit 3 for both groups, and at 
Visit 9 for Group 1 only. At Visit 6 (for Group 1 only) an ECG is only done if clinically 
indicated. ECGs will be evaluated by a centralized procedure. The workflow and communication 
flow will be provided in a separate manual. 
Cardiac Risk Factors 
The individual cardiac risk factor is calculated before the first vaccination (for subjects 20 years 
of age and older), using the National Heart, Lung and Blood Institute’s risk assessment tool 
(http://cvdrisk.nhlbi.nih.gov/calculator.asp). Subjects with a 10 percent or greater risk of 
developing a myocardial infarction or coronary death within the next 10 years are excluded from 
trial participation. 
In addition, the family cardiac risk factor is evaluated at the Screening Visit. Subjects with an 
immediate family member (father, mother, brother, or sister), who has had onset of ischemic 
heart disease before 50 years of age are also excluded from trial participation. 
Troponin I 
Troponin I will be measured at the Screening Visit and at Visit 3, and at Visit 9 for Group 1 only. 
At any other visits troponin I will only be measured if clinically indicated. 
Cardiac events fulfill the definition of an AESI as described in Section 8.3.2. The investigator 
will be asked to assess the clinical significance of the case. 
Case definitions as published by the CDC (MMWR, May 30, 2003) are provided in Appendix III; 
Section 17.3 in order to: 
• 
help investigators to recognize possible events of acute myocarditis and/or pericarditis and  
• 
distinguish from unspecific and isolated ECG abnormalities without or with unclear clinical 
significance. 
Questions: 
The following specific cardiac questions will be routinely asked to the subject at the trial visits on 
the day of each vaccination; and the trial visits 2 weeks following each vaccination (Visits 3, 6 

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and 9 for Group 1; Visit 3 for Group 2) and 4 weeks following each vaccination (Visits 4, 7 and 
10 for Group 1; Visit 4 for Group 2). 
• 
Since your last visit, have you developed any chest pain, pressure, or discomfort that is 
beyond what is usual for you? 
• 
Since your last visit, have you developed any shortness of breath at rest or exertion that is 
beyond what is usual for you? 
• 
Since your last visit, have you noticed any swelling of your ankles, feet, or legs that is 
beyond what is usual for you? 
If the answer to one of the question is "yes", further evaluations as outlined in Figure 1 are 
initiated. 
Subjects who develop any kind of cardiac signs or symptoms during the trial such as, but not 
limited to chest pain, dyspnea, arrhythmia or edema are referred to a local cardiologist for cardiac 
evaluation as described in the DoD Clinical Guidelines for Post-Smallpox Vaccine Associated 
Myopericarditis (Appendix II; Section 17.2). All treatment emergent AESIs will be followed up 
until complete resolution or until the sequelae are stable and considered to be permanent. 
In any case of cardiac signs or symptoms, or increased laboratory results for Troponin I, the 
subject will be asked to attend for an unscheduled visit at the site, in order to perform or repeat 
Troponin I testing, to perform a physical examination for cardiac symptoms and to record an 
unscheduled ECG. 
Further details regarding the follow-up of AESIs are described in the ‘Investigator’s Manual – 
Follow-up of Adverse Events of Special Interest’. 
Figure 1 outlines the algorithm for assessment of cardiac events. 

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Figure 1:  Algorithm for Assessment of Cardiac Events 
 
*At any protocol-scheduled ECG and/or troponin I abnormality, the algorithm will begin at this point. 
no 
yes 
yes 
no 
yes 
Subject presents with any cardiac symptom such as chest pain, 
shortness of breath, edema, or palpitations 
ECG, Troponin* 
no 
No further work-up or 
expedited reporting 
required 
Cardiac complications? 
Symptomatic at 
time of exam? 
Physical exam 
Possible cardiac 
complications? 
Evaluation according the DoD 
Clinical Guidelines 
Further work-up as determined by 
the cardiologist and reported as a 
Special Interest AE regardless of 
severity 

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8.2.8 Safety Laboratory Measurements 
The intensity of laboratory / systemic quantitatively measured toxicities will be graded according 
to the toxicity scale in Appendix I; Section 17.1. These grading scales include the laboratory 
values determined with the routine safety parameters. In case of other laboratory values not 
included in the routine safety laboratory and not listed in Appendix I; Section 17.1, the National 
Cancer Institute Common Toxicity Criteria Table, Version 4.03, published June 14, 2010 will be 
used for grading of laboratory toxicities. 
Safety laboratory (hematology and serum chemistry) is determined at the Screening Visit and 
Visit 3 for all subjects and at Visit 6 and Visit 9 for Group 1 only. If clinically indicated Safety 
laboratory tests can be performed at any other visit(s). The safety laboratory measurements are 
performed at the site specific local laboratory. Laboratory normal ranges are provided by the 
local laboratory and filed in the Regulatory File. Safety laboratory parameters to be evaluated are: 
Hematology:  
Complete blood count (CBC) with total and differential white blood cell count (WBC) 
Serum chemistry:  
Total bilirubin, Alk Phos, AST, ALT, serum creatinine, sodium, potassium, calcium, troponin I 
(troponin I mandatory at the Screening Visit, Visit 3, Visit 9 and in addition at any other visits 
only if clinically indicated) 
Pregnancy test: 
A β-human choriogonadotropin (HCG) pregnancy test will be conducted for all WOCBP at 
screening, within 24 hours prior to each vaccination  and at the individual last active trial phase 
visit . At Screening Visit, a serum β-HCG pregnancy test will be performed; all other pregnancy 
tests will be conducted as either urine or serum β-HCG tests. 
The following parameters will only be evaluated during the screening period for assessment of 
inclusion / exclusion criteria: 
HIV 
Hepatitis B surface antigen  
Antibodies against hepatitis C virus  
Cholesterol (total Cholesterol, HDL, LDL) 
8.2.9 Pregnancy 
As per inclusion criteria, women of childbearing potential must have a negative serum pregnancy 
test at Screening Visit and a negative serum or urine pregnancy test within 24 hours prior to each 
vaccination. In addition, they 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 28 days after the last vaccination. Nevertheless, IMP 

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exposed pregnancies cannot be excluded with certainty. Subjects who become pregnant prior to 
the first vaccination will be excluded from the trial and are regarded as screening failure. Subjects 
who become pregnant during the active trial period (up to and including one month [minimum 28 
days] after receiving a dose of vaccine) must not receive additional doses of vaccine but may 
continue other trial procedures at the discretion of the investigator (Withdrawal from Further 
Trial Vaccination see Section 4.2.5). All IMP exposed pregnancies (i.e. up to 28 days after IMP 
administration) should be followed up until term or termination. 
Subjects should be instructed to notify the investigator or designee if it is determined – also after 
completion of the trial - that they became pregnant either during the trial or within one month 
(minimum 28 days) after receiving the last vaccine dose. 
8.3 Reporting 
8.3.1 Reporting of Serious Adverse Events 
All SAEs occurring throughout the entire course of the trial have to be reported to the CRO Drug 
Safety (DS) Department. The clinical trial site has to send by e-mail or fax the completed SAE 
form to the CRO DS Department within 24 hours of becoming aware of the SAE.  
SAE reports should be faxed to the following number:  
 
 
 
 
The investigator should not delay reporting because of missing information. Nonetheless, the 
report should be as complete as possible. This initial notification should include, as a minimum, 
sufficient information to permit identification of the following:  
• 
the reporter (investigator's name and contact information) 
• 
the subject 
• 
involved trial medication 
• 
AE(s) 
• 
Seriousness criterion and/or criterion for AE 
• 
date of onset 
 
(b) (1) (A)

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The CRO DS Department alerts BN Pharmacovigilance (PV) Department of all SAEs and 
provides the available information within 24 hours. BN is responsible for expedited as well as 
periodic reporting to the involved regulatory authorities (e.g. FDA, Paul-Ehrlich-Institut) 
according to applicable laws and guidelines. Regulatory authorities will be notified as soon as 
possible but no later than 7 days after first knowledge of fatal or life-threatening unexpected SAE 
with an at least possible relationship to the IMP (serious adverse drug reaction [SADR]) and no 
later than 15 days after knowledge of any other unexpected SADR. In addition BN will report the 
SAEs to the responsible Biomedical Advanced Research and Development Authority (BARDA) 
representative when applicable and forward them to the DSMB. All unanticipated problems 
involving risk to subjects or others and SAEs related to trial participation will be promptly 
reported to the HQ USAMRMC IRB by phone (
), by e-mail 
(
), or by facsimile (
), 
or sent to the U.S. Army Medical Research and Materiel Command, ATTN: 
 
. A complete written report will follow the 
initial notification. All other adverse events will be reported at Continuing Review. Figure 2 
outlines the reporting process and timelines for SAEs. 
(b) (1) (A)
(b) (1) (A)
(b) (1) (A)
(b) (1) (A)

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Figure 2 
Algorithm for Reporting of SAEs 
 
yes 
no 
AE 
SAE entered into safety 
database and Safety reports 
created 
Is the AE serious? 
Investigator reports SAE to 
CRO DS and to IRB within 
24 h  
Report Event in the  
AE Section of the CRF 
BN PV forwards Safety 
reports within max.15d/7d to 
BARDA (final) 
max. 15d/7d to competent 
authorities (final) 
15d/7d to DSMB (final) 
CRO DS reports SAE to BN 
PV within 24 h 
no 
yes 
Expedited reporting 
necessary? 
CRO DS forwards final 
Safety report within 
max.15d/7d to concerned 
IRBs, IECs and Investigators 
SAE entered into safety 
database 

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8.3.2 Reporting of Adverse Event of Special Interests 
AESIs occurring throughout the entire course of the trial will be reported as outlined in Figure 3. 
Figure 3 
Algorithm for Reporting of AESIs 
 
 
AE 
Report Event as defined in 
Figure 2 
Report SAE as defined in Figure 2 
Is the AE serious? 
Complete AESI report and send to 
CRO DS within 24 h 
yes 
no 
yes 
no 
Is the AESI 
related to 
IMP? 
no 
yes 
BN PV forwards related AESI 
reports to DSMB as defined in 
DSMB charter 
Complete AESI reporting 
Is this an AESI 
according to definition 
in Section 8.1.3.3? 
 
