Open-label Phase Iv Study To Investigate The Seropersistence Of Tick-borne Encephalitis (Tbe) Virus Antibodies After The First Booster And The Response To A Second Booster Vaccination With Fsme-immun In Children, Adolescents And Young Adults (Follow-up To Study 700401)
Phase: PHASE4
Conditions: Encephalitis, Tick-Borne
Sponsor: Pfizer

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CLINICAL STUDY PROTOCOL
FSME-IMMUN 0.25 ml Junior and 
FSME-IMMUN 0.5 ml
OPEN-LABEL PHASE IV STUDY TO INVESTIGATE THE 
SEROPERSISTENCE OF TICK-BORNE ENCEPHALITIS (TBE) VIRUS 
ANTIBODIES AFTER THE FIRST BOOSTER AND THE RESPONSE TO A 
SECOND BOOSTER VACCINATION WITH FSME-IMMUN IN CHILDREN, 
ADOLESCENTS AND YOUNG ADULTS
(FOLLOW UP TO STUDY 700401)
Short Title: TBE SEROPERSISTENCE AFTER FIRST BOOSTER IN 
CHILDREN (FOLLOW-UP TO STUDY 700401)
PROTOCOL NUMBER: B9371021 (Formerly Baxter 700802)
AMENDMENT 4: 25 JUN 2015 (including non-substantial changes upon 
sponsorship change)
Replaces Amendment 3: 07 SEP 2011
EUDRACT NUMBER: 2009-009324-36
Study Sponsor(s): 
Pfizer, Inc.
235 East 42nd Street
New York, NY  10017, US
Other Collaborator(s):
 GERMANY
PPD

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1. STUDY PERSONNEL
Authorized Representative 
Medical 
Development and Scientific/Clinical Affairs
Pfizer Vaccines
 
United States
Tel:  
Sponsor’s Medical Expert
 
 (European Union), Vaccines Medical 
Development Group and Scientific Affairs
Pfizer
France
Tel: 
Study Monitoring 
POLAND, AUSTRIA, GERMANY
, 
Germany
Tel: 
Fax: 
1.1 Study Organization
The name and contact information of the individuals involved with the study (e.g. 
Investigator(s), Sponsor’s representative(s), laboratories, steering committees, data 
monitoring committees (DMCs), and ethics committees (ECs) will be maintained by the 
Sponsor and provided to the Investigator.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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2. SERIOUS ADVERSE EVENT REPORTING
The Investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs. For information on the definition and assessment of 
adverse events (AEs), refer to Section 12.2.
ALL SAEs ARE TO BE REPORTED ON THE CLINICAL TRIAL SERIOUS 
ADVERSE EVENT (CT SAE) REPORT FORM AND FAXED TO THE SPONSOR 
WITHIN 24 HOURS OF BECOMING AWARE OF THE EVENT
Austria
Fax: 
Germany
Fax:  Toll-Free (local): 
From Abroad:  
Poland
Fax:  Toll-Free (local): 
Alt. 1:  
PPD
PPD
PPD
PPD
PPD

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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
FSME-IMMUN 0.25 ml Junior; FSME-IMMUN 0.5 ml
Name(s) of Active Ingredient(s)
Tick-Borne Encephalitis Virus (strain Neudoerfl)
CLINICAL CONDITION(S)/INDICATION(S)

Active (prophylactic) immunization against TBE
PROTOCOL NUMBER
B9371021 (Formerly Baxter 700802)
PROTOCOL TITLE
Open-label Phase IV Study to Investigate the Seropersistence of 
Tick-Borne Encephalitis (TBE) Virus Antibodies after the First 
Booster Vaccination and the Response to a Second Booster 
Vaccination with FSME-IMMUN in Children,Adolescents and 
Young Adults (Follow-Up to Study 700401)
Short Title
TBE Seropersistence after First Booster in Children, Adolescents 
and Young Adults (Follow-Up to Study 700401)
STUDY PHASE
Ph IV (post-marketing)
PLANNED STUDY PERIOD
Initiation
March 2009
Completion
June 2017
Duration
Approximately 8 years
STUDY OBJECTIVES AND PURPOSE 
Study Purpose

The main purpose of this study is to assess the seropersistence of TBE virus antibodies in children, 
adolescents and young adults who received the first booster vaccination with either FSME-
IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml in Study 700401.
Primary Objective

To assess TBE antibody persistence at yearly intervals from approximately 3 years (38 months) to 
10 years (118 months) after the first booster vaccination (as applicable) with either FSME-
IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml by means of neutralization test (NT) (according 
to Adner et al., 2001 1) and ELISA (IMMUNOZYM FSME Immunoglobulin G [IgG]).
Secondary Objective(s)

To assess the antibody response to a second booster vaccination with either FSME-IMMUN 
0.25 ml Junior or FSME-IMMUN 0.5 ml administered in the present study, by means of ELISA 
and NT.

To assess the safety of FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml after 
administration of the second booster vaccination in the present study.

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STUDY DESIGN
Study Type
Immunogenicity
Control Type
Not applicable
Study Indication 
Type
Prevention
Blinding Schema
Open-label
Study Design
This is a phase IV, follow-up, open-label, multicenter study in a total of 
202 children, adolescents and young adults who received their first TBE booster 
vaccination in Study 700401 with the aim to assess seropersistence of TBE 
antibodies at yearly intervals from approximately 3 years (38 months) to 10 years 
(118 months) after the first booster vaccination (as applicable), as well as 
antibody response to a second booster vaccination with either FSME-IMMUN 
0.25 ml Junior or FSME-IMMUN 0.5 ml according to the subject’s age. Timing 
of the second booster vaccination will depend on the level of serum TBE 
antibodies detected at the defined assessment time points. Subjects who may not 
be protected against TBE for an entire further tick season (NT titer ≤20 and / or 
ELISA value ≤126 VIE U/ml) will be invited to receive the second booster 
vaccination at either the 40, 48, 60, 72, 84, 96, 108, or 120 month time point.
Planned Duration of 
Subject 
Participation
Approximately 7 years
Primary Endpoint
Immunogenicity:

Seropositivity rate as determined by NT from approximately 3 years (38 months) to 10 years (118 
months) after the first booster vaccination administered in Study 700401 and after the second 
booster vaccination administered in this study.

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Secondary Endpoint(s)
Immunogenicity:

Seropositivity rate as determined by ELISA from approximately 3 years (38 months) to 10 years 
(118 months) after the first booster vaccination in Study 700401 and after the second booster 
vaccination in this study;

Antibody response as determined by ELISA from approximately 3 years (38 months) to 10 years 
(118 months) after the first booster vaccination in Study 700401 and after the second booster 
vaccination in this study;

Antibody response as determined by NT from approximately 3 years (38 months) to 10 years (118 
months) after the first booster vaccination in Study 700401 and after the second booster 
vaccination in this study;

Fold increase of antibody concentration determined by ELISA after the second booster vaccination 
as compared to before the second booster vaccination in this study;

Fold increase of antibody titer determined by NT after the second booster vaccination as compared 
to before the second booster vaccination in this study.
Safety:

Injection site reactions observed in the period from the second booster vaccination until the 
following blood draw;

Systemic reactions observed in the period from the second booster vaccination until the following 
blood draw.
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Investigational 
Product(s)
FSME-IMMUN 0.25 ml Junior (1.2 µg TBE antigen/0.25 ml)
FSME-IMMUN 0.5 ml (2.4 µg TBE antigen/0.5 ml)
Dosage form: solution/suspension; injectable
Dosage frequency: Once 
Mode of 
Administration
Intramuscular
SUBJECT SELECTION
Planned Number of 
Subjects
202 (Study population will consist of subjects who were administered the 
first booster vaccination in Study 700401 at 3 or 4 years after the third 
vaccination in Study 209).
Inclusion Criteria
Subjects who participated in Study 700401 and meet ALL of the following criteria are eligible for 
participation in this study:

Subject / parent(s) / legal guardian(s) provide(s) written informed consent (according to 
national law);

Subject provides written assent to the study according to age and capacity of understanding;

Subject received the first booster vaccination with either FSME-IMMUN 0.25 ml Junior or 
FSME-IMMUN 0.5 ml during the course of Study 700401;

Blood was drawn after the first booster vaccination in Study 700401;

Subject / parent(s) / legal guardian(s) understand(s) the nature of the study and is / are willing 
to comply with the requirements of the protocol (e.g., return for follow-up visits, completion 
of the Subject Diary).

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Exclusion Criteria
Subjects who participated in Study 700401 and meet ANY of the following criteria are not eligible for 
participation in this study:

Subject received any TBE vaccination since his / her first booster vaccination in Study 
700401;

Subject has a history of infection with or vaccination against other flaviviruses (e.g., Dengue 
fever, yellow fever, Japanese B encephalitis) since his / her first booster vaccination in 
Study 700401;

Subject is known to be HIV positive (a special HIV test is not required for the purpose of the 
study) since his / her first booster vaccination in Study 700401;

Subject received a blood product or immunoglobulins within 90 days before any blood draw 
or in the period between the blood draw and the booster vaccination (as applicable);

Subject has a known or suspected problem with drug or alcohol abuse (> 4 liters of wine/week 
or equivalent level of other alcoholic beverages);

Subject / parent(s) / legal guardian(s) is / are in a dependent relationship with the study 
investigator or with a study team member. Dependent relationship includes close relatives 
(i.e., children or grandchildren, partner / spouse, siblings) as well as employees of the 
Investigator or the site conducting the study.

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Eligibility criteria for booster vaccination
Subjects who meet ANY of the following criteria are not eligible for the booster vaccination:

Subject is not clinically healthy (i.e., the physician would have reservations vaccinating with a 
TBE vaccine outside the scope of a clinical trial);

Subject is suffering from a disease (e.g., autoimmune disease) or is undergoing a form of 
treatment (e.g., systemic corticosteroids) that can be expected to influence immunological 
functions;

Subject has developed severe allergic reactions, in particular a sensitivity or allergy to any 
component of the vaccine, since the first booster vaccination in Study 700401;

If female - subject is pregnant or lactating;

Subject has participated in another clinical study involving an IP or medical device within 
30 days prior to the planned booster vaccination or is scheduled to participate in another 
clinical study involving an IP or medical device.

Females capable of bearing children if they do not agree to employ adequate birth control 
measures from 4 weeks before the booster vaccination until the end of the study.
Vaccination will be delayed if one of the following applies:

Subject has an acute illness with or without elevated body temperature (37.5C) within 
3 days prior to the scheduled booster vaccination. The subject may be vaccinated at a repeat 
visit provided that the illness has resolved (body temperature < 37.5°C);

Subject has received any live vaccine within 4 weeks or any inactivated vaccine within 
2 weeks prior to the scheduled booster vaccination. Vaccination may be performed when an 
interval of 4 or 2 weeks, respectively, has passed;

Subject has received antipyretics within 4 hours prior to the scheduled time of vaccination. 
Vaccination may be performed at a later date;

Subject was bitten by a tick within 4 weeks prior to the scheduled booster vaccination. 
Vaccination shall be postponed until an interval of 4 weeks has passed;

Subject has donated blood or plasma within 30 days of the scheduled booster vaccination. 
Vaccination shall be postponed until an interval of 30 days has passed.
STATISTICAL ANALYSIS
Sample Size Calculation
A total of 202 subjects who were administered the first booster vaccination in Study 700401 at 3 or 4 years 
after the third vaccination in Study 209 will be invited to participate in this study. Of these, approximately 
175 study participants are expected to return and provide information on antibody persistence after the first 
booster vaccination with either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml. With this sample 
size, the 95% confidence interval (CI) of the seropositivity rate will extend no more than 5.8% from the 
observed rate assuming the observed rate lies in the region of 90%.
Planned Statistical Analysis
Point estimates and 95% confidence intervals for the seropositivity rate at each time point when blood is 
drawn after the booster vaccination in Study 700401 and separately at each time point after the booster 
vaccination in this study as measured by NT will be calculated.
The dependence of seropositivity of study participants on demographic factors (age, weight, gender) at 
yearly intervals from approximately 3 years (38 months) to 10 years (118 months) after the first booster 
vaccination will be analyzed by logistic regression at the end of the study period.

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The antibody levels as measured by NT and ELISA at each blood draw after the first booster will be used 
to determine the annual decline rate.
The analysis of immunogenicity before the second booster vaccination will be carried out separately in the 
three age classes defined previously in Study 209. Subjects will remain in the same age class they were 
assigned to at the beginning of Study 209 (1 - 2 years, 3 – 6 years, 7 – 15 years). For the analysis of 
immunogenicity and safety after the booster vaccination the oldest age class will be further divided into 
those who received FSME-IMMUN 0.25 ml Junior and those who received FSME-IMMUN 0.5 ml.
The occurrence of fever and the 95% confidence interval of the probability of occurrence will be given. 
The fever rate after the second booster vaccination will be categorized by severity grade.
Local and systemic reaction rates, other than fever, after the booster vaccination will be provided in tabular 
format, and the probabilities of the occurrence of the adverse event (AE) rates and their 95% confidence 
intervals will be calculated.
For each symptom queried in the Subject Diary, the number of subjects who experienced the symptom, as 
well as the probabilities of the occurrence and the 95% confidence interval will be given. 

