A Randomized, Double-blind, Phase 3 Trial to Assess Clinical Efficacy, Safety and Reactogenicity of the Recombinant MVA-BN® -RSV Vaccine in Adults ≥60 Years of Age
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Bavarian Nordic

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Clinical Trial Protocol
RSV-MVA-004
A Randomized, Double-blind, Phase 3 Trial to Assess Clinical 
Efficacy, Safety and Reactogenicity of the Recombinant 
MVA-BN®-RSV Vaccine in Adults
Years of Age
Edition 5.0
15-Feb-2023
NCT # 05238025 
EudraCT # 2021-004923-34 
IND 16511
Edition 3.0: China extension study

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Table of Contents 
List of Tables ................................................................................................ 7
List of Figures .............................................................................................. 7
1
General Information ........................................................................... 9
1.1
List of Abbreviations ........................................................................... 9
1.2
Definitions ........................................................................................... 12
1.3
Protocol Synopsis ............................................................................... 13
1.4
Trial Schedule .................................................................................... 27
1.4.1
Trial Schedule for Vaccination and Site Follow Up During RSV 
Season after Vaccination ............................................................... 27
1.4.2
Trial Schedule for Follow-Up for Durability of Protection ........ 32
1.4.3
Trial Schedule for Subject Use of ePRO Application ................. 35
2
Background Information and Scientific Rationale ........................ 37
2.1
Introduction to RSV Disease ............................................................ 37
2.2
MVA-BN-RSV Vaccine ..................................................................... 40
2.3
Origin and Characteristics of MVA-BN Vector Backbone ........... 41
2.4
Summary of Non-clinical Studies with MVA-BN-RSV Vaccine ... 42
2.5
Clinical Profile of MVA-BN and Recombinant MVA-based 
Vaccines .............................................................................................. 42
2.5.1
Safety Overview .............................................................................. 43
2.5.2
Safety Profile of MVA-BN-based Recombinant Vaccines in 
Healthy Compared to Special Populations .................................. 44
2.5.3
Dose Finding for MVA-BN-RSV Vaccine .................................... 49
2.6
Clinical Trial Data with MVA-BN-RSV Vaccine ........................... 49
2.7
Rationale ............................................................................................. 55
2.8
Trial Population ................................................................................. 56
2.9
Risk/Benefit Assessment .................................................................... 57
2.9.1
Potential Risk .................................................................................. 57
2.9.2
Benefit .............................................................................................. 57
3
Objectives ........................................................................................... 58

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4
Trial Design ........................................................................................ 58
4.1
Experimental Design ......................................................................... 58
4.1.1
Screening Visit / Visit 1 .................................................................. 61
4.1.2
Disease Surveillance and Monthly Telephone Visits ................... 62
4.1.3
Symptom Visit ................................................................................. 63
4.1.3.1
Imaging ..........................................................................................64
4.1.3.2
Home Healthcare Visits ...............................................................66
4.1.3.3
Self-Swabbing by Subject ............................................................66
4.1.4
Electronic Patient Reported Outcome (ePRO) Application ....... 66
4.1.4.1
RiiQ ................................................................................................66
4.1.4.2
EQ-5D-5L ......................................................................................66
4.1.4.3
15D .................................................................................................66
4.1.4.4
Tilburg Frailty Indicator .............................................................67
4.1.5
6-month Follow-up Visit ................................................................ 67
4.1.6
End of Study Visit........................................................................... 67
4.1.7
Immunogenicity Visit / Visit 2a/2b / Visit FU-D1 / Visit FU-D .. 68
4.1.8
Unscheduled Visits ......................................................................... 68
4.1.9
Early Discontinuation .................................................................... 68
4.1.10 Durability Follow Up (FU-D1)  During Second Year after 
Vaccination ...................................................................................... 69
4.1.11 Durability 6-Month Follow-Up Visit (FU) / 18 months after 
vaccination (6 months after FU-D1) ............................................. 70
4.1.12 Durability End of Trial / approximately 24 months after 
vaccination (12 months after FU-D1) ........................................... 70
4.2
Emergency Unblinding ...................................................................... 70
4.3
Trial Duration .................................................................................... 71
4.4
Data Monitoring Committee ............................................................. 71
4.5
Adjudication Committee ................................................................... 72
4.6
Trial Halting Rules ............................................................................ 72
5
Selection of Subjects .......................................................................... 73
5.1
Recruitment Procedure ..................................................................... 73

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5.2
Inclusion Criteria ............................................................................... 73
5.3
Exclusion Criteria .............................................................................. 74
6
Investigational Medicinal Product .................................................. 74
6.1
Production, Packaging and Labeling ............................................... 74
6.2
Shipment, Storage and Handling ..................................................... 74
6.3
Preparation, Administration and Dosage ........................................ 75
6.4
Accountability and Disposal ............................................................. 75
6.5
Randomization and Blinding ............................................................ 75
7
Assessment of Efficacy ...................................................................... 77
7.1
Signs and Symptoms of Respiratory Tract Disease........................ 77
7.2
Respiratory Pathogen Panel ............................................................. 78
7.3
RSV-specific Symptoms and Complications ................................... 78
7.4
Adjudication Committee for Efficacy Endpoints ........................... 79
8
Immunogenicity Assessment ............................................................ 80
8.1
Systemic Humoral Immune Responses ........................................... 80
8.2
Cellular Immune Responses ............................................................. 81
8.3
Future Use of Lab Specimen ............................................................. 81
9
Safety and Reactogenicity................................................................. 82
9.1
Definitions ........................................................................................... 82
9.1.1
Medical History .............................................................................. 82
9.1.2
Adverse Events ............................................................................... 82
9.1.2.1
Unsolicited AEs .............................................................................82
9.1.2.2
Solicited AEs .................................................................................82
9.1.2.3
SAEs ...............................................................................................83
9.2
Assessments ........................................................................................ 83
9.2.1
Relevant Medical History .............................................................. 83
9.2.2
Prior and Concomitant Medication .............................................. 84
9.2.3
Physical Examination ..................................................................... 84
9.2.4
Vital Signs ....................................................................................... 85
9.2.5
Unsolicited AEs ............................................................................... 85

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9.2.6
Solicited AEs ................................................................................... 87
9.2.6.1
Solicited Local AEs.......................................................................88
9.2.6.2
Solicited Systemic AEs .................................................................89
9.2.7
Laboratory Measurements ............................................................ 90
9.2.8
Pregnancy ........................................................................................ 90
9.3
Reporting ............................................................................................ 90
9.3.1
Reporting of SAEs .......................................................................... 90
9.3.2
Reporting of Pregnancies ............................................................... 91
10
Burden of Disease Assessments ........................................................ 92
10.1 Respiratory Intensity and Impact Questionnaire (RiiQ) ............... 92
10.2 EuroQoL 5-Dimension 5-Level (EQ-5D-5L) Questionnaire ......... 92
10.3 15-Dimension (15D) Health-related Quality of Life Instrument... 93
10.4 Tilburg Frailty Indicator .................................................................. 93
11
Statistical Analysis Plan .................................................................... 93
11.1 Randomization and Unblinding Procedure .................................... 93
11.2 Primary Trial Hypothesis ................................................................. 93
11.3 Endpoints ............................................................................................ 94
11.4 Multiplicity ......................................................................................... 94
11.5 Sample Size Calculation .................................................................... 94
11.5.1 Efficacy Analysis ............................................................................. 94
11.5.2 Immunogenicity Analysis .............................................................. 95
11.6 Analysis Sets ....................................................................................... 95
11.7 Analysis Methods ............................................................................... 96
11.7.1 Efficacy ............................................................................................ 96
11.7.1.1
Population Level Summary and Analysis of Primary Endpoints
 96
11.7.1.2
Analysis of Secondary Efficacy Endpoints ................................97
11.7.1.3
Handling of Potential Intercurrent Events for the Primary and 
Secondary Efficacy Endpoints ....................................................98
11.7.1.4
Supplementary and Sensitivity Analyses of Primary and 
Secondary Efficacy Endpoints ....................................................98

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11.7.1.5
Subgroup Analysis of Primary and Secondary VE Endpoints 98
11.7.1.6
Analysis on the Durability of VE ................................................99
11.7.1.7
Analysis on Overall Vaccine Efficacy for Two RSV Seasons ...99
11.7.1.8
Analysis on Vaccine Efficacy Against Other Respiratory 
Pathogens ......................................................................................99
11.7.1.9
Handling of Missing Data for Efficacy Analysis .......................99
11.7.2 Safety ............................................................................................. 100
11.7.2.1
Reactogenicity .............................................................................100
11.7.2.2
Unsolicited AEs ...........................................................................101
11.7.2.3
Data Handling .............................................................................101
11.7.3 Burden of Disease and Health-Related Quality of Life ............ 101
11.8 Safety Monitoring and Futility Analysis (if applicable) ............... 102
12
Data Management and Electronic Records .................................. 103
12.1 Data Management ............................................................................ 103
12.2 Electronic Case Report Forms ....................................................... 103
12.3 ePRO Data Collection ..................................................................... 103
12.4 Retention of Records ....................................................................... 104
13
Ethical Aspects................................................................................. 105
13.1 Ethical and Legal Regulations ........................................................ 105
13.2 Approval by IEC/IRB/IBC ............................................................. 105
14
Informed Consent ............................................................................ 106
15
Monitoring of the Trial ................................................................... 106
15.1 Protocol Deviations .......................................................................... 107
16
Audits and Inspections .................................................................... 107
17
Responsibility of the Investigator .................................................. 108
18
References ........................................................................................ 110
19
Appendices ....................................................................................... 113
Appendix 1: Toxicity Scale for Laboratory Values ............................. 114
Appendix 2: Signature Pages ................................................................. 117

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List of Tables 
Table 1
Treatment Groups .................................................................................................. 21
Table 2 
Suspected Adverse Drug Reactions Repo
Completed MVA-BN Clinical Trialsa (N=8992b) ................................................ 43
Table 3
Incidence of Solicited Local and Systemic Adverse Events (Per Subject) 
in Clinical Trials with MVA-BN-RSVa for 8 Days Starting at Day of 
Vaccination ............................................................................................................. 46
Table 4
Summary of Adverse Events (Per Subject) in Clinical Trials with 
MVA-BN-RSVa ....................................................................................................... 47
Table 5
Incidence of Treatment-Emergent Unsolicited Adverse Events (Per 
Subject) in Clinical Trials with MVA-BN-
Subjects ................................................................................................................... 48
Table 6 
Treatment Groups in Phase 1 Clinical Trial RSV-MVA-001 ............................ 50
Table 7
Treatment Groups in Phase 2 RSV-MVA-002 - Main Part ............................... 52
Table 8
Treatment Groups in Phase 2 RSV-MVA-002 - Booster Sub-study ................. 52
Table 9
Treatment Groups in the Human Challenge Trial ............................................. 53
Table 10
Age stratification and Enrollment Target ........................................................... 58
Table 11
Grading of Local Symptoms from the 
 .......................... 88
Table 12
 .................... 89
Table 13
Toxicity Scale for Serum Chemistry .................................................................. 115
Table 14
Toxicity Scale for Hematology ............................................................................ 116
Table 15
Grading for Troponin I ....................................................................................... 116
List of Figures 
Figure 1
Estimated Annual RSV-Associated Mortality Rates in Different Age 
Groups per 100,000 Person-Years for the 1990-1991 Through 1998-1999 
Seasons (Thompson, 2003) .................................................................................... 38
Figure 2
Eosinophil Concentration in Bronchoalveolar Lavage in Mice after 
Administration of MVA-BN-RSV and Formalin-Inactivated (FI) RSV 
Vaccine .................................................................................................................... 40
Figure 3
Human Challenge Trial Design (Lambkin; 2018) ............................................... 54

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Figure 4
 Mean Value Over Time in Viral Load of RSV-A Memphis 37b 
Determined by qRT-PCR from Nasal Washes  Per Protocol Analysis Set ..... 55
Figure 5 
Flowchart with 2 Scenarios and Durability ......................................................... 60
Figure 6
Flowchart LRTD (severe)  Decision Tree for X-Rays ...................................... 65
Figure 7:
Flowchart LRTD/ARD  Process Adjudication Committee .............................. 80

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1
General Information 
1.1
List of Abbreviations 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARD
acute respiratory disease
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
BN 
Bavarian Nordic 
CDC 
Centers for Disease Control and Prevention 
CHF 
congestive heart failure 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CRA 
clinical research associate 
CRO 
contract research organization 
CSPV 
clinical safety and pharmacovigilance 
CSR 
clinical study report 
CTS
clinical trial site
DMC
data monitoring committee
DNA 
deoxyribonucleic acid 
DS 
drug safety 
EC 
ethics committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
ER 
emergency room 
ePRO 
electronic patient reported outcome  
EQ-5D-5L 
EuroQol 5-dimension 5-level health questionnaire 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FI 
formalin-inactivated 
FU 
follow-up 
FU1 
follow-up visit 1  
FU2
follow-up visit 2 
FU-D 
follow-up durability 
GCP 
good clinical practice 

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GLP 
good laboratory practice 
GMSFU 
geometric mean spot forming unit 
GMT
geometric mean titer
HIV 
human immunodeficiency virus 
IB 
IBC 
institutional biosafety committee 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC
independent ethics committee
IgA
immunoglobulin A
IgG 
immunoglobulin G 
IM 
intramuscular  
IMP 
investigational medicinal product 
Inf.U 
infectious units 
IRB 
institutional review board 
IUD
intrauterine devices
IUS 
intrauterine systems 
IXRS 
interactive voice/web-response system 
LF 
liquid frozen 
LRTD 
lower respiratory tract disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
medicinal product 
MVA 
modified vaccinia Ankara strain 
MVA-BN®
modified vaccinia Ankara from Bavarian Nordic;  
also named Jynneos®, Imvamune® or Imvanex®
n/N 
number 
NIH 
National Institutes of Health 
NP
nasopharyngeal
OBA 
Office of Biotechnology Activities 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PI 
principal investigator 
PRNT 
plaque reduction neutralization test 
PT 
preferred term 
PV
pharmacovigilance
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction 
RAC 
recombinant DNA advisory committee 
RiiQ 
Respiratory Intensity and Impact Questionnaire 
RNA 
ribonucleic acid 
RR 
respiratory rate 
RSV 
respiratory syncytial virus 
RVP 
respiratory viral panel 
PCR 
polymerase chain reaction 

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SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SC
subcutaneous
SCR 
screening 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamate pyruvate transaminase 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
SV
symptom visit
TBS
tris-buffered saline
TCID50
tissue culture infectious dose 50% 
TEAE 
treatment-emergent adverse event 
Th1/Th2 
t-helper cells, type 1/type 2 
TFI 
Tilburg Frailty Indicator (part B only) 
UK 
United Kingdom 
ULN
upper limit of normal
URTI 
upper respiratory tract infection 
US 
United States 
V 
visit 
VACV 
vaccinia virus 
VE 
vaccine efficacy 
VACV 
vaccinia virus 
VE 
vaccine efficacy 
VL 
viral load 
WBC 
white blood cell count 
WOCBP 
women of childbearing potential 
15D 
15-dimension health-related quality of life instrument 

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1.2
Definitions 
RSV season 
Currently the onset and end of RSV seasons are 
changing from the pattern experienced before the 
COVID pandemic (i.e., peak season in winter 
months) and cannot be predicted for the coming 
years. Subjects are followed up for efficacy 
endpoints for at least 1 RSV season, i.e up to 12 
months. 
6-month follow-up visit 
The visit is performed 6 months after vaccination 
and, depending on RSV seasonality, might 
coincide with the end of the first RSV season after 
vaccination. If applicable, end of season is defined 
by the Centers for Disease Control and Prevention 
(CDC) surveillance data.  
RSV season 1 
First RSV season after first vaccination of 
approximately 20,000 subjects, who are followed 
up for efficacy endpoints (RSV-related LRTD for at 
least this season, up to12 months, after vaccination). 
RSV season 2 
In case the required number of events (LRTD 
cases) was not met in the first season and the pre-
specified futility boundary was not crossed after 
season 1, additional subjects (approximately 4000) 
will be vaccinated and followed up for at least 
1 RSV season (up to 12 months after vaccination). 
Durability follow-up 
Starting 1 year after vaccination, subjects 
vaccinated before RSV season 1 who are willing to 
continue to participate in durability follow-up are 
followed up for at least 6 months and up to 
12 months to assess durability of vaccine efficacy 
by collecting RSV-related ARD/LRTD events. 
Approximately 16,000 subjects, which allows for a 
20% dropout from randomization, will be followed 
up for durability. 
Vaccination 
Intramuscular injection with MVA-BN-RSV 
vaccine or placebo. 
ePRO 
Electronic device (either subject-owned or 
provided by vendor) with clinical trial-specific 
applications including functions for weekly 
reminders and completion of the memory aid 
diary, and other patient reported outcome tools if 
applicable. 

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1.3
Protocol Synopsis
Title
A Randomized, Double-blind, Phase 3 Trial to Assess Clinical 
Efficacy, Safety and Reactogenicity of the Recombinant 
MVA-BN-RSV Vaccine in A
Years of Age
Clinical Phase
Phase 3
Sponsor
Coordinating 
Investigator
Number of Sites and 
Country/ies
Number of sites: up to 140
Countries: United States of America Germany and UK
Vaccination Dose and 
Schedule
Each subject will receive a single administration with either 
0.5 mL MVA-mBN294B (with a titer of at least 3×10E8 infectious 
units [Inf.U] per dose; common name MVA-BN-RSV vaccine) or 
with 0.5 mL placebo at Day 1.
MVA-mBN294B is a liquid frozen (LF) suspension. Tris-buffered 
saline (TBS) will be used as placebo. 
Route of Administration
MVA-BN-RSV vaccine/placebo is administered intramuscularly 
(IM) into the deltoid muscle of the upper arm (preferably the non-
dominant arm).
Trial Duration
Up to 24 months per subject (up to 30 months for the total trial)

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Primary Objective 
 To assess the clinical efficacy of MVA-BN-RSV vaccine against 
lower respiratory tract disease (LRTD) associated with RSV.  
The estimand corresponding to the primary objective to assess 
vaccine efficacy is defined as 1 minus the hazard ratio of LRTD 
associated with RSV infection in the 2 vaccination groups in the 
population who are randomized and receive the study vaccination, 
regardless of early termination during the RSV season. 
Secondary Objectives 
 To assess the clinical efficacy of MVA-BN-RSV vaccine against 
acute respiratory disease (ARD) associated with RSV.  
The estimand corresponding to this secondary objective of assessing 
vaccine efficacy is defined as 1 minus the hazard ratio of ARD 
associated with RSV disease in the 2 vaccination groups in the 
population who are randomized and receive the study vaccination, 
regardless of early termination during the RSV season.  
To assess clinical efficacy of MVA-BN-RSV vaccine against 
complications or hospitalization related to confirmed RSV disease.  
To assess safety and reactogenicity of the MVA-BN-RSV vaccine in 
medically stable subjects 
To assess the RSV-specific humoral and cellular immunity elicited 
by MVA-BN-RSV in a subset of the study population.  
Exploratory 
Objectives 
 Surveillance over a second year after vaccination for subjects 
vaccinated in the previous season, to assess durability of efficacy. 
To assess the post-vaccination impact on the burden of RSV disease 
in the study population. 
To assess the RSV-specific humoral immunity (IgA) in a subset of 
the study population. 
To assess the orthopox-specific humoral neutralizing immunity 
against the vector backbone MVA-BN in a subset of the study 
population. 
To assess healthcare utilization and health-related quality of life. 
To assess the clinical efficacy of MVA-BN-RSV vaccine against 
ARD associated with Human Metapneumovirus (hMPV). 

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To assess the clinical efficacy of MVA-BN-RSV vaccine against 
ARD associated with prespecified viral respiratory pathogens. 
To assess clinical efficacy of MVA-BN-RSV vaccine against 
hospitalization (all cause, pneumonia, cardiovascular specific) or 
mortality (all cause, pneumonia, cardiovascular specific) related to 
confirmed RSV disease.  
Primary Endpoints 
Occurrence of LRTD (
) associated with RSV until the 
end of one RSV season (up to 12 months after vaccination). RSV-
associated LRTD is defined by the presence of clinical evidence of 
at least 1 sign or symptom of ARD (see below) and at least 3 of the 
following signs or symptoms 
 days following 
vaccination until the end of one RSV season (up to 12 months after 
vaccination), confirmed and documented by a medical professional, 
together with RSV disease confirmed by polymerase chain reaction 
(PCR) (nasopharyngeal (NP) swab to be collected within 5 days of 
symptom onset; preferably within 72 hours of symptom onset). 
hypoxemia (oxygen saturation <92% at rest in conjunction 
with an at least 3% decrease from baseline)  
respiratory rate >25 breaths/Min  
imaging evidence of new onset of bronchitis, bronchiolitis, or
pneumonia 
new wheezing or worsening of pre-existing wheezing 
new shortness of breath or worsening of pre-existing 
shortness of breath 
new cough or worsening of pre-existing cough 
new sputum production or worsening of pre-existing sputum 
production 
Occurrence of LRTD
) associated with RSV until the 
end of 1 RSV season (up to 12 months after vaccination). RSV-
associated LRTD is defined by the presence of clinical evidence of 
at least 1 sign or symptom of ARD (see below) and at least 2 (for 
less severe disease) of the following signs or symptoms with onset 
 days following vaccination until the end of 1 RSV season (up to 
12 months after vaccination), confirmed and documented by a 
medical professional, together with RSV disease confirmed by 
polymerase chain reaction (PCR) (nasopharyngeal (NP) swab to be 
collected within 5 days of symptom onset; preferably within 
72 hours of symptom onset). 

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hypoxemia (oxygen saturation <92% at rest in conjunction 
with an at least 3% decrease from baseline)  
respiratory rate >25 breaths/Min  
imaging evidence of new onset of bronchitis, bronchiolitis, or 
pneumonia 
new wheezing or worsening of pre-existing wheezing 
new shortness of breath or worsening of pre-existing 
shortness of breath 
new cough or worsening of pre-existing cough 
new sputum production or worsening of pre-existing sputum 
production
Secondary Endpoints 
 Efficacy 
(Key secondary) Occurrence of ARD associated with RSV until 
the end of one RSV season (up to 12 months after vaccination). 
RSV-associated ARD is defined by the presence of either one (1) 
ARD symptom lasting for at least 24 hours or two (2) 
simultaneously occurring ARD symptoms (irrespective of duration), 
 days following vaccination until the end of one RSV 
season (up to 12 months after vaccination). RSV disease must be 
laboratory-confirmed by PCR (NP swab to be collected within 
5 days of symptom onset, preferably within 72 hours of symptom 
onset).  
ARD symptoms include: 
rhinorrhoea 
nasal congestion 
pharyngitis 
earache 
new cough or worsening of pre-existing cough 
new wheezing or worsening of pre-existing wheezing 
new sputum production or worsening of pre-existing sputum 
production 
new shortness of breath or worsening of pre-existing 
shortness of breath  
fever >100°F / >37.8°C (oral temperature)
Occurrence of complications related to PCR-confirmed RSV 
disease.  
Occurrence of hospitalization due to confirmed RSV disease or due 
to any complication related to RSV-confirmed respiratory disease. 