 

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8.3.3 Reporting of Pregnancy 
If a subject becomes pregnant during the active trial period (up to and including one month 
[minimum 28 days] after receiving a dose of vaccine) this pregnancy must be reported to BN on a 
Pregnancy Report Form within 24 hours of the investigator's becoming aware of the event. If 
ACAM2000® is administered during pregnancy or if the vaccinee lives in the same household 
with or has close contact with a pregnant woman the vaccinee should be apprised of the potential 
hazard to the fetus. These cases will be reported to the OHU&E and/or HQ USAMRMC IRB as 
appropriate. 
A reportable pregnancy should be followed to term, any premature terminations reported, and the 
health status of the mother and child including date of delivery and the child's gender and weight 
should be reported to BN as soon as possible after delivery. 
Any event during pregnancy fulfilling the criteria for an SAE will be reported as SAE to BN PV. 
However, hospitalization for delivery is a prospectively planned hospitalization and is not 
considered a SAE per se. 
8.3.4 Health Recordkeeping Requirements for Investigational New Drug Products 
In accordance with Army Regulation (AR) 40-562, all IND vaccines that are administered must 
be recorded in the individual’s permanent health record or DoD approved electronic 
Immunization Tracking System. For vaccines, the documentation is the same as that required for 
other vaccines with an annotation “IND” with the vaccine name. This recordkeeping requirement 
is in addition to any recordkeeping requirements of the FDA-approved IND protocol. 
9 Statistical Considerations 
9.1 Randomization Procedure 
Randomized treatment assignments for the subjects will be done after confirmation of subject’s 
eligibility. The randomization will be performed in a 1:1 ratio using a validated Interactive Web 
Randomization (IWR) portal provided by a third party organization (Endpoint). Endpoint will 
store the randomization list in a secure environment. A fixed block size will be used for the 
randomization, but the block size will not be generally known by the clinical trial team. 
9.2 Co-Primary Trial Hypotheses 
9.2.1 Immunogenicity Hypothesis 
The immunogenicity co-primary endpoint is to assess non-inferiority of MVA-BN® compared to 
ACAM2000® in terms of antibody response at the Peak Visit, i.e. 28 days after an ACAM2000® 

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vaccination and 42 days after the first MVA-BN® vaccination measured by validated vaccinia-
specific PRNT. 
Suppose m1 is the PRNT log10 titer mean in Group 1 (MVA-BN® followed by ACAM2000®) and 
m2 is the PRNT log10 titer mean in Group 2 (ACAM2000® only). The test of non-inferiority will 
be applied for the following hypothesis: 
 
H0: 
m1 – m2 ≤ -Δ versus  H1: 
m1 – m2 > -Δ where 
Δ is the non-inferiority margin. For the PRNT the non-inferiority margin will be 0.301 on the 
log10 scale (which is equivalent to a doubling on the original titer scale for the GMT). This is the 
same Δ as was used for the assessment of non-inferiority of ACAM2000® to Dryvax® 
(ACAM2000 VRBPAC Briefing Document, April 2007).  
The above hypotheses will be tested for the PRNT using a t-test on the difference of the two 
means based on the assumption that the log10 titer values have a normal distribution (which has 
been the case in all previous MVA-BN® studies). Specifically, a one-sided 97.5% confidence 
interval for the difference of the log10 titer means (based on the assumption of a common 
standard deviation [SD]) will be calculated. If the lower limit of this confidence interval is greater 
than –Δ, then the null hypothesis will be rejected for the respective assay and non-inferiority of 
MVA-BN® to ACAM2000® will have been demonstrated. 
9.2.2 Efficacy Hypothesis 
The efficacy co-primary hypothesis of the trial is to assess if the median of the MLA following 
ACAM2000® vaccination is significantly reduced for subjects in Group 1 who received prior 
MVA-BN® vaccinations compared to those in Group 2 who received no prior MVA-BN® 
vaccinations. Specifically the ratio of each median plus one will be tested: 
H0:  
λ
≤
−
2
1
1
M
M
 
 
versus   
H1:  
λ
>
−
2
1
1
M
M
 
 
 
i.e. the null hypothesis (H0) is that 1 minus the ratio in median MLA in Group 1 (M1) over the 
median MLA in Group 2 (M2) is less than or equal to a predefined constant λ, which is tested 
against the one-sided alternative hypothesis (H1) that the ratio > λ. This test will be performed by 
using the 95% asymptotic Hodges-Lehmann confidence interval (Lehmann, 1975) on the log10 
MLA values and the confidence limits will be anti-logged back on to the original scale (see 
Statistical Analysis Plan for further details). Specifically, only the anti-log of the upper 95% 
Hodges-Lehmann confidence interval of the log10 MLA values between groups is used, with a 
one-sided significance level of 2.5%, and this needs to be below 1-λ for the null hypothesis to be 
rejected, and thus the co-primary endpoint will be met. However, for completeness the upper and 
lower confidence limits along with the point estimate of the Hodges-Lehmann shift estimator 
(which can be slightly different from the ratio of medians) will be reported. Note that a positive 

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offset of 1 will be added to any zero MLA values in order  to avoid problems with taking 
logarithms of zero.     
The clinical justification of the choice of λ=40% is that this is the reduction that has been seen in 
vaccinia-experienced subjects compared to vaccinia-naïve subjects who were (re-)vaccinated 
with a first generation smallpox vaccine (Talbot, 2006) and is discussed further in the attached 
Statistical Analysis Plan. 
If one or both of the day 6-8 or day 13-15 photographs are missing then the photograph will be 
recorded as missing and the assessment of attenuation will not be made. 
9.3 Endpoints 
9.3.1 Co-Primary Endpoints 
• 
PRNT GMT at the Peak Visits  
• 
MLA in mm²  after scarification with ACAM2000® 
9.3.2 Secondary Endpoints 
Immunogenicity 
GMT at the Peak Visits and individual peak measured by vaccinia-specific ELISA. 
GMTs at the individual peak measured by vaccinia-specific PRNT. 
GMTs at all antibody blood sample time points measured by vaccinia-specific PRNT and 
vaccinia-specific ELISA. 
PRNT seroconversion rates at Peak Visits defined as the percentage of initially seronegative 
subjects with appearance of antibody titers equal or greater than the ACV in a vaccinia-specific 
PRNT. 
ELISA seroconversion rates at Peak Visits defined as the percentage of initially seronegative 
subjects with appearance of antibody titers equal or greater than the ACV in a vaccinia-specific 
ELISA. 
Efficacy 
Investigator assessed Maximum Lesion Diameter (MLD) in mm after scarification with 
ACAM2000® 
Investigator assessed Lesion diameter in mm at Day 6-8 after scarification with ACAM2000® 

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Investigator assessed Lesion diameter in mm at Day 13-15 after scarification with ACAM2000® 
The individual take will be classified as either full or partial or absent take by a blinded ITRC. 
Lesion area in mm² at day 6-8 after scarification with ACAM2000® 
Lesion area in mm² at day 13-15 after scarification with ACAM2000® 
(The correct measurement of the lesion area will be confirmed by a blinded ITRC). 
Safety and Reactogenicity 
Occurrence, relationship to vaccine and intensity of any SAE. 
Occurrence of any cardiac sign or symptom indicating a case of myo-/pericarditis, i.e. AESIs  
Occurrence of any Grade 3 or 4 AEs possibly, probably or definitely related to vaccine within 28 
days after each vaccination. 
Occurrence, relationship to vaccine and intensity of any non-serious AEs within 28 days after 
each vaccination. 
Occurrence of solicited general AEs (body temperature, headache, myalgia, chills, nausea, 
fatigue, malaise, swollen lymph nodes) within 15 days after each vaccination (days 0-14): 
Intensity, duration and relationship to vaccination. 
Occurrence of solicited local AEs (pain, redness (erythema), swelling, induration, itching 
(pruritus), and vaccination site appearance (normal/healed, red spot, bump, reddish blister, 
whitish blister, scab, ulcer/crater, warmth, swollen >3in, red streaks, drainage) within 15 days 
after each vaccination (days 0-14): Intensity and duration. 
Daily measurement of lesion size, erythema and induration based on physical appearance of 
vaccination site as documented in the memory aid. 
• 
major lesion diameter (mm) each day  
• 
major erythema diameter (mm) each day  
• 
major induration diameter (mm) each day  
If the shape of the lesion, erythema (excludes lymphangitis) and induration observed is not round 
but rather asymmetrical then the largest (or major) cross-sectional measurement would be 
recorded. 

