Phase 2 Clinical Trial of the BioMed rTSST-1 Variant Vaccine in Healthy Adults
Phase: PHASE2
Conditions: Toxic Shock Syndrome
Sponsor: Biomedizinische Forschungs gmbH

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 1 of 47 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Study Name: 
 
Phase 2 Clinical Trial of the BioMed rTSST-1 Variant Vaccine in Healthy Adults 
 
 
Study identifying number: 
 
BioMed 0515 
 
 
 
Version 1.6 /   March 20, 2020 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the 
sponsor of this study. It is therefore provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an Independent Ethics Committee or 
Institutional Review Board. It is understood that this information will not be disclosed to others 
without written authorization from  Biomedizinische Forschung und Bio-Produkte AG, except to the 
extent necessary to obtain informed consent from those persons to whom the study test or 
reference preparation may be administered. 
 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 2 of 47 
 
 
 
 
 
 
 
 
Test drug (IMP) and  
Pharmaceutical Company  
rTSST-1 Variant Vaccine  
Biomedizinische Forschung und Bio-Produkte AG Lazarettgasse 19, 1090 
Vienna Austria 
Protocol authors 
Prof. Martha Eibl, MD 
Investigator 
Prof. Bernd Jilma, MD 
Clinical Pharmacology 
University of Vienna Medical School 
Währinger Gürtel 18-20 
1090 Vienna 
Document type 
Clinical study protocol 
Study phase 
2 
Document status 
Version 1.6 
Date 
  March 20, 2020 
Number of pages 
47  

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
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1. 
SPONSOR, INVESTIGATOR, MONITOR AND SIGNATURES 
 
Sponsor/or representative  (AMG §§ 2a, 31,32) 
 
Biomedizinische Forschung und Bio-Produkte AG 
Lazarettgasse 19 
1090 Vienna 
represented by Prof. Martha Eibl, MD 
 
________________ 
 
___________ 
Signature  
 
 
Date 
 
 
Investigator (AMG §§ 2a, 35,36) 
 
 
Prof. Bernd Jilma, MD 
Clinical Pharmacology 
University of Vienna Medical School 
Währinger Gürtel 18 - 20 
1090 Vienna 
 
 
_________________ 
 
___________ 
Signature 
 
 
Date 
 
 
Monitor/ or Representative of CRO (AMG §§ 2a, 33,34) 
 
 
Ines Mader, MD 
Creta - cancer research & trial agency GmbH 
Hauptstrasse (Langeck) 6 
7442 Langeck im Burgenland 
 
____________________              _____________ 
Signature 
 
 
  Date 
 
 
 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
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Clinical Trial Center: 
Clinical Pharmacology 
University of Vienna Medical School 
Währinger Gürtel 18 - 20 
1090 Vienna 
 
 
Associated Departments 
 
Clinical Institute of Medical and  
Chemical Laboratory Diagnostics 
Head: Prof. Oswald Wagner, MD 
Währinger Gürtel 18 - 20 
1090 Vienna 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 5 of 47 
 
2. 
PROTOCOL SYNOPSIS 
TITLE 
Phase 2 Clinical Trial of the BioMed r-TSST-1 Variant Vaccine in Healthy 
Adults 
OBJECTIVES 
Primary Objective 
To demonstrate the safety and tolerability of two doses of the BioMed 
rTSST-1 Variant Vaccine after one to three vaccinations in healthy 
adults. 
 
Secondary Objectives 
  
Secondary objectives of the study are to assess the immunogenicity 
and persistence of   TSST-1 binding and neutralizing antibodies after 
one, two, and three immunizations with two doses of the vaccine in 
healthy adults over a period of 12-14 or optionally 27-29 months. 
 
 
DESIGN / PHASE 
Prospective, single center, randomized, parallel group, double-blind, 
adjuvant controlled, phase 2 study. 
STUDY PLANNED DURATION First subject 
First visit 
Q1 
 2016 
Last subject 
First visit 
Q1 
  2018 
Last subject 
Last visit 
Q3 
 2020 
CENTER(S) 
/ COUNTRY(IES)  
One 
Austria 
SUBJECTS / GROUPS 
Each subject of a total of seven groups will receive three injections 
(first injection day 0; second injection 3 months ± 4 weeks after the 
first, third injection 6 months ± 4 weeks after the second) of one of two 
different doses of Vaccine or Adjuvant, each group comprising 20 
subjects, as shown below:  
 
Group 
Sample 
Size 
Vaccine 
Strength 
Number of 
Immunizati
ons 
Adjuvant 
Al(OH)3 
Number of 
Immunizations 
1 
20 
10 µg 
1 
1 mg 
2 
2 
20 
10 µg 
2 
1 mg 
1 
3 
20 
10 µg 
3 
1 mg 
0 
4 
20 
100 µg 
1 
1 mg 
2 
5 
20 
100 µg 
2 
1 mg 
1 
6 
20 
100 µg 
3 
1 mg 
0 
7 
20 
--- 
--- 
1 mg 
3 
 
Subjects will be controlled 24 h post vaccination. Follow-up will last 3 
or optionally 18 months on the average, with visits every three months 
(± 2 weeks). 
 
Response to treatment is defined by seroconversion from a TSST-1 
binding Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 binding 
Ab titer.  
SCREENING 
Over a period of  sixty days prior to first vaccination, subjects will be 
screened for eligibility using the criteria below, plus HIV Ab,  HCV Ab,  
HBs Ag, and binding and neutralizing TSST-1 Ab. 
INCLUSION CRITERIA 
 
males or females aged 18-64 years 

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EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
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 
signed informed consent 
 
physical exam: no abnormal findings unless considered irrelevant 
by the investigator 
 
 uneventful medical history 
 
Females with childbearing potential: adequate contraception 
EXCLUSION CRITERIA 
 
females with childbearing potential: pregnancy, lactation or 
unreliable contraception 
 
positive HIV Ab and/or positive HCV Ab and/or positive HBsAG 
 
signs and symptoms of  autoimmunity 
 
TSST-1  Ab titer >  1:1000 
 
current or recent (< 1 month) immunosuppressive therapy with 
corticosteroids or immunomodulators 
STUDY PERIODS 
 Screening:                    60 days 
 Immunization:             9 months (± 8 weeks) 
 Follow-up:                   3 months (± 2 weeks) or optionally  18 months   
(± 2 weeks) 
 Total:                            12 – 14 months or optionally –27-29 months 
INVESTIGATIONAL DRUG 
rTSST-1 variant vaccine  
10 µg  and 100 µg 
 
 
COMPARATIVE DRUG 
/CONTROL CONDITION 
Al(0H)3 
CONCOMITANT 
MEDICATION 
No concomitant medication allowed that would interfere with the 
assessment of trial specific results as assessed by the investigator. 
TOLERABILITY / SAFETY 
(PRIMARY) ENDPOINTS  
Adverse events 
Abnormal laboratory findings 
Local reactions 
EFFICACY ENDPOINTS 
 TSST-1binding and neutralizing Ab  
Persistence of TSST-1 binding and neutralizing Ab  
EXPLORATORY ENDPOINTS 
  
 2nd test of neutralizing Ab  
PARAMETERS 
Vital Signs:                      BP, PR, body temperature 
Hematology:                   RBC 
                                          WBC 
                                          Leukocyte differential count (absolute 
values of neutrophils, basophils, eosinophils,  
monocytes, and lymphocytes) 
                                           Platelet count 
                                           Hemoglobin 
                                           Hematocrit 
 
Clinical Chemistry:         ALT 
                                           BUN 
                                           Creatinine 
                                           Glucose 
                                           Total protein 
C-Reactive Protein 
TSST-1 Ab (binding and neutralizing) 
Local Reactions 
Adverse Events 
 

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Tests to be performed prior and 24 h (+ 3 h) after each vaccination, and 
every three months (± 2 weeks) during the follow-up period. In the 
case of abnormal findings, the respective tests will be repeated in 
between. 
TSST-1 Ab tests will be performed prior to each vaccination and at the  
three-month follow-up visits . 
 
STATISTICS 
Primary Endpoints:  
Descriptive 
 
Other Endpoints: 
Antibody titers will be analyzed by one-way or repeated measures 
ANOVA. Subjects with antibody titers of 200 to 1000 at entry will be 
stratified.  Mann-Whitney-U and Wilcoxon signed rank tests will be 
used post hoc for comparison among groups and Ab persistence, 
respectively, to determine statistical significance. 
 
A statistical difference, if any, in the rate of Ab response among 
treatment groups and between treatment and control groups will be 
tested by Chi square statistics. 
 
 
3. 
LIST OF ABBREVATIONS 
 
 
  Ab 
 
 
 
 
antibody 
 
  Ag 
 
 
 
 
antigen 
 
  AE 
 
 
 
 
adverse event 
 
  AGES  
 
 
 
Österreichische Agentur für Gesundheit und  
 
 
 
 
 
 
Ernährungssicherheit GmbH 
 
  AMG  
 
 
 
Arzneimittelgesetz 
 
  ALT 
 
 
 
 
alanine aminotransferase 
 
   BASG  
 
 
 
Bundesamt für Sicherheit im Gesundheitswesen 
BP 
 
 
 
 
blood pressure 
BUN  
 
 
 
blood urea nitrogen 
b.w.  
 