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Occurrence of LRTD (severe LRTD) associated with RSV until 
the end of one RSV season (up to 12 months after vaccination). 
RSV-associated LRTD is defined by the presence of clinical 
evidence of at least 1 sign or symptom of ARD (see above) and at 
least 1 of the following signs 
 days 
following vaccination until the end of one RSV season (up to 
12 months after vaccination), confirmed and documented by a 
medical professional, together with RSV disease confirmed by 
polymerase chain reaction (PCR) (nasopharyngeal (NP) swab to be 
collected within 5 days of symptom onset; preferably within 
72 hours of symptom onset). 
hypoxemia (oxygen saturation <92% at rest in conjunction 
with an at least 3% decrease from baseline)  
respiratory rate >25 breaths/Min  
imaging evidence of new onset of bronchitis, bronchiolitis, or 
pneumonia
Safety 
Occurrence of any serious adverse events at any time during the trial 
period. 
Occurrence of any grade 3 or higher adverse events assessed as 
related to study vaccine within 29 days after vaccination. 
Occurrence of solicited local adverse events (pain, swelling, 
pruritus, erythema, induration) within 8 days after vaccination. 
Occurrence of solicited systemic adverse events (body temperature, 
headache, fatigue, myalgia, nausea, chills) within 8 days after 
vaccination. 
Occurrence of any unsolicited adverse events within 29 days after 
vaccination. 
Immunogenicity (selected sites) 
RSV-specific serum IgG antibody titers 2 weeks, 1 year and 2 years 
after vaccination.  
RSV-specific serum neutralizing antibody titers 2 weeks, 1 year and 
2 years after vaccination (subtype A and B). 
RSV-specific T-cell responses measured 1 week, 1 year and 2 years 
after vaccination.  

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Exploratory Endpoints 
 Occurrence of hospitalization (all cause, pneumonia, cardiovascular 
specific) or mortality (all cause, pneumonia, cardiovascular specific) 
related to confirmed RSV disease  
Durability 
Occurrence of LRTD associated with RSV during a second year 
after vaccination. Case definition is the same as for the primary, 
endpoints and severe LRTD endpoint. 
Occurrence of ARD associated with RSV during a second year after 
vaccination. Case definition is the same as for the secondary 
endpoint.  
Overall Vaccine Efficacy for up to 2 Years after Vaccination 
Occurrence of LRTD associated with RSV during the entire follow-
up period. Case definition is the same as for the primary endpoints, 
and severe LRTD endpoint. 
If 2 events occur in the same individual, only the first event will be 
counted. 
Occurrence of ARD associated with RSV during the entire follow-
up period. Case definition is the same as for the secondary endpoint. 
If 2 events occur in the same individual, only the first event will be 
counted.
Burden of Disease 
Change in symptoms on the Respiratory Intensity and Impact 
Questionnaire (RiiQ):  
The area under the curve (AUC) of the change from baseline 
in RiiQ total and domain-specific symptom scores from 
onset of symptoms to 6 days later (7 days total) and, in the 
case of ongoing symptoms, up to 20 days later (21 days 
total) in participants with confirmed RSV.  
The maximum change from baseline in daily RiiQ total and 
domain-specific scores for onset of symptoms to 6 days later 
(7 days total) and, in the case of ongoing symptoms, up to 
20 days later (21 days total) in participants with confirmed 
RSV.  
Health-Related Quality of Life 

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Change from baseline in the EuroQol 5-dimension 5-level (EQ-5D-
5L) health questionnaire utility score at onset of symptoms, day 6 
and 1, 3, 6 and 12 months after confirmed RSV.  
Change from baseline in the 15-dimension (15D) health-related 
quality of life instrument utility score at onset of symptoms, day 6 
and 1, 3, 6, and 12 months after confirmed RSV.  
Number of stays in the intensive care unit, uses of respiratory/life 
support, and antibiotic prescriptions due to confirmed RSV disease 
or due to complications related to RSV-confirmed disease. 
Immunogenicity (selected sites) 
RSV-specific serum antibody titers 2 weeks, 1 year and 2 years after 
vaccination assessed by RSV-specific IgA enzyme-linked 
immunosorbent assay (ELISA). 
Orthopox-specific serum neutralizing antibody titers 2 weeks, 1 year 
and 2 years after vaccination.  
Efficacy against other respiratory pathogens 
Occurrence of ARD associated with hMPV until the end of 1 RSV 
season. 
Occurrence of ARD associated with pre-specified viral respiratory 
pathogens until the end of 1 RSV season. 
Sample Size 
 The expected vaccine efficacy of MVA-BN-RSV vaccine against 
LRTD with 
is 80%. For an alpha = 0.05 two-sided test 
against a null hypothesis of 20% vaccine efficacy, a total of 22 
events will be required for 90% power. Assuming the rate of LRTD 
with 
is 0.2% in the placebo group during an RSV 
season, approximately 20,000 subjects vaccinated in 2 treatment 
groups receiving either MVA-BN-RSV vaccine or placebo will 
allow the observation of at least 22 events. If the number of LRTD 
with 
events required for the primary endpoint analysis 
is accruing slower than anticipated, approximately 4000 additional 
subjects may be recruited in RSV season 2 (section 11.5).
The expected vaccine efficacy of MVA-BN-RSV vaccine against 
LRTD with 
-sided test 
against a null hypothesis of 20% vaccine efficacy, a total of 
53 events will be required for 85% power. Assuming the rate of 

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LRTD with 
RSV season, approximately 20,000 subjects vaccinated in 2 
treatment groups receiving either MVA-BN-RSV vaccine or placebo 
will allow the observation of at least 53 events. If the number of 
LRTD with 
 events required for the primary endpoint 
analysis is accruing slower than anticipated, approximately 4000 
additional subjects may be recruited in RSV season 2 (section 11.5).
Assuming the rate of ARD is 1.6% in the placebo group during an 
RSV season, approximately 240 events will be observed if the 
vaccine efficacy is 50%. This will result in at least 95% power for an 
alpha = 0.05 two-sided test against a null hypothesis of 20% 
vaccine efficacy. 
Trial Design  
 
Randomized, double-blind, placebo-controlled.
In season 1, 20,000 subjects will be randomized into 2 groups. All 
vaccinated subjects will be followed up for respiratory tract disease 
starting the day after vaccination until the end of RSV season 1 (for 
up to 12 months after vaccination). 
Per definition an RSV season has ended according to the specific 
RSV surveillance data for the northern hemisphere (e.g., provided by 
the CDC for US sites 
https://www.cdc.gov/surveillance/nrevss/rsv/index.htmL) or site- and 
region-specific surveillance data for sites outside the US. In case of 
no distinct seasonality, subjects will be followed up for up to 12 
months after vaccination, for efficacy endpoint assessment.  
Futility decision towards the end of RSV season 1:
Scenario 1
If the number of LRTD events met the sample size requirement for 
the primary endpoint analyses (minimum of 22 LRTD with 3 
symptoms and minimum of 53 LRTD with 
) with 
approximately 6 months of follow-up (depending on the end of the 
RSV season at different locations) after vaccination of 20,000 
subjects, perform primary analyses. Continue if the success criterion 
for the primary endpoint is met with follow-up of subjects who are 
willing to continue participation for assessment of durability of 
protection starting 1 year after vaccination.  
Scenario 2 
If the number of LRTD events from season 1 did not meet the sample 
size requirement for the primary endpoints analyses towards the end 
of the RSV season, perform futility analyses (by an independent 
vendor). If the futility criterion is not met, continue to enroll, 

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vaccinate, and follow up further subjects for at least 1 RSV season 
(for up to 12 months) and continue follow up of subjects from season 
1 who are willing to continue participation for assessment of 
durability of protection starting 1 year after vaccination.  
Approximately 4000 additional subjects will be randomized into 
2 treatment groups receiving either placebo or MVA-BN-RSV 
vaccine and will be followed for at least one RSV season (6 months 
up to 12 months). Exact numbers of subjects required will be based 
on the number of events already observed and the probability of 
observing the additional required number of events, conditional on 
the observed overall event rate in season 1 (section 11.5).  
Table 1 
Treatment Groups  
Gro
up
N 
Age 
[yea
rs] 
Vaccin
ation 
Dose 
[Inf.U/0.5
 mL] 
IM 
Durabili
ty 
Follow 
up onlyb
Season 
2a
1
10,000
Placeb
o
- 
8000b
2000
2
10,000
MVA-
BN-
RSV
at least 
3×10E8
Inf.U
8000b
2000
Tot
al
20,000 subjects for primary endpoints
Approximately 16,000 (~20% dropout) for second year 
follow up after vaccination
24,000
Abbreviations: IM = intramuscular; Inf.U = infectious units; N = number of 
subjects per group. 
a If predefined number of required events is not met, further subjects (e.g., 2000 to 
4000) will be enrolled and vaccinated: sample size might be adapted based on 
number of events after first RSV season.  
b Subjects vaccinated before RSV season 1 who are willing to participate in the 
follow up for durability. They will be followed up for respiratory tract disease 
during a second year after vaccination if trial is not stopped due to futility. 
Subjects will be stratified by age into 4 cohorts by years: 60 to 64 (up 
to 10% of total vaccinated subjects), 65 to 74; 75 to 84 
(approximately 25% of subjects) and 
(approximately 5%). 
Enrollment should include at least 20% of overall subjects with at 
least 1 comorbidity associated with higher risk of LRTD, including 
chronic cardiac diseases and chronic lung diseases (asthma and 
chronic obstructive pulmonary disease [COPD]), congestive heart 
failure (CHF), and hypertension. All subjects will complete a frailty 
index questionnaire at screening/vaccination visit. 

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Subjects will be followed for disease surveillance via monthly 
telephone calls and electronic alerts 3× weekly from 2 weeks after 
vaccination until the end of the RSV season (up to 12 months after 
vaccination), to trigger a symptom visit (SV) if any respiratory tract 
symptoms are noted. Surveillance will proceed until up to 12 months 
with a planned 6-month telephone visit. If the trial continues after the 
analysis at the end of RSV season 1, subjects will be followed for 
disease surveillance up to 24 months.   
Except for the combined screening and vaccination visit (SCR/V1), 
symptom visits (SV) for collection of nasopharyngeal swabs for PCR 
to confirm RSV disease, unscheduled visits (e.g., due to AEs and 
evaluation of symptoms), and visits for blood draws for 
immunogenicity testing in a subgroup, all contacts with the subjects 
will take place by telephone calls.  
At the time point of vaccination (Day 1) until Day 8, solicited local 
and systemic symptoms will be recorded daily in an electronic 
patient diary. Any symptom(s) will be followed up until resolution.  
Starting after vaccination, sites will call subjects monthly (calendar 
month) to assess for new RSV symptoms (Disease Surveillance 
Telephone Visits). Telephone assessment includes inquiring of new 
symptoms, worsening of pre-existing symptoms from prior reported 
illness, resolution of symptoms, unsolicited adverse events and 
serious adverse events and follow up after vaccination.  
In addition to the telephone calls, subjects will get a text alert 3 times 
per week from the electronic patient reported outcome (ePRO) 
application asking about the presence of respiratory symptoms. 
Additional phone calls will be made in case the subject is not 
responsive to text alerts for more than a week. 
In case of any protocol-defined RSV-related symptoms, an onsite SV 
will be performed (target is within 72 hours after symptom 
occurrence, within 5 days is acceptable). Clinical evidence of the 
signs and symptoms needs to be verified and documented by a 
medical professional by questioning the subject regarding symptoms 
and performing specific exams and / or tests assessing, e.g., 
pharyngitis, oxygen saturation, respiratory rate, imaging evidence of 
new onset of bronchitis, bronchiolitis, or pneumonia and start of 
questionnaires EQ-5D-5L and 15D (4.1.4). 
A nasopharyngeal swab must be taken to confirm RSV disease by 
PCR testing at the central lab. 

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All subjects who experience any RSV-specific symptoms need to 
complete the RiiQ about their symptoms at symptom onset. The 
questionnaire is provided to the subjects via the ePRO application 
and will be filled out for 7 days and up to 20 days in case of ongoing 
symptoms, independent of whether RSV is confirmed by PCR.  
Selected sites: 
Serum and PBMC samples will be taken from a defined 
sub-population for immunogenicity analysis at specific sites. 
Additional specifications after futility analysis and continuation of 
the trial for follow-up of durability or/and inclusion of further 
subjects: 
Scenario 1 above:  
Blinding of subject-level treatment assignment will remain for 
follow-up of durability starting approximately 12 months after 
vaccination. A blinded statistician will be assigned to continue to 
support the operational team. 
Scenario 2 above:  
The entire team will remain blinded until subjects vaccinated after 
the first RSV season are followed up until at least the end of the RSV 
season 2 (up to 24 months after vaccination). 
A detailed visit schedule is provided in the Trial Schedule section 1.4
Analysis and 
Reports 
 
The primary analyses will occur when at least 53 LRTD 
 symptoms) events have been observed. Of those, at least 22 LRTD 
events need to have at least 3 symptoms. The primary endpoints and 
the key secondary efficacy endpoint of RSV-associated ARD will then 
be formally tested. The fixed-sequenced method will be used to control 
the overall familywise type I error rate. The hypothesis related to 
vaccine efficacy for LRTD with 
will be tested against the 
20% first, followed by testing the hypothesis 
related to vaccine efficacy for LRTD with 
 against the 
Finally, the hypothesis related to vaccine 
efficacy for ARD will be tested 
The main analyses will be based on a Cox proportional hazards 
regression model with treatment and age groups as fixed factors. 
Vaccine efficacy is defined as 1 minus the hazard ratio. 

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An analysis for vaccine efficacy during the second year after 
vaccination (durability) and vaccine efficacy up to 2 years since 
vaccination (2-year vaccine efficacy) will be performed after the last 
visit is completed.  
If less than 53 LRTD with 
events or less than 22 LRTD 
with 
 symptoms events are observed towards the end of the first 
RSV season, a futility analysis will be performed by an independent 
unblinded statistical service vendor and assessed by the Data 
Monitoring Committee (DMC) for the trial. Details can be found in 
section 4.4 and will be described in the DMC Charter. 
If the futility boundary is not crossed and the DMC recommends 
continuing, more subjects will be vaccinated in season 2. However, the 
number of subjects to be vaccinated in season 2 will be based on the 
number of events already observed (blinded). Primary analyses will be 
performed at the end of season 2 with combined data from the 
2 seasons. Analysis for durability and two-year vaccine efficacy based 
on the subjects who are vaccinated in season 1 will also be performed 
at approximately the same time. 
Eligibility Criteria 
Inclusion Criteria 
1.
 years of age. 
2.
Informed Consent signed by the subject. 
3.
Subjects may have one or more chronic medical conditions e.g., 
mild to moderate underlying illnesses such as chronic cardiac 
diseases and chronic lung diseases (asthma and chronic 
obstructive pulmonary disease [COPD]), congestive heart failure 
(CHF), hypertension, type 2 diabetes mellitus, 
hyperlipoproteinemia, or hypothyroidism, that is clinically stable 
as assessed by the investigator. 
4.
Absence of known, current, and life-limiting diagnoses that render 
survival to completion of the protocol unlikely. 
5.
Ability to comply with trial requirements, which necessitates 
access to transportation to on-site visits, including symptom visits 
for a nasopharyngeal swab.  
6.
Willingness and ability to utilize an application on a personal 
device (i.e., smartphone, tablet, etc.) or a provisioned device to 
record solicited events and record all per protocol required data 
during the surveillance period. 
7.
For women of childbearing potential (WOCBP), agreement to use 
an acceptable method of contraception during the trial and a 
negative urine pregnancy test within 24 hours prior to vaccination.

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Note: A woman is considered of childbearing potential unless post-menopausal 
 months without a menstrual period) or who is permanently 
sterile (i.e., is at least 6 months post-surgical sterilization via hysterectomy or 
bilateral oophorectomy). Acceptable contraception methods are restricted to 
abstinence, barrier contraceptives, intrauterine devices (IUD), intrauterine 
systems (IUS), licensed hormonal products or tubal ligation.
Exclusion Criteria 
1.
History of or current clinical manifestation of any serious medical 
condition that in the opinion of the investigator would 
compromise the safety of the subject, confound data 
interpretation, 
trial.  
2.
History of or active autoimmune disease, including diabetes 
mellitus type I. Vitiligo or hypothyroidism requiring thyroid 
replacement therapy are not exclusions. Rheumatoid arthritis not 
requiring immunomodulatory and/or immunosuppressant 
treatment is not an exclusion. 
3.
Known or suspected impairment of immunologic functions, 
including chronic inflammatory bowel disorders.  
4.
Clinically significant mental disorder that would prevent patients 
from giving informed consent and complying with study 
procedures (e.g., completion of the electronic diary). 
5.
Active or recent (within 6 months before enrollment) history of 
chronic alcohol abuse. 
6.
History of a serious reaction to any prior vaccination or Guillain-
Barré syndrome (GBS) within 6 weeks of any prior influenza 
immunization. 
7.
History of allergic disease or reactions likely to be exacerbated by 
any component of the vaccine, e.g., tris(hydroxymethyl)-amino 
methane, chicken embryo fibroblast proteins, gentamycin, 
ciprofloxacin; this includes: 
Known allergy to eggs or aminoglycosides. 
History of anaphylaxis or severe allergic reaction to any 
vaccine. 
8.
Any administration or planned administration of: 
A licensed live or vector-based vaccine within 30 days prior to 
or after trial vaccine administration. 
A licensed inactivated or ribonucleic acid (RNA)-based 
vaccine within 14 days prior to or after trial vaccine 
administration. 
9.
Previous vaccination with an RSV vaccine, or any planned 
vaccination with an RSV vaccine other than the trial vaccine. 

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10. Planned chronic, systemic administration (defined as more than 
14 days) of >10 mg prednisone (or equivalent)/day or any other 
systemic use of immune-modifying drugs during a period starting 
from 3 months prior to first administration of the trial vaccine and 
ending at the End of Study Visit (EOS). The use of topical, 
inhaled, ophthalmic and nasal glucocorticoids is permitted. 
11. Administration or planned administration of immunoglobulins 
and/or any blood products during a period starting from 3 months 
prior to first administration of the trial vaccine and during the trial 
12. Known uncontrolled coagulation disorder. Anticoagulant 
treatment under adequate control for cardiovascular prophylaxis 
or prophylaxis of thromboembolic disease or stroke in the setting 
of atrial fibrillation are permitted.
13. Use of any investigational or non-registered drug or vaccine other 
than the trial vaccine within 30 days prior to the administration of 
the trial vaccine, or planned administration of such a drug or 
vaccine between enrollment in the trial and until 4 weeks after the 
trial vaccine administration. 
14. Involvement with this trial as research personnel. 
15. Planned leave or holiday of 4 consecutive weeks or more during 
the RSV season covered by the study, that would prohibit the 
reporting of ARI cases and attendance at symptom visits. 
16. Pregnancy or breast-feeding. 

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2
Background Information and Scientific Rationale 
2.1
Introduction to RSV Disease 
Respiratory Syncytial Virus (RSV) is a ribonucleic acid (RNA) virus of the Pneumoviridae 
family. The RSV genome encodes eleven proteins, 2 of which play a key role for pathogenesis 
and are important antigens for generating protective immunity: Glycoprotein G, responsible for 
viral attachment, and the fusion protein F, which mediates viral penetration and syncytium 
formation. There are 2 different subtypes of RSV circulating concurrently, A and B, which are 
distinguished mainly by variations within the G protein (Hall, 2001). 
RSV is highly infectious and transmitted primarily by contact with infectious respiratory 
secretions or contaminated objects. Seasonal epidemics overlapping with the influenza season 
occur yearly in autumn/winter in temperate climates and in the wet season in the tropics. 
Typically, the primary disease begins with fever, coryza and cough, lasting 10 to 14 days. In 
more severe infections, the disease spreads from the upper down to the lower respiratory tract and 
results in bronchiolitis leading to inflammation-induced airway obstruction with associated 
tachypnea and wheezing, sometimes requiring oxygen support to avoid progression to pneumonia 
with respiratory failure.  
RSV has been recognized as a significant cause of respiratory illness in all age groups. The 
disease is predominated by febrile upper respiratory tract infections (URTI) in older children and 
adults and is the leading cause of LRTD in newborns, infants and younger children (Azzari, 
2021). While the burden of RSV is highly recognized in the pediatric population, particularly in 
the very young and those with cardio-respiratory disease, RSV disease is also a serious health 
concern in the older adults/ elderlies and in immunocompromised adults. Indeed, about 78% of 
deaths due to RSV-related underlying respiratory and circulatory disease occur among the 
Thompson, 2003) (see Figure 1). 

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Figure 1
Estimated Annual RSV-Associated Mortality Rates in Different Age Groups per 
100,000 Person-Years for the 1990-1991 Through 1998-1999 Seasons (Thompson, 2003)
RSV disease in the older adults, elderly and high-risk adult population in the United States (US)
has shown to be a significant health issue. Approximately 170,000 hospitalizations and 
10,000 deaths occur annually in people over the age of 65 years (Murata, 2007). Epidemiological 
surveys performed over several RSV seasons indicate that 3-7% of healthy elderly and 4-10% of 
high-risk adults are diagnosed with RSV per year (Korsten, 2021). Similar to influenza, RSV 
disease has been identified as resulting in significant burden in older individuals, causing severe 
lower respiratory disease such as pneumonia and exacerbation of chronic obstructive pulmonary 
disease (COPD). COPD patients are even suspected to constitute a reservoir for RSV.
The immunologic factors that are responsible for protection against RSV are not completely 
understood. RSV infection induces secretory antibodies, serum neutralizing antibodies and T-cell 
immunity, with some protective effect against LRTD provided by high levels of serum 
neutralizing antibodies (Groothuis, 1993, Walsh, 2004). The F and G proteins are the main 
targets for induction of neutralizing antibodies, and whilst there is a trend between higher levels 
of neutralizing antibodies and protection from severe disease, it is still possible to experimentally 
re-infect adults with RSV regardless of their systemic antibody levels. A deficiency in RSV F-
specific T-cell responses has also been suggested to contribute to susceptibility to severe RSV 
disease in older adults and the elderly population (Hall, 1991; Cherukuri, 2013). However, 
naturally acquired immunity is neither complete nor durable (Glezen, 1986; Hall, 2001). 
An estimated 90% of the population experiences their first RSV infection within the first 2 years 
of life (Glezen, 1986; Castilow, 2007). However, immune responses after primary infection in 
young infants are usually weak and short-lived due to immunological immaturity and suppression 
by maternal antibodies (Karron, 1999; Power, 2008). Re-infections with RSV are common at all 
0
5
10
15
20
25
30
35
40
<1
1-4
5-49
50-64
. 
Age Group
RSV

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ages, although of decreasing severity, since with recurring infections the disease becomes more 
limited to the upper respiratory tract (Glezen, 1986). Morbidity and disease severity increases 
again in people >50 years (McClure, 2014).  
While the anti-RSV-F monoclonal antibody palivizumab (Synagis ) is effective for prevention of 
serious RSV disease in premature and other high-risk infants, options for the healthy pediatric 
and adult populations are limited to supportive measures as there is neither an approved RSV 
vaccine nor any specific treatment available. One of the key setbacks to further development of 
RSV vaccines in infants and children has been the failed approach with a formalin-inactivated 
vaccine in the 1960s, which caused enhanced disease in vaccinated infants after natural exposure 
to RSV (Fulginiti, 1969). Enhanced disease is believed to be (at least partly) caused by an 
immoderate Th2 memory response (Castilow, 2007) in a population previously naïve to RSV and 
is characterized by pulmonary eosinophilia. The clinical testing of several newly developed RSV 
vaccine candidates during the last decade has not revealed any safety concern and particularly 
live viral vaccines seem not to be associated with enhanced RSV disease (Wright, 2007). Most 
importantly, the RSV vaccine candidate described here, which is based on the modified vaccinia 
Ankara strain (MVA), induces a balanced Th1/Th2 (T-helper cells, Type1/Type2) response 
combined with a humoral immune response without any signs of enhanced disease in animal 
models (Figure 2).  