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9.4 Sample Size Calculation 
The immunogenicity co-primary objective of the trial is to demonstrate that the main 
immunogenicity endpoint can be met, i.e. to demonstrate the non-inferiority of MVA-BN® to 
ACAM2000® in terms of neutralizing antibody response at the Peak Visit. Hence the following 
sample size calculation was performed for the main immunogenicity endpoint. 
Assuming a standard significance level of 5%, a power of ≥ 90% and the same expected PRNT 
GMTs in the MVA-BN® group and the ACAM2000® group, then the only remaining parameter 
is the SD of the log10 mean of the titers. As a basis for calculation, the overall calculated value of 
this SD at Visit 4 in 3 phase II MVA-BN® trials (POX-MVA-005, POX-MVA-008, POX-MVA-
011) is 0.807. However, this value of 0.807 is an estimate and an approximate 95% confidence 
interval can be placed around it, namely (0.756, 0.866). Adopting the worst case scenario of the 
upper limit of the confidence interval, i.e. SD = 0.866, this yields a required sample size for this 
trial of 175 in the PPS in both groups. 
In order to account for an approximate 20% rate for exclusion from the PPS, a total of 220 
subjects will be recruited into each of the groups. 
The efficacy co-primary endpoint is to determine if there is a relative reduction in MLA between 
the two groups. Using the Hodges-Lehmann method, the confidence interval of the median of the 
differences of the log10 MLA values of the two groups was calculated.  
To calculate the likely power for this analysis data from the NIH sponsored POX-MVA-002 trial 
was used as a basis for calculations, which was performed using Bootstrap methodology. In the 
POX-MVA-002 trial some subjects were randomly assigned either MVA-BN®/MVA-
BN®/Dryvax® (M/M/D) or Placebo/Placebo/Dryvax® (P/P/D). After the Dryvax® vaccination, the 
major diameter of the lesion was measured at various visits, including a Day 6-8 visit and a Day 
13-15 visit. From these the maximum lesion area was also estimated by assuming the lesions 
were elliptical with a major axis given by the reported diameter, which was twice as large as the 
minor axis of the ellipse. It should be noted that assuming the lesions to be perfectly circular 
generates the largest possible difference in areas for two different diameters, and therefore is the 
best possible scenario for the power calculation. The assumption of the lesion having an elliptical 
form is considered a more realistic assumption. 
Using this data a simple case resampling non-parametric bootstrap simulation was performed to 
estimate the likely ratio of the medians of the maximum lesion area that could be detected using 
the above test with 90% power. The proposed sample size of n=175 subjects in the PPS of each 
group gave a power at least 90% to show a significant reduction in the median of Group 1 
compared to the median of Group 2 of at least λ=40% (further details of the calculations are 
given in the attached Statistical Analysis Plan).    

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Hence the overall power for meeting both co-primary endpoints is at least 80% (as 90% × 90% > 
80%). 
9.5 Trial Cohorts/Datasets to be Evaluated 
For the statistical analysis the included subjects will be divided up into the following datasets: 
Full Analysis Set (FAS): This is the subset of subjects who received at least one dose of vaccine 
and for whom safety data are available.  
The analysis of safety will be performed on this analysis set. 
Per Protocol Set (PPS): This is the subset of subjects who adhere to all protocol requirements 
applicable to that particular trial group for the active trial phase without a major protocol 
violation. The decision whether a protocol deviation is major or not, for the classification of 
subjects to subsets, will be made case-by-case in a data review meeting prior to database closure.  
The primary endpoint dataset will be the PPS. All confirmatory testing is based on this subgroup. 
For further descriptive purposes, the same statistical procedures will be applied to the FAS. 
Initially Seronegative Subset (ISS): A subject of the PPS will be part of the initially seronegative 
subgroup, if the subject is seronegative for both ELISA and PRNT at baseline. The 
immunogenicity analysis will be repeated on this subgroup as a robustness analysis to confirm 
that there is no effect on the result of subjects who may have been initially seropositive 
influencing the analysis. 
9.6 Biometrical Evaluation 
As soon as the last subject has completed the remote FU and after any necessary settlement of 
queries etc. in the CRFs, data will be locked. A full analysis of the data available will be 
performed. 
All data obtained in this trial and documented in the CRFs will be listed. For parameters of 
interest, summary tables with descriptive group statistics for continuous variables will be 
prepared. For ordinal/dichotomous variables summary tables showing the absolute and relative 
count in each category will be prepared. 
Full details of the analyses will be defined in a Statistical Analysis Plan which will be finalized 
prior to database lock. The CRO will be responsible for data management and statistical 
evaluation. Data will be analyzed using SAS®. The procedure for accounting for missing, unused 
and spurious data will be given in the Statistical Analysis Plan. 
Antibody titers and resulting seroconversion rates will be assessed by vaccinia-specific PRNT 
and vaccinia-specific ELISA methods as described in Section 7. The primary immunogenicity 

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endpoint are the GMTs for PRNT at the Peak Visit (the most important secondary 
immunogenicity endpoint are the GMTs for the ELISA at Peak Visit). The primary 
immunogenicity hypothesis is to show that the humoral immune response of the trial Group 1 is 
not statistically inferior compared to the trial Group 2 for the PRNT endpoint. 
In a first step, the co-primary null hypotheses, as stated in Section 9.2, will be tested. All 
statistical tests for secondary endpoints and comparisons are regarded as descriptive. No 
adjustment for multiple testing will therefore be done. 
Clinical laboratory test results will be marked whether the result is below, within or above the 
respective reference range. The number of values outside of the reference range will be counted. 
The ECGs will be evaluated by a centralized procedure as described in the ECG Assessment 
Plan. Detailed descriptive analysis of the reasons/category of ECG abnormalities will be 
performed. 
The occurrence of solicited local and general AEs within 2 week after each vaccination will be 
summarized on a per subject and per vaccination basis.  
Unsolicited AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding terminology. The intensity of unsolicited AEs will be graded according to 
Section 8.2.5. 
AESIs will be separately listed and tabulated. 
SAEs will be listed separately. Each SAE will be described individually in detail. 
10 Ethical Aspects 
10.1 Ethical and Legal Regulations 
The PIs are to ensure that this clinical trial is conducted in complete accordance with the 
provisions of the 2013 version of the Declaration of Helsinki, the Belmont Report, the national 
laws and other guidelines for the conduct of clinical trials like ICH GCP to guarantee the greatest 
possible subject protection. 
10.2 Good Clinical Practice 
The procedures set forth in this protocol are designed to ensure that all protocol personnel abide 
by the national laws in which the trial is conducted, Code of Federal Regulations (CFR) 
governing IRBs and informed consent (32 CFR 219 and Army Regulation (AR) 70-25), 
USAMRIID 70-25, and ICH Guidelines for GCP and protection of human subjects. Clinical 
research protocols using FDA-regulated investigational products will be conducted in accordance 
with Title 21 CFR, Title 32 CFR, and Defense and Army regulations including DODI 3216.01 , 

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DODI 3216.02, DODI 6200.02 , AR 40-38 (for clinical investigations), and AR 70-25 (for 
RDT&E research) to afford research participants protection of their rights and welfare.  
Proper training of the investigational staff, a careful Informed Consent process, and the oversight 
of an IRB experienced in the review of clinical research involving military staff will be used to 
assure that their trial participation is ethical.  
The PI confirms this by signing this protocol. 
10.3 Approval by an IEC/IRB 
Prior to initiation of the trial, the PI or designee will submit the trial protocol, sample ICD, 
recruiting message/poster and/or e-mail, and other requested documents to the Institutional 
Review Board (IRB) for review and approval. It is the responsibility of the Investigator or the 
research site coordinator to promptly report changes or unanticipated problems during the 
conduct of the trial and submit annual and final study reports to the IRB as required. 
All changes to the protocol must be submitted for review and approval by the HQ USMRMC 
IRB before initiating the changes.  The ICD must be revised to concur with any modifications, as 
appropriate, and also must be reviewed and approved with the modifications. A subject already 
enrolled in the trial will be informed about the revision and asked to sign the revised ICD if the 
modification directly affects the subject. A copy of the revised, signed, and dated ICD will be 
given to the subject. All original versions of the ICD will be retained as part of the subject’s trial 
record and retained at USAMRIID. 
The protocol must be reviewed by the competent IEC/IRB according to the national laws of the 
respective clinical trial site before the first subject is included in this trial. 
To especially cover the ethical aspects of subjects in a military setting, a respective IRB approved 
by the DoD will review all relevant trial documents.  
If one of the investigators is a member of one of these committees, he/she may not vote on any 
aspect of the review of this protocol. 
The Sponsor will assure that the IEC / IRB is informed of any amendment to the protocol and any 
unanticipated problems involving risks to human subjects included in the trial. Such information 
will be provided to the IEC / IRB at intervals appropriate to the degree of subject risk involved, 
but not less than once a year. Copies of all correspondence between the investigator and the IEC / 
IRB must be forwarded immediately to the Sponsor. In case of withdrawal of IEC / IRB approval 
of the trial, the Sponsor has to be contacted immediately by facsimile, e-mail or telephone. 

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10.4 Confidentiality and Data Protection 
The PI of the respective clinical trial site is obliged to ensure anonymity of the subject. He/she 
has to make sure that all documents including CRFs provided (e.g. in the course of a marketing 
authorization procedure) to third parties (in this case: to the manufacturer of MVA-BN® or to an 
authority) contain no subject names. 
Only a subject and center number may identify subjects. Their name or medical record number 
may not be used. The PI keeps separate confidential subject logs for trial enrollment which 
allows subject numbers to be matched with names and addresses of subjects at any time. 
Documents not meant to be passed on to third parties have to be stored confidentially by the PI. 
According to USAMRIID policy, each individual enrolled in the trial will be assigned a subject’s 
identification number following the format identified in the USAMRIID SOP 
: 
Clinical Trials Enrollment: Assignment of Subject Study Identification Numbers and 
Documentation of Subject Study Participation. Upon receipt of an individual’s consent, the 
volunteer will be considered officially enrolled as a trial participant. Subject information will be 
entered onto the current version of the USAMRIID Study Enrollment/Withdrawal Log 
(USAMRIID SOP 
). 
In addition, Subject Identification Numbers (SIN) will be used in the event it becomes necessary 
to identify data specific to a single subject. All data and medical information obtained about 
subjects during the course of this research will be considered privileged and confidential. 
Subjects will not be identified by name in any published report, presentation of results, or 
protected health information (PHI) provided to collaborating institutions (Privacy Act of 1974, 5 
U.S.C., Section 552A and AR 340-21). Completed trial records to include signed ICD, logs, 
CRFs will be stored in a secure fashion by the PI (or a designee) at USAMRIID. Representatives 
of the USAMRIID OHU&E and the HQ USAMRMC IRB may review research records as a part 
of their responsibility to protect human volunteers in research.  
Clinical members of the team will be able to identify subjects because of the written consent 
process to be followed. The Health Insurance Portability and Accountability Act (HIPAA) 
requires that researchers obtain volunteers’ permission (Authorization) to use health information 
about them that is either created by or used in connection with the research proposed in this 
protocol. For this trial, PHI will include a volunteer’s medical/immunization records, and clinical 
data obtained during the course of this trial. There is no expiration date for this Authorization.  
Data that are considered PHI under HIPAA legislation as described earlier are coded, linked to 
subjects only via a SIN, and acceptable under HIPAA as a limited data set. Identified data (signed 
consent documents and enrollment logs linking subject names and SINs) collected during the 
course of the trial will be given to the PI (or designee) and maintained in a secure fashion in 
accordance with standard procedures at USAMRIID.  
(b) (1) (A)
(b) (1) (A)

