A Randomized, Single-blind, Placebo Controlled, Dose-ranging Phase II Trial in ≥ 55 Year Old Adults to Evaluate the Safety and Immunogenicity of the Recombinant MVA-BN-RSV Vaccine
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Bavarian Nordic

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RSV-MVA-002 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in 
≥ 55 year old adults to evaluate the safety and immunogenicity of the 
recombinant MVA-BN-RSV vaccine 
Clinical Trial Protocol, Edition 4.0 
26-Apr-2018
NCT02873286

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1 General Information 
1.1 Investigator Signature Page 
Herewith I agree that I have read and fully understand this protocol: 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in ≥ 55 year old adults 
to evaluate the safety and immunogenicity of the recombinant MVA-BN-RSV vaccine. 
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 
 
 
 
 
(Date) 
 
(Signature)  [Name, Department] 
 

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1.4 Responsibilities 
Trial Number 
 
RSV-MVA-002 
 
 
 
Title 
 
A randomized, single-blind, placebo controlled, dose-
ranging Phase II trial in ≥ 55 year old adults to evaluate 
the safety and immunogenicity of the recombinant  
MVA-BN-RSV vaccine.  
 
 
 
 
 
Coordinating Investigator  
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Sponsor and Product 
Supply MVA-BN-RSV 
vaccine 
 
 
Phone 
 
Fax 
 
 
 
 
 
Project Leader 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Director 
Pharmacovigilance 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
 

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Medical Monitor 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Trial Statistician 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
CRO Project Manager 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Laboratory 
(Safety, Serum & nasal 
swab processing) 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Laboratory 
(PBMC processing) 
 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 

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Laboratory 
(PBMC processing) 
 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
Laboratory 
(PBMC processing) 
 
 
Phone 
Fax 
E-mail 
 
 
 
Laboratory 
(Immunogenicity Testing) 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
Site payments 
 
Phone 
 
Fax 
 
E-mail 
 
 
 
 
 
ECG 
 
Phone 
 
Fax 
 
E-mail 
 
 
 

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Drug Depot 
 
Phone 
 
Fax 
 
E-mail 
 

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Table of Contents 
1 
General Information ........................................................................................ 2 
1.1 Investigator Signature Page ............................................................................. 2 
1.2 Coordinating Investigator Signature Page ..................................................... 3 
1.3 Sponsor Signature Page ................................................................................... 4 
1.4 Responsibilities .................................................................................................. 5 
Table of Contents ...................................................................................................... 9 
List of Tables ........................................................................................................... 14 
List of Figures ......................................................................................................... 15 
List of Abbreviations .............................................................................................. 16 
Definitions ............................................................................................................... 19 
1.5 Protocol Synopsis ............................................................................................ 20 
1.6 Main Trial Schedule ....................................................................................... 32 
1.7 Trial Schedule Booster Substudy .................................................................. 36 
2 
Background Information and Scientific Rationale ..................................... 39 
2.1 Introduction to RSV Disease ......................................................................... 39 
2.2 MVA-BN-RSV Vaccine .................................................................................. 42 
2.3 Origin and Characteristics of MVA-BN Vector Backbone ........................ 43 
2.4 Summary of Nonclinical Studies with MVA-BN-RSV Vaccine ................. 44 
2.5 Clinical Profile of MVA-BN and Recombinant MVA-based Vaccines ..... 44 
2.5.1 
Safety Overview of MVA-BN and Recombinant MVA-based 
Vaccines ........................................................................................................ 45 
2.5.2 
Safety Profile of MVA-BN-based Recombinant Vaccines in Healthy 
Compared to Special Populations .............................................................. 50 
2.5.3 
Immunogenicity Overview of MVA-BN .................................................... 52 
2.6 Clinical Trial Data with MVA-BN-RSV Vaccine ........................................ 53 
2.7 Rationale .......................................................................................................... 58 
2.8 Trial Population .............................................................................................. 59 

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2.9 Risk/Benefit Assessment ................................................................................. 59 
2.9.1 
Potential Risks ............................................................................................. 59 
2.9.2 
Benefits ......................................................................................................... 60 
3 
Objectives ........................................................................................................ 60 
4 
Trial Design ..................................................................................................... 61 
4.1 Experimental Design Forecast ....................................................................... 61 
4.2 Description of Trial Procedures .................................................................... 62 
4.2.1 
Main Trial .................................................................................................... 62 
4.2.1.1 
Screening Phase ..........................................................................................62 
4.2.1.2 
Active Trial Phase ......................................................................................63 
4.2.1.3 
Follow-Up (FU) Phase ................................................................................69 
4.2.2 
Booster Substudy ......................................................................................... 70 
4.2.2.1 
Booster Visit 0 .............................................................................................70 
4.2.2.2 
Booster Substudy Active Trial Phase .......................................................71 
4.2.2.3 
Booster Follow-Up (BFU) Phase ...............................................................74 
4.2.3 
Unscheduled Visits ...................................................................................... 75 
4.2.4 
Early Discontinuation ................................................................................. 75 
4.3 Trial Duration ................................................................................................. 76 
4.4 Safety Review .................................................................................................. 77 
4.4.1 
Safety Monitoring Team ............................................................................. 77 
4.4.2 
Safety Monitoring Committee .................................................................... 77 
4.5 Trial Halting Rules ......................................................................................... 77 
5 
Selection of Subjects ....................................................................................... 78 
5.1 Recruitment Procedure .................................................................................. 78 
5.2 Inclusion Criteria ............................................................................................ 78 
5.3 Exclusion Criteria ........................................................................................... 79 
6 
Investigational Medicinal Product and Diluent .......................................... 79 
6.1 Production, Packaging and Labeling ............................................................ 79 

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6.2 Shipment, Storage and Handling .................................................................. 79 
6.3 Preparation, Administration and Dosage ..................................................... 80 
6.4 Accountability and Disposal .......................................................................... 80 
7 
Assessment of Immunogenicity ..................................................................... 80 
7.1 Systemic Humoral Immune Responses......................................................... 81 
7.1.1 
RSV-specific ELISA .................................................................................... 81 
7.1.2 
RSV-specific PRNT ..................................................................................... 82 
7.2 Mucosal Immune Responses .......................................................................... 82 
7.3 Systemic Cellular Immune Responses .......................................................... 83 
7.4 Future Use of Lab Specimen .......................................................................... 84 
8 
Safety and Reactogenicity .............................................................................. 84 
8.1 Definitions ........................................................................................................ 84 
8.1.1 
Medical History ........................................................................................... 84 
8.1.2 
AEs ................................................................................................................ 84 
8.1.2.1 
Unsolicited AEs ...........................................................................................84 
8.1.2.2 
Solicited AEs ...............................................................................................85 
8.1.2.3 
SAEs .............................................................................................................85 
8.2 Assessment ....................................................................................................... 86 
8.2.1 
Relevant Medical History ........................................................................... 86 
8.2.2 
Prior and Concomitant Medication ........................................................... 86 
8.2.3 
Physical Examination .................................................................................. 87 
8.2.4 
Vital Signs .................................................................................................... 87 
8.2.5 
Unsolicited AEs ............................................................................................ 87 
8.2.6 
Solicited AEs ................................................................................................ 89 
8.2.6.1 
Solicited Local AEs .....................................................................................89 
8.2.6.2 
Solicited General AEs ................................................................................90 
8.2.7 
Respiratory Viral Panel (Main Trial) ........................................................ 91 
8.2.8 
RSV-specific symptoms ............................................................................... 91 

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8.2.9 
Cardiac Assessment ..................................................................................... 92 
8.2.10 Safety Laboratory Measurements ............................................................. 94 
8.2.11 Pregnancy ..................................................................................................... 95 
8.3 Reporting ......................................................................................................... 96 
8.3.1 
Reporting of SAEs ....................................................................................... 96 
8.3.2 
Reporting of Pregnancy .............................................................................. 98 
9 
Statistical Considerations .............................................................................. 98 
9.1 Randomization Procedure and Blinding ...................................................... 98 
9.2 Sample Size Calculation ................................................................................. 98 
9.2.1 
Treatment Groups/Datasets to be Evaluated .......................................... 100 
9.3 Biometrical Evaluation ................................................................................. 101 
9.3.1 
Analysis ....................................................................................................... 101 
9.3.2 
Presentation of Data .................................................................................. 102 
10 
Ethical Aspects .............................................................................................. 103 
10.1 Ethical and Legal Regulations ..................................................................... 103 
10.2 Approval by an IEC/IRB and IBC .............................................................. 103 
10.3 Confidentiality and Data Protection ........................................................... 103 
11 
Informed Consent ......................................................................................... 104 
12 
eCRF, Retention of Records and Monitoring ............................................ 104 
12.1 eCRF .............................................................................................................. 104 
12.2 Retention of Records .................................................................................... 105 
12.3 Monitoring of the Trial ................................................................................ 105 
13 
Audits and Inspections ................................................................................. 106 
14 
Responsibilities of the PI ............................................................................. 106 
15 
References ..................................................................................................... 107 
Appendix 1: Toxicity Scale for Laboratory Values .......................................... 109 
Appendix 2: Interpretation Support for Assessment of Screening ECGs ...... 112 

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Appendix 3: Grading Scale for Lymphadenopathy .......................................... 114 
Appendix 4: Amendment#1 to the Clinical Trial Protocol Edition 1.0 
dated 07-Jul-2016 ......................................................................................... 115 
Rationale ................................................................................................................ 116 
Changes .................................................................................................................. 116 
Appendix 5: Amendment#2 to the Clinical Trial Protocol .............................. 127 
Rationale ................................................................................................................ 128 
Changes .................................................................................................................. 128 
Appendix 6: Amendment#3 to the Clinical Trial Protocol .............................. 156 
Rationale: ............................................................................................................... 157 
Changes: ................................................................................................................. 157 

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List of Tables 
Table 1 
Treatment Groups .................................................................................................. 24 
Table 2 
Treatment Groups Booster Substudy................................................................... 26 
Table 3 
Suspected Adverse Drug Reactions Reported by ≥ 1 % of Subjects in 
Completed  MVA-BN Clinical Trials* (N = 7099 subjects) ............................... 46 
Table 4 
Serious Suspected Adverse Drug Reactions (Assessed by the Investigator 
to Be At Least Possibly Related to MVA-BN) ..................................................... 48 
Table 5 
Solicited and Common Unsolicited Adverse Events in Clinical Trial HIV-
NEF-004 .................................................................................................................. 51 
Table 6 
Unsolicited and Solicited Adverse Events in Clinical Trial HIV-POL-002 ...... 52 
Table 7  
Treatment Groups in Phase I Clinical Trial RSV-MVA-001 ............................ 53 
Table 8 
RSV-MVA-001 Trial Summary of Adverse Events per Subject - FAS ............ 54 
Table 9 
Solicited Local Adverse Events (Overall per Subject) – FAS ............................ 55 
Table 10 
Related Solicited General Adverse Events (Overall per Subject) - FAS........... 55 
Table 11 
Serum RSV-Specific Baseline and Individual Peak Geometric Mean 
Titers – FAS and PPS ............................................................................................ 57 
Table 12 
PBMC ELISPOT: IFN-γ/IL-4 Responder Rates – FAS and PPS ..................... 58 
Table 13 
Treatment Groups Main Trial .............................................................................. 62 
Table 14 
Grading of General Symptoms from the Subject’s Memory Aid ...................... 91 
Table 15 
Toxicity Scale for Serum Chemistry .................................................................. 110 
Table 16 
Toxicity Scale for Hematology ............................................................................ 111 
Table 17 
Grading for Troponin I ....................................................................................... 111 
 

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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)..................................................................................... 40 
Figure 2 
Eosinophil Concentration in Bronchoalveolar Lavage in Mice after 
Administration of MVA-BN-RSV and Formalin Inactivated (FI) RSV 
Vaccine .................................................................................................................... 42 
Figure 3 
Algorithm for Cardiac Follow-up ......................................................................... 93 
Figure 4 
Algorithm for Reporting of SAEs ......................................................................... 97 
 

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List of Abbreviations 
AD 
Atopic Dermatitis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BFU 
Booster Follow-Up 
BFU1 
Booster Follow-Up Visit 1 
BFU2 
Booster Follow-Up Visit 2 
BFU3 
Booster Follow-Up Visit 3 
BMI 
Body Mass Index 
BN 
Bavarian Nordic 
BV 
Booster Visit 
CDISC 
Clinical Data Interchange Standards Consortium 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTS 
Clinical Trial Site 
DNA 
Deoxyribonucleic Acid 
DS 
Drug Safety 
EAP 
End of Active Trial Phase 
ECG 
Electrocardiogram 
eCRF(s) 
Electronic Case Report Form(s) 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISPOT 
Enzyme-linked Immuno Spot Technique 
EMA 
European Medicines Agency 
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  
GCP 
Good Clinical Practice 
GH-RH 
Growth-Hormone Releasing Hormone 
GMT 
Geometric Mean Titer 
GMFI 
Geometric Mean Fold Increase 
HbA1c 
Glycated hemoglobin 
HBsAG 
Hepatitis B Surface Antigen 
HCG 
Human Choriogonadotropin 

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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IAS 
Immunogenicity Analysis Set 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization  
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
IL-4 
Interleukin 4 
IMP 
Investigational Medicinal Product 
Inf.U 
Infectious Units 
IRB 
Institutional Review Board 
LF 
Liquid Frozen 
LLN 
Lower Limit of Normal 
LRTI 
Lower Respiratory Tract Infection 
MCH 
Mean Corpuscular/Cellular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration  
MCV 
Mean Corpuscular/Cell Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Medicinal Product 
MVA 
Modified Vaccinia Ankara Strain 
MVA-BN 
Modified Vaccinia Ankara – Bavarian Nordic  
also named IMVAMUNE or IMVANEX 
n/N 
Number 
NIH 
National Institutes of Health 
ODM 
Operational Data Modeling 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PEI 
Paul Ehrlich Institute 
PI 
Principal Investigator 
PPS 
Per Protocol Set 
PRNT 
Plaque Reduction Neutralization Test 
PV 
Pharmacovigilance 
PVC 
Premature Ventricular Contractions 
RDW 
Red Blood Cell Distribution Width 
RSV 
Respiratory Syncytial Virus 
RVP 
Respiratory Viral Panel 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 

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SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCR 
Screening 
SD 
Standard Deviation 
SFU 
Spot Forming Unit 
SMC 
Safety Monitoring Committee 
SMT 
Safety Monitoring Team 
SOP 
Standard Operating Procedure 
TBS 
Tris-buffered Saline 
TCID50 
Tissue Culture Infectious Dose 50 % 
TEAE 
Treatment-emergent Adverse Event 
Th1/Th2 
T-Helper Cells, Type 1/Type 2 
ULN 
Upper Limit of Normal 
URTI 
Upper Respiratory Tract Infection 
V 
Visit 
VACV 
Vaccinia Virus 
VS 
Staggering Visit 
WBC 
White Blood Cell Count 
WOCBP 
Women of Childbearing Potential 

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Definitions 
Active trial phase 
The trial phase starting with and including (Booster) Visit 1 and ending 
with and including (B)EAP (End of active trial phase) (V3/BV1 + 28-
35 days; for details see Section 1.6 and Section 1.7). 
Booster Baseline 
Immune reponses measured at BV0 
Booster Substudy 
Administration of a single (booster) dose of MVA-BN-RSV vaccine 
approximately one year after the first MVA-BN-RSV vaccination in 
subjects previously vaccinated with MVA-BN-RSV in the main trial. 
Dose 1  
Represents the nominal titer of 1 x 108 Infectious Unit (Inf.U) per 
0.5 mL. 
Dose 2 
Represents the nominal titer of 5 x108 Inf.U per 0.5 mL. 
End of active trial phase 
([B]EAP) 
The last visit of the active trial phase (for details see Section 1.6 and 
Section 1.7). 
Fold increase 
The fold increase is defined as a subject’s post-baseline titer at Visit X, 
divided by the baseline titer 
Main Trial 
In the main trial subjects receive two administrations 4 weeks apart 
consisting of MVA-BN-RSV Dose 1 (1 x 108 Inf.U), MVA-BN-
RSV Dose 2 (5 x 108 Inf.U) or Placebo (TBS). 
Nominal titer  
The MVA-BN-RSV (Respiratory Syncytial Virus) vaccine is 
formulated at a nominal titer of 5 x 108 Inf.U per dose (0.5 mL). The 
actual titer will be evaluated by stability data. 
Staggering visit (VS) 
A visit only required by subjects enrolled into the sentinel and safety 
cohort in the main trial. 
Subgroup 
The subgroup consists of 20 subjects per treatment group in the main 
trial who have peripheral blood mononuclear cells (PBMC) collection 
as well as an additional serum and nasal swab sample collection time 
point one week post each vaccination. 
Out of this subgroup, approximately 13 subjects per treatment group 
will be recruited into the booster substudy. 
Treatment group 
Subjects are recruited into one of five treatment groups receiving 
different investigational medicinal product (IMP) doses and schedules. 
Vaccination 
Intramuscular administration of active MVA-BN-RSV vaccine or Tris-
buffered saline (TBS) 
 

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1.5 Protocol Synopsis 
Title 
 
A randomized, single-blind, placebo controlled, dose-ranging 
Phase II trial in ≥ 55 year old adults to evaluate the safety and 
immunogenicity of the recombinant MVA-BN-RSV vaccine  
Clinical phase 
 
Phase II 
Sponsor 
 
Bavarian Nordic A/S 
Hejreskovvej 10A,  
3490 Kvistgård, Denmark 
Coordinating 
Investigator 
 
Number of sites 
and Country/ies 
 
up to 16 sites in the USA 
Vaccination dose 
and schedule 
 
Liquid frozen (LF) suspension of MVA-mBN294B (common 
name MVA-BN-RSV vaccine), containing a nominal titer of 
5 x 108 Inf.U per 0.5 mL.  
In total 400 subjects will be recruited into this trial. Subjects 
will receive two administrations 4 weeks apart which will 
consist of MVA-BN-RSV Dose 1 (1 x 108 Inf.U), MVA-BN-
RSV Dose 2 (5 x 108 Inf.U) or Placebo (TBS). To obtain 
Dose 1 the MVA-BN- RSV vaccine will be diluted in MVA-
BN formulation buffer (TBS) according to the study specific 
administration instructions. Following the main trial, two 
subgroups will be identified, which will continue in the booster 
substudy. The selection is based on safety and immunogenicity 
data obtained in the main trial. 
86 subjects from 2 treatment groups (43 per treatment group) 
are supposed to receive one (booster) dose of MVA-BN-RSV 
vaccine approximately one year after their first vaccination. In 
this booster substudy, eligible subjects will receive the same 
dose they received during the main trial. 
For details on the treatment groups see Table 1 

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Route of 
administration 
 
MVA-BN-RSV vaccine/TBS is administered intramuscularly 
(IM) into the deltoid muscle of the upper arm (preferably the 
non-dominant arm). 
Trial duration 
 
Up to 39 weeks per subject in the main trial and up to 
additional 56 weeks per subject enrolled in the booster 
substudy. 
Sample size main 
trial 
 
A total of 400 subjects will be recruited into 5 treatment groups 
à 80 subjects. PBMC collection will be performed in a 
subgroup of 20 subjects in each treatment group (total of 
100 subjects). This subgroup will also have an additional serum 
and nasal swab sample collection time point one week post 
each vaccination in addition to the serum and nasal swab 
sample collection time points scheduled for all subjects. 
Sample size booster 
substudy 
 
From two treatment groups selected based on 
immunogenicity/safety parameters following primary 
vaccination (as determined by the sponsor), 43 subjects will be 
recruited into the booster substudy (86 subjects in total). Out of 
these, in total approximately 26 subjects will be recruited from 
the PBMC subgroup, approximately 13 subjects for each of the 
two selected treatment groups. Subjects will receive a single 
booster vaccination approximately 1 year after the first vaccine 
administration with the same dose they received during the 
main trial. 
Primary objective 
 
To assess the optimal dose and schedule of the MVA-BN-
RSV vaccine in adult and elderly subjects in terms of 
immunogenicity. 
Secondary 
objectives 
 
To assess safety and reactogenicity of the MVA-BN-
RSV vaccine in adult/elderly subjects  
To assess the RSV-specific humoral immune responses (in all 
subjects) and cellular immune responses (in a subgroup 
population of each group) against the MVA-BN-RSV vaccine 
in adult/elderly subjects. 

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To explore a potential correlation of the RSV-specific immune 
response to RSV related respiratory disease symptoms. 
To assess the RSV-specific immune responses (in subjects of 
the selected treatment groups) one year after the last 
vaccination in the main trial in adult/elderly subjects. 
To assess the RSV-specific humoral immune responses (in 
subjects of the selected treatment groups) and cellular immune 
responses (in the respective subgroup population of the selected 
treatment groups) following a one year booster MVA-BN-
RSV vaccination in adult/elderly subjects. 
To identify further potential differences in durability and/or 
boostability of immune responses in the two chosen MVA-BN-
RSV dose regimens. 
To assess safety and reactogenicity of the MVA-BN-RSV 
vaccine following the booster vaccination in adult/elderly 
subjects. 
Primary endpoint 
 
Geometric Mean Titers (GMTs) after one or two MVA-BN-
RSV vaccinations or placebo measured by Plaque Reduction 
Neutralization Test (PRNT; against strain A) 2 weeks post last 
vaccination 
Secondary 
endpoints 
 
Safety 
Occurrence, relationship to the trial vaccine and intensity of any 
serious adverse event (SAE).  
Occurrence of any Grade 3 or higher adverse events (AE) 
possibly, probably or definitely related to the trial vaccine 
within 4 weeks after each vaccination.  
Occurrence, intensity and duration of solicited local AEs during 
the 8-day period (day of vaccination and the following 7 days) 
after each vaccination. 
Occurrence, relationship to the trial vaccine, intensity and 
duration of solicited general AEs during the 8-day period (day 
of vaccination and the following 7 days) after each vaccination.  

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Occurrence, relationship to the trial vaccine and intensity of 
unsolicited non-serious AEs within 4 weeks after each 
vaccination. 
Immunogenicity  
RSV-specific antibody response rate measured by 
Immunoglobulin G (IgG) Enzyme-linked Immunosorbent 
Assay (ELISA) (total RSV, G protein A strain, G protein B 
strain) at all post vaccination immunogenicity serum sampling 
time points and based on the individual peak titers (separately 
for main trial and booster substudy of the clinical trial). 
RSV-specific GMT measured by IgG ELISA at all 
immunogenicity serum sampling time points and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial).  
RSV-specific antibody response rate measured by 
Immunoglobulin A (IgA) ELISA at all post vaccination 
immunogenicity serum sampling time points and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific GMT measured by IgA ELISA at all 
immunogenicity serum sampling time points and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific antibody response rate measured by PRNT (RSV 
strain A) at all post vaccination immunogenicity serum 
sampling time points and based on the individual peak titers 
(separately for main trial and booster substudy of the clinical 
trial). 
RSV-specific GMT measured by PRNT (RSV strain A) at all 
immunogenicity serum sampling time points and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific antibody response rate measured by PRNT (RSV 
strain B) at all post vaccination immunogenicity serum 
sampling time points and based on the individual peak titers 

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(separately for main trial and booster substudy of the clinical 
trial).  
RSV-specific GMT measured by PRNT (RSV strain B) at all 
immunogenicity serum sampling time points and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific antibody response rate measured by IgA ELISA 
at all post vaccination nasal swab sampling time points 
(mucosal IgA) and based on the individual peak titers 
(separately for main trial and booster substudy of the clinical 
trial). 
RSV-specific GMT measured by IgA ELISA at all nasal swab 
sampling time points (mucosal IgA) and based on the 
individual peak titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific response and responder rates measured by 
Interferon gamma (IFN-) and Interleukin 4 (IL-4) Enzyme-
linked Immuno Spot Technique (ELISPOT) at all post 
vaccination PBMC sampling time points until EAP and until 
BEAP. 
RSV-specific median and geometric mean Spot Forming Units 
(SFU) measured by IFN- / IL-4 ELISPOT at all PBMC 
sampling time points until EAP and until BEAP. 
RSV-specific memory B cells measured at FU1 and FU2 as 
well as Booster Follow Up Visit 1 (BFU1) and Booster Follow 
Up Visit 2 (BFU2). 
Incidence of RSV-specific disease and correlation with 
immunogenicity readouts. 
Trial design  
main trial 
 
Randomized, single-blind, placebo controlled, dose-ranging 
Table 1 
Treatment Groups  
Group N 
Age 
[years] 
Volume per 
dose [mL] 
1st vaccination 
Day 0 
[Inf.U] 
2nd vaccination  
Day 28 
[Inf.U] 
Route 
1 
80 
≥ 55 
0.5 
1 x 108  
 Placebo 
IM 

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2 
80 
≥ 55 
0.5  
1 x 108 
1 x 108 
IM  
3 
80 
≥ 55 
0.5  
5 x 108  
 Placebo 
IM 
4 
80 
≥ 55 
0.5  
5 x 108 
5 x 108 
IM 
5 
80 
≥ 55 
0.5 
Placebo 
Placebo 
IM 
Total 400 
 
 
 
 
 
 
Subjects will be stratified by age into two groups: 55 < 70 and 
≥ 70 years of age. In order to have the highest power to detect 
differences between the strata recruitment will be aimed for 
equal distribution across the age strata; a minimum of 
20 subjects per treatment group in the age stratum ≥ 70 years 
are required. 
Recruitment into the trial will be performed in a staggered 
manner. The staggering process will be performed at one 
clinical trial site. The trial will start with a sentinel cohort with 
2 subjects, of whom one subject will be recruited into Group 2 
and the other subject into Group 4 (i.e. 1:1 subjects receiving 
Dose 1 and Dose 2). Each subject will receive a priming 
vaccination followed 4 weeks later by a boosting vaccination of 
the same dose. Safety will be assessed prior to and 3 days post 
first vaccination. Safety assessments will be based on solicited 
and unsolicited adverse event data evaluated by the Safety 
Monitoring Team (SMT) comprising of the national co-
ordinating investigator, investigator and the medical monitors 
(BN and CRO). Following a positive safety assessment after the 
first vaccination in both subjects recruited into the sentinel 
cohort, recruitment in the safety cohort will start.  
The safety cohort will include a total of 10 subjects: 5 subjects 
will be recruited each into Groups 2 and 4 (i.e. 5:5 subjects 
receiving Dose 1 and Dose 2). Following a positive safety 
assessment by the SMT based upon solicited and unsolicited 
adverse event data 3 days post first vaccination recruitment in 
all groups for the remaining subjects will be opened.  
In addition, after completion of the staggering steps, an 
independent Safety Monitoring Committee (see Section 4.4.2) 
will oversee the clinical trial evaluating safety data on a regular 
basis. 

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Trial Design  
booster substudy 
 
 
From each of the two treatment groups chosen for the booster 
substudy, 43 subjects will be recruited to receive a booster 
vaccination approximately one year after their first vaccination in 
the main trial. Subjects will receive the same dose as in the main 
trial. All 86 subjects will be followed up for 12 months after their 
last vaccination. 
Table 2 
Treatment Groups Booster Substudy 
Group N 
Age 
[years] 
Volume per 
dose [mL] 
Booster vaccination 
Day 0 
Route 
1 
43 
≥ 55 
0.5 
Same dose as 
defined in main trial  
IM 
2 
43 
≥ 55 
0.5  
Same dose as 
defined in main trial 
IM  
Total 86* 
 
 
 
 
*at least 40 evaluable subjects from the two chosen treatment groups 
 
Reports 
 
Final Clinical Study Report (including safety and immunogenicity 
data until 3 months follow-up visit) 
Clinical Study Report Addendum 1 (including additional 
immunogenicity data not yet included in the Final Clinical Study 
Report and 6 months follow-up data for safety and 
immunogenicity)  
Clinical Study Report Addendum 2 (including safety and 
immunogenicity data of thebooster substudy and additional 
immunogenicity data not yet included in the Final Clinical Study 
Report or Addendum 1) 
Main Trial - Subject entry criteria 
Inclusion criteria  
 
1. Male and female subjects, ≥ 55 years of age. 
2. Prior to performance of any trial specific procedures, the 
subject has read, signed and dated an informed consent form, 
having been advised of the risks and benefits of the trial in a 
language understood by the subject, and has signed the Health 
Insurance Portability and Accountability Act (HIPAA) 
authorization form. 
3. Subjects without symptomatic cardiopulmonary and/or 
metabolic disease. Note that subjects who have any active 

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symptoms related to cardiac and/or pulmonary and/or 
metabolic disease (including e.g. uncontrolled asthma, angina 
pectoris, hyperglycaemia or other episodic symptoms), or who 
receive ongoing therapy to control current, active symptoms, 
are not eligible. Subjects on stable treatment (no change in 
≥ 1 month) for previous and controlled symptoms or 
conditions are eligible. The following are examples of subjects 
who may bear cardiopulmonary or metabolic diagnoses but 
who would remain eligible: 
o Subjects on stable (no change in ≥ 1 month) therapy for 
findings (e.g. hypertension, hyperlipidemia) which are not 
associated with current symptoms or disability. 
o Subjects with type II diabetes mellitus are considered 
eligible as long as they are stable on oral antidiabetics and 
have either a documented glycated hemoglobin (HbA1c) 
of ≤ 8 % within three months prior to trial participation or 
confirmation of controlled blood glucose level must be 
obtained at the SCR (screening) visit by a lab test. 
o Subjects who receive short term treatment for temporary 
conditions.  
o Other clinically insignificant findings not deemed to be 
associated with increased risk for respiratory viral 
infections as determined by the investigator. 
4. Able to comply with trial requirements; including access to 
transportation for trial visits. 
5. Body mass index (BMI) ≥ 18.5 and ≤ 39.9 
 
BMI formula for pounds and inches: 
BMI =    (bodyweight in pounds) * 703 
             (bodyheight in inches)2 
 
6. Women of childbearing potential (WOCBP) must have used an 
acceptable method of contraception for at least 30 days prior to 
the first vaccination, must agree to use an acceptable method 
of contraception (as defined in Section 8.2.11) during the trial, 
and must avoid becoming pregnant for at least 28 days after 
the last vaccination. WOCBP must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test 
prior to each vaccination 

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7. Not clinically significant laboratory values as defined in the 
protocol, excluding any Grade ≥ 3 toxicity. 
8. Negative human immunodeficiency virus antibody test (anti-
HIV), negative hepatitis B surface antigen (HBsAG) and 
negative antibody test to hepatitis C virus. 
9. Electrocardiogram (ECG) without clinically significant acute 
findings (e.g. findings suggestive of current ischemia, 
ventricular arrhythmias, congestive heart failure and 
ventricular hypertrophy).  
 