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Figure 2 
Eosinophil Concentration in Bronchoalveolar Lavage in Mice after Administration of 
MVA-BN-RSV and Formalin-Inactivated (FI) RSV Vaccine 
Given the severity of disease in elderly and the lack of treatment options, there is an unmet 
medical need to prevent RSV-induced respiratory disease, which accounts for hospitalizations 
due to chronic COPD, pneumonia, asthma and congestive heart failure (CHF). Thus, the 
significant impact on public health with a growing elderly community makes the development of 
a safe and protective RSV vaccine a high priority. Since adults have already experienced several 
RSV infections, they are no longer naïve to the virus and vaccination is expected to boost a pre-
existing, yet not fully protective immune response, i.e., to induce high levels of antibodies 
combined with a robust T-cell response. 
2.2
MVA-BN-RSV Vaccine 
Bavarian Nordic (BN) has developed a vaccine candidate against RSV by including RSV surface 
protein-encoding genes from both circulating RSV subtypes (A and B), as well as conserved 
internal antigen-encoding genes of the virus, into the MVA-BN vector. The vaccine is designed 
for a broad reactivity to prevent acute and severe respiratory tract infection caused by RSV (e.g., 
LRTD such as RSV bronchiolitis and pneumonia) both in the elderly and in adults with 

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underlying conditions such as cardiovascular disease and immunosuppression, i.e., populations 
known to have an increased risk of complications associated with RSV. 
The recombinant RSV vaccine candidate MVA-BN-RSV (construct MVA-mBN294B) consists 
of MVA-BN encoding the following RSV antigens: 
The RSV surface proteins F (Fusion) and G (Glycoprotein for subtype A and B), which 
induce humoral and cell-mediated immunity in animal models (mice and cotton rats). 
Two internal proteins N (Nucleoprotein) and M2-1 (a transcription elongation factor), 
which are expected to enhance immunogenicity, especially in terms of cytotoxic T-cell 
responses, but also cross-protection to infection with other subtypes, since these 2 proteins 
are highly conserved among the different circulating RSV subtypes. 
2.3
Origin and Characteristics of MVA-BN Vector Backbone 
Vaccinia virus (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 
deoxyribonucleic acid (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 6 major deletions, resulting in the loss of 13% 
(approximately 27 kbp) 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 strongly 
attenuated replication in susceptible cell types, its genes are efficiently transcribed, with the block 
in viral replication occurring at the level of virus assembly and egress (Sutter, 1992; Carroll, 
1997). 
Bavarian Nordic, an international biopharmaceutical company, has developed a proprietary strain 
of modified vaccinia Ankara (MVA-BN, trade name IMVANEX in the European Union, 
IMVAMUNE in Canada, and JYNNEOS in the United States) for use as a prophylactic smallpox 
vaccine. 
MVA-BN is a highly attenuated, purified live vaccine produced under serum-free conditions in 
chicken embryo fibroblast cells. In contrast to replicating smallpox vaccines, MVA-BN can be 
administered by subcutaneous (SC) or IM injection, and not by scarification. The standard route 
and schedule of MVA-BN are 2 subcutaneous injections administered 4 weeks apart. Since 
MVA-BN is non-
Mayr, 1975). 

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For IMVANEX, a marketing authorization under exceptional circumstances was granted by the 
European Commission in July 2013. A marketing authorization for IMVAMUNE® was granted 
by Health Canada in November 2013, for JYNNEOS in the United States September 2019. 
2.4
Summary of Non-clinical Studies with MVA-BN-RSV Vaccine 
BN has performed more than 20 good laboratory practice (GLP)-compliant safety studies for 
either the vector backbone MVA-BN or MVA-BN-based recombinant vaccines. These studies 
demonstrated that all products investigated are safe and well tolerated. Similarly, the current 
MVA-BN-RSV vaccine candidate (MVA-mBN294B) was tested in 2 GLP-compliant repeat-dose 
toxicity and local tolerance studies in rabbits and found to be safe. MVA-BN-RSV was locally 
well tolerated at the dose of 1×10E8 TCID50 (Tissue Culture Infectious Dose 50% corresponding 
to 1×10E8 infectious units [Inf.U]) even when administered 4 times (in 3-week intervals). There 
were no MVA-BN-RSV-related mortalities or clinical observations and no vaccine-related 
findings in the hematology, clinical chemistry, and histopathology. At 2×10E9 Inf.U, a 4-fold 
higher dose than the maximal human dose of 5×10E8 Inf.U, adverse lesions at injection sites 
were observed 2 days after the fourth administration with ongoing reversibility after a 28-day 
recovery period. Again, there were no mortalities or relevant clinical signs. Transient changes in 
hematology and biochemistry parameters were most likely related to inflammation at the 
injection site, reflecting induced immune responses by the vaccine. At pathology, there were no 
systemic findings. Findings were related to the antigenic stimulation by the test item elicited at 
the injection sites.  
For more detailed information on preclinical data, refer to the respective sections of the 
2.5
Clinical Profile of MVA-BN and Recombinant MVA-based Vaccines 
To date, 23 clinical trials evaluating the safety and immunogenicity of MVA-BN have been 
completed. More than 8900 subjects have been vaccinated with MVA-BN in completed clinical 
trials, including risk groups with contraindications to conventional smallpox vaccines, such as 
human immunodeficiency virus (HIV)-infected subjects and subjects with atopic dermatitis. 
Further, MVA-BN has been evaluated in adults and older adults, i.e., subjects 56 to 80 years of 
age.  
In total, BN has evaluated the safety and immunogenicity of MVA-BN and MVA-BN-based 
recombinant vaccines in more than 51,000 subjects including healthy subjects, HIV-infected 
individuals, populations with cancer, and children in completed and ongoing clinical trials. In 
trials with recombinant MVA vaccines, doses up to 5×10E8 TCID50 were administered applying 
varying schedules of repeat vaccinations. For example, a 3-dose schedule was used for 
recombinant HIV vaccines, and multiple vaccinations have also been performed in subjects 
receiving a recombinant therapeutic breast cancer vaccine (MVA-BN-HER2).  

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Details on the clinical trials with MVA-BN-RSV are provided in Section 2.6. 
2.5.1 Safety Overview 
In all completed and ongoing clinical trials, vaccinations with MVA-BN or MVA-BN-based 
vaccines have shown to have a good safety profile and to be well tolerated in all populations 
tested (healthy, elderly, immunocompromised) and at all doses tested (up to 5×10E8 TCID50). No 
cases of death assessed as being possibly related have been reported for a subject in a clinical trial 
using MVA-BN or recombinant MVA-BN-based vaccines. 
Results obtained from completed phase 1 and phase 2 trials and ongoing trials with several 
recombinant MVA-BN-based vaccines in healthy adults, children, people infected with HIV, and 
individuals with cancer demonstrate a similar safety profile as MVA-BN alone.  
Additional information on the safety profile of MVA-BN and recombinant MVA-based vaccines 
is provided in the IB.  
Adverse Drug Reactions (ADRs)
Table 2 summarizes the pooled ADR data of all completed MVA-BN trials. The safety profile of 
each of the trials with recombinant MVA-BN-based vaccines is comparable to the safety profile 
displayed in Table 2, as the occurrence of the ADRs is considered to be a reaction to the vector 
rather than the insert, based on previous experience with recombinant MVA-BN vaccine 
candidates. 
Table 2  
Suspected Adverse Drug Reactions Reported by 
 of Subjects in the Completed 
MVA-BN Clinical Trialsa (N=8992b) 
Preferred Term 
No. of subjects 
Frequency 
Injection site pain 
7370 
82.0% 
Injection site erythema 
5875 
65.3% 
Injection site swelling 
4488 
49.9% 
Injection site induration 
3988 
44.4% 
Injection site pruritus 
3573 
39.7% 
Myalgia
3017
33.6%
Fatigue 
2886 
32.1% 
Headache 
2704 
30.1% 
Nausea 
1316 
14.6% 
Rigors/chills 
842 
9.4% 
Body temperature increased 
269 
3.0% 
Pyrexia 
259 
2.9% 
Injection site nodule 
228 
2.5% 
Appetite disorder 
218 
2.4% 
Arthralgia 
209 
2.3% 
Injection site discolouration
207
2.3%

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Pain in extremity
148
1.7%
Injection site haematoma
107
1.2%
Axillary pain
93
1.0%
Injection site warmth
90
1.0%
a
POX-MVA-001, -002, -004, -005, -006, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, 
-031, -036, -037, -03X, HIV-NEF-004 and HIV-POL-002. 
b
8 subjects exposed but not included in analysis. 7 subjects in POX-MVA-009 received Dryvax either on the 
same day or within 7 days after MVA-BN administration and were therefore not included to avoid a potential 
bias in the adverse event reporting. 1 subject in POX-MVA-029 was not vaccinated according to the 
randomization, therefore removed from analysis set.
The vast majority of these reactions were reported to be mild to moderate in intensity and 
resolved completely without intervention within the first 7 days following vaccination. To date, 
no trends have been identified that suggest the occurrence of any particular unexpected adverse 
reactions or classes of adverse reactions following vaccinations with MVA-BN.
Cardiac Signs and Symptoms
Based on observations with replicating smallpox vaccines, particular attention has been placed on 
monitoring for cardiac signs and symptoms in all clinical trials using MVA-BN. Despite close 
cardiac monitoring, no confirmed event indicating a case of myo-/pericarditis has been observed 
in any completed MVA-BN trial as well as from post-marketing experience so far. Furthermore, 
no confirmed case of myo-/pericarditis has been observed after administration with 
MVA-BN-RSV in any of the completed or ongoing studies.
Serious Suspected Adverse Drug Reactions
A total of 7 (7 out of 10,713 vaccinated subjects = 0.07 %) serious suspected ADRs have been 
reported for MVA-BN smallpox vaccine in completed and ongoing trials. All of them have been 
thoroughly reviewed by BN and the trial-specific Data Safety Monitoring Boards (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.
2.5.2 Safety Profile of MVA-BN-based Recombinant Vaccines in Healthy 
Compared to Special Populations
BN has evaluated the safety and immunogenicity of MVA-BN-based recombinant vaccines for 
several indications such as cancer, HIV, Ebola and measles. Results obtained from these phase 1
to phase 3 trials demonstrate a similar safety profile and vector immunogenicity as compared to 
MVA-BN alone.

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In respect to the MVA-BN-RSV vaccine, subject exposure in the 3 clinical trials RSV-MVA-001, 
RSV-MVA-002, and RSV-MVA-015 amounted to a total number of 427 subjects. Hence, data 
were pooled to obtain a better overview of the safety profile of the vaccine.  
The safety profile obtained from this pooled safety data analysis is considered as Reference 
Safety Information for the MVA-BN-RSV vaccine (see also the IB).  
The safety population included 427 adult subjects from 18 to 70 years of age who were 
randomized to receive MVA-BN-RSV vaccine in various doses under placebo-controlled 
conditions. The frequency of the pooled adverse events (AEs) after vaccination with 
MVA-BN-RSV vaccine or placebo are listed in Table 3 (solicited AEs).  
Solicited Adverse Events (8 days following vaccination) 
In the analysis of unsolicited AEs, the post-vaccination period was restricted to 8 days following 
vaccination. The majority of all reported AEs represent solicited local and systemic reactions, 
such as injection site pain, injection site redness and injection site swelling or muscle pain, 
headache and fatigue. These findings are in line with those previously observed during the 
clinical development program of the MVA-BN backbone. 

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Table 3 
Incidence of Solicited Local and Systemic Adverse Events (Per Subject) in Clinical 
Trials with MVA-BN-RSVa for 8 Days Starting at Day of Vaccination 
Treatment Groups 
MVA-BN-RSV 
Placebo 
 Pooled 
(N=424)a
1×10E7  
TCID50b
(N=18)c
1×10E8  
TCID50/ 
Inf.Ub
18-69 yrs 
(N=150)d
1×10E8  
Inf.U 
(N=51)e
5×10E8  
Inf.U 
18-69 yrs 
(N=154)f
5×10E8  
Inf.U 
(N=51)e
(N=129)a
Preferred 
Term 
(MedDRA)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Systemic
Body 
Temperature 
37 (8.7) 
5 (27.8) 
8 (5.3) 
1 (2.0) 
17 (11.0) 
6 (11.8) 
1 (0.8) 
Chills 
59 (13.9) 
0 (0.0) 
14 (9.3) 
4 (7.8) 
30 (19.5) 
11 (21.6) 
9 (7.0) 
Fatigue
124 (29.2)
3 (16.7)
29 (19.3)
13 (25.5)
57 (37.0)
22 (43.1)
25 (19.4)
Headache 
132 (31.1) 
6 (33.3) 
38 (25.3) 
12 (23.5) 
59 (38.3) 
17 (33.3) 
26 (20.2) 
Muscle pain 
160 (37.7) 
2 (11.1) 
42 (28.0) 
9 (17.6) 
86 (55.8) 
21 (41.2) 
15 (11.6) 
Nausea 
40 (9.4) 
1 (5.6) 
13 (8.7) 
6 (11.8) 
11 (7.1) 
9 (17.6) 
7 (5.4) 
Local
Induration 
71 (16.7) 
0 (0.0) 
15 (10.0) 
8 (15.7) 
38 (24.7) 
10 (19.6) 
6 (4.7) 
Itching 
63 (14.9) 
2 (11.1) 
18 (12.0) 
9 (17.6) 
23 (14.9) 
11 (21.6) 
7 (5.4) 
Pain 
300 (70.8) 
3 (16.7) 
100 (66.7)
28 (54.9) 
130 (84.4)
39 (76.5) 
19 (14.7) 
Redness 
129 (30.4) 
5 (27.8) 
39 (26.0) 
9 (17.6) 
56 (36.4) 
20 (39.2) 
26 (20.2) 
Swelling 
91 (21.5) 
1 (5.6) 
27 (18.0) 
7 (13.7) 
45 (29.2) 
11 (21.6) 
6 (4.7) 
Abbreviations: Inf.U = infectious units; MedDRA = Medical Dictionary for Regulatory Activities; N = number of 
subjects in specified group with available data (i.e., memory aid completed); RSV = respiratory syncytial 
virus; TCID50 = tissue culture infectious dose 50; yrs = years 
The number of AEs reported from RSV-MVA-015 may be subject to change after all data cleaning is completed 
at the end of the study. 
a RSV-MVA-001, RSV-MVA-002, and RSV-MVA-015 
b The dose for the phase 1 clinical trial was expressed as TCID50, corresponding to Inf.U 
c RSV-MVA-001 only 
d RSV-MVA-001 and RSV-MVA-002 
e RSV-MVA-002 only  
f RSV-MVA-002 and RSV-MVA-015 
g RSV-MVA-002 and RSV-MVA-015 

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Table 4 
Summary of Adverse Events (Per Subject) in Clinical Trials with MVA-BN-RSVa 
Treatment Groups
MVA-BN-RSV
Placebo
Pooled  
(N=427)a
1×10E7  
TCID50b
(N=18)c
1×10E8  
TCID50/ 
Inf.Ub
18-69 
yrs
(N=150)d
1×10E8  
Inf.U 
(N=53)e
5×10E8  
Inf.U 
18-69 
yrs
(N=155)f
5×10E8  
Inf.U 
(N=51)e
(N=129)a
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
Subjects 
(%)
TEAE 
379 
(88.8) 
 15 
(83.3) 
123 
(82.0) 
 45 
(84.9) 
148 
(95.5) 
 48 
(94.1) 
 95 
(73.6) 
Non-serious 
TEAE 
376 
(88.1) 
 15 
(83.3) 
121 
(80.7) 
 44 
(83.0) 
148 
(95.5) 
 48 
(94.1) 
94  
(72.9) 
SAE 
 12 (2.8) 
  0 (0.0) 
  4 (2.7) 
  3 (5.7) 
  3 (1.9) 
  2 (3.9) 
  5 (3.9) 
Relatedg TEAE 
232 
(54.3) 
  8 (44.4) 
60 (40.0) 
23 (43.4) 
104 
(67.1) 
37 (72.5) 
52 (40.3) 
TEAE Grade 
56 (13.1) 
 0 (0.0) 
15 (10.0) 
  6 (11.3) 
28 (18.1) 
7 (13.7) 
6 (4.7) 
Relatedg TEAE 
 30 (7.0) 
  0 (0.0) 
  8 (5.3) 
  2 (3.8) 
16 (10.3) 
  4 (7.8) 
  1 (0.8) 
Abbreviations: Inf.U = infectious units; N = number of subjects in the specified group; RSV = respiratory 
syncytial virus; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TCID50 = 
tissue culture infectious dose 50; yrs = years.  
Serious adverse events are considered treatment-emergent even if they exceed the 29-day follow-up period 
after each vaccination. 
Adverse events (irrespective of seriousness) occurring after inoculation with the RSV challenge virus in 
trial RSV-MVA-015 are not included. 
The number of AEs reported in RSV-MVA-015 may be subject to change after all data cleaning is 
completed at the end of the study. 
a RSV-MVA-001, RSV-MVA-002, and RSV-MVA-015 
b The dose for the phase 1 clinical trial was expressed as TCID50, corresponding to Inf.U. 
c RSV-MVA-001 only 
d RSV-MVA-001 and RSV-MVA-002 
e RSV-MVA-002 only  
f RSV-MVA-002 and RSV-MVA-015 
g Unsolicited or systemic solicited adverse events the investigator considered to have possible, probable, 
definite or missing relationship to trial vaccine; although solicited local events are by definition always 
adverse drug reactions, they are not included here 

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Unsolicited Adverse Events 
In the analysis of unsolicited AEs, the post-vaccination period was restricted to 28 days following 
vaccination. The most frequently observed unsolicited AEs were URTI in the system organ class 
(SOC) Infections and Infestations, rhinorrhoea in the SOC Respiratory, Thoracic and Mediastinal 
Disorders and increased blood potassium in the SOC Investigations (Table 5). 
Table 5 
Incidence of Treatment-Emergent Unsolicited Adverse Events (Per Subject) in Clinical 
Trials with MVA-BN-RSV Reported by 1% of Subjects 
MVA-BN-RSV  
Pooled 
(N=427)a
System Organ Class 
Preferred Term (MedDRA) 
Subjects (%) 
Any Adverse Event
184 (43.1) 
Infections and infestations
79 (18.5) 
Upper respiratory tract infection 
30 (7.0) 
Pharyngitis 
10 (2.3) 
Sinusitis 
10 (2.3) 
Nasopharyngitis 
7 (1.6) 
Urinary tract infection 
6 (1.4) 
Respiratory, thoracic and mediastinal disorders
49 (11.5) 
Rhinorrhoea 
28 (6.6) 
Cough 
22 (5.2) 
Nasal congestion 
18 (4.2) 
Productive cough 
9 (2.1) 
Dyspnoea 
5 (1.2) 
Investigations
39 (9.1) 
Blood potassium increased 
12 (2.8) 
Blood sodium increased 
8 (1.9) 
General disorders and administration site conditions
29 (6.8) 
Injection site pain 
13 (3.0) 
Fatigue 
7 (1.6) 
Injection site swelling 
6 (1.4) 
Injection site erythema 
5 (1.2) 
Musculoskeletal and connective tissue disorders
26 (6.1) 
Myalgia 
13 (3.0) 
Gastrointestinal disorders
17 (4.0) 
Nausea 
6 (1.4) 
Nervous system disorders
19 (4.4) 
Headache 
13 (3.0) 
Injury, poisoning and procedural complications
10 (2.3) 

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Abbreviations: MedDRA = medical dictionary for regulatory activities; N = number of subjects in specified 
group; RSV = respiratory syncytial virus 
Serious adverse events are considered treatment-emergent even if they exceed the 29-day follow-up period after 
each vaccination including the booster vaccination in the booster sub-study; this table contains unsolicited 
adverse events 
. 
Adverse events (irrespective of seriousness) occurring after inoculation with the RSV challenge virus in the trial 
RSV-MVA-015 are not included. 
Numbers of unsolicited adverse events from RSV-MVA-015 may be subject to change after all data cleaning is 
completed at the end of the study. 
a RSV-MVA-001, RSV-MVA-002, and RSV-MVA-015 
In summary, the majority of the solicited and unsolicited AEs over all clinical studies were mild 
(Grade 1) or moderate (Grade 2) in intensity, and all were transient in nature and resolved without 
sequelae. Grade 3 TEAEs were reported in 13.1% of subjects, and related TEAEs (mainly solicited 
AEs) in 7%. No related serious adverse events were reported so far. The safety and tolerability were 
generally comparable across different treatment groups and dosages.
2.5.3 Dose Finding for MVA-BN-RSV Vaccine 
For MVA-BN, the standard dose and schedule for the general population is 2 doses of at least 
5×10E7 TCID50 MVA-BN (nominal titer of 1×10E8 TCID50 per dose) administered SC 4 weeks 
apart. A trial in adult and elderly (56-80 years old) vaccinia-experienced subjects indicated that it 
is sufficient to vaccinate this population only once with MVA-BN (Greenberg, 2016). 
In the first clinical trial with the MVA-BN-RSV vaccine (RSV-MVA-001 phase 1 trial), a low 
dose with a nominal titer of 1×10E7 TCID50 per dose was compared against a dose with a 
nominal titer of 1×10E8 TCID50 per dose (see Section 2.6). 
In the second RSV trial (RSV-MVA-002 phase 2 trial) different doses and schedules were 
evaluated: all subjects received 2 vaccinations
either both vaccinations with 
MVA-BN-RSV vaccine 1×10E8 Inf.U per 0.5 mL, 5×10E8 Inf.U per 0.5 mL, or placebo, or the 
first vaccination with MVA-BN-RSV vaccine 1×10E8 Inf.U or 5×10E8 Inf.U per 0.5 mL 
followed by the second vaccination with placebo (Table 7). Please note that the dose was 
expressed as TCID50 for the phase 1 clinical trial with 1×10E8 TCID50 per dose corresponding to 
1×10E8 Inf.U per dose. 
2.6
Clinical Trial Data with MVA-BN-RSV Vaccine 
The following clinical trials with the MVA-BN-RSV vaccine have been fully enrolled and final 
follow-up visits have been completed:   
A randomized, single-blind, placebo-controlled, monocentric phase 1 trial to assess the 
safety, tolerability, and immunogenicity of the recombinant MVA-BN-RSV vaccine in 
healthy adult subjects (RSV-MVA-001). 

