Randomized, Open-label Phase II Trial to Assess the Safety and Immunogenicity of MVA-BN Smallpox Vaccine When Increasing the Number of Injections Compared to the Standard Regimen in Immunocompromised Subjects With HIV Infection
Phase: PHASE2
Conditions: Smallpox
Sponsor: Bavarian Nordic

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POX-MVA-037
Randomized, open-label Phase II trial to assess the safety and 
immunogenicity of MVA-BN® smallpox vaccine when increasing the 
number of injections compared to the standard regimen in 
immunocompromised subjects with HIV infection
18-NOV-2014
NCT02038881
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0

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1
General Information
1.1
Investigator Signature Page
Herewith I agree that I have read and fully understand this protocol:
Randomized, open-label Phase II trial to assess the safety and immunogenicity of MVA-BN®
smallpox vaccine when increasing the number of injections compared to the standard regimen in
immunocompromised subjects with HIV infection Edition 5.0.
This protocol describes necessary information to conduct the trial. I agree that I will conduct the
trial according to the instructions given within this protocol. Furthermore, I agree that I will
conduct this trial according to International Conference of Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice
(GCP), the 2013 version of the Declaration of Helsinki, 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 (IEC) review and regulatory inspections, providing direct access
to source data/documents.
__________________
Date
__________________________________
[name]
Principal Investigator (PI), [site]
__________________________________
__________________________________
__________________________________
[clinical trial site address]

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Table of Contents
1
General Information ................................................................................ 2
1.1
Investigator Signature Page.........................................................................2
1.2
Coordinating Investigator Signature Page.................................................3
1.3
Sponsor Signature Page ...............................................................................4
1.4
Responsibilities..............................................................................................5
1.5
Protocol Synopsis........................................................................................15
1.6
Trial Procedure Schedule...........................................................................22
2
Background Information and Scientific Rationale............................... 24
2.1
Introduction.................................................................................................24
2.2
First Generation Smallpox Vaccines.........................................................24
2.3
Second Generation Smallpox Vaccines.....................................................25
2.4
Origin and Characteristics of MVA-BN® Smallpox Vaccine.................26
2.5
Summary of Nonclinical Studies with MVA-BN® Smallpox Vaccine ...27
2.6
Clinical Profile of MVA-BN® Smallpox Vaccine.....................................27
2.6.1
Safety Overview of MVA-BN® ............................................................28
2.6.2
Safety of MVA-BN® Smallpox Vaccine Given in High Dose..............33
2.6.3
Safety Profile of MVA-BN® Smallpox Vaccine in Healthy Compared to
Special Populations ..............................................................................33
2.6.4
Immunogenicity Overview of MVA-BN®............................................34
2.7
Rationale......................................................................................................35
2.8
Trial Population..........................................................................................37
2.9
Risk/Benefit Assessment.............................................................................37
2.9.1
Potential Risks......................................................................................37
2.9.2
Benefits .................................................................................................38
3
Objectives................................................................................................ 38
4
Trial Design ............................................................................................ 38
4.1
Experimental Design ..................................................................................38
4.2
Description of Trial Procedures................................................................39

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4.2.1
Screening Phase....................................................................................39
4.2.2
Active Trial Phase ................................................................................40
4.2.3
Follow-Up (FU) Phase..........................................................................45
4.2.3.1
FU 1.........................................................................................................45
4.2.3.2
FU 2.........................................................................................................45
4.2.4
Unscheduled Visits ...............................................................................46
4.2.5
Withdrawal from Second or Booster Vaccination..............................46
4.2.6
Premature Discontinuation..................................................................47
4.3
Trial Duration .............................................................................................47
4.4
Data Safety Monitoring Board..................................................................47
4.5
Trial Halting Rules .....................................................................................48
5
Selection of Subjects............................................................................... 48
5.1
Recruitment Procedure..............................................................................48
5.2
Inclusion Criteria........................................................................................49
5.3
Exclusion Criteria.......................................................................................49
6
Investigational Medicinal Product ........................................................ 49
6.1
Production, Packaging and Labeling........................................................49
6.2
Shipment, Storage and Handling ..............................................................49
6.3
Preparation, Administration and Dosage.................................................50
6.4
Accountability and Disposal ......................................................................50
7
Assessment of Immunogenicity.............................................................. 50
7.1
Humoral Immunogenicity..........................................................................51
7.1.1
ELISA...................................................................................................51
7.1.2
PRNT....................................................................................................51
7.2
Future Use of Lab Specimen......................................................................52
8
Safety and Reactogenicity...................................................................... 52
8.1
Definitions....................................................................................................52
8.1.1
Medical History....................................................................................52
8.1.2
AEs........................................................................................................52

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8.1.2.1
Unsolicited AEs......................................................................................52
8.1.2.2
Solicited AEs..........................................................................................53
8.1.2.3
AESIs......................................................................................................53
8.1.2.4
SAEs........................................................................................................53
8.2
Assessment...................................................................................................54
8.2.1
Relevant Medical History ....................................................................54
8.2.2
Prior and Concomitant Medications...................................................54
8.2.3
Physical Examination...........................................................................55
8.2.4
Vital Signs.............................................................................................55
8.2.5
Unsolicited AEs ....................................................................................55
8.2.6
Solicited AEs.........................................................................................57
8.2.6.1
Solicited Local AEs................................................................................58
8.2.6.2
Solicited General AEs ...........................................................................58
8.2.7
Cardiac Assessment .............................................................................59
8.2.8
Safety Laboratory Measurements.......................................................62
8.2.9
Pregnancy.............................................................................................63
8.3
Reporting.....................................................................................................63
8.3.1
Reporting of SAEs................................................................................63
8.3.2
Reporting of AESIs ..............................................................................66
8.3.3
Reporting of Pregnancy.......................................................................66
9
Statistical Considerations....................................................................... 68
9.1
Randomization Procedure .........................................................................68
9.2
Sample Size Calculation.............................................................................68
9.3
Trial Cohorts/Datasets to be Evaluated....................................................68
9.4
Biometrical Evaluation...............................................................................69
9.4.1
Main Analysis.......................................................................................69
9.4.2
Presentation of Data.............................................................................69
10
Ethical Aspects ....................................................................................... 70
10.1 Ethical and Legal Regulations...................................................................70
10.2 Approval by an IEC / IRB .........................................................................70

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10.3 Confidentiality and Data Protection.........................................................70
11
Informed Consent................................................................................... 71
12
eCRFs and Retention of Records........................................................... 71
12.1 eCRF ............................................................................................................71
12.2 Retention of Records ..................................................................................71
12.3 Monitoring of the Trial ..............................................................................72
13
Audits and Inspections........................................................................... 72
14
Responsibilities of the PI........................................................................ 72
15
References............................................................................................... 74
16
Appendices.............................................................................................. 78
16.1 Appendix I: Toxicity Scale for Laboratory Values .................................78
16.2 Appendix II: Case Definitions Acute Myocarditis / Pericarditis ...........80
16.2.1 Case Definition for Acute Myocarditis................................................80
16.2.2 Case Definition for Acute Pericarditis ................................................81
16.3 Appendix III: Interpretation Support for Assessment of Screening ECGs
......................................................................................................................82
16.4 Appendix IV: Grading Scale for Lymphadenopathy..............................83
16.5 Appendix V: Amendment #4 .....................................................................84

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Table of Tables
Table 1
Frequency of Adverse Drug Reactions
28
Table 2
Serious Suspected ADRs (SAEs Assessed by the Investigator to be at Least
Possibly Related to MVA-BN®)
31
Table 3
Demographic Data of HIV-infected Subjects Enrolled in the Clinical Trial
POX-MVA-011 (FAS, N = 482)
33
Table 4
Distribution of the Three Treatment Groups
39
Table 5
Grading of General Symptoms from the Subject’s Memory Aid
59
Table 6
Toxicity Scale for Serum Chemistry
79
Table 7
Toxicity Scale for Hematology
79
Table of Figures
Figure 1
Algorithm for Assessment of Cardiac Events
61
Figure 2
Algorithm for Reporting of SAEs
65
Figure 3
Algorithm for Reporting of AESIs
67

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List of Abbreviations
AD
Atopic Dermatitis
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIDS
Acquired Immune Deficiency Syndrome
ALT
Alanine Aminotransferase
ART
Antiretroviral Therapy
AST
Aspartate Aminotransferase
BN
Bavarian Nordic
CD
Cluster of Differentiation
CDISC
Clinical Data Interchange Standards Consortium
CrCl
Creatinine Clearance
CRA
Clinical Research Associate
CRO
Contract Research Organization
CSR
Clinical Study Report
CTS
Clinical Trial Site
DMID
Division of Microbiology and Infectious Diseases
DNA
Deoxyribonucleic Acid
DS
Drug Safety
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF(s)
Electronic Case Report Form(s)
ELISA
Enzyme-linked Immunosorbent Assay
EMA
European Medicines Agency
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
HDL
High-density Lipoprotein
GMT
Geometric Mean Titer
HCG
Human Choriogonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HSCT
Hematopoietic Stem Cell Transplant
ICF
Informed Consent Form
ICH
International Conference of Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
LDL
Low-density Lipoprotein
LF
Liquid frozen

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LLN
Lower Limit of Normal
LV
Left Ventricular
MCH
Mean Corpuscular/cellular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular/cell Volume
MedDRA
Medical Dictionary for Regulatory Activities
MMWR
Morbidity and Mortality Weekly Report
MP
Medicinal Product
MPXV
Monkeypox Virus
MVA
Modified Vaccinia Ankara Strain
MVA-BN
Modified Vaccinia Ankara – Bavarian Nordic
also named IMVAMUNEor IMVANEX
N/A
Not Applicable
n/N
Number
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
PCR
Polymerase Chain Reaction
PEI
Paul Ehrlich Institut
PI
Principal Investigator
PPS
Per Protocol Set
PRNT
Plaque Reduction Neutralization Test
PVC
Premature Ventricular Contractions
RDW
Red Blood Cell Distribution Width
RNA
Ribonucleic Acid
SADR
Serious Adverse Drug Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SCR
Screening
SD
Standard Deviation
SOP
Standard Operating Procedure
TCID50
Tissue Culture Infectious Dose 50%
ULN
Upper Limit of Normal
US(A)
United States (of America)
V
Visit
VRBPAC
Vaccines and Related Biological Products Advisory Committee
VACV
Vaccinia Virus
WBC
White Blood Cell Count
WHO
World Health Organization
WOCBP
Women of Childbearing Potential

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Route of
administration
Each MVA-BN® vaccination is administered subcutaneously (s.c.) in
the upper arm.
Trial duration
Up to 75 weeks per subject
Sample size
90 (30 subjects per group)
Primary objective
To assess the safety of MVA-BN® smallpox vaccine when increasing
the dose or number of injections compared to the standard 2-dose
regimen
Secondary objectives
To compare the immunogenicity and safety of three different
vaccination strategies of MVA-BN® smallpox vaccine
Primary endpoint
Occurrence, relationship and intensity of any serious and / or
unexpected Adverse Event at any time during the trial.
Secondary endpoints
Immunogenicity
Geometric mean titers (GMTs) after vaccination with MVA-BN®
smallpox vaccine measured by Enzyme-linked Immunosorbent Assay
(ELISA) and Plaque Reduction Neutralization Test (PRNT) at trial
Visit 4 for Group 2 compared to Group 1 and Group 3 (combined).
GMTs after vaccination with MVA-BN® smallpox vaccine measured
by ELISA and PRNT at trial Visit 7 of Group 3 compared to Visit 4 of
Group 1 and Group 2 (separately).
GMTs after vaccination with MVA-BN® smallpox vaccine measured
by ELISA and PRNT at six months Follow-up 1 (FU 1) and one year
FU 2 Visit of Group 3 compared to respective FU Visits of Group 1
and Group 2 (separately).
Seroconversion after vaccination with MVA-BN® smallpox vaccine
measured by ELISA and PRNT at trial Visit 4 of Group 2 compared to
Group 1 and 3 (combined).
Seroconversion after vaccination with MVA-BN® smallpox vaccine

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measured by ELISA and PRNT at trial Visit 7 of Group 3 compared to
Visit 4 of Group 1 and Group 2 (separately).
Seroconversion after vaccination with MVA-BN® smallpox vaccine
measured by ELISA and PRNT at six months FU 1 and one year FU 2
Visit of Group 3 compared to respective FU Visits of Group 1 and
Group 2 (separately).
GMTs and seroconversion after vaccination with MVA-BN® smallpox
vaccine measured by ELISA and PRNT at all other immunogenicity
sampling points (Visit 1, 3, 4, six months FU 1, one year FU 2) of
Group 2 and 3 (separately) compared to Group 1.
GMTs and seroconversion after vaccination with MVA-BN® smallpox
vaccine measured by ELISA and PRNT at trial Visit 6 and 7 of
Group 3.
Safety and Reactogenicity
Occurrence, relationship to the trial vaccine and intensity of any
Adverse Event of Special Interest (AESI).
Occurrence of any Grade 3 or 4 Adverse Events (AEs) possibly,
probably or definitely related to the trial vaccine within 28 days after
each vaccination.
Occurrence, relationship to the trial vaccine and intensity of unsolicited
non-serious AEs within 28 days after each vaccination.
Occurrence, intensity and duration of solicited local AEs (redness,
swelling, induration, pruritus and pain) during the 8-day period (day of
vaccination and the following 7 days) after each vaccination.
Occurrence, relationship to the trial vaccine, intensity and duration of
solicited general AEs (pyrexia, headache, myalgia, nausea, fatigue and
chills) during the 8-day period (day of vaccination and the following 7
days) after each vaccination.
Change in CD4 T cell counts in Human Immunodeficiency Virus
(HIV)-infected subjects two weeks after each vaccination.