Exclusion criteria 
 
1. Pregnant or breast-feeding women. 
2. Uncontrolled serious infection, i.e. not responding to 
antimicrobial therapy. 
3. History or current clinical manifestation of any serious medical 
condition, which in the opinion of the investigator would 
compromise the safety of the subject or would limit the 
subject’s ability to complete the trial.  
o History of cerebrovascular disorders, including stroke. 
Patients with history of transient ischaemic attack 
(TIA) ≥ 1 year prior to trial participation remain eligible. 
o History of myocardial infarction within ≤ 1 year prior to 
trial participation, current clinical manifestation of angina 
pectoris, current clinical manifestation of congestive heart 
failure ≥ New York Heart Association (NYHA) Grade II, 
uncontrolled high blood pressure defined as systolic blood 
pressure ≥ 150 mmHg and/or diastolic ≥ 100 mmHg 
within the last 2 months. 
4. History of or active autoimmune disease. Persons with vitiligo 
or thyroid disease taking thyroid replacement are not excluded. 
Persons with rheumatoid arthritis not requiring 
immunomodulatory and/or immunosuppressant treatment are 
not excluded. 
5. Known or suspected impairment of immunologic functions 
including, but not limited to chronic inflammatory bowel 
disorders, diabetes mellitus type I. 
6. History of malignancy other than squamous cell or basal cell 
skin cancer, unless there has been surgical excision at least 6 
months ago that is considered to have achieved cure. Subjects 

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with history of skin cancer should not be vaccinated at the 
previous tumor site.  
7.  Clinically significant mental disorder, not adequately 
controlled by medical treatment. 
8. Active or recent (within the time period of six months before 
trial participation) history of chronic alcohol abuse and/or 
intravenous and/or nasal drug abuse. 
9. 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. 
10. Known allergy to eggs or aminoglycosides. 
11. History of anaphylaxis or severe allergic reaction to any 
vaccine. 
12. Having received any vaccinations or planned vaccinations with 
a live vaccine within 30 days prior to or after trial vaccination. 
13. Having received any vaccinations or planned vaccinations with 
an inactivated vaccine within 14 days prior to or after trial 
vaccination. 
14. Chronic systemic administration (defined as more than 
14 days) of > 5 mg prednisone (or equivalent)/day or any other 
immune-modifying drugs during a period starting from three 
months prior to first administration of the trial vaccination and 
ending at the last visit of the active trial phase. The use of 
topical, inhaled, ophthalmic and nasal glucocorticoids is 
permitted. 
15. Administration or planned administration of immunoglobulins 
and/or any blood products during a period starting from three 
months prior to first administration of the trial vaccination and 
ending at the last visit of the active trial phase. 
16. Use of any investigational or non-registered drug or vaccine 
other than the trial vaccine within 30 days preceding the first 
trial vaccination, or planned administration of such a drug 
between participation in the trial and until 4 weeks after last 
trial vaccination. 
17. Previous or planned vaccination with a RSV vaccine/vaccine 
candidate. 

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18. Clinical trial personnel working on the current trial. 
 
Booster Substudy - Subject entry criteria  
Inclusion Criteria 
 
1. Prior to performance of any booster substudy specific 
procedures, the subject has read, signed and dated an informed 
consent form, having been advised of the risks and benefits of 
the trial in a language understood by the subject. 
2. Subject has completed all vaccinations of the main trial 
according to protocol. 
Exclusion 
Criteria 
 
 
1. Any condition that, in the opinion of the investigator, makes it 
unsafe for the subject to receive a further vaccination.  
2. Pregnancy. 
3. An anaphylactic reaction following the administration of any 
vaccine(s). 
4. Clinical need for concomitant or ancillary therapy not 
permitted in the trial as outlined in Section 8.2.2. 
5. Having received any vaccinations or planned vaccinations with 
a live vaccine within 30 days prior to or after booster 
vaccination. 
6. Having received any vaccinations or planned vaccinations with 
an inactivated vaccine within 14 days prior to or after booster 
vaccination. 
7. Chronic systemic administration (defined as more than 
14 days) of > 5 mg prednisone (or equivalent)/day or any other 
immune-modifying drugs during a period starting from 
3 months prior to administration of the booster vaccine and 
ending at the last visit of the booster active trial phase. The use 
of topical, inhaled, ophthalmic and nasal glucocorticoids is 
permitted. 
8. Administration or planned administration of immunoglobulins 
and/or any blood products during a period starting from 

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3 months prior to administration of the booster vaccine and 
ending at the last visit of the booster active trial phase. 
9. Use of any investigational or non-registered drug or vaccine 
other than the trial vaccine within 30 days preceding the 
booster vaccination, or planned administration of such a drug 
during participation in the booster substudy and until 4 weeks 
after booster vaccination. 
10. Subject’s request to discontinue or subject’s refusal to receive 
booster vaccination. 
11. Subject unwilling or unable to comply with trial requirements.  
12. Any reason that, in the opinion of the investigator contradicts 
administration of the booster vaccination or otherwise requires 
early discontinuation of a subject. 

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1.6 Main Trial Schedule  
 
Visit (V) 
 
SCR 
V1 
VS 13 
V1b 9 
V2 
V3  
V3b 9  
V4  
EAP  
FU1  
FU2  
3m FU 
6m FU 
Day/Visit +… Day  
-28 - -1 
0 
V1  
+ 3-4 
V1  
+ 7-9 
V1  
+ 12-16 
V1  
+ 28-35 
V3  
+ 7-9 
V3  
+ 12-16 
V3  
+ 28-35 
V3  
+ 84-98 
V3 
+ 182-210 
Target week 
-4 
0 
0S 13 
1 
2 
4 
5 
6 
8 
16  
30  
Procedures 
Informed consent & 
HIPAA 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion / 
exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
Check eligibility for 
second vaccination 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination incl. 
auscultation of heart & 
lungs; measurement of 
body height & weight 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical exam 
incl. auscultation of the 
heart and lung 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
ECG 4 
 
 
 
 
 
4 
 
 
 
4 
 
4 
4 
Recording of prior / 
concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
Counseling on 
avoidance of pregnancy 
for WOCBP 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
 
 
 
 
2 
2 

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Visit (V) 
 
SCR 
V1 
VS 13 
V1b 9 
V2 
V3  
V3b 9  
V4  
EAP  
FU1  
FU2  
3m FU 
6m FU 
Day/Visit +… Day  
-28 - -1 
0 
V1  
+ 3-4 
V1  
+ 7-9 
V1  
+ 12-16 
V1  
+ 28-35 
V3  
+ 7-9 
V3  
+ 12-16 
V3  
+ 28-35 
V3  
+ 84-98 
V3 
+ 182-210 
Target week 
-4 
0 
0S 13 
1 
2 
4 
5 
6 
8 
16  
30  
Lab 
Pregnancy test for 
WOCBP 3 
 
 
 
 
 
 
 
 
 
 
 
Obtaining blood for 
safety lab 4, 5 
 
 
 
 
 
 
 
 
 
4 
4 
Troponin I testing 4 
 
 
 
 
4 
 
 
4 
 
4 
4 
Nasal swab collection 
for RVP PCR 
(Polymerase Chain 
Reaction) 8  
 
 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Blood draw for serum 
collection 5  
 
 
 
 
 
 
 
 
 
 
 
Nasal swab collection 
for mucosal immune 
response 11 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for PBMC 
collection 5, 9 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit (V) 
 
SCR 
V1 
VS 13 
V1b 9 
V2 
V3  
V3b 9  
V4  
EAP  
FU1  
FU2  
3m FU 
6m FU 
Day/Visit +… Day  
-28 - -1 
0 
V1  
+ 3-4 
V1  
+ 7-9 
V1  
+ 12-16 
V1  
+ 28-35 
V3  
+ 7-9 
V3  
+ 12-16 
V3  
+ 28-35 
V3  
+ 84-98 
V3 
+ 182-210 
Target week 
-4 
0 
0S 13 
1 
2 
4 
5 
6 
8 
16  
30  
Vaccination 
Randomization 
 
 
 
 
 
 
 
 
  
  
Vaccine/TBS 
administration and ≥ 30 
minutes subject 
observation 
 
 
 
 
 
 
 
 
  
  
Recording of immediate 
AEs/ SAEs after 
vaccination 10 
 
 
 
 
 
 
 
 
  
  
Handout of memory 
aid 6 
 
 
 
 
 
 
 
 
  
  
Review/ of memory 
aid 7, 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of memory 
aid 7 
 
 
 
 
 
 
 
 
  
  
Examination of 
injection site  
 
 
 
 
 
 
 
 
  
  
 = mandatory;  = in case of medical need or any underlying condition that requires further examinations;  = Subgroup only 
1 Review of acceptable contraceptive methods and recent menstrual history with WOCBP. 
2 New SAEs, new AEs indicating a respiratory tract infection and changes to AEs/SAEs ongoing at the previous visit only. 
3 At Screening Visit, a serum pregnancy test must be performed. At all other visits, a urine pregnancy test is to be performed.  
4 Additional safety measures can be taken at any other trial visit or at unscheduled visits, if clinically indicated. 
5 Approximate amounts of single blood draws: Safety lab: 11 mL (at V2, V4, FU1 and FU2; if applicable), including hematology (3 mL), serum chemistry 
(including pregnancy test; 8 mL), virology: 5ml (at SCR:)Hepatitits B and C, HIV); Safety lab 17 mL (at SCR), including all above plus HbA1c (3 mL; if 

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applicable); Troponin I: 3 mL; serum collection (antibody testing): 9 mL; PBMC collection (T cell collection): 64 mL. Maximal total amount of blood 
taken/subject: up to 176 mL (642 mL for subjects in the  subgroup). 
6 The memory aid should be completed daily for an 8-day period (Day 0 to Day 7), starting with the day of vaccination. If symptoms are ongoing after Day 7, 
temperature/symptom measurements should continue each day until resolved and the last day of the symptom and maximum intensity will be recorded on 
the memory aid. 
7 The entries on the memory aid card need to be reviewed together with the subject. 
8 Only in the presence of symptoms indicating a respiratory infection at any time point after first vaccination, defined by any case of rhinorrhea, nasal 
congestion, pharyngitis, cough, wheezing (or increase in baseline wheezing), sputum production (or increase / change in nature of baseline sputum 
production) or new (or worsening of) shortness of breath. Subjects need to be instructed to return to the site within 3 days after start of symptoms.  
9 Subgroup only.  
10 Refer to Section 8.2.9 for Cardiac Assessment 
11 Nasal swabs will be taken from both nostrils.  
12 During the staggering phase, data from the memory aid need to be transferred to the Electronic Case Report Form (eCRF) immediately for SMT (Safety 
Monitoring Team) review and the memory aid card will be returned to the subject to complete entries for the remaining days.  
13 Visit VS (Staggering Visit) is only required for the subjects in the staggering phase, i.e. sentinel cohort and safety cohort; the target week is named as 0S. 

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1.7 Trial Schedule Booster Substudy 
 
 
 
Visit (V) 
 
BV0 
BV1 11 
BV1b 8 
BV2 
B 
EAP 
BFU1 
BFU2 
BFU315 
3m FU 
6m FU 
12m FU 
Day/Visit +… Day 
-28 - -1 
0 
BV1  
+ 7-9 
BV1  
+ 12-16 
BV1  
+ 28-35 
BV1  
+ 84-98 
BV1 
+ 182-210 
BV1 
+364-392 
Target week 
-4 
0 
1 
2 
4 
12  
26  
52 
Procedures 
 
 
 
 
 
 
 
 
Informed consent & 
HIPAA 
 
 
 
 
 
 
 
 
Check inclusion / 
exclusion criteria for 
booster substudy 
 
 
 
 
 
 
 
 
Check eligibility for 
booster vaccination 
criteria 
 
 
 
 
 
 
 
 
Recording of SAEs 
since last FU visit in 
main trial 
 
 
 
 
 
 
 
 
Complete physical 
examination incl. 
auscultation of heart & 
lungs; measurement of 
body weight 
 
 
 
 
 
 
 
 
Targeted physical exam 
incl. auscultation of the 
heart and lung 12 
 
12 
12 
12 
12 
12 
12 
 
 
Vital signs 
 
 
 
 
 
 
 
 
Recording of 
concomitant medication 
14 
 
 
 
 
13 
13 
 
 

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Visit (V) 
 
BV0 
BV1 11 
BV1b 8 
BV2 
B 
EAP 
BFU1 
BFU2 
BFU315 
3m FU 
6m FU 
12m FU 
Day/Visit +… Day 
-28 - -1 
0 
BV1  
+ 7-9 
BV1  
+ 12-16 
BV1  
+ 28-35 
BV1  
+ 84-98 
BV1 
+ 182-210 
BV1 
+364-392 
Target week 
-4 
0 
1 
2 
4 
12  
26  
52 
Counseling on 
avoidance of pregnancy 
for WOCBP 1 
 
 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
 
 
2 
2 
 
Laboratory 
 
 
 
 
 
 
 
 
Pregnancy test for 
WOCBP 3 
 
 
 
 
 
 
 
 
Obtaining blood for 
safety lab 4, 5 
 
 
 
 
 
4 
4 
 
 
Blood draw for serum 
collection 5 
 
 
 
 
 
 
 
 
 
Nasal swab collection 
for mucosal immune 
response 10 
 
 
 
 
 
 
 
 
Blood draw for PBMC 
collection 5, 8 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
 
 
 
 
 
 
 
Vaccine administration 
and ≥ 30 minutes 
subject observation 
 
 
 
 
 
 
 
 
Recording of immediate 
AEs/ SAEs after 
vaccination 9 
 
 
 
 
 
 
 
 
Handout of memory 
aid 6 
 
 
 
 
 
 
 
 
Review/ of memory 
aid 7 
 
 
 
 
 
 
 
 

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Visit (V) 
 
BV0 
BV1 11 
BV1b 8 
BV2 
B 
EAP 
BFU1 
BFU2 
BFU315 
3m FU 
6m FU 
12m FU 
Day/Visit +… Day 
-28 - -1 
0 
BV1  
+ 7-9 
BV1  
+ 12-16 
BV1  
+ 28-35 
BV1  
+ 84-98 
BV1 
+ 182-210 
BV1 
+364-392 
Target week 
-4 
0 
1 
2 
4 
12  
26  
52 
Collection of memory 
aid 7 
 
 
 
 
 
 
 
 
Examination of 
injection site 
 
 
 
 
 
 
 
 
 = mandatory;  = in case of medical need or any underlying condition that requires further examinations;  = PBMC Subgroup only 
1 Review of acceptable contraceptive methods and recent menstrual history with WOCBP. 
2 New SAEs and changes to AEs/SAEs ongoing at the previous visit only. 
3 Urine pregnancy test  
4 Additional safety measures can be taken at any other trial visit or at unscheduled visits, if clinically indicated. 
5 Approximate amounts of single blood draws: Safety lab: 11 mL (at BV0 and BV2; BFU1and BFU2 if applicable), including Haematology (3 mL), serum 
chemistry (including pregnancy test; 8 mL); serum collection (antibody testing): 9 mL; PBMC collection (T cell collection): 64 mL.   
6 The memory aid should be completed daily for an 8-day period (Day 0 to Day 7), starting with the day of vaccination. If symptoms are ongoing after Day 7, 
temperature/symptom measurements should continue each day until resolved and the last day of the symptom and maximum intensity will be recorded on 
the memory aid. 
7 The entries on the memory aid card need to be reviewed together with the subject. 
8 PBMC subgroup only.  
9 Refer to Section 8.2.9 for Cardiac Assessment 
10 Nasal swabs will be taken from both nostrils.  
11 BV1 approximately 11-13 months after the first vaccination in the main part of the trial 
12 A targeted physical examination is only needed if guided by any signs or symptoms previously identified or any new symptoms that the subject has 
experienced since the last visit 
13 Concomitant medication at BFU visits are only to be captured in case the concomitant medication is related to a new SAE and changes to AEs/SAEs 
ongoing at the previous visit 
14 Concomitant medication between FU2 and BV0 are only to be captured in case the concomitant medication is related to a SAE. 
15 At BFU3 only blood draw for immunogenicity serum collection will be performed (9 mL) 
 

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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 Paramyxoviridae 
family. The RSV genome encodes eleven proteins, two 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 two different strains 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 infection 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 lower respiratory tract infections (LRTI) in newborns, infants 
and younger children. While the burden of RSV is highly recognized in the pediatric population, 
particularly in the very young and those with cardio-respiratory disease, RSV infections are also a 
serious health concern in the elderly and in immunocompromised adults. Indeed, about 78 % of 
deaths due to RSV-related underlying respiratory and circulatory disease occur among the 
population ≥ 65 years of age (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 infection in the 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. Similar to influenza, the burden of RSV disease has been 
identified as significant 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 LRTI provided by high levels of serum 
neutralizing antibodies (Groothuis, 1993). The F and G proteins are the main targets for induction 
of neutralizing antibodies. 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 two 
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 ages, although of decreasing severity, since with recurring infections the disease 
0
5
10
15
20
25
30
35
40
<1
1-4
5-49
50-64
≥65
Mortality Rate
Per 100,000 person-years
. 
Age Group
RSV

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becomes more limited to the upper respiratory tract (Glezen, 1986). Morbidity and disease 
severity increases again in people > 50 years.  
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 for the adult population are limited to supportive measures as there is neither an approved 
RSV vaccine nor any specific treatment available. One of the key set-backs to further 
development of RSV vaccines in infants and children has been the failed approach with a 
formalin-inactivated (FI) 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 Modified Vaccinia Ankara Strain (MVA) based 
RSV vaccine candidate described here 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 elderlies and the lack of treatment options, there is an unmet 
medical need to prevent RSV-induced respiratory disease which accounts for hospitalizations due 
to COPD, pneumonia, asthma and congestive heart failure. 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 
BN has developed a vaccine candidate against RSV by including RSV surface proteins encoding 
genes from both circulating RSV strains (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 severe RSV LRTI (e.g. RSV bronchiolitis, pneumonia) in both elderlies and 

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in adults with 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) which induce humoral and cell 
mediated immunity in animal models (mice and cotton rats). 
• 
Two internal proteins N (Nucleoprotein) and M2 (Matrix protein) are expected to enhance 
immunogenicity, especially in terms of cytotoxic T cell responses, but also cross-protection 
to infection with other strains, since these two proteins are highly conserved among the 
different RSV strains. 
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 six major deletions, resulting in the loss of 15 % 
(31 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 a strongly attenuated 
replication in susceptible cell types, its genes are efficiently transcribed with the block in viral 
replication being at the level of virus assembly and egress (Sutter, 1992; Carroll, 1997). 
Bavarian Nordic A/S (BN), an international biopharmaceutical company, is developing a 
proprietary strain of Modified Vaccinia Ankara (MVA-BN, trade name IMVAMUNE outside the 
European Union [EU], invented name IMVANEX in the EU) for use as a prophylactic smallpox 
vaccine. 
MVA-BN is a highly attenuated, purified live vaccine produced under serum-free conditions in 
chicken embryo fibroblasts cells. In contrast to replicating smallpox vaccines MVA-BN can be 
administered subcutaneously (SC) or IM, and not by scarification. The standard route and 
schedule of MVA-BN are two subcutaneous injections administered 4 weeks apart. Since MVA-
BN is non-replicating in human cells it does not form vesicles (“takes”) (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. 
2.4 Summary of Nonclinical Studies with MVA-BN-RSV Vaccine 
BN has already performed almost 20 GLP-compliant safety studies for either the vector backbone 
MVA-BN or MVA-BN based recombinant vaccines. All these studies demonstrated that these 
investigational products are safe and well tolerated. Similarly, the current MVA-BN-RSV 
vaccine candidate (MVA-mBN294B) was tested in a GLP-compliant repeat-dose toxicity and 
local tolerance study in rabbits and found to be safe and well tolerated. There were no MVA-BN-
RSV related mortality or clinical observations and no vaccine related findings in the hematology, 
clinical chemistry, and histopathology. 
For more detailed information on preclinical data refer to the respective sections of the 
Investigator’s Brochure (IB). 
2.5 Clinical Profile of MVA-BN and Recombinant MVA-based Vaccines 
To date, 19 clinical trials (13 sponsored by BN and 6 sponsored by the NIH [National Institutes 
of Health]) evaluating the safety and immunogenicity of MVA-BN have been completed. 
Currently three clinical trials are ongoing - two sponsored by BN and one sponsored by the NIH. 
More than 7100 subjects have been vaccinated with MVA-BN in completed clinical trials, 
including risk groups with contraindications to conventional smallpox vaccines, such as HIV- 
infected patients and patients with atopic dermatitis (AD). Further, MVA-BN has been evaluated 
in an elderly population, i.e. subjects 56 to 80 years of age. Including the ongoing clinical trials, 
more than 7700 subjects have been exposed to MVA-BN.  
Furthermore, BN has evaluated the safety and immunogenicity of MVA-BN-based recombinant 
vaccines (including MVA-BN-Filo®) in more than 700 subjects including healthy subjects, HIV 
infected individuals and populations with cancer and children in completed trials. In trials with 
recombinant MVA vaccines, doses up to 5 x 108 TCID50 (Tissue Culture Infectious Dose 50 %) 
were administered applying varying schedules of repeat vaccinations, e.g. 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).  
Recently the first Phase I clinical trials with an MVA-BN-based recombinant vaccine against 
filoviruses (MVA-BN Filo®) were completed. Several other Phase I, Phase II and Phase III 
clinical trials are ongoing. The preliminary safety data are consistent with the experience with 
MVA-BN, and no related SAEs have been observed so far in these trials. 
As of May 2016, more than 1500 subjects have received vaccinations with MVA-BN-Filo, in 
addition to the 8100 subjects who have received MVA-BN and the MVA-BN based recombinant 

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products (other than MVA-BN-Filo), which in total sums up to more than 9600 exposed subjects 
to the MVA-BN platform technology to date.  
Details on the first clinical trial with MVA-BN-RSV are provided in Section 2.6. 
2.5.1 Safety Overview of MVA-BN and Recombinant MVA-based Vaccines 
In all completed and ongoing clinical trials, vaccinations with MVA-BN or MVA-BN based 
vaccines have shown to be safe and well tolerated in in all populations tested (healthy; elderly; 
immunocompromised) and at all doses tested (up to 5 x 108 TCID50). No cases of death, assessed 
as being even possibly related, have been reported for a subject in a clinical trial using MVA-BN. 
Results obtained from completed Phase I and II trials and ongoing trials with several recombinant 
MVA-BN based vaccines in healthy adults and children, HIV infected and cancer patients 
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 3 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 
as displayed in Table 3 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. 

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Table 3 
Suspected Adverse Drug Reactions Reported by ≥ 1 % of Subjects in Completed  
MVA-BN Clinical Trials* (N = 7099 subjects) 
Preferred Term (PT) 
No. of reports by subjects 
Frequency (%) 
Injection site pain 
5798 
81.7 
Injection site erythema 
4577 
64.5 
Injection site swelling 
3341 
47.1 
Injection site induration   
3253 
45.8 
Injection site induration (solicited) 
3248 out of 7013 
46.3 
Injection site induration (unsolicited) 
5 out of 86 
5.8 
Fatigue 
2121 
29.9 
Injection site pruritus  
2607 
36.7 
Injection site pruritus (solicited) 
2396 out of 5904 
40.6 
Injection site pruritus (unsolicited) 
211 out of 1213 
17.4 
Fatigue (solicited) + 
2121 out of 5904 
35.9 
Myalgia 
2258 
31.8 
Myalgia (solicited) 
2257 out of 7013 
32.2 
Myalgia (unsolicited) 
1 out of 86 
1.2 
Headache 
2177 
30.7 
Headache (solicited) 
2176 out of 7013 
31.0 
Headache (unsolicited) 
1 out of 86 
1.2 
Nausea 
999 
14.1 
Nausea (solicited) 
998 out of 7013 
14.2 
Nausea (unsolicited) 
1 out of 86 
1.2 
Rigors/chills 
604 
8.5 
Rigors/chills (solicited) 
603 out of 6297 
9.6 
Rigors/chills (unsolicited) 
1 out of 802 
0.1 
Body temperature increased 
255 
3.6 
Injection site discoloration 
190 
2.7 
Appetite disorder 
150 
2.1 
Appetite disorder (solicited) ++ 
150 out of 1366 
11.0 
Injection site nodule 
149 
2.1 
Pain in extremity 
147 
2.1 
Pain in extremity (solicited) 
139 out of 1346 
10.3 
Pain in extremity (unsolicited) 
8 out of 5753 
0.1 
Arthralgia 
129 
1.8 
Injection site hematoma 
107 
1.5 
* POX-MVA-001, -002, -004, -005, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, HIV-
NEF-004 and HIV-POL-002; 7 subjects in POX-MVA-009 received Dryvax® either on the same day or within 
7 days after MVA-BN administration and were therefore not included to avoid a potential bias in the adverse 
event reporting.  + not in POX-MVA-001; ++ only in NIH trials 
Looking only at the events that were reported by at least 1 % of subjects, the majority of ADRs 
represented local vaccination site reactions as well as common systemic reactions typical for 
modern injectable vaccines and were classified as being mild to moderate in intensity and 
resolved completely without intervention within the first 7 days following vaccination. To date, 
no trends have been identified suggesting the occurrence of any particular unexpected adverse 
reactions or classes of adverse reactions following vaccinations with MVA-BN.  

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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. 
Serious Suspected Adverse Drug Reactions  
A total of seven (7 out of 7758 vaccinated subjects = 0.09 %) serious suspected ADRs have been 
reported for MVA-BN smallpox vaccine in completed and ongoing trials (see Table 4). 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.  
 

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Table 4 
Serious Suspected Adverse Drug Reactions (Assessed by the Investigator to Be At Least Possibly Related to MVA-BN) 
Trial 
Code 
Age/ 
Gender 
Days After 
Vaccination 
Event 
Outcome 
Underlying Diseases/ Circumstances 
PI  
Assessment  
BN 
Opinion 
POX-
MVA-
005 
 
 
70 days after 
2nd 
vaccination 
Sarcoidosis 
Stable 
and 
asympto-
matic 
Urinary tract infection with Chlamydia 
trachomatis at time of first symptoms 
(arthralgia) 
Possibly 
related 
Possibly 
related 
POX-
MVA-
005 
 
 
26 months 
after 2nd 
vaccination 
Crohn’s disease 
Stable 
and 
asympto-
matic 
under 
therapy  
Abnormal lab results (elevated alkaline 
phosphatase, absolute neutrophils and 
platelet counts) at screening for  
2-year follow-up trial  
POX-MVA-023 (excluded) 
Possibly 
related 
Possibly 
related  
POX-
MVA-
008 
 
 
8 days after 
2nd 
vaccination 
Transitory ocular 
muscle paresis 
Resolved 
without 
sequelae 
No relevant medical history 
Probably 
related 
Possibly 
related 
POX-
MVA-
010 
 
 
133 days 
after 2nd 
vaccination 
Congestive heart 
failure due to cardio-
myopathy 
Stable 
under 
cardiac 
medi-
cations 
Surgery for ventricular septal defect as 
child. HIV infection. Concomitant 
(denied, therefore previously unknown to 
BN) participation in a Growth-Hormone 
Releasing Hormone (GH-RH) trial; event 
also assessed as possibly related to GH-
RH 
Possibly 
related 
Unlikely 
related 
POX-
MVA-
011 
 
 
1 day after 
2nd 
vaccination 
Simple pneumonia and 
pleurisy 
Resolved 
without 
sequelae 
HIV infection (CD4 count 4 weeks prior 
to second vaccination was 299 cells/µL). 
History of chronic obstructive pulmonary 
disease. Acute sinusitis and nasal 
congestion due to swimmer’s ear which 
triggered hospital admittance. 
Possibly 
related 
Unlikely 
related 

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Trial 
Code 
Age/ 
Gender 
Days After 
Vaccination 
Event 
Outcome 
Underlying Diseases/ Circumstances 
PI  
Assessment  
BN 
Opinion 
POX-
MVA-
036 
 
 
0 days after 
2nd 
vaccination 
Throat tightness and 
other hypersensitivity 
symptoms such as 
hives, pruritus, tender 
vaccination site, 
swollen axilla, 
angioedema of 
forearms 
Resolved 
without 
sequelae 
The subject received her second dose of 
MVA-BN 21 days after the first dose and 
after 2 hours developed symptoms such 
as skin reactions and throat tightness 
which was responsive to epinephrine 
treatment. She had no wheezing and was 
not hypotensive. Symptoms subsided 
after several days under prednisone and 
diphenhydramine treatment. She has a 
family history of allergies and a medical 
history of shingles. She has received 
multiple vaccines before but never had 
previous hives or other problems with 
vaccines. 
Possibly 
related 
Possibly 
related 
POX-
MVA-
036 
 117 days 
after 1st 
vaccination 
Non ST segment 
elevation myocardial 
infarction 
Resolved 
without 
sequelae 
Positive family history for cardiovascular 
diseases (both grandfathers had 
myocardial infarctions in their 50ies, 
father had blood clots), as well as 
overweight with a BMI above 33. A few 
days before event onset, subject returned 
from a trip to India with diarrhoea and 
was started on ciprofloxacine treatment 
(which per US prescribing information is 
associated with angina pectoris and 
myocardial infarction). He showed chest 
pain and increased troponin I, but no ST 
segment changes in the ECG and no 
coronary artery disease in cardiac 
catheterization. A post-infectious 
myocarditis (published case reports exist 
for campylobacter, shigella, salmonella) 
was considered as alternative etiology for 
the reported event. 
Possibly 
related 
Unlikely 
related 

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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 and measles in more than 700 subjects including healthy 
and HIV infected populations. In trials with recombinant MVA-BN based vaccines, doses up to 
5 x 108 TCID50 were administered applying varying schedules of repeated vaccinations, e.g. 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). Results obtained from these Phase I and II trials demonstrate a similar safety profile and 
vector immunogenicity as compared to MVA-BN alone.  
Two of the trials with recombinant vaccines allowed for a direct comparison with MVA-BN as an 
active control. These trials (HIV-POL-002 and HIV-NEF-004) were performed to evaluate two 
different recombinant MVA-based HIV vaccine candidates in HIV-infected subjects. In both 
trials, a total of three vaccinations with either the recombinant HIV vaccine or MVA-BN were 
performed according to a 0, 8 and 16 week regimen.  
Table 5 and Table 6 summarize the safety results of these two trials and demonstrate that there 
were no significant differences between the recombinant MVA-based vaccine candidates and 
MVA-BN. For clinical trial HIV-POL-002, singular adverse events are not presented due to the 
small sample size in this clinical trial (N = 30). 