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Activities pertaining to this trial will be performed in compliance with HIPAA legislation. 
Government and contractor staff will be trained in the provisions of the HIPAA prior to contact 
with trial subjects. Certifications for staff already trained will be submitted to USAMRIID for 
approval. The PI will be responsible for retaining sufficient information about each subject, i.e., 
name, address, telephone number, social security number, and identity in the trial so that the 
USAMRIID OHU&E AND HQ USAMRMC IRB  may have review this information should the 
need arise. There is the possibility that findings from analysis of the blood provided for this trial 
may be used in other research studies and could potentially have some commercial application. 
Any information collected in the course of the trial may be made available only to persons 
directly involved in this trial (PI and his staff members, monitors, statisticians) or to authorized 
persons by the Sponsor or the PI or authorities. The Sponsor of the trial will only receive 
pseudonymized data for analysis. 
11 Informed Consent 
Written informed consent, in compliance with 21 CFR 50, 32 CFR 219, AR 70-25 and ICH 
guidelines will be obtained before any trial-related procedures are initiated. The PI or designee 
will present the protocol in lay terms to the subject singly or in groups. Unit officers and senior 
NCOs in the chain of command will not be present at the time of research subject solicitation and 
consent during any research recruitment sessions in which members of units under their 
command are afforded the opportunity to participate as research subjects (DODI 3216.02). 
However, it is not the intent to recruit from assembled units. Questions regarding the nature of 
the protocol, the means by which the trial is to be conducted, and the risks to the participants will 
be solicited on an individual basis. Any question that cannot be answered by the investigator or 
designee will be referred to the PI. No subject will be expected to grant consent until questions 
have been answered to his/her satisfaction. By signing the appropriate place(s) on the IRB 
approved ICD, subjects are giving permission for the following: 
• 
Blood samples to be collected as specified in this protocol 
• 
Trial personnel to access PHI per HIPAA Authorization 
• 
Authorize the monitor, quality assurance personnel (of the CRO and Sponsor) and 
regulatory authorities to inspect source documents for quality assurance purposes. (Such 
verifications will always be conducted at the clinical trial site and under the ethical 
supervision of the PI. All aspects of the confidentiality of the subject’s data will be 
guaranteed.) 
• 
Unused serum to be stored for possible future testing. 
Informed consent principle mandates that subjects be informed of the primary potential risks and 
benefits of participating in the trial. This information will allow the subject to make a personal 
risk-versus-benefit decision and understand the following general principles: 

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• 
The individual is free to ask any questions that will allow him/her to understand the nature 
of the protocol 
• 
Participation is entirely voluntary 
• 
Refusal to participate involves no penalty 
• 
Withdrawal from participation at any time is allowed without penalty or loss of benefits to 
which the subject is otherwise entitled. 
The ICD must be signed and dated and retained by the PI as part of the trial records. Should the 
protocol be modified, the ICD must be revised to reflect the changes to the protocol. If the subject 
is directly affected by the change, the volunteer will receive a copy of the revised ICD for review. 
If the subject decides to continue participation then the subject must sign and date the ICD. Each 
subject will receive a copy of the signed and dated ICD. 
The informed consent regulations of Title 21, Part 50 (Protection of Human Subjects) of the CFR 
require a statement in the informed consent document regarding the availability of clinical trial 
information on ClinicalTrials.gov. In accordance with Section 801 of the Food and Drug 
Administration Amendments Act (FDAAA 801) a description of this clinical trial will be made 
available on http://www.ClinicalTrials.gov, as required by U.S. Law. The Web site will not 
include information that can identify the subject. At most, the Web site will include a summary of 
the results. 
A signed copy of the informed consent must be given to each subject and the signed original must 
remain at the clinical trial site and be available for verification by the monitor or competent 
regulatory authorities at any time. 
12 Case Report Forms and Retention of Records 
12.1 Case Report Forms 
In this trial, an electronic CRF will be used.  
All CRFs are to be filled out completely by the trial personnel, then reviewed and signed by the 
PI or designee to confirm their correctness. 
It is the PI’s responsibility to ensure that all subject data entered including discontinuations or 
changes in trial or other medications in the CRF are accurate and supported by the subject's 
medical records unless the CRF has been declared as source documentation by BN. The CRFs for 
any subject leaving the trial should be completed at the time of the final visit or shortly thereafter. 

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12.2 Retention of Records 
Essential documents as listed in ICH GCP need to be archived according to ICH GCP and 
national law, whatever is longer. 
To meet regulatory requirements, the original source data and a copy of the CRF data will be 
stored at USAMRIID. In case an electronic CRF will be used in the trial, data will be stored and 
archived according to the Clinical Data Interchange Standards Consortium (CDISC) Operational 
Data Modeling (ODM) (see www.cdisc.org for details). Since CDISC ODM is also the source for 
the Electronic Data Capture-web-based system, no transcription of data is necessary. If needed, 
paper copies (file printouts) can be created from the ODM file. 
It is the policy of the USAMRMC that data sheets are to be completed for all subjects 
participating in research (Form 60-R, Volunteer Registry Data Sheet). The data sheets will be 
entered into this Command’s Volunteer Registry Database. The information to be entered into 
this confidential data base includes the subject’s name, address, and Social Security Number; 
study title; and dates of participation. The intent of this data base is twofold: first, to readily 
answer questions concerning an individual’s participation in research sponsored by USAMRMC; 
and second, to ensure that USAMRMC can exercise its obligation to ensure research subjects are 
adequately warned (duty to warn) of risks and to provide new information as it becomes 
available. The information will be stored at USAMRMC for a minimum of 75 years. The 
Volunteer Registry Database is a separate entity and is not linked to the study database. Copies of 
forms completed for the database (60-Rs) are kept in the regulatory file for the protocol. 
12.3 Monitoring of the Trial 
A Clinical Research Associate (CRA) will be contracted by BN to perform monitoring services 
according to ICH GCP.  
Monitoring will be conducted according to the monitoring plan which must be approved by BN 
and the CRO. The monitoring plan will specify in detail the items for source data verification and 
other tasks to be performed by the CRA during the clinical trial site visit. 
The CRA is responsible for obtaining an overview of the course of the trial in co-operation with 
the investigators, checking if the clinical trial protocol is being observed, and helping the 
investigators to solve any problems which may arise. All documents in the context with this 
clinical trial will be handled confidentially at all times. 
The PI has agreed to give the CRA access to relevant hospital or clinical records to confirm their 
consistency with the CRF entries and to obtain an adequate overview of the course of the trial. 
The CRA verifies that the entries in the CRF are complete, accurate, correct and supported by 
source documents. In addition the CRA will verify that all required data documented in the 

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source were transferred accurately in the CRF. This will be done under preservation of data 
protection. 
The source data verification must be performed by direct insight in the subject's medical record. 
If a subject refuses to consent to this procedure, he/she may not be enrolled in the trial. The 
clinical trial site will provide direct access to all trial related data for the purpose of monitoring 
and auditing by local and regulatory authorities. The PI (or a representative) has further agreed to 
support the monitor in solving any problems he/she discovers during his/her visits. 
13 USAMRIID Relevant Administrative Procedures 
13.1 Protocol Modifications 
All changes to the protocol must be submitted for review and approval by the HQ USMRMC 
IRB before initiating the changes. The ICD must be revised to concur with any modifications, as 
appropriate, and also must be reviewed and approved with the modifications. A subject already 
enrolled in the trial will be informed about the revision and asked to review and (if in agreement) 
sign the revised ICD if the modification directly affects the subject. A copy of the revised, signed, 
and dated ICD will be given to the subject. All original versions of the ICD will be retained as 
part of the subject’s trial record and retained at USAMRIID or other secured storage facility for 
75 years, per USAMRIID regulations. 
13.2 Exceptions 
An exception is any action that differs from the current version of the protocol and is not part of 
the ordinary operations or standards regarding trial procedures. Prior to implementation, such 
exceptions will require approval by the IRB to include the HQ USAMRMC IRB . 
13.3 Protocol Deviation Procedures 
The PI or designee will be responsible for identifying and recording all deviations which are 
defined as isolated occurrences involving a procedure that did not follow the protocol or a 
protocol-specific procedure. All deviations from the protocol and actions taken will be recorded 
on the appropriate CRF and placed in the trial specific regulatory file. Any deviation from the 
protocol that affects subjects' safety or rights and/or the integrity of the study must be promptly 
reported to the HQ USAMRMC IRB (e-mail: 
 and include them in the annual and final trial 
reports.. 
13.4 Compensation 
Subjects will receive $50 compensation for each trial blood draw. Subjects will be paid for trial 
blood draw within an appropriate time frame. Compensation for this protocol will comply with 
(b) (1) (A)

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24 USC 30 and DoDI 3206.02. In addition, subjects will be compensated for travel expenses 
required to get to and from the clinical trial site.  
13.5 Medical Care for Research-Related Injuries 
All subjects taking part in research conducted by the Army are authorized to receive medical care 
in Army MTFs for research-related injuries, in accordance with AR 70-25 and 40-38. The AR 40-
400, paragraph 3-56, affirms that medical care is available at Army MTFs for research-related 
injuries of subjects participating in research under Army regulation 70-25 or 40-38, and that 
medical care charges will be waived. 
If a subject is injured because of participation in this research and is a DoD healthcare beneficiary 
(e.g., active duty military, military spouse or dependents) the subject is entitled to medical care 
for that injury within the DoD healthcare system, as long as the subject remains a DoD healthcare 
beneficiary and medical care will be free. 
Transportation to and from Army hospital(s) or clinic(s) will not be provided. The PI is the 
primary contact for the subject who believes they have sustained a research related injury. 
13.6 Problems or Questions 
Problems or questions about this trial should be addressed to the Principal Investigator, 
 