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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 10
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 18
6.1 Description of Investigational Product ............................................................... 18
6.2 Clinical Condition/Indication .............................................................................. 20
6.2.1 Clinical Characteristics................................................................................. 20
6.2.2 Clinical Course in Children .......................................................................... 20
6.3 Population to be Studied ...................................................................................... 22
6.4 Findings from Nonclinical and Clinical Studies................................................. 23
6.4.1 Clinical Experience with FSME-IMMUN 0.5 ml in Adults....................... 23
6.4.2 Clinical Experience with FSME-IMMUN 0.25 ml in Children................. 29
6.5 Relevant Literature and Data.............................................................................. 35
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 35
6.6.1 Possible Benefits for the Subject .................................................................. 35
6.6.2 Possible Benefits for Society ......................................................................... 36
6.6.3 Possible Risks / Inconveniences for the Subject.......................................... 36
6.7 Compliance Statement.......................................................................................... 37

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7. STUDY PURPOSE AND OBJECTIVES ................................................................. 38
7.1 Study Purpose ....................................................................................................... 38
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.3.1 Immunogenicity ............................................................................................. 39
7.3.2 Safety............................................................................................................... 39
8. STUDY DESIGN......................................................................................................... 40
8.1 Overall Study Design............................................................................................ 40
8.2 Duration of Study Period(s) and Subject Participation .................................... 41
8.3 Endpoints............................................................................................................... 41
8.3.1 Primary Endpoint.......................................................................................... 41
8.3.2 Secondary Endpoints..................................................................................... 41
8.3.2.1 Immunogenicity ...................................................................................... 41
8.3.2.2 Safety........................................................................................................ 42
8.4 Randomization and Blinding............................................................................... 42
8.5 Study Stopping Rules............................................................................................ 42
8.6 Investigational Product(s).................................................................................... 42
8.6.1 Packaging, Labeling, and Storage................................................................ 42
8.6.1.1 Dosage Form for Investigational Products........................................... 42
8.6.1.2 Packaging and Labeling......................................................................... 42
8.6.1.3 Storage ..................................................................................................... 43
8.6.2 Administration ............................................................................................... 43
8.6.2.1 Route of administration ......................................................................... 43
8.6.2.2 Vaccine preparation ............................................................................... 43
8.6.2.3 Vaccine administration .......................................................................... 44
8.6.3 Description of Treatment.............................................................................. 44
8.6.4 Investigational Product Accountability ....................................................... 44
8.7 Data Recorded Directly on Case Report Forms ................................................ 45

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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 46
9.1 Inclusion Criteria.................................................................................................. 46
9.2 Exclusion Criteria................................................................................................. 46
9.3 Eligibility criteria for booster vaccination.......................................................... 47
9.4 Delay criteria......................................................................................................... 47
9.5 Withdrawal and Discontinuation ........................................................................ 48
10. STUDY PROCEDURES .......................................................................................... 49
10.1 Informed Consent and Enrollment ................................................................... 49
10.2 Subject Identification Code................................................................................ 49
10.3 Screening and Study Visits................................................................................. 49
10.3.1 Screening ...................................................................................................... 49
10.3.2 Study visits.................................................................................................... 50
10.3.2.1 Blood draw (investigation of TBE antibody persistence).................. 50
10.3.2.2 Booster Vaccination Visit..................................................................... 52
10.3.2.3 Post-Booster Visit.................................................................................. 54
10.3.3 Unscheduled Visit ........................................................................................ 54
10.4 Medications and Non-Drug Therapies.............................................................. 55
10.5 Subject Diary....................................................................................................... 56
10.6 Subject Completion/Discontinuation ................................................................ 57
10.7 Procedures for Monitoring Subject Compliance............................................. 57
11. ASSESSMENT OF IMMUNOGENICITY ............................................................ 58
11.1 Assessment of Immune Response...................................................................... 58
12. ASSESSMENT OF SAFETY................................................................................... 59
12.1 Vaccine-Specific Safety Parameters Assessed.................................................. 59
12.1.1 Body Temperature....................................................................................... 59

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12.1.2 Injection Site Reactions............................................................................... 60
12.2 Adverse Events.................................................................................................... 60
12.2.1 Occupational Exposure ............................................................................... 60
12.2.2 Serious Adverse Event................................................................................. 60
12.2.3 Exposure During Pregnancy....................................................................... 61
12.2.4 Non-Serious Adverse Event ........................................................................ 63
12.2.5 Severity ......................................................................................................... 63
12.2.6 Causality ....................................................................................................... 63
12.2.7 Preexisting Diseases..................................................................................... 64
12.2.8 Untoward Medical Occurrences Not Considered Adverse Events ......... 65
12.2.9 Assessment of Adverse Events.................................................................... 65
12.2.10 Sponsor Reporting Requirements to Regulatory Authorities ............... 66
12.3 Medical, Medication, and Non-Drug Therapy History................................... 66
12.3.1 Medical history............................................................................................. 66
12.3.2 Medication and Non-Drug Therapy........................................................... 66
12.4 Physical Examinations........................................................................................ 67
12.5 Clinical Laboratory Parameters........................................................................ 67
12.5.1 Assessment of Abnormal Laboratory Values............................................ 67
12.6 Vital Signs............................................................................................................ 67
12.7 Responsibilities of the DMC............................................................................... 68
12.7.1 Responsibilities of the DMC ....................................................................... 68
13. STATISTICS............................................................................................................. 69
13.1 Sample Size and Power Calculations ................................................................ 69
13.2 Datasets and Analysis Cohorts .......................................................................... 69
13.3 Handling of Missing, Unused, and Spurious Data........................................... 69
13.4 Methods of Analysis............................................................................................ 70
13.4.1 Primary Endpoint........................................................................................ 70
13.4.2 Secondary Endpoints................................................................................... 70

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13.4.3 Exploratory Endpoints................................................................................ 71
13.5 Planned Interim Analysis of the Study ............................................................. 71
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 71
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 71
15.1 Investigator’s Responsibility.............................................................................. 72
15.1.1 Investigator Report and Final Clinical Study Report.............................. 72
15.2 Training ............................................................................................................... 73
15.3 Monitoring........................................................................................................... 73
15.4 Auditing ............................................................................................................... 73
15.5 Non-Compliance with the Protocol ................................................................... 73
15.6 Laboratory and Reader Standardization ......................................................... 74
16. ETHICS ..................................................................................................................... 75
16.1 Subject Privacy ................................................................................................... 75
16.2 Ethics Committee and Regulatory Authorities................................................ 75
16.3 Informed Consent ............................................................................................... 75
16.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
................................................................................................................................ 76
17. DATA HANDLING AND RECORD KEEPING................................................... 77
17.1 Confidentiality Policy ......................................................................................... 77
17.2 Study Documents and Case Report Forms....................................................... 77
17.2.1 Case Report Forms...................................................................................... 77
17.2.2 Investigator File ........................................................................................... 78
17.3 Document and Data Retention........................................................................... 78

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18. FINANCING AND INSURANCE........................................................................... 78
19. PUBLICATION POLICY........................................................................................ 78
20. SUPPLEMENTS....................................................................................................... 79
20.1 Study Flow Chart................................................................................................ 79
20.2 Schedule of Study Procedures and Assessments.............................................. 81
20.3 Grading of Adverse Experiences – Vaccine Specific Criteria ........................ 84
21. REFERENCES.......................................................................................................... 85
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 91

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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
B19V
Parvovirus B 19
CRF
Case report form
CRO
Contract research organization
CTC
Common Toxicity Criteria
DMC
Data monitoring committee
EC
Ethics committee
ELISA
Enzyme-linked immunosorbent assay
FSME
Frühsommer-Meningo-Enzephalitis – German term for “tick-
borne encephalitis“
FSME-IMMUN 0.25 ml 
Junior 
TBE vaccine for children
FSME-IMMUN 0.5 ml
TBE vaccine for adults 
GCP
Good Clinical Practice
GDP
Good Documentation Practice
GmbH
Gesellschaft mit beschränkter Haftung – German term for a 
company which does not trade its shares on the stock market
GMC
Geometric mean concentration
GMT
Geometric mean titer
HAV
Hepatitis A Virus
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HEV
Hepatitis E Virus
HIV
Human immunodeficiency virus
HSA
Human serum albumin
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use
ICU
Intensive care unit
IgG
Immunoglobulin G

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Abbreviation
Definition
IP
Investigational product
MedDRA
Medical Dictionary for Regulatory Activities
NT
Neutralization test
SAE
Serious adverse event
SIC
Subject identification code
SmPC
Summary of product characteristics
SOP
Standard operating procedure
TBE
Tick-borne encephalitis
Th
Thiomersal
VIE U/ml
Vienna Units per milliliter (unit of anti-TBE IgG 
concentration as determined by the ELISA test kit 
Immunozym FSME-IgG; PROGEN Biotechnik Heidelberg, 
Germany)
SAER
Serious adverse event report

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6. BACKGROUND INFORMATION
Tick-borne encephalitis (TBE) virus is a member of the family Flaviviridae, which 
comprises approximately 70 different viruses that cause many serious diseases in a wide 
variety of vertebrates, including humans. Among the flaviviruses, TBE virus has one of 
the highest impacts as a human pathogen, as indicated by the disease prevalence in 
endemic areas in certain parts of Europe and the East. The clinical course of the disease is 
largely determined by TBE virus subtype. By sequence analysis of TBE virus isolates 
from different endemic areas, three subtypes of the virus have been identified: Far-
Eastern, Siberian and European/Western.2;3
The distribution of the TBE virus covers almost the entire southern part of the nontropical 
Eurasian forest belt, from Alsace Lorraine in the west to Vladivostok and northern and 
eastern regions of China in the east through to Hokkaido in Japan. In Europe, changes in 
the endemicity of TBE have recently been observed: several new TBE foci have been 
found or rediscovered in the Nordic countries, such as Bornholm in Denmark, southern 
Norway and several foci in the south of Sweden.4;5
In Europe, eight species of ticks, the main vector for the disease, have been identified so 
far that are capable of transmitting TBE virus. Ixodes ricinus, the common castor bean 
tick, is the primary vector and thus is mainly responsible for the spread of the virus in 
western and central Europe and the European region of Russia.6
6.1 Description of Investigational Product
FSME-IMMUN 0.25 ml Junior / FSME-IMMUN 0.5 ml is a formaldehyde-inactivated, 
sucrose gradient purified TBE virus (strain Neudoerfl) antigen solution, adsorbed on 
aluminum hydroxide (0.17 mg Al³+ / 0.35 mg Al³+, respectively), hydrated and stabilized 
with human serum albumin (HSA). FSME-IMMUN vaccine is thiomersal free. The TBE 
antigen content in FSME-IMMUN 0.25 ml Junior is approximately 1.2 µg, whereas in 
FSME-IMMUN 0.5 ml it is approximately 2.4 µg (Table 6.1-1). The pharmacodynamic 
effect of the product consists of the induction of a sufficiently high concentration of anti-
TBE antibodies to provide protection against TBE virus.

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Table 6.1-1
Composition of TBE Vaccines
Composition of a single dose 
FSME-IMMUN 0.25 ml
FSME-IMMUN 0.5 ml
Formaldehyde-inactivated TBE virus
target 1.2 µg
(range 1.00-1.38 µg)
target 2.4 µg 
(range 2.00 – 2.75 µg )
Origin of production virus seed
supernatant from chick 
embryo cells*
supernatant from chick embryo 
cells*
Aluminum hydroxide, hydrated
0.17 mg Al³+
0.35 mg Al³+
Human serum albumin
0.25 mg
0.5 mg
Sodium chloride
1.725 mg
3.45 mg
Disodium hydrogen phosphate
0.11 mg
0.22.mg
Potassium dihydrogen phosphate
0.023 mg
0.045 mg
Sucrose
max. 7.5 mg
max 15 mg
Formaldehyde
max. 2.5 µg
max. 5 µg
Protaminsulfate
max. 0.25 µg (in traces)
max. 0.5 µg (in traces)
Neomycin and Gentamicin
in traces
in traces
Water for injection
ad 0.25 ml
ad 0.5 ml
* infected with working virus seed generated from chick embryo cells
Both FSME-IMMUN 0.25 ml Junior and FSME-IMMUN 0.5 ml are licensed for 
intramuscular injection. The vaccines will be administered in accordance with the 
Summary of Product Characteristics (SmPC): FSME-IMMUN 0.25 ml Junior is indicated 
for children and adolescents aged 1-15 years (until the last day before the 16th birthday)
whereas FSME-IMMUN 0.5 ml has been approved for use in adults from 16 years of age 
(i.e. from the 16th birthday).
According to the current SmPC for FSME-IMMUN 0.25 ml Junior / FSME-IMMUN 
0.5 ml, the first booster vaccination should be given at 3 years after completion of the 
primary vaccination series (which consists of 3 vaccinations). Subsequent booster 
vaccinations are recommended at 3 to 5 year intervals in children and adolescents as well 
as in adults up to 60 years of age. 
The Sponsor will provide the Investigator with sufficient vaccine to conduct the study as 
well as the appropriate certificates of analysis for the investigational products.

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6.2 Clinical Condition/Indication 
6.2.1 Clinical Characteristics
After Lyme disease, TBE is the most prevalent tick-transmitted disease in Europe.7 The 
typical course of the Western subtype is biphasic and can be outlined as follows: the 
incubation period, which is clinically silent, may last between 2 and 28 days 8, but in 
most cases it lasts approximately 8 days.9 The first stage, which may last for 1 to 8 days, 
corresponds to the viremic phase. Exceptionally high initial fevers may occasionally 
occur, rising as high as 40.9°C.10;11 These may be accompanied by headache, malaise 
and muscle pain, lasting about 4 days.12
An afebrile interval follows the first stage of TBE, and lasting 3 to 21 days (median 
7 days 12). During this time, patients are usually free of symptoms. Another sudden rise in 
temperature marks the beginning of the second stage. Only 20-30% of those infected with 
the TBE virus proceed into the second phase of the disease. The clinical manifestations of 
this second febrile episode are far more serious and involve the central nervous system 
with symptoms of meningitis (e.g., fever, headache, and a stiff neck) or encephalitis (e.g., 
drowsiness, confusion, sensory disturbances, and/or motor abnormalities such as 
paralysis) or meningoencephalitis.10
Hospitalization varies between 3 days and 40 weeks 13;14, depending on the severity of the 
illness. TBE-infected patients older than approximately 40 years of age increasingly 
develop the encephalitic form of the disease. In elderly patients, especially those older 
than 60 years of age, TBE can take a severe course, leading to paralysis and occasionally 
resulting in death.15;16 Paralysis occurs in 30% of patients who enter the acute phase of 
the illness.17
Not all those infected with TBE run the entire course of the disease. In approximately 
65% of cases, the infection remains silent, although viremia can be demonstrated; in 
some cases, the patient presents the clinical picture of the initial phase of TBE, but the 
symptoms subside without developing into full-blown TBE.
6.2.2 Clinical Course in Children
Persons of all ages are thought to be equally susceptible to infection. In Slovenia between 
1959 and 2000, children represented 23.5% of the 1578 confirmed TBE cases in the 
country.7 Direct comparison of clinical and epidemiological characteristics of TBE in 

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children and adults has revealed differences in several clinical and laboratory features, 
but has corroborated the conclusion that the course of illness is the same in both groups.18
Although TBE in children is a milder illness than in adults, an unusually high percentage 
of children experiencing a severe course of TBE and development of neurologic sequelae 
were identified in a retrospective study with patients (aged 0 to 15 years) hospitalized 
between 1993 and 1998 at the Department of Infectious Diseases in Ljubljana, 
Slovenia.19;20 Of 133 children diagnosed with TBE infection, 49% had aseptic 
meningitis, 49% had meningoencephalitis and 3% had meningoencephalomyelitis. Seven 
patients (5.2%) with cerebrospinal fluid changes, compatible with aseptic meningitis, and 
an abnormal electroencephalogram were treated in the intensive care unit (ICU). 
Other studies in children (up to 14 years of age) with a history of TBE, which were 
published between 1962 and 1999, showed 78% meningitis, 21% meningoencephalitis 
and 1% encephalomyelitis cases.20;21;22;23;24;25;26 Rakar reported on sequelae in 6 out of 
160 children (paresis, seizures, emotional disturbance), who were studied in Slovenia 
between 1978 and 1992.26 However, the medical details of children with an unfavorable 
prognosis have mostly been presented as individual reports. Roggendorf and colleagues 
described a severe case of meningoencephalitis in a child (12 years old) who experienced 
epileptic seizures after 9 months of hospitalization.27 Failure to recognize abdominal 
symptoms as criteria of the prodromal stage of TBE has been reported as a reason for 
fatal outcome of the disease resulting in TBE-induced brainstem encephalitis and general 
sinus thrombosis.24 In 1992, Grubbauer and colleagues reported a 3.5 month old baby 
experiencing severe meningoencephalitis resulting from TBE, which led to an epileptic 
state and required neurointensive care.28 The first neonatal case of TBE was reported by 
Jones and colleagues (2007) 29 in a 17-day old newborn resulting in severe neurologic 
impairment.