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Table 5 
Solicited and Common Unsolicited Adverse Events in Clinical Trial HIV-NEF-004 
 
MVA-NEF 
1 x 108 TCID50 
(N = 25) 
MVA-NEF 
5 x 108 TCID50 
(N = 26) 
MVA-BN 
1 x 108 TCID50 
(N = 26) 
n 
% 
n 
% 
n 
% 
Solicited AE 
Injection Site Pain 
23 
92 
26 
100 
26 
100 
Injection Site Erythema 
22 
88 
24 
92 
20 
77 
Injection Site Swelling 
22 
88 
23 
89 
19 
73 
Injection Site Induration 
19 
76 
23 
89 
20 
77 
Fatigue 
16 
64 
21 
81 
15 
58 
Headache 
17 
68 
20 
77 
14 
54 
Myalgia 
14 
56 
18 
69 
12 
46 
Body temp. increased 
3 
12 
8 
31 
8 
31 
Nausea 
5 
20 
4 
15 
6 
23 
Chills 
2 
8 
10 
39 
2 
8 
Unsolicited AE, irrespective of drug-event relationship / time of onset (N total > 5) 
Nasopharyngitis 
6 
24 
5 
19 
11 
42 
Lymphadenopathy 
6 
24 
3 
12 
6 
23 
Diarrhea 
3 
12 
5 
19 
4 
15 
Headache 
4 
16 
4 
15 
2 
8 
Injection site pruritus 
1 
4 
5 
19 
3 
12 
Cough 
4 
16 
2 
8 
2 
8 
Influenza 
3 
12 
3 
12 
2 
8 
Night sweats 
2 
8 
4 
15 
2 
8 
Arthralgia 
3 
12 
2 
8 
2 
8 
Herpes simplex 
3 
12 
2 
8 
1 
4 
Paraesthesia 
2 
8 
3 
12 
1 
4 
Unsolicited treatment-related AE during vaccination period (N total > 2) 
Injection site pruritus 
1 
4 
5 
19 
3 
12 
Lymphadenopathy 
2 
8 
2 
8 
2 
8 
N = Number of subjects in the group; n=number of subjects with AE 
Percentages are calculated based on the total number of subjects in the respective group  
Source: HIV-NEF-004 Clinical Study Report (August 07, 2008), Table 29. 
 

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Table 6 
Unsolicited and Solicited Adverse Events in Clinical Trial HIV-POL-002 
 
MVA-BN Polytope 
1 x 108 TCID50 
(N = 20) 
MVA-BN 
1 x 108 TCID50 
(N = 10) 
 
n (%) 
n (%) 
Total no. of patients included 
20 (100.0) 
10 (100.0) 
Number of patients with at least one SAE 
0 
0 
Unsolicited AE 
Number of patients with 
 
 
- at least one AE 
14 (70.0) 
7 (70.0) 
- at least one related AE 
6 (30.0) 
4 (40.0) 
Unsolicited AEs: Number of AE 
 
 
- reported AE 
37 
19 
- average number of AE per subject 
1.85 
1.90 
Solicited local AE 
Number of patients with 
 
 
- at least one AE 
17 (85.0) 
10 (100.0) 
Number of solicited local AE 
133 
69 
- average number of AE per subject 
6.65 
6.90 
Solicited general AE 
Number of patients with 
 
 
- at least one AE 
11 (55.0) 
7 (70.0) 
Number of solicited general AE 
44 
28 
- average number of AE per subject 
2.20 
2.80 
N = number of patients per treatment group; n = number of patients with AE; % = (n/N)*100; 
Percentages for 'Number of patients with...' were based on the total number of patients included per group. 
Solicited local AE: redness, pain, swelling, induration at the injection site; solicited general AEs: body 
temperature increased, headache, myalgia, rigor/chills, nausea, fatigue  
Source: HIV-POL-002 Clinical Study Report (January 12, 2009), Tables 14.3.1.1 and 14.3.5. 
2.5.3 Immunogenicity Overview of MVA-BN 
MVA-BN was tested for safety and immunogenicity among healthy volunteers in 3 Phase I and II 
dose finding trials (Vollmar, 2006; Frey, 2007; Von Krempelhuber, 2010). Across these trials a 
linear dose relationship was observed between the vaccine doses and both vaccinia ELISA and 
PRNT titers. Maximum ELISA seroconversion rates and peak titers were reached 2 weeks after 
the second vaccination, with 100 % seroconversion after the second dose for all dose groups 
receiving at least 2 x 107 TCID50 per 0.5 mL dose of MVA-BN. Statistical analysis indicated 
lower doses to be inferior to the standard dose tested throughout all dose ranging trials, whereas 
the standard dose achieved ELISA seroconversion rates between 81 and 100 % already after the 
first dose. For the PRNT, the same trend was observed with about 77 % seroconversion rates 2 
weeks after the second MVA-BN administration in all groups receiving the highest dose. 

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The early onset of seroconversion and the higher titers of total and neutralizing antibodies 
combined with an excellent safety profile qualified the dose of at least 5 x 107 TCID50 as the most 
suitable human dose. The final optimal (standard) dose and schedule for the general population 
was decided to be two doses of at least 5 x 107 TCID50 MVA-BN (nominal titer of 1 x 108 
TCID50 per dose) administered SC 4 weeks apart. A trial in elderly, i.e. 56-80 years old vaccinia-
experienced subjects, indicates that it is sufficient to vaccinate this population only once with 
MVA-BN. 
In the first clinical trial with the MVA-BN-RSV vaccine (RSV-MVA-001 Phase I trial) a low 
dose with a nominal titer of 1 x 107 TCID50 per dose was compared against a dose with a nominal 
titer of 1 x 108 TCID50 per dose (see Section 2.6). 
In this RSV trial (RSV-MVA-002) different doses and schedules will be evaluated: all subjects 
will receive two vaccinations - either both vaccinations with MVA-BN-RSV vaccine 
1 x 108 Inf.U per 0.5 mL, 5 x 108 Inf.U per 0.5 mL or Placebo or the first vaccination with MVA-
BN-RSV vaccine 1 x 108 Inf.U or 5 x 108 Inf.U per 0.5  mL followed by the second vaccination 
with Placebo (see Table 1). Please note that the dose was expressed as TCID50 for the Phase I 
clinical trial with 1 x 108 TCID50 per dose corresponding to 1 x 108 Inf.U per dose. 
2.6 Clinical Trial Data with MVA-BN-RSV Vaccine 
Safety, tolerability and immunogenicity of the recombinant MVA-BN-RSV vaccine were 
evaluated in the randomized, single-blind, placebo-controlled Phase I trial (RSV-MVA-001). In 
total 63 healthy adult subjects were vaccinated with either placebo, low or normal dose of MVA-
BN-RSV vaccine (Table 7). 
Table 7  
Treatment Groups in Phase I Clinical Trial RSV-MVA-001 
Group 
N* 
Age 
(years) 
Vaccine: nominal titer 
per dose (TCID50) 
Volume per 
dose 
[mL] 
Schedule 
(vaccination 
days) 
Route 
1 
18 + 3 
18-49 
1 x 107 
0.5  
0; 28 
IM 
2 
18 + 3 
18-49 
1 x 108 
0.5  
0; 28 
IM 
3 
18 + 3 
50-65 
1 x 108 
0.5  
0; 28 
IM 
Total 
63 
 
IM = intramuscular; TCID50 = tissue culture infectious dose 50% 
*18 subjects in each treatment group receiving MVA-BN-RSV vaccine and 3 subjects in each treatment group 
receiving placebo 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Table 1. 
63 subjects received two vaccinations 4 weeks apart and completed the active trial phase 4 weeks 
after the last vaccination. To evaluate long-term safety and immunogenicity of the MVA-BN-
RSV vaccine, subjects completed a follow-up (FU) visit 6 months after the second vaccination.  

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Safety Data 
The trial demonstrated that MVA-BN-RSV was well tolerated in adult and elderly subjects 
receiving either a low dose (1 x 107 TCID50) or normal dose (1 x 108 TCID50) of the vaccine. No 
SAEs occurred and no subject discontinued the trial due to an AE. The incidence of solicited 
local or solicited general AEs was generally low and comparable between analysis groups. A 
summary of solicited AEs and unsolicited treatment-emergent Adverse Events (TEAEs) is 
presented in Table 8. 
Table 8 
RSV-MVA-001 Trial Summary of Adverse Events per Subject - FAS 
 
Analysis group 
Adult low 
(N=18) 
Adult normal 
(N=18) 
Elderly normal 
(N=18) 
Placeboa 
(N=9) 
n (%) 
E 
n (%) 
E 
n (%) 
E 
n (%) 
E 
Overall (per subject) 
 
 
 
 
 
 
 
 
TEAE 
14 (77.8) 
29 
11 (61.1) 
26 
9 (50.0) 
15 
5 (55.6) 
5 
Non-serious TEAE 
14 (77.8) 
29 
11 (61.1) 
26 
9 (50.0) 
15 
5 (55.6) 
5 
SAEb 
0 
0 
0 
0 
0 
0 
0 
0 
Related TEAEc 
8 (44.4) 
11 
7 (38.9) 
11 
3 (16.7) 
5 
2 (22.2) 
2 
TEAE Grade ≥3 
0 
0 
1 (5.6) 
2 
1 (5.6) 
1 
0 
0 
Related TEAE Grade ≥3c 
0 
0 
0 
0 
0 
0 
0 
0 
E = number of events; FAS = full analysis set; SAE = serious adverse event; TEAE = treatment-emergent 
adverse event; N = number of subjects per group, n = number of subjects experiencing an AE 
a Adult and elderly placebo combined. 
b SAEs are included even if they exceed the 28-day follow-up period after each vaccination. 
c Unsolicited or general solicited AE the investigator considered to have possible, probable, definite or missing 
relationship to trial vaccine; although solicited local events are by definition always ADRs they are not 
included here. 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Table 15.3.1.1.2. 
The most frequently reported unsolicited TEAE was URTI, followed by blood potassium 
increased. Overall, only few unsolicited TEAEs were considered to be related to trial treatment, 
all of which were assessed as Grade 1. Furthermore, only 2 subjects were reported as having 
unsolicited TEAEs assessed as Grade 3 (gastroenteritis and URTI); the majority of subjects had 
unsolicited TEAEs assessed as Grade 1 and not related to trial treatment. 
The most frequent solicited local AEs were injection site pain, injection site erythema, and 
injection site pruritus; the most frequent solicited general AEs were body temperature increased, 
fatigue and headache in accordance with the safety profile of the vector backbone MVA-BN (for 
further details see IB). Solicited local AEs are summarized in Table 9 and related solicited 
general AEs are summarized in Table 10. 
The majority of the solicited local or solicited general AEs were assessed as Grade 1; only few 
subjects had Grade 2 solicited AEs. Only 1 subject experienced a Grade ≥3 solicited general AE 

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of nausea, which was reported as not related to trial treatment. All solicited local and general AEs 
resolved within 8 days (median ≤5 days). 
Table 9 
Solicited Local Adverse Events (Overall per Subject) – FAS 
 
Number (%) of subjects 
Adult low 
(N=18) 
Adult normal 
(N=18) 
Elderly normal 
(N=18) 
Placeboa 
(N=9) 
Overall (per subject) 
 
 
 
 
Injection site erythema 
5 (27.8) 
4 (22.2) 
4 (22.2) 
2 (22.2) 
Injection site induration 
0 
1 (5.6) 
1 (5.6) 
1 (11.1) 
Injection site pain 
3 (16.7) 
9 (50.0) 
11 (61.1) 
1 (11.1) 
Injection site pruritus 
2 (11.1) 
1 (5.6) 
6 (33.3) 
0 
Injection site swelling 
1 (5.6) 
1 (5.6) 
1 (5.6) 
0 
FAS = full analysis set 
a Adult and elderly placebo combined. 
Note: no Grade ≥ 3 local Solicited AE was reported 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Table 15.3.1.2.3. 
Table 10 
Related Solicited General Adverse Events (Overall per Subject) - FAS 
 
Number (%) of subjects 
Adult low 
(N=18) 
Adult normal 
(N=18) 
Elderly normal 
(N=18) 
Placeboa 
(N=9) 
Body temperature increased 
4 (22.2) 
3 (16.7) 
0 
0 
Chills 
0 
0 
0 
0 
Fatigue 
3 (16.7) 
2 (11.1) 
1 (5.6) 
1 (11.1) 
Headache 
1 (5.6) 
2 (11.1) 
2 (11.1) 
0 
Myalgia 
1 (5.6) 
0 
2 (11.1) 
0 
Nausea 
1 (5.6) 
1 (5.6) 
0 
0 
FAS = full analysis set 
a Adult and elderly placebo combined. 
Note: Relationship summarized as all symptoms determined by the investigator with reasonable possibility 
that the vaccine contributed to them (relationship to vaccine documented as 'possible', 'probable', 'definite' 
or missing). 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Table 15.3.1.3.5. 

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Immunogenicity Data 
The primary objective of this Phase I trial was the collection of safety data. The trial had a small 
sample size and was not powered for testing RSV-specific immunogenicity thus the 
immunogenicity results are descriptive and only of exploratory nature. 
Antibody Analyses: 
RSV-specific GMTs increased after vaccination in all groups receiving MVA-BN-
RSV compared with placebo in the ELISA and PRNT strain A analyses. An at least 2-fold 
increase was shown for the adult standard dose group for both assays and for the elderly standard 
dose group for the RSV-specific ELISA. The neutralizing antibody titer measured by PRNT in 
the elderly standard dose group was lower than in the adult standard dose group; serum RSV-
specific baseline and individual peak geometric mean titers by ELISA, PRNT (strain A) and 
PRNT (strain B) are summarized in Table 11. 

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Table 11 
Serum RSV-Specific Baseline and Individual Peak Geometric Mean Titers – FAS and 
PPS 
 
Analysis group 
Adult low 
(N=18b) 
Adult standard 
(N=18) 
Elderly standard 
(N=18) 
Placeboa 
(N=9) 
Week (Vi
sit) 
GM
T 
95% CI 
GMT 
95% CI 
GMT 
95% CI 
GMT 
95% CI 
Serum RSV-specific IgG ELISA GMT 
Week 0 
(V1) 
1146 
915, 1437 
1121 
830, 1512 
913 
726, 1149 
1005 
710, 1422 
Individual 
Peak 
GMT 
1807 
1435, 2276 
2238 
1622, 3089 
2286 
1725, 
3030 
1289 
913, 1820 
Serum RSV-specific PRNT (strain A) GMT 
Week 0 
(V1) 
546 
380, 783 
652 
474, 897 
625 
456, 857 
524 
374, 734 
Individual 
Peak 
GMT 
926 
676, 1268 
1394 
1087, 1788 
944 
677, 1315 
782 
560, 1093 
Serum RSV-specific PRNT (strain B) GMT 
Week 0 
(V1) 
256 
173, 379 
327 
190, 561 
242 
154, 380 
231 
116, 456 
Individual 
Peak 
GMT 
379 
245, 587 
512 
322, 814 
374 
231, 604 
347 
189, 636 
CI = confidence interval; ELISA = enzyme-linked immunosorbent assay; FAS = full analysis set; 
GMT = geometric mean titers; IgG = immunoglobulin G; PPS = per protocol set; RSV = respiratory 
syncytial virus 
a Adult and elderly placebo combined. 
b Only 17 of 18 subjects had available data in this group at Week 8 (V7). 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Tables 15.2.2.5, 15.2.4.5 and 15.2.5.5. 
The cellular immune response was assessed using an IFN-γ/IL-4 ELISPOT assay using three 
different RSV peptide pools (F, G and N) as well as RSV for stimulation. IFN- secreting T cells 
specific for the F, G and N protein increased in all active treatment groups, with no substantial 
differences between vaccine dose and age whereas numbers of IL-4 producing T cells were low 
or below the detection limit. No dose dependency was seen in terms of Geometric Mean Spot 
Forming Units (GMSFUs). The T cell response boosted by the normal dose in the adult and 
elderly group was comparable. The responder rate based on IFN-γ producing PBMCs was highest 
in the elderly standard dose group, ranging from 66.7% (12/18) to 94.4% (17/18) of subjects for 
all stimulating agents. Responder rates based on IFN-γ and IL-4 producing PBMCs are 
summarized in Table 12. 

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These results showed that the MVA-BN-RSV candidate leads to an increase in the number of 
IFN- producing T cells without inducing IL-4 secreting T cells, thus limiting the risk for 
emergence of enhanced disease by biasing the immune response strongly towards a Th1 type 
response.  
Table 12 
PBMC ELISPOT: IFN-γ/IL-4 Responder Rates – FAS and PPS 
 
Analysis group 
Adult lowa 
(N=18) 
Adult standard 
(N=18) 
Elderly standard 
(N=18) 
Placebob 
(N=9) 
IFN-γ 
IL-4 
IFN-γ 
IL-4 
IFN-γ 
IL-4 
IFN-γ 
IL-4 
 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
ER (%) 
95% CI 
Pool F 
7 (43.8) 
19.8, 
70.1 
1 (6.3) 
0.2, 30.2 
7 (38.9) 
17.3, 
64.3 
1 (5.6) 
0.1, 27.3 
14 (77.8) 
52.4, 
93.6 
1 (5.6) 
0.1, 27.3 
0 
0.0, 33.6 
0 
0.0, 33.6 
Pool G 
7 (43.8) 
19.8, 
70.1 
2 (12.5) 
1.6, 38.3 
16 (88.9) 
65.3, 
98.6 
1 (5.6) 
0.1, 27.3 
17 (94.4) 
72.7, 
99.9 
1 (5.6) 
0.1, 27.3 
0 
0.0, 33.6 
0 
0.0, 33.6 
Pool N 
7 (43.8) 
19.8, 
70.1 
1 (6.3) 
0.2, 30.2 
10 (55.6) 
30.8, 
78.5 
0 
0.0, 18.5 
12 (66.7) 
41.0, 
86.7 
0 
0.0, 18.5 
1 (11.1) 
0.3, 48.2 
0 
0.0, 33.6 
RSV 
8 (50.0) 
24.7, 
75.3 
2 (12.5) 
1.6, 38.3 
10 (55.6) 
30.8, 
78.5 
5 (27.8) 
9.7, 53.5 
15 (83.3) 
58.6, 
96.4 
1 (5.6) 
0.1, 27.3 
0 
0.0, 33.6 
0 
0.0, 33.6 
CI = confidence interval; ELISPOT = enzyme-linked immunospot technique; FAS = full analysis set; 
IFN-γ = interferon gamma; IL-4 = interleukin 4; PPS = per protocol set; ER (%) = Number of subjects with 
positive ELISPOT responder status (percentage of subjects with positive responder status based on number 
of subjects with available data); RSV = respiratory syncytial virus 
a Only 16 of 18 subjects had available data in this group. 
b Adult and elderly placebo combined. 
Note: At least 2 post Week /V1 responses are required for the subject to be defined as a responder. 
Source: MVA-RSV-001 Clinical Study Report (Ed. 1), Table 15.2.16.1 and Table 15.2.16.3. 
2.7 Rationale 
As outlined in Section 2, RSV is an important cause of serious respiratory disease in all age 
groups. The recently completed Phase I clinical trial RSV-MVA-001 generated first safety and 
immunogenicity data of the recombinant MVA-BN-RSV vaccine in healthy adult subjects 18-
65 years of age. This trial confirmed that the vaccine is safe and well tolerated and was able to 
increase humoral and cellular immune responses in the population tested. 
The main trial is designed to evaluate different doses of the MVA-BN-RSV vaccine in a target 
population of adult/elderly subjects in terms of immunogenicity and safety.  

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As RSV is a seasonal disease with peak occurrence in the winter months in the northern 
hemisphere vaccination for protection against moderate to severe respiratory tract infections 
caused by RSV would be scheduled shortly before the start of the RSV season. Depending on the 
durability of the immune responses elicited by a vaccination a yearly booster before the next RSV 
season might be necessary. Hence a substudy applying a booster vaccination in a subgroup of the 
main trial will evaluate the durability of the immune response and the ability to booster with the 
MVA-BN-RSV vaccine.  
The objective of the booster substudy is to demonstrate that the immune response of subjects 
previously vaccinated with MVA-BN-RSV vaccine can be boosted one year later with a single 
MVA-BN-RSV vaccination. Assessment of individual antibody titers within short time intervals 
following the booster vaccination and up to 12 months after the vaccination will provide 
information on how fast and effective measurable antibody titers can be regained. The booster 
substudy will also evaluate the durability of immune responses 12 months following the primary 
vaccination (baseline measurement prior to administration of the booster dose) and 12 months 
following the booster vaccination.  
The selection of the treatment groups to be included in the booster substudy is based on the 
results of the main trial. Selecting subjects of two groups for a booster vaccination will add a one 
year time point for the two most promising dose regimen treatment groups and will allow to 
identify further potential differences in durability or boostability of immune responses in the 
chosen dose regimens. Half of the subjects enrolled for the main part of the trial in the two 
chosen treatment groups will receive the same vaccine dose (either 1 x 108 or 5 x 108 Inf.U) as in 
the main part. The two groups to continue into the booster substudy will be selected by the 
sponsor. The subjects from the remaining groups will be excluded from the booster substudy as 
the further development of their dose regimen is unlikely at the current time. 
2.8 Trial Population 
Any ≥ 55 year old women and men of any ethnicity who meet all of the inclusion and none of the 
exclusion criteria are eligible for participation in this trial.  
Groups will be stratified by age: 55 to < 70, ≥ 70 years in the main part of the trial. For the 
booster substudy 43 evaluable subjects will be chosen randomly from each of the two selected 
treatment groups. No further age stratification will be done in the booster substudy. 
2.9 Risk/Benefit Assessment 
2.9.1 Potential Risks 
Blood drawing may cause discomfort, bruising, light-headedness or fainting. Rarely, a blood 
draw may result in infection at the site of venipuncture. Nasal swab collection may cause 
irritation or dryness at the sampling sites for a short time, usually less than 5 minutes.  

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Some subjects in the trial will get Placebo instead of 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 I clinical trial RSV-MVA-001 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 or MVA-BN based recombinant vaccines 
and/or those typically seen with other modern vaccines. Main risks involve the development of 
local reactions at the injection site, e.g. erythema, pain, swelling and induration. 
As with all 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 might occur, appropriate medical treatment and supervision will 
be readily available. 
2.9.2 Benefits 
There will be no direct benefit to the trial participants. Trial participants will contribute 
significantly to the development of a RSV vaccine which is a potential benefit for adults with 
underlying cardiovascular or pulmonary disease, elderly and children to reduce 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 in clinical trials are expected to acquire protection against smallpox infection and 
might potentially also acquire protection against disease symptoms caused by RSV. The 
immunogenicity results of the first clinical trial 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. 
Analysis of the samples collected will not directly benefit the subject.  
3 Objectives 
Refer to trial protocol synopsis Section 1.5. 

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4 Trial Design 
4.1 Experimental Design Forecast 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in ≥ 55 year old adults 
to evaluate the safety and immunogenicity of the recombinant MVA-BN-RSV vaccine. 
In total 400 subjects will be recruited into the main trial. Subjects will receive two 
administrations 4 weeks apart which will consist of MVA-BN-RSV Dose 1, MVA-BN-
RSV Dose 2 or placebo (TBS). To obtain Dose 1 the vaccine will be diluted in TBS according to 
the vaccination instructions. For details on the treatment groups see Table 13. 
Approximately one year after their first vaccination 86 subjects in the selected treatment groups 
of the main trial will be recruited to participate in the booster substudy and will receive one dose 
of MVA-BN-RSV vaccine. 
Recruitment into the main trial will be performed into a staggered manner as outlined below. Any 
occurring events as defined in the trial halting rules in Section 4.5 would stop the staggering 
procedure until further clarification.  
Staggering Procedure: 
The staggering process will be performed at one clinical trial site. The main trial will start with a 
sentinel cohort with 2 subjects, of whom one subject will be recruited into Group 2 and the other 
subject into Group 4 (i.e. 1:1 subjects receiving Dose 1 and Dose 2). Each subject will receive a 
priming vaccination followed 4 weeks later by a boosting vaccination of the same dose. Safety 
will be assessed prior to and 3 days post first vaccination. Safety assessments will be based on 
solicited and unsolicited adverse event data evaluated by the Safety Monitoring Team (SMT) 
comprising of the national coordinating investigator, investigator and the medical monitors (BN 
and CRO). Following a positive safety assessment after the first vaccination in both subjects 
recruited into the sentinel cohort, recruitment in the safety cohort will start.  
The safety cohort will include a total of 10 subjects: 5 subjects will be recruited each into 
Groups 2 and 4 (i.e. 5:5 subjects receiving Dose 1 and Dose 2). Following a positive safety 
assessment by the SMT based upon solicited and unsolicited adverse event data 3 days post first 
vaccination recruitment in all groups for the remaining subjects will be opened.  
The principal investigator, national coordinating investigator and the medical monitors (BN and 
CRO) must participate in the SMT meeting and decide on the next staggering step. Project leader 
BN, Contract Research Organization (CRO), statistician and Clinical Research Associate (CRA) 
can participate in the meeting, if further information on the trial conduct is required, but will not 
participate in the decision to go to the next staggering step. In total, two staggering steps and 
SMT meetings are required until all groups can be recruited in parallel.  

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Table 13 
Treatment Groups Main Trial 
Group 
N 
Age 
[years] 
Volume per 
dose [mL] 
1st vaccination 
Day 0 
[Inf.U] 
2nd vaccination  
Day 28 
[Inf.U] 
Route 
1 
80 
≥ 55 
0.5 
1 x 108  
 Placebo 
IM 
2 
80 
≥ 55 
0.5  
1 x 108 
1 x 108 
IM 
3 
80 
≥ 55 
0.5  
5 x 108  
 Placebo 
IM 
4 
80 
≥ 55 
0.5  
5 x 108 
5 x 108 
IM 
5 
80 
≥ 55 
0.5 
Placebo 
Placebo 
IM 
Total 
400 
 
 
 
 
 
Booster Substudy 
In total 86 evaluable subjects  will receive a booster vaccination approximately one year after 
their first vaccination in the main trial receiving the same dose they received during the main 
trial. To obtain 40 evaluable subjects per group up to 43 subjects per selected group will be 
recruited. Subjects are then followed up for 12 months after their last vaccination. 
4.2 Description of Trial Procedures 
The trial procedures will be conducted according to the trial procedure schedule (Section 1.5, 
Section 1.6 and Section 1.7) and as described on the following pages. Visits must be scheduled 
within the intervals/visit windows given below. 
4.2.1 Main Trial 
4.2.1.1 Screening Phase 
All subjects must be thoroughly informed of all aspects of the trial (e.g. trial visit schedule, 
required evaluations and procedures, risks and benefits) as described in the informed consent 
form (ICF). The ICF and the statement about the HIPAA must be reviewed with the subject and 
signed and dated by the subject and the investigator, or person designated by the investigator, 
who conducted the informed consent discussion before proceeding with any evaluations or 
procedures required by this protocol. 
After ICF has been collected, subjects will enter a screening period of up to 28 days before the 
first vaccination. 
Screening Visit (Days -28 to -1) 
The following tasks will be performed: 
• 
Subject to read, sign and date ICF and HIPAA 
• 
Check inclusion/exclusion criteria 
• 
Obtain medical history 

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Screening Visit (Days -28 to -1) 
• 
Complete physical examination including auscultation of heart and lungs and 
measurement of body weight and height 
• 
Evaluation of vital signs 
• 
Perform Electrocardiogram (ECG) reading 
• 
Recording of prior and concomitant medication 
• 
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and 
recent menstrual history with WOCBP 
• 
Recording of AEs/SAEs 
• 
Blood draw for safety laboratory 22 mL including  
o Serum pregnancy test (WOCBP only) 
o Hematology & serum chemistry 
o Hepatitis B and C; HIV 
o Troponin I 
o If applicable: HbA1c (additional blood draw of 3 mL) 
If a subject is screened and cannot be vaccinated because of a certain transient condition (e.g. 
abnormal lab value due to an acute condition or a missing lab evaluation e.g. due to mishandling 
of the sample), then the subject can be re-screened on one further occasion only and the 
respective test(s) should be repeated as a “partial” re-screening rather than a full re-screening. 
The re-Screening Visit must be within the 28 day window started by the first Screening Visit and 
the window Day -28 to -1 before first vaccination must not be exceeded. If a subject cannot be 
vaccinated due to other circumstances (e.g. completion of a wash-out period for a medication or 
vaccine not allowed during the trial) or the 28 day period is exceeded, the complete Screening 
Visit needs to be repeated and a new Screening number will be assigned. The clock then re-starts 
at the re-screening visit with Day -28 before the first vaccination. 
4.2.1.2 Active Trial Phase 
After successfully passing the screening evaluations, the eligible volunteers can enter the active 
trial phase (Visit 1 to EAP) starting with Visit 1 and ending at either EAP or premature 
discontinuation. 
The first 12 subjects are recruited in a staggered fashion. After completion of the staggering steps 
all remaining subjects can be vaccinated. The staggering process is described in detail in 
Section 4.1 and in the Synopsis in Section 1.5. 
The procedures performed at Visit 1 and all following visits are listed below. Collection of 
immunogenicity samples and all other examinations listed above the vaccination event must 
always be performed prior to vaccine/TBS administration. 