. Questions concerning an 
individual’s rights as a trial volunteer should be addressed to Office of Human Use and Ethics, 
 
. 
14 Audits 
d Inspections 
Audits and inspections may be carried out by the quality assurance department, local authorities, 
or authorities to whom information on this trial has been submitted. All documents pertinent to 
the trial must be made available for such audits / inspection after an adequate announcement. 
Informed consent of subjects participating in this trial has to include the consent in this access to 
source documents. 
15 Responsibilities of the Principal Investigator 
The PI agrees to carry out the trial in accordance with the guidelines and procedures outlined in 
this clinical trial protocol. The PI especially consents to strictly adhere to the ethical principles 
mentioned in Section 10.1 of this protocol. 
(b) (1) (A)
(b) (1) (A)
(b) 
(1)

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Changes to the protocol require written "Amendments to the protocol” and written approval by 
the Principal Investigator. Changes are allowed only if the trial value is not reduced and if they 
are ethically justifiable. The amendment must be passed on to all participating investigators with 
the obligation to adhere to its provisions. If warranted, the subject information has to be changed 
accordingly.  
It is within the responsibility of the investigator that the CRF has to be completed in a timely 
manner after each subject visit and signed after the subject has finished the trial for each subject 
participating in the trial. 
At the conclusion of the trial, the investigator will return all partly used, unused and empty 
vaccine containers to the Sponsor or the vaccine containers will be destroyed at the clinical trial 
site according to local legal requirements.  
The investigator may ask to terminate the trial due to administrative or other reasons. If this 
should be the case, appropriate measures which safeguard the interests of the participating 
subjects must be taken after verification and consultation with the PI. 
Each investigator will maintain appropriate medical and research records for this trial, in 
compliance with ICH GCP (E6), Section 4.9, and regulatory and institutional requirements for 
the protection of confidentiality of subjects. He/she will permit authorized representatives of the 
Sponsor and regulatory agencies to review (and, when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the trial 
safety and progress. 
The PI agrees to follow the detailed publication policy included in the clinical trial agreement. 
By signing this protocol, the PI confirms that he/she has read the entire clinical trial protocol, 
agrees to its procedures, and will comply strictly with the formulated guidelines. 
 
 

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17 Appendices 
17.1 Appendix I: Toxicity Scale for Laboratory Values 
Grade 1 or Grade 2 toxicity is only graded according to Table 4 and Table 5, if the value is 
outside of the institutional normal range applicable for this trial. 
Estimating severity grade 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and not 
interfering with activities of daily living. 
 
Grade 2 
An AE which is sufficiently discomforting to interfere with activities. 
 
Grade 3 
An AE which prevents activities of daily living. Such an AE would, for example, 
prevent attendance at work and would necessitate the administration of corrective 
therapy. 
 
Grade 4 
Life-threatening or disabling 
 
Serious or life-threatening AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a Grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: Seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
 

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Table 4  
Toxicity Scale for Serum Chemistry 
Lab Value 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Sodium – 
Hyponatremia mmol/L 
< Lower Limit of 
Normal (LLN) - 
132 
130 - 131 
125 - 129 
< 125 
Sodium – 
Hypernatremia  mmol/L 
> ULN – 149 
150 - 154 
155 - 159 
≥ 160 
Potassium – 
Hyperkalemia mmol/L 
> ULN – 5.9 
6.0 - 6.5 
6.6 - 7.0 
> 7.0 
Potassium – 
Hypokalemia mmol/L 
< LLN – 3.1 
2.5 - 3.0 
2.0 - 2.4 
< 2.0 
Calcium – 
Hypercalcaemia  
mmol/L 
> ULN – 2.89 
2.90 - 3.09 
3.10 - 3.30 
> 3.30 
Calcium- 
Hypocalcaemia mmol/L 
< LLN – 2.00 
1.76 - 2.00 
1.50 -1.75 
< 1.50 
Serum creatinine 
mg/dl 
> ULN– -< 1.5 x 
ULN 
≥ 1.5 - < 3 x 
ULN 
≥ 3- 6 x ULN 
> 6 x ULN 
Alkaline Phosphatase 
increase by factor 
> 1.25 – < 2.0 x 
ULN 
≥ 2.0 - < 3.0 x 
ULN 
≥ 3.0  x ULN 
 
Liver Function Tests 
increase by factor 
> 1.0 – < 2.5 x 
ULN 
≥ 2.5 - < 4 x 
ULN 
≥ 4 x ULN 
 
Total Bilirubin 
increase by factor 
> ULN – 1.5 x 
ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 10.0 x 
ULN 
> 10.0 x ULN 
Cardiac troponin I  
increase by factor 
>ULN – <2.0 x 
ULN 
≥  2.0 - < 5.0 x 
ULN 
≥ 5.0 x ULN 
 
Total Cholesterol 
mg/dl 
> ULN – 300 
> 300 - 400 
> 400 
 
 

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Table 5  
Toxicity Scale for Hematology 
Lab Value 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) 
g/dl 
< LLN - ≥ 10.5 
< 10.5 - ≥ 10.0 
< 10.0 
 
Hemoglobin (Male) 
g/dl 
< LLN - ≥ 12.5 
< 12.5 - ≥ 11.0 
< 11.0 
 
WBC Increase 
cell/mm3 
> ULN - < 15,000 
≥  15,000 - < 
20,000 
≥ 20,000 
 
WBC Decrease 
cell/mm3 
< LLN - ≥ 2,500 
< 2,500 - ≥ 
1,500 
< 1,500 
 
Lymphocytes Decrease 
cell/mm3 
< LLN - ≥ 750 
< 750 - ≥ 500 
< 500 
 
Neutrophils Decrease 
cell/mm3 
< LLN - ≥ 1,500 
< 1,500 - ≥ 
1,000 
< 1,000 
 
Platelets Decreased 
cell/mm3 
< LLN - ≥ 75,000 
< 75,000 - ≥  
50,000 
< 50,000 
 

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17.2 Appendix II: DoD Clinical Guidelines for Post-Smallpox Vaccine Associated 
Myopericarditis, Vaccine Healthcare Centers Network 
 
 

Version 8
Last Reviewed March 2013
DoD Clinical Guidelines for Post-Smallpox Vaccine Associated Myopericarditis
Vaccine Healthcare Centers Network (VHCN)
Consultation: Call the DoD Vaccine Clinical Call Center at
to request VHC and/or
military cardiology clinical consultation.
Clinical symptoms: Chest pain, shortness of breath, palpitations,
syncope, dry cough, or any suspected cardiopulmonary symptom(s)
A. Cardiology Consultation
Document normal ECG,
troponin, CK, CRP, other
studies as indicated during
acute symptoms5,6
Consider non-cardiac
etiology7
Therapeutic options8: NSAIDs
+/- colchicine, other Rx
Management & Recovery9
Activity based on exercise
tolerance and clinical
assessment
4 week clinical F/U visit,
ECG, echocardiogram, and
exercise stress test to clear
for return to full duty
For ongoing or persistent
symptoms, refer to
cardiology (stress test not
recommended)
B3. Includes B2 and any of the
following: LVEF < 45%, sustained
dysrhythmias, and/or hemodynamic
instability11
Early Transfer to Tertiary Care
Center - consider myocardial Biopsy
Therapeutic options: see Footnote 8
Management & Recovery9
No strenuous activity for 6 weeks
Close clinical F/U as directed by
cardiologists (echocardiogram, ECG,
exercise stress test)
Activity as tolerated & deployment
restriction for a minimum of 6 months
Cardiology F/U at 6 months for repeat
evaluation (reassess deployability)
Refer all cases to VHC Network for clinical case review, entry into DoD Smallpox Vaccine Myopericarditis Registry,
filing of VAERS report and natural history surveillance.10 With referral include: Patient and provider contact
information, Echocardiograms, ECG, cardiac isoenzyme results, & copies of pertinent records.
Vaccine(s) administered in past 30 days
Initial Evaluation
History: Characterize symptoms1
Physical Examination4
Past medical history2
Laboratory5 (Troponin I/T, BNP, ESR, usCRP, CK-MB, Viral surveillance)
Include detailed vaccination hx
Diagnostics6 (Electrocardiogram, Echocardiogram, CXR (PA/Lat), Pulmonary
Risk factors for cardiac symptoms3
function testing, Imaging studies (Cardiac MRI with Gadolinium)
A. Symptoms only
B1. Symptoms with objective
ECG abnormality but without
positive cardiac enzymes or
LV dysfunction11
Therapeutic options8: NSAIDs
+/- colchicine, other Rx
Management & Recovery9
No strenuous activity for 6
weeks
6 week clinical F/U visit,
ECG, echocardiogram,
exercise stress test to clear
for return to full duty; repeat
abnormal studies
For ongoing or persistent
symptoms, refer to
cardiology (stress test not
recommended)
B2. Symptoms with positive
cardiac enzymes, depressed LV
function, and/or imaging c/w
myocarditis11
Therapeutic options8: NSAIDs,
other Rx
Management & Recovery9
No strenuous activity for 6
weeks
6 week clinical F/U visit,
ECG, echocardiogram,
exercise stress test as clinically
indicated; repeat abnormal
studies (including cardiac
enzymes)
Activity as tolerated &
deployment restriction for a
minimum of 6 months
Cardiology F/U at 6 months
B. Symptoms + objective
abnormality11
B. Cardiology Consultation
Differential includes myo-pericarditis and acute coronary syndrome5,6,7,11
Special labs and diagnostics5,6 as indicated
(b) (1) (A)