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Trial design
Multicenter, randomized
Visit Schedule:
Visit (V)
Day
Target
Week
Vaccination
SCR
Day -28 to -1
-4
V1
Day 0
0
X
V2
V1 + 12 to 16 days
2
V3
V1 + 28 to 35 days
4
X
V4
V3 + 12 to 16 days
6
V5
V3 + 28 to 35 days
8
V6*
V1+ 84 to 96 days
12
X*
V7*
V6 + 12 to 16 days
14
V8*
V6 + 28 to 35 days
16
FU 1
V3 (V6*) +182 to
210 days
30 (38*)
FU 2
V3 (V6*) +364 to
392 days
56 (64*)
*only Group 3
Groups
N
Dose
(TCID50) per
injection (0.5
ml)
Number of
Injections
Vaccination
s (Weeks)
1
30
at least
1 x 108/ml
Standard regime
0 - 4
2
30
at least
1 x 108/ml
Two injections at
each time point
0 - 4
3
30
at least
1 x 108/ml
Standard regime +
additional boost
0 - 4 - 12
Subject entry criteria
Inclusion criteria
1.
Male and female subjects aged between 18-45 years, vaccinia-
naïve.
2.
HIV-1 infection documented by ELISA and confirmed by
Western blot at any time prior to study entry. HIV-1
deoxyribonucleic acid (DNA) polymerase chain reaction (PCR),
plasma HIV-1 ribonucleic acid (RNA), or a second antibody test
other than ELISA is acceptable as an alternative confirmatory
test at any time prior to trial entry. If an original of the test result
cannot be obtained anymore but the subject was diagnosed as

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described and details on how and when the subject was
diagnosed are documented in the subjects source data/medical
records by a current or previous physician or the PI, this is
sufficient and the subject can be enrolled in the trial.
3.
On stable antiretroviral therapy (ART) i.e. Combination ART for
at least three months prior to screening visit in this clinical trial
with no change to the therapy during these three months.
4.
Screening HIV-1 RNA < 200 copies/ml
5.
Screening CD4 counts ≥ 100 cells/µl and ≤ 500 cells/µl. 
6.
Documented nadir CD4 count < 200 cells/µl at any time prior to
screening visit. If nadir is not documented lowest documented
CD4 count < 200 cells/µl at any time prior to screening visit.
7.
Hemoglobin ≥ 9.0 g/dl for female subjects, ≥ 10.0 g/dl for male 
subjects.
8.
Platelets ≥ 100,000/mm3.
9.
Ability and willingness of subject to provide written informed
consent.
10.
Body Mass Index (BMI) ≥ 18.5 and < 35 kg/m2.
11.
Women of childbearing potential (WOCBP) must have used an
acceptable method of contraception for 30 days prior to the first
vaccination, must agree to use an acceptable method of
contraception during the trial, and must avoid becoming pregnant
for at least 28 days after the last vaccination. A woman is
considered of childbearing potential unless post-menopausal
(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.
12.
WOCBP must have a negative serum pregnancy test at screening
(SCR) and a negative urine pregnancy test within 24 hours prior
to each vaccination.
13.
Absolute neutrophil cell count ≥ 750/mm3.
14.
Adequate renal function defined as a calculated Creatinine
Clearance (CrCl) > 60 ml/min as estimated by the Cockcroft-
Gault equation.
a)
For men: (140 – age in years) x (body weight in kg) ÷ (serum
creatinine in mg/dl x 72) = CrCl (ml/min)
b)
For women: multiply the result for men by 0.85 = CrCl (ml/min).
15.
Adequate hepatic function defined as: Total bilirubin 2 x upper
limit normal (ULN) in the absence of other evidence of
significant liver disease. Subjects with elevated bilirubin due to
an Atazanavir therapy can be enrolled. Aspartate
aminotransferase (AST), alanine aminotransferase (ALT) and
alkaline phosphatase 2.5 x ULN.
16.
Screening Troponin I < 2 x ULN .

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17.
Electrocardiogram (ECG) without clinically significant findings
(e.g. any kind of atrioventricular or intraventricular conditions or
blocks such as complete left or right bundle branch block, AV
node block, QTc or PR prolongation, premature atrial
contractions or other atrial arrhythmia, sustained ventricular
arrhythmia, two premature ventricular contractions (PVC) in a
row, ST elevation consistent with ischemia).
Exclusion criteria
1.
Pregnant or breast-feeding women.
2.
Typical vaccinia scar.
3.
Known or suspected history of smallpox vaccination.
4.
History of vaccination with any poxvirus-based vaccine.
5.
Uncontrolled serious infection, i.e. not responding to
antimicrobial therapy.
6.
History of any serious medical condition, which in the opinion of
the investigator would compromise the safety of the subject or
would limit the subject’s ability to complete the trial including
uncontrolled diabetes as according to the 'Division of Acquired
Immune Deficiency Syndrome (AIDS) Table for Grading the
Severity of Adult and Pediatric Adverse Events' Version 1.0,
December 2004, Clarification August 2009.
7.
History of or active autoimmune disease. Persons with vitiligo or
thyroid disease taking thyroid replacement are not excluded.
8.
Known or suspected impairment of immunologic function except
those defined in the inclusion criteria, including, but not limited
to clinically significant liver disease, diabetes mellitus type I and
moderate to severe kidney impairment.
9.
History of malignancy other than squamous cell or basal cell skin
cancer, unless there has been surgical excision that is considered
to have achieved cure. Subjects with history of skin cancer must
not be vaccinated at the previous tumor site. Subjects with a
history of Kaposi sarcoma who did not have a surgical excision,
are clinically stable and are in remission are not excluded.
10.
History or clinical manifestation of clinically significant and
severe hematological, pulmonary, central nervous, cardiovascular
or gastrointestinal disorders (except HIV infection, chronic or
active Hepatitis-B-Virus or Hepatitis-C-Virus infection).
11.
Clinically significant psychiatric disorder not adequately
controlled by medical treatment.
12.
History of coronary heart disease, myocardial infarction, angina
pectoris, congestive heart failure, cardiomyopathy, stroke or
transient ischemic attack, uncontrolled high blood pressure, or
any other heart condition under the care of a doctor.
13.
Known history of an immediate family member (father, mother,
brother, or sister) who has had onset of ischemic heart disease
before age 50 years.

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14.
Ten percent or greater risk of developing a myocardial infarction
or coronary death within the next 10 years using the National
Cholesterol Education Program’s risk assessment tool
(http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof).
NOTE: This criterion applies only to subjects 20 years of age and
older.
15.
Current alcohol abuse (40 g/day for at least six months) and/or
intravenous and/or intranasal drug abuse (within the past six
months).
16.
Known allergy to MVA-BN® vaccine or any of its constituents,
e.g. tris (hydroxymethyl)-amino methane, including known
allergy to egg or aminoglycosides.
17.
History of anaphylaxis or severe allergic reaction to any vaccine.
18.
Acute disease (illness with or without a fever) at the time of
screening or at any time of vaccine administration.
19.
Body temperature 100.4°F (38.0°C) at the time of screening or
at any time of vaccine administration.
20.
Having received any vaccinations or planned vaccinations with a
live vaccine within 30 days prior to or after trial vaccination.
21.
Having received any vaccinations or planned vaccinations with a
killed vaccine within 14 days prior to or after trial vaccination.
22.
Use of immunosuppressant or immunomodulatory agents
including systemic glucocorticoids (excluding nasal or inhaled
steroids), tacrolimus, sirolimus, rapamycin, mycophenolate,
cyclosporine, TNF-alpha blockers or antagonists, azathioprine,
interferon or growth factors, or intravenous immunoglobulin in
the 60 days prior to screening in this clinical trial.
23.
Post organ and/or stem cell transplant subjects whether or not
receiving chronic immunosuppressive therapy.
24.
Administration or planned administration of immunoglobulins
and/or any blood products during a period starting from three
months prior to administration of the vaccine and ending at last
physical trial visit.
25.
Use of any investigational or non-registered drug or vaccine
other than the trial vaccine within 30 days preceding the first
dose of the trial vaccine, or planned administration of such a
product during the trial period.
26.
Trial personnel.

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1.6
Trial Procedure Schedule
Visit (V)
SCR
V1
V2
V3
V4
V5
V6*
V7*
V8*
FU 1
FU 2
Day / Visit +…
Day
-28--1
0
V1+
12-16
V1+
28-35
V3+
12-16
V3+
28-35
V1+
84-96
V6+
12-16
V6+
28-35
V3
(V6*)+
182-210
V3
(V6*)+
364-392
Target week
- 4
0
2
4
6
8
12
14
16
30 (38*)
56 (64*)
Procedures
Informed consent
& HIPAA
X
X8
Check incl. / excl.
criteria
X
X
Medical
History/HIV
specific medical
history
X
Check criteria for
withdrawal of next
vaccination
X
X
Assessment for
previous smallpox
vaccination
including check
for a scar
X
Complete physical
exam
X
Evaluation of vital
signs
X
X
X
X
X
X
X
X
X
X
X
Calculate
individual cardiac
risk factor
X
Evaluation of
family cardiac risk
factors
X
Targeted physical
exam incl.
auscultation of the
heart and lung
X
X
X
X
X
X
X
X
X
X
ECG4
X
X
(X)1
(X)1
Recording of prior
and concomitant
medication
X
X
X
X
X
X
X
X
X
Counseling on
avoidance of
pregnancy for
WOCBP6
X
X
X
X
AE/SAE/AESI
recording
X
X
X
X
X
X
X
X
X
X2
X2
Lab
Pregnancy test for
WOCBP3
X
X
X
X
X
X
Obtaining blood
for safety lab4
X
X
X
X
(X)1
(X)1

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Visit (V)
SCR
V1
V2
V3
V4
V5
V6*
V7*
V8*
FU 1
FU 2
Day / Visit +…
Day
-28--1
0
V1+
12-16
V1+
28-35
V3+
12-16
V3+
28-35
V1+
84-96
V6+
12-16
V6+
28-35
V3
(V6*)+
182-210
V3
(V6*)+
364-392
Target week
- 4
0
2
4
6
8
12
14
16
30 (38*)
56 (64*)
Total, HDL and
LDL cholesterol
X
Troponin I testing4
X
X
X
X
Serum collection
for
immunogenicity
testing
X
X
X
X
X
X
X
CD4 count
X
X
X
X
X
X
X
Viral Load7
X
X
Vaccination
Vaccine
administration
& Subject
observation
X
X
X
Recording of
immediate AEs
X
X
X
Handout of
memory aid
X
X
X
Collection of
memory aid
X
X
X
Examination of
injection site
X
X
X
Blood volume
Appr. blood
volume drawn
(ml)4,5
13
9
13
9
18
0
9
18
2
11
11
Cumulative blood
volume drawn
(ml)4
13
22
35
44
62
62
71
89
91
102
113
*Visits performed for subjects in Group 3 only
(x)1Only to be performed if clinically indicated, i.e. in the presence of cardiac signs or symptoms.
2 New Serious Adverse Events (SAEs)/ AESIs and changes to SAEs/AESIs/AEs ongoing at V5 (Group 1/2)
or V8 (Group 3) only.
3 At SCR, a serum test must be performed. At other visits, a urine pregnancy test will be performed.
4 If clinically indicated, additional safety measures can be taken at any other trial visits or at unscheduled
visits.
5 Approximate amounts of single blood draws: Safety lab including all tests: 7 ml; immunogenicity testing: 9
ml; viral load: 4ml; /CD4 count: 2 ml.
6 Review of acceptable contraceptive methods and recent menstrual history with WOCBP.
7 Viral load will be determined during treatment period if clinically indicated.
8 FU 2 procedures added after initial trial entry informed consent; i.e. subjects need to sign updated informed
consent form at or before FU2.

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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 including
also the immunocompromised population.
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
prophylactic vaccine protecting against smallpox infection. For IMVANEX® a marketing
authorization under exceptional circumstances was granted on 31 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 Vaccinia Virus (VACV)
strains, e.g. Lister-Elstree strain 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 per year still died from complications due to smallpox vaccination during the
eradication campaign (McElwain, 1972).
Replication competent smallpox vaccines could be lethal if given to immune compromised
individuals and are therefore contraindicated for e.g. persons who have received organ
transplantation, persons with cancer, Atopic Dermatitis (AD) or HIV infection. A trial published
in 1991 (Guillaume, 1991) reported two cases of HIV-infected, immunocompromised patients
who experienced necrotic skin lesions due to generalized vaccinia infections that led to death.