 
 
body weight 
C 
 
 
 
 
centigrade, Celsius 
CA 
 
 
 
 
competent authority 
CBC  
 
 
 
complete blood count 
CRF 
 
 
 
 
case report form 
CSR 
 
 
 
 
clinical study report 
DOH  
 
 
 
Declaration of Helsinki 
d 
 
 
 
 
day 
EC 
 
 
 
 
Ethics Committee 
ECG  
 
 
 
electrocardiogram 
ELISA                                                            enzyme-linked immunosorbent assay 
EOS  
 
 
 
End of Study 
EudraCT 
 
 
 
European Clinical Trial Database 
GCP  
 
 
 
Good Clinical Practice 

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h  
 
 
 
 
hour (s) 
HBsAg 
 
 
 
hepatitis B virus surface antigen 
HCV  
 
 
 
hepatitis C virus 
HIV 
 
 
 
 
human immune deficiency virus 
IB 
 
 
 
 
Investigator's Brochure 
IEC 
 
 
 
 
Institutional Ethics Committee 
ICH 
 
 
 
 
International Conference on Harmonization 
ID 
 
 
 
 
identification 
IgG 
 
 
 
 
immunoglobulin G 
i.m. 
 
 
 
 
intramuscular(ly) 
IMP  
 
 
 
Investigational Medicinal Product 
IRB 
 
 
 
 
Institutional Review Board 
kg   
 
 
 
 
kilogram 
LLT 
 
 
 
 
lower level term 
n.a. 
 
 
 
 
not applicable 
ng 
 
 
 
 
nanogram 
µg 
 
 
 
 
microgram 
mg 
 
 
 
 
milligram 
MedRA 
 
 
 
Medical Dictionary for Regulatory Activities 
MHC  
 
 
 
major histocompatibility complex 
min 
 
 
 
  
minute (s) 
ml 
 
 
 
 
milliliter 
MNC  
 
 
 
mononuclear cells 
n.a.   
 
 
 
not applicable 
neg 
 
 
 
 
negative 
PBS 
 
 
 
 
phosphate buffered saline 
PI 
 
 
 
 
principal investigator 
PR 
 
 
 
 
pulse rate 
RBC  
 
 
 
red blood count 
RT 
 
 
 
 
room temperature 
rTSST-1 
 
 
 
recombinant TSST-1 
SAE 
 
 
 
 
serious adverse event 
S.aureus 
 
 
 
Staphylococcus aureus 
SmPC  
 
 
 
Summary of Product Characteristics 
SOP  
 
 
 
Standard Operating Procedure 
SUSAR 
 
 
 
suspected unexpected serious reaction 
TCR  
 
 
 
T cell receptor 
TSS 
 
 
 
 
toxic shock syndrome 
TSST-1 
 
 
 
toxic shock syndrome toxin –1  
Vβ chain 
 
 
 
Variable beta chain 
WBC  
 
 
 
white blood count 
WMA  
 
 
 
World Medical Association 
 
 
 
 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
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4. 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL 
1 
1. 
SPONSOR, INVESTIGATOR, MONITOR AND SIGNATURES 
3 
2. 
PROTOCOL SYNOPSIS 
5 
3. 
LIST OF ABBREVATIONS 
7 
4. 
TABLE OF CONTENTS 
9 
TABLE 1.  DOSES AND SAMPLE SIZES 
12 
5. 
BACKGROUND INFORMATION 
14 
5.1 BACKGROUND 
14 
5.2 STUDY RATIONALE 
17 
6. 
STUDY OBJECTIVES (HYPOTHESIS) 
17 
6.1 PRIMARY OBJECTIVE 
17 
6.2 SECONDARY OBJECTIVES (HYPOTHESIS) 
17 
7. 
STUDY DESIGN 
17 
7.1 STUDY POPULATION 
18 
7.1.1 STUDY POPULATION 
18 
7.1.2 INCLUSION CRITERIA 
18 
7.1.3 EXCLUSION CRITERIA 
18 
7.1.4 FEMALES WITH CHILDBEARING POTENTIAL 
19 
7.1.5 STUDY DURATION 
19 
7.1.6 WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
19 
7.1.7 PREMATURE TERMINATION OF THE STUDY 
20 
8. 
METHODOLOGY 
20 
8.1 STUDY MEDICATION 
20 
8.1.1 DOSAGE AND ADMINISTRATION 
22 
8.1.2 STUDY-DRUG UP- AND DOWN TITRATION 
22 
8.1.3 STUDY DRUG INTERRUPTION OR DISCONTINUATION 
23 
8.1.4 STUDY DRUG INTERRUPTION 
23 
8.1.5 STUDY DRUG PREMATURE PERMANENT DISCONTINUATION 
23 

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8.1.6 STUDY DRUG DELIVERY & DRUG STORAGE CONDITIONS 
23 
8.1.7 STUDY DRUG PACKAGING AND LABELING 
24 
8.1.8 IMP ADMINISTRATION & HANDLING 
24 
8.1.9 DRUG ACCOUNTABILITY 
24 
8.1.10 PROCEDURES TO ASSESS SUBJECTS COMPLIANCE 
24 
8.1.11 CONCOMITANT MEDICATION 
24 
8.2 RANDOMIZATION  
24 
8.3 BLINDING 
25 
8.3.1 EMERGENCY PROCEDURE FOR UNBLINDING 
25 
8.3.2 UNBLINDING AT THE END OF THE STUDY. 
26 
8.4 BENEFIT AND RISK ASSESSMENT 
26 
8.5 STUDY PROCEDURES 
26 
8.5.1 GENERAL RULES FOR TRIAL PROCEDURES 
26 
8.5.2 SCREENING INVESTIGATION 
26 
8.5.3 LABORATORY TESTS 
27 
8.5.4 OTHER TESTS 
28 
8.5.5 ENDPOINTS 
28 
9. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
29 
9.1 AVERSE EVENTS (AES) 
29 
9.1.1 SUMMARY OF KNOWN AND POTENTIAL RISKS OF THE STUDY DRUG 
29 
9.1.2 DEFINITION OF ADVERSE EVENTS 
29 
9.2 SERIOUS ADVERSE EVENTS (SAES) 
29 
9.2.1 HOSPITALIZATION – PROLONGATION OF EXISTING HOSPITALIZATION 
29 
9.2.2 SAES RELATED TO STUDY-MANDATED PROCEDURES 
30 
9.2.3 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
30 
9.2.4 PREGNANCY 
30 
9.3 SEVERITY OF ADVERSE EVENTS 
30 
9.4 RELATIONSHIP TO STUDY DRUG 
31 
9.5 REPORTING PROCEDURES 
32 
9.5.1 REPORTING PROCEDURES FOR SAES 
32 
9.5.2 REPORTING PROCEDURES FOR SUSARS 
33 
9.5.3 ANNUAL SAFETY REPORT 
34 
10. FOLLOW-UP 
34 
10.1 FOLLOW-UP OF STUDY PARTICIPANTS INCLUDING FOLLOW-UP OF ADVERSE EVENTS 
34 
10.2 TREATMENT AFTER END OF STUDY 
34 
11. STATISTICAL METHODOLOGY AND ANALYSIS 
34 
11.1 ANALYSIS SETS 
34 
11.2 SAMPLE SIZE CONSIDERATIONS 
34 

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11.3 RELEVANT PROTOCOL DEVIATIONS 
35 
11.4 STATISTICAL ANALYSIS PLAN 
35 
11.5 MISSING, UNUSED AND SPURIOUS DATA 
35 
11.6 ENDPOINTS ANALYSES 
35 
11.6.1 PRIMARY ENDPOINT ANALYSIS 
35 
11.6.2 SECONDARY ENDPOINT ANALYSIS 
35 
11.6.3 EXPLORATORY ENDPOINT 
35 
11.6.4 BASELINE PARAMETERS AND CONCOMITANT MEDICATIONS 
36 
11.7 INTERIM ANALYSIS 
36 
11.8 SOFTWARE PROGRAM(S) 
36 
12. DOCUMENTATION AND DATA MANAGEMENT 
36 
12.1 STUDY DOCUMENTS AND CASE REPORT FORMS 
36 
12.1.1 CASE REPORT FORM (CRF) 
36 
12.2 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
37 
12.3 RETENTION OF CLINICAL TRIAL DOCUMENTATION 
37 
12.4 QUALITY CONTROL AND QUALITY ASSURANCE 
37 
12.4.1 PERIODIC MONITORING 
37 
12.4.2 UNBLINDED MONITORING AND IMP HANDLING 
38 
12.4.3 AUDIT AND INSPECTIONS 
38 
12.5 REPORTING AND PUBLICATION 
38 
12.5.1 PUBLICATION OF STUDY RESULTS 
38 
13. ETHICAL AND LEGAL ASPECTS 
39 
13.1 INFORMED CONSENT OF SUBJECTS 
39 
13.2 ACKNOWLEDGEMENT / APPROVAL OF THE STUDY 
39 
13.2.1 CHANGES IN THE CONDUCT OF THE STUDY 
39 
13.3 INSURANCE 
40 
13.4 CONFIDENTIALITY 
40 
13.5 ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
40 
14. REFERENCES 
41 
15. APPENDICES 
43 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
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TABLE 1.  DOSES AND SAMPLE SIZES 
 
GROUPS: 
TREATMENT : 
CONTROL : 
 