Version 8
Last Reviewed March 2013
FOOTNOTES: The following guidance is for reference. Not every suggestion will be applicable to every patient. Recommendations
are to be applied as diagnostic and therapeutic needs or questions arise and should be in conjunction with VHC staff consultation.
Footnote
1
Characterize symptoms,
including chest pain type
Specify symptom location, character, onset, duration, intensity/severity, frequency,
accompanying/associated symptoms, and alleviating/aggravating factors. All
associated clinical symptoms should be detailed.
Categorize patient’s chest pain type if present (choose one):
1.
Pericarditis chest pain: Chest pain that is typical and made worse by
supine position, improved with leaning forward, pleuritic, constant
a.
Detailed history is critical to case definition of suspect pericarditis –
see case definitions, page 5
2.
Myocarditis chest pain: angina-like, diffuse; not necessarily positional or
pleuritic
3.
Atypical chest pain: Pain, pressure, or discomfort in the chest, neck, or
arms not clearly exceptional or not otherwise consistent with pain or
discomfort of myocardial ischemic origin.
Reference:
Box 10, Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions.
(2006, February 3) MMWR:Morbidity and Mortality Weekly Report, 55(RR01);1-16.
Retrieved from http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5501a1.htm
Footnote
2
Assess past medical history
Detailed review of all systems, with attention to the following disorders:

Lung disease

Gastrointestinal disease

Vascular disease (e.g., stroke, transient ischemic attack, peripheral arterial
disease)

Musculoskeletal disorders (e.g., impingement syndrome, thoracic outlet
syndrome)

Vaccination history and adverse events (with specific lot number, if available)
Reference:
PMH study guide http://medinfo.ufl.edu/year1/bcs96/clist/history.html
Footnote
3
Risk Factors for Cardiac
Symptoms

Personal History of angina, myocardial infarction (MI), congestive heart failure
(CHF), percutaneous coronary intervention (e.g., balloon angioplasty, stent,
atherectomy), coronary artery bypass graft (CABG), catheterization with
stenosis ≥ 50%. 

Age, sex, race/ethnicity (ethnicity: Hispanic or Latino, Not Hispanic or Latino;
Race: American Indian or Alaska Native, Asian, Native Hawaiian or Other
Pacific Islander, Black or African American, White))

Diabetes, hypertension, smoking, dyslipidemia, family history of CAD
(especially prior to age 55), obesity, physical inactivity, stress, and excessive
alcohol consumption.
Reference:
http://www.americanheart.org/presenter.jhtml?identifier=4726
Footnote
4
Physical Examination
Perform a focused PE to include: gender and race/ethnicity, vital signs, ht, wt,
detailed exam to include vaccination site, cardiac (jugular venous pressure if able),
pulmonary, peripheral edema and lymphadenopathy.
Reference:
http://meded.ucsd.edu/clinicalmed/introduction.htm
Footnote
5
Laboratory studies
Report normal range as defined by individual hospital laboratory standards. Record
units and normal range for laboratory.
Laboratory studies: All patients
Complete blood count
CBC at presentation, to include differential, with emphasis on eosinophil and
lymphocyte count should be noted.
Cardiac enzymes
All Creatinine Kinase (CK), CK-MB, and troponin (I/T) values should be noted. For
troponin data, document 99th percentile cut-off for testing system used as well as
name of testing system if available.
Inflammatory markers
All erythrocyte sed rate and C-reactive protein (CRP) (ultrasensitive, if available)
values should be noted.
Laboratory studies as clinically indicated:
Immune complex screening
All Complement related assay studies (including C3, C4, CH50, C1q & C3D-binding
assays) with values should be noted.
Brain natriuretic peptide
Consider BNP if dyspnea is present.
Viral surveillance
Smallpox vaccine related myopericarditis is a diagnosis of exclusion. No
smallpox vaccine related cases have exhibited viral etiology to date. When
considering other etiologies, viral surveillance is indicated.
Serologies and PCR
Consider ID consultation; PCR for vaccinia if available (consult CDC/VHC). All
coxsackie A/B (enteroviruses), adenovirus, CMV, Parvovirus B19, influenza
A/B, HHV-6, HSV-1, HIV, RSV, dengue, echovirus, encephalomyelitis, Epstein-

Version 8
Last Reviewed March 2013
Barr, Lyme, rhabdovirus, varicella, variola, yellow fever, hepatitis A/B/C IgM, and
core IgG values and titers during the evaluation should be noted; obtain specimens
for convalescent titers at 4 week interval.
Other Cultures
Consider ID consultation; all viral cultures (nasal wash, urine, feces) for adenovirus,
influenza viruses, parvovirus B19 or enteroviruses should be noted.
Autoimmunity screening
Note all ANA, Anti-DS DNA, ENA, and similar values during the evaluation.
Consider additional special studies such as myocardial auto-antibodies. Consult
VHC Network for current information.
Footnote
6
Diagnostics
Diagnostics: All patients
Electrocardiogram (ECG)
Note date, time, rate, rhythm, the presence of ectopy and abnormalities in waves,
intervals and segments. Provide copies of relevant ECGs to patient and incorporate in
record.
Typical ECG manifestations:
Pericarditis:
Acute
1.
Diffuse ST segment elevation, particularly leads I,II, III, aVF, aVL, and
V5-V6
2.
Diffuse PR segment depression
3.
PR segment elevation in lead aVR
Evolving
1.
T-wave changes: notched, biphasic. Or low-voltage inversions.
Myocarditis:
1.
Diffuse T-wave inversions without ST segment abnormality
2.
Incomplete atrioventricular conduction blocks (usually transient)
3.
Intraventricular conduction blocks (usually transient)
*When myocarditis and pericarditis occur together, ST segment abnormalities also
may be evident.
Reference:
Demangone, D. (2006) ECG manifestations: Noncoronary heart disease. Emergency
Medicine Clinics of North America. (24) pp.113-131.
Chest X-ray
PA and Lateral
Other diagnostics as clinically indicated:
Echocardiogram
If only a range is estimated for ejection fraction (EF), note the midpoint of the range.
For pericardial effusions, record estimate of size and/or clinical significance (small
effusions may not be diagnostic).
Pulmonary functions
With DLCO if indicated; diffusion capacity corrected for hemoglobin is a sensitive
measure of pulmonary interstitial disease and increased risk for hypoxia with
activity.
Stress test
Indicate whether an exercise tolerance, stress-echocardiogram, or
nuclear/pharmacological stress test was performed during the hospital stay and the
result of the testing, if performed.
Clinical correlation is recommended in the cases of a negative stress test result.
Cardiac catheterization
If vessel occlusion identified, note the anatomical region affected and the degree of
stenosis present.
Holter & Event Monitor
Consider for dysrhythmia evaluation
Imaging
Consider cardiac MRI with gadolinium (with T2W imaging and early/delayed
enhancement) for cases with depressed EF and/or elevated Troponin as soon as
feasible after onset of symptoms.
Reference:
Friedrich et al. Cardiovascular Magnetic Resonance in Myocarditis: A JACC White
Paper. JACC, 2009; 53(17):1475-87.
Myocardial Biopsy
Consider myocardial biopsy if heart failure is severe or worsening.
Footnote
7
Differential Diagnosis
Consider viral myocarditis, acute coronary syndrome (myocardial infarction), aortic
dissection, pneumothorax, pulmonary embolism, musculoskeletal pain, esophageal
disorder (gastroesophageal reflux, esophageal spasm), systemic autoimmune
disease.
Footnote
8
Therapeutic options
Consult VHC Network for current information.
Symptoms only (A) OR
symptoms with objective
findings, but with negative
cardiac enzymes and no LV
dysfunction (B1)
Non-steroidal anti-inflammatory therapy with or without colchicine (colchicine in
addition to Conventional Therapy for acute pericarditis: Results of the colchicine for
acute pericarditis (COPE) trial. Imazio M, et al. Circulation 2005; 112:2012-16.)

Version 8
Last Reviewed March 2013
Symptoms w/ positive cardiac
enzymes or depressed LV
function or imaging c/w
myocarditis (B2)
Non-steroidal anti-inflammatory therapy. Other treatments to be considered in
consultation with Cardiology and the VHCN to include corticosteroid treatment
(after biopsy if possible). Consider biopsy for viral PCR, culture and assessment of
inflammation (presence of eosinophils). Consider corticosteroids with evidence of
eosinophilic inflammation and clinical deterioration.
Progressive symptoms (LVEF
< 45%, sustained
dysrhythmias, hemodynamic
instability) (B3)

Conventional heart failure treatments (e.g., ACE inhibitors, nitrates, diuretics,
select beta-blockers such as carvedilol or metoprolol succinate)

Strongly consider early referral for myocardial biopsy to guide optimal treatment.

Consider corticosteroids (preferably after biopsy) if no evidence of active
infection and/or with evidence of eosinophils in inflammatory infiltrate.

Consider Vaccinia Immune Globulin (VIG)/IVIG only with expert consultant
case review via VHC Network.
Footnote
9
Management and Recovery
Whenever possible, standardized follow up should be coordinated with the Vaccine
Healthcare Centers Network.
Reference (Deployment Restriction):
Maron et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse,
myocarditis, and Marfan syndrome. JACC;45 (8):1340–5.
http://content.onlinejacc.org/cgi/content/full/45/8/1340.
Symptoms only (A) OR
Symptoms with objective
findings, but without positive
cardiac enzymes or LV
dysfunction (B1)

Light physical activity at own pace for 4 weeks (A)

No strenuous activity for 6 weeks (B1)

Follow up in 4 weeks (A) to 6 weeks (B1)
Asymptomatic at follow-up

Repeat any previously abnormal studies

Clinical evaluation to include stress test to assess exercise tolerance prior to
clearance for return to duty

Long-term follow-up will be completed by VHC Network
Symptomatic and/or persistent/abnormal findings at follow-up

Repeat any previously abnormal studies

Clinical evaluation to include stress test (unless contraindicated)

Repeat MRI if had previous enhancements or if symptomatic. Repeat at 12-18
months

Consult cardiology for further recommendations

Long-term follow-up will be completed by VHC Network
Symptoms with positive
cardiac enzymes or mild
depressed LV function or
imaging c/w myocarditis (B2)
OR Progressive symptoms
(LVEF < 45%, sustained
dysrhythmias, hemodynamic
instability) (B3)

No strenuous activity for 6 weeks; deployment restriction for 6 months

Clinical evaluation at 6 weeks and 6-12 months
Asymptomatic at follow-up

Repeat any previously abnormal studies at 6 weeks and 6-12 months

Stress test at 6 weeks to assess exercise tolerance for rehabilitation; repeat at 6-12
months to assess exercise tolerance prior to clearance for deployment

Long-term follow-up will be completed by VHC Network
Symptomatic and/or persistent/abnormal findings at follow-up

Clinical evaluation to include enzymes, ultra sensitive CRP, ECG, ECHO, stress
test (unless contraindicated)

Repeat MRI if had previous enhancements or if symptomatic. Repeat at 6 months
to assess for clearance for deployment.