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However, complications following vaccinations with vaccinia can also occur in HIV-infected
individuals with T cell counts in the normal range and who are otherwise healthy (Redfield,
1987).
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
clinical trials using Dryvax® confirmed a success rate by vesicle formation in vaccinia-naïve
volunteers of 95 to 99% (Frey, 2002; ACAM2000 Vaccines and Related Biological Products
Advisory Committee [VRBPAC] Briefing Document, 2007).
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 modern 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® developed by Acambis Inc. is based on the Dryvax® NYCBH strain (Monath,
2004). In preparation of a Biologics License Application at the 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® and Dryvax®. In total, the ratio of individuals in these trials receiving
ACAM2000® and Dryvax® was 3:1 (ACAM2000 Vaccines and Related Biological Products
Advisory Committee [VRBPAC] Briefing Document, 2007).
Safety information available from these trials suggests that 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
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 against VACV using a 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

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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 for the special
risks of this conventional second generation smallpox vaccine.
2.4
Origin and Characteristics of MVA-BN® Smallpox Vaccine
VACV is considered the best known member of the poxvirus family and the prototype of a live
viral smallpox vaccine. VACV replicates in the cytoplasm of the host cell, its DNA does not
integrate into the host cell genome and it is non-oncogenic.
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® vaccine has been derived from MVA-572 and is a highly attenuated, purified live
vaccine produced under serum-free conditions in chicken embryo fibroblasts 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 weeks apart. Since MVA-BN® is non-replicating in human cells it does not
form vesicles (“takes”) (Mayr, 1975).
For further details on MVA-BN®, please refer to the relevant sections in the Investigator’s
Brochure.

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2.5
Summary of Nonclinical Studies with MVA-BN® Smallpox Vaccine
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
traditional smallpox vaccines (e.g. ACAM2000®, Dryvax®) as well as other MVA strains. MVA-
BN® does not replicate in any of the human cell lines tested (Chaplin, 2002) and is not lethal for
severely immunocompromised animals (Suter, 2009). Repeated administrations (s.c. or intra-
muscular) of MVA-BN® resulted in injection site irritations and some lymphoid changes;
however, these effects were minimal and self-limited and are therefore not considered to be dose-
limiting.
Two developmental toxicity studies in rats and rabbits demonstrated that none of the tested doses
of MVA-BN® vaccine (1 x 107 TCID50 or 1 x 108 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 (antibodies and T cells) as traditional 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.
2.6
Clinical Profile of MVA-BN® Smallpox Vaccine
To date, 16 clinical trials (11 sponsored by BN, thereof seven under Investigational New Drug
(IND) 11596; five sponsored by the Division of Microbiology and Infectious Diseases (DMID),
NIAID, NIH under IND 11229) evaluating the safety and immunogenicity of MVA-BN® have
been completed. Currently five clinical trials are ongoing - four sponsored by BN under IND
11596 and IND 15316, respectively; one sponsored by the DMID (NIAID, NIH) under IND
11229). As of September 1, 2013 3,452 subjects have been vaccinated with MVA-BN® in

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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 eight (8 out of 7,428 vaccinated subjects = 0.11%) serious suspected Adverse Drug
Reactions (ADRs) have been reported for MVA-BN® smallpox vaccine 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. No pattern regarding Serious ADRs (SADRs) could be
detected.
In the ongoing clinical trial POX-MVA-013, in which 4,005 subjects have been recruited until
September 1, 2013, one serious ADR is reported (see Table 2). As the trial is not unblinded yet, it
is unknown whether the case occurred in the Placebo or in the MVA-BN® group.
Adverse Drug Reactions
Suspected ADRs were reported in completed clinical trials POX-MVA-001, -002, -004, -005, -
007, -008, -009, -010, -011, -023, -024, -028, -029 -030, HIV-NEF-004 and HIV-POL-002 (N =
3,445) as following (see Table 1):
Table 1
Frequency of Adverse Drug Reactions
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
Influenza
Upper respiratory tract
infection
Sinusitis
Conjunctivitis
Blood and Lymphatic
System Disorders
-
-
Lymphadenopathy
-
Metabolism and
Nutrition Disorders
-
Appetite disorder
-
-
Psychiatric Disorders
-
-
Sleep disorder
-
Nervous System
Disorders
Headache
Dizziness
Paraesthesia
Peripheral sensory
neuropathy
Ear and Labyrinth
Disorders
-
-
Vertigo
-
Cardiac Disorders
-
-
-
Tachycardia
Respiratory, Thoracic
and Mediastinal
-
-
Pharyngolaryngeal
pain
-

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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)
Disorders
Rhinitis
Cough
Gastrointestinal
Disorders
Nausea
-
Diarrhoea
Vomiting
Dry mouth
Abdominal Pain
-
Skin and
Subcutaneous Tissue
Disorders
-
-
Rash
Pruritus
Dermatitis
Skin discolouration
Ecchymosis
Hyperhidrosis
Urticaria
Night sweats
Angioedema
Musculoskeletal and
Connective Tissue
Disorders
Myalgia
Pain in extremity
Arthralgia
Back pain
Neck pain
Musculoskeletal
stiffness
Muscle spasms
Musculoskeletal pain
Muscular weakness
General Disorders and
Administration Site
Conditions
Injection
site pain
Injection
site
erythema
Injection
site
induration
Injection
site swelling
Injection
site pruritus
Fatigue
Injection site
discolouration
Injection site nodule
Injection site
haematoma
Injection site warmth
Chills
Underarm swelling
Injection site irritation
Injection site
haemorrhage
Injection site
exfoliation
Injection site
paraesthesia
Injection site
inflammation
Injection site reaction
Injection site rash
Injection site
movement impairment
Application site
anesthesia
Flushing
Axillary pain
Chest pain
Asthenia
Malaise
Oedema peripheral
Investigations
-
Body temperature
increased
Troponin I increased
Pyrexia
Hepatic enzyme
increased
White blood cell count
decreased
Mean platelet volume
decreased
White blood cell count
increased
-
Injury, Poisoning and
Procedural
Complications
-
-
Contusion
-

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* Medical Dictionary for Regulatory Activities (MedDRA)
+ Rare for which 3 events were recorded
Looking only at the events that were reported by at least 1% of subject, 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 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
clinical trials using MVA-BN®. Despite close cardiac monitoring, no event indicating a case of
myo-/pericarditis has been observed in any completed MVA-BN® trial.

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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 vaccination
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 vaccination
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 vaccination
Transitory ocular
muscle paresis
Resolved
without
sequelae
No relevant medical history
Probably
related
Possibly
related
POX-MVA-010
30/Female
133 days after
2nd vaccination
Congestive heart
failure due to
cardiomyopathy
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 vaccination
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
POX-MVA-
013*
24/Male
5 days after 1st
vaccination
Seizure
Resolved
without
sequelae
The subject has a family history as well as a
previous history of grand mal seizures in
childhood, which is considered to be a risk
factor for the re-emergence of seizure
episodes.
Possibly related
Unlikely
related
POX-MVA-036
27/Female
0 days after 2nd
vaccination
Throat tightness
and other
hypersensitivity
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
Possibly related
Possibly
related

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Trial
Age/
Gender
Days After
Vaccination
Event
Outcome
Underlying Diseases/
Circumstances
Investigator
Assessment
BN
Opinion
medical history of shingles. She has received
multiple vaccines before but never had
previous hives or other problems with
vaccines.
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
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.
Possibly related
Unlikely
related
* This trial is still blinded, vaccination wither either MVA-BN® or Placebo.

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2.6.2 Safety of MVA-BN® Smallpox Vaccine Given in High Dose
A single high dose of MVA-BN® (5 x 108 TCID50) has been tested in 45 subjects in a NIH
sponsored trial. The occurrence of serious and non-serious adverse events associated with
vaccination and the local and systemic reactogenicity were compared to that elicited by the
standard dose regimen of MVA-BN®. No significant difference in the number or severity of
solicited or unsolicited adverse events or the number of events associated with vaccine between
the high dose group and the standard dose group were observed. The only severe events that
occurred in the study were reactogenicity (i.e. solicited) events. No serious events or severe
unsolicited adverse events were reported. This study has shown that the safety profile of a high
dose of MVA-BN® is comparable to that of the standard dose (see further details in the
Investigator’s Brochure).
2.6.3 Safety Profile of MVA-BN® Smallpox Vaccine in Healthy Compared to
Special Populations
MVA-BN® smallpox vaccine has been tested in nearly 1,000 subjects with contraindications to
conventional smallpox vaccines, i.e. individuals diagnosed with HIV infection or AD and
hematopoietic stem cell transplant recipients (Walsh, 2013). In two separate Phase II trials (POX-
MVA-010 [Greenberg, 2013] and POX-MVA-011) the safety of MVA-BN® smallpox vaccine in
healthy subjects and subjects infected with HIV has been directly compared. When comparing
the frequencies of overall ADRs the results from both trials revealed a comparable safety profile
for healthy and HIV-infected subjects following vaccinations with MVA-BN® smallpox vaccine.
The POX-MVA-011 trial was designed to evaluate safety and immunogenicity in HIV-infected
subjects after vaccination with the MVA-BN® smallpox vaccine compared to healthy subjects.
The trial population in the full analysis set (FAS) consisted of 97 healthy, vaccinia-naive and
vaccinia-experienced subjects as a control group compared to 482 vaccinia-naïve and
experienced HIV-infected subjects. Their CD4 counts at time of trial enrollment ranged from
200-750 cells/µl which was split in three subgroups based on their CD4 counts (Table 3) for
further analysis. A substantial proportion of HIV-infected trial population (38%) had a
documented nadir of below 200 cells/µl in their medical history.
Table 3
Demographic Data of HIV-infected Subjects Enrolled in the Clinical Trial POX-MVA-
011 (FAS, N = 482)
Variable
Vaccinia
Status
HIV Overall
CD4
200-349
cells/µl
CD4
350-500
cells/µl
CD4
501-750
cells/µl
Sample size [n]
naïve
351
89
163
99
experienced
131
24
61
46
CD = cluster of differentiation; FAS = full analysis set; n = number of subjects
Data source: Clinical Study Report (CSR) of POX-MVA-011; Synopsis and Section 15, Table 3.2
Almost a quarter of the HIV-infected trial population (23%) reported at least one AIDS defining
condition in their medical history and more than a third (36%) of the HIV-infected subjects

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presented with a history of at least one infection indicative of severe immunosuppression and
clinical AIDS.
The safety of MVA-BN® smallpox vaccine was still comparable to that observed in healthy
subjects. Of note is the even lower incidence of solicited local AEs in HIV-infected subjects
compared to healthy subjects which was observed already in the previous Phase II trial and may
be at least partly attributed to the possible underreporting expected in HIV-infected subjects
given expected lower reactogenicity in an immunocompromised population.
The safety data collected from these special populations are of particular importance, as they
demonstrate that MVA-BN® smallpox vaccine is well tolerated even by subjects with impaired
immune systems, which are known to be at risk of developing severe and/or serious adverse
reactions to conventional replicating smallpox vaccines.
2.6.4 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). 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 2 x 107 TCID50 of MVA-BN® or higher. Statistical analysis indicated lower
doses to be inferior to a nominal titer of 1 x 108 TCID50 tested throughout all dose ranging
studies, whereas the highest dose tested (nominal titer of 1 x 108 TCID50, which means an end of
shelf-life titer of no less than 5 x 107 TCID50) 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 dose of no less than 5 x 107 TCID50
(nominal titer of 1 x 108 TCID50) as the most suitable human dose. Therefore, based on the results
of 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
no less than 5 x 107 TCID50 MVA-BN® administered (s.c.) four weeks apart.
Although antibody responses measured by ELISA in HIV-infected subjects tend to be lower
compared to GMTs in healthy 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. 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) the immune responses induced by MVA-BN® were compared to the
conventional smallpox vaccine Dryvax®. In total 97.8% of subjects vaccinated with a single

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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 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 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 among vaccinia-
naïve volunteers. Data on cellular immune responses, analyzed in various trials using intracellular
cytokine staining for detection of vaccinia-specific Interferon-γ producing CD4 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
BN received marketing authorization for MVA-BN® smallpox vaccine (IMVANEX®) from the
European Medicines Agency (EMA) on 31 July 2013. The dossier included clinical data from
trials in healthy adults and populations contraindicated to receive live smallpox vaccines, namely
HIV-infected or subjects diagnosed with AD. MVA-BN® has shown to be safe and well tolerated
in all tested populations.
Data obtained in clinical trials enrolling HIV-infected subjects have consistently shown that the
collective (PRNT and ELISA) seroconversion rates and induction of a sufficient magnitude of
GMTs after a standard dose regimen of MVA-BN® supports the proposed vaccination strategy in
this population. The finding that GMTs were lower in the HIV-infected compared to the healthy
subjects indicates that these individuals in general had a suppressed immune response due to their