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At Visit 1/Day 0, subjects will receive the first vaccination with 0.5 mL of the recombinant 
MVA-BN-RSV or TBS given IM preferably in the non-dominant upper arm. Subjects will be 
blinded to the treatment assignment, i.e. will not be told which group they were assigned until 
after completion of the main trial. 
Following each vaccination subjects will be kept under close observation at the clinical trial site 
for at least 30 minutes, with appropriate medical treatment readily available in case of a rare 
anaphylactic reaction following the vaccine administration. Any AEs that occur during or after 
vaccine administration will be recorded.  
Solicited local and general AEs will be collected on a memory aid, completed by the subject for 
an 8-day period (Days 0-7), beginning with the day of vaccination. The memory aid will be 
returned to the clinic staff at the following visit. If symptoms persist at Day 7, daily symptoms 
and temperature will continue to be measured each day until resolved and the last day of 
symptoms and maximum intensity is recorded on the memory aid.  
 
Visit 1 (Day 0) 
Tasks to be performed prior to randomization and vaccination:  
• 
Confirmation of inclusion / exclusion criteria  
• 
Targeted physical examination including auscultation of the heart and lungs  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and 
recent menstrual history with WOCBP 
• 
Recording of AEs/SAEs 
• 
Urine pregnancy test (WOCBP only) 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Only for the subgroup: PBMC collection (64 mL)  
 
If eligible for participation in this trial the subject will be randomized (for the first 12 
subjects please refer to Sections 1.5 and 4.1. for details on the staggering procedure). The 
following tasks will be performed after randomization:  
• 
First MVA-BN-RSV vaccination 
• 
Subject observation by CTS staff for at least 30 minutes after vaccination 
• 
Recording of immediate AEs/SAEs 
• 
Handout of memory aid for first vaccination, ruler and thermometer 
 

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Visit 1 (Day 0) 
Temporary deferral of vaccination: If an acute illness is present the subject may be vaccinated 
at a later date within the accepted time window. The vaccine/TBS can be administered to 
persons with a minor illness such as diarrhea or any other mild condition with or without low-
grade febrile illness, i.e. oral temperature < 100.4 °F (< 38.0 °C). In case of minor illness 
involving the upper respiratory tract, such as mild upper respiratory infection, with or without 
low-grade febrile illness, the vaccination should be deferred within the accepted time window, 
until the subject is symptom-free. 
 
Visit VS (V1 + 3-4 days) 
 Sentinel Cohort, Safety Cohort (first 12 [2 + 10] subjects)  
Groups 2 and 4 
The following tasks will be performed: 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 
• 
Review of the memory aid handed out at Visit 1  
Note: transfer entries to eCRF for SMT review within 24 hours, keep photocopy of the 
memory aid and return original to the subject to complete entries for the remaining days. 
• 
Examination of the injection site 
 
Only if clinically indicated:  
• 
Nasal swab collection for Respiratory Viral Panel (RVP) PCR in case of symptoms 
indicating a respiratory infection 
 
Visit 1b (V1 + 7-9 days)  
Subgroup only 
The following tasks will be performed: 
• Targeted physical exam incl. auscultation of the heart and lung 
• Evaluation of vital signs  
• Recording of concomitant medication 
• Recording of AEs/SAEs 
• Review of the Memory Aid Card handed out at Visit 1  
• Collection of the Memory Aid Card  
• Blood draw for serum collection (9 mL) and PBMC collection (64 mL)  
• Nasal swab collection for mucosal immune response (swabs are taken from both 
nostrils) 

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Visit 1b (V1 + 7-9 days)  
Subgroup only 
• Examination of the injection site 
 
Only if clinically indicated: 
• Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
 
 
Visit 2 (V1 + 12-16 days) 
The following tasks will be performed: 
• 
Targeted physical examination including auscultation of the heart and lungs 
• 
Evaluation of vital signs 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Review of the memory aid handed out at Visit 1 
• 
Collection of the memory aid  
• 
Examination of the injection site 
• 
Only for the subgroup: PBMC collection (64 mL) 
 
Only if clinically indicated: 
• 
Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
• 
ECG  
• 
Troponin I (additional blood draw of 3 mL) 
 
Visit 3 (V1 + 28-35 days)  
Tasks to be performed prior to vaccination:  
• 
Check eligibility for second vaccination (refer to Section 4.2.4) 
• 
Targeted physical examination including auscultation of the heart and lungs 
• 
Evaluation of vital signs 
• 
Recording of concomitant medications  

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Visit 3 (V1 + 28-35 days)  
• 
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and 
recent menstrual history with WOCBP 
• 
Recording of AEs/SAEs 
• 
Urine pregnancy test (WOCBP only) 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
 
Only if clinically indicated: 
• 
Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
 
If the subject is eligible to receive the second vaccination the following tasks will be 
performed: 
• 
Second MVA-BN-RSV vaccination 
• 
Subject observation by CTS staff for at least 30 minutes after vaccination 
• 
Recording of immediate AEs/SAEs 
• 
Handout of memory aid  
 
If the subject is not eligible to receive the second vaccination, continue with visit EAP. 
 
Temporary deferral of vaccination: If an acute illness is present the subject may be vaccinated 
at a later date within the accepted time window. The vaccine/TBS can be administered to 
persons with a minor illness such as diarrhea or any other mild condition with or without low-
grade febrile illness, i.e. oral temperature < 100.4 °F (< 38.0 °C). In case of minor illness 
involving the upper respiratory tract, such as mild upper respiratory infection, with or without 
low-grade febrile illness, the vaccination should be deferred within the accepted time window, 
until the subject is symptom-free. 
 
Visit 3b (V3 + 7-9 days)  
Subgroup only  
The following tasks will be performed: 
• Targeted physical exam incl. auscultation of the heart and lung 
• Evaluation of vital signs  
• Recording of concomitant medication 
• Recording of AEs/SAEs 
• Blood draw for serum collection (9 mL) and PBMC collection (64 mL)  

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Visit 3b (V3 + 7-9 days)  
Subgroup only  
• Nasal swab collection for mucosal immune response (swabs are taken from both 
nostrils) 
• Review of the memory aid handed out at Visit 3 
• Collection of the memory aid  
• Examination of the injection site 
Only if clinically indicated: 
• Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
 
 
Visit 4 (V3 + 12-16 days)  
The following tasks will be performed: 
• 
Targeted physical examination including auscultation of the heart and lungs 
• 
Evaluation of vital signs 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Review of the memory aid handed out at Visit 3  
• 
Collection of the memory aid  
• 
Examination of the injection site 
• 
Only for the subgroup: PBMC collection (64 mL) 
 
Only if clinically indicated: 
• 
ECG 
• 
Troponin I (additional blood draw of 3 mL) 
• 
Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
 
Visit EAP (V3 + 28-35 days)  
The following tasks will be performed: 
• 
Targeted physical examination including auscultation of the heart and lungs 

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Visit EAP (V3 + 28-35 days)  
• 
Evaluation of vital signs 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 
• 
Urine pregnancy test (WOCBP only) 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
 
Only if clinically indicated: 
• 
Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
4.2.1.3 Follow-Up (FU) Phase 
To monitor long-term safety and antibody persistence, subjects will come to the CTS for follow-
up (FU) visits three months (FU1 Visit) and six months (FU2 Visit) after the last vaccination. 
After all tasks for the trial were performed at FU2 Visit the subject may be unblinded to the 
assigned dosage group by the investigator. 
For subjects who do not receive the second vaccine/TBS administration for any reason, the 
FU1 Visit will be performed three months after the first vaccination and the FU2 Visit will be 
performed 6 months after the first vaccination (see Section 4.2.4). 
FU1 Visit (V3 + 84-98 days) 
The following tasks will be performed: 
• 
Recording of new SAE and new RSV-specific symptoms and changes to AEs /SAEs 
ongoing at last active trial Visit EAP  
• 
Targeted physical examination including auscultation of the heart and lungs  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Only for the subgroup: PBMC collection (64 mL)  
 
Only if clinically indicated: 
• 
ECG  
• 
Troponin I (additional blood draw of 3 mL) 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Nasal swab collection for RSV PCR in case of symptoms indicating a respiratory 
infection 
 

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FU2 Visit (V3 + 182-210 days) 
The following tasks will be performed: 
• 
Recording of new SAEs, new RSV-specific symptoms and changes to AEs/SAEs 
ongoing at the FU1 Visit 
• 
Targeted physical examination including auscultation of the heart and lungs 
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Only for the subgroup: PBMC collection (64 mL)  
 
 
Only if clinically indicated: 
• 
ECG  
• 
Troponin I (additional blood drawl of 3 mL) 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Nasal swab collection for RVP PCR in case of symptoms indicating a respiratory 
infection 
 
4.2.2 Booster Substudy 
4.2.2.1 Booster Visit 0 
All subjects eligible to take part in the booster substudy must be thoroughly informed of all 
aspects of the booster substudy (e.g. substudy visit schedule, required evaluations and 
procedures, risks and benefits) as described in the informed consent form (ICF). The ICF and the 
statement about the HIPAA must be reviewed with the subject and signed and dated by the 
subject and the investigator, or person designated by the investigator, who conducted the 
informed consent discussion before proceeding with any evaluations or procedures required by 
this protocol. 
After ICF has been collected, subjects will enter a baseline period of up to 28 days before the 
1 year booster vaccination. 
Booster Visit 0 (Days -28 to -1) 
The following tasks will be performed: 
• 
Subject to read, sign and date ICF and HIPAA 
• 
Check Inclusion/Exclusion criteria for booster substudy 
• 
Recording of SAEs since last FU visit in main trial 

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Booster Visit 0 (Days -28 to -1) 
• 
Complete physical examination including auscultation of heart and lungs and 
measurement of body weight 
• 
Evaluation of vital signs 
• 
Recording of prior and concomitant medication 
• 
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and 
recent menstrual history with WOCBP 
• 
Recording of AEs/SAEs after ICF signature 
• 
Blood draw for safety laboratory 11 mL including  
o Hematology & serum chemistry 
 
 
Additional safety measures (which may include troponin testing, ECG, etc.) can be taken at this 
or at any other trial visit or at unscheduled visits, if clinically indicated. 
4.2.2.2 Booster Substudy Active Trial Phase 
After successfully passing the baseline evaluations, the eligible volunteers can enter the active 
phase of the booster substudy (Visit BV1 to BEAP) starting with Visit BV1 and ending at either 
BEAP or premature discontinuation. 
The procedures performed at BV1 and all following visits are listed below. Collection of 
immunogenicity samples and all other examinations listed above the vaccination event must 
always be performed prior to vaccine administration. 
At BV1/Day 0, subjects will receive the booster vaccination with 0.5 mL of the recombinant 
MVA-BN-RSV given IM preferably in the non-dominant upper arm. 
Following the vaccination subjects will be kept under close observation at the clinical trial site for 
at least 30 minutes, with appropriate medical treatment readily available in case of a rare 
anaphylactic reaction following the vaccine administration. Any AEs that occur during or after 
vaccine administration will be recorded.  
Solicited local and general AEs will be collected on a memory aid, completed by the subject for 
an 8-day period (Days 0-7), beginning with the day of vaccination. The memory aid will be 
returned to the clinic staff at the following visit. If symptoms persist at Day 7, daily symptoms 
and temperature will continue to be measured each day until resolved and the last day of 
symptoms and maximum intensity is recorded on the memory aid.  

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Booster Visit 1 (Day 0) 
Tasks to be performed prior to vaccination:  
• 
Check eligibility for booster vaccination (see “Reasons for early discontinuation”, 
Section 4.2.4) 
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Counseling on avoidance of pregnancy: Review of acceptable contraceptive methods and 
recent menstrual history with WOCBP 
• 
Recording of AEs/SAEs 
• 
Urine pregnancy test (WOCBP only) 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
 
Only for the subgroup: PBMC collection (64 mL)  
 
Only if clinically indicated: 
Targeted physical examination (see Section 8.2.3) 
 
If eligible for booster vaccination the following tasks will be performed:  
• 
MVA-BN-RSV vaccination 
• 
Subject observation by CTS staff for at least 30 minutes after vaccination 
• 
Recording of immediate AEs/SAEs 
• 
Handout of memory aid for booster vaccination, ruler and thermometer 
 
Temporary deferral of vaccination: If an acute illness is present the subject may be vaccinated 
at a later date within the accepted time window. The vaccine can be administered to persons 
with a minor illness such as diarrhea or any other mild condition with or without low-grade 
febrile illness, i.e. oral temperature < 100.4 °F (< 38.0 °C). In case of minor illness involving 
the upper respiratory tract, such as mild upper respiratory infection, with or without low-grade 
febrile illness, the vaccination should be deferred within the accepted time window, until the 
subject is symptom-free. 
 
Booster Visit 1b (BV1 + 7-9 days)  
Subgroup only 
The following tasks will be performed: 
• Evaluation of vital signs  
• Recording of concomitant medication 

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Booster Visit 1b (BV1 + 7-9 days)  
Subgroup only 
• Recording of AEs/SAEs 
• Review of the memory aid handed out at BV1 
• Collection of the memory aid  
• Blood draw for serum collection (9 mL) and PBMC collection (64 mL)  
• Nasal swab collection for mucosal immune response (swabs are taken from both 
nostrils) 
• Examination of the injection site 
 
Only if clinically indicated: 
Targeted physical examination (see Section 8.2.3) 
 
Booster Visit 2 (BV1 + 12-16 days) 
The following tasks will be performed: 
• 
Evaluation of vital signs 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Review of the memory aid handed out at BV1 
• 
Collection of the memory aid  
• 
Examination of the injection site 
 
Only for the subgroup: PBMC collection (64 mL) 
 
Only if clinically indicated:  
Targeted physical examination (see Section 8.2.3) 
 
 
Booster EAP (BV1 + 28-35 days)  
The following tasks will be performed: 
• 
Evaluation of vital signs 
• 
Recording of concomitant medication 
• 
Recording of AEs/SAEs 

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Booster EAP (BV1 + 28-35 days)  
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
 
Only if clinically indicated: 
Targeted physical examination (see Section 8.2.3) 
4.2.2.3 Booster Follow-Up (BFU) Phase 
To monitor long-term safety and antibody persistence, subjects will come to the CTS for follow-
up (FU) visits 3 months (BFU1 Visit), 6 months (BFU2 Visit) and 12 months (BFU3 Visit) after 
the booster vaccination. 
Booster FU1 Visit (BV1 + 84-98 days) 
The following tasks will be performed: 
• 
Recording of new SAEs and changes to AEs /SAEs ongoing at last active trial 
Visit BEAP  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication for ongoing AEs/SAEs since BEAP or new SAEs 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
 
Only for the subgroup: PBMC collection (64 mL)  
 
Only if clinically indicated: 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Targeted physical examination (see Section 8.2.3) 
 

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Booster FU2 Visit (BV1 + 182-210 days) 
The following tasks will be performed: 
• 
Recording of new SAE and changes to AEs /SAEs ongoing at BFU1  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication for ongoing AEs/SAEs since BFU1 or new SAEs 
• 
Blood draw for serum collection (9 mL) 
• 
Nasal swab collection for mucosal immune response (swabs are taken from both nostrils) 
• 
Only for the subgroup: PBMC collection (64 mL)  
 
Only if clinically indicated: 
• 
Blood draw for safety laboratory (hematology & serum chemistry, 11 mL)  
• 
Targeted physical examination (see Section 8.2.3) 
 
Booster FU3 Visit (BV1 + 364-392 days) 
The following task will be performed: 
• 
Blood draw for serum collection (9 mL) 
 
 
4.2.3 Unscheduled Visits 
If clinically indicated, additional visits may be necessary between scheduled visits. Unscheduled 
visits may be performed to repeat laboratory testing or physical exams due to a new development. 
Examinations performed at unscheduled visits will be documented in the source documents as 
well as in the respective eCRF sections for unscheduled visits. 
4.2.4 Early Discontinuation  
Reasons for early discontinuations: 
A subject may be discontinued from the trial early for different reasons. 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:  
• 
An AE/SAE that, in the opinion of the investigator, makes it unsafe for the subject to 
receive a further vaccination  
• 
Pregnancy 
• 
An anaphylactic reaction following the administration of any vaccine(s) 

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• 
Clinical need for concomitant or ancillary therapy not permitted in the trial as outlined in 
Section 8.2.2 
• 
Subject’s request to discontinue  
• 
Subject’s refusal to receive second / booster vaccination. 
• 
Subject unwilling or unable to comply with trial requirements.  
• 
Any reason that, in the opinion of the investigator contradicts administration of the second / 
booster vaccination or otherwise requires early discontinuation of a subject. 
Handling of early discontinuations main trial 
• 
If a subject discontinues from the trial after first but prior to the second vaccination or does 
not receive the second vaccination for any reason, the subject should follow the abbreviated 
visit schedule outlined below:  
• 
Visits 3, 3b (for subgroup) and 4 will not be performed; 
• 
Visit schedule for all following visits will be calculated based on the 1st vaccination, i.e.  
o 
Visit EAP will be performed 4 weeks post the 1st vaccination 
o The 3 and 6 months FU visits (FU1 and FU2) will be performed 3 and 6 months post 
the 1st vaccination, respectively.  
Handling of early discontinuations booster substudy 
• 
If a subject recruited for the booster substudy (after signature of the ICF for the booster 
substudy) discontinues from the trial prior to the booster vaccination or does not receive the 
booster vaccination for any reason, the subject should undergo a concluding safety visit 
(including pregnancy test for WOCBP).  
• 
If a subject recruited for the booster substudy discontinues from the trial after the booster 
vaccination, it is highly recommended that the subject undergoes an abbreviated visit 
schedule (including BEAP, BFU1 and BFU2).  
Furthermore, each subject has the right to terminate their trial participation completely at any 
time for whatever reason and the investigator may terminate a subject’s trial participation. 
Subjects who’s trial participation is terminated completely should undergo a concluding safety 
visit (including pregnancy test for WOCBP), i.e. subjects will be offered to have an optional 
safety visit performed. The subject has the right to refuse.  
4.3 Trial Duration 
The total duration of the main trial for each subject including the screening period and follow-up 
visits will be up to 39 weeks. The total duration of the booster substudy including baseline and 

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follow up visits will be 56 weeks. The duration of the trial as a whole depends on the recruitment 
period. 
4.4 Safety Review 
4.4.1 Safety Monitoring Team 
The SMT is a board that oversees the safety of subjects participating in the trial during the 
staggering phase only. The members of the SMT are the national coordinating investigator, 
principal investigator (of the staggering site) and the medical monitors (BN and CRO) of the 
clinical trial. The primary responsibility of the SMT is to review and evaluate the accumulated 
trial data for safety after each staggering step and make decision to proceed to the next staggering 
step.  
A separate charter describes in detail relevant operational procedures, communication pathways 
and roles and responsibilities of the SMT .  
4.4.2 Safety Monitoring Committee  
The Safety Monitoring Committee (SMC) is an independent board that oversees the safety of 
subjects participating in the trial. The SMC consists of three members who are independent, i.e. 
not involved as investigators in any BN sponsored trials and have no direct or indirect financial 
interests in BN or the CRO managing the trial. The primary responsibilities of the SMC are to 
periodically review and evaluate the accumulated trial data for participant safety, trial conduct 
and progress, and make recommendations to BN and the Coordinating Investigator and Principal 
Investigators (PI) concerning the continuation, modification, or termination of the trial. The SMC 
considers trial specific data as well as relevant background knowledge about the disease, test 
agent, and subject population under trial. A separate charter describes in detail relevant 
operational procedures, communication pathways and roles and responsibilities of the SMC. 
If an event occurs which fulfills the trial halting rules (see Section 4.5 for further details) the 
SMC will review the event in a timely manner and give a recommendation to BN and the 
Coordinating Investigator and PIs to halt, resume or terminate the trial participation of the 
affected subject and/or the trial as a whole. 
4.5 Trial Halting Rules 
A temporary halting or termination of the trial as a whole can be decided by the SMT (during the 
staggering phase) or the SMC in case of an occurrence of  
• 
an SAE 
• 
an unexpected (i.e. not listed in the current IB) Grade 3 or higher systemic reaction or lab 
toxicity (Appendix 1: Toxicity Scale for Laboratory Values) 

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with an at least reasonable possibility of a causal relationship to the administration of MVA-BN-
RSV vaccine, i.e. the relationship cannot be ruled out. 
These parameters are not all-inclusive. Other AEs could occur that would trigger a SMC review. 
If an event fulfilling the trial halting criteria reaches the investigator’s attention, the investigator 
has the liability to alert the responsible Pharmacovigilance (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 8.3.1. 
5 Selection of Subjects 
Each investigator will keep a log of subjects screened for the trial, and provide the reason in case 
of exclusion. Information about every subject entering the trial will be documented in the eCRF. 
For subjects not fulfilling the eligibility criteria the minimum information documented in the 
eCRF is confirmation of ICF signature, demographics and reason for screen failure. 
5.1 Recruitment Procedure 
Subjects will be recruited actively. Recruitment strategies, including IRB approved 
advertisements, will be evaluated by the Sponsor. 
80 subjects will be recruited in each group (400 in total) according to the treatment group 
schedule, Table 13. 
After signing the ICF and HIPAA, subjects undergo screening procedures to check eligibility 
according to the inclusion/exclusion criteria. In the event of a screening failure due to mild or 
limited acute illness or abnormal laboratory values, the subject may be re-screened after 
resolution of the event. Re-screening may require only an additional blood draw or a complete re-
screening evaluation, depending on the circumstances of and the time interval from the initial 
screening failure (see also Section 4.2.1). 
From each of the two treatment groups selected for the booster substudy, 43 subjects will be 
randomly recruited to receive a booster vaccination approximately one year after their first 
vaccination with the same dose they had received during the main trial. Out of these 86 subjects, 
in total approximately 26 subjects will be recruited from the PBMC subgroup resulting in 
approximately 13 subjects for each of the two selected treatment groups.  
5.2 Inclusion Criteria 
Refer to trial protocol synopsis Section 1.5. 

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5.3 Exclusion Criteria 
Refer to trial protocol synopsis Section 1.5 
6 Investigational Medicinal Product and Diluent 
MVA-mBN294B (common name MVA-BN-RSV vaccine), highly attenuated, live recombinant 
virus based on the viral vector MVA-BN, provided as a LF formulation. It is administered as 
intramuscular application. The packages and vials will be labeled according to the respective 
Product Specifications. 
One vaccine dose has a nominal virus titer of 5 x 108 Inf.U (0.5 mL volume) if used undiluted. 
To obtain a nominal titer of 1 x 108 Inf.U (per 0.5 mL) (Dose 1) the vaccine has to be diluted with 
MVA-BN formulation buffer, TBS.  
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 
current version of the IB. 
6.1 Production, Packaging and Labeling 
The MVA-BN-RSV bulk drug substance and the TBS are manufactured by Bavarian Nordic A/S, 
DK.  
Address: 
Bavarian Nordic A/S 
6.2 Shipment, Storage and Handling 
TBS and MVA-BN-RSV vaccine are packed separately and will be shipped temperature 
controlled and monitored to the CTS (if applicable via a warehouse). At the CTS, the package is 
handed over to the personnel in charge of vaccine preparation, e.g. the pharmacist. After receipt 
the CTS personnel are responsible for proper storage of vaccine and diluent. 
MVA-BN-RSV vaccine is shipped and stored frozen 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 of the LF formulation of MVA-BN-RSV vaccine are provided in BN Standard 
Operating Procedure (SOP) 
 

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 (see also Section 6.3). 
TBS has to be shipped and stored refrigerated at 36°F to 46°F (+2°C to +8°C). 
6.3 Preparation, Administration and Dosage 
Details on vaccine storage, preparation and administration of MVA-BN-RSV vaccine are 
provided in 
 
 
 
Study specific vaccination instructions detailing the preparation/dilution and application 
procedure and handling of TBS will be provided to the CTS. 
6.4 Accountability and Disposal 
After receipt of the IMP, the CTS 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 in the pharmacy file.  
Used and unused vials must be stored in a safe place and remain the property of BN. The 
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 the 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.  
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. 
Furthermore, used syringes/ancillary supply should be autoclaved or incinerated and discarded at 
the CTS according to local regulations. 
7 Assessment of Immunogenicity 
The immunogenicity of the vaccine will be assessed by measuring humoral, cellular and mucosal 
immune responses on collected serum, nasal swab and PBMC samples. 
• 
RSV-specific, G protein A strain-specific, G protein B strain-specific systemic antibody 
levels will be determined from serum samples using IgG/IgA ELISAs. Further, two 

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separate PRNTs will be performed to measure neutralizing antibody levels to RSV strains 
A and B.  
• 
RSV-specific mucosal antibody levels will be determined from nasal swab samples using 
an RSV-specific IgA ELISA. 
• 
IFN-γ and IL-4 secreting, RSV-specific T cells will be quantified using an ELISPOT assay 
on PBMC samples. 
• 
RSV-specific Memory B cells will be measured on PBMC samples obtained at the (B)FU 
visits and compared between treatment groups 
All immunogenicity testing will be performed at Bavarian Nordic GmbH, 
 
Testing SOPs, effective at the time of testing will be filed in the electronic Trial Master File. 
The procedures for collection, preparation, storage and shipment of specimens for 
immunogenicity testing (i.e. serum, nasal swabs and PBMC) 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 
procedures will be trained during the investigator meeting / site initiation visit. 
7.1 Systemic Humoral Immune Responses  
Serum samples will be collected as outlined in the trials procedure schedule in Section 1.6. 
All samples for immunogenicity testing obtained on vaccination visits will be collected prior to 
vaccination. 
The procedures for the immunogenicity tests performed are outlined in Sections 7.1.1 and 7.1.2 
below.  
7.1.1 RSV-specific ELISA  
RSV-specific IgG/IgA antibody responses will be determined using several ELISAs. Details of 
the procedure are defined in the SOP 
 “ELISA to determine RSV-Specific Antibody 
Titers (IgG) in Human Serum Samples”, SOP 
 “ELISA to determine RSV-Specific 
IgA Titers in Human Serum Samples”, SOP 
 “ELISA to determine RSV G Protein 
(A-strain) Specific Antibody Titers (IgG) in Human Serum Samples” and SOP 
 
“ELISA to determine RSV G Protein (B1-strain) Specific Antibody Titers (IgG) in Human Serum 
Samples”. 
The individual peak titer is calculated as the maximum of all post baseline titer measurements for 
that individual. The individual peak titer is only missing if all post baseline titers are missing, 
otherwise the maximum of the available post baseline titers is used. 

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The GMT is calculated per visit as well as based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer transformations. The Geometric Mean Fold Increase 
(GMFI) is calculated analogously per post-baseline visit as the geometric mean of the individual 
fold increases, i.e. the subjects’ post-baseline titers at Visit X, divided by their corresponding 
baseline titer. 
The RSV-specific antibody response rate (applicable only to post-baseline visits) is calculated per 
visit as well as based on individual peak titers and is defined as the percentage of subjects with 
antibody response based on the total number of subjects with test results available. The response 
status is assessed with regard to the corresponding baseline (Visit 1) test result. 
7.1.2 RSV-specific PRNT 
Two PRNTs will be performed to determine RSV-specific neutralizing antibody titers against 
RSV strain A and B, respectively. Details on the procedures can be found in SOP 
 
(for strain A) “PRNT to determine RSV A Strain Specific Neutralizing Antibody Titers in 
Human Serum Samples“ and 
 (for strain B) “PRNT to determine RSV B Strain 
Specific Neutralizing Antibody Titers in Human Serum Samples”. 
The individual peak titer is calculated as the maximum of all post baseline titer measurements for 
that individual. The individual peak titer is only missing if all post baseline titers are missing, 
otherwise the maximum of the available post baseline titers is used. 
The GMT is calculated per visit as well as based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer transformations. The GMFI is calculated analogously 
per post-baseline visit as the geometric mean of the individual fold increases, i.e. the subjects’ 
post-baseline titers at Visit X, divided by their corresponding baseline titer. 
The RSV-specific antibody response rate (applicable only to post-baseline visits) is calculated per 
visit as well as based on individual peak titers and is defined as the percentage of subjects with 
antibody response based on the total number of subjects with test results available. The response 
status is assessed with regard to the corresponding baseline (Visit 1) test result. 
7.2 Mucosal Immune Responses  
Nasal swab samples will be collected as outlined in Section 1.6 and Section 1.7. Nasal samples 
will be collected from both nostrils using nylon flocked swabs (
). Samples 
obtained on vaccination visits will be taken prior to vaccination. RSV-specific IgA antibody 
responses will be determined using an ELISA. Details of the procedure are defined in SOP 
 “ELISA to determine RSV-specific Antibody Titers (IgA) in Human Nasal Swab 
Samples”. 