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In Austria, between 1971 and 1981, a period when TBE vaccination was not performed in 
children (the first TBE vaccine was formulated for adult use and became available in 
Austria in 1976), approximately 540 cases of TBE infection in children were observed 
(personal communication 
, Institute of Virology, Medical University 
of Vienna) giving a mean incidence rate of approximately 49 cases per year. In Styria, 
between 1980 and 1990, four TBE-infected children were admitted to an ICU (however, 
these children did not suffer from any sequelae).30 Seven children diagnosed with TBE 
also suffered from different sequelae: epilepsy (n=2), moderate to severe hypacusis 
(n=2), transient hypacusis (n=2) and one child with mild hypacusis.31
These data demonstrate that the course of TBE in children and adolescents can be 
associated with an unfavorable outcome and permanent neurological damage. Due to the 
risk of a severe course of the disease, immunization against TBE is also recommended 
for infants and children living in, or traveling to, highly endemic areas.
6.3 Population to be Studied
A total of 202 healthy children, adolescents and young adults of both genders who  
participated in Study 700401 and received the first booster vaccination with either 
FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml at 3 or 4 years after the third 
vaccination will comprise the subject population of the study.
The majority of subjects will be enrolled in the current study in late spring 2009 at 
approximately 38 months after their first booster vaccination in Study 700401 (which 
they received at 3 years after their third vaccination). 
Those 29 subjects who were administered the first booster vaccination at 4 years after 
their third vaccination in Study 700401, will enter the current study in 2010. For these 
subjects the first visit will be shifted to take place at approximately 34 months after their 
first booster vaccination.
PPD

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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Clinical Experience with FSME-IMMUN 0.5 ml in Adults
The safety and immunogenicity of FSME-IMMUN 0.5 ml has been evaluated by Baxter 
in eleven clinical studies in adults, including two studies investigating either 
immunogenicity or safety only. One study is currently still ongoing (B9371010, Formerly 
Baxter 691101), follow up to Study 223/690701).
Study IMAG-062 was a prospective, four-arm, randomized, controlled, double blind 
phase III study in 1191 subjects. The objective of this study was to assess the equivalence 
of FSME-IMMUN produced by the new production method (chick-chick), either with or 
without thiomersal, with FSME-IMMUN produced by the previous production method 
(mouse brain). To this end, the subjects were assigned to receive three vaccinations with 
one of the following formulations:

FSME-IMMUN (chick-chick) without thiomersal (FSME-IMMUN 0.5 ml);

FSME-IMMUN (chick-chick) with thiomersal;

FSME-IMMUN (mouse brain) with thiomersal; 

Placebo.
FSME-IMMUN 0.5 ml was shown to be highly immunogenic and equivalent to the 
previous generation FSME-IMMUN vaccine in terms of seroconversion rate as 
determined by Enzyme-Linked Immunosorbent Assay (ELISA) and neutralization test 
(NT) after the second vaccination (28–35 days after first vaccination). A seroconversion 
rate of 92.9% was achieved with FSME-IMMUN 0.5 ml, and 98.2% with FSME-
IMMUN. Statistical equivalence of the vaccines was shown, as the difference between 
these rates (5.3%) is within a range of ± 10%. After the third vaccination, the 
seroconversion rate was 100% with both FSME-IMMUN and FSME-IMMUN 0.5 ml. 
After completion of the primary vaccination series, subjects who had received the 
placebo were randomized to receive three vaccinations with one of the study vaccines. 
The seroconversion rates with FSME-IMMUN 0.5 ml as determined by ELISA and NT 
were 97.1% after the second and 96.6% after the third vaccination.
FSME-IMMUN 0.5 ml was shown to be well-tolerated; no severe, serious or unexpected 
AEs occurred within the observation period after vaccination with FSME-IMMUN 
0.5 ml. In Parts A and B, most AEs after vaccination were mild (11.8% after the first, 

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4.1% after the second and 8.3% after the third vaccination), with a few moderate AEs 
(1.7% after the third vaccination only). Similar tendencies were observed in Part C.
 
 
 
 
 
 
 
 
 
 
 
 
 
A dose-finding study (Study 201) to determine the optimal dosage of FSME-IMMUN 
0.5 ml with respect to safety and immunogenicity was conducted in 405 adults aged 16 to 
65 years.32 The subjects were randomized to receive two vaccinations administered at an 
interval of 21 to 35 days with one of three different antigen amounts: 0.6 µg, 1.2 µg or 
2.4 µg. Subjects received a third vaccination with the same antigen dose administered in 
this study during the follow-up Study 202. The seroconversion rates determined by 
ELISA and/or NT after the second vaccination were 85.8%, 96.9% and 97.0% with the 
doses 0.6 µg, 1.2 µg and 2.4 µg respectively. The 2.4 µg dose was determined to be the 
optimal dose, firstly as only the 1.2 µg and 2.4 µg doses induced a sufficiently high 
seroconversion rate (according to the predefined criteria), and secondly because the 
2.4 µg dose was found to be non-inferior to the 1.2 µg dose with respect to fever rate 
after the first vaccination. 
The conclusion of the dose-finding study on FSME-IMMUN 0.5 ml was confirmed by 
the results of a follow-up study (Study 202), in which a third vaccination was 
administered. The 2.4 µg dose was found to be the optimal dose of the FSME-IMMUN 
0.5ml vaccine for adults, as it induced a 100% seroconversion rate and a low rate of AEs 
after the third vaccination.32

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Study 208 was designed as a single-blind, randomized, multicenter safety study 
compared two TBE vaccines in 3966 healthy subjects aged 16 to 65 years. FSME-
IMMUN 0.5 ml was found to be non-inferior to Encepur with respect to fever rate after 
the first vaccination, as the upper limit of the 95% confidence interval of the difference in 
fever rate after the first vaccination was below the predefined +3% limit. Fever after the 
first vaccination was mainly mild in nature and occurred at a very low frequency (0.8%) 
in the FSME-IMMUN 0.5 ml study group, compared to the Encepur study group, in 
which a rate of 5.6% was determined. Only one moderate fever case was reported and 
this case occurred following vaccination with Encepur. As observed for the overall fever 
rate after the first vaccination, fever classed as being related to the first vaccination was 
also considerably lower in the FSME-IMMUN 0.5 ml study group (0.6%) than in the 
Encepur group (4.9%). Overall, the study demonstrated that the FSME-IMMUN 0.5 ml 
vaccine is safe and induces considerably lower reaction rates than Encepur.33
An open-label, multicenter, phase III, follow-up study to Study 208 (Study 213) 
investigated the safety of the third vaccination of FSME-IMMUN 0.5 ml in subjects aged 
16 to 66 years who had received the first two vaccinations with either FSME-IMMUN 
0.5 ml (n=2790) or Encepur (n=915) during Study 208. Immunogenicity variables were 
assessed pre- and post-vaccination in a subgroup of subjects (n=566 analyzed). 
Regardless of whether FSME-IMMUN 0.5 ml or Encepur had been administered for the 
two previous vaccinations in Study 208, seroconversion rates as determined by ELISA 
and/or NT after the third vaccination with FSME-IMMUN 0.5 ml (compared to baseline) 
were very high (99.5% and 99.3% respectively). The geometric mean concentrations 
(GMCs, as determined by ELISA) after the third vaccination were higher in the FSME-
IMMUN 0.5 ml only group (1935.7 VIE U/ml vs. 1508.7 VIE U/ml), while the geometric 
mean titers (GMTs, as determined by NT) after the third vaccination were higher in the 
group of subjects who had previously received Encepur (259.0 vs. 371.4). Local and 
systemic reactions were mainly mild. Fever occurred at a negligible level (0.5%). In 
summary, these results demonstrate the excellent safety profile of the FSME-IMMUN 
0.5 ml vaccine for the third vaccination in healthy adults. The results further confirm that, 
regardless of which TBE vaccine was administered for the first two vaccinations, a third 
vaccination with FSME-IMMUN 0.5 ml is well tolerated and induces a strong immune 
response when administered 6 months after the first vaccination.33

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Study 223 was an open-label follow-up study to Study 213 to investigate TBE antibody 
persistence at 2 and 3 years after the third TBE vaccination with FSME-IMMUN 0.5 ml, 
as well as TBE antibody response to a booster vaccination with FSME-IMMUN 0.5 ml 
(administered 3 years after the third vaccination) by means of ELISA and NT (n=328 
analyzed). Local and systemic reactions were monitored after administration of the 
booster vaccination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 As expected, 
immune response was age dependent, with older subjects (aged 51-67 years) attaining 
GMC and GMT values (determined one month, two and three years after the third 
vaccination in Study 213) which were approximately half of the values for younger 
subjects(18-50 years of age). The majority of subjects experienced no reaction to the 
booster vaccination. The rate of occurrence of local and systemic adverse events was low, 
as expected with the administration of a booster vaccination three years after the third 
vaccination.
The seropositivity data obtained three years after the third vaccination suggest that it is 
sufficient for the first booster to be administered three years after the completion of the 
primary vaccination series. This study also demonstrated that FSME-IMMUN 0.5ml is 
extremely well tolerated as a booster vaccination.

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Study 225 investigated the safety and immunogenicity of 2 vaccinations with FSME-
IMMUN “NEW” 0.5 ml administered using a rapid immunization schedule (Day 0, 
Day 12±2) in healthy adults aged 16 to 65 years (n=60). The main objective of the study 
was to investigate the antibody kinetics after the second vaccination in order to establish 
the earliest time point at which vaccinees attained seropositive antibody levels. A total of 
60 subjects received both vaccinations in this clinical study. Blood was drawn from each 
subject prior to the first vaccination and on Days 3, 7, 14, 21 and 42 after the second 
vaccination. Of the 60 subjects enrolled, 4 were seropositive for TBE virus antibody prior 
to the first vaccination and were excluded from immunological analyses. The 
seropositivity rates as determined by ELISA among the remaining 56 subjects reached 
92.9% by Day 14 and 98.2% by Day 42 after the second vaccination. Seropositivity rates 
determined by NT after the second vaccination were higher and increased more rapidly 
than the corresponding rates determined by ELISA. The proportion of subjects who were 
seropositive as determined by NT on Day 3 was 89.3% and the rate increased to 98.2% 
by Day 14. At Days 21 and 42 after the second vaccination all subjects showed 
seropositive titers as measured by NT.
Safety constituted a secondary endpoint in the study, and was measured by the 
occurrence of local and systemic reactions after each vaccination. Safety data were 
collected on all 60 subjects through study completion on Day 42 following the second 
vaccination. No SAEs were reported after either vaccination in the study. Among the 
non-serious AEs reported in the course the study, the majority were mild, very few 
moderate and none severe. Local pain and tenderness were the most frequently reported 
queried local symptoms.
The results from Study 225 demonstrate that rapid immunization comprising two 
vaccinations (on Days 0 and 12 ± 2) with FSME-IMMUN 0.5 ml results in high 
seropositivity rates by Day 14 after the second vaccination. In addition, two vaccinations 
with FSME-IMMUN 0.25 ml given according to a rapid immunization schedule were 
well tolerated by the subjects participating in this study.

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Study 690501 investigated the immunogenicity and safety of a third vaccination with 
FSME-IMMUN 0.5 ml given approximately 12 months after the second vaccination in 
Study 225. In Study 225, two vaccinations were given using a rapid immunization 
schedule 12 2 days apart. In Study 690501 a total of 44 subjects received two 
vaccinations with FSME-IMMUN “NEW” 0.5 ml, and 41 were included in the 
immunogenicity dataset. Seropositivity rates for TBE virus antibody were determined by 
ELISA and NT separately at 3, 7, 14 and 21 days after the third vaccination. 
Immunogenicity results obtained just before the third vaccination was administered 
showed that titers had decreased to levels very close to or below the seropositivity cut-off 
for both tests (GMC 113 VIE U/ml; ELISA >126 VIE U/ml is considered positive and 
GMT 13.4; GMT ≥10 is considered positive). Following the third vaccination, a strong 
antibody response was observed, with maximum GMC of 2938.8 VIE U/ml and GMTs of 
360.2 at Day 21 post-vaccination. At Day 3 post-vaccination, 36.6% demonstrated 
seropositivity according to ELISA, while NT only analysis determined a higher 
seropositivity rate of 78.0% of all subjects. All (100%) subjects were determined to be 
seropositive by Day 7 post-vaccination and at all later assessment dates in both tests. The 
majority of subjects experienced no reaction to the vaccination and no SAEs were 
reported during this study. All local and systemic reactions were mild in nature and 
occurred at a frequency of 34.1% and 13.6% of subjects, respectively. 
The results from Study 690501 support the need for the third vaccination for achieving 
longer term protection against TBE, and confirm existing data from previous studies 
(Studies 202 and 213) on the excellent immunogenicity of the third vaccination with 
FSME-IMMUN 0.5 ml. This study also verified previous clinical experience that the 
third vaccination with FSME-IMMUN 0.5 ml is safe for use in a healthy adult 
population.
Study 690601 was designed to evaluate the immunogenicity and safety of FSME-
IMMUN 0.5 ml with the first and second vaccination being administered according to the 
rapid immunization schedule (12±2 days apart) and the third vaccination administered 
about 6 months after the first dose in healthy adults (n=330). The seropositivity rates 
attained in Stratum A (16- 49 years) and Stratum B (50 years) after the second 
vaccination as determined by ELISA, significantly increased from Day 7 (7.8% and 
5.7%, respectively) to Day 14 (73.9% and 48.8%, respectively) and reached maximum 
levels at Day 21 (84.3% and 69.6%, respectively). Seropositivity rates determined by NT 
after the second vaccination were higher and increased more rapidly than the 
corresponding rates determined by ELISA. The proportion of subjects who had 