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HIV infection. However, antibody titers were still at high levels, clearly justifying the conclusion
that a strong immune response had been induced in this immunocompromised population.
As part of the post authorization obligations further clinical trial data are requested to explore the
safety of MVA-BN® in a highly immunocompromised population.
Immunodeficiency is characterized by a compromised or even absent ability of the immune
system to cope effectively with infectious pathogens. A well characterized state of
immunodeficiency is the result of the infection with HIV. Other immunodeficiency states include
those secondarily caused by immunosuppressive drugs, e.g. chemotherapy or glucocorticoids, for
treatment of autoimmune diseases or to prevent solid organ rejection in transplant patients. In
addition, some diseases directly or indirectly can cause immunosuppression, e.g. cancer, or renal
failure requiring long-term hemodialysis, as well as chronic infections.
MVA-BN® smallpox vaccine has been tested in nearly 1,000 subjects with contraindications to
conventional smallpox vaccines, i.e. individuals diagnosed with HIV infection or AD and
hematopoietic stem cell transplant (HSCT) recipients. Data obtained in patients with a history of
HSCT showed that MVA-BN® was safe and generally well tolerated in this immunosuppressed
population (Walsh, 2013). The placebo controlled clinical trial was conducted by the US Division
of Microbiology and Infectious Diseases of the National Institutes of Health (NIH/DMID) who
used a low and standard dose for vaccination in this patient population with a history of HSCT.
Vaccination with traditional, replication-competent smallpox vaccines is contraindicated in
persons with a history of HSCT (Wharton, 2003).
Several trials in HIV-infected subjects suggest that MVA-BN® is safe and immunogenic in
immunocompromised subjects (Harrer, 2005, Greenberg, 2013). In the POX-MVA-011 trial
safety and immunogenicity was evaluated in HIV-infected compared to healthy subjects. In this
trial, the CD4 count of the HIV-infected study population prior to enrollment into the study
ranged from 200-750 cells/µl. Based on their medical history, a substantial proportion of these
subjects (38%) had a documented nadir of CD4 cells below 200 cells/µl, 23% had reported at
least one AIDS defining condition and more than a third (36%) had previously presented with a
history of at least one infection indicative of severe immunosuppression and clinical AIDS.
Safety analysis demonstrated that this trial population could receive MVA-BN® without any
safety concerns.
More than 34 Million people are HIV infected and a considerable part is classified as having
Aquired Immunodeficiency Syndrome (AIDS). The classification system for HIV infection
which includes AIDS was simplified in 2008 retaining the 26 AIDS defining conditions besides
three CD4 T-lymphocyte categories: stage 1 to 3 (with stage 3 being classified as AIDS). This
case definition underlines the role of CD4 T-lymphocyte counts which are regarded as an
objective measure of immune suppression. The severity of immunodeficiency increases with HIV
disease progression – once a patient is classified into the stage 3 – AIDS – e.g. nadir < 200
cells/µl, they cannot be reclassified into a less severe stage (Morbidity and Mortality Weekly
Report (MMWR) Dec 5, 2008). Hence even sub-clinically HIV infected subjects with reasonably
restored CD4 counts under ART still have an impaired immune system with severe abnormalities
in T and B cells (Miedema, 1988). Immunodeficiency is the hallmark of AIDS. Since HIV

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directly infects T helper cells, and also indirectly impairs other immune system responses, HIV
infection can be considered as representing a particularly severe form of immunodeficiency.
Since HIV-infected subjects constitute a significant proportion of immunocompromised people in
the general population and are engaged in care at large outpatient clinics they are considered
excellent candidates to represent the highly immunocompromised population for enrollment in
this trial.
The targeted population will be HIV-infected subjects with a current CD4 count between 100 and
500 cells/µl combined with a nadir CD4 cell count category 3 (documented CD4 count < 200
cells/µl at any time prior to enrollment). To account for the expected impact on the immune
response to vaccination in this population, the trial will evaluate whether increasing the number
of doses can improve the immune response to MVA-BN® compared to the standard dose regimen
in highly immunocompromised individuals, while still being comparably safe and well tolerated.
MVA-BN® will be administered either by simultaneous administration of two standard doses to
achieve a higher total dose, or in a three dose schedule by adding a third standard dose as early
booster 12 weeks after the first vaccination. Durability of immune response in this population
will be evaluated at the six months FU visit - which is comparable to the accepted follow-up
period in already completed clinical trials in healthy and HIV populations vaccinated with MVA-
BN® smallpox vaccine.
This trial will generate important additional data in a highly immunocompromised population.
2.8
Trial Population
Vaccinia-naïve HIV-infected women and men of any ethnicity aged 18 to 45 years who meet all
of the inclusion and none of the exclusion criteria are able to enroll into this trial.
2.9
Risk/Benefit Assessment
2.9.1 Potential Risks
Blood drawing may cause discomfort, bruising or light-headedness. Rarely, a blood draw may
result in infection at the site where the blood is taken.
Preclinical data with MVA-BN® in rats and rabbits have revealed no special hazard for humans
based on conventional studies of safety.
Based on the available data for MVA-BN® as well as for MVA-based vaccines in healthy and
immunocompromised subjects, adverse reactions 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
injection site, e.g. erythema, pain swelling and induration.
As with all injectable vaccines, there is a risk of an allergic reaction or an anaphylactic event.
Trial site staff will watch subjects for at least 30 minutes after each vaccination and in the event

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that a severe allergic reaction might occur, appropriate medical treatment and supervision will be
readily available.
The severe and life-threatening adverse reactions such as progressive vaccinia, eczema
vaccinatum, generalized vaccinia and inadvertent inoculation that have been observed after the
administration of conventional smallpox vaccines are due to the replication of these vaccinia
strains. MVA-BN® is replication incompetent in human cells and consequently has a better 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 better
safety profile with regard to severe reactions, the available clinical experience with MVA-BN®
shows that it is generally better tolerated, for example with regard to local reactions, than
conventional smallpox vaccines.
2.9.2 Benefits
There will be no direct benefit to the trial participants. Trial participants 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. Based on the current
immunogenicity and efficacy data collected in non-clinical and clinical studies, participants in
clinical trials are expected to acquire protection against smallpox infection.
Analysis of the samples collected will not directly benefit the subject. BN may learn more about
smallpox and other diseases: how to prevent them, how to treat them, or how to cure them.
3
Objectives
Please refer to trial protocol synopsis Section 1.5.
4
Trial Design
4.1
Experimental Design
Randomized, open-label Phase II trial to assess the safety and immunogenicity of MVA-BN®
smallpox vaccine when increasing the number of injections compared to the standard regimen in
immunocompromised subjects with HIV infection
In total, 90 vaccinia-naïve subjects will be enrolled in this trial (see Table 4). All subjects will be
randomly assigned (1:1:1) to Group 1, Group 2 or Group 3. Group 1 will receive the standard
regime – two vaccinations at Day 0 and Day 28. Group 2 will receive two injections at each
vaccination day in the standard schedule and Group 3 will receive the standard regime and an
additional early boost 12 weeks after the first dose of the standard vaccination schedule with
MVA-BN® smallpox vaccine.

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Table 4
Distribution of the Three Treatment Groups
Groups
N
Dose (TCID50)
per Injection (0.5
ml)
Number of Injections
Vaccinations
(Weeks)
1
30
at least 1 x 108/ml
Standard regime
0 - 4
2
30
at least 1 x 108/ml
Two injections at each time point
0 - 4
3
30
at least 1 x 108/ml
Standard regime + additional boost
0 - 4 - 12
4.2
Description of Trial Procedures
The trial procedures will be conducted according to the trial procedure schedule (Section 1.6) and
as described on the following pages. Visits must be scheduled within the intervals / visit windows
given below.
4.2.1 Screening Phase
All subjects must be thoroughly informed of all aspects of the trial (e.g. trial visit schedule,
required evaluations and procedures, risks and benefits) as described in the informed consent
form (ICF). The ICF and the statement about the Health Insurance Portability and Accountability
Act (HIPAA) must be reviewed with the subject and signed and dated by the subject and the
Investigator, or person designated by the investigator, who conducted the informed consent
discussion before proceeding with any evaluations or procedures required by this protocol.
After ICF has been collected, subjects will enter a screening period of up to 28 days before the
first vaccination.
Screening Visit (Days -28 to -1)
The following tasks will be performed

Subject to read, sign and date ICF and HIPAA

Check inclusion/exclusion criteria

Obtaining medical history

Obtaining HIV specific medical history

Check vaccination history (previous smallpox vaccination or vaccination with a pox-
virus-based vaccine) and absence of smallpox vaccination scar

Complete physical examination including auscultation of heart and lungs and
measurement of body weight and height

Evaluation of vital signs

Cardiac assessment (Section 8.2.7)
○
Calculation of the individual cardiac risk factor (after receipt of lab results for
cholesterol)
○
Evaluation of family cardiac risk factors
○
Perform baseline ECG

Recording of AEs/SAEs/AESIs

Recording of prior and concomitant medication

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
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and
recent menstrual history with WOCBP

Blood draw (2 ml) for CD4 count

Blood Draw (4 ml) for viral load

Blood draw for safety laboratory (7 ml) including
○
Serum pregnancy test (WOCBP only)
○
Hematology & serum chemistry
○
Troponin I
○
Total cholesterol, High-density Lipoprotein (HDL) and Low-density Lipoprotein
(LDL)
If a subject is screened and cannot be enrolled, 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
test(s) should be repeated as a “partial” re-screening rather than a full re-screening. The re-
screening visit must be within the 28 day window started by the first screening visit and the
window -28 to -1 before first vaccination must not be exceeded. A “partial” re-screening visit is
indicated by filling out only the respective re-screening sections in the electronic Case Report
Form (eCRF).
If a subject cannot be enrolled due to other circumstances (e.g. completion of a wash-out period
for a medication or vaccine not allowed during the trial) or the 28 day period is exceeded, a
complete re-screening assessment including physical examination, lab examination, and ECG
must be performed. The clock then re-starts at the re-screening visit with Day -28 before the first
vaccination.
4.2.2 Active Trial Phase
After successfully passing the screening evaluations, the eligible volunteers can enter the active
trial phase (Visit 1 to Visit 5 for Group 1 and Group 2 / Visit 1 to Visit 8 for Group 3) starting
with Visit 1.
At Visit 1 subjects will be assigned randomly to Group 1, Group 2 or Group 3 after re-
confirmation of the subject’s eligibility. The randomization scheme is 1:1:1 (Group 1, 2, 3). An
automated randomization system will be used. The detailed process will be described in a trial
specific procedure.
The procedures performed at Visit 1 and all following visits are listed below. Blood draws and
all other examinations listed above the vaccination events must always be performed prior
to vaccination.
At Visit 1 / Day 0, subjects will receive the first s.c. vaccination with 0.5 ml of MVA-BN® in the
upper arm.
Following each vaccination subjects will be kept under close observation at the clinical trial site
(CTS) for at least 30 minutes, with appropriate medical treatment readily available in case of a

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rare anaphylactic reaction following the administration of vaccines. Any AEs that occur during or
after vaccination will be recorded.
Reactogenicity and AEs will be collected on a subject memory aid by having the subject record
local and general symptoms for an 8-day period (Days 0-7), beginning with the day of
vaccination. The memory aid will be returned to the clinic staff at the following visit. If
symptoms persist at Day 7, daily symptoms and temperature will continue to be measured each
day until resolved and the last day of symptoms and maximum intensity is recorded on the
memory aid. Unsolicited AEs will be assessed at all visits except FU 1 and FU 2 (Screening to
Visit 5 for Group 1 and 2 / Screening to Visit 8 for Group 3).
Visit 1 (Day 0)
Tasks to be performed prior to randomization and vaccination

Confirmation of inclusion / exclusion criteria

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of AEs/SAEs/AESIs

Recording of concomitant medications

Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and
recent menstrual history with WOCBP

Urine pregnancy test (WOCBP only)

Blood draw (9 ml; serum collection) for immunogenicity testing (baseline)
If the subject is still eligible for participation in this trial the subject will be randomized.
The following tasks will be performed after randomization:

Administration of first MVA-BN® vaccination

Subject observation by CTS staff for at least 30 minutes after vaccination

Recording of immediate AEs/AESIs/SAEs

Handout of memory aid for first vaccination, ruler and thermometer
Temporary deferral of vaccination: If an acute illness is present the subject may be vaccinated
at a later date within the accepted 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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Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
Visit 2 (V1 + 12-16 days)
The following tasks will be performed

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Performing of ECG

Recording of concomitant medication

Recording of AEs/SAEs/AESIs

Blood draw (2 ml) for CD4 count

Blood Draw (4 ml) for viral load

Blood draw (7 ml) for safety laboratory including
○
Troponin I
○
Hematology & serum chemistry

Collection of the memory aid handed out at Visit 1, review with subject

Examination of the vaccination site(s)
Visit 3 (V1 + 28-35 days)
Tasks to be performed prior vaccination

Check withdrawal criteria (see Section 4.2.5)

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medications

Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and
recent menstrual history with WOCBP

Recording of AEs/SAEs/AESIs

Urine pregnancy test (WOCBP only)

Blood draw (9 ml; serum collection) for immunogenicity testing
If the subject is still eligible to receive the second vaccination the following tasks will be
performed

Administration of second MVA-BN® vaccination

Subject observation by CTS staff for at least 30 minutes after vaccination

Recording and documentation of immediate AEs/SAEs/AESIs

Handout of the memory aid for second vaccination
Temporary deferral of second vaccination: If an acute illness is present the subject may be
vaccinated at a later date within the accepted 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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Bavarian Nordic A/S
Restricted Business Proprietary
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
Visit 4 (V3 + 12-16 days)
The following tasks will be performed

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medication

Recording of AEs/SAEs/AESIs

Blood draw (2 ml) for CD4 count

Blood draw (7 ml) for safety laboratory including
○
Hematology & serum chemistry
○
Troponin I

Blood draw (9 ml; serum collection) for immunogenicity testing

Collection of the memory aid handed out at Visit 3, review with subject

Examination of the vaccination site(s)