DOSES 
Adjuvanted 
rTSST-1 Variant 
Vaccine 
containing 
antigen below 
VOLUME 
Number of 
Administrations 
Adjuvant  containing 
Al(0H)3 
as shown below 
VOLUME 
Number of 
Administrations 
1 
10 µg  
0.5 ml 
1 
1.0 mg 
0.5 ml 
2 
2 
10 µg 
0.5 ml 
2 
1.0 mg 
0.5 ml 
1 
3 
10 µg  
0.5 ml 
3 
1.0 mg  
0.5 ml 
--- 
4 
100 µg 
0.5 ml 
1 
1.0 mg 
0.5 ml 
2 
5 
100 µg 
0.5 ml 
2 
1.0 mg 
0.5 ml 
1 
6 
100µg 
0.5 ml 
3 
1.0 mg 
0.5 ml 
--- 
7 
--- 
-- 
-- 
1.0 mg 
0.5 ml 
3 
 
Sample Size is 20 in each Group 
  
 
 
 
 
 
 
 

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TABLE 2 . VISIT AND ASSESSMENT SCHEDULE FOR Groups 1 - 7 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
 
Duration 
 
9 months (± 8 weeks) 
18 months (± 2 weeks) 
VISITS 
Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9* 
10* 
11* 
12* 
13* 
 
Name 
Screening 
Randomization / 
Immunization  
 1 
Control  
1 
Immun 
 2 
Control 
2 
Immun 
3 
Control 
3 
Fup 1 
Fup 2* 
Fup 3* 
Fup 4* 
Fup 5* 
Fup 6* 
 
 
Time 
- 60 days to 
Day 0 
Day 0 
 
Day 1 
(24 h post 
Imm 1) 
Mo° 
 3** 
24 h 
post 
Imm 2 
Mo°° 
 6** 
24 h 
post 
Imm 3 
Mo°   
12** 
Mo°  
15** 
Mo°* 
18** 
Mo°  
21** 
Mo°*  
24** 
Mo° 
27** 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, PR, temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-reactive Protein 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSST-1 binding Ab 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Neutralizing Ab: inhibition of 
cytokine gene expression 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Neutralizing Ab: Inhibition of T-cell 
activation 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Local Reactions 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
° months from first immunization  °° months from second immunization *optional **idealized

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5. 
BACKGROUND INFORMATION 
5.1 
Background  
 
The incidence of community or hospital acquired infections is about 500 000 in each, Europe and the 
U.S.A. Some 20 % of the patients with such infections require intensive care either immediately or 
after some time. Of the patients in intensive care, about 50% - 70% can be saved, however, many of 
them suffer from late sequelae, persisting for years. About 10% to 20% of the hospital or community 
acquired infections are caused by S.aureus. Most strains of S. aureus produce toxins, such as 
superantigens, including the Toxic Shock Syndrome Toxin-1 (TSST-1). These toxins cause significant 
illnesses, including pneumonia, acute kidney injury, infective endocarditis, and toxic shock syndrome 
(TSS) (Salgado-Pabon 2013). TSST-1 alone or in combination with other S.aureus virulence factors 
(such as SEA, SEB, and SEC) leads to toxic shock sydrome (TSS).  
 
TSST-1 belongs to the pyrogenic toxin class of superantigens and plays a pivotal role as a causative 
agent in TSS and septic shock (Dinges et al.2000; McCormick et al.2001).  Superantigens are produced 
by both methicillin-resistant and sensitive S.aureus strains (Hu et al 2008). It has been estimated that 
TSST-1 is involved in 50 % of nonmenstrual-associated TSS cases due to S. aureus and essentially all 
cases of menstrual-associated TSS (Dinges et al.2000). Experimental application of superantigens leads 
to an overwhelming inflammatory response (Hopkins et al.2005; Krakauer 2003; Dauwalder et al.2006) 
with uncontrolled release of inflammatory cytokines resulting in shock and multi organ failure (Miethke 
et al.1993; Faulkner et al.2005; Krakauer et al.2010; Dinges et al.2001; Stich et al.2010). 
 
Treatment of infections with antibiotics has become increasingly difficult due to the widespread 
occurrence of antibiotic-resistant S. aureus strains (Chambers 1997; McCormick et al. 2001; Foster et 
al.2005; Zetola et al., 2005). The prevalence of multiresistant organisms such as Methicillin-resistant 
S. aureus is strongly increasing (Zetola et al. 2005). This being the case, it is generally agreed upon 
that it is desirable to develop a vaccine and specific immunoglobulin for active and passive 
immunization which could be used also in combination with antibiotics to save a greater number of 
patients and/or shorten the persistence of severe sequelae shortening patients´ lives.  
 
Therapies have included the application of intravenous immunoglobulin (IVIG) which have been useful 
also in clinical trials (Kaul et al. 1998). Numerous efforts have been undertaken to develop a specific 
therapy (Krakauer 2013). 
 
In a rabbit model, animals were immunized with atoxicTSST-1 mutants three times. Immunization 
protected them when challenged one week after the last immunization with otherwise lethal doses of 
native TSST-1 in miniosmotic pumps (Spaulding et al., 2012). In another model, 83% of mice that were 
vaccinated three times with mutant TSST-1 survived when challenged with viable S. aureus (Hu et al., 
2003). Other experiments in mice showed that immunizations three times with mutants of the 
superantigens SEA, SEB, SEC1, or TSST-1 led to protection of the mice upon subsequent challenge with 
native superantigens plus endotoxin (Bavari et al, 1999).  
 
The  BioMed r-TSST-1 Variant and Vaccine: 
 
Based on information on the structure and functional relationship of S. aureus TSST-1, mutants have 
been established with the objective of eradicating the toxic and superantigenic properties, while 

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leaving specific immunogenicity and protectivity unimpaired (Roggiani et al.2000; Ulrich et al 1998; 
Gampfer et al.2002). After molecular characterization and thorough biological and immunological 
testing, a TSST-1 double mutant (G31R-H135A) has been chosen for the rTSST-1 Variant Vaccine 
(Gampfer et al.2002). Amino acid changes in position 31 have been shown to result in impaired 
interaction with MHC class II molecules (Kum et al.1996), whereas mutation of histidine 135 to alanine 
negatively affects the binding of TSST-1 to the T cell receptor (McCormick et al.2003). The double 
mutant has been expressed in E. coli BL21, purified by chromatography and formulated with Al(OH)3 as 
a vaccine, this being referred to as the BioMed rTSST-1 Variant Vaccine.  
 
Proof of concept: 
 
A non-clinical, prospective, controlled, randomized open Immunogenicity and Protection Study (Study 
Bio&Bio 031114) was conducted in conformity with GLP to evaluate the immogenicity and protection 
of the BioMed rTSST-1 Variant Vaccine in a rabbit model.  
 
TSST-1 antibody negative rabbits were randomized and immmunized with the test or the reference 
item four times at three-week intervals. Blood samples were drawn prior to entry (baseline), one day 
prior to the second, third, and fourth immunizations, and three weeks after the fourth immunization 
to determine TSST-1 antibody levels. Thereafter, animals in both groups were challenged with TSST-1 
and four hours later with lipopolysaccharide (LPS) and observed for survival for five days. 
 
Results: 20 female rabbits weighing 1,672 g on average with TSST-1 antibody titers of < 20 were 
randomly assigned to Group 1 (adjuvanted vaccine) or Group 2 (adjuvant alone). TSST-1 antibody titers 
in the immunized group rose to a GM of 624 as early as three weeks after the 2nd immunization and 
reached a GM of 22,328 and 37,217 three weeks after the third and fourth, respectively. In Group 2, 
TSST-1 antibody titers remained < 20 throughout. All animals in Group 1 seroconverted (i.e. had > 4-
fold increases in TSST-1 antibody titer with respect to baseline) after the third immunization. None did 
so in Group 2 (p < 0.001). All animals in Group 1 survived the challenge with TSST-1 and LPS, while all 
animals in Group 2 succumbed (p < 0.001). 
 
 
No evidence of superantigenicity:  
 
Non-clinical experiments in vivo have shown that rTSST-1 variant lacks super-antigen activity and does 
not lead to T-cell activation or induce an increase in IL-2 gene activation in the spleen of rabbits. Lack 
of super-antigen activity has also been demonstrated in mice. IL-2 concentrations remain at 
background level after injection of rTSST-1 variant. 
 
Non-clinical experiments in vitro have shown r-TSST-1 variant not to induce IL-2 gene activation up to 
concentrations of 1000 ng/ml in human mononuclear cells proving rTSST-1 variant to be detoxified. 
Lack of activation and release of inflammatory cytokines could be proven. rTSST-1 variant lost its super-
antigen property by the detoxifying mutations. rTSST-1 variant does not induce T-cell proliferation of 
human mononuclear cells as estimated by H3thymidin incorporation   in concentrations up to 01 to 
1µg.  It lacks the characteristics of a super-antigen and behaves as a normal antigen. 
 
No evidence of toxicity: 
 
rTSST-1 variant was tested in rabbits in doses up to 1 mg per rabbit , and doses this high were well 
tolerated 
 

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 in vivo experiments in rabbits have shown that the rTSST-1 Variant Vaccine antigen does not induce 
fever, leukopenia or lympohopenia . Studies performed in mice and rabbits have demonstrated that 
super-antigen activity and toxicity with respect to activation and release of the inflammatory 
cytokines TNFα , INF-γ, and IL6 have been eliminated due to the mutations in rTSST-1 variant. 
Suprantigen toxins are known to increase the lethal effect of endotoxin (LPS) up to over 1000-fold. 
rTSST-1 variant has been extensively tested in rabbits and mice and did not increase LPS lethality. 
 