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seropositive titers at Day 7 as determined by NT was 76.5% and 48.4% in Stratum A and 
Stratum B, respectively. Rates of 94.8% and 80.9% (Day 14) and 96.7% and 88.0% 
(Day 21) were determined respectfully for the two age strata.
After the third vaccination an increase in seropositive ELISA titers was seen at Day 7 
(Stratum A: 87.6%; Stratum B: 65.4%) with the highest rates found at Day 21 (Stratum 
A: 99.3% and Stratum B: 96.1%). This trend was also observed in the NT, with rates of 
97.2% and 84.3% at Day 7, and maximum rates of 100% and 98.7% at Day 21 in Stratum 
A and B, respectively, after the third vaccination.
There were no SAEs related to vaccination reported during this study. All local reactions 
which occurred after the first and second vaccinations were mild or moderate in nature 
and were more often reported in Stratum A (17.6% and 19.2%, respectively), than in 
Stratum B (13.5% and 17.3%, respectively). Systemic reactions were also rated as mild 
and not clinically relevant.
Overall, results of this study demonstrated that basic immunization with two vaccinations 
given according to the rapid immunization schedule induces seropositivity in the majority 
of subjects in both age strata. After the third vaccination, only 1 subject in Stratum B was 
found to be unresponsive to vaccination as determined by both ELISA and NT. 
Furthermore, FSME-IMMUN 0.5 ml has been demonstrated to be safe and well tolerated 
upon administration according to the rapid immunization schedule.
Study 690701 was an open-label follow-up study to Study 223 to investigate TBE 
antibody persistence at approximately 27, 34, 46 and 58 months after the first TBE 
booster vaccination with FSME-IMMUN 0.5 ml by means of ELISA and NT. A second 
booster vaccination with FSME-IMMUN 0.5 ml was administered depending on the level 
of serum TBE antibodies detected at the defined assessment time points. The antibody 
response was assessed approximately 1 month after the booster vaccination. The study 
was initiated in 2007 and was completed in March 2011.
6.4.2 Clinical Experience with FSME-IMMUN 0.25 ml in Children
Ten clinical studies and one postmarketing surveillance have been completed in children 
with FSME-IMMUN 0.25 ml (1.2 µg TBE virus antigen).
The aim of Postmarketing surveillance 197 was to observe the occurrence of fever 
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surveillance was carried out by registered pediatricians and general practitioners in 
Austria, between January 08, 2001 and August 23, 2001. A total of 1922 children, aged 
6 months to 12 years, were vaccinated at 110 medical centers throughout Austria. Each 
child was observed closely and rectal temperature measurements were taken (by the 
parents/legal guardian) for a total of four days after vaccination (including vaccination 
day).34 The majority of children were aged between 1 and 3 years (n=1198). Fever rates 
were highest in 1 – 2 year old children and an overall fever occurrence of 20.3 % was 
observed across all age groups.
Study 198 was an open, multicenter pilot study that examined the immunogenicity and 
safety of two vaccinations (administered 14-32 days apart) with 1.2 µg TBE antigen 
FSME-IMMUN “NEW” 0.25 ml in 101 children aged 1-12 years. Considering the high 
vaccination rate in children over the age of 4 years in Austria, the majority of children 
enrolled in the study were, as expected, aged 1 to 3 years (92.1%). The aim of the study 
was to examine the seroconversion rates of FSME-IMMUN 0.25 ml after the second 
vaccination, as well as the tolerability, assessed by body temperature measurements and 
monitoring of adverse events, after the first and second vaccinations in children. 
High seroconversion rates (99%) as determined by ELISA were observed after the second 
vaccination. Most AEs were mild and transient in nature and none were graded as severe. 
Fever related to the first vaccination occurred in 29.7%; most cases were mild and none 
were severe. The most common systemic AEs (apart from fever) were appetite loss and 
sleep disorders after the first vaccination.
Study 215 was designed as an open, multicenter, follow-up phase II study to Study 198 
for all subjects aged 1-12 years who had received two vaccinations with FSME-IMMUN 
“NEW” 0.25 ml (1.2 µg TBE antigen) during Study 198. The study investigated safety 
and immunogenicity of the third vaccination, administered 9-10 months after the second 
vaccination, as measured by seroconversion rates and adverse event monitoring.
Serological results of this study showed that the third vaccination with the 1.2 µg TBE 
antigen is highly immunogenic. After the third vaccination, a seroconversion rate of 
100% was observed (98/98 children).
Systemic reactions were rare and mild to moderate in intensity. The most commonly 
reported systemic AEs were appetite loss and sleep disorders. Fever was reported in 
12 cases and 9 of these were judged by the Investigator as related to the third vaccination. 

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The most commonly reported local reaction was injection site pain. There were no local 
reactions graded as severe.
Study 199 was a double-blind, randomized, multicenter dose-finding study that assessed 
the safety and immunogenicity of the first two doses of FSME-IMMUN “NEW” 0.25 ml 
administered 21-35 days apart in 643 subjects aged 1-6 years (until the last day before the 
6th birthday). Subjects were assigned to one of three study arms (0.3 µg, 0.6 µg and 
1.2 µg antigen) at a ratio of 1:1:1 using a blocked randomization system with a block size
of > 3. The primary aim of the study, with respect to safety, was to select the highest dose 
of FSME-IMMUN “NEW” that is non-inferior (with respect to fever rate after the first 
vaccination) to the lowest eligible dose (as determined by immunogenicity).
With regards to immunogenicity, only the doses at which the lower limit of the 95% 
confidence interval of the seroconversion rate was not lower than 85% were included in 
the analysis. As calculated from the results of ELISA and/or NT, seroconversion rates 
after the second vaccination were high (>93%) with all three investigated doses (93.2%, 
98.1% and 100% after vaccination with 0.3 µg, 0.6 µg and 1.2 µg TBE antigen, 
respectively). These results confirmed the induction of sufficient seroconversion rates 
with all three doses, therefore all three doses were included in the analysis of the optimal 
dose. The 1.2 µg dose was shown to be the optimal dose due to predefined safety criteria 
(i.e. to select the highest dose of TBE antigen that is non-inferior (with respect to fever 
after the first vaccination) to the lowest eligible dose (as determined by immunogenicity).
Occurrence of fever after the first vaccination was not dose-dependent. Fever cases were 
predominantly mild in intensity and none were severe. Fever occurrence was age-
dependent with the highest fever rate occurring in children 1 and 2 years of age (33.3% 
and 19.7%, respectively) and lower rates observed among children aged 5 years (6.3% of 
the total age group).
The 1.2 µg dose was determined to be safe for children aged 1-6 years and was 
determined to be the optimal dose of FSME-IMMUN “NEW” 0.25 ml in children in this 
age group.
Study 206 was designed as a follow-up study to Study 199 for subjects (aged 1 – 6 years) 
who had received the first two vaccinations as part of Study 199 (n=625). In Study 206, 
the safety and immunogenicity of the third vaccination (administered 6 months 

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(± 14 days) after the first vaccination) was examined. Subjects received the same dose 
(0.3 µg, 0.6 µg or 1.2 µg antigen) as for the previous two vaccinations. 
The seroconversion rate as determined by ELISA and/or NT was highest in the 1.2 µg 
dose group (100%) with rates of 99.5% and 98.5% observed in the 0.6 µg and 0.3 µg 
dose groups, respectively The 1.2 µg dose was shown to be the optimal dose due to the 
predefined safety criteria. 
Fever occurrence after the third vaccination was not dose-dependent. Systemic reactions 
as a whole showed no dose-dependent response. Restlessness and insomnia were the 
most frequently reported systemic reactions. The occurrence of local reactions after the 
third vaccination was also comparable between the three study groups.
Study 205 was a double-blind, randomized, multicenter dose-finding study that assessed 
the safety and immunogenicity of the first two doses of FSME-IMMUN “NEW” 0.25 ml 
in 644 subjects aged 6-15 years (until the last day before the 16th birthday). Subjects were 
assigned to one of three study arms (0.3 µg, 0.6 µg and 1.2 µg antigen) at a ratio of 1:1:1 
using a blocked randomization system with a block size of > 3. The two vaccinations 
were administered 21-35 days apart. 
Seroconversion rates calculated from ELISA and /or NT were high (>96%) with both 
0.6 µg and 1.2 µg doses of TBE vaccine. The lower rates of the 0.3 µg dose led to 
exclusion of this dose from the analysis of the optimal dose.
No difference in the fever rate was observed between the study groups. Fever after the 
first vaccination was predominantly mild and no severe fever cases were reported. No 
clear age-dependency trend was found with respect to fever after either vaccination. No 
dose-dependency was observed with the occurrence of local and systemic reactions after 
the first vaccination. Fatigue and headache were the most frequently reported systemic 
reactions in this study.
The 1.2 µg dose was determined to be safe for use and, according to both 
immunogenicity and safety criteria, was found to be the optimal dose of FSME-IMMUN 
0.25 ml in children aged 6-16 years.
Study 207 was designed as a follow-up study to Study 205 for subjects 
(aged 6 – 16 years) who had received the first two vaccinations as part of Study 205 

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(n= 618). In Study 207, the safety and immunogenicity of the third vaccination 
(administered 6 months (± 14 days) after the first) was examined. Subjects received the 
same dose (0.3 µg, 0.6 µg or 1.2 µg antigen) as for the previous two vaccinations. 
After the third vaccination, the seroconversion rate as determined by ELISA and/or NT 
was the highest in the 1.2 µg dose group (100%), with rates of 99.1% and 95.8% 
observed in the 0.3 µg, 0.6 µg dose groups, respectively. 
Fever occurrence after the third vaccination was low and no dose-dependency was 
observed. Local and systemic reactions were predominantly mild and not dose-dependent 
in frequency. The most commonly reported local reaction was injection site pain. 
Headache and fatigue were the most frequent systemic reactions, which occurred at a low 
rate and were comparable between study groups.
These results demonstrated that the 1.2 µg TBE-virus antigen dose of FSME-IMMUN 
0.25 ml – which was found to be the optimal dose according to pre-defined criteria in 
Study 205 – is safe and highly immunogenic for the third vaccination in children and 
adolescents aged 6 – 16 years.
In Study 209, the safety of five consecutive lots of FSME-IMMUN “NEW” 0.25 ml 
(1.2 µg TBE antigen) was investigated in healthy children aged 1-15 years, who received 
3 consecutive vaccinations (the first two 21-35 days apart; the third vaccination 6 months 
±14 days after the first). The main objective was the assessment of fever rate after the 
first vaccination in three different age groups (1-2 years, 3-6 years, 7-15 years), and to 
assess lot consistency. In addition, immunogenicity was investigated by ELISA and NT 
in a subgroup of subjects. A total of 2419 children were enrolled in Part A of the study, 
which comprised the first and second vaccinations. The third vaccination was 
administered in Part B of the study, in which 2404 subjects who had completed Part A of 
the study were enrolled.
A high overall seroconversion rate (96%) was observed 21-35 days after the second 
vaccination as determined by ELISA and/or NT. After the third vaccination, all subjects 
were shown to have seroconverted compared to baseline. 
As expected, fever occurred at a substantially lower rate after the second and third 
vaccination than after the first vaccination, and was more frequently observed in younger 
than in older children after all three vaccinations. The majority of fever cases after all 

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three vaccinations were mild, and most fever cases subsided within 24 hours. No severe 
fever was observed after the first vaccination.
Local reactions occurred less frequently after the second and third vaccinations than after 
the first. After all three vaccinations, the majority of local reactions were mild and the 
lowest frequency was reported in children aged 1-2 years, with comparable rates of local 
reactions in the 3-6 years and 7-15 years age groups. As expected, the most common 
local reactions after vaccination were local pain and tenderness.
The majority of systemic reactions (excluding fever) after all three vaccinations were 
mild. Systemic reactions (excluding fever) were reported most frequently in children 
aged 1–2 years, however, no significant difference was observed between the age groups. 
Headache was the most frequently reported systemic reaction, followed by restlessness 
(in subjects aged 1-5 years only), fatigue (in subjects aged 6-15 years only), myalgia and 
malaise (in subjects aged 6-15 years only).
These results confirm the consistent safety and high immunogenicity of FSME-IMMUN 
0.25 ml for the vaccination of children and adolescents aged 1-15 years.
Study 700401 was designed to investigate the seropersistence of TBE antibodies 
approximately 24, 34, 46 and 58 months after completion of the primary immunization 
schedule (3 vaccinations administered at months 0, 1 and 6 in Study 209) with FSME-
IMMUN 0.25 ml in children and adolescents aged 3 to 18 years. Subjects were offered a 
booster vaccination at either 36, 48 or 60 months after the third vaccination with either 
FSME-IMMUN 0.25 ml or FSME-IMMUN 0.5 ml according to their age, depending on 
their individual TBE antibody levels. The antibody response was again assessed 
approximately 1 month after the booster vaccination. The study was completed in 
July 2009.
Study 700501 aimed to investigate the seropersistence of TBE virus antibodies 
approximately 3 years after a booster vaccination with FSME-IMMUN 0.25 ml Junior in 
children who participated in Study IMAG-146A and were administered three 
vaccinations with either Ticovac 0.25 ml or Ticovac 0.5 ml (without HSA) during this 
study. Children were aged 6 months – 3 years at the time of their first vaccination. The 
analysis of the primary endpoint (seropositivity rate measured by ELISA and/or NT) 
showed that all (100%) subjects had seropositive levels of TBE virus antibodies 
approximately 3 years after the first booster vaccination. The results of this study confirm 

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the excellent immunogenicity of the primary vaccination series followed by a booster 
vaccination with FSME-IMMUN 0.25 ml Junior 3 to 4 years after the third vaccination.
Study 700801 was designed as a single-blind, randomized, phase III b multicenter study 
aiming to investigate the immunogenicity, safety and interchangeability of FSME-
IMMUN 0.25 ml Junior with Encepur 0.25 ml Children administered according to a 
conventional schedule (three vaccinations administered at 0, 28 and 360 days). In this 
study children aged 1 – 11 years will be administered the first and second vaccinations 
with either FSME-IMMUN 0.25 ml Junior or Encepur 0.25 ml Children and the third 
vaccination with FSME-IMMUN 0.25 ml Junior only. The study was completed 
February 2010.
6.5 Relevant Literature and Data
Relevant literature and data are discussed in Section 6.1 to Section 6.4.
Complete information for this compound may be found in the SmPC, the single reference 
safety document for this study.
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
6.6.1 Possible Benefits for the Subject
During this study, in accordance with the current recommendation in the SmPC, subjects 
will be offered the second TBE booster vaccination with either FSME-IMMUN 0.25 ml 
Junior or FSME-IMMUN 0.5 ml according to their age, following a first booster 
administered during the course of Study 700401. The recommendation regarding booster 
intervals as given in the SmPC was based on retrospective analysis of TBE antibody 
seropersistence in adults. However, so far there are only limited prospective clinical data 
from studies conducted in children to investigate seropersistence of TBE antibodies. 

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Although children generally show a very good immune response after vaccination with 
FSME IMMUN, isolated cases of vaccination failures have been observed. Therefore in 
this study TBE antibodies seropersistence will be investigated in the three sub-
populations - children, adolescents and young adults who received their primary 
vaccination series at the age of 1-15 years in Study 209 and their first booster vaccination 
in the context of Study 700401, 3-4 years after the third vaccination. Blood obtained at 
yearly intervals from approximately 3 to 10 years after the first booster vaccination will 
allow for determination of the subject’s level of TBE antibodies in order to assess the 
individual need for a second booster vaccination and to avoid an unnecessary early 
booster. A blood draw after the second booster vaccination will be performed to 
investigate the booster response. These results will be communicated to the subjects.
6.6.2 Possible Benefits for Society
At present, prospective clinical trial data on long-term TBE serum antibody persistence 
after vaccination are limited, particularly in children and adolescents. This study will 
provide information on antibody status at yearly intervals from approximately 3 to 
10 years after the first booster with FSME-IMMUN administered 3-4 years after the 
completion of the primary vaccination series. Results of this study will contribute to 
identification of the optimal booster interval and thereby influence future TBE 
vaccination practices. This study will further investigate TBE antibody persistence in 
subjects who started their primary vaccination with FSME-IMMUN 0.25 ml Junior at the 
age of 12 – 15 years, to confirm the appropriateness of the priming dose in this age 
group.
6.6.3 Possible Risks / Inconveniences for the Subject
As a result of drawing blood, pain, hematoma, and, in very rare cases, infection at the 
blood sample site may occur. In order to minimize pain, a local anesthetic cream or 
plaster (e.g. EMLA®) may be offered for application at the venipuncture site prior to 
each blood draw for younger children.
The most commonly reported AEs after administration of TBE vaccines in children are 
pain at the injection site, injection site tenderness and headache. As is the case with all 
inactivated vaccines, redness, induration and/or swelling at the injection site can also 
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Undesirable systemic reactions such as fatigue, malaise, nausea, vomiting, muscle or 
joint pain, appetite loss and sleep disorders may also be observed.
Fever may occur in children after the first immunization in particular in the very young. 
In general, the fever subsides within 24 hours. Fever rates reported after the second 
vaccination are generally lower as compared to the fever rates after the first vaccination. 
In very rare cases, febrile convulsions in small children have been reported, in particular 
after administration of the first dose. However, in the context of this study, a low fever 
rate is expected after the booster vaccination due to the age of the study subjects. In case 
of fever antipyretic therapy should be considered.
As with any vaccination, allergic reactions, including anaphylactic shock, cannot be 
completely ruled out, although their occurrence in connection with vaccination is 
extremely rare. Anaphylactic reactions to vaccines, including TBE vaccines, are very 
rare, but can occur. Therefore, appropriate emergency equipment and medication must be 
at hand whenever an immunization is performed.
In the presence of an autoimmune disorder (e.g. multiple sclerosis) or respective genetic 
disposition, vaccination might have an adverse effect on the course of the disease.
As with any other vaccination, central and peripheral nervous system disturbances cannot 
be completely ruled out.
All AEs stated in the package insert for FSME-IMMUN 0.5 ml or FSME-IMMUN 
0.25 ml Junior can also occur after administration of the vaccine.
The occurrence of unknown adverse effects cannot be excluded with the administration 
of any medicinal product. This statement also applies to this clinical study.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 
1996) 35, the European Clinical Trial Directive and the GCP Directive (2001/20/EC 36 and 
2005/28/EC 37, respectively), and applicable national and local regulatory requirements.