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The individual peak titer is calculated as the maximum of all post baseline titer measurements for 
that individual. The individual peak titer is only missing if all post baseline titers are missing, 
otherwise the maximum of the available post baseline titers is used. 
The GMT is calculated per visit as well as based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer transformations. The GMFI is calculated analogously 
per post-baseline visit as the geometric mean of the individual fold increases, i.e. the subjects’ 
post-baseline titers at Visit X, divided by their corresponding baseline titer. 
The RSV-specific antibody response rate (applicable only to post-baseline visits) is calculated per 
visit as well as based on individual peak titers and is defined as the percentage of subjects with 
antibody response based on the total number of subjects with test results available. The response 
status is assessed with regard to the corresponding baseline (Visit 1) test result. 
7.3 Systemic Cellular Immune Responses 
PBMC samples will be collected as outlined in Section 1.6 and Section 1.7. 
Blood samples obtained on vaccination visits will be drawn prior to vaccination.  
SFU per 1 x 106 PBMC will be determined using an IFN-γ / IL-4 ELISPOT assay using five 
different RSV peptide pools as well as RSV as stimulating agent. Details of the ELISPOT 
procedure are defined in SOP 
 “Dual Color (IFN-/IL-4) RSV ELISPOT using 
Human PBMC”.  
The geometric mean SFU/1 x 106 PBMC are calculated per visit.  
The response rate is calculated per visit and is defined as the percentage of subjects with a 
response based on the total number of subjects with test results on the respective visit. The 
response status is assessed with regard to the corresponding baseline (Visit 1) test result.  
The number of ELISPOT pools where there is a response is also calculated on a per subject basis 
per visit. 
A subject is an ELISPOT responder to the vaccine in a particular test agent (e.g. RSV virus) if the 
subject has a response for at least two post baseline visits within the same test agent. 
The responder rate for each test agent is the percentage of subjects who are responders to the 
relevant test agent out of the number of subjects with a non-missing responder status. 
Furthermore, PBMC collected at the (B)FU visits will be used to determine memory B cells 
secreting IgG and/or IgA in an ELISPOT. Details of the procedure are defined in SOP 
 “Fluorospot to measure RSV-specific IgG/IgA secreting cells in human PBMCs”.   

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7.4 Future Use of Lab Specimen 
Serum, PBMC and nasal swab samples remaining after completion of all immunogenicity testing 
for the trial will be stored for future testing supporting the licensure path of 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 
protection measures. Specimens will be stored in BN’s secured laboratory area or at an external 
storage facility in a coded, pseudonymized manner to ensure data protection. Genetic testing will 
not be performed. 
8 Safety and Reactogenicity 
Safety will be monitored by performing physical examinations including vital signs, routine 
laboratory measurements as well as by evaluating local and general solicited AEs and unsolicited 
AEs.  
8.1 Definitions 
8.1.1 Medical History 
Symptoms present before or at the Screening Visit will be documented in the medical history. 
8.1.2 AEs 
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, 
symptoms or changes in health starting after ICF signature are documented in the subjects’ 
records and the AE section of the eCRF (data collection requirements for screen failures see 
Section 12.1). AEs are recorded based on unsolicited and solicited questioning (Section 8.1.2.1 
and 8.1.2.2). 
8.1.2.1 Unsolicited AEs 
Unsolicited AEs are defined as AEs observed by the subject/investigator or which are not pre-
listed on the memory aid card. AEs (e.g. feeling of ill-health, subjective symptoms and objective 
signs, intercurrent diseases, accidents, etc.) observed by the investigator and/or reported by the 
subject must be recorded in the eCRF regardless of the assessment of causality in relationship 
with the IMP/MP. 

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After the first vaccination, abnormal laboratory values assessed as being clinically significant by 
the investigator are to be documented as AEs. In addition, after first vaccination, abnormal 
laboratory values fulfilling the Grade 3 or Grade 4 criteria according to the toxicity scale 
(Appendix 1: Toxicity Scale for Laboratory Values) are to be documented as AE in the eCRF, 
regardless of whether they are considered clinically relevant or not. For lab values fulfilling the 
Grade 3 or Grade 4 criteria, the decision to repeat the labs is left at the discretion of the PI. 
Toxicity grade and seriousness of an AE will be assessed separately, i.e. a Grade 3 or Grade 4 AE 
will not automatically be regarded as serious. 
The investigator should ask the subjects if they have experienced any AEs since their last visit. 
All intercurrent diseases reported by the subject need to be recorded by the investigator in the 
appropriate section of the eCRF. 
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. 
8.1.2.2 Solicited AEs 
In this clinical trial protocol solicited AEs are defined as all symptoms specifically listed in the 
memory aid provided to the subjects following each 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 general symptoms (i.e. body temperature, headache, 
chills, myalgia, nausea and fatigue) in the memory aid daily for the day of vaccination and the 
following 7 days (Days 0-7, 8 day period).  
8.1.2.3 SAEs 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death, if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect 
• 
Is an otherwise important medical event, e.g. leads to suspicion of transmission of an 
infectious agent. 

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Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
8.2 Assessment 
8.2.1 Relevant Medical History 
Relevant medical history will be documented at screening and will focus particularly on any 
important diseases and in case of infections or tumors, the pathogen involved or the pathological 
diagnosis, if available. Special attention should be given to history of prior allergic reactions, 
especially to vaccines.  
8.2.2 Prior and Concomitant Medication 
Exclusionary medication or medication where washouts periods need to be adhered to are defined 
in the eligibility criteria in Section 1.5. 
All concomitant (ongoing) medication except homeopathic substances and dietary supplements 
must be recorded in the eCRF and the subject’s medical record including information about the 
indication, dosage regimen, and the onset and end of treatment. 
The following medication, taken within 3 months prior to screening or BV0, will also be recorded 
in the eCRF and the subjects 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. 
If given after the first but prior to the second or the booster vaccination, the following will result 
in subject’s ineligibility to receive the second or booster vaccination and the subject should 
follow the abbreviated visit schedule (see Section 4.2.4) 
• 
Vaccination with any licensed live vaccine within 30 days prior to or after trial vaccination 
or any licensed inactivated vaccine within 14 days prior to or after trial vaccination. 
• 
Start of chronic systemic administration (defined as more than 14 days) of > 5 mg 
prednisone (or equivalent) per day or any other systemic use of immune-modifying drugs.  
• 
Administration of immunoglobulins and/or any blood products. 

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• 
Use of any investigational or non-registered drug or vaccine other than the trial vaccine. 
8.2.3 Physical Examination 
Complete physical examination 
A complete physical examination will be performed at screening and BV0. The examination 
includes a review of major organ systems as well as body height and weight. The examination 
should be directed at finding evidence of any infections, tumors and lymphadenopathy (a grading 
scale for lymphadenopathy is included in Appendix 3: Grading Scale for Lymphadenopathy). In 
addition, auscultation of the heart and lungs will be performed to check specifically for signs of 
any heart condition. 
Targeted physical examination 
In the main trial, a targeted physical examination, guided by any signs or symptoms previously 
identified or any new symptoms that the subject has experienced since the last visit, is required at 
all visits starting at Visit 1 except VS.  
In the booster substudy, a targeted physical examination will only be performed if clinically 
indicated, by the presence of signs/symptoms since last visit at BV1 to BFU2. If performed, 
auscultation of the heart and lungs will be included. 
8.2.4 Vital Signs 
At all visits except the Staggering Visit and BFU3, blood pressure and pulse rate will be taken 
after the subject has been sitting upright for approximately two minutes. Body temperature will 
be measured orally. 
8.2.5 Unsolicited AEs 
All intercurrent diseases reported when the investigator actively inquires the subject will be 
documented and all required details (e.g. start and stop date, intensity) will be assessed. 
Unsolicited AEs will be reported in the respective section of the eCRF and the subject’s medical 
record (requirements for screen failures see Section 12.1).  
Unsolicited AEs will be assessed and documented as indicated in the trial schedule (see Section 
1.6 and Section 1.7).  
SAEs will be assessed and documented at all trial visits, excluding the BFU3 Visit. SAEs will be 
followed up until resolution or achievement of stable clinical conditions. 
In the main trial, new AEs related to respiratory tract infections will be assessed and documented 
at all trial visits, including the FU Visits.  

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Assessment of Intensity  
For all unsolicited AEs not represented in the toxicity scale for Laboratory Values (Appendix 1: 
Toxicity Scale for Laboratory Values), the maximum intensity will be based on the following 
descriptions: 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and 
not interfering with daily activities. 
Grade 2 
An AE which is sufficiently discomforting to interfere with daily activities. 
Grade 3 
An AE which prevents daily activities. Such an AE would, for example, prevent 
attendance at work and would necessitate corrective therapy. 
Grade 4 
Life-threatening or disabling 
Assessment of Causality  
The relationship between the occurrence of an AE and the IMP will be assessed using the 
categories presented below. For expedited reporting and all other purposes, the categories “none” 
and “unlikely” will represent no evidence or argument to suggest a causal relationship, while 
“possible”, “probable” and “definite” will be seen to convey that there is evidence or argument to 
suggest a causal relationship. Following worst case scenario all AEs without a causality 
assessment from the investigator will be classified as “possible”. 
None 
The time interval between 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. 
8.2.6 Solicited AEs 
After each vaccination, subjects receive a memory aid to record solicited local and general AEs 
most likely to occur on the day of vaccination and the following seven days (Days 0-7; 8-day 
period). 
All solicited symptoms observed after vaccination with details concerning the intensity and the 
course of the reaction should be documented there. The investigator will collect this information 
during the following scheduled visits and transfer it to the eCRF and the subject’s medical record. 
Local and general reactions still ongoing after 7 days will be measured or examined each day 
until resolution or until no further change can reasonably be expected, and the last day of 
symptoms and maximum intensity will be documented in the memory aid. 
In case of severe and unexpected local and/or general reactions, the subject should be instructed 
to contact the trial physician outside of scheduled trial visits. 
8.2.6.1 Solicited Local AEs  
The solicited local symptoms erythema, swelling, induration, pruritus and pain at the injection 
site are to be documented in the memory aid by the subjects. 
To standardize procedures, uniform rulers will be handed out to subjects for measurements of 
erythema, swelling and induration diameters.  
Assessment of Intensity 
Injection site erythema 
size measured in diameter 
Injection site swelling 
size measured in diameter 
Injection site induration 
size measured in diameter 

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The maximum severity will be scored as follows: 
0 
= 
0 
1 
= 
< 30 mm 
2 
= 
≥ 30 – < 100 mm 
3 
= 
≥ 100 mm 
Injection site pruritus: 
0 
= 
Absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Injection site pain: 
0 
= 
Absent 
1 
= 
Painful on touch 
2 
= 
Painful when limb is moved 
3 
= 
Spontaneously painful / prevents normal activity 
Assessment of Causality  
Solicited local AEs are defined as being related to the vaccine. 
8.2.6.2 Solicited General AEs 
The solicited general symptoms body temperature, headache, myalgia, nausea, chills and fatigue 
are to be documented in the memory aid by the subjects. To standardize procedures, digital 
thermometers for oral measurements of body temperature will be handed out to subjects. 
Assessment of Intensity  
Subjects are asked to document the solicited general AEs in the memory aid as described in 
Table 14 below. In the subject’s memory aid, the grading of maximum symptom intensity is 
described in basic, easily understood language based on the following descriptions: 

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Table 14 
Grading of General Symptoms from the Subject’s Memory Aid 
MedDRA coded Preferred Term 
General AEs 
Grade 
Maximum Severity 
Body temperature* 
0 
< 99.5°F (< 37.5°C) 
1 
≥ 99.5 – < 100.4°F (≥ 37.5 – < 38.0°C) 
2 
≥ 100.4 – < 102.2°F (≥ 38.0 – < 39.0°C) 
3 
≥ 102.2 – < 104.0°F (≥ 39.0 – < 40.0°C) 
4 
≥ 104.0°F (≥ 40.0°C)  
Headache, Myalgia, Nausea, Chills and 
Fatigue 
0 
None 
1 
Mild: easily tolerated, minimal discomfort and 
no interference with daily activity 
2 
Moderate: Some interference with daily activity 
3 
Severe: Prevents daily activity 
*Pyrexia is defined as oral temperature ≥ 100.4°F (≥ 38.0°C). 
Assessment of Causality  
Causal relationship between solicited general AEs and the vaccine will be assessed by the 
investigator using the same categories as for unsolicited AEs (see Section 8.2.5). 
8.2.7 Respiratory Viral Panel (Main Trial) 
In case of any symptoms indicating a respiratory tract infection at any time point after the first 
vaccination a nasal swab will be obtained at scheduled or unscheduled visits to assess if a current 
RSV infection is underlying. This determination will be done in the central laboratory by 
measuring the standard respiratory viral panel (RVP) utilizing Nanosphere Verigene RP Flex 
technology. Subjects need to be instructed to return to the site within 3 days after start of 
symptoms as specified in Section 8.2.8. 
8.2.8 RSV-specific symptoms 
RSV-specific symptoms are defined by any case of rhinorrhea, nasal congestion, pharyngitis, 
cough, wheezing (or increase in baseline wheezing), sputum production (or increase or change in 
nature of baseline sputum production) or new (or worsening of) shortness of breath plus RSV 
infection confirmed by the RVP (see Section 8.2.7) within 3 days of symptom(s) (main trial 
only). RSV-specific symptoms are documented as Adverse Event from Visit 1 until the last 
FU Visit.  

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8.2.9 Cardiac Assessment 
Electrocardiogram 
A standard 12-lead ECG will be taken in the main trial at the Screening Visit. At Visit 2, Visit 4 
and FU Visits an ECG is only done if clinically indicated. A central ECG reading center will 
assess if ECGs are normal, normal variant or abnormal.  
The clinical investigator will assess the clinical significance for abnormal ECGs. Interpretation 
support for screening ECGs is provided in Appendix 2: Interpretation Support for Assessment of 
Screening ECGs. 
Troponin I 
Troponin I will be measured in the main trial at screening and if clinically indicated on the 
following visits: Visit 2, Visit 4, FU1 and FU2 Visits or at unscheduled visits. 
Any kind of cardiac signs (i.e. discovered by the physician during examination of the patient) or 
symptom(s) (i.e. experienced and reported by the subject) detected during the trial, such as but 
not limited to, chest pain, dyspnea, arrhythmia or edema will be documented as adverse events 
and will require cardiac follow-up at a local cardiologist as outlined in Figure 3. The cardiologic 
examination should include at a minimum an ECG and troponin I determination.   
The cardiologist should further evaluate the case as deemed necessary (e.g. by application of 
long-term or treadmill ECG, measurement of further cardiac enzymes and/or echocardiogram). 
Depending on the results of these evaluations, further diagnostic tests may be done as 
recommended by the cardiologist. 

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Figure 3 
Algorithm for Cardiac Follow-up 
 
no 
yes 
yes 
no 
positive 
Subject presents with any symptoms such as chest pain, 
shortness of breath, edema or palpitations  
Referral to cardiologist 
and ensure ECG and 
troponin I are measured 
ECG, troponin I 
negative 
No further work-up 
or expedited 
reporting required 
Cardiac 
complications 
Symptomatic at 
time of exam? 
Possible cardiac 
complications 
Further evaluation as 
determined necessary by 
the cardiologist 
Further work-up as 
determined by the 
cardiologist  
Physical Examination 

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8.2.10 Safety Laboratory Measurements 
The intensity of laboratory / systemic toxicities measured quantitatively will be graded according 
to the toxicity scale in Appendix 1: Toxicity Scale for Laboratory Values. These grading scales 
include the laboratory values determined with the routine safety parameters. In case of other 
laboratory values not included in the routine safety laboratory and not listed in Appendix 1: 
Toxicity Scale for Laboratory Values, the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Guidance for Industry, 
U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Biologics Evaluation and Research, September 2007) will be used for grading of laboratory 
toxicities.  
Safety laboratory is determined at screening, Visit 2 and Visit 4 in the main trial and at BV0 and 
BV2 during the booster substudy and at any other visit(s) if clinically indicated. The safety 
laboratory measurements are performed at a central laboratory. Laboratory normal ranges are 
provided by the central laboratory and filed in the Investigator File. Safety laboratory parameters 
to be evaluated are: 
Hematology:  
Red blood cell count, hemoglobin, total and differential White Blood Cell count (WBC), platelet 
count (Hematocrit, mean corpuscular/cell volume (MCV), mean corpuscular/cellular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell distribution 
width (RDW) are routinely performed as part of the complete blood cell count and will be 
included in the laboratory report.  
Serum chemistry:  
Total bilirubin, Alkaline Phosphatase (AP), Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), serum creatinine, sodium, potassium, calcium, troponin I (troponin 
mandatory only at SCR Visit).  
For subjects with type II diabetes mellitus HbA1c is assessed at the SCR visit only in case 
documented HbA1c result within three months prior to SCR is not available. 
Pregnancy test: 
In the main trial, a β-human choriogonadotropin (HCG) pregnancy test will be conducted for all 
WOCBP at SCR Visit, prior to each vaccination and at the individual last active trial phase visit 
(Visits 1, 3 and EAP). At SCR Visit a serum β-HCG pregnancy test will be performed; all other 
pregnancy tests will be conducted as urine β-HCG tests.  
In the booster substudy, a β-human choriogonadotropin (HCG) pregnancy test will be conducted 
for all WOCBP at BV1, prior to the booster vaccination. 

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Virology: 
The following parameters will only be evaluated during the screening period for assessment of 
inclusion / exclusion criteria and at the following visits only if clinically indicated: 
HIV antibody test (anti HIV) 
HBsAG 
Hepatitis C antibody test 
8.2.11 Pregnancy 
As per inclusion criteria, women of childbearing potential must have a negative serum pregnancy 
test at SCR Visit and a negative urine pregnancy test prior to each vaccination. In addition, they 
must have used an acceptable method of contraception for 30 days prior to the first vaccination, 
must agree to use an acceptable method of contraception during the trial, and must avoid 
becoming pregnant for at least 28 days after the last vaccination. Nevertheless, IMP exposed 
pregnancies cannot be excluded with certainty. Subjects who become pregnant prior to the first 
vaccination will be excluded from the trial and are regarded as screening failure. Subjects who 
become pregnant during the active trial period (up to and including one month [minimum 28 
days] after receiving a dose of vaccine) must not receive additional doses of vaccine but may 
continue other trial procedures at the discretion of the investigator (see Section 4.2.4). All reports, 
where the embryo or foetus may have been exposed to the IMP (either through maternal exposure 
or transmission of a medicinal product via semen following paternal exposure), 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-menopausal (defined as ≥ 12 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. 
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. 

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8.3 Reporting 
8.3.1 Reporting of SAEs 
All SAEs occurring throughout the entire course of the trial have to be reported to the CRO Drug 
Safety (DS) Department. The CTS has to send the completed SAE form by e-mail or fax to the 
CRO DS Department within 24 hours of becoming aware of the AE.  
SAE should be sent to:  
The investigator should not delay reporting because of missing information. Nonetheless, the 
report should be as complete as possible. This initial notification should include, as a minimum, 
sufficient information to permit identification of the following:  
• 
the reporter (investigator’s name and contact information) 
• 
the subject 
• 
involved trial medication 
• 
AE(s) 
• 
seriousness criterion  
• 
date of onset 
The CRO DS Department alerts BN PV of all SAEs and provides the available information 
within 24 hours to BN PV. BN is responsible for expedited as well as periodic reporting to the 
involved regulatory authorities (e.g. Food and Drug Administration, European Medicines Agency 
(EMA), Paul Ehrlich Institut [PEI]) 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 
(SUSAR) and no later than 15 days after knowledge of any other unexpected SADR. The 
investigator or the CRO is responsible for reporting to the Ethics Committees or IRBs. Figure 4 
outlines the reporting process and timelines for SAEs. 

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Figure 4 
Algorithm for Reporting of SAEs 
 
yes 
No
<
AE 
SAE entered into safety 
database and safety 
reports created 
Is the AE serious? 
Investigator reports SAE 
to CRO DS within 24 h 
Record Event in the  
AE section of the eCRF 
BN PV forwards safety 
reports within  
max. 15d/7d to competent 
authorities (final) and to CRO 
DS 
CRO DS reports SAE to 
BN PV within 24 h 
no 
yes 
Expedited reporting 
necessary? 
CRO DS forwards final safety 
reports within max. 15d/7d to 
concerned IRBs, IECs and 
Investigators 
SAE entered into safety 
database 
SMC discusses 
electronically (via 
email/teleconference) 
and forwards opinion to 
the Chair; Chair forwards 
opinions to POI  to BN 

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8.3.2 Reporting of Pregnancy 
If a subject becomes pregnant during the active trial period (up to and including one month 
[minimum 28 days] after receiving a dose of vaccine) this must be reported to BN on a Pregnancy 
Report Form (via eCRF) within 24 hours of the investigator’s becoming aware of the event.  
A pregnancy should be followed to term, any premature terminations reported, and the health 
status of the mother and child including date of delivery and the child’s gender and weight should 
be reported to BN as soon as possible after delivery. 
Any event during pregnancy fulfilling the criteria for an SAE will be reported as SAE to BN 
PV/CRO DS (see Section 8.3.1). However, hospitalization for delivery is a prospectively planned 
hospitalization and is not considered a SAE per se. 
9 Statistical Considerations 
The primary endpoint of this trial is to determine the GMTs after one or two MVA-BN-
RSV vaccinations or placebo measured by PRNT (against strain A) 2 weeks post last vaccination.  
9.1 Randomization Procedure and Blinding  
The main part of the trial is randomized using an automated randomization system, integrated in 
the eCRF: Details on the randomization will be outlined in a separate randomization 
specification. 
Assignment to the groups is done in a randomized manner. The main trial is single-blinded, i.e. 
subjects will be blinded to the group assignment.  
In total 86 subjects from two selected treatment groups will be chosen randomly for the booster 
substudy outlined in a separate randomization specification. 
For details on staggering and randomization refer to trial protocol synopsis (see Sections 1.5 
and 4.1). 
9.2 Sample Size Calculation 
The primary analysis will be performed on the PRNT (A strain) titers 2 weeks after the last 
vaccination in the main trial. Testing of the primary objective will be performed by assuming that 
the log10 of the titers are normally distributed. Testing will be conducted in a descriptive manner 
and no adjustment for multiple testing will be performed. 
The upper 95% confidence limit of the standard deviation (SD) of the log10 titers from the Phase I 
trial RSV-MVA-001 at Visit 6 (2 weeks post second vaccination) was calculated as 0.46 (the SD 
was very similar in all groups).  

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The GMTs, GMFIs from baseline, and the response rates and associated 95 % confidence limits 
will be presented for each group at each sampling point. 
The following descriptive comparison of the ratios of the GMTs between groups will be 
calculated along with the corresponding 95% Confidence Interval by assuming that the log10 
PRNT (A strain) titers are normally distributed: 
1. 
Group 2 / Group 1 – Two vaccinations compared to one vaccination using Dose 1 
2. 
Group 4 / Group 3 – Two vaccinations compared to one vaccination using Dose 2 
3. 
Group 3 / Group 1 – Dose 2 compared to Dose 1 using one vaccination 
4. 
Group 4 / Group 2 – Dose 2 compared to Dose 1 using two vaccinations  
5. 
Group 2 / Group 5 – Two vaccinations using Dose 1 compared to Placebo 
6. 
Group 4 / Group 5 – Two vaccinations using Dose 2 compared to Placebo 
With a group sample size of 70 per group (recruiting 80 per group to account for 12 % dropouts), 
and an assumed SD of 0.46 for the log10 PRNT titers (A strain), this will give 80 % power to 
detect a relative change in titers from the Group 1 of a 66 % increase. The SD is similar to what 
was seen in the RSV Phase I trial (RSV-MVA-001).  
A secondary descriptive quadratic orthogonal regression of the log10 titers for the three doses 
using Group 2, Group 4 and Group 5 will also be performed. If the linear contrast (i.e. slope) of 
the regression fit is significant at the standard significance level of 0.05 then a dose response 
relationship will have been demonstrated. If the quadratic contrast is significantly different from 
zero then this will indicate that the dose response is not linear within the dose range used in this 
trial. Assuming the quadratic effect is negative over the higher dose ranges, this will be seen as 
confirmation of a plateau effect in terms of responses for higher dose. 
In addition, an explorative two way ANOVA will be conducted on the log10 titers using dose (2 
levels) and number of vaccinations (2 levels) fitting both main effects and the interaction term.  
All other immunogenicity results (PRNT strain B, ELISPOT, ELISA IgG/IgA) will be considered 
as secondary descriptive analyzes and will be analyzed similarly to the primary endpoint analysis. 
The actual variability observed for the log10 titers for PRNT (A strain) 2 weeks after the second 
vaccination in RSV-MVA-002 turned out to be lower than anticipated from the Phase I trial 
results. Thus, based on an adapted assumption for the SD of 0.335 for the log10 titers to be 
measured 2 weeks after the booster vaccination, a number of 40 evaluable subjects per group will 
provide 80% power to detect a difference of 0.213 (log10-scale) at a significance level of 5% 
(two-sided), which corresponds to a ratio of GMTs between groups of 1.63. Accounting for a 
drop-out rate of 5% 43 subjects per group are to receive a booster vaccination. However, only a 
descriptive comparison is planned between the two dose groups in the sub-study. 

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9.2.1 Treatment Groups/Datasets to be Evaluated 
Analysis of immunogenicity variables will be done on a valid case basis, i.e. for missing 
observations no imputation technique such as “Last observation carried forward” will be applied, 
since this could introduce an optimistic bias into the analysis. 
Full Analysis Set (FAS): 
This is the subset of subjects from the main trial who received at least one vaccination and for 
whom any data are available.  
The main analysis of safety as well as humoral and mucosal immunogenicity endpoints of the 
main trial will be performed on this analysis set.  
Per Protocol Set (PPS): 
This is the subset of subjects in the FAS who have received all vaccinations in the main trial, 
completed all visits of the active trial phase (Visit 1 to EAP) and adhered to all protocol 
conditions. Subjects with only minor (not relevant) protocol deviations are included into this 
dataset.  
The decision whether a protocol deviation is major or not for the classification of subjects into 
the various datasets will be made on a case-by-case basis in a data review meeting (DRM) prior 
to database lock. 
The statistical procedures applied to the FAS for humoral and mucosal immunogenicity 
endpoints will also be applied to the PPS. 
Immunogenicity Analysis Set (IAS): 
This is the subset of subjects in the FAS which were assigned to the PBMC subgroup. 
The main analysis of the cellular immunogenicity endpoints of the main trial will be performed 
on the IAS. 
Booster Full Analysis Set (BFAS): 
This is the subset of subjects who received a booster vaccination and for whom any post-booster 
data are available.  
The analysis of safety as well as humoral and mucosal immunogenicity endpoints of the booster 
trial will be performed on this analysis set.  
Booster Immunogenicity Analysis Set (BIAS): 

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This is the subset of subjects in the BFAS which were assigned to the PBMC subgroup. 
The analysis of the cellular immunogenicity endpoints of the booster trial will be performed on 
the BIAS. 
Additional analysis sets may need to be defined during the data review meeting and would be 
described in the clinical study report. 
9.3 Biometrical Evaluation 
9.3.1 Analysis 
As soon as the last subject has completed Visit FU1 and after any necessary settlement of queries 
etc. in the eCRFs a data review meeting will be held and the subjects will be assigned to the data 
sets defined for the main trial (FAS, PPS, IAS, see Section 9.2.1). After the data review meeting 
and necessary settlement of queries that may arise during the data review meeting, the database 
will be locked. The safety analysis will then be performed based on this assignment and will 
include all safety data up to Visit FU1. Results will be reported in the clinical study report. 
As soon as the last subject has completed FU2 Visit and after any necessary settlement of queries 
etc. in the eCRFs a data review meeting will be held. The assignment of the subjects to the 
datasets as described in Section 9.2.1 will be the same as in the CSR. After the data review 
meeting and necessary settlement of queries that may arise during the data review meeting, the 
database will be locked. The final analysis of the main trial will then be performed and will 
include all immunogenicity results as well as the follow-up safety data. Results of this analysis 
will be reported in an addendum to the clinical study report. 
For the booster substudy, there will be a topline readout when the last subject included in the 
booster substudy has completed the BFU1 visit, the immunogenicity data up to BFU1 are 
available, and the data in EDC have been properly cleaned.  The set of topline tables and figures 
will be specified in the statistical analysis plan.  
As soon as the last subject included in the booster substudy has completed BFU3 Visit and after 
any necessary settlement of queries etc. in the eCRFs a data review meeting will be held. 
Protocol deviations will be reviewed to determine whether an additional analysis set compared to 
those described in Section 9.2.1 will be needed.  After the data review meeting and necessary 
settlement of queries that may arise during the data review meeting, the database will be locked. 
The booster substudy analysis will then be performed and will include all immunogenicity results 
as well as the follow-up safety data. Results of this final analysis will be reported in an addendum 
to the clinical study report. 