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A randomized, single-blind, placebo-controlled, dose-ranging p
55 year old 
adults to evaluate the safety and immunogenicity of the recombinant MVA-BN-RSV 
vaccine (RSV-MVA-002). 
RSV-MVA-015: A phase 2a, randomized, placebo-controlled human challenge trial in 
which administration of MVA-BN-RSV or placebo was followed by inoculation with an 
RSV strain known to cause mild to moderate symptoms in healthy adults. 
Phase 1: RSV-MVA-001 
Safety, tolerability and immunogenicity of the recombinant MVA-BN-RSV vaccine were 
evaluated in the randomized, single-blind, placebo-controlled phase 1 trial (RSV-MVA-001). In 
total, 63 healthy adult subjects received 2 vaccinations of placebo, the 1×10E7 TCID50 dose, or 
the 1×10E8 TCID50 dose of MVA-BN-RSV vaccine (Table 6). 
Table 6
Treatment Groups in Phase 1 Clinical Trial RSV-MVA-001 
Group 
Na
Age 
(years) 
Vaccine: nominal titer 
per dose (TCID50) 
Volume per 
dose 
[mL] 
Schedule 
(vaccination 
days) 
Route 
1 
18 + 3 
18-49 
1×10E7 
0.5 
0; 28 
IM 
2 
18 + 3 
18-49 
1×10E8 
0.5 
0; 28 
IM 
3 
18 + 3 
50-65 
1×10E8 
0.5 
0; 28 
IM 
Total 
63
Abbreviations: IM = intramuscular; N = number of subjects per group; TCID50 = tissue culture infectious dose 
50% 
a 18 subjects in each treatment group receiving MVA-BN-RSV vaccine and 3 subjects in each treatment 
group receiving placebo 
Data Source: MVA-RSV-001 Clinical Study Report (Ed. 1.0 dated 04 July 2016, Table 1). 
To evaluate long-term safety and immunogenicity of the MVA-BN-RSV vaccine, subjects 
completed a FU visit 6 months after the second vaccination.  
Safety Data 
The trial demonstrated that a 2-dose regimen of MVA-BN-RSV was well tolerated in adult and 
elderly subjects receiving either the 1×10E7 TCID50 dose or the 1×10E8 TCID50 dose of the 
vaccine, confirming observations previously made during the clinical development programs of 
the MVA-BN backbone and other recombinant MVA-BN based vaccines. No SAEs or adverse 
events of special interest (AESI) occurred and no subject discontinued the trial due to an AE. The 
incidence of solicited local or solicited systemic AEs was generally low and comparable between 
groups. No clinically significant findings were reported for physical examination assessments. 

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Immunogenicity Data 
Despite the fact that the trial was not powered for statistical analysis of the RSV-specific 
immunogenicity profile, the results suggest that MVA-BN-RSV increases humoral and cellular 
immune responses in different doses and across different age groups, including elderly adults.  
The humoral immune response was durable for at least 6 months, which is sufficient to cover a 
full RSV season. The vaccine showed a broad cellular immune response against all vaccine 
inserts as well as a humoral immune response to both RSV subtypes A and B.  
Phase 2 Dose-ranging RSV-MVA-002 Trial 
The RSV-MVA-002 was a randomized, single-blind, placebo-controlled, multicenter, dose-
ranging phase 2 trial to evaluate safety and immunogenicity of the recombinant MVA-BN-RSV 
vaccine in adult and elderly subjects 
. The primary endpoint of this trial was to 
assess the optimal dose and schedule of the MVA-BN-RSV vaccine in adult and elderly subjects 
in terms of antibody geometric mean titers (GMTs) after 1 or 2 MVA-BN-RSV vaccinations or 
placebo measured by the Plaque Reduction Neutralization Test (PRNT) against subtype A 
2 weeks after the last vaccination.  
The immune correlate for protective efficacy against RSV is currently not fully understood. 
Though neutralizing antibody titers are often used to evaluate potential protection against 
RSV-related severe disease, recent scientific evidence indicates that the immune responses 
required to protect against RSV are more complex and will likely also require  in addition to 
serum antibodies  mucosal antibodies and cell-mediated immune responses. 
Clinical efficacy was not evaluated in this dose-ranging trial and sample size was not powered to 
detect any significant differences in incidence rate of RSV-related respiratory tract disease. 
However, as the immune correlate for protective efficacy against RSV is currently not fully 
understood, cellular, humoral and mucosal immune responses induced by the MVA-BN-RSV 
vaccine were assessed. After completing the active trial phase, all subjects entered a FU phase of 
6 months to monitor long-term safety and immunogenicity. Subjects were enrolled into 
5 treatment groups (Table 7). In each treatment group, subjects were stratified by age (55 to 70 
and 70 years of age), and a minimum of 20 subjects per treatment group was required in the age 
stratum 70 years. A subgroup of each treatment group (at least 20 subjects) had additional blood 
draws for T- and memory B-cell analysis. 

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Table 7 
Treatment Groups in Phase 2 RSV-MVA-002 - Main Part 
Treatment 
Group
N 
Age [years] 
First Vaccination 
(Day 1) 
 [Inf.U/0.5 mL]  
Second Vaccination 
(Day 28) 
 [Inf.U/0.5 mL]  
Route 
1 
78 
55 
1×10E8 
placebo
IM 
2
89 
55 
1×10E8 
1×10E8 
IM 
3
80 
55 
5×10E8 
placebo
IM 
4
90 
55 
5×10E8 
5×10E8 
IM 
5
83 
55 
placebo
placebo
IM 
Total 
420 
Abbreviations: IM = intramuscular; Inf.U = infectious units; N = number of subjects per group  
Data Source: RSV-MVA-002 Clinical Study Report Ed. 3.0, dated 19 November 2018, Table 1.
One year after the last vaccination, subjects from 2 treatment groups having received 
1 vaccination with the 1×10E8 Inf.U or the 5×10E8 Inf.U dose of the MVA-BN-RSV vaccine 
(Groups 1 and 3) were selected to receive an annual booster vaccination of the same dose 
(Table 8). Those subjects were followed up for another 12 months to evaluate immune responses 
to the vaccine elicited after a yearly booster vaccination. 
Table 8 
Treatment Groups in Phase 2 RSV-MVA-002 - Booster Sub-study 
Treatment Group 
N 
N [immunogenicity 
subset] 
Age [years]
Booster 
vaccinationa
[Inf.U/0.5 mL]
Route 
1×10E8  
(Group 1) 
43 
15 
1×10E8 
IM 
5×10E8  
(Group 3) 
45 
15 
5×10E8 
IM  
Total 
88b
30 
Abbreviations: IM = intramuscular; Inf.U = infectious units; N = number of subjects per group 
a Same dose as defined in the main trial for respective Groups 1 and 3 of main trial 
b at least 40 evaluable subjects from the treatment Group 1 (receiving 1×10E8 Inf.U per dose) and Group 3 
(receiving 5×10E8 Inf.U per dose) from the main part of the trial (CTP edition 4.0, 26-Apr-2018) 
This phase 2 trial has shown that the different MVA-BN-RSV vaccine doses administered once 
or twice have an acceptable safety profile, were well tolerated, and induced a robust and broad 
humoral, cellular and mucosal immune response in older and elderly adults:  
The incidences of solicited systemic 
 years versus 
 years) were low and comparable to that seen overall and across age groups. The 
incidences of unsolicited treatment-emergent adverse events (TEAEs) were similar among 
the treatment groups. No relevant differences in hematology and serum chemistry 
parameters were registered. The data have confirmed the good safety and tolerability 
profile observed during the phase 1 trial and are in line with the favorable safety profile 

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observed throughout the clinical development program of the MVA-BN backbone and in 
clinical trials evaluating other recombinant MVA-BN based vaccines. 
A single administration of the MVA-BN-RSV vaccine is sufficient to induce a robust 
immune response against both circulating RSV subtypes (A and B), as seen in post-
vaccination increases in RSV-specific neutralizing antibodies (PRNT using subtype A and 
B) and total antibodies (RSV-specific immunoglobulin G [IgG], immunoglobulin A [IgA] 
ELISA, and RSV G protein-specific IgG ELISA [subtype A and B]). 
A single administration of the MVA-BN-RSV vaccine is sufficient to induce a robust 
mucosal immune response, as seen in post-vaccination increases in mucosal antibodies 
using an RSV-specific IgA ELISA. 
Vaccine-induced antibody responses (GMTs and response rates) remained above baseline 
levels after 30 weeks, indicating durability of humoral immune responses.  
Vaccine-induced antibody responses measured by a variety of serum assays were generally 
higher after administration of the 5×10E8 dose compared to the 1×10E8 dose, possibly 
indicating a dose-response effect.  
The MVA-BN-RSV vaccine has been shown to induce a broad, robust, and Th1-biased 
cellular immune response to all 5 inserts encoded in the vaccine, irrespective of the dose 
and administration regimen employed. 
Phase 2a Human Challenge Trial RSV-MVA-015: 
Safety, efficacy, and immunogenicity of MVA-BN-RSV against challenge with an RSV virus 
was assessed in healthy adults in the phase 2a, randomized, placebo-controlled Human Challenge 
Trial. In total, 73 subjects were vaccinated via IM injection with a single dose (0.5 mL) 
MVA-BN-RSV (nominal titer 5×10E8 Inf.U per 0.5 mL) or placebo (Table 9). Of these, 
63 subjects were then challenged 4 weeks later by intranasal delivery of the RSV-A 
Memphis 37b strain (total dose of approximately 4.5 log10 plaque forming units) (Figure 3). The 
primary endpoint was area under the viral load-time curve (AUC), measured from nasal washes 
obtained from subjects while in quarantine after the RSV-A Memphis 37b challenge. Viral load 
(VL) for the primary analysis was obtained by quantitative reverse transcriptase PCR (RT-qPCR) 
from washes collected from 2 days after challenge to discharge from quarantine. 
Table 9 
Treatment Groups in the Human Challenge Trial 
Groups
Number of 
subjects
MVA-BN-RSV vaccine 
Dose [Inf.U/0.5mL]
RSV Virus Challenge dose 
(day 14-28 after 
vaccination)
1
36
nominal titer 5×10E8
4.5 log10 plaque forming 
units 
2
36
Placebo
4.5 log10 plaque forming 
units
Total planned
N = 60 (72 vaccinated to account for dropouts)

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Figure 3 
Human Challenge Trial Design (Lambkin; 2018) 
The areas under the curve for RSV-A Memphis 37b VL as measured by qRT-PCR are presented 
in the mean VL plotted over time is illustrated in Figure 4.  
The primary endpoint of the trial was met: VL AUC of RSV-A Memphis determined by 
qRT-PCR was significantly lower for the MVA-BN-RSV group compared to the placebo group 
(p-value 0.017). The median VL AUC for the vaccine group was 0, while it was 49 for the 
placebo group. Solicited adverse events reported for 8 days starting at day of vaccination were 
comparable to results obtained in the completed phase 1 and 2 clinical studies and pooled in 
Table 3. 

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Figure 4 
 Mean Value Over Time in Viral Load of RSV-A Memphis 37b Determined by 
qRT-PCR from Nasal Washes  Per Protocol Analysis Set 
Source: TLFs (23Sep2021), Figure 15.2.1.2.2 
Abbreviations: qRT-PCR = quantitative reverse transcription polymerase chain reaction 
Therefore, the MVA-BN-RSV vaccine seems to be safe and well tolerated and immunogenic in a 
population of older subjects considered to be at higher risk of suffering seasonal RSV-related 
respiratory disease; the inserts contained within the novel MVA-BN-RSV candidate do not 
induce additional safety concerns in RSV at-risk populations. In addition, vaccine efficacy was 
demonstrated in the human challenge trial model. Further details on trial data are summarized in 
the current IB. 
2.7
Rationale 
RSV is an important cause of serious respiratory disease in all age groups especially in very 
young infants experiencing their first infection with RSV but also in the older adults and elderly 
population above 60 years of age. The completed phase 2 clinical trial RSV-MVA-002 generated 
safety and immunogenicity data of the recombinant MVA-BN-RSV vaccine in healthy adult 
subjects 
5 years of age. This trial confirmed safety and immunogenicity results from the 
phase 1 clinical trial in healthy younger and older adults (RSV-MVA-001). The vaccine had an 
acceptable safety profile, was well tolerated and able to increase RSV-specific humoral and 
cellular immune responses in the population tested. Immune responses elicited by the primary 
MVA-BN-RSV vaccination were durable for at least 6 months and could be boosted by another 

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MVA-BN-RSV vaccination after 12 months as shown in a booster sub-study of the phase 2 trial. 
One vaccination with MVA-BN-RSV vaccine was sufficient to raise an immune response 
without significant additional rise after the second dose. Additionally, immunogenicity results 
indicated that a higher dose elicits consistently higher antibody titers, which might be beneficial 
for protection of infection. Efficacy could not be assessed in either in the phase 1 or in the 
phase 2 trial due to the low sample size of the trial relative to the low incidence rate of a 
laboratory-confirmed RSV disease. However, efficacy was demonstrated in the phase 2a human 
challenge trial, which showed significant reduction in VL AUC for the MVA-BN-RSV-
vaccinated subjects compared to placebo as well as VL AUC over time, PCR-confirmed RSV 
disease and total symptom score over time in healthy adults aged 18 to 50. 
Hence this placebo-controlled, randomized, double-blind phase 3 trial is designed to assess real-
world efficacy after one injection of the MVA-BN-RSV vaccine (corresponding to the higher 
dose given in the phase 2 trial (nominal titer of 5×10E8 Inf.U)) in the target high-risk population 
of adult/elderly subjects 
 compared to placebo. 
Outbreaks of RSV are observed worldwide and follow a seasonal pattern in most parts of the 
world, with significant occurrence during winter months. Ideally, vaccination for protection 
against respiratory tract disease caused by RSV would be scheduled shortly before the start of the 
RSV season. However, sanitary measures, social distancing, and lockdown periods to control the 
spread of SARS-CoV-2 have also affected the seasonality of RSV, with outbreaks reported in 
some countries outside of the typical RSV season. Therefore, while it is intended to enroll and 
vaccinate the trial population before an RSV season and to perform the trial follow-up over the 
course of that season, because the seasonality of RSV has been disrupted by COVID-19, it is not 
certain when RSV peaks will occur. For this reason, the follow-up time for subjects is designated 
as approximately 6 months and up to 12 months, to optimize the likelihood that subjects will be 
observed during a season of peak RSV infection. 
All 20,000 subjects will be enrolled and vaccinated in the phase 3 clinical trial and followed up 
for PCR-confirmed RSV disease for at least one RSV season (up to 12 months after vaccination). 
In case the number of events is not met after 6 months after the last vaccination or at the end of 
the RSV season 1, up to 4000 further subjects will be added and followed up for at least one RSV 
season (up to 12 months after vaccination). In addition, all subjects from the initial enrollment 
will be followed up for a second year after vaccination (without any further booster vaccination) 
to address the question of durability of protection against RSV disease for more than one RSV 
season and the potential need for a yearly booster vaccination to continuously protect against 
RSV-related disease.  
2.8
Trial Population 
Any medically stable 
-year-old women and men of any ethnicity who meet all of the 
inclusion criteria and none of the exclusion criteria are eligible for participation in this trial.  

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2.9
Risk/Benefit Assessment 
2.9.1 Potential Risk 
Half of the subjects in the trial will receive placebo, and half will receive the 
MVA-BN-RSV vaccine. The placebo consists of the MVA-BN formulation buffer TBS. Placebos 
are harmless, inactive substances made to look like the real vaccine, used in the clinical trial and 
contain no active ingredient. The subject may experience discomfort at the injection site, such as 
pain. 
Preclinical data with recombinant MVA-BN-RSV vaccine in rats and rabbits have revealed no 
special hazard for humans based on conventional studies of safety.  
There is substantial safety data available for the vector backbone MVA-BN and for other 
MVA-based recombinant vaccines in healthy and immunocompromised subjects as well as the 
first safety data for the MVA-BN-RSV vaccine (phase 1 clinical trial RSV-MVA-001 in healthy 
adult subjects; phase 2 clinical trial RSV-MVA-002 in healthy 
; and phase 2a 
clinical trial RSV-MVA-015 in healthy adult subjects, see Section 2.6). Adverse reactions in this 
trial setting are expected to be comparable to adverse reactions previously reported for MVA-BN, 
MVA-BN-based recombinant vaccines, MVA-BN-RSV, and those typically seen with other 
vaccines. Main risks involve the development of local reactions at the injection site, e.g., 
erythema, pain, swelling and induration, and temporary systemic reactions such as headache, 
fatigue and myalgia. 
As with all 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 that a severe 
allergic reaction and/or dyspnea occurs, appropriate medical treatment and supervision will be 
readily available. 
Nasopharyngeal (NP) swabs are taken in case of respiratory tract disease to assess causality of 
RSV. This may cause the subject to gag and may cause irritation or dryness at the sampling sites 
for a short time, usually less than 5 minutes. 
2.9.2 Benefit 
There will be no direct benefit to the trial participants receiving placebo; however, there is a 
possibility that the MVA-BN-RSV group may derive benefit from vaccination if the vaccine is 
proven to be efficacious against RSV-related LRTI. Trial participants will contribute significantly 
to the testing of an RSV vaccine, which could potentially benefit older and elderly adults and 
adults with underlying cardiovascular or pulmonary disease by reducing their risk of severe 
illness and mortality due to infection with RSV. In addition, based on the current immunogenicity 
and efficacy data collected in non-clinical and clinical studies with MVA-BN, participants may 
acquire protection against smallpox infection as well as protection against disease symptoms 

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caused by RSV. The immunogenicity results of the phase 1 and 2 trials with the 
MVA-BN-RSV vaccine indicate that RSV-specific humoral and cellular immune responses are 
significantly boosted by the vaccine. However, it cannot be said if the vaccine is efficacious 
against the disease, as data available up to date are limited and do not allow for conclusions on 
protection against RSV. 
Subjects may also receive IRB/EC-approved stipends for time and travel, depending on the 
country regulation. 
3
Objectives 
Please refer to protocol synopsis Section 1.3.
4
Trial Design 
4.1
Experimental Design 
This is a randomized, double-blind, phase 3 trial to assess clinical efficacy, safety, and 
reactogenicity of the recombinant MVA-BN-RSV vaccine in 
 years of age. 
It is intended to enroll and vaccinate the trial population before an RSV season and to perform the 
trial follow-up over the course of that season. Twenty thousand 
years of age are planned to be enrolled and randomized to receive one administration of either 
placebo or MVA-BN-RSV vaccine. They will be stratified by age into 4 age groups as shown in 
the table below, with enrollment goals intended to ensure adequate representation of the older age 
strata. In addition to the age stratification, the trial will also aim to enroll at least 20% of the 
subjects that 
-
i.e., who have at least one comorbidity associated 
with higher risk of LRTD, including chronic cardiac diseases and chronic lung disease (asthma 
and chronic obstructive pulmonary disease [COPD]), CHF, and hypertension. 
Table 10 
Age stratification and Enrollment Target 
Age range (years) 
Enrollment target 
60 to 64 
Up to 10% 
65 to 74 
75 to 84 
Approximately 25% of the enrollment  
Approximately 5% of the enrollment 
All subjects will be monitored for lower and upper respiratory tract disease until at least the end 
of one RSV season (up to 12 months after vaccination). If subjects develop RSV-specific 
symptoms, they will be scheduled for a symptom visit (SV) at the clinical site, and a NP swab 
will be collected for RSV PCR testing.  

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All participants will be asked to complete a questionnaire on respiratory disease-related 
symptoms (RiiQ), quality of life and frailty questionnaire (Section 4.1.4) at Visit 1 and complete 
all questionnaires, except the frailty index, also at symptom onset or symptom visit and for a set 
time period afterwards.  
Additionally, serum samples will be collected for immunogenicity testing from a sub-group of 
approximately 600 subjects (300 per study arm) at pre-defined clinical sites. PBMC samples will 
also be collected from a sub-group of approximately 300 subjects (150 per study arm) at pre-
defined clinical sites. As the clinical trial is double-blind serum and PMBC samples will be 
collected from both treatment groups (MVA-BN-RSV and placebo).  
In case both the defined number of LRTD cases required for the primary analysis and the success 
criteria are met, subjects will be followed up for durability of potential protection against RSV 
disease up to 24 months after vaccination (scenario 1; Figure 5). It is estimated that 
approximately 16,000 subjects (accounting for dropouts during follow-up), will participate in this 
additional monitoring for respiratory tract disease. 
In case the defined number of LRTD cases required for the primary analysis is met but not the 
primary endpoints of efficacy, the trial will be stopped and no further follow up for durability will 
be done (Figure 5).  
In case the defined number of LRTD cases required for the primary analysis is not met after RSV 
season 1  (less than 53 cases of LRTD with 
 symptoms or less than 22 cases of LRTD with 3 
symptoms) and the futility criterion is not met per the futility analysis, additional (approximately 
4000) subjects will be enrolled (scenario 2) and vaccinated (Figure 5). These subjects will be 
monitored for respiratory tract symptoms until at least the end of 1 RSV season (for up to 
12 months after vaccination). Those already enrolled and vaccinated in season 1 will be followed 
up for durability of potential protection against RSV disease up to 24 months after vaccination.  
The trial procedures will be conducted according to the trial procedure schedule (Section 1.4) and 
as described on the following pages.  