A prospective, controlled, randomized, open repeated dose toxicity and local tolerance study of the 
BioMed rTSST-1 Variant Vaccine (Study Bio & Bio 101115) was conducted in conformity with GLP to 
evaluate the toxicity and local tolerance of the Biomed rTSST-1 Variant Vaccine after repeated 
applications in a rabbit model. 
 
Ten male and ten female rabbits were randomly assigned to one of two groups: Group 1 received 1 ml 
30 µg of rTSST-1 Variant Vaccine, Group 2 was given 1 ml of adjuvant (Al(OH)3) four times at intervals 
of three weeks. Blood was  drawn prior to the first immunization and at specified time points during 
the study for  hematology, coagulation, clinical chemistry, electrolytes, C-reactive protein, antibody 
against antigenic substances that can cross react with human tissue, and immune complexes. TSST-1 
antibody was determined prior to the fourth immunization. Vital signs, body weight, and intake of food 
and water were monitored.  Clinical and physical observations were made on scheduled days. General 
health was assessed daily. Local tolerance was determined by visual inspection before and at several 
time points after each vaccination for indications of reactogenicity. Moribundity/mortality, clinical and 
physical observations and general health were monitored throughout the treatment and observation 
periods.  
 
Two to three days after the last immunization, the animals were euthanized. Opthalmoscopy was 
performed prior to sacrifice. Post mortem examinations included gross pathology and histopathology 
of a number of organs, including the injection site tissue. 
 
Results and Conclusion: This repeated dose toxicity study investigated a number of parameters 
including hematology, clinical chemistry,coagulation, induction of autoantibodies, CRP, local tolerance, 
vital signs, ophthamology, gross pathology, and histopathology. There were a few differences between 
groups, most of them small and gender specific and within the variability of the normal range. These 
variations are considered as clinically irrelevant.  The study reveals that rTSST-1 Variant Vaccine does 
not have any toxicity at the human dose in this animal model after four immunizations.  
 
 
 
in vitro experiments have shown that rTSST-1 variant does not induce the release of TNFα , INF-γ, and 
IL6 incultures of human mononuclear cells.   
 
Summarizing, the safety of rTSST-1 variant has been shown in numerous state-of-the art experiments 
and non-clinical studies. Innocuity with respect to increasing LPS activity has also been demonstated 
up to dose levels of 10 times the intended dose to be used in humans. 
 
Phase 1 study in healthy adults 
 
A phase 1 dose-escalation study of 100 ng, 300 ng, 1 µg, 3 µg, 10 µg, and 30 µg the rTSST-1 Variant 
Vaccine in 49 healthy human subjects has been completed. There have been no product related serious 
expected or unexpected adverse events. 
 
Secondary objective of the study was to assess the immunogenicity of the BioMed rTSST-1 Variant 
Vaccine in healthy adults.  
 

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In an investigatory study in this trial neutralizing antibodies were tested. The results demonstrated the 
induction of high titer neutralizing antibodies of uncontrolled T cell activation and cytokine induction 
(Roetzer et al. 2016; Schwameis et al. 2016). 
 
With these results, the rTSST-1 Variant Vaccine is proposed to be tested in a phase 2 clinical trial using 
two doses of the vaccine in one to three immunizations to further demonstrate its safety and 
immunogenicity in healthy individuals and determine antibody persistence.  
 
 
Residual risk 
 
There were no safety concerns with any of the doses ranging from 100 ng to 30 µg in the phase 1 study, 
however, the  100 µg dose has not been tested in humans thus far. Any dose escalation is associated 
with a residual risk. Nevertheless, local tolerance and adverse reactions are expected to be no greater 
than with any other vaccine.  
 
5.2 
Study Rationale 
 
The BioMed rTSST-1 Variant Vaccine has been developed by Biomedizinische Forschungund Bio-Produkte 
AG as one component of a polyvalent staphylococcal vaccine for the prevention of toxic shock and 
hyperimmunization of donors for the production of TSST-1 immunoglobulin.  
6. 
STUDY OBJECTIVES (HYPOTHESIS) 
 
6.1 
Primary Objective  
 
Primary objective of the study is to demonstrate the safety and tolerability of two doses of 
the BioMed rTSST-1 Variant Vaccine after one to three administrations in healthy adults. 
6.2 
Secondary Objectives (Hypothesis) 
 
Secondary objectives of the study are to assess the immunogenicity and persistence of   
TSST-1 binding and neutralizing antibodies after one, two, and three immunizations with two 
doses of the vaccine in healthy adults over a period of 12-14 or optionally 27-29 months. 
 
 
The hypothesis is  that the higher dose and more frequent administrations of the vaccine will 
 
produce higher binding and neutralizing antibodies in vaccinated subjects and that these 
 
will persist for a longer period of time than in subjects vaccinated with the lower dose or in 
 
the control group. 
 
7. 
STUDY DESIGN 
 
This is a prospective,  randomized, parallel control, phase 2 study of the safety , local tolerance, 
immunogenicity, and TSST-1 antibody persistence in healthy human subjects who have been 

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vaccinated with one of two doses of the BioMed rTSST1 Variant Vaccine or Adjuvant one, two, or 
three times.   
 
 Over a period of 60 days prior to entry into the study, 145 male and female subjects 18 - 64 years of 
age will be screened for eligibility.  Screening criteria will include physical examination, medical 
history, pregnancy/ adequate contraception in females, HIV Ab, HCV Ab, HBs Ag and TSST-1 Ab.  140 
qualifying subjects will be entered into the study.  
 
The 140 qualifying subjects will be randomly assigned to one of seven groups of 20 each. Subjects in 
each group will receive three injections, the first at time 0, the second three months + 4 weeks after 
the first, and the third 6 months + 4 weeks after the second: 
 
 Group 1 will receive 10 µg of rTSST-1 Variant Vaccine and two administrations of Adjuvant ; Group 2 
will receive the same dose of Vaccine twice and one dose of Adjuvant; and Group 3 will be injected the 
10 µg of the Vaccine three times. Groups 4 to 6 will be given 100 µg of Vaccine following the same 
pattern.  Group 7 will receive Al(OH3) adjuvant three times. See Table 1. 
 
Prior to, and 24 h (+3 h) after each vaccination, the subjects will be examined for vital signs. Blood will 
be drawn for hematology, clinical chemistry tests, and C-reactive protein.  Local reactions and adverse 
events will be assessed in all post vaccination visits. 
 
The subjects will be followed up for a period of 3 months (± 2 weeks) or optionally 18 months (± 2 
weeks) if they decide to take part in the long-term follow-up, during which they will return to the clinic 
every three months (± 2 weeks). Tests performed will include vital signs, local reactions, clinical 
chemistry, C-reactive protein. Adverse events will be noted. See Table 2. 
 
Binding and neutralizing TSST-1 antibodies will be determined prior to each vaccination and every 
three months during the treatment and follow-up periods. 
 
7.1 
Study Population 
 
7.1.1 
Study Population 
 
            healthy male or female subjects 
 
 
7.1.2 
Inclusion Criteria 
 
 
males or females aged 18-64 years 
 
signed informed consent 
 
physical exam: no abnormal findings unless considered irrelevant by the investigator 
 
uneventful medical history 
 
females with childbearing potential: adequate contraception (see 7.1.4 below) 
 
 
 
7.1.3 
Exclusion Criteria 
 

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 females with childbearing potential: pregnancy, lactation or unreliable contraception 
 
 
positive HIV Ab and/or positive HCV Ab and/or positive HBsAG 
 
 
 
 
 
signs and symptoms of autoimmunity 
 
TSST-1 Ab titer  > 1:1000 
current or recent (< 1 month) immunosuppressive therapy with corticosteroids or 
immunomodulators 
 
7.1.4 
Females with Childbearing Potential 
 
Females of childbearing potential will be required to perform pregnancy tests at screening and prior 
to each immunization and to be practicing an acceptable method of birth control during the study. 
Acceptable methods of birth control include barrier methods (including male and female condoms), 
diaphragms (cervical caps) with intravaginal spermicide (including jellies, foams, and suppositories), 
intra-uterine devices, hormonal contraceptives, or same sex relationships. 
 
7.1.5 
Study Duration 
 
Each participant will be in the study for 12 to 14 or optionally 27 to 29 months, if they decide to take 
part in the long-term follow-up. 
 
7.1.6 
Withdrawal and Replacement of Subjects 
 
Criteria for Withdrawal 
 
Subjects may prematurely discontinue from the study at any time. Premature discontinuation from 
the study is to be understood when the subject did not undergo End of Study (EOS) examination and 
/ or all pivotal assessments during the study. 
 
Subjects must be withdrawn under the following circumstances: 
 
 
at their own request 
 
if the investigator feels it would not be in the best interest of the subject to continue 
 
if the subject violates conditions laid out in the consent form / information sheet or 
disregards instructions by the study personal 
 
if a female subject becomes pregnant 
 
in the case of intolerable adverse reactions 
 
In all cases, the reason why subjects are withdrawn will be recorded in detail in the CRF and in the 
subject’s medical records. Should the study be discontinued prematurely, all study materials 
(complete, partially completed and empty CRFs) will be retained. 

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Follow-up of Subjects Withdrawn from the Study 
 
In case of premature discontinuation of the study, the investigations scheduled for the EOS visit will 
be performed at least one week after the last immunization. The subjects will be advised that 
participation in these investigations is voluntary. Furthermore, they may request that from the time 
point of withdrawal no more data will be recorded and that all biological samples collected in the 
course of the study will be destroyed. 
 