Only if clinically indicated

Perform ECG reading
Visit 5 (V3 + 28-35 days)
The following tasks will be performed

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medication

Recording of AEs/SAEs/AESIs

Urine pregnancy test (WOCBP)
Group 3 only: Visit 6 (V1 + 84-96 days)
Tasks to be performed prior to vaccination

Check withdrawal criteria (see Section 4.2.5)

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medications

Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and
recent menstrual history with WOCBP

Recording of AEs/SAEs/AESIs

Urine pregnancy test (WOCBP only)

Blood draw (9 ml; serum collection) for immunogenicity testing
If the subject is still eligible to receive the booster vaccination the following tasks will be

Page 44 of 91
Bavarian Nordic A/S
Restricted Business Proprietary
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
performed

Administration of booster MVA-BN® vaccination

Subject observation by CTS staff for at least 30 minutes after vaccination

Recording and documentation of immediate AEs/SAEs/AESIs

Handout of the memory aid for booster vaccination
Temporary deferral of booster vaccination: If an acute illness is present the subject may be
vaccinated at a later date within the accepted 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).
Group 3 only: Visit 7 (V6 + 12-16 days)
The following tasks will be performed

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medication

Recording of AEs/SAEs/AESIs

Blood draw (2 ml) for CD4 count

Blood draw (7 ml) for safety laboratory including
○
Hematology & serum chemistry
○
Troponin I

Blood draw (9 ml; serum collection) for immunogenicity testing

Collection of the memory aid handed out at Visit 6, review with subject

Examination of the vaccination site
Only if clinically indicated

Perform ECG reading
Group 3 only: Visit 8 (V6 + 28-35 days)
The following tasks will be performed

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Recording of concomitant medication

Recording of AEs/SAEs/AESIs

Urine pregnancy test (WOCBP only)

Blood draw (2 ml) for CD4 count

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Restricted Business Proprietary
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
4.2.3 Follow-Up (FU) Phase
To monitor long-term safety, subjects will come six months (FU 1) after the last vaccination and
12 months after the last vaccination (FU 2) to the CTS. It will be checked if an SAE/AESI has
occurred since the last trial visit and if there is any new information on SAEs/AESIs/AEs
ongoing at last trial visit. A targeted physical examination, evaluation of vital signs and a blood
draw for immunogenicity and CD4 count will be done.
4.2.3.1 FU 1
For subjects who were withdrawn from the second MVA-BN® vaccination, the FU 1 will be
performed six months after the 1st vaccination and for subjects who were withdrawn from the
booster MVA-BN® vaccination, the FU 1 will be performed six months after the 2nd vaccination
(see Section 4.2.5).
FU 1 (V3 + 182-210 days for Group 1 and 2 / V6 + 182-210 days for Group 3)
The following tasks will be performed

Recording of SAEs/AESIs and AEs ongoing at last active trial visit (Visit 5 for Group 1
and 2, Visit 8 for Group 3).

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Blood draw (9 ml; serum collection) for immunogenicity testing

Blood draw (2 ml) for CD4 count
Only if clinically indicated

Blood draw for safety laboratory (7 ml)

Other safety evaluations, if required
4.2.3.2 FU 2
For subjects who were withdrawn from the second MVA-BN® vaccination, the FU 2 will be
performed 12 months after the 1st vaccination and for subjects who were withdrawn from the
booster MVA-BN® vaccination, the FU 2 will be performed 12 months after the 2nd vaccination
(see Section 4.2.5).
FU 2 (V3 + 364-392 days for Group 1 and 2 / V6 + 364-392 days for Group 3)
The following tasks will be performed

Subject to read, date and sign updated ICF (adding FU 2 to the original trial schedule)

Recording of SAEs/AESIs and AEs ongoing at last active trial visit.

Targeted physical examination including auscultation of the heart and lungs

Evaluation of vital signs

Blood draw (9 ml; serum collection) for immunogenicity testing

Blood draw (2 ml) for CD4 count
Only if clinically indicated

Blood draw for safety laboratory (7 ml)

Other safety evaluations, if required

Page 46 of 91
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Restricted Business Proprietary
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
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.
Examinations, performed at unscheduled visits will be documented in the source documents as
well as in the respective eCRF sections for unscheduled visits.
4.2.5 Withdrawal from Second or Booster Vaccination
The decision not to administer the second/booster vaccination can be made by the investigator or
by the subject.
Criteria:
The following criteria should be checked prior to second/booster vaccination. If any are
applicable, the subject should not receive any further vaccination(s):

Any clinically significant cardiac sign and symptom (i.e. AESI) defined in Section 8.1.2.3.

An AE that, in the opinion of the investigator, makes it unsafe for the subject to receive a
further vaccination. In this case, the appropriate measures will be taken.

Anaphylactic reaction following the administration of any vaccine(s).

Clinical need for concomitant or ancillary therapy not permitted in the trial, i.e.
o
Vaccination with any licensed live vaccine within 30 days prior or after trial
vaccinations or any licensed killed vaccine within 14 days prior or after trial
vaccinations
o
Start of chronic systemic administration (defined as more than 14 days) of > 5 mg
prednisone (or equivalent) per day or any other systemic use of immune-modifying
drugs.
o
Administration of immunoglobulins and/or any blood products.

Use of any investigational or non-registered drug or vaccine other than the trial vaccine.

Pregnancy

Subject refuses to receive second vaccination.

Any condition which contradicts administration of the second vaccination in the opinion of
the investigator.
Procedure:
If a subject did not receive the second trial vaccination the reason for this decision must be
recorded in the eCRF. Visit 3 and Visit 4 are not required and the procedures below should be
followed:

Visit 5 procedures have to be performed 28 to 35 days after last vaccination

Page 47 of 91
Bavarian Nordic A/S
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Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014

FU 1 procedures have to be performed 182 to 210 days after last vaccination

FU 2 procedures have to be performed 364 to 392 days after last vaccination.
If a subject from treatment Group 3 did not receive the second or booster vaccination the reason
for this decision must be recorded in the eCRF. Visits 6, 7 and 8 are not required and the
procedures below should be followed:

FU 1 procedures have to be performed 182 to 210 days after last vaccination.

FU 2 procedures have to be performed 364 to 392 days after last vaccination.
4.2.6 Premature Discontinuation
The trial may be discontinued prematurely for a subject at any time. The decision to discontinue
the trial for a subject prematurely can be made by the investigator or by the subject. Reasons for
discontinuing the trial prematurely may include, but are not limited to the following:
Criteria:

Subject’s request to discontinue prematurely (withdrawal of informed consent).

Subject unwilling or unable to comply with trial requirements.

Discontinuation due to an AE.

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 must be recorded in the eCRF.
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 as reason for
premature discontinuation.
4.3
Trial Duration
The total duration of the trial for each subject including the screening period and Follow-up visits
will be up to 75 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

Page 48 of 91
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Doc. No. 92000015
Edition 5.0
18-NOV-2014
Organization (CRO) managing the trial. The primary responsibilities of the DSMB are to
periodically review and evaluate the accumulated trial data for participant safety, trial conduct
and progress, and make recommendations to BN and the Coordinating and 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.
If an event occurs which fulfills the trial halting rules the DSMB will review the event in a timely
manner and give a recommendation to BN and the Coordinating Investigator and 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 case
of an occurrence of

an SAE

an unexpected Grade 3 or higher systemic reaction or lab toxicity (Section 16.1; Appendix
I: Toxicity Scale for Laboratory Values)
with an at least reasonable possibility of a causal relationship to the administration of MVA-BN®
smallpox vaccine, i.e. the relationship cannot be ruled out.
These parameters are not all-inclusive. Other AEs could occur that would trigger a DSMB
review. Any member of the DSMB, any PI and/or the BN Drug Safety (DS) 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 liability 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
Each investigator will keep a log of subjects screened for the trial, and provide the reason in case
of exclusion. Information about every subject entering the trial will be documented in the eCRF.
5.1
Recruitment Procedure
Subjects will be recruited actively. Recruitment strategies, including IRB approved
advertisements, will be evaluated by the Sponsor.
30 subjects will be enrolled in each group (90 in total).

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7.2
Future Use of Lab Specimen
Serum remaining after completion of all immunogenicity testing for the trial will be stored for
future analysis supporting the licensure path of MVA-BN® smallpox vaccine. Future analysis
will facilitate the bridging of trial results to animal immunogenicity results and/or to immune
response data collected from subjects vaccinated with traditional smallpox vaccines. Subjects will
be asked to consent to storage / future 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.
8
Safety and Reactogenicity
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 vaccinia-based smallpox vaccines during smallpox vaccination
programs in the US during the last years, cases of acute myocarditis and pericarditis were
observed (Cassimatis, 2004). No confirmed cases of myo- or pericarditis have been observed for
MVA-BN® smallpox vaccine. However, as a precautionary measure, special cardiac monitoring
assessments will be performed.
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 AEs
Any new signs, symptoms or changes in health starting after ICF signature are documented in the
AE section of the eCRF. AEs are recorded based on unsolicited and solicited questioning
(Section 8.1.2.1 and 8.1.2.2).
8.1.2.1 Unsolicited AEs
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 IMP or a medical product
(MP) which does not necessarily have a causal relationship with this IMP/MP. For Group 1 and 2
up to Visit 5 (Week 8) and for Group 3 up to Visit 8 (Week 16) 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 eCRF regardless of the
assessment of causality in relationship with the IMP/MP.

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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 (Section 16.1; Appendix I: Toxicity Scale for Laboratory
Values) are to be documented as AE in the eCRF, regardless of whether they are considered
clinically relevant or not. For lab values fulfilling the Grade 3 or 4 criterion, the decision to repeat
the labs is left at the discretion of the PI. 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.
The investigator should 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 section of the eCRF.
8.1.2.2 Solicited AEs
Within this clinical trial protocol 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. erythema, swelling, induration, pruritus and pain at
the injection site) as well as general symptoms (i.e. body temperature, headache, chills, myalgia,
nausea and fatigue) in the memory aid daily for the day of vaccination and the following seven
days (Days 0-7, 8 day period).
8.1.2.3 AESIs
An AESI is defined in this trial as:

Any cardiac sign or symptom developed since the first vaccination

ECG changes determined to be clinically significant

Cardiac enzyme troponin I ≥ 2 x ULN 
8.1.2.4 SAEs
A SAE is any untoward medical occurrence 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
patient 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

Results in a congenital anomaly or birth defect

or is an otherwise important medical event, e.g. leads to suspicion of transmission of an
infectious agent

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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.
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 SCR 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.
Diagnosis of HIV and disease state has to be documented separately: date of diagnosis, nadir,
CD4 count and highest viral load up to six months before SCR.
In addition, smallpox vaccination history must be checked (check for a smallpox vaccination scar
and any documentation of previous smallpox vaccination, if available; Note: check also for
smallpox vaccination programs during military service or for smallpox response teams or history
of vaccination with a poxvirus-based vaccine e.g. in the course of a clinical trial).
8.2.2 Prior and Concomitant Medications
All concomitant (ongoing) medication except homeopathic substances and dietary supplements
must be recorded in the eCRF and the subject’s medical record including information about the
indication, dosage regimen, and the onset and end of treatment.
The following medication, taken within three months prior to screening, will also be recorded in
the eCRF and the subjects medical record: vaccines, corticosteroids (via any route of
administration), other immune-modulating drugs, immunoglobulin and/or any blood products,
investigational drugs and depot preparations which are still active at the date of SCR.
The antiretroviral medications, taken within six months prior to SCR, will also be recorded in the
eCRF and the subject’s medical record.

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8.2.3 Physical Examination
Complete physical examination
A complete physical examination will be performed at the SCR. 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 (a grading scale for
lymphadenopathy is included in Section 16.4; Appendix IV: Grading Scale for
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 required at all visits starting
at Visit 1. In addition, auscultation of the heart and lungs will be performed.
8.2.4 Vital Signs
Blood pressure and pulse rate will be taken after the subject has been sitting for approximately
two minutes. Body temperature will be measured orally.
8.2.5 Unsolicited AEs
All intercurrent diseases reported when the investigator actively inquires the subject will be
documented in the source and all required details (e.g. start and stop date, severity) will be
assessed. Unsolicited AEs will be reported in the respective section of the eCRF and the subject’s
medical record.
AEs for Group 1 and 2 will be assessed and documented at all visits except FU 1 and FU 2 (i.e.
Screening to Visit 5) and if ongoing at Visit 5, followed until resolution or until the FU 2 at the
latest.
AEs for Group 3 will be assessed and documented at all visits except FU 1 and FU 2 (i.e.
Screening to Visit 8) and if ongoing at Visit 8, followed until resolution or until the FU 2 at the
latest.
SAEs/AESIs will be assessed and documented at all trial visits, including the FU 1 and FU 2.
Ongoing AESIs which occurred after at least one vaccination will be followed up until resolution
or achievement of stable clinical conditions. SAEs 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 (Section 16.1;
Appendix I: Toxicity Scale for Laboratory Values), 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 daily activities.
Grade 2
An AE which is sufficiently discomforting to interfere with daily activities.
Grade 3
An AE which prevents daily activities. (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 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”.
None
The time interval between the administration of the IMP 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.
Unlikely
The time interval between administration of the IMP and the occurrence or worsening
of the AE makes a causal relationship unlikely, and/or
the known effects of the IMP or substance class provide no indication of a
(concomitant) causal connection with or worsening caused by the IMP and there is
another cause which serves as an adequate explanation, and/or
although the known effects of the IMP 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 is unlikely.