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Figure 5  
Flowchart with 2 Scenarios and Durability 
59 

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4.1.1 Screening Visit / Visit 1 
All subjects should preferably undergo the screening and vaccination procedures in one day 
(SCR/V1 on Day 1). If a subject is screened and cannot be vaccinated because of a certain 
transient condition, then the subject can perform/repeat the respective outstanding visit tasks in 
one day within a 7-day time period in combination with the vaccination. Vaccination needs to be 
performed on Day 8 at the latest.  
If a subject cannot be vaccinated due to other circumstances (e.g., ongoing wash-out period for a 
medication or vaccine that is not allowed during the trial) or if the 7-day time period is exceeded, 
the complete screening process needs to be repeated and a new subject number will be assigned. 
All subjects must be thoroughly informed of all aspects of the trial (e.g., trial visit schedule, 
required evaluations and procedures, risks and benefits). Written informed consent must be 
obtained according to local requirements before any trial-related assessment will be carried out. 
All screening tasks will be performed according to the trial procedures outlined in Section 1.4. 
Among other visit tasks the inclusion and exclusion criteria need to be checked to assess the 
eligibility of the subjects. A complete physical examination will be performed only at screening, 
whereas a targeted physical examination will be performed at all other applicable study visits. 
If the subject belongs to one of the immunogenicity subgroups a blood draw will be taken before 
vaccination. 
An ePRO application will be installed onsite 
 or tablet (in case the 
 personal device is not compatible or they refuse to download the app, a device will be 
provisioned and the ePRO application instructions will be handed out and a thorough usage 
training given to the subjects).  
All subjects will complete the EQ-5D-5L, RiiQ, 15D and Tilburg Frailty Indicator (TFI) (part B) 
questionnaires (further details in Section 4.1.4) at the screening/vaccination visit prior 
vaccination. 
Randomized treatment assignments for the subjects will be done at this visit via interactive voice- 
or web-response system (IWRS) after confir
specified in Section 1.3. 
After the subjects are assigned to one specific treatment group, placebo or MVA-BN-RSV 
vaccine will be administered into the deltoid muscle of the upper arm (preferably the 
non-dominant arm). The 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 
rare anaphylactic reaction following the vaccination.  

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Starting after vaccination the subjects are guided on entering data into the ePRO application to 
confirm their understanding of the ePRO application entry requirements: an electronic diary 
(eDiary) must be completed on a daily basis, covering all solicited local and systemic symptoms 
in the ePRO application until Day 8 after vaccination. For symptoms which are ongoing after 
Day 8, temperature/symptom measurements should continue to be recorded in the eDiary each 
day until resolved.  
Additionally, the site instructs the subjects to start after vaccination reporting the presence of any 
symptoms potentially related to a respiratory tract disease caused by RSV into ePRO application 
immediately after onset of the symptom. Subjects will be reminded of this process 3 times per 
week by ePRO application notifications and by monthly site calls. Each reporting of symptoms 
by the subjects will trigger an ePRO application alert to the site staff, who will immediately 
contact the subjects and schedule an onsite SV within the given time frame (target 72 hours after 
onset, up to 5 days accepted). Additionally, subjects will be reminded by sites calls if the subject 
has not responded to notifications in their ePRO device for over a week. 
4.1.2 Disease Surveillance and Monthly Telephone Visits  
Enrolled and vaccinated subjects will enter the active trial phase. Disease surveillance will start 
for these subjects with ePRO reminders 3 times per week to report the presence of respiratory 
symptoms starting after the day of vaccination. The ePRO application will issue an alert to the 
site in case of a reported symptom, and the site needs to call the subject to schedule an onsite 
visit.   
Additionally, the site staff performs monthly telephone calls to subjects in order to follow up on 
the presence of any symptoms, to remind the subjects to report symptoms, or to follow up on low 
compliance with regard to eDiary entries. In case of predefined respiratory tract symptoms, 
subjects need to be called in for an onsite SV within 72 hours (up to 5 days accepted) after the 
first symptom occurred (see Section 4.1.3). Subjects are reminded to continuously report any 
symptom occurrence. 
The monthly telephone visits start after vaccination (SCR/V1 (Section 1.4 and 4.1.1)) and will 
continue until the End of Study (EOS) visit. This time period is expected to cover at least one 
RSV season (up to 12 months after vaccination). 
During the monthly telephone calls from the site, the following items also will be assessed in 
addition to the occurrence of any respiratory tract symptoms: 
the worsening of pre-existing symptoms from prior reported illness (AEs) 
any needed follow-up on solicited AEs reported via ePRO for the 8-day period (memory 
aid) beginning with the day of vaccination, until resolution, if still ongoing 
unsolicited AEs, which are to be recorded until 29 days after vaccination, and those which 
are still ongoing at Day 29 will be followed up until resolved  

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new SAEs or changes to existing SAEs will be assessed until the EOS Visit. 
The site staff will be trained for making these monthly calls based on standard scripts. If the 
subject misses any previous call visits and has not responded to the ePRO application reminder, 
occurrence of any respiratory tract symptoms during this time will be inquired by the site staff. 
Data cannot be retrospectively entered in the ePRO application, but site can document the start 
date of symptoms after a telephone call with the subject. 
4.1.3
Symptom Visit 
Subjects must return for an SV at the site in case they reported the presence of respiratory 
symptoms as defined in Section 7.3 during the monthly telephone calls or via ePRO application. 
Clinical evidence of any of the symptom(s) below must be verified and documented by a medical 
professional by performing specific exams and/or tests to assess: 
rhinorrhoea 
nasal congestion 
pharyngitis 
earache  
new cough or worsening of pre-existing cough 
new wheezing or worsening of pre-existing wheezing 
new sputum production or worsening of pre-existing sputum production 
new shortness of breath or worsening of pre-existing shortness of breath  
fever >100 °F / >37.8 °C (oral temperature) (High, 2009) 
any other sign or symptom leading to the suspicion of a respiratory disease 
Additionally, tests or exams for the below must be performed if appropriate: 
hypoxemia (oxygen saturation <92% at rest in conjunction with an at least 3% decrease 
from baseline)  
respiratory rate >25 breaths/Min  
imaging evidence of new onset of bronchitis, bronchiolitis, or pneumonia 
A NP swab must be taken for PCR testing at the central laboratory to confirm RSV disease. In 
addition, vital signs, targeted physical examination and presence, onset and/or duration of RSV-
specific symptoms will be documented.  

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During the SV at the site in addition to the occurrence of any respiratory tract symptoms also the 
following items will be assessed: 
the worsening of pre-existing symptoms from prior reported illness (AEs) 
concomitant medications if applicable (Section 1.4). 
resolution of symptoms 
any needed follow-up on solicited AEs reported via ePRO for the 8-day period beginning 
with the day of vaccination, until resolution if still ongoing 
unsolicited AEs, which are to be recorded until 29 days after vaccination and those which 
are still ongoing at Day 29 will be followed up until resolved 
new SAEs or changes to existing SAEs will be assessed until the EOS visit 
targeted physical examination assessment of vital signs. 
4.1.3.1 Imaging 
In case of suspicion of severe LRTD based on e.g. clinical status or auscultation an x-ray can be 
ordered if none of the severe LRTD specific symptoms: hypoxemia and increased respiratory rate 
(definitions in Section 1.3) are met and medical need as judged by the investigator is present 
(Figure 6). 

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Figure 6 
Flowchart LRTD (severe)  Decision Tree for X-Rays 
a A nasopharyngeal swab must be taken in case of presence of respiratory disease symptoms independent of 
LRTD or ARD determination to confirm presence or absence of RS virus. 
b maximum timeline for imaging (analog to nasopharyngeal swabbing, ideally within 72 hours of symptom 
onset, but at maximum within 5 days) 
c X-ray to be performed 
tion based on medical need 
If a subject does not return to the site for an SV and if a respiratory disease triggers a visit to the 
emergency room (ER), subjects will be provided with a kit including a NP swab and instructions 
for the ER staff on sampling, storage and how to inform the site. Nasopharyngeal swabs can be 
taken by the ER staff, sites will be informed accordingly, and transportation for storage at the site 
will be organized by the site. The procedure describing the process in detail is documented in the 
laboratory manual handed out to the site. 
All documented respiratory tract symptoms with confirmed RSV positive PCR test will be 
adjudicated to be either ARD, LRTD (three LRTD definitions) or no endpoint at all by an 
adjudication committee, further described in Section 4.5. 
Is there any suspicion for 
LRTI , based on either 
clinical status or 
auscultation?a
Yes
Are the criteria for LRTD either 
hypoxemia or increased respiratory 
rate met? (see section 7.1)a
Yes
Document as 
LRTDa
No
Order x-raya,b,c
No
Document as ARD if applicable 
(see section 7.1)a

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4.1.3.2 Home Healthcare Visits 
In case subject cannot return to the site for a symptom visit in the recommend time to assess the 
RSV-specific symptoms and to take a NP swab for confirmation of RSV-related disease, a home 
healthcare visit either by the site study team or a contracted specialized provider might be used to 
collect these assessments. 
4.1.3.3 Self-Swabbing by Subject 
Only if neither a home healthcare visit nor a visit to the site is feasible, the subject might be 
provided with a self-swabbing kit. In such as case, detailed swabbing instructions will be 
provided by the site. 
4.1.4 Electronic Patient Reported Outcome (ePRO) Application 
Besides serving as reminders for symptom visits and electronic diaries to record reactogenicity 
following vaccination, the ePRO application will also be used to collect the following patient 
reported burden of disease and health-related quality of life data. 
If the long-term follow-up time points (e.g., 12 months after symptom visit) for the EQ-5D-5L 
and the 15D questionnaire fall beyond the first 12 months of follow-up after vaccination of the 
subject, the outstanding questionnaires are to be completed during the durability phase of the 
trial, if it is conducted. 
4.1.4.1 RiiQ 
Subjects will need to complete a questionnaire on respiratory disease-related symptoms (RiiQ) at 
screening/vaccination visit. This questionnaire will also be activated via the ePRO application at 
symptom onset and for 7 days after (8 days total), or until either symptom resolution or a 
maximum of 20 days after onset of symptoms (21 days total) is reached. 
4.1.4.2 EQ-5D-5L 
An EQ-5D-5L Questionnaire will completed by all subjects at screening/vaccination visit, at the 
symptom visit if an NP swab is obtained, and on day 6 and at 1, 3, 6, and 12 months after the 
symptom visit.  
4.1.4.3 15D 
The 15-dimension health-related quality of life instrument (15D) will be filled out at 
screening/vaccination visit, at the symptom visit if an NP swab is obtained, and on day 6 and at 1, 
3, 6, and 12 months after the symptom visit.   

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4.1.4.4 Tilburg Frailty Indicator 
TFI part B only will be assessed at screening for all subjects. 
4.1.5
6-month Follow-up Visit 
The 6-month follow-up visit (per telephone) will be scheduled at 6 months after vaccination. The 
visit might coincide with the end of the first RSV season, which will be determined by the 
sponsor but informed by country-specific RSV surveillance data (e.g. US: defined by the CDC 
surveillance data, https://www.cdc.gov/surveillance/nrevss/rsv/index.htmL and RKI Robert Koch 
Institute, https://survstat.rki.de/). BN will continuously monitor regional RSV data related to 
clinical sites of the trial.   
For US, the end of season can be declared by BN at the earliest when at least 3 out of 5 regions 
have an RSV test percent positivity rate below 10% both with antigen and PCR testing. It will be 
declared at the latest when all 5 regions have RSV test percent positivity rate below 5% both with 
antigen and PCR testing.  
For Germany and UK, available surveillance data relating to the regions and/or clinical trial sites 
in the respective countries will be monitored and based on either national criteria or CDC criteria 
to determine the end of RSV season (up to 12 months after vaccination). 
At the 6-month FU visit, new SAEs and changes to SAEs/AEs ongoing at Day 29 need to be 
recorded. In case of 6-month FU visit and EOS visit are at the same day please also follow 
procedure listed under Section 4.1.6.
4.1.6 End of Study Visit 
The end of study visit (per telephone) will be scheduled at approximately 12 months after 
vaccination. Only in case the trial is terminated early (due to lack of efficacy) this visit will be 
scheduled soon after the futility analysis. 
If number of events for the primary endpoints is not met by the end of season 1, disease 
surveillance and monthly calls will continue until the sponsor notifies sites to conduct the EOS 
visits. 
At the EOS visit, new SAEs and changes to SAEs/AEs ongoing at Day 29 need to be recorded. 
Any provisioned device for ePRO application needs to be returned by the subject to the site 
directly or shipped according to instructions provided at clinical trial start if the subject is not 
proceeding to the durability part of the trial. 

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4.1.7 Immunogenicity Visit / Visit 2a/2b / Visit FU-D1 / Visit FU-D 
For the PBMC immunogenicity subgroup of 300 subjects (150 per study arm) at designated sites, 
a blood draw will be performed at the combined SCR/V1 before vaccination and one additional 
onsite blood draw 1 week after vaccination (at Day 7 to 10) (Visit 2a). 
For the serum immunogenicity subgroup of 600 subjects (300 per study arm) at designated sites, 
a blood draw will be performed at the combined SCR/V1 before vaccination and one additional 
onsite blood draw 2 weeks after vaccination (at Day 14 to 16) (Visit 2b).  
For PBMC and serum immunogenicity subgroup vaccinated before the first RSV season onsite 
blood draws will be performed approximately 1 year after vaccination at Durability Follow-up 
Visit (FU-D1) and approximately 2 years after vaccination at End of Durability Follow Up Visit 
(FU-D) (Section 1.4.2). Only subjects in the immunogenicity subgroup will therefore have an 
onsite visit FU-D for scheduled 2 year blood draw for either serum or PBMC. 
In addition, the following procedures will be done at the immunogenicity visits: 
the worsening of pre-existing symptoms from prior reported illness (AEs) 
concomitant medications if applicable (Section 1.4). 
any needed follow-up on solicited AEs reported via ePRO for the 8-day period beginning 
with the day of vaccination, until resolution if still ongoing 
unsolicited AEs, which are to be recorded until 29 days after vaccination and those which 
are still ongoing at Day 29 will be followed up until resolved 
new SAEs or changes to existing SAEs  
4.1.8 Unscheduled Visits 
Additional visits may be necessary between scheduled visits 
 (SAEs, worsening of AEs, worsening of RSV-specific 
symptoms). Examinations performed at unscheduled visits will be documented in the source 
documents as well as in the respective electronic case report form (eCRF) sections for 
unscheduled visits. Assessment of RSV-specific symptoms will be done if present at that visit. 
4.1.9 Early Discontinuation 
Reasons for early discontinuations: 
The decision to discontinue a trial subject early can be made by the investigator or by the subject. 
Reasons for early discontinuation of a subject may include but are not limited to:  

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An AE/SAE that, in the opinion of the investigator, makes it impossible or unsafe for the 
subject to continue with the trial routine or to receive the single vaccination after 
randomization 
Clinical need for concomitant or ancillary therapy not permitted in the trial as outlined in 
Section 9.2.2
Subject s unwillingness or inability to comply with trial requirements, e.g., usage of ePRO 
application, returning to the site for SVs  
Any reason that, in the opinion of the investigator, requires early discontinuation of a 
subject 
Handling of early discontinuations: 
Subjects must be informed unequivocally 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 at or relationship with the clinical site. 
If a subject discontinues early for any reason, every attempt should be made to document the 
reason for the discontinuation.  
4.1.10 Durability Follow Up (FU-D1)  During Second Year after Vaccination 
Based on the number of LRTD cases observed until end of RSV season 1 (up to 12 months after 
vaccination) and results of the futility analysis, the trial may be: 
1.
terminated if the futility criterion is met, or  
2.
additional subjects (approximately 4000) will be vaccinated if the number of LRTD cases is 
less than 53 
and the futility criterion is not met. 
Already enrolled subjects will continue to be followed-up for RSV-related diseases until up 
to 2-year post-vaccination to assess durability of protection against RSV disease. (Section
11.5.1). 
3.
if the number of LRTD cases is at least 53 
, the study 
may continue until end of RSV season 1 for the primary analysis. If the primary success 
criterion is met, subjects will continue to be followed-up during a second year post-
vaccination to assess durability. 
If the decision is made to continue the trial, subjects vaccinated in season 1 who are willing to 
participate in the durability follow-up part of the trial (starting approximately 12 months and up 
to 24 months after vaccination) will be scheduled for this visit. Approximately 1 year after 
vaccination, subjects will return to the site for a start of durability visit. The visit should coincide 
with the EOS Visit for season 1. 

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This onsite visit starts at Day 1 (approximately 12 months after vaccination); vital signs and 
symptoms will be assessed, and a targeted physical examination performed.  
Any SAEs occurring from the last SAE assessment (telephone call or onsite visit) until the start 
of the durability follow up visit will be collected retrospectively. 
During the first visit, the site personnel need to re-check the functionality of the ePRO 
application and the device or provide a new device in case the subject had returned the 
provisioned device at a prior visit. Subjects are reminded to report the presence of any respiratory 
disease-specific symptoms in ePRO application. 
If the long-term follow-up time points (e.g., 12 months after symptom visit) for the EQ-5D-5L 
and the 15D questionnaire fall beyond the 12 months of follow-up after vaccination of the 
subject, the outstanding questionnaires are to be completed during the durability phase of the 
trial, if it is conducted. 
The subjects are notified that respiratory disease symptom assessment via monthly calls is 
performed for disease surveillance and will be supported by ePRO reminders 3 times per week, 
asking for presence of respiratory symptoms.  
All ePRO application entries will be monitored remotely (and at potential onsite visits) for 
compliance and reactions. 
4.1.11 Durability 6-Month Follow-Up Visit (FU) / 18 months after vaccination (6 months 
after FU-D1) 
The Durability 6-month follow up visit (per telephone) will be scheduled approximately 
18 months after vaccination corresponding to 6 months after the durability start visit.  
4.1.12 Durability End of Trial / approximately 24 months after vaccination (12 months 
after FU-D1) 
The durability end of trial visit (per telephone) will be scheduled approximately 24 months after 
vaccination. Only for subjects participating in the immunogencity subgroup this visit will be an 
onsite visit in case a blood draw is performed (see section 4.1.7). 
At this visit new SAEs and changes to SAEs/AEs ongoing at Day 29 need to be recorded. Any 
provisioned device for ePRO application needs to be returned by the subject to the site directly or 
shipped according to instructions provided at clinical trial start.  
4.2
Emergency Unblinding 
Unblinding for adverse events should only be performed in emergencies where knowledge of the 
group 

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group assignment under any other circumstances will be considered a 
protocol violation. In case of an emergency, the Principal Investigator (PI) has the sole 
warranted. Participant safety must always be the first consideration in making such a 
determination. The investigator must also immediately notify the Sponsor and the Medical 
Monitor that the code has been broken. If possible, the Sponsor should be consulted before the 
code is broken, but this will only occur if the safety of the participant will not be compromised. 
Although the Medical Monitor should be contacted, 
communicated to the Medical Monitor. Emergency unblinding for adverse events will be 
performed through an IXRS. All calls resulting in an unblinding event are recorded and reported 
by the IXRS. Emergency unblinding must also be appropriately documented at the trial site. The 
Medical Monitor will receive notification of unblinding from IXRS but will not be notified of the 
As emergency unblinding is performed via electronic systems (IXRS) unblinding of treatment 
will be provided. The detailed process for emergency unblinding will be described in a trial-
specific procedure. 
Subjects who become unblinded for any reason during their participation in the trial will not be 
replaced and will be withdrawn from the trial. 
BN Clinical Safety and Pharmacovigilance (CSPV) and Pharmacovigilance (PV) Vendor will 
have appointed designee(s) that may receive the unblinded data should a subject be unblinded 
due to safety concern / SAE (i.e., when regulatory reporting is required). This will be described in 
the Safety Management Plan. 
4.3
Trial Duration 
The overall duration of the trial is approximately 24 months. For the potential additional subjects 
that will be enrolled in RSV season 2 the trial duration would only be approximately 12 months. 
RSV season 1  approximately 6 months (starting from screening of first subject of RSV season 1 
to the end of this RSV season (up to 12 months)). 
RSV season 2 (if applicable)  approximately 6 months (starting from screening of first subject 
enrolled in season 2 to the end of this RSV season (up to 12 months)). 
Durability follow up  starting approximately 12 months after vaccination for subjects enrolled in 
season 1 until up to 24 months after vaccination. 
4.4
Data Monitoring Committee 
The data monitoring committee (DMC) is an independent board that will oversee the safety of 
subjects participating in the trial, evaluate the efficacy data, and make the recommendation to 

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either discontinue or continue to RSV season 2 based on pre-specified decision rules if the 
number of LRTD events is less than 53 
at the end of season 
1. The members of the DMC are independent, i.e., are not involved as investigators in any 
MVA-BN-RSV trials and have no direct or indirect financial interests in BN or the Contract 
Research Organization (CRO) managing the trial. The primary responsibilities of the DMC are to 
periodically review and evaluate the accumulated trial data for participant safety, efficacy of the 
vaccine, trial conduct and progress, and to make recommendations to BN, the Coordinating 
Investigator, and PIs concerning the continuation, modification, or termination of the trial 
program. The DMC considers trial-specific data as well as relevant background knowledge about 
the disease, test agent, and subject population under study.  
If an event occurs which fulfills the trial halting rules, the DMC will review the event in a timely 
manner and give a recommendation to BN, the Coordinating Investigator, and PIs to halt, resume, 
or terminate the trial participation of the affected subject and/or the trial as a whole. 
A separate charter describes in detail relevant operational procedures, communication pathways, 
roles, and responsibilities of the DMC. 
4.5
Adjudication Committee 
The adjudication committee is an independent board that oversees the adjudication of ARD and 
LRTD for cases of confirmed RSV infection for primary and key secondary efficacy endpoints. 
The committee will consist of 3 members including a medical expert in infectious diseases or 
pulmonologist, a radiologist, and an internal medicine physician who are blinded to the trial 
treatment subjects received. One of them will act as a chairperson with responsibilities described 
in a charter. 
The adjudication committee will receive on an ongoing basis case packages of all diagnosed 
ARD and LRTD with confirmed RSV infection. Case packages will at a minimum include PCR 
test results, respiratory tract symptom documentation, and x-ray (if present). The radiologist of 
the adjudication committee will always rate the x-rays and check for confirmation of LRTD 
diagnosis. The adjudication committee will review all case packages in a timely manner and 
adjudicate whether cases are ARD or/and LRTD 
oms, 2 symptoms or/and severe 
LRTD). Details of the procedures, responsibilities and timelines will be specified in Section 7.4
and in an adjudication manual.  
4.6
Trial Halting Rules 
At the end of season 1, if the number of LRTD cases observed is less than 53 
 (the minimum number of cases for the primary analysis), a futility analysis 
will be performed. Based on the results of the futility analysis recruitment and durability 
surveillance during a second year after vaccination may move forward or be terminated. If the 
number of LRTD cases observed is at least 53 
, durability 

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surveillance for RSV during the second year after vaccination depends on results of the primary 
analysis at the end of season 1. Details and decision rules are described in Section 11.8.
A temporary halting or termination for the trial may also be decided by the DMC in case of an 
occurrence of:  
A vaccine-related SAE; or  
An unexpected (i.e., not listed in the current IB) grade 3 or higher systemic reaction or lab 
toxicity as defined in Appendix 1. 
These parameters are not all-inclusive. Other AEs could occur that would trigger a DMC review.  
If an event that meets the trial 
is required to alert the responsible PV Department immediately (within 24 hours) and provide a 
comprehensive documentation of the event. Contact details of the responsible PV Department are 
provided in Section 9.3.1. 
5
Selection of Subjects 
Each investigator will keep a log of subjects screened for the trial and provide the reason for 
exclusion. Information about every subject entering the trial will be documented in the eCRF. 
For subjects not fulfilling the eligibility criteria, the minimum information documented in the 
eCRF is confirmation of informed consent form (ICF) signature, demographics, eligibility 
criteria, adverse and serious adverse events, and reason for screen failure (Section 12.2). 
Subjects who participate in the trial during RSV season 1 will be encouraged by the site to 
continue with the trial during a second year after vaccination. They will be called by the site 4 to 
6 weeks prior the start of the durability portion of the trial. Subjects  agreement or 
discontinuation will be entered into the eCRF. 
5.1
Recruitment Procedure 
Subjects will be recruited actively. Recruitment strategies, including IRB-approved 
advertisements, will be evaluated by the Sponsor. Subjects identified as potential participants in 
the trial will be provided with all necessary information required to make an informed decision 
about their participation in the trial. 
5.2
Inclusion Criteria 
Please refer to Protocol Synopsis Section 1.3.