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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The main purpose of this study is to assess the seropersistence of TBE virus antibodies in 
children, adolescents and young adults who received the first booster vaccination with 
either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml in Study 700401.
The current protocol is being conducted to obtain prospective clinical trial data on long-
term TBE serum antibody persistence beyond the first booster and to verify the current 
TBE booster recommendations. The study investigates TBE virus antibody persistence at 
yearly intervals from approximately 3 years (38 months) to 10 years (118 months) after 
the first booster vaccination (as applicable). The decision whether to administer the 
second booster vaccination in this study and the timing thereof will depend on the level 
of serum TBE antibodies detected at the defined assessment time points. Subjects who 
may not be protected against TBE for an entire further tick season (NT titer ≤20 and / or 
ELISA value ≤126 VIE U/ml), should be invited to receive the booster vaccination at 
either the 40, 48, 60, 72, 84, 96, 108, or 120 month time point. Recommendations as to 
whether or not to administer the booster vaccination will be given by the Sponsor on an 
individual basis. The Data Monitoring Committee (DMC) will be consulted for their 
opinion in case of inconclusive serological data (e.g. contradictory results in ELISA and 
NT).
The cut-off level for an NT titer of 1:20 as described above was chosen based on the 
annual decline rate determined in the precursor studies 209 and 700401i, in which 
antibody persistence was investigated 1, 24 , 34, 46 and 58 months after completion of 
the TBE primary vaccination series. Annual decline rates were calculated on the basis of 
log-transformed antibody titers. The mean annual decline rates determined for subjects 
aged 1-2 years, 3 – 6 years and 7 – 15 years were -0.50, -0.38 and -0.46, respectively. 
Therefore, an NT titer of 20 at a specified time point would on average be reduced to 
12.2, 13.6 or 12.6 within a year for the 3 age categories, respectively, which is just above 
the cut-off level for seropositivity (NT ≥ 1:10). Also, subjects should receive the booster 
vaccination in the current study if their ELISA value has declined below the level of 
seropositivity, i.e. ≤126 VIE U/ml.38
                                                
i Study 700401: Open-label Follow-up Study to Investigate the Seropersistence of TBE Antibodies and the 
Booster Response to a Tick-borne Encephalitis Vaccine in Children and Adolescents aged 3 – 18 Years. 
Statistical Analysis dated November 24, 2008

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7.2 Primary Objective
To assess TBE antibody persistence at yearly intervals from approximately 3 years 
(38 months) to 10 years (118 months) after the first booster vaccination (as applicable) 
with either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml by means of NT 
(according to Adner et al., 2001) 1  and ELISA [IMMUNOZYM FSME Immunoglobulin 
G (IgG)] .
7.3 Secondary Objectives
7.3.1 Immunogenicity
To assess the antibody response to a second booster vaccination with either FSME-
IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml administered in the present study, by 
means of ELISA and NT.
7.3.2 Safety
To assess the safety of FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml after 
administration of the second booster vaccination in the present study.

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8. STUDY DESIGN
8.1 Overall Study Design
This is a phase IV, follow-up, open-label, multicenter study in a total of 202 children, 
adolescents and young adults who received their first TBE booster vaccination in Study 
700401 with the aim to assess seropersistence of TBE antibodies at yearly intervals from 
approximately 3 years (38 months) to 10 years (118 months) after the first booster 
vaccination (as applicable), as well as antibody response to a second booster vaccination 
with either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml according to the 
subject’s age. 
Blood draws will be performed to assess the seropersistence of TBE virus antibodies at 
yearly intervals from approximately 3 years (38 months) to 10 years (118 months) after 
the first booster vaccination previously administered during Study 700401.
Timing of the second booster vaccination will depend on the level of serum TBE 
antibodies detected at the defined assessment time points. Subjects who may not be 
protected against TBE for an entire further tick season as confirmed by relatively low 
TBE serum antibody levels evaluated by NT and / or ELISA (i.e. NT titer ≤20 and / or 
ELISA value ≤126 VIE U/ml), will be invited to receive the second booster vaccination 
at either the 40, 48, 60, 72, 84, 96, 108, or 120 month time point (see Section 10.3.2). 
Recommendations as to whether or not to administer the booster vaccination will be 
given by the Sponsor on an individual basis. The Data Monitoring Committee will be 
consulted for their opinion in case of inconclusive serological data (e.g., contradictory 
results in ELISA and NT).
A blood draw will be performed approximately 21 - 35 days after vaccination to assess 
the booster response.
The overall study design is illustrated in Figure 20.1-1 and Figure 20.1-2
(Supplement 20.1).

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8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 8 years from study initiation (i.e. first 
subject enrolled) to study completion (i.e. last subject last visit).
The subject participation period is approximately 7 years from enrollment to subject 
completion (i.e. last study visit), unless the booster vaccination is administered at an 
earlier time point or the subject is prematurely discontinued. 
8.3 Endpoints
8.3.1 Primary Endpoint
The primary endpoint is:
Immunogenicity:

Seropositivity rate as determined by NT from approximately 3 years (38 
months) to 10 years (118 months) after the first booster vaccination 
administered in Study 700401 and after the second booster vaccination 
administered in this study.
8.3.2 Secondary Endpoints
8.3.2.1 Immunogenicity

Seropositivity rate as determined by ELISA from approximately 3 years (38 
months) to 10 years (118 months) after the first booster vaccination in Study 
700401 and after the second booster vaccination in this study;

Antibody response as determined by ELISA from approximately 3 years (38 
months) to 10 years (118 months) after the first booster vaccination in Study 
700401 and after the second booster vaccination in this study;

Antibody response as determined by NT from approximately 3 years (38 
months) to 10 years (118 months) after the first booster vaccination in Study 
700401 and after the second booster vaccination in this study;

Fold increase of antibody concentration determined by ELISA after the 
second booster vaccination as compared to before the second booster 
vaccination in this study;

Fold increase of antibody titer determined by NT after the second booster 
vaccination as compared to before the second booster vaccination in this 
study.

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8.3.2.2 Safety

Injection site reactions observed in the period from the second booster 
vaccination until the following blood draw;

Systemic reactions observed in the period from the second booster vaccination 
until the following blood draw.
8.4 Randomization and Blinding
This is an un-randomized, open-label clinical study. Subjects will be vaccinated with 
either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml according to their age.
8.5 Study Stopping Rules 
The study may be prematurely terminated if SAEs or other significant vaccine related 
side effects occur. In addition, the Sponsor may stop the entire study for any medical 
reason at any time.
In the event of premature study termination resulting from an AE, clinical and / or 
laboratory investigations that are beyond the scope of the required study may be 
performed as part of the evaluation of the event. These investigations will take place 
under the direction of the Investigator in consultation with the Sponsor, and the details of 
the outcome will be reported to the appropriate regulatory authorities by the Sponsor. 
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 Dosage Form for Investigational Products
The dosage form of both FSME-IMMUN 0.25 ml Junior and FSME-IMMUN 0.5 ml is 
suspension for injection in a pre-filled syringe.
8.6.1.2 Packaging and Labeling
The investigational product will be provided in single-use pre-filled syringes. One single 
dose of FSME-IMMUN 0.5 ml contains 2.00 – 2.75 µg (target: 2.4 µg) TBE antigen. One 
single dose of FSME-IMMUN 0.25 ml Junior contains half the adult dose, i.e. 1.00-
1.38 µg (target 1.2 µg) TBE antigen. After shaking, the vaccine is an off-white, 
opalescent suspension.
The investigational product will be labeled according to the valid regulatory requirements 

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for clinical trials.
8.6.1.3 Storage
The vaccine must be stored under refrigeration at +2°C to +8°C, with a minimum-
maximum thermometer).The vaccine must be protected from light. Deep freezing and 
storage at higher temperatures should be avoided because of potential impairment of 
immunogenicity and tolerability.
In order to guarantee proper storage conditions, the temperature shall be checked and 
documented daily on forms provided by the Sponsor. 
FSME-IMMUN 0.5 ml and FSME-IMMUN 0.25 ml Junior pre-filled in “readyject” type 
syringes (with integrated needle) have a shelf-life of 30 months, and for FSME-IMMUN 
Junior “Tip Cap” the shelf-life is 30 months from the date of manufacture. The vaccine 
must not be used after the expiry date indicated on the package.
The Investigator should inform the monitor about any temperature deviations on a regular 
basis. In case of accidental freezing of the vaccine, the Sponsor must be contacted 
immediately for further follow-up decision.
8.6.2 Administration
8.6.2.1 Route of administration
The vaccine should be given by intramuscular injection into the right or left upper arm 
(deltoid muscle).
8.6.2.2 Vaccine preparation
Before vaccine administration:

the syringe should reach room temperature before administration of the vaccine;

the syringe should be shaken for five to ten seconds;

the syringe should be checked visually for foreign particulate matter and / or 
variation in physical appearance before administration of the vaccine. Syringes 
found to contain particulate matter, to be discolored or to leak may not be used.

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8.6.2.3 Vaccine administration
Before vaccine administration:

“Readyject” type syringe (with integrated needle): detach the needle guard;

Tip cap syringe: remove the tip-cap and attach the needle provided by the 
Sponsor to the syringe.

the injection site should be prepared according to standard clinical procedures;

the vaccine should be given by intramuscular injection into the right or left 
upper arm (deltoid muscle);

under no circumstances should FSME-IMMUN be administered 
intravascularly, as this could lead to hypersensitivity reactions such as shock.

for further information please refer to the Pharmacy Manual provided in the 
Investigator File.
Each subject will receive one vaccination according to his / her age as described in 
Section 10.3.2.2 of Study Procedures.
Anaphylactic reactions to vaccines, including TBE vaccines, are very rare, but can 
occur. Therefore, appropriate emergency equipment and medication must be at 
hand whenever an immunization is performed.
8.6.3 Description of Treatment
A second booster vaccination will be administered with either FSME-IMMUN 0.25 ml 
Junior or FSME-IMMUN 0.5 ml according to the subject’s age. Timing of the 
vaccination will depend on the level of serum TBE antibodies detected at the defined 
assessment time points. Subjects who may not be protected against TBE for an entire 
further tick season as confirmed by relatively low TBE serum antibody levels evaluated 
at yearly intervals from approximately 3 years (38 months) to 10 years (118 months) after 
the first booster (NT titer ≤20 and / or ELISA value ≤126 VIE U/ml) will be invited to 
receive the second booster vaccination at either the 40, 48, 60, 72, 84, 96, 108, or 120 
month time point.
8.6.4 Investigational Product Accountability
The Investigator will ensure that IP is stored as specified in the protocol and that the 
storage area is secured, with access limited to authorized study personnel, as described in 
the Clinical Study Agreement. The Investigator will maintain records that the IP was 

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received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. IP must be dispensed only at the 
institution specified for each study site. Records will be maintained that include the 
subject identification code (SIC), dispensation date, and amount dispensed. All remaining 
partially used and/or unused IP will be returned to the Sponsor or Sponsor’s 
representative after study completion/termination, or destroyed with the permission of the 
Sponsor in accordance with applicable laws and study site procedures, as described in the 
Clinical Study Agreement. If IP(s) is to be destroyed, the Investigator will provide 
documentation in accordance with Sponsor’s specifications.
8.7 Data Recorded Directly on Case Report Forms
The Sponsor will provide a list of data, if any, that are to be entered directly into the 
CRF, and are therefore considered source data. 

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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who participated in Study 700401 and meet ALL of the following criteria are 
eligible for participation in this study:

Subject / parent(s)/legal guardian(s) provide(s) written informed consent 
(according to national law);

Subject provides written assent to the study according to age and capacity of 
understanding;

Subject received the first booster vaccination with either FSME-IMMUN 
0.25 ml Junior or FSME-IMMUN 0.5 ml during the course of Study 700401;

Blood was drawn after the first booster vaccination in Study 700401;

Subject / parent(s) / legal guardian(s) understand(s) the nature of the study and 
is/are willing to comply with the requirements of the protocol (e.g. return for 
follow-up visits, completion of the Subject Diary).
9.2 Exclusion Criteria
Subjects who participated in Study 700401 and meet ANY of the following criteria are 
not eligible for participation in this study:

Subject received any TBE vaccination since his/her first booster vaccination 
in Study 700401;

Subject has a history of infection with or vaccination against other flaviviruses 
(e.g., Dengue fever, yellow fever, Japanese B encephalitis) since his / her first 
booster vaccination in Study 700401;

Subject is known to be HIV positive (a special HIV test is not required for the 
purpose of the study) since his/her first booster vaccination in Study 700401;

Subject received a blood product or immunoglobulins within 90 days before 
any blood draw or in the period between the blood draw and the booster 
vaccination (as applicable);

Subject has a known or suspected problem with drug or alcohol abuse 
(> 4 liters of wine/week or equivalent level of other alcoholic beverages);

Subject / parent(s) / legal guardian(s) is / are in a dependent relationship with 
the study investigator or with a study team member. Dependent relationship 
includes close relatives (i.e., children or grandchildren, partner / spouse, 
siblings) as well as employees of the Investigator or the site conducting the 
study.

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9.3 Eligibility criteria for booster vaccination
Subjects who meet ANY of the following criteria are not eligible for the booster 
vaccination:

Subject is not clinically healthy (i.e., the physician would have reservations 
vaccinating with a TBE vaccine outside the scope of a clinical trial);

Subject is suffering from a disease (e.g., autoimmune disease) or is 
undergoing a form of treatment (e.g., systemic corticosteroids) that can be 
expected to influence immunological functions;

Subject has developed severe allergic reactions, in particular a sensitivity or 
allergy to any component of the vaccine, since the first booster vaccination in 
Study 700401;

If female - subject is pregnant or lactating;

Subject has participated in another clinical study involving an IP or medical 
device within 30 days prior to the planned booster vaccination or is scheduled 
to participate in another clinical study involving an IP or medical device.