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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 or
substance class. However, other approximately equally likely causes are known, or
although the pharmacological properties of the IMP 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 trial medication or substance class, and/or
the course of the AE after discontinuation of the IMP and possible subsequent re-
exposure, and/or
specific findings (e.g. positive allergy test or antibodies against the IMP / metabolites )
suggest a (concomitant) causal connection with / worsening of the AE resulting from
the IMP, however another cause cannot completely be ruled out.
Definite
The pharmacological properties of the IMP or substance class and/or
the course of the AE after discontinuation of the IMP and possible subsequent re-
exposure, and/or
specific findings (e.g. positive allergy test or antibodies against the IMP / metabolites )
definitely indicate that there is a (concomitant) causal connection with / worsening of
the AE resulting from the IMP and there are no indications of other causes.
8.2.6 Solicited AEs
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 seven days (Days 0-7; 8-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 will collect this information
during the following scheduled visits and transfer it to the eCRF and the subject’s medical record.
Local and general reactions still ongoing after seven days will be measured or examined each day
until resolution or until no further change can reasonably be expected, and the last day of
symptoms and maximum intensity will be documented in the memory aid.
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.

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8.2.6.1 Solicited Local AEs
The solicited local symptoms erythema, swelling, induration, pruritus and pain at the injection
site 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
=
Absent
1
=
Mild
2
=
Moderate
3
=
Severe
Injection site pain:
0
=
Absent
1
=
Painful on touch
2
=
Painful when limb is moved
3
=
Spontaneously painful / prevents normal activity
Assessment of Causality
Solicited local AEs are defined as being related to the vaccine.
8.2.6.2 Solicited General AEs
The solicited general symptoms body temperature, headache, myalgia, nausea, chills and fatigue
are to be documented in the memory aid by the subject.
Assessment of Intensity

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Subjects are asked to document the solicited general AEs in the memory aid as described in Table
5 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 5
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 – <104.0°F ( ≥ 39.0 – < 40.0°C) 
4
≥ 104.0°F (≥ 40.0°C)  
Headache, Myalgia, Nausea, Chills and
Fatigue
0
None
1
Mild: easily tolerated, minimal discomfort and
no interference with daily activity
2
Moderate: Some interference with daily activity
3
Severe: Prevents daily activity
*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).
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 patient) 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 SCR and at Visit 2. At Visit 4 and Visit 7 (Group 3
only) an ECG is only done if clinically indicated. ECGs will be evaluated by a central ECG
reading center. The workflow and communication flow will be provided in a separate manual.
Cardiac Risk Factors
The individual cardiac risk factor is calculated at SCR (for subjects 20 years of age and older),
using the National Cholesterol Education Program’s risk assessment tool

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(http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof). Subjects with a 10% 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 SCR. Subjects with an immediate family
member (father, mother, brother, or sister), who has had onset of ischemic heart diseases before
50 years of age, are also excluded from trial participation.
Troponin I
Troponin I will be measured at SCR and on the following visits: Visit 2, Visit 4 and Visit 7
(Group 3 only).
Cardiac events fulfill the definition of an AESI as described in Section 8.1.2.3. The investigator
will be asked to assess the clinical significance of the case.
Case definitions as published by the CDC (Morbidity and Mortality Weekly Report [MMWR]
May 30, 2003) are provided in Section 16.2; Appendix II: Case Definitions Acute Myocarditis /
Pericarditis in order to:

help investigators to recognize possible events of acute myocarditis and/or pericarditis and

distinguish from unspecific and isolated ECG changes without or with unclear clinical
significance.
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 such as (treadmill) ECG, measurement of cardiac enzyme and/or echocardiogram.
Depending on the results of these evaluations, further diagnostic tests will be done as
recommended by the cardiologist and subjects will be followed up at a frequency determined by
the cardiologist. Any AESIs occurring after at least one vaccination 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
positive
Subject presents with any symptoms such as chest pain,
shortness of breath, edema or palpitations
Referral to cardiologist
and ensure ECG and
troponin I are measured
ECG, troponin I*
negative
No further work-up
or expedited
reporting required
Cardiac
complications
Symptomatic at
time of exam?
Physical examination
Possible cardiac
complications
Further evaluation as
determined necessary by
the cardiologist
Further work-up as
determined by the
cardiologist and reported
as an AESI or SAE

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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 Section 16.1; Appendix I: Toxicity Scale for Laboratory Values. 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
Section 16.1; Appendix I: Toxicity Scale for Laboratory Values, the Division of AIDS Table for
Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004,
Clarification August 2009 will be used for grading of laboratory toxicities.
Safety laboratory is determined at SCR, Visit 2, Visit 4, Visit 7 (Group 3 only) and at any other
visit(s) if clinically indicated. The safety laboratory measurements are performed at a central
laboratory. Laboratory normal ranges are provided by the central laboratory and filed in the
Investigator File. Safety laboratory parameters to be evaluated are:
Hematology: Red blood cell count, hemoglobin, total and differential White Blood Cell count
(WBC), platelet count (Hematocrit, mean corpuscular/cell volume (MCV), mean
corpuscular/cellular hemoglobin (MCH) , mean corpuscular hemoglobin concentration (MCHC)
and red blood cell distribution width (RDW) are routinely performed as part of the complete
blood cell count and will be included in the laboratory report).
HIV specific parameters: CD4 count will be determined with every safety laboratory and at Visit
8 and FU 1 and FU 2. Viral load will be determined at SCR and at Visit 2. Viral load will be
determined at any other visit if clinically indicated.
Serum chemistry:
Total bilirubin, AP, AST, ALT, serum creatinine (for calculation of CrCl at SCR), sodium,
potassium, calcium, troponin I (troponin mandatory at SCR and in addition Visit 2, Visit 4 and
Visit 7 (Group 3 only)).
Pregnancy test:
A β-human choriogonadotropin (HCG) pregnancy test will be conducted for all WOCBP at SCR, 
within 24 hours prior to each vaccination and at the individual last active trial phase visit (i.e.
Visits 1, 3, 5 and Visits 6 and 8 for Group 3 respectively). At SCR a serum β-HCG pregnancy 
test will be performed; all other pregnancy tests will be conducted as urine β-HCG tests.  
The following parameters will only be evaluated during the screening period for assessment of
inclusion / exclusion criteria and at the following visits only if clinically indicated:
Cholesterol
Total, HDL and LDL

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
the subject

involved trial medication

AE(s)

seriousness criterion and/or criterion for AESI

date of onset
The CRO DS Department alerts BN DS Department of all SAEs and provides the available
information within 24 hours to BN DS. BN is responsible for expedited as well as periodic
reporting to the involved regulatory authorities (e.g. FDA, EMA, Paul Ehrlich Institut [PEI])
according to applicable laws and guidelines. Regulatory authorities will be notified as soon as
possible but no later than seven days after first knowledge of fatal or life-threatening unexpected
SAE with an at least possible relationship to the IMP (SADR) and no later than 15 days after
knowledge of any other unexpected SADR. In addition BN will report the SAEs to the DSMB,
while the investigator or the CRO is responsible for reporting to the Ethics Committees or
Institutional Review Boards. Figure 2 outlines the reporting process and timelines for SAEs.

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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 within 24 h
Record Event in the
AE Section of the CRF
BN DS forwards Safety
reports within
max. 15d/7d to competent
authorities (final)
15d/7d to DSMB (final)
CRO DS reports SAE to
BN DS within 24 h
no
yes
Expedited reporting
necessary?
CRO DS forwards final
Safety reports within max.
15d/7d to concerned IRBs,
IECs and Investigators
SAE entered into safety
database

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8.3.2 Reporting of AESIs
AESIs occurring throughout the entire course of the trial will be reported in the AE section of the
eCRF by marking the appropriate tick box. AESIs have to be reported in the eCRF immediately
after detection. An automatic email notification will be sent to the relevant project members as
soon as an AESI was reported. A periodic report of AESIs will be provided from the CRO to BN
Drug Safety.
Figure 3 outlines the reporting process and timelines for AESIs.
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 must be reported to BN on a Pregnancy
Report Form within 24 hours of the investigator’s becoming aware of the event.
A 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/CRO DS (see Section 8.3.1). However, hospitalization for delivery is a prospectively planned
hospitalization and is not considered a SAE per se.

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Figure 3
Algorithm for Reporting of AESIs
AE
Is the AE
serious?
Report Event in the
AE Section of the eCRF
Refer to Figure 2: Algorithm for
Reporting SAEs
Investigator reports AESI to
CRO DS within 24h
Is the AE an AESI
according to
definition?
Complete AE reporting
yes
no
yes
no
Is the AESI
related to
IMP?
no
yes
BN DS forwards related
AESI reports to DSMB (as
defined in the DSMB
Charter)
Complete AESI reporting

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9
Statistical Considerations
The primary endpoint of this trial is to compare the occurrence, relationship and intensity of any
serious and / or unexpected Adverse Event at any time during the trial. This analysis will be
descriptive.
9.1
Randomization Procedure
Randomized treatment assignments for the subjects will be done after confirmation of subject’s
eligibility. Subjects will be allocated randomly across the trial into Group 1, Group 2 or Group 3.
Randomization will be stratified by CTS in a 1:1:1 ratio.
Please refer to trial protocol synopsis (see Section 1.5).
9.2
Sample Size Calculation
In addition to the below sample size calculations for the immunogenicity endpoints, a sample size
of 30 per group also allows for the detection of AEs with an incidence of at least 1 in 10 with a
probability of detection of 95% or more.
A sample size of 30 in each group will have 80% power to detect a difference in means of 0.74 x
standard deviation (SD) using a two-group t-test with a 5% two-sided significance level. This
means that a difference Δ can be detected with Δ / SD > 0.74. Taking into account the relative SD 
of 0.85 for the log10 PRNT titers the detection of a log10 PRNT difference of 0.629 can be
detected (or a four-fold increase in titers on the original titer scale). For the ELISA where the
log10 SD is at most 0.42 a difference of 0.31 can be detected, i.e. a two-fold increase in titers can
be detected.
9.3
Trial Cohorts/Datasets to be Evaluated
Analysis of immunogenicity variables will be done on a valid case basis, i.e. for missing
observations no imputation technique such as "Last observation carried forward" (LOCF) will be
applied, since this could introduce an optimistic bias into the analysis.
Full Analysis Set (FAS):
This is the subset of subjects who received at least one vaccination and for whom any data are
available.
The main analysis of safety will be performed on this analysis set.
Per Protocol Set (PPS):
This is the subset of subjects in the FAS who have received all vaccinations, completed all visits
of the active trial phase (Visit 1 to Visit 5 and additionally Visit 6 to Visit 8 for Group 3) and

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adhered to all protocol conditions. Subjects with only minor (not relevant) protocol deviations are
included into this dataset.
The decision whether a protocol deviation is major or not for the classification of subjects into
the various subsets will be made on a case-by-case basis in a data review meeting prior to
database lock.
The main analysis of the immunogenicity endpoints will be performed on the PPS. The same
statistical procedures will also be applied to the FAS.
9.4
Biometrical Evaluation
9.4.1 Main Analysis
As soon as the last subject has completed FU 2 and after any necessary settlement of queries etc.
in the eCRFs a data review meeting will be held and the subjects will be assigned to the datasets
as described in Section 9.3. After the data review meeting and necessary settlement of queries
that may arise during the data review meeting, the database will be locked. The final analysis will
then be performed and will include all immunogenicity and safety data up to and including FU 2.
Results of the final analysis will be reported in the Clinical Study Report (CSR).
9.4.2 Presentation of Data
For biometrical analysis, data obtained in this trial and documented in the eCRFs will be listed.
For parameters of interest, summary tables with descriptive group statistics for metrical variables
will be prepared. For categorical / 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 the Statistical Analysis Plan (SAP). The SAP will
be finalized prior to the respective database lock. The CRO will be responsible for data
management and statistical evaluation. Data will be analyzed using SAS®.
Antibody titers and derived parameters, e.g. GMTs and seroconversion rates, will be assessed by
vaccinia-specific ELISA and vaccinia-specific PRNT methods as described in Section 7.1.
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 corresponding reference range
will be counted.
All 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 during the 8-day period post vaccination (Days
0–7) will be summarized on a per subject and per vaccination basis.