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5.3
Exclusion Criteria
Please refer to Protocol Synopsis Section 1.3.
6
Investigational Medicinal Product
MVA-mBN294B (common name MVA-BN-RSV vaccine) is a highly attenuated, live 
recombinant virus based on the viral vector MVA-BN. It is supplied in single use vials at a dose 
level of nominal titer of at least 3×10E8 Inf.U (0.5 mL volume) if used undiluted, provided as a 
LF formulation. It is administered as an intramuscular injection.
The actual titer upon vaccination will be reported in the clinical study report (CSR) based on 
results from the ongoing stability studies. For further details on MVA-BN-RSV vaccine, see the
current version of the IB.
Placebo consists of TBS. TBS will be provided in liquid aliquots of 0.5 mL. One dose of 0.5 mL
placebo contains 0.605 mg trometamol (tris-hydroxymethyl-amino methane) and 4.09 mg sodium 
chloride. It is administered as an intramuscular injection.
6.1
Production, Packaging and Labeling
MVA-BN-RSV bulk drug substance and TBS are manufactured by Bavarian Nordic A/S, DK. 
The packages and vials of liquid frozen MVA-BN-RSV vaccine and placebo are labeled taking
into consideration the regulatory requirements for the respective countries.
6.2
Shipment, Storage and Handling
MVA-BN-RSV vaccine and placebo are packed separately in an open-labeled manner and will be 
shipped under temperature control and monitoring to the warehouse and from the warehouse to 
the CTSs. At the CTS, the package is handed over to the unblinded personnel in charge of 
vaccine preparation, e.g., the pharmacist. At the CTS, the unblinded personnel are the only 
individuals with knowledge as to which vaccine formulation subjects receive. They are not 
allowed to disclose this information. Upon receipt the unblinded CTS personnel are responsible 
for proper storage of vaccine and placebo.
MVA-BN-RSV vaccine is shipped and stored at -4°F ± 9°F (-20°C ± 5°C) avoiding direct light. 
A vial must not be re-frozen once it has been thawed. Details on shipment, storage and handling 

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of the LF formulation of MVA-BN-RSV vaccine are provided in trial-specific shipment/storage 
and vaccination instruction.  
Placebo must be shipped and stored at 36°F to 46°F (+2°C to +8°C).
6.3
Preparation, Administration and Dosage 
The preparation of the vaccine will be performed by authorized, unblinded personnel only. The 
unblinded personnel must not be involved in the trial treatment and/or the evaluation of the trial 
subjects. The administration of the vaccine will be performed by authorized, blinded personnel 
only. 
Trial-specific vaccination instructions detailing the preparation and application procedure will be 
provided to the CTS. 
6.4
Accountability and Disposal 
After receipt of the investigational medicinal product (IMP), the unblinded personnel have the 
ultimate responsibility for distribution, proper storage, and drug accountability. Records of 
receipt, inventory, use by each subject, return or disposal, and temperature control must be 
maintained with access limited to the unblinded personnel in the unblinded pharmacy file. 
Used and unused vials should be stored in a safe place and remain the property of BN. The 
unblinded personnel of the respective CTS are responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP 
(quantity and condition) and IMP accountability using an IMP inventory log. The IMP inventory 
log will document quantity of IMP received, quantity of IMP used for vaccination (including lot 
number, date dispensed, subject identification number, and initials of the person dispensing the 
IMP) and quantity of IMP returned to BN or destroyed. An unblinded clinical research associate 
(CRA) will review the vaccine management process, temperature logs, and accountability. 
Additionally, the quantity of IMP returned to BN or destroyed must be documented on an IMP 
return/destruction form. If destruction at the CTS is agreed upon, material should be autoclaved 
or incinerated and discarded according to local regulations. 
Hazardous materials such as used syringes and needles with hazardous content should be 
discarded immediately in a safe manner, e.g., autoclaved or incinerated and discarded at the CTS 
according to local regulations and will therefore not be retained for accountability purpose.   
6.5
Randomization and Blinding 
This is a double-blind clinical trial with blinding and unblinding procedures governed by a study 
specific manual. A third party is responsible for creating and maintaining the randomization 

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schedule, as well as implementing the randomization system. Details will be described in a trial-
specific charter. 
Subjects will be randomized in a 1:1 ratio to either the MVA-BN-RSV group or the placebo 
group stratified by age group (60 to 64, 65 to 74, 75 to 84
after 
Since MVA-BN-RSV vaccine and placebo are packed in an open-labeled manner, dedicated team 
members at the CRO and the sponsor will form an unblinded trial team to oversee all aspects of 
handling, preparation and accountability of IMP. At the CTS, the unblinded personnel are the 
only individuals with knowledge related to which substance subjects receive. The unblinded CTS 
personnel will be in charge of IMP handling, preparation and accountability at the site. Syringes 
will be labeled in a way that subjects cannot see the content.  
Unblinded team members are not allowed to disclose this information. Communication between 
the unblinded and blinded team members will be outlined in a trial-specific procedure. 
When at least 53 
LRTD events have been observed at the 
end of RSV season 1, the biostatistics (including statistical programming) team at the statistical 
service provider will be unblinded and the primary analyses will be performed. The operational 
team, including data management, clinical operations, and at least one statistician who will 
support the operational team will remain blinded until the decision concerning follow-up for 
durability during a second year after vaccination is made. 
If the success criterion for the primary endpoints is met at the end of RSV season 1, the trial will 
continue to follow-up of subjects for durability of protection. The operational team, including 
data management and clinical operations will remain blinded on subject-level randomization or 
vaccination information until the end of RSV season 2 and the clinical database is locked. A 
blinded statistician will be assigned to continue to support the operational team during the period 
of follow-up for durability. However, no major protocol amendment that may affect the primary 
and secondary efficacy endpoints will be allowed.  
If the success criterion for the primary endpoints is not met at the end of season 1, the trial will be 
terminated. 
If the number of LRTD events from season 1 did not meet the sample size requirement for the 
primary endpoints, a futility analysis will be performed by an independent vendor. If the futility 
criterion is not met as determined by the DMC, the trial will continue and enroll/vaccinate further 
subjects. No one will be unblinded. 
The clinical database will be locked after proper data cleaning and the entire clinical trial team 
will be unblinded after the decision to terminate the trial is made.

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7
Assessment of Efficacy 
7.1
Signs and Symptoms of Respiratory Tract Disease 
The presence of signs and symptoms for respiratory illness will be collected via an eDiary 
starting the day after vaccination to end of at least 1 RSV season (i.e., up to 12 months after 
vaccination), details in Section 4.1.2
Lower Respiratory Tract Disease (LRTD; 
)  
RSV-associated LRTD is defined by the presence of clinical evidence of at least 1 sign or 
symptom of ARD (see below) and at least 3 (or 2) of the following signs or symptoms with onset 
 days following vaccination, confirmed and documented by a medical professional, and RSV 
infection confirmed by PCR analysis of NP swab collected within 5 days (preferably 72 hours) of 
symptom onset. 
hypoxemia (oxygen saturation <92% at rest in conjunction with an at least 3% decrease 
from baseline)  
respiratory rate >25 breaths/Min (High, 2009) 
imaging evidence of new onset of bronchitis, bronchiolitis, or pneumonia 
new cough or worsening of pre-existing cough 
new wheezing or worsening of pre-existing wheezing 
new sputum production or worsening of pre-existing sputum production 
new shortness of breath or worsening of pre-existing shortness of breath  
Lower Respiratory Tract Disease (severe LRTD)  
RSV-associated LRTD is defined by the presence of clinical evidence of at least 1 sign or 
symptom of ARD (see below) and at least 1 of the following signs or symptoms with onset 
 days following vaccination, confirmed and documented by a medical professional, and RSV 
infection confirmed by PCR analysis of NP swab collected within 5 days (preferably 72 hours) of 
symptom onset. 
hypoxemia (oxygen saturation <92% at rest in conjunction with an at least 3% decrease 
from baseline)  
respiratory rate >25 breaths/Min (High, 2009) 
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Acute Respiratory Disease (ARD) 
RSV-associated ARD is defined by the presence of either 1 ARD symptom lasting for at least 
24 hours or 2 simultaneously occurring ARD symptoms (irrespective of duration), with onset 
starting 14 days following vaccination, with RSV infection confirmed. NP sample collection for 
PCR and targeted physical exam must be completed amongst other procedures within 5 days 
(preferably 72 hours) of symptom onset.  
rhinorrhea 
nasal congestion 
pharyngitis 
earache  
new cough or worsening of pre-existing cough 
new wheezing or worsening of pre-existing wheezing 
new sputum production or worsening of pre-existing sputum production 
new shortness of breath or worsening of pre-existing shortness of breath  
fever >100°F / >37.8°C (oral temperature) (High, 2009) 
7.2
Respiratory Pathogen Panel 
Whether ARD or LRTD is associated with RSV or not is assessed via respiratory viral panel 
(RVP) testing. Samples for the RVP need to be collected preferably within 72 hours but no later 
than 5 days of symptom onset.  
In case of any symptoms indicating a respiratory tract disease (Section 1.3) following vaccination 
to end of RSV season, the subject needs to return to the CTS and a NP swab will be obtained at 
the onsite SV to assess if a current RSV disease is underlying. This determination will be done in 
the central laboratory by running an RVP differentiating also between RSV subtype A and B in 
addition to several other pathogens (to account for e.g. multiple infections) utilizing a technology 
which will be specified in the laboratory manual. Subjects need to be instructed to return to the 
site preferably within 72 hours but not later than 5 days after start of symptoms. The results of the 
RVP will not be available to the site for immediate treatment decisions. If needed in the context 
of further subject treatment, the site is encouraged to additionally perform a locally available test.  
7.3
RSV-specific Symptoms and Complications 
RSV-specific symptoms are defined by any case of rhinorrhea, nasal congestion, pharyngitis, 
cough (or worsening of), earache, wheezing (or increase in baseline wheezing), sputum 
production (or increase / change in nature of baseline sputum production), new (or worsening of) 
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the PCR testing (Section 7.1) from nasopharyngeal swabs collected preferably within 72 hours 
but no later than 5 days of symptom(s) onset. The presence of RSV-specific symptoms are 
collected during the symptom visit starting after vaccination until up to 12 months later 
(Section 4.1.2).   
RSV-specific complications include presence of acute clinical consequences of RSV infection, 
such as pneumonia (incl. bacterial superinfection), sepsis, positive blood culture, and 
pneumothorax as well as longer term consequences of RSV-specific symptoms, such as persistent 
worsening of chronic conditions (e.g. COPD), new onset of persistent medical conditions (e.g. 
chronically impaired lung function, asthma) or a worsening of the functional status of the patient, 
e.g. new onset of nursing or assisted living need. 
7.4
Adjudication Committee for Efficacy Endpoints 
The adjudication committee (refer to Section 4.5) will adjudicate all cases of RSV laboratory-
confirmed respiratory tract disease and rate if criteria  for the primary endpoints LRTD with 
3 symptoms, primary endpoint LRTD with 2 symptoms, the secondary endpoints severe 
LRTD  and ARD  are met (Figure 7). The committee will work continuously during the whole 
trial. Processes, responsibilities, set up of the committee and decision making are described in the 
adjudication committee charter. Based on described decision rules, the adjudication committee 
will decide whether criteria for primary or secondary efficacy endpoints are met. The 
adjudication committee will receive blinded information only as specified in the charter. Any 
deviation from the charter will be documented and corrective actions will be established. The 
radiologist in the adjudication committee will perform an independent read out of the available 
x-rays obtained for suspected LRTD cases. 
The adjudication committee will receive only those cases with confirmed positive RSV PCR. 

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Figure 7:
Flowchart LRTD/ARD
Process Adjudication Committee
The adjudication committee should review all cases with positive RSV panel to ensure alignment 
on symptom assessment and discuss all ARD and LRTD ( 3 or 2 symptoms or severe LRTD)
cases with positive RSV PCR. The committee will consist of three members: an infectious 
disease expert, an internal medicine physician, and a radiologist.
8
Immunogenicity Assessment
8.1
Systemic Humoral Immune Responses
Serum samples will be collected from a subset of subjects as outlined in the trial procedure 
schedule in Section 1.4. Samples for immunogenicity testing will be obtained at the vaccination 
visit prior to vaccination and approximately 2 weeks after vaccination (Day 14 to 16). Additional 
samples will be taken from the same subgroup approximately 1 and 2 years after vaccination 
(Section1.4.2).
RSV-specific (e.g. by IgG/IgA ELISA or PRNT assays) and vaccinia-specific antibody responses 
will be assessed in vaccinated subjects. Serum assays will be performed at Bavarian Nordic 
.
The procedures for collection, preparation, storage and shipment of serum samples are specified 
in separate Study Specific Instructions, which will be provided to the investigators / clinical trial 
site personnel as well as to the processing laboratories before recruitment commences. 
Yes
No
Package compiled by CRO and distributed to the 
adjudication committee members
RSV confirmed by PCR
Feedback to investigator,
document event 
ARD and/or LRTD confirmed

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Additionally, the personnel will be trained on the procedures during the investigator meeting / 
site initiation visit for the sites participating in the immunogenicity sampling.
8.2
Cellular Immune Responses
PBMC samples will be collected from a subset of subjects as outlined in the trial procedure 
schedule in Section 1.4. Samples for immunogenicity testing will be obtained on the vaccination 
visit prior to vaccination and approximately 1 week after vaccination (Day 7 to 10). Additional 
samples will be taken from the same subgroup approximately 1 and 2 years after vaccination 
Section (1.4.2).
RSV-specific cellular immune responses will be assessed in vaccinated subjects. PBMC assays 
will be performed at Bavarian Nordic 
 
The procedures for collection, preparation, storage and shipment of PBMC samples are specified 
in separate Study Specific Instructions, which will be provided to the investigators / clinical trial 
site personnel as well as to the processing laboratories before recruitment commences. 
Additionally, the personnel will be trained on the procedures during the investigator meeting / 
site initiation visit for the sites participating in the immunogenicity sampling.
8.3
Future Use of Lab Specimen
Serum samples will be stored for future testing as described above in Section 8.1 and for 
supporting the licensure path of MVA-BN-RSV vaccine and other recombinant MVA-BN 
vaccines. Future testing will facilitate the bridging of trial results to animal immunogenicity 
results and/or to immune response data collected from subjects vaccinated with competitor 
vaccines. Further, remaining samples might be used for assay development and controls. Subjects 
will be asked to consent to storage / future use of samples and will be informed about data 
storage facility in a coded, pseudonymized manner to ensure data protection. Genetic testing will 
not be performed.

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9
Safety and Reactogenicity 
Safety will be monitored by collection of medical history including onset of new chronic disease 
and by performing physical examinations including vital signs when appropriate. Reactogenicity 
for local and systemic solicited AEs will be collected for 8 days post vaccination via an eDiary as 
application on ePRO. Ongoing symptoms after day 8 will be collected until resolution.  
9.1
Definitions 
9.1.1 Medical History 
Symptoms and conditions present before or at SCR/V1 will be documented in the medical 
history. 
9.1.2 Adverse Events 
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 medicinal product (MP) 
which does not necessarily have a causal relationship with this IMP/MP. Any new signs, 
records and the AE section of the eCRF (data collection requirements for screen failures see 
Section 12.2). AEs are recorded based on unsolicited and solicited questioning (Section 9.1.2.1
and 9.1.2.2). 
9.1.2.1 Unsolicited AEs 
Unsolicited AEs are defined as AEs which are not pre-listed on the eDiary/memory aid. 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. 
The investigator should ask the subjects if they have experienced any AEs or visited a medical 
care provider 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. 
Any adverse events starting during the screening phase, i.e., after informed consent is given but 
before the first vaccination, are considered as pre-treatment adverse events. 
9.1.2.2 Solicited AEs 
In this clinical trial protocol solicited AEs are defined as all local and systemic symptoms 
specifically listed in the eDiary/memory aid provided to the subjects following the vaccination. 
After 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 systemic 

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symptoms (i.e., body temperature, headache, chills, myalgia, nausea and fatigue) in the 
eDiary/memory aid daily for the day of vaccination and the following 7 days (Days 1 to 8, 8-day 
period) or until resolution if still ongoing at Day 8. 
9.1.2.3 SAEs 
An SAE is any untoward medical occurrence that: 
Results in death 
Is life-threatening 
-
rs 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 
Is an otherwise important medical event, e.g., leads to suspicion of transmission of an 
infectious agent. 
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. 
9.2
Assessments 
9.2.1 Relevant Medical History 
Relevant medical history will be documented at screening and will focus particularly on any 
important diseases, chronic conditions 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 and to any recent exacerbations or therapy changes to 
any chronic disease. 

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9.2.2 Prior and Concomitant Medication 
All concomitant (ongoing) medication except homeopathic substances and dietary supplements 
must be recorded in 
 record and in the eCRF including information about the 
indication, dosage regimen, and the onset and end of treatment. 
The following medications, taken within three months prior to screening, will also be recorded in 
the eCRF and the subject s medical record: vaccines (e.g. Influenza/Pneumococcal), 
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 screening.  
Exclusionary medications or medication use where washout periods need to be adhered to are 
(see also eligibility criteria in Section 1.3):
Vaccinations or planned vaccinations with a licensed live or vector-based vaccine within 30 
days prior to or after trial vaccine administration or with a licensed inactivated or RNA-
based vaccine within 14 days prior to or after trial vaccine administration.  
Chronic systemic use (defined as more than 14 days) of >10 mg prednisone (or equivalent) 
per day or any other systemic use of immune-modifying drugs. during a period starting 
from 3 months prior to first administration of the trial vaccine and ending at the EOS. The 
use of topical, inhaled, ophthalmic and nasal glucocorticoids will be permitted. 
Administration or planned administration of immunoglobulins and/or any blood products 
during a period starting from 3 months prior to first administration of the trial vaccine and 
ending at the last visit of the EOS. 
Uncontrolled anticoagulant treatment. Anticoagulant treatment under adequate control for 
cardiovascular prophylaxis or prophylaxis of thromboembolic disease or stroke in the 
setting of atrial fibrillation are not excluded. 
Use of any investigational or non-registered drug or vaccine other than the trial vaccine 
within 30 days preceding the administration of the trial vaccine, or planned administration 
of such a drug between enrollment in the trial and until the end of the clinical trial including 
follow-up. 
Prior or planned vaccination with an RSV vaccine/vaccine candidate. 
9.2.3 Physical Examination 
Complete physical examination  
A complete physical examination will be performed at screening (including body height and 
weight, body mass index (BMI) assessment). Complete or targeted physical exams may be 
performed at visits other than those indicated based on i

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Any clinically significant findings at the baseline physical examination will be recorded as 
medical history events, and any new or worsening of clinically significant findings post-treatment 
will be captured as adverse events. The only data captured in the eCRF for the physical 
examination itself will be the date it was 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 SV. Any new 
or worsening of clinically significant findings from the treatment period physical examinations 
will be recorded as AEs. 
9.2.4 Vital Signs 
At all visits, saturation of peripheral oxygen, respiratory rate, blood pressure and pulse rate will 
be taken after the subject has been sitting upright for approximately 2 minutes. Body temperature 
will be measured orally. 
9.2.5 Unsolicited AEs 
All intercurrent diseases reported when the investigator actively questions the subject will be 
documented and all required details (e.g., start and stop date, intensity) will be assessed. 
Unsolic
 and respective AE eCRF 
(requirements for screen failures see Section 12.2). 
Unsolicited AEs will be assessed and documented from ICF signature to end of active trial phase 
corresponding to 29 days post vaccination and if ongoing, followed until resolution or until the 
subject s last trial visit.  
SAEs and new AEs related to potential RSV respiratory disease (as defined in the ARD/LRTD 
definitions) will be assessed and documented at all trial visits until EOS. 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 (Appendix 1), 
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 corrective therapy. 
Grade 4 
Grade 5  
Life-threatening, causing hospitalization, or disabling. 
Fatal 
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 
suggest a causal relationship. Following worst case scenario all AEs without a causality 
None 
The time interval between 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. 
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. 

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Probable 
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) 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. 
9.2.6 Solicited AEs 
After the vaccination, subjects receive an eDiary/memory aid to record solicited local and 
systemic AEs most likely to occur on the day of vaccination and the following 7 days (Days 1 to 
8; 8-day period). Local and systemic symptoms still ongoing after Day 8 will be measured or 
examined each day until resolution or until no further change can reasonably be expected and will 
be documented in the eDiary/memory aid. 
To standardize procedures, uniform rulers will be handed out to subjects for measurements of 
erythema, swelling and induration diameters, as will digital thermometers for oral measurements 
of body temperature. 
The investigator will discuss this information during the following scheduled visits and will 
perform an assessment of the events including causality (for solicited systemic AEs), seriousness, 
outcome, and any intervention required.  
In case of severe and unexpected local and/or systemic reactions, the subject should be instructed 
to contact the trial physician outside of scheduled trial visits. 