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9.3.2 Presentation of Data 
For biometrical analysis, data obtained in this trial and documented in the eCRFs will be listed. 
For parameters of interest, summary tables with descriptive group statistics for metrical variables 
will be prepared. For categorical / dichotomous variables summary tables showing the absolute 
and relative count in each category will be prepared. 
Full details of the analyses will be defined in the Statistical Analysis Plan (SAP). The SAP will 
be finalized prior to the respective database lock. The analyses as defined in the SAP will be 
followed. 
If any unforeseen additional analysis is included in the clinical study report it will be clearly 
flagged as an additional unplanned explorative analysis. The CRO will be responsible for data 
management and statistical evaluation. Data will be analyzed using SAS®.  
GMTs, GMFIs and antibody response rates for RSV-specific humoral immune responses 
determined from serum and nasal swab samples will be determined as described in Section 7.1 
and Section 1.5. 
Median and geometric mean SFU/1 x 106 PBMC, GMFIs as well as response and responder rates 
for RSV-specific cellular immune responses will be determined as described in Section 1.5 
Clinical laboratory test results will be marked whether the result is below, within or above the 
respective reference range. The number of values outside of the corresponding reference range 
will be counted.  
Details for all ECGs will be listed. In addition the central ECG assessment of either normal, 
normal variant and abnormal as well as the investigator’s interpretation as to whether ECGs, 
assessed as abnormal by the central ECG assessor, are clinically significant or not clinically 
significant will be summarized.  
The occurrence of solicited local and general AEs during the 8-day period post vaccination 
(Days 0–7) will be summarized on a per subject and per vaccination basis.  
Unsolicited AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
coding terminology. The intensity of AEs will be graded according to Section 8.2. 
SAEs will be listed separately. Each SAE will be described individually in detail. 

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10 Ethical Aspects 
10.1 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. 
10.2 Approval by an IEC/IRB and IBC 
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. 
The MVA-BN-RSV vaccine meets the exemption criteria set forth in Appendix M-VI-A of the 
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. 
10.3 Confidentiality and Data Protection 
The PI of the respective CTS is obliged to ensure anonymity of the subject. He/she has to make 
sure that all documents including eCRFs provided (e.g. in the course of a marketing authorization 
procedure) to third parties (in this case: to the manufacturer of MVA-BN-RSV vaccine or to an 
authority) contain no subject names. 
Only a subject and site number may identify subjects. Their name or clinic and subject’s medical 
record number may not be used. The PI keeps separate confidential subject logs for trial 
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. 

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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. 
11 Informed Consent 
No subject can participate in this trial without having given informed consent in writing after the 
investigator or his delegate has informed the subject clearly and completely, verbally and in 
writing, over the purpose, procedures, the potential future use of blood samples (see Section 7.4) 
and potential benefits and risks of the trial prior to any trial specific procedure. 
One signed copy of the Informed Consent including HIPAA must be given to each subject and 
one signed copy must remain in the Investigator Site File and be available for verification by the 
monitor, Sponsor/CRO auditor or competent regulatory authorities at any time. 
Subjects must be informed unequivocally that they may refuse participation in the trial and that 
they may withdraw from the trial at any time and for whatever reason and that withdrawal of 
consent will not affect their subsequent medical treatment or relationship with the treating 
physician. 
Subjects also consent to authorize the monitor, quality assurance personnel and regulatory 
authorities to inspect source documents for data verification and quality assurance purposes. Such 
verifications will always be conducted at the CTS and under the ethical supervision of the 
investigator. All aspects of the confidentiality of the subject’s data will be guaranteed. 
Subjects eligible for the booster substudy have to sign a new ICF at BV0.  
The Informed Consent will be prepared in accordance with ICH GCP guidelines and must be 
approved by the appropriate IEC/IRB. 
12 eCRF, Retention of Records and Monitoring 
12.1 eCRF 
In this trial, the use of an eCRF is planned. 
All eCRFs are to be filled out completely by the trial personnel, then reviewed and signed 
electronically by the PI to confirm their correctness in a timely manner. It is the PI’s 
responsibility to ensure that all subject data entered in the eCRF (including discontinuations or 
changes in trial vaccine or other medications) are accurate and supported by the subject’s medical 
records unless the eCRF has been declared as source documentation by BN. The eCRFs for any 
subject leaving the trial should be completed at the time of the final visit or shortly thereafter. 

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For subjects not fulfilling the eligibility criteria the minimum information documented in the 
eCRF is the ICF information, demographics and reason for screen failure. 
12.2 Retention of Records 
Essential documents as listed in ICH GCP need to be archived according to ICH GCP or national 
law, whatever is longer. 
To meet regulatory requirements, the original source data and an electronic copy of the eCRF 
data will be stored at the respective CTS.  
The eCRF data will be stored and archived according to the Clinical Data Interchange Standards 
Consortium (CDISC) Operational Data Modeling (ODM) (see www.cdisc.org for details). Since 
CDISC ODM is also the source for the Electronic Data Capture web-based system, no 
transcription of data is necessary. If needed, paper copies (file printouts) can be created from the 
ODM file. 
12.3 Monitoring of the Trial 
The CRO (contact information to be found in the “Responsibilities” section in the beginning of 
this protocol) will be contracted to perform monitoring services according to ICH GCP. 
Monitoring will be conducted according to the monitoring plan which must be approved by BN 
and the CRO. The monitoring plan will specify in detail the items for source data verification and 
other tasks, to be performed by the CRA during the CTS visit. 
The CRA is responsible for obtaining an overview of the course of the trial in co-operation with 
the investigators, checking if the clinical trial protocol is being observed, and helping the 
investigators to solve any problems which may arise. All documents in the context with this 
clinical trial will be handled confidentially at all times. 
The PI has agreed to give the CRA access to relevant hospital or clinical records to confirm their 
consistency with the eCRF entries and to obtain an adequate overview of the course of the trial. 
The CRA verifies that the entries in the eCRF are complete, accurate and supported by source 
documents. In addition the CRA will verify that all required data documented in the source were 
transferred accurately in the eCRF. This will be done under preservation of data protection. 
The source data verification must be performed by direct insight into the subject’s record. If a 
subject refuses to consent to this procedure, he/she may not participate in the trial. The CTS will 
provide direct access to all trial related data for the purpose of monitoring and inspection by local 
and regulatory authorities. The PI (or a representative) has further agreed to support the monitor 
in solving any problems he/she discovers during his/her visits. 

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13 Audits and Inspections 
Site audits and inspections may be carried out by the BN quality assurance department, local 
authorities, or authorities to whom information on this trial has been submitted. All documents 
pertinent to the trial must be made available for such audits / inspections. Informed consent of 
subjects participating in this trial has to include the consent in this access to source documents. 
14 Responsibilities of the PI 
The PI agrees to carry out the trial in accordance with the guidelines and procedures outlined in 
this clinical trial protocol. The PI especially consents to strictly adhere to the ethical aspects (see 
Section 10 of this protocol). 
Changes to the protocol require written “Amendments to the protocol” and written approval by 
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 ICH E6 (R1) Guideline for GCP and regulatory and institutional requirements 
for 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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15 References 
Antoine G, Scheiflinger F, Dorner F and Falkner F (1998) The complete genomic sequence of the 
modified vaccinia Ankara strain: comparison with other orthopoxviruses. Virology 244(2):365-
396. 
Blanchard T, Alcamí A, Andrea P and Smith G (1998) Modified vaccinia virus Ankara 
undergoes limited replication in human cells and lacks several immunomodulatory proteins: 
implications for use as a human vaccine. J Gen Virol. 79(5):1159-1167. 
Carroll M and Moss B (1997) Host range and cytopathogenicity of the highly attenuated MVA 
strain of vaccinia virus: propagation and generation of recombinant viruses in a nonhuman 
mammalian cell line. Virology 238(2):198-211. 
Castilow E, Olson M, and Varga S (2007) Understanding respiratory syncytial virus (RSV) 
vaccine-enhanced disease. Immunol Res 39(1-3):225-239. 
Drexler I, Heller K, Wahren B, Erfle V and Sutter G (1998) Highly attenuated modified vaccinia 
virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but 
not in various human transformed and primary cells. J Gen Virol. 79(2):347-352. 
Frey S, Newman F, Kennedy J, Sobek V, Ennis F, Hill H, Yan L, Chaplin P, Vollmar J, 
Chaitman B and Belshe R (2007) Clinical and immunologic responses to multiple doses of 
IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax challenge. Vaccine 25(51):8562-
8573. 
Fulginiti V, Eller J, Sieber O, Joyner J, Minamitani M and Meiklejohn G (1969) Respiratory 
virus immunization. A field trial of two inactivated respiratory virus vaccines; an aqueous 
trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. 
Am J Epidemiol 89(4):435-448.  
Glezen W, Taber L, Frank A and Kasel J (1986) Risk of primary infection and reinfection with 
rspiratory syncytial virus. AJDC 140(6):543-546. 
Groothuis J, Simoes E, Levin M, Hall C, Long C, Rodriguez W, Arrobio J, Meissner H, Fulton 
D, Welliver R, Tristam D, Silber G, Prince G, Van Raden M, Hemming V and the respiratory 
syncytial virus immune globulin study group (1993) Prophylactic administration of respiratory 
syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 
329(21):1524-1530. 
Hall C (2001) Respiratory syncytial virus and parainfluenza virus. N Engl J Med 344(25):1917-
1928. 
Karron R, Singleton R, Bulkow L, Parkinson A, Kruse D, DeSmet I, Indorf C, Petersen K, 
Leombruno D, Hurlburt D, Santosham M and Harrison L (1999) Severe respiratory syncytial 
virus disease in Alaska native children RSV Alaska Study Group. J Inf Dis 180(1):41-49. 

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Mayr A, Hochstein-Mintzel V and Stickl H (1975) Abstammung, Eigenschaften und 
Verwendung des attenuierten Vaccinia-Stammes MVA. Passage History, Properties, and Use of 
the Attenuated Vaccinia Virus Strain MVA. Infection 3(1):6-14. 
Meyer H, Sutter G and Mayr A (1991) Mapping of deletions in the genome of the highly 
attenuated vaccinia virus MVA and their influence on virulence. J Gen Virol 72(5):1031-1038. 
Murata Y and Falsey A (2007) Respiratory syncytial virus infection in adults. Antiviral Therapy 
12(4 PT B):659-670.  
Power U (2008) Respiratory syncytial virus (RSV) vaccines – Two steps back for one leap 
forward. J Clin Virol 41(1):38-44. 
Rosel J, Earl P, Weir J and Moss B (1986) Conserved TAAATG sequence at the transcriptional 
and translational initiation sites of vaccinia virus late genes deduced by structural and functional 
analysis of the HindIII H genome fragment. J Virol 60(2):436-449. 
Sutter G and Moss B (1992) Nonreplicating vaccinia vector efficiently expresses recombinant 
genes. Proc Natl Acad Sci USA 89(22):10847-10851. 
Thompson W, Shay D, Weintraub E, Brammer L, Cox N, Anderson L and Fukuda K (2003) 
Mortality Associated with Influenza and Respiratory Syncytial Virus in the United States. JAMA 
289(2):179-186. 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, Guidance for Industry, U.S. Department of Health and Human Services, 
Food and Drug Administration (FDA), Center for Biologics Evaluation and Research, September 
2007. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Vaccines/ucm074775.htm 
Vollmar J, Arndtz N, Eckl K, Thomsen T, Petzold B, Mateo L, Schlereth B, Handley A, King L, 
Hülsemann V, Tzatzaris M, Merkl K, Wulff N and Chaplin P (2006) Safety and immunogenicity 
of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine 
24(12):2065-2070. 
Von Krempelhuber A, Vollmar J, Pokorny R, Rapp P, Wulff N, Petzold B, Handley A, Mateo L, 
Siersbol H, Kollaritsch H and Chaplin P (2010) A randomized, double-blind, dose-finding Phase 
II study to evaluate immunogenicity and safety of the third generation smallpox vaccine 
candidate IMVAMUNE. Vaccine 28 (5):1209-1216. 
Wright P, Karron R, Belshe R, Shi J, Randolph V, Collins P, O'Shea A, Gruber W and Murphy B 
(2007) The absence of enhanced disease with wild type respiratory syncytial virus infection 
occurring after receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine 
25(42):7372-7378. 

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Appendix 1: Toxicity Scale for Laboratory Values 
Grade 1 or Grade 2 toxicity is only graded according to Table 15, Table 16 and Table 17 if the 
value is outside of the institutional normal range applicable for this trial. Any laboratory value 
that is between either the Lower Limit of Normal (LLN) or Upper Limit of Normal (ULN) and 
Grade 1 should not be graded. The values provided in Table 15, Table 16 and Table 17 are based 
on the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, (Guidance for Industry, U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, 
September 2007). 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to estimate 
grade of severity: 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and 
not interfering with daily activities. 
Grade 2 
An AE which is sufficiently discomforting to interfere with daily activities. 
Grade 3 
An AE which prevents daily activities. Such an AE would, for example, prevent 
attendance at work and would necessitate the administration of corrective therapy. 
Grade 4 
Life-threatening, hospitalization or disabling. 
Serious or life-threatening AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a Grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: Seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 

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Table 15 
Toxicity Scale for Serum Chemistry 
Lab Value, Serum* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – 
Hyponatremia mmoL/L 
132 < 136 
130-131 
125-129 
< 125 
Sodium – 
Hypernatremia 
mmoL/L 
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  
3.3 
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 x ULN 
2.1-3.0 x ULN 
3.1-10.0 x ULN 
> 10.0 x ULN 
ALT (SGPT) and AST 
(SGOT) increase by 
factor 
1.1-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10.0 x ULN 
> 10.0 x ULN 
Bilirubin – when 
accompanied by any 
increase in Liver 
Function Test; 
increase by factor 
1.10-
1.25 x ULN 
1.26-
1.50 x ULN 
1.51-
1.75 x ULN 
> 1.75 x ULN 
Bilirubin – when Liver 
Function Test is 
normal; 
increase by factor 
1.1-1.5 x ULN 
1.6-2.0 x ULN 
2.1-3.0 x ULN 
> 3.0 x ULN 
* 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.  
** 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.  
“ULN” is the upper limit of the normal range. 

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Table 16 
Toxicity Scale for Hematology 
Lab Value, 
Haematology* 
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 
* 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 17 
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 x ULN 
≥ 2-< 5 x ULN 
≥ 5 x ULN 
N/A 
“ULN” is the upper limit of the normal range. 

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Appendix 2: Interpretation Support for Assessment of Screening ECGs 
For a clearer and mutual understanding of inclusion criterion #9 of the main trial (see 
Section 1.5), the following provides clarifying explanations and examples pertaining to eligibility 
for trial participation. 
Examples of subjects eligible for participation in the trial: 
• 
Non-specific ST and T wave changes are not considered clinically significant and subject 
can participate 
• 
Sinus bradycardia which does not require clinical intervention is not considered clinically 
significant and subject can participate. 
• 
Subjects who present with atrial disease which does not require clinical intervention, e.g. a 
pacemaker or drug treatment, are allowed to be enrolled, as this can be considered not 
clinically significant. Examples are premature atrial contractions or ectopic atrial beats. 
• 
Occasional Premature Ventricular Contractions (PVCs) which do not require clinical 
intervention are not considered clinically significant and subject can participate. 
• 
First degree atrioventricular block or PR interval prolongations are also acceptable as long 
as they do not require clinical intervention, i.e. do not represent an indication for a 
pacemaker, and therefore the condition can be classified as not clinically significant. 
• 
Right or left axis deviation which does not require clinical intervention is not considered 
clinically significant and subject can participate. 
• 
QTc prolongations < 500 ms which do not require clinical intervention are not considered 
clinically significant and subject can be enrolled. QTc prolongations ≥ 500 ms which do not 
require clinical intervention should be discussed with the Medical Monitor before 
participation. 

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Examples of subjects NOT eligible for participation in the trial: 
• 
Second or third degree atrioventricular block could represent significant heart disease and 
subject should not participate. 
• 
Incomplete left bundle branch blocks could represent significant heart disease and subject 
should not participate. 
• 
Significant ventricular disease represented by complete intraventricular conduction defects 
(complete left or right bundle branch block) must be considered clinically significant and 
subjects presenting with any such condition should not be enrolled. Left anterior or 
posterior intraventricular fascicular blocks or hemiblock could represent ventricular disease 
and subject should not participate. 
• 
ST elevation consistent with ischemia, subject should not participate. 
• 
Two PVCs in a row, subject should not participate.  
 

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

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Appendix 4: Amendment#1 to the Clinical Trial Protocol 
Edition 1.0 dated 07-Jul-2016  
 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in 
≥ 55 year old adults to evaluate the safety and immunogenicity of the 
recombinant MVA-BN-RSV vaccine 
 
 
Amendment#1 to the Clinical Trial Protocol 
Edition 1.0 dated 07-Jul-2016 
 
 
Date of Amendment#1: 27-Jan-2017 
 
 

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Rationale 
The protocol Edition 1.0 is set up to measure cellular immune responses at Baseline (Visit 1) and 
one and two weeks following each vaccination in a subset of each treatment group. To measure 
the memory B cell responses to the trial vaccinations the protocol Edition 2.0 is generated and 
includes increased blood volume due to two additional blood draws to be taken for PBMC 
collection in these subgroups at the 3 month FU1 and 6 month FU2 visit . The respective protocol 
sections were amended accordingly.  
These changes and additional minor changes are outlined in section 2 below. 
The reason for the protocol amendment#1 is the implementation of two additional blood draw 
time points for PBMC collection: Additonal blood draw at the FU1 and FU2 visit. Consequently, 
an additional secondary endpoint is included. 
Changes 
General changes: 
• 
Update of Section 1.3 (Sponsor Signature Page) and 1.4 (Responsibilities) to reflect the 
change of the BN Biostatistician. 
 left the company and is replaced by 
 
 
• 
Update of Section 1.4 (Responsibilities)  to reflect the change of the ACM (safety) 
Laboratory contact person: 
 is replaced by 
  
• 
Update of Section 1.4 (Responsibilities)  to add the contact person, 
, for the 
 PBMC Laboratory 
• 
Update of section 4.2.2 (Active Trial Phase; Task sections): order of tasks was harmonized, 
‘swabs are taken from both nostrils’ was added to harmonize the task sections 
• 
Spelling and formatting was corrected 
Major changes are as follows: 
Changes/ added terms are highlighted in bold letters in the text (table below), removed terms are 
marked using strikethrough. 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Page 17, 1.5 Protocol Synopsis  
Page 18, 1.5 Protocol Synopsis 
Secondary Objective 
To assess the RSV-specific humoral and 
cellular immune responses against the 
MVA-BN-RSV vaccine in adult/elderly 
subjects in a subgroup population of each 
group. 
 
Secondary Objective 
To assess the RSV-specific humoral 
immune responses (in all subjects) and 
cellular immune responses (in a subgroup 
population of each group) against the 
MVA-BN-RSV vaccine in adult/elderly 
subjects . 
Reason for change:  
Clarification of analysis group for humoral 
immune responses against the MVA-BN-RSV 
vaccine. 
Page 19, 1.5 Protocol Synopsis  
Page 20, 1.5 Protocol Synopsis 
Secondary Endpoints Immunogenicity 
RSV-specific median and geometric mean 
Spot Forming Units (SFU) measured by 
IFN-ɣ / IL-4 ELISPOT at all PBMC 
sampling time points. 
 
Secondary Endpoints Immunogenicity 
RSV-specific median and geometric mean 
Spot Forming Units (SFU) measured by 
IFN-ɣ / IL-4 ELISPOT at all PBMC 
sampling time points until EAP. 
Reason for change:  
Specification of PBMC sampling time points 
for measurement by the IFN-ɣ / IL-4 
ELISPOT assay. 
 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Page 19, 1.5 Protocol Synopsis  
Page 20, 1.5 Protocol Synopsis 
Secondary Endpoints Immunogenicity 
 
Secondary Endpoints Immunogenicity 
Additional endpoint added: 
RSV-specific memory B cells measured at 
FU1 and FU2. 
 
Reason for change:  
Evaluation of memory B cell response to 
measure durability of immune response after 
administration of MVA-BN-RSV vaccine. 
 
Page 25/26, 1.6 Trial Schedule and 
footnote 
Page 26/27, 1.6 Trial Schedule and 
footnote 
Blood draw for PMBC collection checked at 
visits: V1, V1b, V2, V3b, V4 
Maximal total amount of blood 
taken/subject: up to 176 mL (514 mL for 
subjects in the  subgroup). 
 
Blood draw for PMBC collection checked at 
visits: V1, V1b, V2, V3b, V4, FU1, FU2 
Maximal total amount of blood 
taken/subject: up to 176 mL (514 642 mL 
for subjects in the  subgroup). 
 
Reason for change:  
Additional blood draw for PBMC collection 
at the follow–up visits FU1 and FU2 added 
to get two further time points 3 and 6 month 
after EAP for immune response analysis 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Page 44, 2.6 Clinical Trial Data with 
MVA-BN-RSV Vaccine, Table 7 
Page 45, 2.6 Clinical Trial Data with 
MVA-BN-RSV Vaccine, Table 7 
Footnote b missing 
 
Footnote b added 
 
b SAEs are included even if they exceed the 28-day 
follow-up period after each vaccination. 
 
Reason for change:  
Missing information (footnote) added. 
Page 58/59, 4.2.2 Active Trial Phase 
Page 60, 4.2.2 Active Trial Phase 
FU1 Visit (V3 + 84-98 days) 
The following tasks will be performed: 
• 
Recording of new SAE and new RSV-
specific symptoms and changes to AEs 
/SAEs ongoing at last active trial 
Visit EAP  
• 
Targeted physical examination 
including auscultation of the heart and 
lungs  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Nasal swab collection for mucosal 
immune response, swabs taken from 
both nostrils) 
• 
Blood draw for serum collection 
(9 mL) 
 
 
 
 
FU1 Visit (V3 + 84-98 days) 
The following tasks will be performed: 
• 
Recording of new SAE and new RSV-
specific symptoms and changes to AEs 
/SAEs ongoing at last active trial 
Visit EAP  
• 
Targeted physical examination 
including auscultation of the heart and 
lungs  
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Blood draw for serum collection 
(9 mL) 
• 
Nasal swab collection for mucosal 
immune response, swabs are taken 
from both nostrils) 
• 
Only for the subgroup: PBMC 
collection (64 mL)  
 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Reason for change:  
Additional blood draw for PBMC collection 
at the follow–up visit FU1 for immune 
response analysis 
FU2 Visit (V3 + 182-210 days) 
The following tasks will be performed: 
• 
Recording of new SAEs, new RSV-
specific symptoms and changes to 
AEs/SAEs ongoing at the FU1 Visit 
• 
Targeted physical examination 
including auscultation of the heart and 
lungs 
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Nasal swab collection for mucosal 
immune response (antibody testing; 
swabs taken from both nostrils) 
• 
Blood draw for serum collection 
(9 mL) 
 
 
 
 
 
 
 
 
 
 
 
FU2 Visit (V3 + 182-210 days) 
The following tasks will be performed: 
• 
Recording of new SAEs, new RSV-
specific symptoms and changes to 
AEs/SAEs ongoing at the FU1 Visit 
• 
Targeted physical examination 
including auscultation of the heart and 
lungs 
• 
Evaluation of vital signs  
• 
Recording of concomitant medication 
• 
Blood draw for serum collection 
(9 mL) 
• 
Nasal swab collection for mucosal 
immune response (antibody testing; 
swabs are taken from both nostrils) 
Only for the subgroup: PBMC collection 
(64 mL)  
Reason for change:  
Additional blood draw for PBMC collection 
at the follow–up visit FU2 for immune 
response analysis 
Page 63, 6.2 Shipment, Storage and 
Handling 
Page 64/65, 6.2 Shipment, Storage and 
Handling 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Details on shipment, storage and handling of 
the LF formulation of MVA-BN-RSV 
vaccine are provided in BN Standard 
Operating Procedure (SOP) 
 
“Storage, Handling and Vaccination 
Procedures of Liquid Frozen MVA-BN 
(IMVAMUNE) and Recombinant MVA-
Based Vaccines in Clinical Trials” (see also 
Section 6.3). 
Details on shipment, storage and handling of 
the LF formulation of MVA-BN-RSV 
vaccine are provided in BN Standard 
Operating Procedure (SOP) 
 
“Storage, Handling and Vaccination 
Procedures of Liquid Frozen MVA-BN 
(IMVAMUNE), Recombinant MVA-Based 
and FPV-Based Vaccines in Clinical Trials” 
(see also Section 6.3). 
Reason for change:  
Correction of SOP title 
 
Page 64, 6.3 Preparation, Administration 
and Dosage 
Page 65, 6.3 Preparation, Administration 
and Dosage 
Details on vaccine storage, preparation and 
administration of MVA-BN-RSV vaccine 
are provided in SOP 
, entitled 
“Storage, Handling and Vaccination 
Procedures of Liquid Frozen MVA-BN 
(IMVAMUNE), Recombinant MVA-Based 
Vaccines in Clinical Trials”. 
 
Details on vaccine storage, preparation and 
administration of MVA-BN-RSV vaccine 
are provided in SOP 
, entitled 
“Storage, Handling and Vaccination 
Procedures of Liquid Frozen MVA-BN 
(IMVAMUNE), Recombinant MVA-Based 
and FPV-Based Vaccines in Clinical 
Trials”. 
Reason for change:  
Correction of SOP title 
Page 65, 7.0 Assessment of 
Immunogenicity 
Page 66, 7.0 Assessment of 
Immunogenicity 
The immunogenicity of the vaccine will be 
assessed by measuring humoral, cellular and 
mucosal immune responses on collected 
serum, nasal swab and PBMC samples. 
• 
RSV-specific systemic antibody levels 
will be determined from serum 
samples using a RSV-specific IgG/IgA 
ELISA. Further, two separate PRNTs 
The immunogenicity of the vaccine will be 
assessed by measuring humoral, cellular and 
mucosal immune responses on collected 
serum, nasal swab and PBMC samples. 
• 
RSV-specific systemic antibody levels 
will be determined from serum 
samples using a RSV-specific IgG/IgA 
ELISA. Further, two separate PRNTs 

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dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
will be performed to measure 
neutralizing antibody levels to RSV 
strains A and B.  
• 
RSV-specific mucosal antibody levels 
will be determined from nasal swab 
samples using an RSV-specific IgA 
ELISA. 
• 
IFN-γ and IL-4 secreting, RSV-
specific T cells will be quantified 
using an ELISPOT assay on PBMC 
samples. 
 
will be performed to measure 
neutralizing antibody levels to RSV 
strains A and B.  
• 
RSV-specific mucosal antibody levels 
will be determined from nasal swab 
samples using an RSV-specific IgA 
ELISA. 
• 
IFN-γ and IL-4 secreting, RSV-
specific T cells will be quantified 
using an ELISPOT assay on PBMC 
samples. 
• 
RSV-specific Memory B cells will be 
measured on PBMC samples 
obtained at the FU visits and 
compared between treatment groups 
Reason for change:  
Immunogenicity assessment for Memory B 
cells added 
 
Page 66, 7.2 Mucosal Immune Responses 
Page 67,7.2 Mucosal Immune Responses 
Nasal swab samples will be collected from 
subjects of all four treatment groups as 
outlined in Section 1.6. Nasal samples will 
be collected from both nostrils using regular 
nylon flocked swabs (
) 
prior to vaccination. RSV-specific IgA 
antibody responses will be determined using 
a direct ELISA. Details of the procedure are 
defined in SOP 
 “ELISA to 
determine RSV-specific Antibody Titers 
(IgA) in Human Nasal Swab Samples”. 
 
Nasal swab samples will be collected from 
subjects of all four treatment groups as 
outlined in Section 1.6. Nasal samples will 
be collected from both nostrils using regular 
nylon flocked swabs (
s). 
Samples obtained on vaccination visits 
will be taken prior to vaccination. RSV-
specific IgA antibody responses will be 
determined using a direct ELISA. Details of 
the procedure are defined in SOP 
 “ELISA to determine RSV-
specific Antibody Titers (IgA) in Human 
Nasal Swab Samples”. 
Reason for change:  

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
Explanation specified 
 
 
Page 67: 7.3 Systemic Cellular Immune 
Responses 
 
Page 68: 7.3 Systemic Cellular Immune 
Responses 
 
PBMC samples will be collected from 
subjects as outlined in Section 1.6. 
Blood samples obtained on vaccination visits 
will be drawn prior to vaccination.  
SFU per 1 x 106 PBMC will be determined 
using an IFN-γ / IL-4 ELISPOT assay using 
three different RSV peptide pools as well as 
RSV virus as stimulating agent. Details of 
the ELISPOT procedure are defined in the 
SOP 
 “Dual Color (IFN-/IL-4) 
RSV ELISPOT using Human PBMC”.  
The geometric mean SFU/1 x 106 PBMC are 
calculated per visit. Any SFU value below 
the assay detection limit is assigned the 
arbitrary value of 1 (negative result). Results 
equal or above the detection limit are 
considered positive test results. 
The response rate is calculated per visit and 
is defined as the percentage of subjects with 
a response based on the total number of 
subjects with test results on the respective 
visit. The response status is assessed with 
regard to the corresponding baseline 
(Visit 1) test result.  
PBMC samples will be collected from 
subjects as outlined in Section 1.6. 
Blood samples obtained on vaccination visits 
will be drawn prior to vaccination.  
SFU per 1 x 106 PBMC will be determined 
using an IFN-γ / IL-4 ELISPOT assay using 
five different RSV peptide pools as well as 
RSV virus as stimulating agent. Details of 
the ELISPOT procedure are defined in SOP 
 “Dual Color (IFN-/IL-4) RSV 
ELISPOT using Human PBMC”.  
The geometric mean SFU/1 x 106 PBMC are 
calculated per visit. Any SFU value below 
the assay detection limit is assigned the 
arbitrary value of 1 (negative result). Results 
equal or above the detection limit are 
considered positive test results. 
The response rate is calculated per visit and 
is defined as the percentage of subjects with 
a response based on the total number of 
subjects with test results on the respective 
visit. The response status is assessed with 
regard to the corresponding baseline 
(Visit 1) test result.  