Females capable of bearing children if they do not agree to employ adequate 
birth control measures from 4 weeks before the booster vaccination until the 
end of the study.
9.4 Delay criteria
Vaccination will be delayed if one of the following applies:

Subject has an acute illness with or without elevated body temperature 
(37.5C) within 3 days prior to the scheduled booster vaccination. The 
subject may be vaccinated at a repeat visit provided that the illness has 
resolved (body temperature < 37.5°C);

Subject has received any live vaccine within 4 weeks or any inactivated 
vaccine within 2 weeks prior to the scheduled booster vaccination. 
Vaccination may be performed when an interval of 4 or 2 weeks, respectively, 
has passed;

Subject has received antipyretics within 4 hours prior to the scheduled time of 
vaccination. Vaccination may be performed at a later date;

Subject was bitten by a tick within 4 weeks prior to the scheduled booster 
vaccination. Vaccination shall be postponed until an interval of 4 weeks has 
passed;

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
Subject has donated blood, blood fractions or plasma within 30 days of the 
scheduled booster vaccination. Vaccination shall be postponed until an 
interval of 30 days has passed.
9.5 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection at any time during the 
study. The reason for withdrawal will be recorded on the Completion / Termination CRF. 
The data collected on withdrawn subjects will be used in the analysis and included in the 
clinical study report.
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e. discontinuation 
by subject without notice or action). Additionally, the Investigator and Sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:

The subject becomes pregnant. IP exposure will be discontinued. Attempts 
will be made to follow her through completion of the pregnancy. The 
Investigator will record a narrative description of the course of the pregnancy 
and its outcome;

The subject begins lactating. IP exposure will be discontinued. The 
Investigator will record a narrative description of the course of the baby’s 
development;

Participation in another investigational drug or medical device study within 30 
days prior to the planned booster vaccination or is scheduled to participate in 
another clinical study involving an IP or medical device.
The Investigator should provide the Sponsor with a written account of any reasons for 
early withdrawal. The Investigator will attempt to complete all discharge procedures 
simultaneously to the subject being discontinued from the study.
For all subjects discharged prematurely the Investigator should make an effort to ensure 
that the subject comes to a final examination visit and complete the study completion 
page in the CRF (see Section 10.6).
Dropouts and subjects who do not complete the entire study for any reason will not be 

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replaced.
10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any healthy volunteer who / whose parent(s) / legal guardian(s) provide(s) informed 
consent (i.e., signs and dates the informed consent form and assent form, if applicable) is 
considered enrolled in the study.
The Investigator will inform the subject / parent(s) / legal guardian(s) (as applicable) 
about the procedures, risks and benefits of the study. Fully informed, written 
assent / consent must be obtained from each subject and / or his / her parent(s) / legal 
guardian(s) prior to any assessment being performed. It is important that the subject is 
allowed sufficient time to decide on his / her participation in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the Subject Identification Code (SIC): 
protocol number (e.g. 700802) to be provided by the Sponsor, 2-digit study site number 
(e.g., 02) to be provided by the Sponsor, and 4-digit subject number (e.g., 0003) 
reflecting the order of enrollment (i.e. signing the informed consent form). For example, 
the third subject who signed an informed consent form at study site 02 will be identified 
as Subject 700802-020003. All study documents (e.g., CRFs, clinical documentation, 
sample containers, drug accountability logs, etc.) will be identified with the SIC.
In this study, subjects will retain the SICs previously assigned to them in Study 700401 
and Study 209.
10.3 Screening and Study Visits
The study site is responsible for maintaining an enrollment log that includes all subjects 
enrolled. 
The overall study design is illustrated in Figure 20.1-1 and Figure 20.1-2
(Supplement 20.1). Details on the procedures to be performed at each study visit can be 
found in Supplement 20.2, Table 20.2-1, Schedule of Study Procedures and Assessments.
10.3.1 Screening
The screening visit is not applicable for this study. 

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10.3.2 Study visits
10.3.2.1 Blood draw (investigation of TBE antibody persistence)
Visit 1: 38 months ± 60 days after the booster vaccination in Study 700401ii.
All subjects who were administered the first booster vaccination in Study 700401 will be 
invited for this visit. Subjects with relatively low TBE serum antibody levels (as 
described further) will proceed to Visit 4 (Booster vaccination) and Visit 5 (Post-booster 
Visit), as applicable (see Figure 20.1-1, Supplement 20.1).
Visit 2: 46 months ± 30 days after the booster vaccination in Study 700401. 
This visit will only be applicable for those subjects who have not yet received the second 
booster vaccination. Subjects with relatively low TBE serum antibody levels will proceed 
to Visit 4 and Visit 5 (see Figure 20.1-1, Supplement 20.1).
Visit 3: 58 months ± 30 days after the booster vaccination in Study 700401. 
This visit will only be applicable for those subjects who have not yet received the second 
booster vaccination. Subjects with relatively low TBE serum antibody levels will proceed 
to Visit 4 and Visit 5 (see Figure 20.1-1, Supplement 20.1).
Visit 6: 70 months ± 30 days after the booster vaccination in Study 700401.
Visit 7: 82 months ± 30 days after the booster vaccination in Study 700401. 
Visit 8: 94 months ± 30 days after the booster vaccination in Study 700401. 
Visit 9: 106 months ± 30 days after the booster vaccination in Study 700401.
Visit 10: 118 months ± 30 days after the booster vaccination in Study 700401. 
These additional blood draw visits are only applicable for subjects who have not yet 
received the second booster vaccination. Subjects with relatively low TBE serum 
antibody levels will proceed to Visit 4 and Visit 5 (see Figure 20.1-2, Supplement 20.1).
                                                
ii The 29 subjects who were administered the first booster vaccination at the 4 year time point in Study 
700401 and who will enter the current study in 2010 will have their Visit 1 at 34 months ± 60 days. For 
Visit 2 and Visit 3 the schedule is to be followed as described in the protocol.

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The following assessments will be performed:

Verification of the signed and dated informed consent/assent of the subject 
prior to any procedures being done (at Visit 1 ONLY);

Inclusion and exclusion criteria (see Section 9.1 and Section 9.2);

Demographic data (at Visit 1 ONLY);

Medical history with particular focus on significant medical events (e.g.,
events fulfilling SAE criteria) experienced in the time period from the last 
study visit in Study 700401 until Visit 1 in this study, and between each blood 
draw visit, as applicable;

History of tick-bites (either since the last visit in Study 700401 or since the 
last blood draw visit in this study, as applicable);

Vital signs (weight and height);

Physical examination;

Blood draw of 5 ml for determination of TBE virus antibodies by ELISA and 
NT;

Recording of any AEs in association with study procedures (e.g. blood draw) 
on the appropriate CRF page.
Serum TBE virus antibody levels measured by ELISA and NT at yearly intervals from 
approximately 3 years (38 months) to 10 years (118 months) after the first booster 
vaccination will be communicated to the centers as soon as they are available and will 
serve as a basis for determining whether to administer the booster. Subjects with 
relatively low TBE serum antibody levels (NT titer ≤20 and / or ELISA value 
≤126 VIEU/ml) at the 40, 48, 60, 72, 84, 96, 108, or 120 month time point may not be 
considered protected against TBE for an entire further tick season. Recommendations 
will be given by the Sponsor on an individual basis. The Data Monitoring Committee 
(DMC) will be consulted for their opinion in case of inconclusive serological data (e.g.,
contradictory results in ELISA and NT).

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10.3.2.2 Booster Vaccination Visit
Visit 4: (40 months ± 60 days, or 48, 60, 72, 84, 96, 108, or 120 months ± 30 days after 
the booster vaccination in Study 700401, as applicable (see Figure 20.1-1 and 
Figure 20.1-2, Supplement 20.1iii).
A booster vaccination will be administered to subjects who may not be protected against 
TBE for an entire further tick season, as determined by antibody levels detected at each 
blood draw (NT titer ≤20 and / or ELISA value ≤126 VIEU/ml).
For subjects who do not receive their second TBE booster vaccination during the entire 
course of this study due to sufficiently high TBE virus antibody levels, a booster 
vaccination will be offered free of charge at an appropriate time point outside the scope 
of this clinical study.
10.3.2.2.1 Before the booster vaccination
The following assessments will be performed:

Review of inclusion and exclusion criteria (see Section 9.1 and Section 9.2); 

History of tick bites since last blood draw visit, as applicable;

Medical History since last blood draw visit, as applicable;

Vital signs (body temperature measured orally, pulse rate and blood pressure 
measured when subjects are in the sitting position); 

Physical examination; 

Females will be asked if first menstruation occurred since the last blood draw 
visit, as applicable. If menarche occurred, it shall be documented in the 
medical history and CRF;

Pregnancy test (urine) in females capable of bearing children;

Eligibility criteria for the booster vaccination (see Section 9.3);

Delay criteria for the booster vaccination (see Section 9.4);
                                                
iii For subjects who received their first booster in Study 700401 at 3 years after the third vaccination and 
were considered as not protected against TBE after Visit 1 in this study, Visit 4 will be performed at 40 
months ± 60 days. If a subject who was administered the first booster vaccination at the 4 year time 
point in Study 700401 is considered as not protected against TBE after Visit 1 in this study, he/she will 
proceed to the Booster Visit (Visit 4) at 36 months ± 60 days.

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10.3.2.2.2 Booster vaccination
BEFORE ADMINISTRATION: WARM SYRINGE TO ROOM TEMPERATURE 
AND SHAKE SYRINGE VIGOROUSLY FOR FIVE TO TEN SECONDS. 
The study site must have appropriate equipment and adequately trained personnel 
available to respond to anaphylaxis or other possibly severe acute, post-immunization 
adverse reactions to vaccines.
The vaccine will be given by intramuscular injection into the right or left upper arm 
(deltoid muscle).
Subjects will be administered either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 
0.5 ml according to their age: FSME-IMMUN 0.25 ml Junior will be administered to 
children and adolescents up to 16 years of age and FSME-IMMUN 0.5 ml to subjects 
aged 16 years and older.
10.3.2.2.3 Post vaccination observations
Following vaccination, the subjects will be observed for at least 30 minutes in order to 
provide appropriate emergency treatment should this be necessary. After the 30 minute 
observation period, the pulse will be taken. Any injection site reactions and systemic AEs 
will also be recorded.
The subject / subject’s parent(s) / legal guardian(s) will receive a Subject Diary for 
documentation of AEs for a total period of 4 days (including the day of vaccination) after 
the booster vaccination. The Investigator must provide sufficient instructions to the 
subject / parents / legal guardians on how to document AEs. The entries in the Subject 
Diary will be evaluated and graded for severity and relatedness by the Investigator at the 
subject’s next visit to the study site. These data will then be entered in the CRFs. The 
Subject Diaries are part of the source data.
For further details refer to Section 10.5, Subject Diary.

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10.3.2.3 Post-Booster Visit
Visit 5: 21 – 35 days after Visit 4
The following activities will be performed:

Vital signs (pulse rate and blood pressure measured when subjects are in the 
sitting position);

Physical examination;

Collect and review the Subject Diary. The Investigator will ask whether any 
other observations or abnormalities not recorded in the Subject Diary were 
observed since Visit 4. The Investigator will document the observations 
recorded in the Subject Diary on the appropriate CRF page;

Recording of any AEs since Visit 4 on the appropriate CRF page;

Blood draw of 5 ml for determination of TBE virus antibodies by ELISA and 
NT;

Complete Study Termination form.
10.3.3 Unscheduled Visit 
An unscheduled visit can be held at any time after the booster vaccination if deemed 
necessary by the Investigator (e.g. follow-up on unexpected AEs or SAEs). Assessments 
performed at an unscheduled visit will be at the Investigator’s discretion. In case of an 
unscheduled visit, the Investigator should complete the “Unscheduled Visit Form” in the 
CRF.

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10.4 Medications and Non-Drug Therapies 
The following medications are not permitted:

any blood products or immunoglobulins - within 90 days before each blood 
draw, in the period between the blood draw and the second booster 
vaccination, and from the second booster vaccination until the Post-booster 
Visit;

any treatment that can be expected to influence immunological functions (e.g.,
systemic corticosteroids) – within 30 days prior to the second booster 
vaccination until the Post-booster Visit.
A subject who has taken any of these medications within the time frames 
specified above before administration of the second booster vaccination will 
be excluded / discontinued from this study. Administration of these 
medications between the second booster vaccination and the Post-booster 
Visit will be considered a protocol deviation;

any live or inactivated vaccine given within 4 weeks or 2 weeks, respectively, 
before the second booster vaccination, until the Post-booster Visit.
Any vaccination (except if given in medical emergencies such as tetanus or 
rabies infection) will be considered a protocol deviation.
The following medications and procedures will delay the booster vaccination:

antipyretics received within 4 hours prior to the scheduled time of vaccination

any live or inactivated vaccine received within 4 or 2 weeks before the booster 
vaccination, respectively.

donation of blood, blood fractions or plasma within 30 days prior to the 
scheduled booster vaccination. Subjects are further requested to refrain from 
donation of blood, blood fractions and plasma until the Post-booster Visit 
(Visit 5).
For further details on Delay Criteria refer to Section 9.4. 
Usage of any other medications or non-drug therapies is not restricted.

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10.5 Subject Diary
The subject or subject’s parent(s)/legal guardian(s) will receive a Subject Diary for 
documentation of AEs for a total period of four days (including the day of vaccination) 
after each vaccination. The Investigator must provide sufficient instructions to the subject 
and/or parent(s) / legal guardian(s) on how to document AEs.
The Subject Diary will be provided at Visit 4 (after the booster vaccination) to record the 
following information:

Measurement of body temperature (orally, once every evening from 
vaccination until Day 3 after vaccination);

Injection site reactions (swelling, induration, redness, injection site pain and 
tenderness, ecchymosis and hematoma);

Systemic symptoms such as headache, nausea, vomiting, muscle pain, joint 
pain, swelling of the lymph nodes, malaise and fatigue;

Other adverse events occurring after the booster vaccination;

Any medication taken after vaccination (including antipyretics, vitamins and 
minerals for therapeutic use).
The Subject Diaries will be returned to the Investigator at the visit following vaccination.
The Subject Diary will serve as source documentation. Entries in the subject diaries will 
be transcribed onto the appropriate CRFs. Any entry on the CRF that does not correspond 
with an entry in the Subject Diary will be explained by the Investigator on the relevant 
Subject Diary page. The entries in the Subject Diary shall be verified and in case they 
constitute an AE shall be graded for severity and relatedness by the Investigator.

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10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, followed the 
protocol. Reasons for completion/discontinuation will be reported on the 
Completion/Termination CRF, including: completed, discontinuation due to an AE, 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], active discontinuation by subject, e.g., dropout), 
physician decision (e.g., pregnancy, progressive disease, non-compliance with 
IP/protocol violation(s), study terminated by Sponsor, or other (reason to be specified by 
the Investigator, e.g., technical problems). Additional reasons may include failure to 
complete all baseline assessments, or subject / subject’s legally acceptable representative 
requests withdrawal from participation in the study (i.e., active discontinuation).
Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
completion / termination visit. The reason for discontinuation will be recorded on the 
CRF, and data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. 
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the Investigator in consultation with the Sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
Sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Apart from filling in the Subject Diary, all study procedures are to be performed under 
the direct supervision of the Investigator/a licensed healthcare professional at the study 
site, and thus, no separate procedures will be used to monitor subject compliance.