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9.2.6.1 Solicited Local AEs  
The solicited local symptoms erythema, swelling, induration, pruritus and pain at the injection 
site are to be documented in the eDiary/memory aid by the subjects. 
Assessment of Intensity 
Injection site erythema, swelling, and induration will be assessed based on the longest diameter 
as measured by the subject in mm and recorded in the memory aid. Subjects are asked to 
document the solicited local AEs in the memory aid as described in Table 11 below. 
Table 11 
Grading of Local 
Grading for 
Analysis  
Grading in Former Version of the 
Protocol   
MedDRA coded 
Preferred Term 
Local Adverse Events 
Grade
Severity Measurea
Severity Measure 
Injection site erythema, 
Injection site swelling, 
and Injection site 
indurationb (longest 
diameter measured in 
mm)
0 
<25 mm 
0 mm 
1 
25 mm - <50 mm 
<30 mm
2
50  <100 mm 
 <100 mm
3 
 mm 
 mm
Injection site pruritis 
0 
Same as assessed at 
diary review 
Absent
1 
Mild
2 
Moderate
3 
Severe
Injection site pain 
0
Same as assessed at 
diary review 
Absent 
1 
Painful on touch 
2 
Painful when limb is moved 
3 
Spontaneously painful/prevents normal 
activity 
a  Per FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in preventive Vaccine Clinical Trials (September 2007). Available at 
https://www.fda.gov/media/73679/download 
b  Per FDA Guidance injection site swelling and induration are combined (ie. injection site swelling/induration). 
Assessment of Causality  
Solicited local AEs are defined as being related to the vaccine. 

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9.2.6.2 Solicited Systemic AEs 
The solicited systemic symptoms body temperature, headache, myalgia, nausea, chills and fatigue 
are to be documented in the memory aid by the subjects.  
Assessment of Intensity  
Subjects are asked to document the solicited systemic AEs in the memory aid as described in 
Table 12 
described in basic, easily understood language based on the following descriptions: 
Table 12 
Grading of Systemic 
Grading for Analysis 
Grading in Former Version 
of the Protocol  
MedDRA coded 
Preferred Term 
Systemic AEs 
Grade 
Severity Measure a
Severity Measure 
Body temperature 
(oral) b
0 
<100.4°F (<38.0°C) 
<99.5°F (<37.5°C)
1 
100.4°F  101.1°F
(38.0°C  38.4°C) 
<100.4°F 
<38.0°C)
2 
101.2°F  102.0°F
(38.5°C  38.9°C) 
<102.2°F 
<39.0°C)
3 
102.1°F  104°F
(39.0°C  40°C) 
<104.0°F 
<40.0°C)
4 
>104°F (>40°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 
a
Per FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in preventive Vaccine Clinical Trials (September 2007). Available at 
https://www.fda.gov/media/73679/download
b Pyrexia is defined as oral temperature 100.4°F ( 38.0°C), which is fever Grade 1 by FDA grading and oral 
temperature Grade 2 as originally collected 
Assessment of Causality  
Causal relationship between solicited systemic AEs and the vaccine will be assessed by the 
investigator using the same categories as for unsolicited AEs (see Section 9.2.5). 

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9.2.7 Laboratory Measurements 
Laboratory measurements will be performed if clinically indicated in the investigator s opinion 
e.g. in the course of an SAE. In this case CTS local laboratory will be used. 
9.2.8 Pregnancy 
It is unlikely that female subjects will be of childbearing potential, given the age criteria for the 
trial. However, as per inclusion criteria, any women of childbearing potential must have a 
negative urine pregnancy test performed within 24 hours prior to the vaccination. In addition, 
they must have used an acceptable method of contraception for 30 days prior to the 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 vaccination. Nevertheless, IMP-exposed 
pregnancies (participating females and female partners of participating males) cannot be excluded 
with certainty. Subjects who become pregnant during the active trial period (up to and including 
one month [minimum 28 days] after receiving the vaccination) may continue other trial 
procedures at the discretion of the investigator. All cases where the embryo or fetus may have 
been exposed to the vaccine should be followed-up until delivery in order to collect information 
on the outcome of the pregnancy. 
A woman is considered of childbearing potential unless post-
without a menstrual period) or permanently sterile (i.e., is at least 6 months post-surgical 
sterilization via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation). Acceptable 
contraception methods are restricted to abstinence, barrier contraceptives, IUD, IUS, and licensed 
hormonal products. 
Subjects should be instructed to notify the investigator if it is determined  also after completion 
of the trial  that they became pregnant either during the trial or within one month (minimum 
28 days) after receiving the last vaccine dose. 
9.3
Reporting 
9.3.1 Reporting of SAEs 
All SAEs (collection starts at signing of ICF) occurring throughout the entire course of the trial 
have to be entered in the eCRF within 24 hours of awareness by the investigators, which triggers 
a notification to the Drug Safety (DS) Department of the contract research organization (CRO).  
In case the eCRF is unavailable, a manual paper SAE report form is to be completed and sent via 
email to the DS Department of the CRO within 24 hours of becoming aware of the SAE. The 
SAE must still be reported in the electronic data capture (EDC) eCRF as soon as it is 
availableCRO:  

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The investigator should not delay reporting because of missing information. Nonetheless, the 
report should be as complete as possible. This initial notification should include, as a minimum, 
sufficient information to permit identification of the following: 
the subject
involved IMP
(S)AE(s)
seriousness criterion 
date of onset
BN is responsible for expedited as well as periodic reporting to the involved regulatory 
authorities (e.g., Food and Drug Administration (FDA)) according to applicable laws and 
guidelines. Regulatory authorities will be notified as soon as possible but no later than 7 days 
after first knowledge of a fatal or life-threatening unexpected SAE with an at least possible 
relationship to the IMP (Suspected Unexpected Serious Adverse Reaction (SUSAR)) and no later 
than 15 days after knowledge of any other SUSAR. The investigator is responsible for reporting 
to the Ethics Committees or IRBs.
9.3.2 Reporting of Pregnancies
All reports where the embryo or fetus may have been exposed to the trial product (either through 
maternal exposure or transmission of trial product via semen following paternal exposure) should 
be followed-up until delivery in order to collect information on the outcome of the pregnancy.
If a female subject or female partner of a male subject becomes pregnant during the active trial 
phase (up to and including 1 month [minimum 28 days] after receiving the trial vaccination), the
positive pregnancy test result must be recorded on the Pregnancy Test eCRF and also reported on 
the manual paper Pregnancy Report Form, within 24 hours of the investigator becoming aware of 
the pregnancy, and forwarded to 
The female partner of a male study 
participant should sign the Pregnant Partner Informed Consent Form for follow up.
A pregnancy will be followed to its outcome to include any premature terminations. The 
investigator should collect details pertaining to the pregnancy outcome to include, but not limited 
to the health status of the mother and

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weight, etc. Within 24 hours of awareness of the pregnancy outcome, the pregnancy outcome 
should be reported on the manual Pregnancy Outcome Follow-up Form and forwarded to 
Any event during pregnancy fulfilling the criteria for an SAE will be reported as an SAE 
(Section 9.3.1). However, hospitalization for delivery is a prospectively planned hospitalization 
and is not considered an SAE per se.
10 Burden of Disease Assessments
10.1 Respiratory Intensity and Impact Questionnaire (RiiQ)
RiiQ is a respiratory illness specific questionnaire (Falsey, 2021) covering 3 domains: upper 
respiratory (nasal congestion, sore throat), lower respiratory (coughing, wheezing, shortness of 
breath, and sputum), and systematic symptoms (headache, fever, neck pain, body aches, fatigue, 
sleep problems, and appetite loss). The symptoms in each domain are measured at 4 levels of 
severity
the mean of the symptom scores gives the domain scores, the mean of the domain 
scores gives the total score.
The RiiQ will be completed at Screening and symptom onset and for 7 days after (8 days total). If 
symptoms continue and RSV PCR test is confirmed positive, the RiiQ will continue to be filled 
out until symptoms resolve or 21 days are completed, whichever comes first. Further details are 
summarized in a study specific instruction.
10.2 EuroQoL 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
The EQ-5D-5L questionnaire is a generic preference-based measure of health covering 
5-dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) 
measured at 5 levels of severity. The health states will be converted into a single score 
The EQ-5D-5L questionnaire will be completed at Screening, at 6 and 12 months for all subjects 
and at a symptom visit if an NP swab is taken, and on day 6 and at 1, 3, 6, and 12 months after 
the symptom visit.
If the long-term follow-up time points (e.g., 12 months after symptom visit) fall beyond the first 
12 months of follow-up after vaccination of the subject, the outstanding questionnaires are to be 
completed during the durability phase of the trial, if it is conducted. Further details are 
summarized in a study specific instruction.

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10.3 15-Dimension (15D) Health-related Quality of Life Instrument  
The 15D questionnaire is a generic preference-based measure of health covering 15-dimensions 
(mobility, vision, hearing, breathing, sleeping, eating, speech, excretion, usual activities, mental 
function, discomfort and symptoms, depression, distress, vitality, and sexual activity). Each 
dimension is measured at 5 levels of severity. The health states will be converted into a single 
The 15D questionnaire will be completed at Screening, at 6 and 12 months for all subjects and at 
symptom visit if an NP swab is taken, and on day 6 and at 1, 3, 6, and 12 months after symptom 
visit. 
If the long-term follow up time points (e.g., 12 months after symptom visit) fall beyond the first 
12 months after vaccination of the subject, the outstanding questionnaires are to be completed 
during the durability phase of the trial, if it is conducted. Further details are summarized in a 
study specific instruction. 
10.4 Tilburg Frailty Indicator 
In addition to the assessments already described above, the TFI part B only will be assessed at 
screening for all subjects. 
The TFI questionnaire is a frailty index. The frailty components include 15 questions - 8 describe 
physical components of frailty, 4 describe psychological components, and 3 describe social 
components. Typically, respondents who are described by 5 or more of the frailty components are 
considered frail (in GFI, the cut-off is at four).
11 Statistical Analysis Plan 
This section outlines statistical methodologies and procedures to be used for the clinical trial.  
11.1 Randomization and Unblinding Procedure 
Please refer to Section 6.5 for further details.  
11.2 Primary Trial Hypothesis 
Vaccination with MVA-BN-RSV will reduce the incidence of LRTD associated with RSV in 
The success criterion for the two primary endpoints is that the lower bound of the 95% (two-
sided) confidence interval (CI) is greater than 20% for the estimated vaccine efficacy against 
LRTD ( 3 or 2 symptoms), respectively. 

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11.3 Endpoints 
Please refer to Protocol Synopsis (Section 1.3). 
11.4 Multiplicity 
If the number of LRTD events does not meet the sample size requirement, a futility analysis will 
be conducted towards the end of RSV season 1 before proceeding to durability follow-up of 
subjects or further enrollment and vaccinations in case needed (refer to Section 11.8). There is 
only one efficacy analysis of the primary and the key secondary efficacy endpoints to confirm the 
trial hypotheses.  
A hierarchical testing strategy will be employed and no multiplicity adjustment will be made. At 
first, the hypothesis related to vaccine efficacy for LRTD with 
at the two sided significance level 
based on the two-sided 95% CI. If the success criterion is met, the hypothesis related to vaccine 
efficacy for LRTD with 
will be evaluated in a confirmatory manner against the null 
at the same nominal significance level. Finally, if vaccine efficacy is 
confirmed for both primary endpoints, the key secondary efficacy endpoint related to RSV-
associated ARD will be tested in a confirmatory manner 
This is consistent with the Gatekeeping procedure, and the type I error rate will not be inflated. 
No multiplicity adjustment will be made for the analyses related to the other secondary and 
exploratory endpoints due to their descriptive nature. 
11.5 Sample Size Calculation 
11.5.1 Efficacy Analysis 
Vaccine Efficacy (VE) is defined as 
 , where the measure of risk 
can be the incidence rate, hazard rate, or cumulative incidence (attack rate) conditional on equal 
exposure to infection. The primary analysis of VE will be based on the hazard rate, and therefore, 
the Cox proportional hazard model will be used.  
In general, the incidence rate will be reported as number of cases in person-time. Since we 
consider the RSV season as unit of 1, cumulative incidence and incidence are the same and will 
only be referred to as incidence. 
The expected vaccine efficacy of MVA-BN-RSV vaccine against LRTD with 
80%. For an alpha = 0.05 two-sided test against a null hypothesis of 20% vaccine efficacy, a 
total of 22 events will be required for 90% power. Assuming the rate of LRTD with 
is 0.2% in the placebo group during an RSV season, approximately 20,000 subjects vaccinated in 
2 treatment groups receiving either MVA-BN-RSV vaccine or placebo will allow the observation 

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of at least 22 events. If the number of events (LRTD with 
) required for the primary 
efficacy analyses is lower than 22 at the end of RSV season 1, approximately 4000 additional 
subjects will be recruited prior to RSV season 2 such that the total number of events (LRTD with 
) will be at least 22, conditional on the blinded observed incidence in season 1 with 
probability of at least 80% to observe the additional required number of events.  
The expected vaccine efficacy of MVA-BN-RSV vaccine against LRTD with 
is 
65%. For an alpha = 0.05 two-sided test against a null hypothesis of 20% vaccine efficacy, a 
total of 53 events will be required for 85% power. Assuming the rate of LRTD is 0.4% in the 
placebo group during an RSV season, approximately 20,000 subjects vaccinated in 2 treatment 
groups receiving either MVA-BN-RSV vaccine or placebo will allow the observation of at least 
53 events. If the number of events (LRTD with 
 symptoms) required for the primary endpoint 
analyses is lower than 53 at the end of RSV season 1, approximately 4000 additional subjects will 
be recruited prior to RSV season 2 such that the total number of events (LRTD with 
symptoms) will be at least 53, conditional on the blinded observed incidence in season 1 with 
probability of at least 80% to observe the additional required number of events.  
Assuming the rate of ARD is 1.6% in the placebo group during an RSV season, approximately 
240 events will be observed if the vaccine efficacy is 50%. This will result in 95% power for an 
alpha=0.05 two-sided test against a null hypothesis of 20% vaccine efficacy. 
11.5.2 Immunogenicity Analysis 
In season 1 a subgroup of about 300 subjects per group will have serum sample draws, and 
150 subjects per group will have PBMC sample draws for immunogenicity analysis prior to 
vaccination (baseline titer) as well as 1 week or 2 weeks thereafter. Additional blood draws will 
be taken from the same subgroup 1 and 2 years after vaccination. 
Moreover, the samples will be stored for potential future analysis to assess immunogenicity in 
MVA-BN-RSV vaccinated subjects, e.g., whether immune responses from different target 
populations in other MVA-BN-RSV trials are non-inferior to those obtained in this phase 3 study 
population. The sample size is chosen to ensure adequate power for future analyses. 
11.6 Analysis Sets 
Analysis sets will be defined for the analyses of the clinical trial data. 
The full analysis set (FAS) will be defined as subjects who are randomized to any treatment arm 
and receive the study vaccination. This is the primary analysis set for efficacy assessments and 
will be based on the treatment group to which the subject is randomized. 
The safety set will include subjects who receive any MVA-BN-RSV vaccine or placebo. This is 
the primary analysis set for safety evaluation and will be based on the actual treatment the subject 

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received. The list, reporting if actual treatment was received, will be maintained by the third party 
vendor who is maintaining the randomization and vaccine distribution system and will be 
provided to the biostatistics teams upon unblinding for interim (unblinded team) or final analyses 
(blinded team). 
Two immunogenicity analysis sets will be defined to assess the humoral and cellular immunity, 
respectively. They will be subsets of the FAS and include those subjects who were selected for 
the respective immunogenicity analysis. 
11.7 Analysis Methods 
11.7.1 Efficacy 
11.7.1.1 Population Level Summary and Analysis of Primary Endpoints 
The primary efficacy endpoints, the incidence of LRTD ( 3 or 2 symptoms) associated with 
RSV during a single RSV season, are defined as the number of PCR-confirmed LRTD ( 3 or 
2 symptoms) cases from vaccination plus 2 weeks to the end of RSV season 1 (up to 12 months 
from vaccination). The case definitions are provided in the Protocol Synopsis Section 1.3. 
For the primary analysis, vaccine efficacy of LRTD is defined as the relative reduction of the 
hazard rate of LRTD associated with RSV in the MVA-BN-RSV vaccinated group compared 
with that in the placebo group. The statistical hypotheses for the VE of LRTD associated with 
RSV are H0: VELRTD
20% versus H1: VELRTD >20%. 
For each of the two primary endpoints, a Cox proportional hazards regression model based on the 
FAS stratified by age groups (60 to 64, 65 to 74, 75 to 84
will be used as the primary 
analysis to establish VE against LRTD in the MVA-BN-RSV vaccinated group compared with 
the placebo group. 
 age group is too small (e.g., <10%), it will be combined 
to 
The follow-up time for subjects who develop LRTD 
associated with RSV will be defined as (first LRTD onset date  vaccination date +1), and LRTD 
onset will be defined as the date when LRTD symptoms are observed, and the later-obtained 
sample is positive for RSV by PCR. Subjects who do not develop any LRTD event will be 
censored at time of dropout (if applicable) or at the end date of RSV season 1. A large number of 
 Cox 
regression model.  
The 95% (two-sided) CI of VE obtained from the Cox regression model will be presented. The 
success criterion is met if the lower bound of the 95% CI is greater than 20% for the estimated 
VE. 

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11.7.1.2 Analysis of Secondary Efficacy Endpoints 
The key secondary efficacy endpoint is the incidence of ARD associated with RSV during a 
single RSV season, defined as the number of PCR-confirmed ARD cases from vaccination plus 
2 weeks to the end of at least one RSV season (up to 12 months after vaccination). Case 
definition is provided in the Protocol Synopsis Section 1.3. 
For the primary analysis of this secondary efficacy endpoint, VE of ARD is defined as the 
relative reduction of the hazard rate of ARD associated with RSV in the MVA-BN-RSV 
vaccinated group compared with that in the placebo group. The statistical hypothesis for VE of 
ARD associated with RSV is H0: VEARD
20% versus H1: VEARD >20%. 
A Cox proportional hazards regression model based on the FAS stratified by age groups 
(60 to 64, 65 to 74, 75 to 84
will be used as the primary analysis to establish VE 
against ARD in the MVA-BN-RSV vaccinated group compared with the placebo group. ARD 
onset will be defined as the date when ARD symptoms are observed, and the later-obtained 
sample is positive for RSV by PCR. Other aspects of the analysis related to follow-up time, 
censoring, and tie handling are identical to the primary analysis of the primary efficacy endpoint. 
The 95% (two-sided) CI for VE obtained from the Cox regression model will be presented. The 
success criterion for the secondary efficacy endpoint is met if the success criteria for the primary 
efficacy endpoints are met (VELRTD >20%) and the lower bound of the 95% CI of VEARD is 
greater than 20%. 
Formal tests for the other secondary endpoints are not planned. Incidence of complications 
related to RSV-confirmed respiratory diseases, or hospitalization due to RSV-confirmed diseases 
or due to complication related to RSV-confirmed respiratory diseases will be summarized and 
vaccine efficacy will be estimated in a similar manner as the primary endpoints. 
RSV-specific serum antibody titers and T-cell responses will be summarized descriptively for the 
respective immunogenicity subset by timepoint and treatment group presenting geometric mean 
titers (GMT)/geometric mean spot forming units (GMSFU) along with the 95% CI. Post-baseline 
results will be compared between the 2 treatment groups using an analysis of covariance 
(ANCOVA) model on the log10-transformed titers/spot forming units for each of the scheduled 
post-baseline time points, respectively. The model will include the treatment group and age group 
as fixed effects and the log10-transformed pre-vaccination titer/spot forming unit as covariate. An 
adjusted difference in least square means (on the log10 scale) between the 2 treatment groups will 
be calculated along with the 95% CI and back-transformed to obtain the adjusted GMT/GMSFU 
ratio with 95% CI. If there is subject in the serum subset experiences any confirmed RSV 
diseases, the subject will be excluded from the immunogenicity analysis for timepoints after 
onset of RSV diseases. If there are enough cases in this subset, correlation between RSV diseases 
and immune responses will be explored. 