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
The number of ELISPOT pools where there 
is a response at each visit is also calculated 
on a per subject basis. 
A subject is an ELISPOT Responder to the 
vaccine in a particular test agent (e.g. RSV 
virus) if the subject has a response for at 
least two post baseline visits within the same 
test agent. 
The responder rate for each test agent is the 
percentage of subjects who are responders to 
the relevant test agent out of the number of 
subjects with a non-missing responder status 
(positive or negative) within the relevant 
analysis population. 
 
The number of ELISPOT pools where there 
is a response at each visit is also calculated 
on a per subject basis. 
A subject is an ELISPOT responder to the 
vaccine in a particular test agent (e.g. RSV 
virus) if the subject has a response for at 
least two post baseline visits within the same 
test agent. 
The responder rate for each test agent is the 
percentage of subjects who are responders to 
the relevant test agent out of the number of 
subjects with a non-missing responder status 
(positive or negative) within the relevant 
analysis population. 
Furthermore, PBMC collected at the FU 
visits will be used to determine memory B 
cells secreting IgG and/or IgA in an 
ELISPOT. Details of the procedure are 
defined in SOP 
 “B Cell 
ELISpot to quantify RSV-specific IgG 
and IgA Secreting Cells in Human CD19 
Positive Cells”.   
Reason for change:  
Details for Memory B cell assay added and 
immune response analysis definitions 
corrected. 
Page 75, 8.2.9 Cardiac Assessment 
Page 77, 8.2.9 Cardiac Assessment 
Troponin I 
Troponin I will be measured at screening 
and if clinically indicated on the following 
Troponin I 
Troponin I will be measured at screening 
and if clinically indicated on the following 

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Clinical Trial Protocol Edition 1.0, 
dated 07-Jul-2016 
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
visits: Visit 2, Visit 4 and FU1 Visit or at 
unscheduled visits. 
 
visits: Visit 2, Visit 4, FU1 and FU2 Visits 
or at unscheduled visits. 
Reason for change:  
Troponin I will be analyzed optionally also 
at FU2 
Page 82, 9 Statistical Considerations 
Page 83, 9 Statistical Considerations 
The primary endpoint of this trial is to 
determine the GMTs after one or two MVA-
BN-RSV vaccinations measured by PRNT 
(against strain A) 2 weeks post last 
vaccination. 
The primary endpoint of this trial is to 
determine the GMTs after one or two MVA-
BN-RSV vaccinations or placebo measured 
by PRNT (against strain A) 2 weeks post last 
vaccination.  
Reason for change:  
‘Placebo’ was added for correctness. 
Page 83, 9.2 Sample Size Calculation 
Page 84, 9.2 Sample Size Calculation 
The following descriptive comparison of the 
ratios of the GMTs between groups will be 
calculated along with the corresponding 95% 
Confidence Interval by assuming that the 
log10 PRNT (A strain) titers are normally 
distributed: 
1. Group 2 / Group 1 – Two 
vaccinations compared to one 
vaccination using Dose 1 
2. Group 4 / Group 3 – Two 
vaccinations compared to one 
vaccination using Dose 2 
The following descriptive comparison of the 
ratios of the GMTs between groups will be 
calculated along with the corresponding 95% 
Confidence Interval by assuming that the 
log10 PRNT (A strain) titers are normally 
distributed: 
1. Group 2 / Group 1 – Two 
vaccinations compared to one 
vaccination using Dose 1 
2. Group 4 / Group 3 – Two 
vaccinations compared to one 
vaccination using Dose 2 

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Clinical Trial Protocol Edition 1.0, 
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Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017 
Changed to: 
3. Group 3 / Group 1 – Dose 2 
compared to Dose 1 using one 
vaccination 
4. Group 4 / Group 2 – Dose 2 
compared to Dose 1 using two 
vaccinations  
5. Group 2 / Group 5 – Two 
vaccinations compared using Dose 1 
compared to Placebo 
6. Group 4 / Group 5 – Two 
vaccinations compared using Dose 2 
compared to Placebo 
 
3. Group 3 / Group 1 – Dose 2 
compared to Dose 1 using one 
vaccination 
4. Group 4 / Group 2 – Dose 2 
compared to Dose 1 using two 
vaccinations  
5. Group 2 / Group 5 – Two 
vaccinations compared using Dose 1 
compared to Placebo 
6. Group 4 / Group 5 – Two 
vaccinations compared using Dose 2 
compared to Placebo 
Reason for change:  
Correction of wording 
Page 83, 9.2 Sample Size Calculation 
Page 84, 9.2 Sample Size Calculation 
With a group sample size of 70 per group 
(recruiting 80 per group to account for 12 % 
dropouts), and an assumed SD of 0.46 for 
the log10 PRNT titers (A strain), this will 
give 80 % power to detect a relative change 
in titers from the Group 1 of a 40 % 
increase. This is a similar range to what is 
expected given what was seen in the RSV 
Phase I trial (RSV-MVA-001).  
 
With a group sample size of 70 per group 
(recruiting 80 per group to account for 12 % 
dropouts), and an assumed SD of 0.46 for 
the log10 PRNT titers (A strain), this will 
give 80 % power to detect a relative change 
in titers from the Group 1 of a 66 % 
increase. The SD is similar to what was 
seen in the RSV Phase I trial (RSV-MVA-
001).  
Reason for change:  
Correction of the percentage of the relative 
change as the sample size was corrected   
 
All changes are considered not to have any negative influence on the trial procedures in general, 
on the safety of the trial participants or on the validity of the main trial result. 

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Appendix 5: Amendment#2 to the Clinical Trial Protocol 
 
 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in 
≥ 55 year old adults to evaluate the safety and immunogenicity of the 
recombinant MVA-BN-RSV vaccine 
 
 
Amendment#2 to the Clinical Trial Protocol 
 
 
 
Date of Amendment#2: 20-Jul-2017 
 
 

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Rationale 
The protocol Edition 3.0 is set up to add a booster substudy after the main part of the trial. 
Subjects from the two treatment groups with the best safety/immunogenicity profile will receive a 
MVA-BN-RSV vaccination to boost their immune response approximately one year after having 
received the first vaccination in the main part of the trial. Assessment of individual antibody titers 
within short time intervals following the booster vaccination will provide information on how fast 
and effective measurable antibody titers can be reactivated. After ICF has been collected, subjects 
will enter a baseline period of up to 28 days before the 1 year booster vaccination. All subjects 
vaccinated in the booster subgroup will be followed up for 6 months after vaccination. Hence, the 
substudy will also evaluate the durability of immune responses 12 months following the primary 
vaccination (i.e. baseline measurement prior to administration of the booster dose) and 6 months 
following the booster vaccination.  
Edition 3.0 was generated to measure safety and immunogenicity after a booster vaccination 
approximately one year after the first vaccination. These changes and additional minor changes 
are outlined below. 
The reason for the protocol amendment#2 is the implementation of the booster substudy which 
includes up to seven additional visits for the participating subjects :  
Changes 
General changes: 
• 
Update of Section 1.3 (Sponsor Signature Page) and 1.4 (Responsibilities) to reflect the 
change of the BN Biostatistician: 
is replaced by 
 
• 
Update of Section 1.4 (Responsibilities) to reflect the change of the ABL (PBMC) 
Laboratory contact person: 
 is replaced by 
 
• 
Update of Section 1.5 (Synopsis) regarding eligibility criteria of booster substudy 
• 
Addition of Section 1.7 (Trial Schedule Booster Substudy) 
• 
Update of Section 2.7 (Rationale) to include rationale for booster substudy 
• 
Addition of  Section 4.2.2 (Description of Trial Procedures – Booster Substudy) 
• 
Spelling, formatting and wording was corrected and adaptions to BN writing conventions 
were made 
 

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Major changes are as follows: 
Changes/ added terms are highlighted in bold letters in the text (table below), removed terms are 
marked using strikethrough. 
Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Page 14, List of Abbreviations  
Page 16, List of Abbreviations 
 
BFU: Booster Follow Up 
BV: Booster Visit 
GMR: Geometric Mean Ration 
GMFI: Geometric Mean Fold Increase 
Page 16, Definitions 
Page 19, Definitions 
Active trial phase: The trial phase starting 
with and including Visit 1 and ending with 
and including Visit EAP (End of active trial 
phase) (V3 + 28-35 days; for details see 
Section 1.6). 
 
 
 
 
 
 
 
End of active trial phase (EAP): The last visit 
of the active trial phase (for details see 
Section 1.6). 
Active trial phase: The trial phase starting 
with and including (Booster) Visit 1 and 
ending with and including (B)EAP (End of 
active trial phase) (V3/BV1 + 28-35 days; for 
details see Section 1.6 and Section 1.7). 
 
Booster Baseline: Immune responses 
measured at BV0 
Booster Substudy: Administration of a 
signle (booster) dose of MVA-BN-RSV 
vaccine approximately one year after the 
first MVA-BN-RSV vaccination in subjects 
previously vaccinated with MVA-BN-RSV 
in the main trial. 
End of active trial phase ([B]EAP): The last 
visit of the active trial phase (for details see 
Section 1.6 and Section 1.7). 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
 
 
 
 
 
 
 
 
Staggering visit (VS): A visit only required 
by subjects enrolled into the sentinel and 
safety cohort. 
 
Subgroup: The subgroup consists of 20 
subjects per treatment group who will have 
peripheral blood mononuclear cells (PBMC) 
collection as well as an additional serum and 
nasal swab sample collection time point 
one week post each vaccination. 
 
Fold increase: The fold increase is defined 
as a subject’s post-baseline titer at Visit X, 
divided by the baseline titer 
Main Trial: In the main trial subjects will 
receive two administrations 4 weeks apart 
consisting of MVA-BN-RSV Dose 1 
(1 x 108 Inf.U), MVA-BN-RSV Dose 2 
(5 x 108 Inf.U) or Placebo (TBS). 
 
Staggering visit (VS): A visit only required 
by subjects enrolled into the sentinel and 
safety cohort in the main trial. 
 
Subgroup: The subgroup consists of 
20 subjects per treatment group in the main 
trial who have peripheral blood mononuclear 
cells (PBMC) collection as well as an 
additional serum and nasal swab sample 
collection time point one week post each 
vaccination. 
Out of this subgroup, approximately 
13 subjects per treatment group will be 
recruited into the booster substudy. 
Page 17ff, 1.5 Synopsis 
Page 20ff, 1.5 Synopsis 
Vaccination Dose and Schedule: 
[…] 
In total 400 subjects will be recruited into this 
trial. Subjects will receive two 
administrations 4 weeks apart which will 
consist of MVA-BN-RSV Dose 1 
Vaccination Dose and Schedule: 
[…] 
In total 400 subjects will be recruited into this 
trial. Subjects will receive two 
administrations 4 weeks apart which will 
consist of MVA-BN-RSV Dose 1 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
(1 x 108 Inf.U), MVA-BN-RSV Dose 2 
(5 x 108 Inf.U) or Placebo (TBS). To obtain 
Dose 1 the MVA-BN- RSV vaccine will be 
diluted in MVA-BN formulation buffer 
(TBS) according to the study specific 
administration instructions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For details on the treatment groups see 
Table 1. 
Subjects in all groups are blinded and will not 
be told to which group they were assigned. 
(1 x 108 Inf.U), MVA-BN-RSV Dose 2 
(5 x 108 Inf.U) or Placebo (TBS). To obtain 
Dose 1 the MVA-BN- RSV vaccine will be 
diluted in MVA-BN formulation buffer 
(TBS) according to the study specific 
administration instructions. Following the 
main trial, two subgroups will be 
identified, which will continue in the 
booster substudy. The selection is based on 
safety and immunogenicity data obtained 
in the main trial. 
86 subjects from 2 treatment groups (43 
per treatment group) are supposed to 
receive one (booster) dose of MVA-BN-
RSV vaccine  approximately one year after 
their first vaccination. In this booster 
substudy, eligible subjects will receive the 
same dose they received during the main 
trial. 
For details on the treatment groups see 
Table 1. 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Trial duration: Up to 39 weeks per subject  
 
 
Sample size: […] 
 
 
 
 
Trial duration: Up to 39 weeks per subject in 
the main trial and up to additional 
34 weeks per subject enrolled in the 
booster substudy. 
Sample size main trial: […] 
Sample size booster substudy: From two 
treatment groups selected based on 
immunogenicity/safety parameters 
following primary vaccination (as 
determined by the sponsor) 43 subjects 
will be recruited into the booster substudy 
(86 subjects in total). Out of these, in total 
26 subjects will be recruited from the 
PBMC subgroup, approximately 13 
subjects for each of the two selected 
treatment groups. Subjects will receive a 
single booster vaccination approximately 
1 year after the first vaccine 
administration with the same dose they 
received during the main trial. 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Secondary objectives:  
[…] 
 
Secondary objectives:  
[…] 
To assess the RSV-specific immune 
responses (in subjects of the selected 
treatment groups) one year after the last 
vaccination in the main trial in 
adult/elderly subjects. 
To assess the RSV-specific humoral 
immune responses (in subjects of the 
selected treatment groups) and cellular 
immune responses (in the respective 
subgroup population of the selected 
treatment groups) following a one year 
booster MVA-BN-RSV vaccination in 
adult/elderly subjects. 
[…] 
Secondary Endpoints: 
Immunogenicity  
RSV-specific antibody response rate 
measured by Immunoglobulin G (IgG) 
Enzyme-linked Immunosorbent Assay  
at all post vaccination immunogenicity serum 
sampling time points and based on the 
individual peak titers. 
 
 
 
[…] 
Secondary Endpoints: 
Immunogenicity  
RSV-specific antibody response rate 
measured by Immunoglobulin G (IgG) 
Enzyme-linked Immunosorbent Assay 
(ELISA) (total RSV, G protein A strain, G 
protein B strain) at all post vaccination 
immunogenicity serum sampling time points 
and based on the individual peak titers 
(separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific GMT measured by IgG ELISA 
at all immunogenicity serum sampling time 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
RSV-specific GMT measured by IgG ELISA 
at all immunogenicity serum sampling time 
points and based on the individual peak titers.  
 
RSV-specific antibody response rate 
measured by Immunoglobulin A (IgA) 
ELISA at all post vaccination 
immunogenicity serum sampling time points 
and based on the individual peak titers. 
 
RSV-specific GMT measured by IgA ELISA 
at all immunogenicity serum sampling time 
points and based on the individual peak titers. 
 
 
RSV-specific antibody response rate 
measured by PRNT (RSV strain A) at all post 
vaccination immunogenicity serum sampling 
time points and based on the individual peak 
titers. 
RSV-specific GMT measured by PRNT 
(RSV strain A) at all immunogenicity serum 
sampling time points and based on the 
individual peak titers. 
 
 
RSV-specific antibody response rate 
measured by PRNT (RSV strain B) at all post 
vaccination immunogenicity serum sampling 
points and based on the individual peak titers 
(separately for main trial and booster 
substudy of the clinical trial).  
RSV-specific antibody response rate 
measured by Immunoglobulin A (IgA) 
ELISA at all post vaccination 
immunogenicity serum sampling time points 
and based on the individual peak titers 
(separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific GMT measured by IgA ELISA 
at all immunogenicity serum sampling time 
points and based on the individual peak titers 
(separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific antibody response rate 
measured by PRNT (RSV strain A) at all post 
vaccination immunogenicity serum sampling 
time points and based on the individual peak 
titers (separately for main trial and booster 
substudy of the clinical trial). 
RSV-specific GMT measured by PRNT 
(RSV strain A) at all immunogenicity serum 
sampling time points and based on the 
individual peak titers (separately for main 
trial and booster substudy of the clinical 
trial). 
RSV-specific antibody response rate 
measured by PRNT (RSV strain B) at all post 
vaccination immunogenicity serum sampling 
time points and based on the individual peak 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
time points and based on the individual peak 
titers. 
 
RSV-specific GMT measured by PRNT 
(RSV strain B) at all immunogenicity serum 
sampling time points and based on the 
individual peak titers. 
 
RSV-specific antibody response rate 
measured by IgA ELISA at all post 
vaccination nasal swab sampling time points 
(mucosal IgA) and based on the individual 
peak titers. 
 
RSV-specific GMT measured by IgA ELISA 
at all nasal swab sampling time points 
(mucosal IgA) and based on the individual 
peak titers. 
 
RSV-specific response and responder rates 
measured by Interferon gamma (IFN-ɣ) and 
Interleukin 4 (IL-4) Enzyme-linked Immuno 
Spot Technique (ELISPOT) at all PBMC post 
vaccination sampling time points until EAP. 
 
RSV-specific median and geometric mean 
Spot Forming Units (SFU) measured by IFN-
ɣ / IL-4 ELISPOT at all PBMC sampling 
time points until EAP. 
titers (separately for main trial and booster 
substudy of the clinical trial).  
RSV-specific GMT measured by PRNT 
(RSV strain B) at all immunogenicity serum 
sampling time points and based on the 
individual peak titers (separately for main 
trial and booster substudy of the clinical 
trial). 
RSV-specific antibody response rate 
measured by IgA ELISA at all post 
vaccination nasal swab sampling time points 
(mucosal IgA) and based on the individual 
peak titers (separately for main trial and 
booster substudy of the clinical trial). 
RSV-specific GMT measured by IgA ELISA 
at all nasal swab sampling time points 
(mucosal IgA) and based on the individual 
peak titers (separately for main trial and 
booster substudy of the clinical trial). 
RSV-specific response and responder rates 
measured by Interferon gamma (IFN-ɣ) and 
Interleukin 4 (IL-4) Enzyme-linked Immuno 
Spot Technique (ELISPOT) at all PBMC post 
vaccination sampling time points until EAP 
and until BEAP. 
RSV-specific median and geometric mean 
Spot Forming Units (SFU) measured by IFN-
ɣ / IL-4 ELISPOT at all PBMC sampling 
time points until EAP and until BEAP. 
RSV-specific memory B cells measured at 
FU1 and FU2 as well as Booster Follow Up 

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RSV-specific memory B cells measured at 
FU1 and FU2. 
[…] 
Visit 1 (BFU1) and Booster Follow Up 
Visit 2 (BFU2). 
[…] 
Trial design  
[…] 
Trial design  
main trial 
[…] 
Trial design booster substudy 
From each of the two treatment groups 
chosen for the booster substudy, 43 
subjects will be recruited to receive a 
booster vaccination approximately one 
year after their first vaccination in the 
main trial. Subjects will receive the same 
dose as in the main trial. All 86 subjects 
will be followed up for 6 months after their 
last vaccination. 
 
Table 2 
Treatment Groups Booster 
Substudy   
Grou
p 
N 
Age 
[years] 
Volume 
per dose 
[mL] 
Booster vaccination 
Day 0 
Route 
1 
43 
≥ 55 
0.5 
Same dose as defined 
in main trial  
IM 
2 
43 
≥ 55 
0.5  
Same dose as defined 
in main trial 
IM  
Total 86* 
 
 
 
 
*at least 40 evaluable subjects from the two chosen treatment groups 
 
Reports: 
Reports 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Final Safety Report after EAP (4 weeks after 
last vaccination) 
Addendum Report (including 
immunogenicity data and 3 and 6 months 
follow-up data for safety and 
immunogenicity) 
Final Clinical Study Report (including 
safety and immunogenicity data until 3 
months follow-up visit) 
Clinical Study Report Addendum 1 
(including additional immunogenicity data 
not yet included in the Final Clinical Study 
Report and 6 months follow-up data for 
safety and immunogenicity)  
Clinical Study Report Addendum 2 
(including safety and immunogenicity data 
of  the 3-month and 6-month follow-up 
visits of the booster substudy 
Page 34, 2.5 Clinical Profile of MVA-BN 
and Recombinant MVA-based Vaccines 
Page 44, 2.5 Clinical Profile of MVA-BN 
and Recombinant MVA-based Vaccines 
To date, 18 clinical trials (13 sponsored by 
BN and 5 sponsored by the NIH [National 
Institutes of Health]) evaluating the safety 
and immunogenicity of MVA-BN have been 
completed. Currently three clinical trials are 
ongoing - two sponsored by BN and one 
sponsored by the NIH. A total of 7,106 
subjects have been vaccinated with MVA-BN 
in completed clinical trials, including risk 
groups with contraindications to conventional 
smallpox vaccines, such as HIV- infected 
patients and patients with atopic dermatitis 
(AD). Further MVA-BN has been evaluated 
in an elderly population, i.e. subjects 56 to 80 
years of age. Including the ongoing clinical 
trials, more than 7,600 subjects have been 
exposed to MVA-BN.  
 
To date, 19 clinical trials (13 sponsored by 
BN and 6 sponsored by the NIH [National 
Institutes of Health]) evaluating the safety 
and immunogenicity of MVA-BN have been 
completed. Currently three clinical trials are 
ongoing - two sponsored by BN and one 
sponsored by the NIH. More than 7100 
subjects have been vaccinated with MVA-BN 
in completed clinical trials, including risk 
groups with contraindications to conventional 
smallpox vaccines, such as HIV- infected 
patients and patients with atopic dermatitis 
(AD). Further MVA-BN has been evaluated 
in an elderly population, i.e. subjects 56 to 80 
years of age. Including the ongoing clinical 
trials, more than 7700 subjects have been 
exposed to MVA-BN.  
Reason for change: 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Update of Investigators Brochure 
Page 35, 2.5.1 Safety Overview of MVA-
BN and Recombinant MVA-based 
Vaccines  
Page 46, 2.5.1 Safety Overview of MVA-
BN and Recombinant MVA-based 
Vaccines 
Serious Suspected Adverse Drug Reactions  
 
As of 31 August 2015 a total of seven (7 out 
of 7,675 vaccinated subjects = 0.09 %) 
serious suspected ADRs have been reported 
for MVA-BN smallpox vaccine in completed 
and ongoing trials (see Table 3). 
Serious Suspected Adverse Drug Reactions  
A total of seven (7 out of 7758 vaccinated 
subjects = 0.09 %) serious suspected ADRs 
have been reported for MVA-BN smallpox 
vaccine in completed and ongoing trials (see 
Table 3). 
Reason for change: 
Update of number of vaccinated subjects 
Page 41, 2.5.2 Safety Profile of MVA-BN-
based Recombinant Vaccines in Healthy 
Compared to Special Populations 
Page 50, 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 and measles in more 
than 400 subjects including healthy and HIV 
infected populations. 
 
 
[…] 
BN has evaluated the safety and 
immunogenicity of MVA-BN-based 
recombinant vaccines for several indications 
such as cancer, HIV and measles in more 
than 700 subjects including healthy and HIV 
infected populations. 
 
[…] 
Reason for change: 
Update of number of vaccinated subjects 
Page 50, 2.8 Trial Population 
Page 59, 2.8 Trial Population 
[…]  
[…]  

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Changed to: 
Groups will be stratified by age: 55 to < 70, 
≥ 70 years. 
Groups will be stratified by age: 55 to < 70, 
≥ 70 years in the main part of the trial. For 
the booster substudy 43 evaluable subjects 
will be chosen randomly from each of the 
two selected treatment groups. No further 
age stratification will be done in the 
booster substudy. 
Page 51f, 4.1 Experimental Design 
Forecast 
Page 60f, 4.1 Experimental Design 
Forecast 
[…] 
In total 400 subjects will be recruited into this 
trial. Subject will receive two administrations 
4 weeks apart which will consist of MVA-
BN-RSV Dose 1, MVA-BN-RSV Dose 2 or 
placebo (TBS). To obtain Dose 1 the vaccine 
will be diluted in TBS according to the 
vaccination instructions. For details on the 
treatment groups see Table 12. 
 
 
 
 
Recruitment into the trial will be performed 
into a staggered manner as outlined below. 
Any occurring events as defined in the trial 
halting rules in Section 4.5 would stop the 
staggering procedure until further 
clarification.  
[…] 
In total 400 subjects will be recruited into the 
main trial. Subjects will receive two 
administrations 4 weeks apart which will 
consist of MVA-BN-RSV Dose 1, MVA-BN-
RSV Dose 2 or placebo (TBS). To obtain 
Dose 1 the vaccine will be diluted in TBS 
according to the vaccination instructions. For 
details on the treatment groups see Table 13. 
Approximately one year after their first 
vaccination 86 subjects in the selected 
treatment groups of the main trial will be 
recruited to participate in the booster 
substudy and will receive one dose of 
MVA-BN-RSV vaccine. 
Recruitment into the main trial will be 
performed into a staggered manner as 
outlined below. Any occurring events as 
defined in the trial halting rules in Section 4.5 
would stop the staggering procedure until 
further clarification.  

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dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Staggering Procedure: 
The staggering process will be performed at 
one clinical trial site. The trial will start with 
a sentinel cohort with 2 subjects, of whom 
one subject will be recruited into Group 2 and 
the other subject into Group 4 (i.e. 1:1 
subjects receiving Dose 1 and Dose 2).  
[…] 
 
Staggering Procedure: 
The staggering process will be performed at 
one clinical trial site. The main trial will start 
with a sentinel cohort with 2 subjects, of 
whom one subject will be recruited into 
Group 2 and the other subject into Group 4 
(i.e. 1:1 subjects receiving Dose 1 and 
Dose 2).  
[…] 
Booster Substudy 
In total 86 evaluable subjects  will receive 
a booster vaccination approximately one 
year after their first vaccination in the 
main trial receiving the same dose they 
received during the main trial. To obtain 
40 evaluable subjects per group up to 43 
subjects per selected group will be 
recruited. Subjects are then followed up 
for 6 months after their last vaccination. 
Page 61, 4.2.4 Early Discontinuation 
Page 75, 4.2.4 Early Discontinuation 
Reasons for early discontinuations: 
[…] 
• 
Subject’s refusal to receive second 
vaccination. 
• 
Subject unwilling or unable to comply 
with trial requirements.  
• 
Any reason that, in the opinion of the 
investigator contradicts administration 
of the second vaccination or otherwise 
Reasons for early discontinuations: 
[…] 
• 
Subject’s refusal to receive second / 
booster vaccination. 
• 
Subject unwilling or unable to comply 
with trial requirements.  
• 
Any reason that, in the opinion of the 
investigator contradicts administration 
of the second / booster vaccination or 

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Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
requires early discontinuation of a 
subject. 
Handling of early discontinuations trial 
[…] 
otherwise requires early discontinuation 
of a subject. 
Handling of early discontinuations main trial 
[…] 
Handling of early discontinuations booster 
substudy 
• 
If a subject recruited for the booster 
substudy (after signature of the ICF 
for the booster substudy) 
discontinues from the trial prior to 
the booster vaccination or does not 
receive the booster vaccination for 
any reason, the subject should 
undergo a concluding safety visit 
(including pregnancy test for 
WOCBP).  
• 
If a subject recruited for the booster 
substudy discontinues from the trial 
after the booster vaccination, is is 
highly recommended that the subject 
undergoes an abbreviated visit 
schedule (including BEAP, BFU1 
and BFU2).  
Page 62, 4.3 Trial Duration 
Page 76, 4.3 Trial Duration 
The total duration of the trial for each subject 
including the screening period and follow-up 
visits will be up to 39 weeks. The duration of 
the trial as a whole depends on the 
recruitment period. 
 
The total duration of the main trial for each 
subject including the screening period and 
follow-up visits will be up to 39 weeks. The 
total duration of the booster substudy 
including baseline and follow up visits will 
be 34 weeks. The duration of the trial as a 
whole depends on the recruitment period. 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Page 63, 4.5 Trial Halting Rules 
Page 77, 4.5 Trial Halting Rules 
A temporary halting or termination of the 
trial as a whole can be decided by the SMT 
(during the staggering phase) or the SMC in 
case of an occurrence of  
• 
an SAE 
• 
an unexpected (i.e. not listed in the 
current IB) Grade 3 or higher systemic 
reaction or lab toxicity (Appendix 1: 
Toxicity Scale for Laboratory Values) 
A temporary halting or termination of the 
trial as a whole can be decided by the SMT 
(during the staggering phase) or the SMC in 
case of an occurrence of  
• 
an SAE 
• 
an unexpected (i.e. not listed in the 
current IB) Grade 3 or higher systemic 
reaction or lab toxicity (Appendix 1: 
Toxicity Scale for Laboratory Values) 
with an at least reasonable possibility of a 
causal relationship to the administration of 
MVA-BN-RSV vaccine, i.e. the 
relationship cannot be ruled out. 
Reason for change: 
Update of halting rules 
Page 63, 5.1 Recruitment Procedure 
Page 78, 5.1 Recruitment Procedure 
[…] 
 
[...] 
From each of the two treatment groups 
selected for the booster substudy, 
43 subjects will be  randomly recruited to 
receive a booster vaccination 
approximately one year after their first 
vaccination with the same dose they had 
received during the main trial. Out of 
these 86 subjects, in total approximately 
26 subjects will be recruited from the 
PBMC subgroup resulting in 

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Clinical Trial Protocol Edition 3.0,  
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Changed to: 
approximately 13 subjects for each of the 
two selected treatment groups.  
Page 65, 7. Assessment of Immunogenicity 
Page 80, 7. Assessment of Immunogenicity 
The immunogenicity of the vaccine will be 
assessed by measuring humoral, cellular and 
mucosal immune responses on collected 
serum, nasal swab and PBMC samples. 
• 
RSV-specific systemic antibody levels 
will be determined from serum samples 
using a RSV-specific IgG/IgA ELISA. 
Further, two separate PRNTs will be 
performed to measure neutralizing 
antibody levels to RSV strains A and B.  
 