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11. ASSESSMENT OF IMMUNOGENICITY
11.1 Assessment of Immune Response
All samples will be handled according to the instructions for the preparation, storage and 
shipment of samples provided in the Investigator File.
Blood samples will be used only for scientific research.  Each sample will be labeled with 
a code so that the laboratory personnel testing the samples will not know the subject’s 
identity.  Some of the samples may be stored by Pfizer for additional testing.  The 
samples will not be used for any unrelated research, and no genetic testing will be 
performed.  The samples will be stored for up to 15 years after the end of the study and 
then destroyed.  
The subject or his / her parent(s) or legal guardian(s) may request that his/her/child’s
samples, if still identifiable, be destroyed at any time; however, any data already 
collected from those samples will still be used for this research. The biological samples 
may be shared with other researchers as long as confidentiality is maintained.
TBE antibody response will be determined by means of ELISA using IMMUNOZYM 
FSME IgG test kit, Progen, Heidelberg, Germany, as well as by means of NT (according 
to Adner et al., 2001).1
The tests will be performed at the following laboratories:

IMMUNOZYM FSME ELISA: 
 
, Austria;

NT (according to Adner et al., 2001) 1: 
 
 Austria.
In the ELISA IMMUNOZYM kit and the NT assay TBE virus antigen derived from 
strain Neudoerfl is used. ELISA values > 126 VIE U/ml obtained by the IMMUNOZYM 
ELISA will be considered positive.38 NT titers 10 will be considered positive. At the 
end of the study, results of immunogenicity assessments will be provided to the 
Investigator for communication to the subjects.

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12. ASSESSMENT OF SAFETY
12.1 Vaccine-Specific Safety Parameters Assessed
12.1.1 Body Temperature 
To optimize the comparability of the documented body temperatures, all parent(s) / legal 
guardian(s) will be provided with a digital thermometer.
Body temperature should be measured once every evening from the day of vaccination 
until Day 3 after vaccination. If fever occurs, body temperature should be measured every 
4 to 8 hours until it returns to normal. All values of temperature measurements should be 
documented in the Subject Diary including date and time. If fever occurs, all 
measurements, including the first value showing a return to normal body temperature, 
should be recorded in the Subject Diary.
All values of body temperature measurement from the day of vaccination until Day 3 
after vaccination will be recorded by the Investigator in the CRF. If more than 1 body 
temperature value is recorded for a given day, the highest body temperature value will be 
documented by the Investigator on the appropriate CRF page.
Severity grading of fever will be performed according to the Common Toxicity Criteria 
manual (CTC, Version 3.0, December 12, 2003) 39, as follows:
mild:
38.0 - 39.0 °C
moderate:
>39.0 - 40.0 °C
severe:
> 40.0 °C
No prophylactic administration of antipyretic medications is envisaged in this study. 
However, upon consultation with the Investigator, the parents / legal guardian may give 
an appropriate antipyretic if necessary.
The digital thermometers provided by the Sponsor may be kept by the subjects after study 
termination.

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12.1.2 Injection Site Reactions
The subject or his / her parent(s) or legal guardian(s) will be properly instructed and 
asked to monitor, measure and document injection site reactions occurring after the 
booster vaccination for a period of four days (including the day of vaccination). These 
reactions include swelling, induration, redness, injection site pain and tenderness, 
ecchymosis and hematoma. Further instructions on how to measure injection site 
reactions will be detailed in the Subject Diary.
Refer to Table 20.3-1 for Grading of Adverse Events – Vaccine-Specific Criteria.
12.2 Adverse Events
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IP, whether or not related to 
the IP.  An AE includes any event, regardless of the presumed causality between the 
event and the IP. Any subject experiencing an AE will be examined by a physician as 
soon as possible according to medical requirements. The physician in attendance will do 
whatever is medically necessary for the safety and well-being of the subject. The subject 
will remain under observation as long as medically indicated in the opinion of the 
Investigator. All abnormalities will be followed until resolved or until medically 
stabilized.
12.2.1 Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to safety within 24 hours of Investigator’s 
awareness, using the SAE Report form, regardless of whether there is an associated 
AE/SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE Report form is maintained in the study master file.
12.2.2 Serious Adverse Event
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:

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
Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the 
judgment of the Investigator, at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death had it been 
more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stayiv.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Results in congenital anomaly / birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definitions above. 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 dependence or drug abuse 
Reviewed and confirmed seroconversion for human immunodeficiency 
virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C 
virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
12.2.3 Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy 
occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (eg, because of treatment or environmental exposure) to the 
investigational product; or the female becomes, or is found to be pregnant after 
discontinuing and/or being exposed to the investigational product; 
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).
                                                
iv Hospitalizations and elective surgeries planned prior to study entry are not considered SAEs if they are 
documented in the patients’ medical records.

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2. A male subject has been exposed (eg, because of treatment or environmental
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit 
this information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report
Form and Exposure During Pregnancy (EDP) supplemental form, regardless of whether 
an SAE has occurred.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (eg, a subject reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) 
using the EDP supplemental form.  This must be done irrespective of whether an AE has 
occurred and within 24 hours of awareness of the exposure.  The information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome 
for all EDP reports with an unknown outcome.  The investigator will follow the 
pregnancy until completion or until pregnancy termination) and notify Pfizer of the 
outcome as a follow-up to the initial EDP supplemental form.  In the case of a live birth,
the structural integrity of the neonate can be assessed at the time of birth.  In the event of 
a termination, the reason(s) for termination should be specified and, if clinically possible, 
the structural integrity of the terminated fetus should be assessed by gross visual 
inspection (unless preprocedure test findings are conclusive for a congenital anomaly and 
the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in 
a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of 
paternal exposure, the investigator will provide the study subject with the Pregnant 
Partner Release of Information Form to deliver to his partner. The investigator must 

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document in the source documents that the subject was given the Pregnant Partner 
Release of Information Form to provide to his partner.
12.2.4 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.2.5 Severity
The Investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant 
manner with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require 
therapeutic intervention.
The AE produces no sequelae.

Severe
The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern.
The AE produces sequelae, which require (prolonged) therapeutic 
intervention.
12.2.6 Causality
Causality is a determination of whether there is a reasonable possibility that an IP is 
etiologically related to/associated with the AE; generally the facts (evidence) or 
arguments to suggest a causal relationship should be provided. Causality assessment 
includes, e.g. assessment of temporal relationships, dechallenge / rechallenge 
information, association (or lack of association) with underlying disease, presence (or 
absence) of a more likely cause, and physiological plausibility. For each AE, the 
Investigator will assess the causal relationship between the IP and the AE using his/her 

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clinical expertise and judgment according to the following most appropriate algorithm for 
the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not related to the IP (i.e. does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely 
alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)v
Follows a strong temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably relatedv
Follows a reasonable temporal relationship to the administration of IP, 
including (any of the circumstances are met): 
o
Reappearance of a similar reaction upon re-administration 
(positive rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the 
IP concentrations in the blood or other bodily fluid.
12.2.7 Preexisting Diseases
Preexisting diseases that are present before entry into the study, described in the medical 
history, and that manifest with the same severity, frequency, or duration after IP 
exposure, will not be recorded as AEs. However, when there is an increase in the severity 
or duration of a preexisting disease, the event must be described on the AE or Medical 
History CRF.
                                                
v For reporting SAEs on the Serious Adverse Event Report (SAER), the categories of possibly and 
probably related are to be reported as “related.”

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12.2.8 Untoward Medical Occurrences Not Considered Adverse Events
Each untoward medical occurrence experienced before the second booster vaccination 
(e.g. from the time of signed informed consent up to but not including the second booster 
vaccination) – except for any events associated with the procedures of the current study 
(e.g. blood draw) - will not be documented, since these events will not be considered as 
AEs.
12.2.9 Assessment of Adverse Events
Each AE from the second booster vaccination until the blood draw 21 - 35 days after the 
booster vaccination will be described on the AE CRF (i.e. 1 AE per form) using the 
medical diagnosis (preferred), symptom, or sign, in standard medical terminology in 
order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.2). Each AE will be evaluated by the Investigator for:

Seriousness as defined in Section 12.2.2

Severity as defined in Section 12.2.5

Causal relationship to IP exposure as defined in Section 12.2.6
For each AE, the outcome (i.e. recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal) and action taken (i.e. 
dose increased, dose not changed, dose reduced, drug interrupted, drug withdrawn), as 
well as treatment of AE will also be recorded on the AE CRF. Recovering/resolving AEs 
will be followed until the AE has resolved or the study completion form is completed for 
the subject, whichever occurs first. Any AE(s) being followed after the subject’s last visit 
in the study (21 – 35 days after the booster vaccination) does not extend the subject’s 
study completion date.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up 
information in an expedited fashion.  This information collected for SAEs is more 
detailed than that captured on the AE CRF.  In general, this will include a description of 
the AE in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications, vaccines, and/or illnesses, must be provided.  
In the case of a subject death, a summary of available autopsy findings must be submitted 
as soon as possible to Pfizer or its designated representative.

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12.2.10 Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried 
out in accordance with applicable local regulations.
12.3 Medical, Medication, and Non-Drug Therapy History
12.3.1 Medical history
At Visit 1, the subject’s medical history will be documented including significant medical 
events (e.g., events fulfilling SAE criteria) experienced since the last study visit in Study 
700401. Medical history will be reviewed / updated at each blood draw visit and at the 
booster vaccination visit (Visit 4) with regard to significant medical events.
12.3.2 Medication and Non-Drug Therapy
All medications, including non-steroidal antirheumatic drugs, vitamins and minerals for 
therapeutic use, taken for up to 2 weeks prior to the booster vaccination until the blood 
draw 21 – 35 days after the booster will be documented in the subject’s clinic / hospital 
and study records using the guidelines set forth by the Sponsor.
The following concomitant medication will be documented in the CRF:

medication to treat fever or pain after vaccination;

medication possibly interfering with the immune response (e.g., systemic 
corticosteroids);

medication to treat SAEs;
including product name (generic name), total daily dose as well as start and end date of 
treatment.
Medication to treat SAEs will also be reported to the Sponsor on SAE reports as 
described in Section 12.2.9.
Any vaccinations given during the entire study period must be documented in the CRF.
In the context of this study, information on non-drug therapy will only be collected in 
relation to SAEs.

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12.4 Physical Examinations
At enrollment and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems being described as normal 
or abnormal: general appearance, head and neck, eyes and ears, nose and throat, chest, 
lungs, heart, abdomen, extremities and joints, lymph nodes, skin, and neurological. At the
yearly blood draw visits (as described in Section 10.3.2.1) and at the Booster Vaccination 
Visit (Visit 4) (as described in Section 10.3.2.2), if significant medical events (e.g. events 
fulfilling SAE criteria) are detected, the condition will be described on the medical 
history CRF. At the Post-booster Visit (Visit 5), if a new abnormal or worsened abnormal 
pre-existing condition is detected, the condition will be described on the AE CRF.
12.5 Clinical Laboratory Parameters
Apart from urinary pregnancy testing, no safety laboratory testing will be conducted in 
this study. 
12.5.1 Assessment of Abnormal Laboratory Values 
In the event of laboratory tests being required for any reason, the Investigator must assess 
the clinical significance of all abnormal laboratory values as defined by the compendium 
of normal values for the reference laboratory. The Investigator’s assessment of each 
abnormal laboratory value is to be recorded in the subject’s medical records. For each 
abnormal laboratory value determined between the second booster vaccination and the 
Post-booster Visit, the Investigator will assess whether the value is also considered an AE 
(see definition in Section 12.2). If yes, the sign, symptom, or medical diagnosis 
(including the abnormal laboratory value) will be recorded on the AE CRF. 
12.6 Vital Signs
Vital signs will include height (cm), weight (kg), body temperature (°C), pulse rate 
(beats/min), and systolic and diastolic blood pressure (mmHg). Weight and height will be 
measured at the yearly blood draw visits. Body temperature will be measured at the 
Booster Vaccination Visit (Visit 4) before administration of the vaccine. Blood pressure 
and pulse rate will be measured before the booster vaccination at the Booster Vaccination 
Visit (Visit 4) and at the Post-booster Visit (Visit 5), when subjects are in the sitting 
position. At the Booster Vaccination Visit (Visits 4) pulse rate will also be measured 30 
minutes after administration of IP.

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Vital sign values are to be recorded on the physical examination CRF. For each vital sign 
value, the Investigator will determine whether the value is considered an AE (see 
definition in Section 12.2). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE CRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the Investigator.
12.7 Responsibilities of the DMC
An independent DMC will be utilized for this study. The DMC will consist of 3 
individuals who will be selected based upon their knowledge in clinical medicine and 
their expertise and understanding of TBE vaccines, clinical research and/or skills. A 
meeting of the DMC may be called at the discretion of the Sponsor, e.g., to address any 
safety concerns arising during the conduct of the study.
12.7.1 Responsibilities of the DMC

Upon Sponsor’s request, provides independent monitoring of safety issues, which 
means it reviews and evaluates all SAE reports and study discontinuations for: (i) 
increases in frequency of SAEs and study discontinuations within the study; and 
(ii) increases in frequency of SAEs and study discontinuations across studies with 
the same preparation; and (iii) SAEs in the study sample compared with the 
population based on what is known from the literature;

Reviews data produced from the study upon the Sponsor’s request to determine 
whether the conditions on which study design is based have remained the same or 
have changed. If changed, the DMC will determine whether or not the changes 
mandate changes to the protocol and suggest a protocol amendment;

Upon the Sponsor’s request, meets for discussion and gives recommendations to 
the Sponsor as to whether the study should progress unchanged, or the study 
requires changes, or the study should be terminated prematurely. Pfizer will 
forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints, to regulatory authorities, 
as appropriate;

Can propose an unplanned safety analysis of clinical trial data.

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13. STATISTICS
The immunogenicity analysis of the ELISA and NT results obtained 38, 46, 58, 70, 82, 
94, 106 and 118 months after the first booster vaccination may be carried out separately 
as soon as the relevant data become available. A final clinical study report including all 
data will be prepared after completion of the study.
13.1 Sample Size and Power Calculations
A total of 202 subjects who were administered the first booster vaccination in Study 
700401 at 3 or 4 years after the third vaccination in Study 209 will be invited to 
participate in this study. Of these, approximately 175 study participants are expected to 
return and to provide information on antibody persistence after the first booster 
vaccination with either FSME-IMMUN 0.25 ml Junior or FSME-IMMUN 0.5 ml. With 
this sample size, the 95% confidence interval of the seropositivity rate will extend no 
more than 5.8% from the observed rate assuming the observed rate lies in the region of 
90%.
13.2 Datasets and Analysis Cohorts
Per-protocol dataset: Subjects will be included in the “per protocol” dataset if they
fulfill inclusion/exclusion criteria
have no major protocol violations
have available serology data
Modified intent to treat dataset: Subjects will be included in the modified “intent to treat” 
analysis if they 
have available serology data
13.3 Handling of Missing, Unused, and Spurious Data
Only subjects with available data will be included in the statistical analysis. Missing 
values for antibody titer at 38 and 46 months will neither be replaced nor estimated. Any 
missing values at later time points (i.e. 58, 70, 82, 94, 106 and 118 months) will be 
estimated if at least three data points are available, assuming an exponential decline in 
antibody titers in time.