Replacement Policy 
 
Drop outs may be replaced by a subject next in line for recruitment. The replacement subject will be 
allocated to the same group the drop-out was in. All available data on the drop-out will be evaluated. 
7.1.7 
Premature Termination of the Study 
 
The sponsor has the right to close this study at any time. The IEC and the competent regulatory 
authority must be informed within 15 days of early termination.  
 
The trial or single dose steps will be terminated prematurely in the following cases: 
 
If adverse events occur which are so severe that the benefit-risk ratio is not acceptable. 
 
If the number of dropouts is so high that proper completion of the trial cannot realistically be 
expected. 
8. 
METHODOLOGY 
8.1 
Study Medication 
 
 
Test Preparation 
 
 
Active Agent and Characteristics:  
 
 
TSST-1 is a staphylococcus toxin with the characteristics of superantigens. Toxicity of  
              TSST-1 is brought about by cross-linking of MHC class II molecules on the antigen 
 
presenting cell with the Vβ chain and the T-cell receptor on the T-cell. This way, 5 to 30% of 
 
the entire T-cell population may be activated.  
 
 
The Toxin was cloned from S. aureus and is genetically modified to lose its toxic 
 
properties. Specific amino acids that determine the binding sites for the MHC and the T-cell 
 
receptor have been changed so that TSST-1 cannot bind to either receptor, and the toxic 
 
characteristics are lost.  
 
 
Mutagenesis of the TCR binding site is performed by exchange of histidine 135 to 
 
alanine. The MHC class II binding site is mutated by exchanging amino acid 31 from 
 
glycine to arginine.  

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While the application of TSST-1 is followed by fever, leukopenia and lymphopenia in 
 
rabbits, and an increase of inflammatory cytokines in human mononuclear cells as well 
 
as in the serum of mice, these toxic characteristics are lost in the rTSST-1 variant 
 
vaccine antigen. 
 
 
The recombinant detoxified toxin is used as the vaccine antigen. 
 
 
 
Trade Name of the Agent:  BioMed rTSST-1 Variant Vaccine 
 
 
Manufacturer:  Biomedizinische Forschung und Bio-Produkte AG 
 
 
 
Lazarettgasse 19 
 
 
 
A 1090 Vienna Austria 
 
 
 
 
 
Drug Supply: 
  
 
 
The final pharmaceutical product is presented in 2.0 ml single dose vials containing  the 
 
following  quantities of rTSST-1 variant and 1.0 mg Al(OH)3  in 0.5 ml PBS with   0.02 % 
 
polysorbate 80 (with overfill) : 
 
 
10 µg rTSST-1 Variant   
               
100 µg rTSST-1 Variant  
     
 
 
Dosage Form: Suspension for i.m. injection. 
 
 
Storage Instructions: 2 - 8°C protected from light 
 
 
Route of Administration:  i.m.  
 
 
 
 
Reference Preparation:  
 
 
 Aluminum hydroxide suspension in phosphate buffered saline   
 
 
(vaccine adjuvant). 
 
 
Trade Name: BioMed Aluminum Hydroxide Suspension 1 mg 
 
 
Manufacturer:      Biomedizinische Forschung und Bio-Produkte AG 
 
 
 
     Lazarettgasse 19 
 
 
 
    A 1090 Vienna 
 
 
 
    Austria 
 

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Drug Supply:      
 
 
The reference preparation is  presented in 2.0 ml single dose  vials containing  1.0 mg Al(OH)3  
 
in 0.5 ml PBS and  0.02 % and polysorbate 80 (with overfill) . 
 
 
Dosage Form:  Suspension for i.m. injection 
 
 
Storage Conditions:  2 - 8° C  
 
 
Route of Administration:  i.m. 
 
8.1.1 
Dosage and Administration 
 
 
Test Preparation (Treatment Groups) 
 
 
 
Preparation of doses for administration: 
 
 
rTSST-1 Variant Vaccine containing 10 µg rTSST-1: 
  
draw 0.5 ml from a vial containing  Vaccine with  10 µg rTSST-1 Variant  
 
 
 into a disposable syringe. 
 
 
rTSST-1 Variant Vaccine containing 100 µg: 
  
draw 0.5 ml from a vial containing  Vaccine with  100 µg rTSST-1 Variant  
 
 
 into a disposable syringe 
 
 
Route of administration:  i.m. 
 
 
 
Administer 0, 1, 2, or 3 times depending on Group assignment.  See Table 1. 
 
 
 
Reference Preparation (Control Group) 
 
 
Preparation for administration: 
 
Adjuvant containing 1 mg Al(0H)3: 
 
 
 
Draw 0.5 ml from a vial containing Adjuvant into a disposable syringe. 
 
 
 
Route of administration:  i.m. 
 
 
Administer 0, 1, 2 or 3 times depending on Group assignment. See Table 1. 
 
 
8.1.2 
Study-Drug up- and down Titration 
 

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n.a. 
 
 
8.1.3 
Study Drug Interruption or Discontinuation 
 
The investigator must temporarily interrupt or permanently discontinue the study drug if continued 
administration of the study drug is believed to be contrary to the best interests of the subject. 
The interruption or premature discontinuation of study drug might be triggered by an AE, a 
diagnostic or therapeutic procedure, an abnormal assessment (e.g., laboratory abnormalities), or for 
administrative reasons, in particular withdrawal of the subject’s consent. 
The reason for study drug interruption or premature permanent discontinuation must be 
documented in the CRF. 
 
8.1.4 
Study Drug Interruption 
 
See 8.1.3. above. 
 
8.1.5 
Study Drug Premature Permanent Discontinuation 
 
See  8.1.3. above 
 
Study drug premature permanent discontinuation due to an adverse event 
 
If the reason for premature permanent discontinuation of study treatment is an AE, the subject will 
have a “Premature End of Study (EOS)” visit with all the assessments performed before the study 
drug discontinuation, whenever possible.  
 
 
Study drug premature permanent discontinuation due to another reason than adverse event 
 
The investigator may discontinue a subject if he feels it is in his best interest.  
 
If the reason for premature permanent discontinuation of study treatment is not an AE, the subject 
will be withdrawn from the study (withdrawal of consent) and have the end of study (EOS) visit with 
all the assessments performed before the study drug discontinuation, whenever possible. 
 
8.1.6 
Study Drug Delivery & Drug Storage Conditions 
 
Test and reference preparations will be delivered in 2 ml vials containing 0.5 ml of Vaccine or 
adjuvant. Store at 2 - 8° C.  
 

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8.1.7 
Study Drug Packaging and Labeling 
 
Study drug and reference preparations will be delivered to the study pharmacist labeled as shown 
below:  
 
Inner label:  
 
See Appendix 1. 
 See 
Outer label:  
 
See Appendix 1. 
 
8.1.8 
IMP Administration & Handling 
 
Bring to RT before injection. Invert before use. Draw 0.5 ml from a vial containing  Vaccine with  10 or 
100 µg rTSST-1 Variant  or Adjuvant into a 1 ml graduated syringe.  See Section 8.1.1. above. 
 
8.1.9 
Drug Accountability 
 
Drug accountability will be recorded on an ongoing basis in paper form. 
 
8.1.10 Procedures to Assess Subjects Compliance 
 
A diary will be used for the subject to record any adverse events between visits to the clinic. 
 
8.1.11 Concomitant Medication 
 
No concomitant medication will be allowed that would interfere with the assessment of trial specific 
results as assessed by the investigator.  
 
8.2 
Randomization   
 
Subjects will be randomized to receive either 10 µg or 100 µg of Vaccine or Al(OH)3 control one to 
three times. Block randomization will be used.  
 
Since the 100 µg dose will be administered for the first time, the first five blocks will provide for an 
only gradually increasing number of subjects to receive that dose as shown below. 
 
 
 
 

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TABLE 3. RANDOMIZATION DURING FIRST FIVE STUDY WEEKS 
 
Group 
Block 1 
n=5 
Week 1 
Block 2 
n=5 
Week 2 
Block 3 
n=5 
Week 3 
Block 4 
n= 6 
Week 4 
Block 5 
n=14 
Week 5 
1 
1 
1 
1 
1 
1 
2 
1 
1 
1 
1 
1 
3 
1 
1 
1 
1 
1 
4 
 
 
 
 
5 
5 
 
 
 
1 
4 
6 
1 
1 
1 
1 
1 
7 
1 
1 
1 
1 
1 
 
 
All subsequent blocks will ensure equal distribution of subjects among groups.  
 
Envelopes will be prepared with consecutive subject numbers containing the group allocation. 
 
Subjects vaccinated in blocks 1 – 4 will be followed by scripted telephone calls one and two weeks 
after vaccination for adverse events, if any. 
 
8.3 
Blinding 
 
Study drug and reference preparations will be delivered to the study pharmacist open label. Since 
the study is to be conducted in a double blinded manner, they will be prepared by a pharmacist or 
other member of the study team not otherwise involved in the trial and be delivered in ready-to use 
syinges to the investigator blinded. 
 
8.3.1 
Emergency Procedure for Unblinding 
 
In the case of serious adverse events, the investigator will have access to the individual code.  
 