The immunogenicity of the vaccine will be 
assessed by measuring humoral, cellular and 
mucosal immune responses on collected 
serum, nasal swab and PBMC samples. 
• 
RSV-specific, G protein A strain-
specific, G protein B strain-specific 
systemic antibody levels will be 
determined from serum samples using a 
RSV-specific IgG/IgA ELISA. Further, 
two separate PRNTs will be performed 
to measure neutralizing antibody levels 
to RSV strains A and B.  
Reason for change: 
Update of immunogenicity definitions 
Page 66, 7.1.1 RSV-specific ELISA 
Page 81, 7.1.1 RSV-specific ELISA 
RSV-specific IgG/IgA antibody responses 
will be determined using a direct ELISA 
utilizing a standard curve for titer calculation. 
Details of the procedure are defined in the 
SOP 
 “ELISA to determine RSV-
Specific Antibody Titers (IgG) in Human 
Serum Samples” and SOP 
 
“ELISA to determine RSV-Specific IgA 
Titers in Human Serum Samples”. 
[…] 
RSV-specific IgG/IgA antibody responses 
will be determined using several ELISAs. 
Details of the procedure are defined in the 
SOP 
 “ELISA to determine RSV-
Specific Antibody Titers (IgG) in Human 
Serum Samples” and SOP 
 
“ELISA to determine RSV-Specific IgA 
Titers in Human Serum Samples”. 
[…] 
 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The Geometric Mean Ratio 
(GMR) is calculated as (GMT at Visit X / 
GMT at Visit 1). 
 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The Geometric Mean Fold 
Increase (GMFI) is calculated analogously 
per post-baseline visit as the geometric 
mean of the individual  fold increases, i.e. 
the subjects’ post-baseline titers at Visit X, 
divided by their corresponding baseline 
titer. 
Reason for change: 
Update of immunogenicity definitions 
Page 67, 7.1.2 RSV-specific PRNT 
Page 82, 7.1.2 RSV-specific PRNT 
Two parallel PRNTs will be performed to 
determine RSV-specific neutralizing 
antibody titers against RSV strain A and B, 
respectively. 
[…] 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The GMR is calculated as 
(GMT at Visit X / GMT at Visit 1). 
 
Two PRNTs will be performed to determine 
RSV-specific neutralizing antibody titers 
against RSV strain A and B, respectively.  
[…] 
 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The GMFI is calculated 
analogously per post-baseline visit as the 
geometric mean of the individual  fold 
increases, i.e. the subjects’ post-baseline 
titers at Visit X, divided by their 
corresponding baseline titer. 
Reason for change: 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Update of immunogenicity definitions 
Page 67, 7.2 Mucosal Immune Response 
Page 82, 7.2 Mucosal Immune Response 
[…] 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The GMR is calculated as 
(GMT at Visit X / GMT at Visit 1). 
[…] 
The GMT is calculated per visit as well as 
based on individual peak titers by taking the 
antilogarithm of the mean of the log10 titer 
transformations. The GMFI is calculated 
analogously per post-baseline visit as the 
geometric mean of the individual fold 
increases, i.e. the subjects’ post-baseline 
titers at Visit X, divided by their 
corresponding baseline titer. 
Reason for change: 
Update of immunogenicity definitions 
Page 68, 7.4 Future Use of Lab Specimen 
Page 83, 7.4 Future Use of Lab Specimen 
[…] 
Specimens will be stored in BN’s secured 
laboratory area or at an external storage 
facility in a coded, anonymized manner to 
ensure data protection. Genetic testing will 
not be performed. 
 
[…] 
Specimens will be stored in BN’s secured 
laboratory area or at an external storage 
facility in a coded, pseudonymized manner 
to ensure data protection. Genetic testing will 
not be performed. 
Reason for change: 
Update to reflect correct wording 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Page 71, 8.2.2 Prior and Concomitant 
Medication 
Page 86, 8.2.2 Prior and Concomitant 
Medication 
[…] 
The following medication, taken within 
3 months prior to screening, will also be 
recorded in the eCRF and the subjects 
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. 
If given after the first but prior to the second 
vaccination, the following will result in 
subject’s ineligibility to receive the second 
vaccination and the subject should follow the 
abbreviated visit schedule (see Section 4.2.4) 
[…] 
The following medication, taken within 
3 months prior to screening or BV0, will also 
be recorded in the eCRF and the subjects 
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. 
If given after the first but prior to the second 
or the booster vaccination, the following 
will result in subject’s ineligibility to receive 
the second or booster vaccination and the 
subject should follow the abbreviated visit 
schedule (see Section 4.2.4) 
Page 71, 8.2.3 Physical Examination 
Page 87, 8.2.3 Physical Examination 
[…] 
Targeted physical examination 
A targeted physical examination, guided by 
any signs or symptoms previously identified 
or any new symptoms that the subject has 
experienced since the last visit, is required at 
all visits starting at Visit 1 except VS. In 
[…] 
Targeted physical examination 
In the main trial, a targeted physical 
examination, guided by any signs or 
symptoms previously identified or any new 
symptoms that the subject has experienced 
since the last visit, is required at all visits 
starting at Visit 1 except VS.  

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
addition, auscultation of the heart and lungs 
will be performed. 
 
In the booster substudy, a targeted 
physical examination will only be 
performed if clinically indicated, by the 
presence of signs/symptoms since last visit. 
If performed, auscultation of the heart and 
lungs will be included. 
Page 72, 8.2.5 Unsolicited AEs 
Page 87, 8.2.5 Unsolicited AEs 
[…] 
Unsolicited AEs will be assessed and 
documented at all visits except FU1 Visit and 
FU2 Visit (i.e. Screening to EAP) and if 
ongoing at EAP, followed until resolution or 
until the FU2 Visit at the latest.  
 
SAEs and new AEs related to respiratory 
tract infections will be assessed and 
documented at all trial visits, including the 
FU Visits. SAEs will be followed up until 
resolution or achievement of stable clinical 
conditions. 
 
 
Assessment of Intensity  
[…] 
Grade 4 
Life-threatening, 
hospitalization or disabling. 
[…] 
Unsolicited AEs will be assessed and 
documented at all visits except (B)FU1 Visit 
and (B)FU2 Visit (i.e. Screening/BV0 to 
EAP/BEAP) and if ongoing at EAP/BEAP, 
followed until resolution or until the 
(B)FU2 Visit at the latest.  
SAEs will be assessed and documented at 
all trial visits, including the (B)FU Visits. 
SAEs will be followed up until resolution 
or achievement of stable clinical 
conditions. 
In the main trial, new AEs related to 
respiratory tract infections will be assessed 
and documented at all trial visits, 
including the FU Visits.  
Assessment of Intensity  
[…] 
Grade 4 
Life-threatening or disabling 
 

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Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Page 76, 8.2.7 Respiratory Viral Panel 
Page 91, 8.2.7 Respiratory Viral Panel 
Respiratory Viral Panel 
Respiratory Viral Panel (Main Trial) 
Page 76, 8.2.9 Cardiac Assessment 
Page 92, 8.2.9 Cardiac Assessment 
Electrocardiogram 
A standard 12-lead ECG will be taken at the 
Screening Visit. At Visit 2, Visit 4 and 
FU Visits an ECG is only done if clinically 
indicated. A central ECG reading center will 
assess if ECGs are normal, normal variant or 
abnormal.  
[…] 
Troponin I 
Troponin I will be measured at screening and 
if clinically indicated on the following visits: 
Visit 2, Visit 4, FU1 and FU2 Visits or at 
unscheduled visits. 
Electrocardiogram 
A standard 12-lead ECG will be taken in the 
main trial at the Screening Visit. At Visit 2, 
Visit 4 and FU Visits an ECG is only done if 
clinically indicated. A central ECG reading 
center will assess if ECGs are normal, normal 
variant or abnormal.  
[…] 
Troponin I 
Troponin I will be measured in the main 
trial at screening and if clinically indicated 
on the following visits: Visit 2, Visit 4, FU1 
and FU2 Visits or at unscheduled visits. 
Page 79, 8.2.10 Safety Laboratory 
Measurement 
Page 94, 8.2.10 Safety Laboratory 
Measurement 
[…] 
Safety laboratory is determined at screening, 
Visit 2 and Visit 4 or at any other visit(s) if 
clinically indicated. The safety laboratory 
measurements are performed at a central 
laboratory. Laboratory normal ranges are 
provided by the central laboratory and filed 
[…] 
Safety laboratory is determined at screening, 
Visit 2 and Visit 4 in the main trial and at 
BV0 and BV2 during the booster substudy 
or at any other visit(s) if clinically indicated. 
The safety laboratory measurements are 
performed at a central laboratory. Laboratory 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
in the Investigator File. Safety laboratory 
parameters to be evaluated are: 
 
[…] 
Pregnancy test: 
A β-human choriogonadotropin (HCG) 
pregnancy test will be conducted for all 
WOCBP at SCR Visit, prior to each 
vaccination and at the individual last active 
trial phase visit (Visits 1, 3 and EAP). At 
SCR Visit a serum β-HCG pregnancy test 
will be performed; all other pregnancy tests 
will be conducted as urine β-HCG tests.  
 
normal ranges are provided by the central 
laboratory and filed in the Investigator File. 
Safety laboratory parameters to be evaluated 
are: 
[…] 
Pregnancy test: 
In the main trial, a β-human 
choriogonadotropin (HCG) pregnancy test 
will be conducted for all WOCBP at 
SCR Visit, prior to each vaccination and at 
the individual last active trial phase visit 
(Visits 1, 3 and EAP). At SCR Visit a serum 
β-HCG pregnancy test will be performed; all 
other pregnancy tests will be conducted as 
urine β-HCG tests.  
In the booster substudy, a β-human 
choriogonadotropin (HCG) pregnancy test 
will be conducted for all WOCBP at BV1, 
prior to the booster vaccination. 
Page 82, Figure 4 Algorithm for Reporting 
of SAEs 
Page 97 , Figure 4 Algorithm for 
Reporting of SAEs 
 
Box added in figure after “BN PV forwards 
safety reports within max. 15d/7d to 
competent authorities (final) and to CRO 
DS”: 
SMC discusses electronically (via 
email/teleconference) and forwards 
opinion to the Chair; Chair forwards 
opinions to POI –> to BN 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Reason for change: 
Update of Algorithm 
Page 83, 9.1 Randomization Procedure 
and Blinding 
Page 98, 9.1 Randomization Procedure 
and Blinding 
This trial is randomized using an automated 
randomization system, integrated in the 
eCRF: Details on the randomization will be 
outlined in a separate randomization 
specification. 
Assignment to the groups is done in a 
randomized manner. The trial is single-
blinded, i.e. subjects will be blinded to the 
group assignment.  
 
The main part of the trial is randomized 
using an automated randomization system, 
integrated in the eCRF: Details on the 
randomization will be outlined in a separate 
randomization specification. 
Assignment to the groups is done in a 
randomized manner. The main trial is single-
blinded, i.e. subjects will be blinded to the 
group assignment.  
In total 86 subjects from two selected 
treatment groups will be chosen randomly 
for the booster substudy outlined in a 
separate randomization specification.  
Page 83, 9.2 Sample Size Calculation 
Page 98, 9.2 Sample Size Calculation 
The primary analysis will be performed on 
the PRNT (A strain) titers 2 weeks after the 
last vaccination.  
[…] 
The GMTs, GMR from baseline, and the 
response rates and associated 95 % 
confidence limits will be presented for each 
group at each sampling point. 
The primary analysis will be performed on 
the PRNT (A strain) titers 2 weeks after the 
last vaccination in the main trial. 
[…] 
The GMTs, GMFIs from baseline, and the 
response rates and associated 95 % 
confidence limits will be presented for each 
group at each sampling point. 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
 
[…] 
The actual variability observed for the 
log10 titers for PRNT (A strain) 2 weeks 
after the second vaccination in RSV-MVA-
002 turned out to be lower than 
anticipated from the Phase I trial results. 
Thus, based on an adapted assumption for 
the SD of 0.335 for the log10 titers to be 
measured 2 weeks after the booster 
vaccination, a number of 40 evaluable 
subjects per group will provide 80% 
power to detect a difference of 0.213 
(log10-scale) at a significance level of 5% 
(two-sided), which corresponds to a ratio 
of GMTs between groups of 1.63. 
Accounting for a drop-out rate of 5% 43 
subjects per group are to receive a booster 
vaccination. 
Page 84,9.2.1 Treatment Groups/Datasets 
to be Evaluated 
Page 100,9.2.1 Treatment Groups/Datasets 
to be Evaluated 
[…] 
Per Protocol Set (PPS): 
This is the subset of subjects in the FAS who 
have received all vaccinations, completed all 
visits of the active trial phase (Visit 1 to 
EAP) and adhered to all protocol conditions. 
Subjects with only minor (not relevant) 
protocol deviations are included into this 
dataset.  
[…] 
[…] 
Per Protocol Set (PPS): 
This is the subset of subjects in the FAS who 
have received all vaccinations in the main 
trial, completed all visits of the active trial 
phase (Visit 1 to EAP) and adhered to all 
protocol conditions. Subjects with only minor 
(not relevant) protocol deviations are 
included into this dataset.  
[…] 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Immunogenicity Analysis Set (IAS): 
This is the subset of subjects in the FAS 
which were assigned to the subgroup. 
The main analysis of the cellular 
immunogenicity endpoints will be performed 
on the IAS. 
 
 
 
 
 
 
 
 
Additional subgroups may need to be defined 
during the data review meeting and would be 
described in the clinical study report. 
 
Immunogenicity Analysis Set (IAS): 
This is the subset of subjects in the FAS 
which were assigned to the PBMC subgroup. 
The main analysis of the cellular 
immunogenicity endpoints will be performed 
on the IAS. 
Booster Full Analysis Set (BFAS): 
This is the subset of subjects who received 
a booster dose of MVA-BN-RSV vaccine 
and for whom any post-booster data are 
available.  
Booster Immunogenicity Analysis Set 
(BIAS): 
This is the subset of subjects in the BFAS 
which were assigned to the PBMC 
subgroup. 
Additional analysis sets may need to be 
defined during the data review meeting and 
would be described in the clinical study 
report. 
Page 85, 9.3.1 Analysis 
Page 101, 9.3.1 Analysis 
As soon as the last subject has completed 
Visit EAP and after any necessary settlement 
of queries etc. in the eCRFs a data review 
meeting will be held and the subjects will be 
As soon as the last subject has completed 
Visit FU1 and after any necessary settlement 
of queries etc. in the eCRFs a data review 
meeting will be held and the subjects will be 
assigned to the data sets defined for the 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
assigned to the datasets as described in 
Section 9.2.1.  
[…] 
 
After the data review meeting and necessary 
settlement of queries that may arise during 
the data review meeting, the database will be 
locked. The final analysis will then be 
performed and will include all 
immunogenicity results as well as the follow-
up safety data. Results of this analysis will be 
reported in an addendum to the clinical study 
report. 
 
main trial (FAS, PPS, IAS, see 
Section 9.2.1).  
[…] 
After the data review meeting and necessary 
settlement of queries that may arise during 
the data review meeting, the database will be 
locked. The final analysis of the main trial 
will then be performed and will include all 
immunogenicity results as well as the follow-
up safety data. Results of this analysis will be 
reported in an addendum to the clinical study 
report. 
As soon as the last subject recruited into 
the booster substudy has completed 
BFU2 Visit and after any necessary 
settlement of queries etc. in the eCRFs a 
data review meeting will be held. The 
assignment of the subjects to the analysis 
sets as described in Section 9.2.1 will be the 
same as for the 2nd addendum to the CSR. 
After the data review meeting and 
necessary settlement of queries that may 
arise during the data review meeting, the 
database will be locked. The booster 
substudy analysis will then be performed 
and will include all immunogenicity results 
as well as the follow-up safety data. Results 
of this analysis will be reported in an 
addendum to the clinical study report. 
Page 86, 9.3.2 Presentation of Data 
Page 101, 9.3.2 Presentation of Data 
[…] 
[…] 

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Clinical Trial Protocol Edition 2.0,  
dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
GMTs and antibody response rates for RSV-
specific humoral immune responses 
determined from serum and nasal swab 
samples will be determined as described in 
Section 7.1 and Section 1.5. 
Median and geometric mean SFU/1 x 106 
PBMC as well as response and responder 
rates for RSV-specific cellular immune 
responses will be determined as described in 
Section 1.5. 
 
GMTs, GMFIs and antibody response rates 
for RSV-specific humoral immune responses 
determined from serum and nasal swab 
samples will be determined as described in 
Section 7.1 and Section 1.5. 
Median and geometric mean SFU/1 x 106 
PBMC, GMFIs as well as response and 
responder rates for RSV-specific cellular 
immune responses will be determined as 
described in Section 1.5. 
Reason for change: 
Update of immunogenicity definitions 
Page 88, 11. Informed Consent 
Page 103, 11. Informed Consent 
[…] 
 
 
The Informed Consent will be prepared in 
accordance with ICH GCP guidelines and 
must be approved by the appropriate 
IEC/IRB 
[…] 
Subjects eligible for the booster substudy 
have to sign a new ICF at BV0.  
The Informed Consent will be prepared in 
accordance with ICH GCP guidelines and 
must be approved by the appropriate 
IEC/IRB 
Page 94, Table 14 Toxicity Scale for Serum 
Chemistry 
Page 111, Table 14 Toxicity Scale for 
Serum Chemistry 
[…] 
Sodium – Hypernatremia mmoL/L 
[…] 
Sodium – Hypernatremia mmoL/L 

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dated 27-Jan-2017  
Previously written: 
Clinical Trial Protocol Edition 3.0,  
dated 20-Jul-2017 
Changed to: 
Mild (Grade 1) > 145-146 
Moderate (Grade 2) 147-148 
Severe (Grade 3) 148-150 
Potentially Life Threatening (Grade 4) > 150 
[…] 
Potassium – Hypokalemia mmoL/L 
Mild (Grade 1) 3.4 < 3.5 
Moderate (Grade 2) 3.3-3.4 
Severe (Grade 3) 3.1-3.2 
Potentially Life Threatening (Grade 4) < 3.1 
 
Mild (Grade 1) 146 
Moderate (Grade 2) 147 
Severe (Grade 3) 148-150 
Potentially Life Threatening (Grade 4) > 150 
[…] 
Potassium – Hypokalemia mmoL/L 
Mild (Grade 1) 3.4 
Moderate (Grade 2) 3.3 
Severe (Grade 3) 3.1-3.2 
Potentially Life Threatening (Grade 4) < 3.1 
Reason for change: 
Correction of former typos, previously 
clarified via file note. 
 
 
 
 
 
 
 
 
 
 

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Appendix 6: Amendment#3 to the Clinical Trial Protocol 
 
 
A randomized, single-blind, placebo controlled, dose-ranging Phase II trial in 
≥ 55 year old adults to evaluate the safety and immunogenicity of the 
recombinant MVA-BN-RSV vaccine 
 
 
Amendment#3 to the Clinical Trial Protocol 
 
 
 
Date of Amendment#3: 26-Apr-2018 
 
 

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Rationale: 
The protocol Edition 4.0 is set up to add a 12 month FU visit to the booster substudy. All subjects 
vaccinated in the booster subgroup will be invited for an additional FU visit approximately 1 year 
after the booster vaccination. Assessment of individual RSV-specific antibody titres will  provide 
data on the durability of immune responses 12 months after a booster vaccination with either of 
the two MVA-BN-RSV vaccine doses 1 x 108 or 5 x 108 Inf.U.  
 
Changes: 
General changes: 
• 
Update of Section 1.3 (Sponsor Signature Page) and 1.4 (Responsibilities) to reflect 
changes in BN personnel. 
• 
Correction of blood volume for safety lab due to typo in previuos edition in Section 1.6 
(Main Trial Schedule; footnote 5) and section 4.2.1.2 (Active Trial Phase) where 
applicable. 
• 
Update of Section 1.7 (Trial Schedule Booster Substudy) to account for additional BFU3 
visit. 
• 
Update of  Section 4.2.2 (Description of Trial Procedures – Booster Substudy): Added 
procedure for BFU3 visit 
• 
Update of section 9.2.1 for further clarification of the data sets used for analysis. 
• 
Throughout the protocol, rewording of some sections for ease of understanding.  
• 
Spelling, formatting and wording was corrected where applicable 
 
Major changes are as follows: 
Changes/ added terms are highlighted in bold letters in the text (table below), removed terms are 
marked using strikethrough. 
 
 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
Page 24 ff, 1.5 Protocol Synopsis 
Page 20 ff, 1.5 Protocol Synopsis 
Trial Duration: 
Up to 39 weeks per subject in the main trial 
and up to additional 34 weeks per subject 
enrolled in the booster substudy. 
Secondary Objectives: 
[…] 
 
 
 
 
 
 
 
Trial Design Booster Substudy: 
[…] 
All 86 subjects will be followed up for 6 
months after their last vaccination. 
Reports: 
Trial Duration: 
Up to 39 weeks per subject in the main trial 
and up to additional 56 weeks per subject 
enrolled in the booster substudy. 
Secondary Objectives: 
[…] 
To identify further potential differences in 
durability and/or boostability of immune 
responses in the two chosen MVA-BN-
RSV dose regimens. 
To assess safety and reactogenicity of the 
MVA-BN-RSV vaccine following the 
booster vaccination in adult/elderly 
subjects. 
Reason for changes: 
Additional secondary objectives added due 
to additional BFU3 visit. 
Trial Design Booster Substudy: 
[…] 
All 86 subjects will be followed up for 12 
months after their last vaccination. 
Reports: 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
[…] 
Clinical Study Report Addendum 2 
(including safety and immunogenicity data 
of the 3-month and 6-month follow-up visits 
of the booster substudy) 
[…] 
Clinical Study Report Addendum 2 
(including safety and immunogenicity data 
of the 3-month and 6-month follow-up visits 
of the booster substudy of the booster 
substudy and additional immunogenicity 
data not yet included in the Final Clinical 
Study Report or Addendum 1) 
Reason for changes: 
All data from booster substudy will be added 
in the Addendum 2 to the clinical study 
report. 
Page 32-34, 1.7 Trial Schedule Booster 
Substudy and Footnotes 
Page 36-38, 1.7 Trial Schedule Booster 
Substudy and Footnotes 
No BFU3 visit 
Additional column added for BFU3 Visit, 
Trial procedure contains serum collection for 
antibody analysis.  
Reason for changes: 
Addition of BFU3 Visit. 
Page 58, 2.7 Rationale 
Page 59, 2.7 Rationale 
[…] 
Assessment of individual antibody titers 
within short time intervals following the 
booster vaccination and up to 6 months after 
the vaccination will provide information on 
[…] 
Assessment of individual antibody titers 
within short time intervals following the 
booster vaccination and up to 12 months 
after the vaccination will provide 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
how fast and effective measurable antibody 
titers can be regained. The booster substudy 
will also evaluate the durability of immune 
responses 12 months following the primary 
vaccination (baseline measurement prior to 
administration of the booster dose) and 6 
months following the booster vaccination. 
information on how fast and effective 
measurable antibody titers can be regained. 
The booster substudy will also evaluate the 
durability of immune responses 12 months 
following the primary vaccination (baseline 
measurement prior to administration of the 
booster dose) and 12 months following the 
booster vaccination. 
Page 62, 4. Trial Design 
Page 62, 4. Trial Design 
Booster Substudy: 
[…] 
To obtain 40 evaluable subjects per group up 
to 43 subjects per selected group will be 
recruited. Subjects are then followed up for 
6 months after their last vaccination. 
Booster Substudy: 
[…] 
To obtain 40 evaluable subjects per group up 
to 43 subjects per selected group will be 
recruited. Subjects are then followed up for 
12 months after their last vaccination. 
Page 74, 4.2.2.3 Booster Follow-Up (BFU) 
Phase 
Page 74, 4.2.2.3 Booster Follow-Up (BFU) 
Phase 
To monitor long-term safety and antibody 
persistence, subjects will come to the CTS 
for follow-up (FU) visits 3 months 
(BFU1 Visit) and 6 months (BFU2 Visit) 
after the booster vaccination. 
 
No additional BFU3 Visit 
To monitor long-term safety and antibody 
persistence, subjects will come to the CTS 
for follow-up (FU) visits 3 months 
(BFU1 Visit), 6 months (BFU2 Visit) and 
12 months (BFU3 Visit) after the booster 
vaccination. 
Addition of tasks performed at BFU3 Visit 
Page 77, 4.3 Trial duration 
Page 76-77, 4.3 Trial duration 
[…] 
[…] 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
The total duration of the booster substudy 
including baseline and follow up visits will 
be 34 weeks. 
The total duration of the booster substudy 
including baseline and follow up visits will 
be 56 weeks. 
Page 83, 7.3 Systemic Cellular Immune 
Responses 
Page 83, 7.3 Systemic Cellular Immune 
Responses 
[…] 
The responder rate for each test agent is the 
percentage of subjects who are responders to 
the relevant test agent out of the number of 
subjects with a non-missing responder status 
within the relevant analysis population. 
Furthermore, PBMC collected at the FU 
visits will be used to determine memory B 
cells secreting IgG and/or IgA in an 
ELISPOT. Details of the procedure are 
defined in SOP BN0004344 “B Cell 
ELISpot to quantify RSV-specific IgG and 
IgA Secreting Cells in Human CD19 
Positive Cells”. 
[…] 
The responder rate for each test agent is the 
percentage of subjects who are responders to 
the relevant test agent out of the number of 
subjects with a non-missing responder status 
within the relevant analysis population. 
Furthermore, PBMC collected at the (B)FU 
visits will be used to determine memory B 
cells secreting IgG and/or IgA in an 
ELISPOT. Details of the procedure are 
defined in SOP BN0004344 “B Cell 
ELISpot to quantify RSV-specific IgG and 
IgA Secreting Cells in Human CD19 
Positive Cells” SOP BN0005663 
“Fluorospot to measure RSV-specific 
IgG/IgA secreting cells in human 
PBMCs”. 
Reason for changes: 
A different assay will be used to measure 
memory B cells. 
Page 87, 8.2.3 Targeted Physical 
Examinations 
Page 87, 8.2.3 Targeted Physical 
Examinations 
[…] 
[…] 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
In the booster substudy, a targeted physical 
examination will only be performed if 
clinically indicated, by the presence of 
signs/symptoms since last visit. If 
performed, auscultation of the heart and 
lungs will be included. 
In the booster substudy, a targeted physical 
examination will only be performed if 
clinically indicated, by the presence of 
signs/symptoms since last visit at BV1 to 
BFU2. If performed, auscultation of the 
heart and lungs will be included. 
Page 87, 8.2.4 Vital Signs 
Page 87, 8.2.4 Vital Signs 
At all visits except the Staggering Visit, 
blood pressure and pulse rate will be taken 
after the subject has been sitting upright for 
approximately two minutes. Body 
temperature will be measured orally. 
At all visits except the Staggering Visit and 
BFU3, blood pressure and pulse rate will be 
taken after the subject has been sitting 
upright for approximately two minutes. 
Body temperature will be measured orally. 
Page 87, 8.2.5 Unsolicited AEs 
Page 87, 8.2.5 Unsolicited AEs 
[…] 
Unsolicited AEs will be assessed and 
documented at all visits except (B)FU1 Visit 
and (B)FU2 Visit (i.e. Screening/BV0 to 
EAP/BEAP) and if ongoing at EAP/BEAP, 
followed until resolution or until the 
(B)FU2 Visit at the latest.  
SAEs will be assessed and documented at all 
trial visits, including the (B)FU Visits. SAEs 
will be followed up until resolution or 
achievement of stable clinical conditions. 
[…] 
Unsolicited AEs will be assessed and 
documented as indicated in the trial 
schedule (see Section 1.6 and Section 1.7).  
 
 
SAEs will be assessed and documented at all 
trial visits, excluding the BFU3 Visit. SAEs 
will be followed up until resolution or 
achievement of stable clinical conditions. 
Reason for changes: 
Adjustments and clarification due to 
additional BFU3 Visit. 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
Page 99, Sample Size Calculation 
Page 99, Sample Size Calculation 
[…] 
Accounting for a drop-out rate of 5% 43 
subjects per group are to receive a booster 
vaccination. 
[…] 
Accounting for a drop-out rate of 5% 43 
subjects per group are to receive a booster 
vaccination. However, only a descriptive 
comparison is planned between the two 
dose groups in the sub-study. 
Page 101, 9.3.1 Analysis 
Page 101, 9.3.1 Analysis 
[…] 
 
 
 
 
 
As soon as the last subject included in the 
booster substudy has completed BFU2 Visit 
and after any necessary settlement of queries 
etc. in the eCRFs a data review meeting will 
be held. The assignment of the subjects to 
the analysis sets as described in 
Section 9.2.1 will be the same as for the 2nd 
addendum to the CSR. 
After the data review meeting and necessary 
settlement of queries that may arise during 
[…] 
For the booster substudy, there will be a 
topline readout when the last subject 
included in the booster substudy has 
completed the BFU1 visit, the 
immunogenicity data up to BFU1 are 
available, and the data in EDC have been 
properly cleaned.  The set of topline tables 
and figures will be specified in the 
statistical analysis plan. 
As soon as the last subject included in the 
booster substudy has completed BFU3 Visit 
and after any necessary settlement of queries 
etc. in the eCRFs a data review meeting will 
be held. Protocol deviations will be 
reviewed to determine whether an 
additional analysis set compared to those 
described in Section 9.2.1 will be needed. 
After the data review meeting and necessary 
settlement of queries that may arise during 

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Clinical Trial Protocol Edition 3.0, 
dated 20-Jul-2017 
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 26-Apr-2018 
Changed to: 
the data review meeting, the database will be 
locked. 
[…] 
the data review meeting, the database will be 
locked. 
[…]