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Unsolicited AEs will be coded using MedDRA coding terminology. The intensity of AEs will be
graded according to Section 8.2.
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 national laws and other
guidelines for the conduct of clinical trials like the ICH GCP to guarantee the greatest possible
subject protection.
10.2 Approval by an IEC / IRB
The clinical trial protocol must be reviewed by the competent IEC / IRB according to the national
laws of the respective CTS before the first subject is included in this trial.
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.
10.3 Confidentiality and Data Protection
The PI of the respective CTS is obliged to ensure anonymity of the subject. He/she has to make
sure that all documents including eCRFs provided (e.g. in the course of a marketing authorization
procedure) to third parties (in this case: to the manufacturer of MVA-BN® smallpox vaccine or to
an authority) contain no subject names.
Only a subject and site number may identify subjects. Their name or clinic and subject’s 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 securely by the
PI.
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

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persons by the Sponsor or the PI or authorities. The Sponsor of the trial will only receive
pseudonymized data for analysis.
11 Informed Consent
No subject can participate in this trial without having given informed consent in writing after the
investigator or his delegate has informed the subject clearly and completely, verbally and in
writing, over the purpose, procedures, the potential future use of blood samples and potential
benefits and risks of the trial prior to any trial specific procedure.
One signed copy of the Informed Consent including HIPAA must be given to each subject and
one signed copy must remain in the Investigator Site File and be available for verification by the
monitor, Sponsor/CRO auditor or competent regulatory authorities at any time.
Subjects must be informed unequivocally that they may refuse participation in the trial and that
they may withdraw from the trial at any time and for whatever reason and that withdrawal of
consent will not affect their subsequent medical treatment or relationship with the treating
physician.
Subjects also consent to authorize the monitor, quality assurance personnel and regulatory
authorities to inspect source documents for data verification and quality assurance purposes. Such
verifications will always be conducted at the CTS and under the ethical supervision of the
investigator. All aspects of the confidentiality of the subject’s data will be guaranteed.
The Informed Consent will be prepared in accordance with ICH GCP guidelines and must be
approved by the appropriate IEC / IRB.
12 eCRFs and Retention of Records
12.1 eCRF
In this trial, the use of an eCRF is planned.
All eCRFs are to be filled out completely by the trial personnel, then reviewed and signed
electronically by the PI to confirm their correctness in a timely manner. It is the PI’s
responsibility to ensure that all subject data entered including discontinuations or changes in trial
or other medications in the eCRF are accurate and supported by the subject’s medical records
unless the eCRF has been declared as source documentation by BN. The eCRFs for any subject
leaving the trial should be completed at the time of the final visit or shortly thereafter.
12.2 Retention of Records
Essential documents as listed in ICH GCP need to be archived according to ICH GCP or national
law, whatever is longer.

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To meet regulatory requirements, the original source data and an electronic copy of the eCRF
data will be stored at the respective CTS. The eCRF 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.
12.3 Monitoring of the Trial
The CRO (contact information to be found in the “Responsibilities” section in the beginning of
this protocol) will be contracted 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 Clinical Research Associate (CRA) during the CTS 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 eCRF entries and to obtain an adequate overview of the course of the trial.
The CRA verifies that the entries in the eCRF are complete, accurate and supported by source
documents. In addition the CRA will verify that all required data documented in the source were
transferred accurately in the eCRF. This will be done under preservation of data protection.
The source data verification must be performed by direct insight in the subject’s record. If a
subject refuses to consent to this procedure, he/she may not be enrolled in the trial. The CTS will
provide direct access to all trial related data for the purpose of monitoring and inspection 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 Audits and Inspections
Audits and inspections may be carried out by the quality assurance department (BN and/or CRO),
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 / inspections. Informed
consent of subjects participating in this trial has to include the consent in this access to source
documents.
14 Responsibilities of the PI
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
(see Section 10 of this protocol).

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Changes to the protocol require written “Amendments to the protocol” and written approval by
the IEC/IRB, the Coordinating Investigator and the PI of the respective CTS. 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 eCRF has to be completed in a timely
manner after each subject visit and electronically 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 drug
containers to the Sponsor or the drug containers will be destroyed at the CTS according to local
legal requirements.
The investigator may ask to terminate participation in 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 E6 (R1) Guideline for GCP, 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 reviews, audits/inspections,
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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15 References
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Stittelaar KJ, van Amerongen G, Kondova I, Kuiken T, van Lavieren RF, Pistoor FH, Niesters
HG, van Doornum G, van der Zeijst BA, Mateo L, Chaplin PJ and Osterhaus AD. 2005,
Modified vaccinia virus Ankara protects macaques against respiratory challenge with monkeypox
virus. J Virol 79(12), 7845-7851.
Suter M., Meisinger-Henschel C, Tzatzaris M, Hülsemann V, Lukassen S, Wulff NH, Hausmann
J, Howley P and Chaplin P. 2009, Modified vaccinia Ankara strains with identical coding
sequences actually represent complex mixtures of viruses that determine the biological properties
of each strain. Vaccine 27, 7442-7450.
Sutter G and Moss B 1992, Nonreplicating vaccinia vector efficiently expresses recombinant
genes. Proc.Natl.Acad.Sci.U.S.A 89, 10847-10851.

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Vollmar J, Arndtz N, Eckl KM, Thomsen T, Petzold B, Mateo L, Schlereth B, Handley A, King
L, Hülsemann V, Tzatzaris M, Merkl K, Wulff N and Chaplin P. 2006, Safety and
Immunogenicity of IMVAMUNE, A promising candidate as a third generation smallpox vaccine.
Vaccine 24, 2065-2070.
Von Krempelhuber A, Vollmar J, Pokorny R, Rapp P, Wulff N, Petzold B, Handley A, Mateo L,
Siersbol H, Kollaritsch H and Chaplin P. 2010, A randomized, double-blind, dose-finding Phase
II study to evaluate immunogenicity and safety of the third generation smallpox vaccine
candidate IMVAMUNE®. Vaccine 28, 1209-1216.
Walsh SR, Wilck MB, Dominguez DJ, Zablowsky E, Bajimaya S, Gagne LS, Verrill KA,
Kleinjan JA, Patel A, Zhang Y, Hill H, Acharyya A, Fisher DC, Antin JH, Seaman MS, Dolin R
and Baden LR. 2013, Safety and immunogenicity of modified vaccinia Ankara in hematopoietic
stem cell transplant recipients: a randomized, controlled trial. J.Inf.Dis. 207, 1888-1897.
Wharton M, Strikas RA, Harpaz R, Rotz LD, Schwartz B, Casey CG, Pearson ML and Anderson
LJ. 2003 Recommendations for using smallpox vaccine in a pre-event vaccination program.
Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP)
and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR
Recomm Rep. 52 (RR-7), 1-16.

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16 Appendices
16.1 Appendix I: Toxicity Scale for Laboratory Values
Grade 1 or Grade 2 toxicity is only graded according to Table 6 and Table 7, if the value is
outside of the institutional normal range applicable for this trial. Any laboratory value that is
between either the LLN or ULN and Grade 1 should not be graded. The values provided in Table
6 and Table 7 are based on the 'Division of AIDS Table for Grading the Severity of Adult and
Pediatric Adverse Events' Version 1.0, December 2004, Clarification August 2009.
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 daily activities.
Grade 2
An AE which is sufficiently discomforting to interfere with daily activities.
Grade 3
An AE which prevents daily activities. 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 6
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
130 - 135
125 - 129
121 - 124
≤ 120 
Sodium – Hypernatremia
mmol/L
146 - 150
151 - 154
155 - 159
≥ 160 
Potassium –
Hyperkalemia mmol/L
5.6 - 6.0
6.1 - 6.5
6.6 - 7.0
> 7.0
Potassium – Hypokalemia
mmol/L
3.0 - 3.4
2.5 - 2.9
2.0 - 2.4
< 2.0
Calcium –
Hypercalcaemia mmol/L
2.65 - 2.88
2.89 - 3.13
3.14 - 3.38
> 3.38
Calcium- Hypocalcaemia
mmol/L
1.95 - 2.10
1.75 - 1.94
1.53 - 1.74
< 1.53
Serum creatinine
mg/dl
1.1 - 1.3 x ULN
1.4 - 1.8 x ULN 
1.9 - 3.4 x ULN 
≥ 3.5 x ULN 
Alkaline Phosphatase
increase by factor
1.25 - 2.5 x ULN
2.6 - 5.0 x ULN
5.1 - 10 x ULN
> 10 x ULN
ALT (SGPT) and AST
(SGOT) increase by factor 1.25 - 2.5 x ULN
2.6 - 5.0 x ULN
5.1 - 10 x ULN
> 10 x ULN
Total Bilirubin
increase by factor
1.1 - 1.5 x ULN
1.6 - 2.5 x ULN
2.6 - 5.0 x ULN
> 5.0 x ULN
Cardiac troponin I
increase by factor
N/A
N/A
N/A
Levels consistent with
myocardial infarction
or unstable angina
Total Cholesterol (fasting)
mg/dl
200 - 239
240 - 300
> 300
N/A
Table 7
Toxicity Scale for Hematology
Lab Value
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening (Grade
4)
Hemoglobin (HIV
positive)
g/dl
8.5 - 10
7.5 - 8.4
6.5 - 7.4
< 6.5
WBC Increase
cell/mm3
> ULN - < 15,000
≥ 15,000 - <
20,000
≥ 20,000 
N/A
WBC Decrease
cell/mm3
2,000 - 2,500
1,500 - 1,999
1,000 - 1,499
< 1,000
Lymphocytes Decrease
cell/mm3
600 - 650
500 - 599
350 - 499
< 350
Neutrophils Decrease
cell/mm3
1,000 - 1,300
750 - 999
500 - 749
< 500
Platelets Decreased
cell/mm3
100,000 - 124,999
50,000 - 99,999
25,000 - 49,999
< 25,000

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16.2 Appendix II: Case Definitions Acute Myocarditis / Pericarditis
16.2.1 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.

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16.2.2 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.

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16.3 Appendix III: Interpretation Support for Assessment of Screening ECGs
For a clearer and mutual understanding of inclusion criterion #17, the following provides
clarifying explanations and examples pertaining to eligibility for enrollment.
Examples of subjects eligible for enrollment:

Non-specific ST and T wave changes are not considered clinically significant and subject
can be enrolled.

Sinus bradycardia which does not require clinical intervention is not considered clinically
significant and subject can be enrolled.

Subjects who present with atrial disease which do not require clinical intervention, e.g. a
pacemaker or drug treatment, are allowed to be enrolled, as these can be considered not
clinically significant. Examples are premature atrial contractions or ectopic atrial beats.

Occasional PVCs which do not require clinical intervention are not considered clinically
significant and subject can be enrolled.

First degree atrioventricular block or PR interval prolongations are also acceptable as long
as they do not require clinical intervention, i.e. do not represent an indication for a
pacemaker, and therefore the condition can be classified as not clinically significant.

Right or left axis deviation which does not require clinical intervention is not considered
clinically significant and subject can be enrolled.

QTc prolongations < 500 ms which do not require clinical intervention are not considered
clinically significant and subject can be enrolled. QTc prolongations > 500 ms which do not
require clinical intervention should be discussed with the Medical Monitor before
enrollment.
Examples of subjects NOT eligible for enrollment:

Second or third degree atrioventricular block could represent significant heart disease and
subject should not be enrolled.

Incomplete left bundle branch blocks could represent significant heart disease and subject
should not be enrolled.

Significant ventricular disease represented by complete intraventricular conduction defects
(complete left or right bundle branch block) must be considered clinically significant and
subjects presenting with any such condition should not be enrolled. Left anterior or
posterior intraventricular fascicular blocks or hemiblock could represent ventricular disease
and subject should not be enrolled.

ST elevation consistent with ischemia, subject should not be enrolled.

Two PVCs in a row, subject should not be enrolled.

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16.4 Appendix IV: Grading Scale for Lymphadenopathy
A grading scale for lymphadenopathy would apply as follows:
Grade 0 (normal finding):
No palpable lymph nodes or lymph nodes up to a diameter of 1
cm, soft, non-tender
Grade 1 (mild):
Slightly palpable lymph nodes or lymph nodes up to a diameter
of 1 cm, bilaterally enlarged lymph nodes, signs of tenderness
Grade 2 (moderate):
Markedly palpable lymph nodes or lymph node diameter exceeds
2 cm, bilaterally enlarged lymph nodes, pain, skin redness,
warmth, limiting instrumental daily life activities
Grade 3 (severe):
Markedly palpable lymph nodes or lymph node diameter exceeds
2 cm, generalized enlargement of lymph nodes, severe pain,
general symptoms like fever and sweating limiting self-care daily
activities

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16.5 Appendix V: Amendment #4
POX-MVA-037
Randomized, open-label Phase II trial to assess the
safety and immunogenicity of MVA-BN® smallpox
vaccine when increasing the number of injections
compared to the standard regimen in
immunocompromised subjects with HIV infection
Amendment # 4 to Clinical Trial Protocol Edition 4.0
dated 20-Aug-2014
Date of Amendment 4: 18-Nov-2014

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1 Rationale
With the objective to collect long term safety and immunogenicity data a one year follow up visit
(FU 2) has been added to the visit schedule.
As a result from the first DSMB meeting conducted on October 30th, 2014 the procedure for
following up on adverse event of special interest was adapted in accordance with the DSMB
recommendation.
Communication with clinical trial site made it obvious that the term ‘enrollment’ is ambiguous
and can be understood in different ways. Triggered by this discussions the inclusion/exclusion
criteria have been reworded for clarity in accordance with the information provided to the clinical
trial sites.
A discrepancy between laboratory measurements as described in the protocol versus actual trial
processes was detected recently and corrected throughout the protocol.
Changes are outlined in the section 2 below.
2 Changes
General Changes:

A one year follow-up visit (FU2) was added to the Trial Procedure Schedule (Section 1.6)
and Section 4.2.3 Follow-Up Phase. For practical reasons this additions are not shown in
the detailed table of changes below. Please refer to respective paragraphs to review the
additions.