Sealed envelopes containing true treatment assigned will be stored in the investigator’s study file. 
The premature breaking of the code should be confined to emergency cases in which knowledge of 
the administered drug is necessary for adequate treatment. Breaking of the code must be recorded 
in the subject file, the CRF and on the envelope (date and reason). The CRA and the sponsor will be 
notified of each unblinding event by PI. Should any code be broken by accident, the respective 

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subject will be withdrawn from further participation in the study and a written explanation must be 
given by the PI. Open and sealed envelopes must be returned to the monitor at the close out visit. 
 
 
8.3.2 
Unblinding at the End of the Study. 
 
Unblinding will take place after data base lock and the BDRM (Blind Data Review Meeting).  
 
8.4 
Benefit and Risk Assessment 
 
At present, immediate benefits cannot be expected for study participants. The aim of the research 
project is to develop a vaccine against a potentially fatal disease, and the study will help to gain 
knowledge and contribute toward that end. 
 
 Extensive studies in vitro, in experimental animals and a phase 1 study in man have shown the 
vaccine to be safe and tolerable.  Nevertheless, risks may be related to the administration of a higher 
dose of the investigational product and are expected to be comparable to the ones associated with 
the administration of any vaccine, such as local reactions and/or fever and/or severe adverse events 
that might make immediate medical intervention necessary. For that reason, study subjects will be 
monitored during the study by the investigator and his team. 
 
8.5 
Study Procedures 
8.5.1 
General Rules for Trial Procedures 
 
 
All study measures like blood sampling and measurements will be documented with date 
(dd:mm:yyyy).  
 
In case several study procedures are scheduled at the same time point, there is no specific 
sequence that should be followed. 
 
The dates of all procedures will be according to the protocol. The time margins will be + 4 
weeks for the second immunization, and + 4 weeks for the third.  For the controls at 24 h of 
any immunization, the window will be +3 hours.  Follow-up visits must be made + two weeks 
of the time points given in Table 2.  If for any reason, a study procedure is not performed 
within scheduled margins, a protocol deviation will be noted, and the procedure will be 
performed as soon as possible or as adequate. 
 
8.5.2 
Screening Investigation 
 
Over a period of 60 days prior to entry into the study, subjects will be screened for  the 
parameters shown  in Table 2., i.e. 
 
 
Inclusion criteria: 
 
males or females aged 18-64 years 
 
 
 
  

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physical exam: no abnormal findings unless considered 
 
 
 
 
 
irrelevant by the investigator 
 
 
 
 
 
 
uneventful medical history 
 
 
 
 
 
females with childbearing potential: adequate contraception 
 
Exclusion criteria:  
 
 
females with childbearing potential: pregnancy, lactation or 
unreliable contraception 
 
positive HIV Ab and/or positive HCV ab and/or positive 
HBsAG 
 
 
 
 
 
 
 
 
 
 
 
TSST-1 Ab ≥ 1:1000 
 
current or recent (< 1 month) immunosuppressive therapy 
with corticosteroids or immunomodulators 
 
 
Medical history 
 
Concomitant medication 
              Body weight and height 
 
 
Vital signs (BP, PR, temperature) 
 
Hematology (see 8.5.3. below) 
 
Clinical chemistry (see 8.5.3. below) 
 
C-reactive protein 
 
TSST-1 Ab (binding and neutralizing) 
 
HIV Ab 
 
HCV Ab 
 
HBsAg 
 
Pregnancy test 
 
 
Informed consent will be invited. 
  
8.5.3 
Laboratory Tests 
 
The following laboratory tests will be performed on blood taken at screening, prior to each 
immunization, 24 h thereafter, and at the follow-up visits shown in Table 2. In the case of 
abnormal findings, the respective tests will be repeated in between. 
 
 
 
 
Hematology: 
 
RBC 
 
 
 
 
WBC 
 
 
 
 
Leukocyte differential count (absolute values of neutrophils,  
 
 
 
 
basophils,eosinophils, monocytes, and lymphocytes) 

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Platelet count 
 
 
 
 
Hemoglobulin 
 
 
 
 
Hematocrit 
 
 
Clinical Chemistry:  
ALT 
 
 
 
 
BUN 
 
 
 
 
Creatinine 
 
 
 
 
Glucose 
 
 
 
 
Total Protein 
 
C-reactive Protein 
 
 
 
 
TSST-1 Ab (binding and neutralizing) will be performed prior to each vaccination and at the 
the three-month follow-up visits. 
 
 
Tests will require 3 ml of EDTA blood and 9 ml of serum or plasma on each occasion.  
 
Tests for TSST-1 Ab  will be performed by Biomedizinische  Forschungsgesellschaft m.b.H. 
 
8.5.4 
Other Tests 
 
At the times indicated under 8.5.3., vital signs (BP, PR and temperature) will be monitored at 
all visits. Pregnancy tests will be performed prior to each immunization.  Local reactions will 
be monitored after each immunization and at the first three-month follow-up visit (with the 
windows described under 8.5.1.) Subjects will be required to keep a diary for adverse events 
after leaving the clinic and present it to the investigator for review at each visit. 
 
8.5.5 
Endpoints 
 
 
Primary (Safety) Endpoints: Adverse events 
 
 
 
       
        Abnormal laboratory findings 
 
 
 
                      Local reactions 
 
 
Secondary (Efficacy) Endpoints:  
                          
                     TSST-1 binding and neutralizing Ab   
 
 
 
 
        
 
 
 
 
       Persistence of TSST-1 binding and neutralizing Ab   
 
 
Exploratory Endpoint:       2nd test of  neutralizing Ab 
 
 
 
 
       
 
 

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9. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 
Averse Events (AEs) 
9.1.1 
Summary of Known and Potential Risks of the Study Drug 
 
The expected risks will be comparable with those accompanying the administration of any vaccine, 
such as local reactions and fever. 
 
9.1.2 
Definition of Adverse Events 
 
An AE is defined as any untoward medical occurrence in a subject administered vaccine or reference 
preparation 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 administration of the vaccine or adjuvant. An AE 
includes any event, regardless of the presumed causality between the event and the preparation 
administered.  
 
9.2 
Serious Adverse Events (SAEs) 
 
A Serious Adverse Event (SAE) is defined by the International Conference on Harmonization (ICH) 
guidelines and WHO GCP guidelines as any AE fulfilling at least one of the following criteria: 
 
Results in deaths. 
 
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. 
 
Requiring subject's hospitalization or prolongation of existing hospitalization – inpatient 
hospitalization refers to any inpatient admission, regardless of length of stay. 
 
Resulting in persistent or significant disability or incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions). 
 
Congenital anomaly or birth defect. 
 
Is medically significant or requires intervention to prevent at least one of the outcomes listed 
above. 
Life-threatening refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event that hypothetically might have caused death if it were more severe. 
Important medical events that may not immediately result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
 
9.2.1 
Hospitalization – Prolongation of Existing Hospitalization 
 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. 

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An additional overnight stay defines a prolongation of existing hospitalization. 
 
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs: 
 
Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
 
9.2.2 
SAEs Related to Study-Mandated Procedures 
 
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal relationship (i.e., 
a relationship cannot be ruled out) to study-mandated procedures (excluding administration of study 
drug) such as discontinuation of subject's previous treatment during a washout period, or  
complication of a mandated invasive procedure (e.g., blood sampling), or car accident on the way to 
the hospital for a study visit, etc. 
 
9.2.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
SUSARs are all serious adverse reactions with suspect causal relationship to the study drug that is 
unexpected (not previously described in the Investigator’s brochure) and serious.  
 
9.2.4 
Pregnancy 
 
Any pregnancy that occurs during study participation must be reported to the investigator/sponsor. 
To ensure subject safety, each pregnancy must be reported to the investigator/sponsor immediately. 
The pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and child.  Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly related to the 
investigational product, must be promptly reported to the principal investigator/sponsor. 
In addition, the investigator must attempt to collect pregnancy information on any female partners 
of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy 
information must be reported to the investigator/sponsor as described above. 
 
9.3 
Severity of Adverse Events 
 
The severity of clinical AEs is graded on a three-point scale: mild, moderate, severe, and reported on 
specific AE pages of the CRF. 
If the severity of an AE worsens during study drug administration, only the worst intensity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required.  
If an AE occurs during a washout or placebo run-in phase and afterwards worsens during the 
treatment phase, a new AE page must be filled in with the intensity observed during study drug 
administration.  
 

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Mild 
Event may be noticeable to subject; does not influence daily activities; the AE resolves spontaneously 
or may require minimal therapeutic intervention;  
 
Moderate 
Event may make subject uncomfortable; performance of daily activities may be influenced; 
intervention may be needed; the AE produces no sequelae. 
 
Severe 
Event may cause noticeable discomfort; usually interferes with daily activities; subject may not be 
able to continue in the study; the AE produces sequelae, which require prolonged therapeutic 
intervention. 
 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe the 
intensity of a specific event (as in mild, moderate, or severe myocardial infarction). However, a 
severe event may be of relatively minor medical significance (such as severe headache) and is not 
necessarily serious. For example, nausea lasting several hours may be rated as severe, but may not 
be clinically serious. Fever of 39°C that is not considered severe may become serious if it prolongs 
hospital discharge by a day. Seriousness rather than severity serves as a guide for defining regulatory 
reporting obligations. 
 