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11.7.1.3 Handling of Potential Intercurrent Events for the Primary and Secondary 
Efficacy Endpoints
Subjects who terminated trial participation after any confirmed RSV LRTD (for the primary 
efficacy endpoints) or ARD (for the key secondary efficacy endpoint) will not be considered as 
having missing data for the primary or secondary efficacy endpoints. Since subjects will only 
receive a single vaccination prior to the start of the RSV season, early termination due to vaccine-
related AE or lack of efficacy is expected to be minimal. Reasons for termination can be related 
to clinical trial procedures (e.g., burden of participation) or other reasons unrelated to the trial 
vaccine, which are expected to have no or minimal effect on estimating the vaccine efficacy. 
Therefore, the treatment-policy strategy will be used to address this type of potential intercurrent 
events. Vaccine efficacy (defined as 1 minus the hazard ratio of the 2 vaccination groups) against 
LRTD or ARD associated with RSV disease in the target population will be assessed regardless 
of whether early termination prior to the end of the RSV season has occurred. 
Dual enrollers are defined as subjects who are enrolled more than once in different clinical trial 
sites for the same RSV trial, or for a different RSV trial during season 1 (from 30 days prior to 
screening and until end of season 1). This type of intercurrent events can have significant impact 
on assessment of vaccine efficacy as the subject can receive both an RSV vaccine and a placebo. 
The while-on-treatment strategy will be used to address this intercurrent event. Subjects will be 
censored at time of the 2nd enrollment. If the subject is enrolled in another RSV trial prior to this 
trial, the subject will be censored on Day 1.  
11.7.1.4 Supplementary and Sensitivity Analyses of Primary and Secondary Efficacy 
Endpoints 
An unstratified Cox model will also be used to estimate VE of LRTD and ARD in the FAS. 
One of the sensitivity analyses is to estimate VELRTD and VEARD based on incidences. Incidences 
of LRTD and ARD at the end of each season will be provided by the vaccination group. A log 
binomial model will be used to estimate the relative risk in subjects who receive the 
MVA-BN-RSV vaccine compared to subjects who receive placebo. This is a generalized linear 
regression model with log-link, incidence of LRTD or ARD as a binary response variable, age 
group, risk of LRTD, geographic region, and vaccination group as independent variables.  
In addition, the primary Cox proportional hazard model will be repeated for both RSV subtypes 
separately, i.e., the vaccine efficacy will be calculated for RSV subtype A and RSV subtype B, 
respectively if there are sufficient number of cases by subtype. 
11.7.1.5 Subgroup Analysis of Primary and Secondary VE Endpoints 
VELRTD and VEARD will also be summarized by age group (60 to 64, 65 to 74, 75 to 84
years), comorbidities associated with LRTD, sex, race, frailty, and by geographic region based on 

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the FAS using the Cox regression model as the primary analysis without stratifying by age group. 
Because the subgroups can be small, the 95% confidence intervals will be considered descriptive 
and exploratory.  
11.7.1.6 Analysis on the Durability of VE 
To evaluate the durability of vaccine efficacy, subjects who were vaccinated in season 1 will be 
followed up for ARD or LRTD ( 3 or 2 symptoms) events in season 2. The incidence of ARD 
or LRTD ( 3 or 2 symptoms) will be summarized by vaccination group for the FAS. A similar 
Cox model as for the primary analysis will be used to estimate VEs and the corresponding 95% 
CIs by post-vaccination RSV season. VE is considered to be 
 if the lower bound of the 95% 
CI for VEARD
VELRTD
20%. Subjects who had 
confirmed RSV infection in season 1 will be excluded from the durability analyses. 
Due to potential dropouts during the RSV follow-up season, the estimates will be less precise, 
and the 95% confidence intervals are expected to be wider. The criteria for 
considered confirmatory. They will provide supportive evidence of VE durability. Subjects who 
are vaccinated in season 2 (if any) will not be included in these analyses. 
11.7.1.7 Analysis on Overall Vaccine Efficacy for Two RSV Seasons 
A combined analysis with LRTD ( 3 or 2 symptoms) or ARD occurred in 2 RSV seasons will 
also be performed. In the event of 2 events occurring in the same individual, only the first event 
will be counted. Subjects who are vaccinated in season 2 (if any) will also be included in these 
analyses.  
The overall incidence of LRTD or ARD will be summarized by vaccination group for the FAS. A 
similar model as for the primary analysis will be used to estimate VEs. 
11.7.1.8 Analysis on Vaccine Efficacy Against Other Respiratory Pathogens 
The occurrence of ARD associated with other respiratory pathogens (e.g. hMPV) tested by the 
central laboratory (Section 7.2) will also be investigated in a descriptive manner. Incidences will 
be summarized by vaccination group for the FAS. For pathogens for which a sufficiently high 
number of ARD events is reported, VE will be estimated based on a Cox proportional hazards 
regression model similar to the primary analysis. 
11.7.1.9 Handling of Missing Data for Efficacy Analysis 
Subjects will receive ePRO alerts 3 times per week and monthly telephone calls from the site to 
assess the occurrence of any potential RSV-related symptoms. If the subject has not responded to 
the ePRO application reminder for more than a week, the subject will receive additional 
telephone calls from the site. Unless the subject terminates clinical trial participation, missing a 

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monthly call will not be considered missing data for the estimation of the primary and secondary 
estimand. 
Since subjects with RSV disease typically have symptoms that are similar to other acute 
respiratory diseases, missing or inadequate nasopharyngeal PCR results for subjects whose 
documented symptoms meet the ARD or LRTD case definitions will be considered missing data. 
Every effort will be made to ensure proper nasopharyngeal samples are collected within 72 hours 
(and no later than 5 days) of symptom onset. 
In the primary analyses of VE based on hazard ratios (Cox model), subjects who withdrew from 
the clinical trial prior to having the event will be censored at time of withdrawal and thus early 
termination will be accounted for in the analyses. For subjects who had documented symptoms 
that meet the primary LRTD case definitions, but PCR results are missing, the test result will be 
assumed to be negative for RSV (since it is not confirmed by PCR) for the primary analysis. The 
following sensitivity analyses will also be performed.  
1.
Missing PCR results will be considered RSV positive 
2.
Best case scenario: PCR results will be considered positive in the placebo group but 
negative in the MVA-BN-RSV group 
3.
Worst case scenario: PCR results will be considered negative in the placebo group but 
positive in the MVA-BN-RSV group 
In the sensitivity analyses of VE based on relative risk (log binomial model), subjects who 
withdrew prior to having the event will be considered as having no RSV disease during the 
season.  
For analysis on durability of VE, subjects who do not continue to participate in the surveillance 
during the subsequent season(s) will be excluded. 
11.7.2 Safety 
11.7.2.1 Reactogenicity 
Recording of solicited local and systemic symptoms will occur on Day 1 to Day 8 after 
vaccination. 
Local and systemic solicited AEs will be summarized by categories (local versus systemic) and 
by vaccination group. The risk differences on these solicited AEs between the 2 vaccination 
groups and the corresponding 95% CI on the risk difference will be provided using the Miettinen 
and Nurminen method (Miettinen, 1985). 
Similarly, solicited AEs with intensity 
systemic solicited AEs, and related 
systemic solicited AEs with intensity 
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For solicited AEs, the duration and relative day of onset (in days) will be summarized. 
11.7.2.2 Unsolicited AEs 
Non-serious AEs will be monitored until 29 days post-vaccination, but serious AEs will be 
monitored throughout the RSV season. 
The incidence of unsolicited AEs will be summarized descriptively by vaccination group and 
Medical Dictionary for Regulatory Activities (MedDRA) SOC and preferred term (PT) in 
descending frequency based on the active vaccination group. The summaries will be provided for 
any TEAEs (defined as AEs occurring on or after date of vaccination and up to the end of the 
post-vaccination observational period for the respective AEs), non-serious TEAEs, related 
TEAEs, TEAEs with intensity 
intensity grade 
withdrawal from the trial, SAEs, and related SAEs. 
11.7.2.3 Data Handling 
Effort will be made to ensure the same event is not recorded multiple times. It is possible that 
similar local reaction AEs and systemic symptom AEs are also recorded as unsolicited AEs.  
Although non-serious AEs will be reported until 29 days post-vaccination, AEs reported up to the 
end of the post-vaccination observational period will also be considered TEAEs.  
If an unsolicited AE has missing or partial onset date or AE end date, relative day to onset or 
duration of AE will not be computed.  
If an unsolicited AE has missing or partial onset date, the event will be considered treatment-
emergent unless the year and month of onset are clearly before date of vaccination. 
Secondary safety endpoints will also be summarized by subgroups specified in Section 11.7.1.5. 
11.7.3 Burden of Disease and Health-Related Quality of Life 
RiiQ is a respiratory illness specific questionnaire covering 3 domains: upper respiratory (nasal 
congestion, sore throat), lower respiratory (coughing, wheezing, shortness of breath, and sputum), 
and systematic symptoms (headache, fever, neck pain, body aches, fatigue, sleep problems, and 
appetite loss). The symptoms in each domain are measured at 4 levels of severity; the mean of the 
symptom scores gives the domain scores; the mean of the domain scores gives the total score. 
For subjects with confirmed RSV disease, AUC of the change from baseline in RiiQ total score 
(defined as mean of all scores) and domain-specific symptom scores, maximum daily change 
from baseline in RiiQ total and domain-specific symptom scores, and duration of any symptoms 
will be summarized descriptively.  

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Besides descriptive summary, the AUC of the change from baseline in RiiQ total score, and the 
maximum daily change from baseline in RiiQ total score will be compared between the 2 
treatment groups. If the score is skewed, transformation of the raw data may be considered. 
The EQ-5D-5L questionnaire is a generic preference-based measure of health covering 
5-dimensions (mobility, self--care, usual activities, pain/discomfort, and anxiety/depression) 
measured at 5 levels of severity. The health states will be converted into a single score 
 The 
EQ-5D-5L data collected in this study will be used for health economic modeling. The analysis 
and results will not be reported in the CSR. 
The 15D questionnaire is a generic preference-based measure of health covering 15-dimensions 
(mobility, vision, hearing, breathing, sleeping, eating, speech, excretion, usual activities, mental 
function, discomfort and symptoms, depression, distress, vitality, and sexual activity). Each 
dimension is measured at 5 levels of severity. The health states will be converted into a single 
ealth). 
The 15D data collected in this study will be used for health economic modeling. The analysis and 
results will not be reported in the CSR. 
11.8 Safety Monitoring and Futility Analysis (if applicable) 
The DMC will monitor safety data closely from enrollment, vaccination to end of the study. 
There is a planned safety data analysis and safety data review meetings at the end of every 
season, unless there are specific safety concerns raised during the trial when an ad-hoc DMC 
meeting will need to be called based on a joint decision of the DMC Chair and the sponsor. In the 
event that SAEs, or vaccine-related death are suspected, the DMC may recommend stopping the 
trial. 
If the number of LRTD events does not meet the sample size requirement, a futility analysis will 
be conducted at the end of season 1 before proceeding to season 2. Upon review of the results 
from the futility analysis, the DMC may recommend to 1) terminate the trial (futility) or 
2) continue to enroll additional subjects and to follow up subjects in season 2.  
The DMC will consist of clinicians and an experienced statistician who is not associated with the 
sponsor and is experienced and familiar with futility analyses and decision rules. Specific futility 
rules and distribution of unblinded information, including list of personnel and contents for 
distribution, will be described in the DMC charter.  

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12 Data Management and Electronic Records 
12.1 Data Management 
Clinical Data Management activities will be performed by a CRO, with oversight by BN. All data 
management procedures will be detailed in a Data Management Plan (DMP). 
12.2 Electronic Case Report Forms 
Subject data will be entered into an eCRF in a 21 CFR 11-compliant electronic data capture 
(EDC) database. The eCRF data will combined with data transmitted from other external systems 
(e.g., lab data). All data transmissions will be secure. Personal identifiers will not be used when 
collecting and storing data. 
All eCRFs will be completed by authorized clinical trial personnel at the site. Trial personnel will 
be appropriately trained in the use of eCRFs and application of electronic signatures before being 
given access to the EDC system. Access to EDC is managed by the CRO or an authorized 
representative.  
All effort will be made by trial personnel and PI to enter the eCRFs within the contractually 
subject data entered in the eCRF are accurate, complete, legible, 
medical records. The investigator attests to this by providing electronic signature within the EDC 
system. 
The CRO will be responsible for entering ranges for local labs (if applicable) and for assigning 
medical coding utilizing Medical Dictionary for Regulatory Activities and World Health 
Organization Drug dictionaries. Data quality checks will be applied using manual and electronic 
verification methods. Original data and any changes in data and reason for change will be 
recorded in an electronic audit trail in EDC. 
After database lock, the investigator will receive a copy of the subject data (e.g., paper, CD-
ROM, or other appropriate media) for archiving at the CTS. 
12.3 ePRO Data Collection   
Sites will assist subjects to download the appropriate application to their device (i.e., smartphone, 
tablet, etc.) once enrolled in the trial. Subjects without their own device will be provisioned a 
device for ePRO data collection during the trial. 
The ePRO data collection will be used for the following items: 
Memory aid for capturing solicited local and systemic symptoms 

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Reminders for capturing the presence of respiratory tract symptoms 
RiiQ questionnaire for subjects with respiratory tract symptoms 
EQ-5D-5L questionnaire at baseline and for subjects with respiratory tract symptom 
15-dimension health-related quality of life instrument (15D) utility score 
Tilburg Frailty Index part B (TFI) total score at baseline for all participants 
Instructions will be provided to the subjects on how to enter data into the ePRO application and 
subjects will be required to demonstrate understanding prior to entering data on their own. Alerts 
will be sent to the site if a subject does not complete their diary as directed in Section 4.2.2. 
Entries will be reviewed by the site staff together with the subject at the next contact (telephone 
call/onsite visit). During the surveillance period, subjects will also receive ePRO application 
alerts 3 times per week asking about the presence of new respiratory symptoms and to contact 
their investigator if so. 
12.4 Retention of Records 
The investigator/trial staff must maintain adequate and accurate records to enable the conduct of 
the trial to be fully documented and the trial data to be subsequently verified. All essential 
documents, as listed in ICH-GCP guidelines, will be retained by the investigator for at least 2 
years after the date the last marketing application is approved for the drug in the indication being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The investigator must notify and obtain written approval from BN before destroying any clinical 
trial documents or images (e.g., scan, radiograph, electrocardiogram (ECG) tracing) at any time. 
The Sponsor will inform the investigator of the date that the trial records may be destroyed or 
returned to BN.  
Should an investigator wish to assign trial records to another party, advance written notice will be 
given to the Sponsor. BN must also be notified in advance and provide express written approval 
of any change in the maintenance of clinical trial documents, should the investigator choose to 
move trial records to another location.   
If the investigator cannot guarantee the aforementioned archiving requirements at the clinical trial 
site, special arrangements must be made between the investigator and BN to store these 
documents in secure sealed containers away from the clinical trial site. These documents must be 
able to be returned in their secure sealed containers to the clinical trial site for auditing purposes. 

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13 Ethical Aspects 
13.1 Ethical and Legal Regulations 
The PI is 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. 
13.2 Approval by IEC/IRB/IBC 
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. 
IBC 
The MVA-BN-RSV vaccine meets the exemption criteria set forth in Appendix M-VI-A of the 
National Institutes of Health (NIH) Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules and is therefore exempt from the requirements of submission of the 
protocol to NIH OBA (Office of Biotechnology Activities), RAC (Recombinant DNA Advisory 
Committee) review, and subsequent reporting but is expected to follow all other requirements of 
the NIH Guidelines. This includes having the protocol reviewed and approved by the responsible 
Institutional Biosafety Committee (IBC) for each site before research participants are recruited.  
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-RSV vaccine or to an authority) contain no subject names. 
Only a subject and 
record number may not be used. The PI keeps separate confidential subject logs for trial 

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recruitment 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 persons 
authorized by the Sponsor or the PI or to authorities. The Sponsor of the trial will only receive 
pseudonymized data for analysis. 
14 Informed Consent 
The informed consent form (ICF) and process must comply with ICH-GCP guidelines, as well as 
specific national regulations and/or local laws in the countries where the trial is conducted and 
must be approved by the appropriate IEC/IRB. 
The ICF will document the trial-specific information the investigator or his/her designee provides 
The investigator, or designee (designee 
must be listed on the Delegation of Authority log), must explain in terms understandable to the 
subject the purpose and nature of the trial; trial procedures; anticipated benefits; potential risks, 
adverse effects, and discomforts; and any potential future use of blood samples (Section 8.3).   
Subjects must be informed unequivocally that they may refuse participation in the trial, 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 
The consent process must be documen
provide a signed and dated ICF before any trial-related (nonstandard of care) activities are 
performed (such as screening). The initial and any amended signed and dated consent forms must 
remain in each 
trial file at the CTS and be available for verification by trial monitor, 
Sponsor/CRO auditor, or competent regulatory authorities at any time. A copy of each signed 
consent form must be given to the subject at the time that it is signed by the subject. 
15 Monitoring of the Trial 
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 outline the monitoring strategy (including rational) and 

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will specify in detail the items for source data verification and other tasks, to be performed by the 
CRA. 
Monitoring will be conducted through personal visits with the investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the trial is conducted in compliance with the protocol, 
SOPs, and other written instructions and regulatory guidelines, and to ensure the quality and 
integrity of the data. An unblinded monitor/CRA will work with the unblinded site person to 
ensure appropriate vaccine storage, accountability, and blinding. 
To assure the accuracy of data collected in the eCRFs, it is mandatory that the monitor have 
direct access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical trial. However, because of the experimental nature of this treatment, the investigator 
agrees to allow the IRB/IEC, representatives of BN, its designated agents and authorized 
employees of the appropriate Regulatory Authority (e.g., FDA) to inspect the facilities used in 
this clinical trial and, for purposes of verification, allow direct access to the hospital or clinic 
records of all enrolled subjects. A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. If a subject 
refuses to consent to this procedure, he/she may not participate in the trial.  
The site needs to maintain records to identify the nature and location of all source documents as 
well as essential documents.  
15.1 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the trial site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
The PI or designee will be responsible for identifying and recording all deviations, which are 
defined as isolated occurrences involving a procedure that did not follow the protocol or a 
protocol-specific procedure. All deviations from the protocol and actions taken will be recorded 
in the source data and placed in the trial-specific regulatory file. Protocol deviations must be sent 
to the local IRB per their guidelines. The site PI/trial staff is responsible for knowing and 
adhering to their IRB requirements. Further details about the handling of protocol deviations will 
be included in a trial-specific procedure. 
16 Audits and Inspections 
Site audits may be carried out by the BN quality assurance department or designee at any time 
during or after completion of this trial. All documents pertinent to the trial must be made 

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available to the designated auditor. Subject privacy must, however, be respected. The investigator 
and clinical staff are to be present and available for consultation during routinely scheduled site 
audit visits conducted by the sponsor or designee. 
In addition, representatives from local, state, or federal regulatory authorities may choose to 
inspect a trial site at any time before, during, or after completion of the clinical trial. The 
investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. In the event of such an inspection, BN will be 
available to assist in the preparation. All pertinent trial data should be made available as 
requested by the Regulatory Authority for verification, audit, or inspection purposes. 
17 Responsibility of the Investigator 
The investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the trial, should meet all the qualifications specified by 
the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae or other relevant documentation requested by the Sponsor, 
the IRB/IEC, or the regulatory authority(ies). 
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 aspects (see 
Section 13 of this protocol). 
the IEC/IRB and IBC, 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 is 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 partially 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 the ICH E6 Guideline for GCP and regulatory and institutional requirements for 

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the protection of confidentiality of subjects. He/she will permit authorized representatives of the 
Sponsor and regulatory authorities 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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18 References 
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undergoes limited replication in human cells and lacks several immunomodulatory proteins: 
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Groothuis J, Simoes E, Levin M, Hall C, Long C, Rodriguez W, Arrobio J, Meissner H, Fulton 
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McClure DL, Kieke BA, Sundaram ME, Simpson MD, Meece JK, Sifakis F, et al. 2014. Seasonal 
incidence of medically attended respiratory syncytial virus infection in a community cohort of 
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Mortality Associated with Influenza and Respiratory Syncytial Virus in the United States. JAMA 
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grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical
Walsh E. E, Peterson D. R, Falsey A. R. (2004) Risk Factors for Severe Respiratory Syncytial 
Virus Infection in Elderly Persons [The Journal of Infectious Diseases, 189:233 8. 
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(2007) The absence of enhanced disease with wild type respiratory syncytial virus infection 
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19 Appendices 

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Appendix 1: Toxicity Scale for Laboratory Values 
This protocol does not schedule any safety labs. Therefore, the provision of toxicity scales for 
laboratory values is not applicable. However, for the purpose of reporting adverse events based 
on ad-hoc findings from local laboratories, the local reference ranges should be considered, and 
an investigator assessment of clinical significance should be performed. Only clinically 
significant laboratory abnormalities should be reported as adverse events. 
For abnormalities NOT found elsewhere in Toxicity Tables, use the scale below to estimate grade 
of intensity: 
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, hospitalization or disabling. 
Serious or life-threatening AEs 
ANY clinical event deemed by the Investigator clinician to be serious (hospitalization, life-
threatening, disability, important medical event) should be considered a grade 4 event. Clinical 
events considered to be serious 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 13 
Toxicity Scale for Serum Chemistry 
Lab Value, Seruma
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
Threatening 
(Grade 4)b
Sodium 
Hyponatremia mmoL/L
132 < 136 
130-131 
125-129 
<125 
Sodium 
Hypernatremia 
mmoL/L 
>145-146 
147 
148-150 
>150 
Potassium 
Hyperkalemia mmoL/L 
>5.1-5.2 
5.3-5.4 
5.5-5.6 
>5.6 
Potassium 
Hypokalemia mmoL/L 
3.4 < 3.5 
3.3 
3.1-3.2 
<3.1 
Calcium 
Hypercalcaemia mg/dL 
>10.2-11.0 
11.1-11.5 
11.6-12.0 
>12.0 
Calcium- 
Hypocalcaemia mg/dL
8.0 < 8.6 
7.5-7.9 
7.0-7.4 
<7.0 
Creatinine 
mg/dL 
1.5-1.7 
1.8-2.0 
2.1-2.5 
>2.5 or requires 
dialysis 
Alkaline Phosphatase 
increase by factor 
1.1-2.0 × ULN 
2.1-3.0 × ULN 
3.1-10 × ULN 
>10 × ULN 
ALT (SGPT) and AST 
(SGOT) increase by 
factor 
1.1-2.5 × ULN 
2.6-5.0 × ULN 
5.1-10 × ULN 
>10 × ULN 
Bilirubin  when 
accompanied by any 
increase in Liver 
Function Test; 
increase by factor 
1.10-
1.25 × ULN 
1.26-
1.50 × ULN 
1.51-
1.75 × ULN 
>1.75 × ULN 
Bilirubin  when Liver 
Function Test is 
normal; 
increase by factor 
1.1-1.5 × ULN 
1.6-2.0 × ULN 
2.1-3.0 × ULN 
>3.0 × ULN 
 upper limit of the normal range. 
a  The laboratory values provided in the table serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
b  The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life-Threatening (Grade 4). For example, a low sodium value that falls 
within a Grade 3 parameter (125-129 mmoL/L) should be recorded as a Grade 4 hyponatremia event if the 
subject had a new seizure associated with the low sodium value.  

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Table 14 
Toxicity Scale for Hematology 
Lab Value, 
Hematologya
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-
Threatening 
(Grade 4) 
Hemoglobin (Female) 
 gm/dL 
11.0-12.0 
9.5-10.9 
8.0-9.4 
<8.0 
Hemoglobin (Male) 
gm/dL 
12.5-13.5 
10.5-12.4 
8.5-10.4 
<8.5 
WBC Increase 
cell/mm3 
>11,000-15,000 
15,001-20,000 
20,001-25,000 
>25,000 
WBC Decrease 
cell/mm3 
2500 < 4500 
1500-2499 
1000-1499 
<1000 
Lymphocytes 
Decrease 
cell/mm3 
750 < 1000 
500-749 
250-499 
<250 
Neutrophils Decrease 
cell/mm3 
1200 < 1800 
1000-1199 
500-999 
<500 
Platelets Decrease 
cell/mm3 
125,000 < 130,00
0 
100,000-124,999 
25,000-99,999 
<25,000 
a  The laboratory values provided in the table serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
Table 15 
Grading for Troponin I 
Lab Value 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-
Threatening 
(Grade 4) 
Cardiac troponin I 
>ULN - <2 × ULN
 - <5 × ULN 
× ULN 
N/A 

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Appendix 2: Signature Pages
Investigator Signature Page
Herewith I agree that I have read and fully understand this protocol:
A Randomized, Double-blind, Phase 3 Trial to Assess Clinical 
Efficacy, Safety, and Reactogenicity of the Recombinant 
MVA-BN®-RSV Vaccine in Adults
Years of Age
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.
Function

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Coordinating Investigator Signature Page
A Randomized, Double-blind, Phase 3 Trial to Assess Clinical 
Efficacy, Safety, and Reactogenicity of the Recombinant 
MVA-BN®-RSV Vaccine in 
Years of Age
I agree that the protocol was written according to international ethical and scientific quality 
standards (ICH-GCP), in compliance with the 2013 version of the Declaration of Helsinki and 
local legal and regulatory requirements applicable in the respective countries.
Function

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Sponsor Signature Page
By signing the protocol:
A Randomized, Double-blind, Phase 3 Trial to Assess Clinical 
Efficacy, Safety, and Reactogenicity of the Recombinant 
MVA-BN®-RSV Vaccine in 
Years of Age
The undersigned parties agree that the protocol was written according to international ethical and
scientific quality standards (ICH-GCP), in compliance with the 2013 version of the Declaration 
of Helsinki and local legal and regulatory requirements applicable in the respective countries.