The protocol (Section 8.2.8) states that CD3 count will be determined in addition to CD4
counts. However, only CD4 counts are determined and reported in course of the safety
laboratory measurements. Section 8.2.8 has been revised accordingly and all references to
CD3 counts have been removed throughout the protocol. Not every single change in this
regard is listed in the table of changes below.

Section 2.6 was reviewed to reflect the status in accordance with current IB. Only safety
relevant changes are shown in table of changes below.

During preparation of this amendment the whole protocol has been reviewed and updated
for formal consistency. Formatting and/or stylistic changes are not listed in the table of
changes below.
Relevant changes are listed in detail in the table of changes below.
Changes / added terms are highlighted in bold letters in the text below, removed terms are in
italic letters.

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Changed to:
Page 15, 1.5 Protocol Synopsis,
Number of sites
Page 15, 1.5 Protocol Synopsis
Number of sites
Up to 8 sites in the USA
Up to 10 sites in the USA
Reason for change: Additional sites needed to
meet enrollment goal.
Page 16, 1.5 Protocol Synopsis,
Trial Duration
Page 16, 1.5 Protocol Synopsis,
Trial Duration
Up to 48 weeks per subject
Up to 75 weeks per subject
Reason for change: Addition of one year
follow up.
Page 16 & 17, 1. 5 Protocol Synopsis,
Secondary Endpoints
Page 16 and 17, 1. 5 Protocol Synopsis,
Secondary Endpoints
GMTs after vaccination with MVA-BN®
smallpox vaccine measured by ELISA and
PRNT at 6 months Follow-up (FU) Visit of
Group 3 compared to respective FU Visit of
Group 1 and Group 2 (separately).
Seroconversion after vaccination with MVA-
BN® smallpox vaccine measured by ELISA
and PRNT at 6 months FU Visit of Group 3
compared to respective FU Visit of Group 1
and Group 2 (separately).
GMTs and seroconversion after vaccination
with MVA-BN® smallpox vaccine measured
by ELISA and PRNT at all other
immunogenicity sampling points (Visit 1, 3, 4,
FU) of Group 2 and 3 (separately) compared to
Group 1.
GMTs after vaccination with MVA-BN®
smallpox vaccine measured by ELISA and
PRNT at six months Follow-up 1 (FU 1) and
one year FU 2 Visit of Group 3 compared to
respective FU Visits of Group 1 and Group 2
(separately).
Seroconversion after vaccination with MVA-
BN® smallpox vaccine measured by ELISA
and PRNT at six months FU 1 and one year
FU 2 Visit of Group 3 compared to respective
FU Visits of Group 1 and Group 2 (separately).
GMTs and seroconversion after vaccination
with MVA-BN® smallpox vaccine measured by
ELISA and PRNT at all other immunogenicity
sampling points (Visit 1, 3, 4, six months FU
1, one year FU 2) of Group 2 and 3
(separately) compared to Group 1.
Reason for change: Addition of one year
follow up.

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dated 20-Aug-2014
Previously written:
Revised Clinical Trial Protocol Edition #5.0,
dated 18-Nov-2014
Changed to:
Page 18, 1. 5 Protocol Synopsis,
Trial Design, Visit Schedule
Page 18, 1. 5 Protocol Synopsis,
Trial Design, Visit Schedule
Visit (V)
Day
Target Week
FU
V3 (V6*) +182 to 210 days 30 (38*)
Visit (V)
Day
Target Week
FU 1
V3 (V6*) +182 to 210 days 30 (38*)
FU 2
V3 (V6*) +364 to 392 days 56 (64*)
Reason for change:
Addition of one year follow up
Page 19 & 20, 1. 5 Protocol Synopsis,
Inclusion Criteria 3, 5, 6, 16
Page 19, 1. 5 Protocol Synopsis,
Inclusion Criteria 3, 5, 6, 16
3. On stable antiretroviral therapy (ART) i.e.
Combination ART for at least 3 months prior
to enrollment visit in this clinical trial with no
change to the therapy during these 3 months.
5. Current CD4 counts ≥ 100 cells/µl ≤ 500 
cells/µl.
6. Documented nadir CD4 count < 200 cells/µl
at any time prior to enrollment. If nadir is not
documented lowest documented CD4 count <
200 cells/µl at any time prior to enrollment.
16. Troponin I < 2 x ULN .
3. On stable antiretroviral therapy (ART) i.e.
Combination ART for at least three months
prior to screening visit in this clinical trial
with no change to the therapy during these
three months.
5. Screening CD4 counts ≥ 100 cells/µl and ≤ 
500 cells/µl.
6. Documented nadir CD4 count < 200 cells/µl
at any time prior to screening visit. If nadir is
not documented lowest documented CD4 count
< 200 cells/µl at any time prior to screening
visit.
16. Screening Troponin I < 2 x ULN.
Reason for change: Modified for clarity.
Page 21, 1.5 Protocol Synopsis,
Exclusion Criteria 18, 19, 22
Page 21, 1.5 Protocol Synopsis,
Exclusion Criteria 18, 19, 22
18. Acute disease (illness with or without a
fever) at the time of enrollment.
19. Body temperature 100.4°F (38.0°C) at
the time enrollment.
22. Use of immunosuppressant or
immunomodulatory agents including systemic
glucocorticoids (excluding nasal or inhaled
18. Acute disease (illness with or without a
fever) at the time of screening or at any time
of vaccine administration.
19. Body temperature 100.4°F (38.0°C) at
the time of screening or at any time of
vaccine administration.
22. Use of immunosuppressant or

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Previously written:
Revised Clinical Trial Protocol Edition #5.0,
dated 18-Nov-2014
Changed to:
steroids), tacrolimus, sirolimus, rapamycin,
mycophenolate, cyclosporine, TNF-alpha
blockers or antagonists, azathioprine,
interferon or growth factors, or intravenous
immunoglobulin in the 60 days prior to
enrollment in this clinical trial.
immunomodulatory agents including systemic
glucocorticoids (excluding nasal or inhaled
steroids), tacrolimus, sirolimus, rapamycin,
mycophenolate, cyclosporine, TNF-alpha
blockers or antagonists, azathioprine, interferon
or growth factors, or intravenous
immunoglobulin in the 60 days prior to
screening in this clinical trial.
Reason for change: Modified for clarity.
Page 29, 2.6.1 Safety Overview of MVA-
BN®, Table 1
Page 29, 2.6.1 Safety Overview of MVA-
BN®, Table 1
Skin and Subcutaneous Tissue Disorders
Rare(≥1/10,000 to <1/1,000) 
Night sweats
Skin and Subcutaneous Tissue Disorders
Rare(≥1/10,000 to <1/1,000) 
Night sweats
Angioedema
Reason for change: Updated with respect to
the latest MVA-BN® Smallpox Vaccine
Investigator’s Brochure.
Page 47,
4.2.5. Withdrawal from Second or Booster
vaccination
Page 46,
4.2.5. Withdrawal from Second or Booster
vaccination
Start of chronic administration (defined as
more than 14 days) of > 5 mg prednisone (or
equivalent) per day or any other immune-
modifying drugs.
Start of chronic systemic administration
(defined as more than 14 days) of > 5 mg
prednisone (or equivalent) per day or any other
systemic use of immune-modifying drugs.
Reason for change: Modified for clarity.
Page 47, 4.2.5. Withdrawal from Second or
Booster Vaccination
Page 47, 4.2.5. Withdrawal from Second or
Booster Vaccination
Procedure:
If a subject did not receive the second trial
vaccination the reason for this decision must
Procedure:
If a subject did not receive the second trial
vaccination the reason for this decision must

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Previously written:
Revised Clinical Trial Protocol Edition #5.0,
dated 18-Nov-2014
Changed to:
be recorded in the eCRF. Visit 3 and Visit 4
are not required and the procedures below
should be followed:

Visit 5 procedures have to be performed
28 to 35 days after last vaccination

FU Visit procedures have to be
performed 182 to 210 days after last
vaccination
If a subject from treatment Group 3 did not
receive the second or booster vaccination the
reason for this decision must be recorded in the
eCRF. Visits 6, 7 and 8 are not required and
the procedures below should be followed:

FU Visit procedures have to be
performed 182 to 210 days after last
vaccination visit.
be recorded in the eCRF. Visit 3 and Visit 4
are not required and the procedures below
should be followed:

Visit 5 procedures have to be performed
28 to 35 days after last vaccination

FU 1 procedures have to be performed
182 to 210 days after last vaccination

FU 2 procedures have to be performed
364 to 392 days after last vaccination.
If a subject from treatment Group 3 did not
receive the second or booster vaccination the
reason for this decision must be recorded in the
eCRF. Visits 6, 7 and 8 are not required and
the procedures below should be followed:

FU 1 procedures have to be performed
182 to 210 days after last vaccination.

FU 2 procedures have to be performed
364 to 392 days after last vaccination.

Reason for change: Addition of one year
follow up.
Page 48,
4.3. Trial Duration
Page 47,
4.3. Trial Duration
The total duration of the trial for each subject
including the screening period and Follow-up
visit will be up to 48 weeks.
The total duration of the trial for each subject
including the screening period and Follow-up
visits will be up to 75 weeks.
Reason for change: Addition of one year
follow up.
Page 51,
7.1. Humoral Immunogenicity
Page 51,
7.1. Humoral Immunogenicity
Immunogenicity testing will be performed on
samples obtained from subjects of all three
groups on trial Visit 1, Visit 3, Visit 4 and FU.
Immunogenicity testing will be performed on
samples obtained from subjects of all three
groups on trial Visit 1, Visit 3, Visit 4, FU1

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Previously written:
Revised Clinical Trial Protocol Edition #5.0,
dated 18-Nov-2014
Changed to:
Further, immunogenicity testing will be
performed on samples obtained from subjects
of Group 3 on trial Visits 6 and 7. Baseline
(i.e., Visit 1, Visit 3 and Visit 6) blood samples
will be drawn prior to vaccination.
and FU 2. Further, immunogenicity testing will
be performed on samples obtained from
subjects of Group 3 on trial Visits 6 and 7.
Blood samples obtained on vaccination visits
(i.e., Visit 1, Visit 3 and Visit 6) will be drawn
prior to vaccination.
Reason for change: Addition of one year
follow up and modification for clarity.
Page 54,
8.2.1. Relevant Medical History
Page 54,
8.2.1. Relevant Medical History
Diagnosis of HIV and disease state has to be
documented separately: date of diagnosis,
disease stage, nadir, viral load and CD4 count
during the last year before SCR.
Diagnosis of HIV and disease state has to be
documented separately: date of diagnosis,
nadir, CD4 count and highest viral load up to
six months before SCR.
Reason for change: Modified to match
procedures performed.
Page 55 & 56,
8.2.5. Unsolicited AEs
Page 55,
8.2.5. Unsolicited AEs
AEs for Group 1 and 2 will be assessed and
documented at all visits except FU visit
(Screening to Visit 5) and if ongoing at Visit 5,
followed until resolution or until the FU Visit
at the latest.
AEs for Group 3 will be assessed and
documented at all visits except FU Visit (i.e.
Screening to Visit 8) and if ongoing at Visit 8,
followed until resolution or until the FU Visit
at the latest.
SAEs/AESIs will be assessed and documented
at all trial visits, including the FU Visit.
Ongoing AESIs which occurred after at least
one vaccination will be followed up until
resolution or achievement of stable clinical
AEs for Group 1 and 2 will be assessed and
documented at all visits except FU 1 and FU 2
(i.e. Screening to Visit 5) and if ongoing at
Visit 5, followed until resolution or until the
FU 2 at the latest.
AEs for Group 3 will be assessed and
documented at all visits except FU 1 and FU 2
(i.e. Screening to Visit 8) and if ongoing at
Visit 8, followed until resolution or until the
FU 2 at the latest.
SAEs/AESIs will be assessed and documented
at all trial visits, including the FU 1 and FU 2.
Ongoing AESIs which occurred after at least
one vaccination will be followed up until
resolution or achievement of stable clinical

Page 91 of 91
Bavarian Nordic A/S
Restricted Business Proprietary
Revised Clinical Trial Protocol
POX-MVA-037
Doc. No. 92000015
Edition 5.0
18-NOV-2014
Clinical Trial Protocol Edition #4.0,
dated 20-Aug-2014
Previously written:
Revised Clinical Trial Protocol Edition #5.0,
dated 18-Nov-2014
Changed to:
conditions. SAEs will be followed up until
resolution or achievement of stable clinical
conditions.
conditions. SAEs will be followed up until
resolution or achievement of stable clinical
conditions.
Reason for change: Addition of one year
follow up.
Page 59 & 60,
8.2.7. Cardiac Assessment
Page 59 & 60,
8.2.7. Cardiac Assessment
No changes to original test, only addition.
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’.
Reason for change: Implementation of DSMB
recommendation.
Page 62
8.2.8. Safety Laboratory Measurements
Page 62
8.2.8. Safety Laboratory Measurements
HIV specific parameters: CD4 count (as well
as CD3 count, which is a standard part of the
CD4 lab panel) will be determined with every
safety laboratory and at Visit 8 and FU Visit.
HIV specific parameters: CD4 count will be
determined with every safety laboratory and at
Visit 8 and FU 1 and FU 2.
Reason for change: Modified to match
procedures performed and addition of one year
follow up.