Clinical evaluation at 6 months to include repeat ECHO, stress test, and MRI

If normal and asymptomatic, clear for deployment

If normal and symptomatic, consult cardiology

If abnormal MRI with continued symptoms, not cleared for deployment

Continue cardiology follow-up at 6 -12 month intervals until asymptomatic

Long-term follow-up will be completed by VHC Network
Footnote
10
Disability Assessment
The majority of patients have recovered within 1 year. The natural history of this
condition remains unknown. Careful functional assessment post-acute phase has
not yielded definitive objective parameters. The long-term natural history of this
condition (e.g., late onset arrhythmias, cardiomyopathy, recurrent myocarditis) has
not been well defined. Development of new cardiac complications within 5 years
following an episode of hypersensitivity myocarditis associated with immunization
should be reported to the VHC Network clinical case management registry.

Version 8
Last Reviewed March 2013
Footnote
11
Case Definitions for Myocarditis and Pericarditis
MMWR:Morbidity and Mortality Weekly Report 2003;52:492-6,
http://www.cdc.gov/mmwr/PDF/wk/mm5221.pdf
MMWR:Morbidity and Mortality Weekly Report, 2006;55(RR01);1-16.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5501a1.htm
Objective abnormalities
Myo-
carditis
Peri-
carditis
Suspect
(1) Symptoms (dyspnea,
palpitations, or chest pain)
(2) ECG abnormalities beyond
normal variants, not documented
previously (ST/T abnormality,
paroxysmal supraventricular
tachycardia, ventricular
tachycardia, atrioventricular block,
frequent atrial or ventricular
ectopy) OR Focal or diffuse
depressed LV function of uncertain
age by an imaging study
(3) Absence of evidence of any
other likely cause
Suspect
(1) Typical chest pain (made worse
by supine position, improved with
leaning forward, pleuritic,
constant)
(2) No evidence for alternative
cause of such pain
Probable
(1) Meets symptom criteria for
suspected myocarditis
(2) In addition, meets one of the
following: Elevated levels of cardiac
enzymes (Creatine Kinase-MB
fraction, Troponin T or Troponin I),
OR new onset of depressed LV
function by imaging, OR abnormal
imaging consistent with myocarditis
(MRI with gadolinium, gallium-67
scanning, anti-myosin antibody
scanning)
Probable
(1) Meets criteria for suspected
pericarditis
(2) Has one or more of the
following: Pericardial rub on
auscultation OR ECG with diffuse
ST-segment elevations or PR
depressions not previously
documented OR echocardiogram
revealing an abnormal pericardial
effusion
Confirmed
Histopathologic evidence of myocarditis by
endomyocardial biopsy or on autopsy.
Confirmed
Histopathologic evidence of pericardial
inflammation in pericardial tissue from
surgery or autopsy
Vaccine Healthcare Centers Network
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Clinical Trial Protocol 
Doc. No. 92000007 
 
FY12-19, HP-12-19, POX-MVA-006 
Edition 8 
29-Sep-2016 
 
Bavarian Nordic 
Restricted Business Proprietary 
Page 127 of 208 
 
17.3 Appendix III: Case Definitions Acute Myocarditis / Pericarditis 
17.3.1 Case Definition for Acute Myocarditis 
A possible case of acute myocarditis is defined by the following criteria and the absence of 
evidence of any other likely cause of symptoms: 
Presence of dyspnea, palpitations, or chest pain of probable cardiac origin in a subject with either 
one of the following: 
• 
ECG abnormalities beyond normal variants, not documented previously, including 
• 
ST-segment or T-wave abnormalities, 
• 
Paroxysmal or sustained atrial or ventricular arrhythmias, 
• 
AV nodal conduction delays or intraventricular conduction defects, or 
• 
Continuous ambulatory electrocardiographic monitoring that detects frequent atrial or 
ventricular ectopy, or 
• 
Evidence of focal or diffuse depressed left ventricular (LV) function of indeterminate age 
identified by an imaging trial (e.g., echocardiography or radionuclide ventriculography). 
A probable case of acute myocarditis, in addition to the above symptoms and in the absence of 
evidence of any other likely cause of symptoms, has one of the following: 
• 
Elevated cardiac enzymes, specifically, abnormal levels of cardiac troponin I, troponin T, 
or creatine kinase myocardial band (a troponin test is preferred); 
• 
Evidence of focal or diffuse depressed LV function identified by an imaging trial (e.g., 
echocardiography or radionuclide ventriculography) that is documented to be of new onset 
or of increased degree of severity (in the absence of a previous trial, findings of depressed 
LV function are considered of new onset if, on FU studies, these findings resolve, improve, 
or worsen); or 
• 
Abnormal result of cardiac radionuclide imaging (e.g., cardiac magnetic resonance imaging 
with gadolinium or gallium-67 imaging) indicating myocardial inflammation. 
 
A case of acute myocarditis is confirmed if histopathologic evidence of myocardial inflammation 
is found at endomyocardial biopsy or autopsy. 

Clinical Trial Protocol 
Doc. No. 92000007 
 
FY12-19, HP-12-19, POX-MVA-006 
Edition 8 
29-Sep-2016 
 
Bavarian Nordic 
Restricted Business Proprietary 
Page 128 of 208 
 
17.3.2 Case Definition for Acute Pericarditis 
A possible case of acute pericarditis is defined by the presence of 
• 
Typical chest pain (i.e., pain made worse by lying down and relieved by sitting up and/or 
leaning forward) and no evidence of any other likely cause of such chest pain. 
 
A probable case of acute pericarditis is a possible case of pericarditis, or a case in a person with 
pleuritic or other chest pain not characteristic of any other disease, that, in addition, has one or 
more of the following: 
• 
Pericardial rub, an auscultatory sign with one to three components per beat, 
• 
ECG with diffuse ST-segment elevations or PR depressions without reciprocal ST 
depressions that are not previously documented, or 
• 
Echocardiogram indicating the presence of an abnormal collection of pericardial fluid (e.g., 
anterior and posterior pericardial effusion or a large posterior pericardial effusion alone). 
 
A case of acute pericarditis is confirmed if histopathologic evidence of pericardial inflammation 
is evident from pericardial tissue obtained at surgery or autopsy. 
 
 

Clinical Trial Protocol 
Doc. No. 92000007 
 
FY12-19, HP-12-19, POX-MVA-006 
Edition 8 
29-Sep-2016 
 
Bavarian Nordic 
Restricted Business Proprietary 
Page 129 of 208 
 
17.4 Appendix IV: US Health Affairs Memorandum 
Update of Clinical Policy for the Department of Defense Smallpox 
Vaccination Program 
 
 

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Clinical Trial Protocol 
Doc. No. 92000007 
 
FY12-19, HP-12-19, POX-MVA-006 
Edition 8 
29-Sep-2016 
 
Bavarian Nordic 
Restricted Business Proprietary 
Page 145 of 208 
 
17.5 Appendix IVa: Attachment 1 to US Health Affairs Memorandum 
‘Medication Guide ACAM2000®’ 
Note: The US Health Affairs Memorandum; Update of Clinical Policy for the Department of 
Defense Smallpox Vaccination Program attaches the version from 14 August 2007 for the 
Medication Guide ACAM2000TM. This CTP replaces the Medication Guide ACAM2000TM 
Version 14 August 2007 with the latest version from June 2012. 
 
 

  
Page 1 of 6 
Medication Guide 
Smallpox (Vaccinia) Vaccine, Live 
ACAM2000® 
 
 
Please read this Medication Guide before you receive a vaccination with ACAM2000.  This Guide does 
not take the place of talking to your healthcare provider about ACAM2000 and the smallpox disease.  
 
What is the most important information I should know about  
the ACAM2000 smallpox vaccine? 
• 
If you are at a high risk for being exposed to smallpox, you should be vaccinated even if you 
have health problems, unless you have certain problems with your immune system.  People 
who have health problems may have a higher chance of getting serious side effects from vaccination 
but are also those who have a higher chance of dying from the smallpox disease. 
• 
ACAM2000 may cause serious heart problems called myocarditis and pericarditis, or swelling 
of the heart tissues.  In studies, about 1 in every 175 persons who got the vaccine for the first time 
may have experienced myocarditis and/or pericarditis.  On rare occasions these conditions can result 
in an irregular heart beat and death.  Your chances of getting heart problems from the vaccine are 
lower if you have already had this vaccine before. You can have myocarditis and/or pericarditis even 
if you have no symptoms.  Call your healthcare provider or get emergency help right away if you 
have: 
o chest pain or pressure 
o fast or irregular heartbeat 
o breathing problems 
See “What are the possible side effects of ACAM2000?”  
• 
Because the vaccine has a live virus, it can spread to other parts of your body or to other 
people if you touch the vaccination site and then touch other parts of your body or other 
people.  The vaccine virus can spread until the vaccination scab falls off (2 to 4 weeks after 
vaccination).  If the virus is spread to a person who should not get the vaccine, the side effects 
can be very serious and life-threatening.   
See “How do I care for the smallpox vaccination site?” 
 