9.4 
Relationship to Study Drug  
 
For all AEs, the investigator will assess the causal relationship between the study test or reference 
preparation and the AE using his/her clinical expertise and judgment according to the following 
algorithm that best fits the circumstances of the AE: 
 
Definitely: Temporal relationship to the administration of the study test or reference preparation 
and course following a known reaction pattern;  
Probably: Good reasons and sufficient documentation to assume a causal relationship; 
Possibly: A causal relationship is conceivable and cannot be dismissed; 
Unlikely: The event is most likely related to an etiology other than the trial treatment; 
Not Related: No temporal relationship to the administration of the drug or other factors have caused 
the event; 
For reporting purposes, the categories “Definitely”, “Probably” and “Possibly” will be summarized as 
“Suspected” Adverse Reactions.  
 
 
 

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9.5 
Reporting Procedures 
 
All events meeting the definition of an adverse event must be collected and reported from the first 
administration of the test or reference preparation until the end of the  post-treatment follow-up 
period. All adverse events, either observed by the investigator or reported by the subject, must be 
recorded by the investigator and evaluated. 
A special section is designated to adverse events in the case report form. The following details must 
thereby be entered: 
 
 
Type of adverse event (The investigator should record the diagnosis, if available. If no 
diagnosis is available the investigator should record each sign and symptom as individual 
Adverse Events.) 
 
Start (date and time) 
 
End (date and time) 
 
Severity (mild, moderate, severe) 
 
Serious (no / yes) 
 
Unexpected (no / yes)  
 
Outcome (recovering/resoving, resolved, resolved with sequelae, ongoing at final 
examination, fatal) 
 
Relation to study drug (definitely, probably, posssible, unlikely, unrelated). 
Adverse events are to be documented in the case report form in accordance with the above 
mentioned criteria.  
 
9.5.1 
Reporting Procedures for SAEs  
 
In the event of serious AEs, the investigator has to use all supportive measures for best subject 
treatment.   If there is any doubt about whether or not an adverse event has to be considered 
serious, the sponsor should be contacted. 
 
All serious adverse events must be reported to Biomedizinische Forschungs GmbH irrespective of 
causality or expectedness. The reporting time period for serious adverse events begins with the day 
the test or reference preparation have been administered  and  ends within 14 days after 
discontinuing the study medication. However, if the terminationvisit takes place more than 14 days 
after the subject 
has discontinued study medication, the reporting time has to be extended until the termination 
visit. 
 
Serious adverse events have to be documented on the Serious Adverse Reporting Form and 
reported by fax or e-mail to 
 
 
Biomedizinische Forschung und Bio-Produkte AG 
Attention: Prof. Martha Eibl, MD 
 
Fax:  01/408 10 91 -13 
Telephone: 01/408 10 91  
Email: " office@biomed-research.at" 
            with copy to 

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           " martha.eibl@meduniwien.ac.at" 
 
The following details should at least be available:      
 
Subject initials and number 
 
Subject: date of birth, sex, ethical origin 
 
The suspected investigational medical product (IMP) 
 
The adverse event assessed as serious 
 
Short description of the event and outcome 
 
If applicable, the initial report should be followed by the Follow up report, indicating the outcome of 
the SAE. 
 
Reporting time-frame for the Investigator is 24 h of learning of its occurrence, even if it is not felt to 
be treatment-related or at the latest the following working day. The Monitor must be informed 
accordingly. The original copy of the SAE form and the fax confirmation sheet must be kept with the 
documentation at the study site.  
 
Please note: Each SAE has also be documented in the CRF as an adverse event. Follow-up information 
about previously reported SAE must also be reported within 24 hours of the investigator receiving it. 
A new SAE form is sent, stating that this is a follow-up to the previously reported SAE and giving the 
date of the original report. The follow-up report should describe whether the event has resolved or 
continues, if and how it was treated, and whether the subject continued or discontinued study 
participation. The original of the SAE form with the follow-up information and the fax confirmation 
sheet must be kept with the documentation at the study site. 
 
9.5.2 
Reporting Procedures for SUSARs 
 
It must be remembered that the regulatory authorities, and in case of SUSARs which could possibly 
concern the safety of the study participants, also the Institutional Review Board / Independent Ethics 
Committee (IRB / IEC) are to be informed. Such reports shall be made by the sponsor and the 
following details should be at least available: 
 
Subject initials and number 
 
Subject: date of birth, sex, ethical origin 
 
Name of investigator and investigating site 
 
Period of administration 
 
The suspected investigational medical product (IMP) 
 
The adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship to the IMP 
 
Concomitant disease and medication 
 
Short description of the event: 
 
Description 
 
Onset and if applicable, end 
 
Therapeutic intervention 
 
Causal relationship 

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 
Hospitalization of prolongation of hospitalization 
 
Death, life-threatening, persistent or significant disability or incapacity 
Electronic reporting should be th 
e expected method for reporting of SUSARs to the competent authority. In that case, the format and 
content as defined by Guidance (28) should be adhered to. The latest version of MedDRA should be 
applied. Lower level terms (LLT) should be used. 
 
9.5.3 
Annual Safety Report 
 
The Annual Safety Report will be provided by the principal investigator at least once a year. 
This report will also be presented annually to the Independent Ethics (IEC) and to the competent 
authorities by the sponsor. 
10. 
FOLLOW-UP 
 
10.1 
Follow-up of Study Participants Including Follow-up of Adverse Events 
 
Subjects will be immunized at the outpatient clinic of the Clinical Pharmacology Department of the 
University of Vienna Medical School. Thereafter, they will be released and allowed to return home 
with a subject diary. They will be expected to return to the clinic at 24 h hours, and at 3-month 
intervals (with the windows described under 8.5.1.). At those time points, the examinations shown in 
Table 2 will be performed and adverse events will be noted. Between visits, they will be expected to 
enter adverse events in the subject diary.  Later occurring adverse events will be noted by study team 
during follow up visits. 
10.2 
Treatment After End of Study 
 
There will not be any treatment after the end of the study. 
11. 
STATISTICAL METHODOLOGY AND ANALYSIS 
 
11.1 
Analysis Sets  
 
Per-protocol anaysis will be used.  
 
The safety population will be the primary population for the safety analysis. The per protocol 
population will be the primary population for the immunogenicity analyses. 
 
11.2 
Sample Size Considerations 
 
Sample sizes in this study are arbitrary 

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11.3 
Relevant Protocol Deviations 
 
Non-compliance in this study will be limited to clinic visits and the keeping of a diary. 
 
All protocol deviations will be listed in the study report.  
 
11.4 
Statistical Analysis Plan 
 
Analyses of the primary endpoints will be limited to descriptive statistics and narratives. 
 
Antibody titers will be analyzed by one-way or repeated measures ANOVA . Subjects with antibody 
titers of 200 to 1000 at entry will be stratified.  Mann-Whitney-U and Wilcoxon signed rank tests will 
be used post hoc for comparison among groups and Ab persistence, respectively,  to determine 
statistical significance. 
 
A statistical difference, if any, in the rate of binding Ab response among treatment groups and between 
treatment and control groups will be tested by Chi square statistics. 
 
Antibody response is defined by seroconversion from a TSST-1 binding Ab titer of < 20 to >40 or a    4-
fold increase in TSST-1 binding Ab titer. 
 
Neutralizing Ab will be monitored. 
 
11.5 
Missing, Unused and Spurious Data 
 
No data imputation is planned for missing and spurious data. 
 
11.6 
Endpoints Analyses 
 
See 11.4. 
11.6.1 Primary Endpoint Analysis 
 
See 11.4. 
11.6.2 Secondary Endpoint Analysis 
 
See 11.4. 
 
11.6.3 Exploratory Endpoint 
 
 See 11.4. 
 

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11.6.4 Baseline Parameters and Concomitant Medications 
 
At baseline, antibody titers will be assessed for comparison with the efficacy endpoint. 
 
11.7 
Interim Analysis 
 
One blinded interim analysis for safety and immunogenicity may be performed. 
 
Criteria for the termination of the trial 
 
n.a. 
11.8 
Software Program(s) 
 
to be determined 
12. 
DOCUMENTATION AND DATA MANAGEMENT 
 
12.1 
Study Documents and Case Report Forms 
 
The investigator will maintain complete and accurate study documentation in a separate file (i.e., 
Investigator Site File). Documentation includes the clinical protocol as well any amendments, the 
agreement(s) between the Sponsor and the Investigator, and all other documents related to the 
study (e.g., 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, enrolment and screening information, CRFs, SAE-Reports, 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. 
 
12.1.1 Case Report Form (CRF) 
 
 
For each subject enrolled, regardless of study test or reference preparation initiation, a CRF will be 
completed and signed by the investigator or a designated sub-investigator. This also applies to those 
subjects who fail to complete the study. If a subject withdraws from the study, the reason will be 
noted on the CRF. CRFs will be provided in electronic form. 
 
Since electronic format CRFs are provided by the Sponsor, only authorized study site personnel will 
record or change data on the CRFs. All data must be recorded in the source documents and should be 
transcribed on the eCRFs in a timely manner after the study visit. Changes to handwritten record or 

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eCRF will require documentation of the reason for each change. An identical (electronic/paper) 
version of the complete set of CRFs for each subject will remain in the investigator site file at the 
study site and in the trial master file at the sponsor in accordance with the data retention policy (see 
section 12.3). 
 
The data will be checked for completeness and correctness by the responsible CRA who 
will subsequently flag the pages with a special “mark” (“SDV done”). Potential queries 
(“discrepancies”) will be generated web-based by the CRA or Data Management. 
Immediately after the queries were authored, they become visible to the Investigator 
(“raised discrepancies”). 
Those eForms which were verified as correct and complete by the Data Management will 
be locked. As a consequence, no additional entries or changes are possible. 
 