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13.4 Methods of Analysis
13.4.1 Primary Endpoint
Point estimates and 95% confidence intervals for the seropositivity rate at each time point 
when blood is drawn (from approximately 38 months to 118 months after the booster 
vaccination in Study 700401, and separately after the booster vaccination) in this study as 
measured by NT (according to Adner et al., 2001) 1 will be calculated. 
The dependence of seropositivity of study participants on demographic factors (age, 
weight, gender) at yearly intervals from approximately 3 years (38 months) to 10 years 
(118 months) after the first booster vaccination will be analyzed by logistic regression at 
the end of the study period.
13.4.2 Secondary Endpoints
The antibody titers as measured by NT (according to Adner et al., 2001) 1 and ELISA at 
yearly intervals from approximately 3 years (38 months) to 10 years (118 months) after 
the first booster will be used to determine the annual decline rate.
The analysis of immunogenicity before the second booster vaccination will be carried out 
separately in the three age classes defined previously in Study 209. Subjects will remain 
in the same age class as they were assigned to at the beginning of Study 209 (1 - 2 years, 
3 – 6 years, 7 – 15 years). For the analysis of immunogenicity and safety after the booster 
vaccination the oldest age class will be further divided into those who received FSME-
IMMUN 0.25 ml Junior and those who received FSME-IMMUN 0.5 ml.
The occurrence of fever and the 95% confidence interval of the probability of occurrence 
will be given. The fever rate after the second booster vaccination will be categorized by 
severity grade.
Local and systemic reaction rates, other than fever, after the booster vaccination will be 
provided in tabular format, and the probabilities of the occurrence of the adverse event 
rates and their 95% confidence intervals will be calculated.
For each symptom queried in the Subject Diary, the number of subjects who experienced 
the symptom, as well as the probabilities of the occurrence and the 95% confidence 
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All AEs reported for each subject, including the same event at different time points, will 
be listed according to Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
13.4.3 Exploratory Endpoints 
Not applicable.
 
 
 
 
 
 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The Investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the Sponsor or Sponsor’s representatives, review by the EC, and inspections by 
applicable regulatory authorities, as described in the Clinical Study Agreement. If 
contacted by an applicable regulatory authority, the Investigator will notify the Sponsor
of contact, cooperate with the authority, provide the Sponsor with copies of all 
documents received from the authority, and allow the Sponsor to comment on any 
responses, as described in the Clinical Study Agreement.
15. QUALITY CONTROL AND QUALITY ASSURANCE
This study will be conducted in accordance with this protocol, the ICH Guideline for 
Good Clinical Practice and the European Clinical Trial Directive.
The following quality control and quality assurance measures will be taken to ensure the 
adherence to GCP and applicable regulatory requirements as well as the accuracy and 
integrity of data obtained from the study:

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The Sponsor will select investigators on the basis of their expertise in the field of 
vaccinology and the study site’s ability to conduct a research study of this nature, 
given the subject load of the institution;
Training for study personnel at the sites as well as for monitors will be provided 
(for more details please refer to Section 15.2);
Co-monitoring visits will be performed by the Sponsor (at intervals described in 
the Monitoring Plan). During co-monitoring visits, the Sponsor will check the 
CRO’s monitoring performance as well as the compliance and working 
procedures of the study site;

In order to assure integrity and accuracy of study data, selected study sites will be 
audited by the Sponsor to review subject files and CRFs for consistency and other 
documentation for compliance with relevant regulations. Discrepancies will be 
addressed and appropriate corrective action will be implemented;

The Sponsor will provide the Investigator with a copy of the insurance liability 
certificate;

External service providers will be qualified according to the Sponsor’s Standard 
Operating Procedures (SOPs).
15.1 Investigator’s Responsibility
The Investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The Investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the Sponsor. The term “Investigator” as used in this protocol and in study 
documents, refers to the investigator or authorized study personnel that the investigator 
has designated to perform certain duties. Sub-investigators or other authorized study 
personnel are eligible to sign for the Investigator, except where the Investigator’s 
signature is specifically required. 
15.1.1 Investigator Report and Final Clinical Study Report 
The Investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
A summary report by the Investigator must be submitted to the EC and the Sponsor
within 30 days after study completion or termination, where required.

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15.2 Training
The study monitor will ensure that the Investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. 
Training for study personnel at the sites as well as for monitors will be provided on the 
correct handling and use of the CRF. Furthermore, monitors will be trained on the 
Sponsor’s SOPs, as applicable. In addition, investigators will also be trained on GCP and 
Good Documentation Practice (GDP) relevant issues (e.g., via Investigator Meetings).
Training may be provided at an investigator’s meeting, at the study site, and/or by 
instruction manuals. In addition, the study monitor will be available for consultation with 
the Investigator and will serve as the liaison between the study site and the Sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The Investigator will permit the study monitor or other authorized representatives to visit 
the study site at appropriate intervals to observe the progress of the study, review study 
records/documentation, and ensure that informed consent has been obtained, as described 
in the Clinical Study Agreement. Monitoring processes specific to the study will be 
described in the clinical monitoring plan. 
15.4 Auditing
The Sponsor and/or Sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The Investigator will permit auditors to visit the study site, as described in the Clinical 
Study Agreement. Auditing processes specific to the study will be described in the 
auditing plan.
15.5 Non-Compliance with the Protocol
The Investigator may deviate from the protocol to eliminate an apparent immediate 
hazard to the subject or when the change(s) involve(s) only logistical or administrative 

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aspects of the study (e.g., change of study monitor, change of phone number). In the 
event(s) of an apparent immediate hazard to the subject, the Investigator will notify the 
Sponsor immediately by phone and confirm notification to the Sponsor in writing as soon 
as possible, but within 5 working days after the change is implemented. The Investigator
will also notify the EC of the emergency change.
If monitoring and / or auditing identify serious and / or persistent non-compliance with 
the protocol, the Sponsor may terminate the Investigator’s participation. The Sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
Not applicable, a central laboratory will be used for all immunological assessments.

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16. ETHICS
16.1 Subject Privacy
The Investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of healthy volunteers into this study, the protocol, informed consent 
form, any promotional material/advertisements (as applicable per local EC and regulatory 
authorities), and any other written information to be provided will be reviewed and 
approved/given favorable opinion by the EC and applicable regulatory authorities. The IB 
and SmPC will be provided for review. The EC’s composition or a statement that the 
EC’s composition meets applicable regulatory criteria will be documented. The study will 
commence only upon the Sponsor’s receipt of approval/favorable opinion from the EC 
and, if required, upon the Sponsor’s notification of applicable regulatory authority(ies) 
approval, as described in the Clinical Study Agreement. 
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the Sponsor’s receipt of approval and, if required, upon the Sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose healthy volunteers for enrollment considering the study 
eligibility criteria. The Investigator will exercise no selectivity so that no bias is 
introduced from this source. 
All healthy volunteers and/or their parent(s) / legally authorized representative must sign 
an informed consent form before entering into the study according to applicable 
regulatory requirements and ICH GCP. An assent form will be provided and should be 
signed by healthy volunteers less than 18 years of age. Before use, the informed consent 
form will be reviewed by the Sponsor and approved by the EC and regulatory 
authority(ies), where applicable (see Section 16.2). The informed consent form will 
include a comprehensive explanation of the proposed treatment without any exculpatory 
statements, in accordance with the elements required by ICH GCP and applicable 

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regulatory requirements. Healthy volunteers and/or their parent(s) / legally authorized 
representative(s) will be allowed sufficient time to consider participation in the study. By 
signing the informed consent form, healthy volunteers and/or their parent(s) / legally 
authorized representative(s) agree that they will complete all evaluations required by the 
study, unless they withdraw voluntarily or are terminated from the study for any reason.
The Sponsor will provide to the Investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, that have been approved by the applicable EC and regulatory authorities, 
where applicable, will be provided by the Investigator to the subjects who consented to 
participate in the study (see Section 16.3 above).
16.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes 
aware of.

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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The Investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documents and Case Report Forms
The Investigator will maintain complete and accurate study documentation in a separate 
file. Documentation may include medical records, records detailing the progress of the 
study for each subject, signed informed consent forms, drug disposition records, 
correspondence with the EC and the study monitor / Sponsor, enrollment information, 
CRFs, SAERs, laboratory reports (if applicable), and data clarifications requested by the 
Sponsor. 
The Investigator will comply with the procedures for data recording and reporting. Any 
corrections to study documentation must be performed as follows: 1) the first entry will 
be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
17.2.1 Case Report Forms
The Investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in paper form. 
Since paper format CRFs are provided by the Sponsor, all required study data, including 
corrections, will be clearly and accurately recorded by authorized study site personnel on 
the CRFs. CRFs will be completed legibly using indelible ink; the use of correction fluid 
and erasing are prohibited. The CRFs will remain at the site until they are reviewed by 
the study monitor or Sponsor’s representative. All original CRFs will be collected by the 
study monitor, and an identical copy of the complete set of CRFs for each subject will 
remain in the Investigator file at the study site in accordance with the document and data 
retention policy (see Section 17.2 above).
The handling of data by the Sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g. ICH GCP) and the standard operating procedures of the 
Sponsor. Data management and control processes specific to the study will be described 
in the data management plan.

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17.2.2 Investigator File
The Investigator ensures that all documents pertaining to the study are filed in a separate 
Investigator file provided by the Sponsor or by authorized representative(s) of the 
Sponsor. These documents include the clinical protocol as well as any amendments, all 
documentation, the agreement(s) between the Sponsor and the Investigator, and all other 
documents related to this study. Also included are all documents regarding the coded 
assignment to the different treatment schemes, if applicable.
17.3 Document and Data Retention 
The Investigator will retain study documentation and data (paper forms) in accordance 
with applicable regulatory requirements and the document and data retention policy, as 
described in the Clinical Study Agreement.
18. FINANCING AND INSURANCE
The Investigator will comply with Investigator financing, Investigator / Sponsor
insurance, and subject compensation policies, if applicable, as described in the Clinical 
Study Agreement.
19. PUBLICATION POLICY
The Investigator will comply with the publication policy as described in the Clinical 
Study Agreement.

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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 20.1-1
Study Design for Pfizer Clinical Study B9371021 (Formerly Baxter 700802)

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Figure 20.1-2
Study Design for Pfizer Clinical Study B9371021 (Formerly Baxter 700802)

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20.2 Schedule of Study Procedures and Assessments
Table 20.2-1
Schedule of Study Procedures and Assessments
Procedure/
Assessment
Visit 1 a
Month 38
(60 days)
Visit 2 b
Month 46
(30 days)
Visit 3 b
Month 58
(30 days)
Visit 4 
Month 40 (60 days) c or 
Month 48 (30 days) or
Month 60 (30 days)
Visit 5
21-35 days after 
Visit 4
Informed consent
X
Inclusion/exclusion criteria
X
X (review)
X (review)
X (review)
Demographic data
X
Medical history e
X
X
X
X
History of tick bites
X
X
X
X
Vital signs including:
       Weight
X
X
X
       Height
X
X
X
       Body temperature 
X
       Pulse 
X
X
       Blood pressure
X
X
Physical examination 
X
X
X
X
X
Pregnancy test f
X
Blood draw 5 ml
X
X
X
X
Eligibility for vaccination
X
Delay criteria for vaccination
X
Vaccination d
X
Subject Diary 
Distribute
Collect / Review
AE Assessment
X g
X g
X g
X h
X

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Table 20.2-1
Schedule of Study Procedures and Assessments
Procedure/
Assessment
Visit 6 b
Month 70
(30 days)
Visit 7 b
Month 82
(30 days)
Visit 8 b
Month 94
(30 days)
Visit 9 b
Month 106
(30 days)
Visit 10 b
Month 118
(30 days)
Visit 4 
Month 72, 84, 96, 108 
or 120 (30 days)
Visit 5
21-35 days after 
Visit 4
Informed consent
Inclusion/exclusion 
criteria
X (review)
X (review)
X (review)
X (review)
X (review)
X (review)
Demographic data
Medical history e
X
X
X
X
X
X
History of tick bites
X
X
X
X
X
X
Vital signs including:
       Weight
X
X
X
X
X
       Height
X
X
X
X
X
       Body temperature 
X
       Pulse 
X
X
       Blood pressure
X
X
Physical examination 
X
X
X
X
X
X
X
Pregnancy test f
X
Blood draw 5 ml
X
X
X
X
X
X
Eligibility for 
vaccination
X
Delay criteria for 
vaccination
X
Vaccination d
X
Subject Diary 
Distribute
Collect / Review
AE Assessment
X g
X g
X g
X g
X g
X h
X

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Table 20.2-1
Schedule of Study Procedures and Assessments
a
All subjects who were administered the first booster vaccination in Study 700401 will be invited for this visit.
b
Visit 2 and Visit 3, and Visit 6 to Visit 10 are applicable for those subjects who did not yet receive the second booster vaccination.
c
For subjects who received their first booster in Study 700401 at 3 years after the third vaccination and were considered as not protected against TBE 
after Visit 1 in this study, Visit 4 will be performed at 40 months ± 60 days. If a subject who was administered the first booster vaccination at the 4 year 
time point in Study 700401 is considered as not protected against TBE after Visit 1 in this study, he/she will proceed to the Booster Visit (Visit 4) at 
36 months ± 60 days.
d
Timing of the booster vaccine will depend on individual TBE antibody levels. Subjects with relatively low TBE serum antibody levels at the preceding 
visit (NT titer ≤20 and / or ELISA value ≤126 VIE U/ml) may not be considered protected against TBE for an entire further tick season and should 
therefore be scheduled to receive the booster vaccination .
e
Medical history with particular focus on significant medical events (e.g. events fulfilling SAE criteria) experienced in the time period from the last 
study visit in Study 700401 until Visit 1 in this study, between the yearly blood draw visits, or between the blood draw visit and the Booster 
Vaccination Visit (Visit 4), as applicable.
f
Pregnancy test (urine) will be done in all female subjects capable of bearing children (documentation of first menstruation in medical history).
g
AE documentation only in association with study procedures.
h
Any injection site reactions and systemic AEs will be recorded.

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20.3 Grading of Adverse Experiences – Vaccine Specific Criteria
Table 20.3-1
Grading of Adverse Events – Vaccine Specific Criteria
Expedited Report not mandatory
EXPEDITED 
REPORT 
MANDATORY
Non-Serious
Serious
Vaccine-specific 
Criteria
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Fever *
38.0 – 39.0 °C
> 39.0 – 40.0 °C
> 40.0 °C
persistent fever 
> 40.0 °C over 5 
days
Redness, 
induration or 
swelling 
(diameter):
1.0 – 2.5 cm
> 2.5 - 5.0 cm
> 5.0 cm
ulceration or 
superinfection or 
phlebitis 
skin necrosis
Pain or tension
mild, no 
impairment of arm
movement
moderate, 
impairment of arm 
movement
severe impairment, 
arm not functioning
*as defined in the Common Toxicity Criteria (CTC), Version 3.0, published on December 12, 2003.39

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31. Spork, D., Pansl, H., Kraigher, A., Mutz, L., Cizman, M., and Zenz, W. 
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36. European Parliament and of the Council of the European Union. Direct 
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pdf

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INVESTIGATOR ACKNOWLEDGEMENT
FSME-IMMUN 0.25 ml Junior and
FSME-IMMUN 0.5 ml
OPEN-LABEL PHASE IV STUDY TO INVESTIGATE THE
SEROPERSISTENCE OF TICK-BORNE ENCEPHALITIS (TBE) VIRUS
ANTIBODIES AFTER THE FIRST BOOSTER AND THE RESPONSE TO A
SECOND BOOSTER VACCINATION WITH FSME-IMMUN IN CHILDREN,
ADOLESCENTS AND YOUNG ADULTS
(FOLLOW UP TO STUDY 700401)
PROTOCOL NUMBER: B9371021 (Formerly Baxter 700802)
AMENDMENT 4: 25 JUN 2015 (including non-substantial changes upon 
sponsorship change)
Replaces Amendment 3: 07 SEP 2011
EUDRACT NUMBER: 2009-009324-36
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
Date