What is the ACAM2000 smallpox vaccine? 
ACAM2000 is a prescription vaccine used to protect people against smallpox disease.  It is for use in 
people who have a high chance of getting the disease.   
ACAM2000 contains live vaccinia virus (a “pox”-type virus) to protect against smallpox disease.  
 
Who should not get the ACAM2000 smallpox vaccine? 

  
Page 2 of 6 
• 
In an emergency, you should be vaccinated if you are at high risk for getting smallpox disease 
even if you have health problems (except if you have certain problems with your immune 
system as discussed below). 
• 
Your healthcare provider may not give you ACAM2000 if you have problems with your immune 
system.  You may have immune system problems if you: 
o have leukemia 
o have lymphoma 
o have had a bone marrow or organ transplant 
o have cancer that has spread 
o have HIV, AIDS 
o have cellular or humoral immune deficiency 
o are being treated with radiation 
o are being treated with steroids, prednisone, or cancer drugs 
 
How do I receive ACAM2000? 
ACAM2000 smallpox vaccine is not a shot like other vaccines.  Your healthcare provider will make 15 
pokes in the skin of your upper arm with a needle containing ACAM2000.  The pokes are not deep, but 
will cause a drop of blood to form.  This is called the vaccination site.   
It is important to care for the vaccination site properly so that the virus doesn’t spread to other 
parts of your body or to other people.  You can infect another part of your body or other people 
until the scab falls off. 
 
How do I care for the ACAM2000 vaccination site? 
 
 
 
 
 
• 
When changing bandages or caring for your vaccination site, wear gloves.  Use an absorbent 
bandage to completely cover your vaccination site.   
o Change your bandage when it begins to soak through (at least every 1 to 3 days).   
o Throw away gloves and used bandages in sealed or double plastic bags.  A small 
amount of bleach can be added to the bag to kill the virus.   
• 
Wear clothes with sleeves to cover the site and prevent scratching the vaccination site.  It is 
especially important to wear a bandage and sleeves to bed to avoid scratching.  
• 
Wash your hands frequently with alcohol-based cleansers or soap and water.   
It is important to ALWAYS: 
1. Wear bandages to cover the entire vaccination site. 
2. Wear sleeves to cover the site. 
3. Wash your hands, wash your hands, wash your hands. 

  
Page 3 of 6 
o Be sure to wash your hands each time you change your bandage or if you touch the 
vaccination site.  
• 
Do not use creams or ointments on the vaccination site because they will delay healing and can 
spread the virus. 
• 
Do not scratch or pick at the vaccination site. 
• 
You can take a bath or shower, but don’t touch or scrub the vaccination site.   
o It is best to cover the vaccination site with a waterproof bandage.   
o If the vaccination site gets wet, dry the site with toilet paper and flush it. (Do not use a 
cloth towel because it can spread the virus.)  
o Cover the vaccination site with a loose gauze bandage after bathing to allow it to dry out. 
• 
Do not use a bandage that blocks air from the vaccination site.  This could cause the skin at the 
vaccination site to soften and wear away.  
• 
If you exercise enough to cause sweat to drip, use a waterproof bandage on the vaccination site 
when exercising.   
• 
Wash clothing, towels, bedding or other items that may have come in contact with the vaccination site 
separately from other wash.  Use hot water with detergent and bleach.   
• 
When the scab falls off, throw it away in a sealed plastic bag with a small amount of bleach. Wash 
your hands afterwards. 
 
What should I expect at the vaccination site and in the weeks following vaccination? 
• 
If vaccination is successful, a red and itchy bump forms at the vaccination site in 2 to 5 days.  Over 
the next few days, the bump becomes a blister and fills with pus.  During the second week, the blister 
dries up and a scab forms.  The scab falls off after 2 to 4 weeks, leaving a scar.  People vaccinated 
for the first time may have a larger reaction than those being revaccinated. See expected responses 
below: 
 
Smallpox Vaccination Site:  
expected response after vaccination 
 
 

  
Page 4 of 6 
 
Note: After 6 to 8 days, check to be sure that your vaccination site looks like one of the pictures 
above. If it does not look like this, see your healthcare provider because you may need to be 
revaccinated. 
• 
If you need medical care in the month after your vaccination, tell your healthcare provider you just got 
a smallpox vaccination. 
• 
Certain people, such as laboratory workers who work with smallpox, are at risk of being exposed to 
smallpox over a long period of time.  These people may need a booster vaccination every 3 years to 
maintain protection against smallpox. 
 
What should I avoid after getting vaccinated with the ACAM2000 smallpox vaccine? 
• 
For 4 weeks after vaccination AND until the vaccination site has healed, you should avoid:  
o getting pregnant. Smallpox vaccine may rarely cause infection in an unborn baby if the 
mother is vaccinated during pregnancy.  This infection usually results in stillbirth or death. 
o handling babies or breastfeeding. 
o swimming or hot tub use. 
o donating blood. 
o Tuberculin (TB) testing. Smallpox vaccine may cause the TB test to give the wrong 
result. 
• 
Avoid rubbing, scratching or touching the vaccination site.  
• 
Until the vaccination scab falls off, do NOT: 
o have contact with people who cannot get the vaccine to prevent accidental spread of the 
vaccine virus. This includes physical contact and household contact.  If there is someone 
in your household who should not get the vaccine, such as a pregnant woman, an infant, 
or someone who has an illness, you should not stay in the house until the vaccination 
scab falls off. 
o share a bed, clothes, towels, linen, or  toiletries with unvaccinated people. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
We don’t know if the vaccine virus can be spread to cats, dogs, or other household pets, or whether 
pets can spread the virus to other people in the household.  Try to keep the vaccine virus from 
reaching your pet. See “How do I care for the smallpox vaccination site?” 
 
Don’t scratch that itch. 
 
Vaccine virus can accidentally spread to 
a family member, close contact, or 
another part of your body. 

  
Page 5 of 6 
 
What are the possible side effects of ACAM2000? 
ACAM2000 may cause serious heart problems, including myocarditis and pericarditis.  This can 
happen within 3 to 4 weeks after you get the vaccine.  Call your healthcare provider or get 
emergency help right away if you have: 
o chest pain or pressure 
o fast or irregular heartbeat  
o breathing problems 
Most people who get myocarditis and/or pericarditis seem to get better after a few weeks.  But heart 
problems may last longer in some people, and in rare cases, could lead to death. 
Other serious side effects include: 
o swelling of the brain or spinal cord 
o problems with the vaccination site blister, such as it becoming infected  
o spreading of the vaccine virus to other parts of your body or to another person 
o severe allergic reaction after vaccination  
o accidental infection of the eye (which may cause swelling of the cornea causing watery 
painful eyes and blurred vision, scarring of the cornea, and blindness) 
Common side effects include: 
o itching 
o swollen lymph nodes 
o sore arm 
o fever 
o headache 
o body ache 
o mild rash 
o fatigue 
The risks for serious vaccine side effects are greater for people who: 
o have skin problems called eczema or atopic dermatitis 
o have skin problems, such as burns, impetigo, contact dermatitis, chickenpox, shingles, psoriasis, 
or uncontrolled acne 
o  have had heart problems  
o have serious heart or blood vessel problems including angina, previous heart attack, artery 
disease, congestive heart failure, stroke, or other cardiac problems 
o smoke or have high blood pressure, high cholesterol, diabetes, high blood sugar, or a family 
history of heart problems 
o are breastfeeding  
o are pregnant, could be pregnant, or plan to become pregnant 
o are less than 1 year old 
o are taking steroid eye drops or ointment 

  
This Medication Guide has been approved by the U.S. Food and Drug Administration. 
 
Sanofi Pasteur Biologics, LLC., 38 Sidney Street, Cambridge, MA  02139 
Version 7.0, June 2012 
 
Page 6 of 6 
 
o have had problems after previous doses or are allergic to ACAM2000 or any part of ACAM2000 
such as antibiotics neomycin or polymyxin B 
Tell your healthcare provider if you have any of the above conditions.   
The virus from your vaccination can spread to other people and cause serious side effects. It is 
important to tell your healthcare provider if you:  
• 
live or work with a person who has skin problems (like eczema, dermatitis, burns, psoriasis, 
bad acne) or is suffering from impetigo, chickenpox or shingles 
• 
live or have close contact with a baby, or a person who is pregnant or breastfeeding 
• 
live or have close contact with a person who has an immune deficiency or cardiac disease 
See “How do I care for the ACAM2000 vaccination site?”  
Tell your healthcare provider about any side effect that bothers you or that does not go away. 
 
To report SUSPECTED SIDE EFFECTS (ADVERSE REACTIONS), contact sanofi pasteur 
Inc. at 
) or VAERS at 
and 
https://vaers.hhs.gov 
 
General information about the safe and effective use of ACAM2000 
 
This Medication Guide provides a summary of the most important information about ACAM2000. 
Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide.  If you 
would like more information or have any questions, talk to your healthcare provider.  You can ask your 
healthcare provider for information about ACAM2000 that is written for healthcare professionals.  You can 
also visit http:www.sanofipasteur.us/acam2000. The vaccine should not be used for a condition other 
than that for which it is prescribed. 
 
What are the ingredients in ACAM2000? 
ACAM2000: live vaccinia virus derived from plaque purification cloning from Dryvax® (Wyeth 
Laboratories, Marietta, PA, calf lymph vaccine, New York City Board of Health Strain) and grown in 
African Green Monkey kidney (Vero) cells  
Inactive ingredients: 6-8 mM HEPES (pH 6.5-7.5), 2% human serum albumin USP, 0.5 – 0.7% sodium 
chloride USP,  5% mannitol USP, and trace amounts of the antibiotics neomycin and polymyxin B 
Diluent for ACAM2000: 50% (v/v) Glycerin USP, 0.25% (v/v) Phenol USP in Water for Injection USP 
 
 
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