 
12.2 
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 competent 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. 
 
12.3 
Retention of Clinical Trial Documentation  
 
Subject notes must be kept for the maximum time period as permitted by the hospital, institution or 
private practice. Other source documents and the investigator’s site file must be retained for at least 
15 years or longer in accordance with local regulation. However, the Subject Identification Codes 
must be kept for at least 15 years. The investigator must agree to archive the documentation 
pertaining to the trial in an archive after completion or discontinuation of the trial, if not otherwise 
notified. If any modifications become necessary or desirable, these will be documented in writing; 
major changes require the approval of all investigators and the ethics committee.   
 
12.4 
Quality Control and Quality Assurance 
 
12.4.1 Periodic 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 designated monitor will contact and visit the investigator regularly and will be allowed to have 
access to all source documents needed to verify the entries in the CRFs and other protocol-related 

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documents provided that subject confidentiality is maintained in agreement with local regulations. It 
will be the monitor's responsibility to inspect the CRFs at regular intervals according to the SOP 
throughout the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs and the recording of the main efficacy, safety, and tolerability endpoints. 
 
The monitor will be working according to SOPs and will provide a monitoring report after each visit 
for the Sponsor. The investigator will resolve discrepancies of data. 
 
Source data verification will be 100% 
 
12.4.2 Unblinded Monitoring and IMP Handling 
 
As complete blinding of the IMP in use is not possible for all parties involved in the study and to 
ensure that blinding is kept during ongoing study an unblinded person for study coordination at site 
and an unblinded monitor will be nominated for this study.  
 
The unblinded study coordinator at site is responsible for all the 
administration/handling/accountability and storage procedures and preparation of the IMP.  
 
Unblinded Monitoring visits will be done to ensure that all handling/storage/accountability and 
dispensing of IMP has been done according protocol and to do Source Data Verification to ensure 
that all subjects are treated according their randomization arm.   
 
12.4.3 Audit and Inspections 
 
Upon request, the investigator will make all study-related source data and records available to a 
qualified quality assurance auditor mandated by the sponsor or to competent authority inspectors. 
The main purposes of an audit or inspection are to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for assessment of safety and efficacy of 
the investigational product have appropriately been reported to the sponsor. 
 
 
12.5 
Reporting and Publication  
 
12.5.1 Publication of Study Results  
 
The findings of this study will be published jointly by the investigator and the sponsor  in a scientific 
journal and presented at scientific meetings. The manuscript will be circulated to all co-investigators 
before submission. Confidentiality of subjects in reports/publications will be guaranteed.  
 
 

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13. 
ETHICAL AND LEGAL ASPECTS 
13.1 
Informed Consent of Subjects 
 
Following comprehensive instruction regarding the nature, significance, impact and risks of this 
clinical trial, the subject must give written consent to participation in the study. 
During the instruction the trial participants are to be made aware of the fact that they can withdraw 
their consent – without giving reasons – at any time without their further medical care being 
influenced in any way. 
 
In addition to the comprehensive instructions given to the trial participants by the investigator, the 
trial participants also receive a written subject information sheet in comprehensible language, 
explaining the nature and purpose of the study and its progress. 
 
The subjects must agree to the possibility of study-related data being passed on to relevant 
authorities. 
 
The subjects must be informed in detail of their obligations in relation to the trial participants 
insurance in order not to jeopardize insurance cover. 
 
13.2 
Acknowledgement / Approval of the Study 
 
The principal investigator will submit this protocol and any related document provided to the subject 
(such as subject information used to obtain informed consent) to the  Ethics Committee (EC) . 
Approval from the committee must be obtained before starting the study.  
 
The clinical trial shall be performed in full compliance with the legal regulations according to the Drug 
Law (AMG - Arzneimittelgesetz) of the Republic of Austria. 
 
An application must also be submitted to the Austrian Competent Authorities (Bundesamt für 
Sicherheit im Gesundheitswesen (BASG) represented by the Agency for Health and Food Safety 
(AGES PharmMed) and registered to the European Clinical Trial Database (EudraCT) using the 
required forms. The timelines for (silent) approval set by national law must be followed before 
starting the study. 
 
13.2.1 Changes in the Conduct of the Study 
 
 
 
Protocol Amendments 
 
Proposed (substantial) amendments must be submitted to the appropriate CA and ECs. Substantial 
amendments may be implemented only after CA/EC approval has been obtained. Amendments that 
are intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
receiving CA/EC approval. However, in this case, approval must be obtained as soon as possible after 
implementation. 

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Study Termination 
 
If the sponsor or the investigator decides to terminate the study before it is completed, they will 
notify each other in writing stating the reasons of early termination. In terminating the study, the 
sponsor and the investigator will ensure the adequate consideration is given to the protection of the 
subject interests. The investigator, sponsor or (designated CRO on behalf of the sponsor) will notify 
the relevant CA and EC. Documentation will be filed in the Trial Master and Investigator Files.     
   
Clinical Study Report (CSR) 
 
Within one year after the final completion of the study, a full CSR will be prepared by the sponsor 
and submitted to the EC and the competent authority. 
The Investigator will be asked to review and sign the final study report. 
 
13.3 
Insurance 
 
During their participation in the clinical trial, the subjects will be insured as defined by legal 
requirements.  The investigator of the clinical trial will receive a copy of the insurance conditions of 
the 'subjects insurance'. The sponsor is providing insurance in order to indemnify (legal and financial 
coverage) the investigator/center against claims arising from the study, except for claims that arise 
from malpractice and/or negligence. The compensation of the subject in the event of study-related 
injuries will comply with the applicable regulations. 
Details on the existing subjects insurance are given in the subject information sheet. 
 
13.4 
Confidentiality  
 
The information contained in this document, especially unpublished data, is the property of the 
Sponsor. It is therefore provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an Ethics Committee or Institutional Review Board. It is 
understood that this information will not be disclosed to others without written authorization from 
the Sponsor. 
 
13.5 
Ethics and Good Clinical Practice (GCP) 
 
The investigator will ensure that this study is conducted in full conformance with the principles of the 
"Declaration of Helsinki" (as amended at the 56th WMA General Assembly, Tokyo, Japan, 2008) and 
with the laws and regulations of the country in which the clinical research is conducted. 
The investigator of the clinical trial shall guarantee that only appropriately trained personnel will be 
involved in the study. All studies must follow the ICH GCP Guidelines (June 1996) and the EU 
Directive embedded in the Austrian drug act. 

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14. 
REFERENCES  
 
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Chambers, H.F.(1997) Methicillin resistance in staphylococci: molecular and biochemical basis 
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Chambers, H.F., DeLeo, F.R.  (2009) Waves of resistance: Staphylococcus aureus in the antibiotic 
era. Nature Rev.Microbiol. 7, 629-641. 
 
Daum, R.S., Spellberg, B. (2012) Progress towards Staphylococcus aureus Vaccine. Clinical 
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Dauwalder, O., Thomas, D., Ferry, T., Debard, A.L., Badiou, C., Vandenesch, F., Etienne, J., Lina, 
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Dinges, M.M., Orwin, P.M., Schlievert, P.M. (2000) Exotoxins of Staphylococcus aureus. Clin. 
Microbio. Rev. 13, 16-34. 
 
Dinges, M.M., Schlievert, P.M. (2001) Comparative Analysis of Lipopolysaccharide-Induced 
Tumor Necrosis Factor Alpha Activity in Serum and Lethality in Mice and Rabbits Pretreated with 
the Staphylococcal Superantigen Toxic Shock Syndrome Toxin 1. Inf.Immun.69,7169-7172. 
 
Faulkner, L., Cooper, A., Fantino, C., Altmann, D.M., Sriskandan, S. (2005) The mechanism of 
superantigen-mediated toxic shock: not a simple Th1 cytokine storm. J. Immunol. 175, 6870-
6877. 
 
Foster, T.J.-(2005) Immune evasion by staphylococci. Nat. Rev.Microbiol. 3,948-958. 
 
Gampfer, J.M., Samstag, A., Waclavicek, M., Wolf, H.M., Eibl, M.M., Gulle, H. (2002) Epitope 
mapping of neutralizing TSST-1 specific antibodies induced by immunization with toxin or 
toxoids. Vaccine. 20, 3675-3684. 
 
Hopkins, P.A., Fraser, J.D., Pridmore, A.C., Russell, H.H., Read, R.C., Sriskandan, S.(2005) 
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15. 
APPENDICES  
 
 
 

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Version 1.6 
 
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Appendix 1 
 
 
Labels for Test (Treatment) and Reference  (Control ) Preparations 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 45 of 47 
 
TEST PREPARATION (Treatment Groups 1-3): 
 
10.0 µg rTSST-1 Variant Vaccine 
 
INNER LABEL 
 
Prüfer: Prof. Dr. Bernd Jilma 
Prüfplan Code: BioMed 0515 
Sponsor: Biomedizinische Forschungund Bio-Produkte AG 
Lazarettgasse 19, A 1090 Wien 
 
rTSST-1 Variant Vakzine  
10 µg rTSST-1 Variant in 0,5 ml, adjuvantiert mit 1 mg Al(OH)3 
 
eine Einzeldosis (0,5 ml) enthält 10 µg rTSST-1 Variant adjuvantiert mit 1 mg Al(OH)3 
 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
Ch. Bez.: 01XYYYZ 
Lagertemperatur: 2-8°C 
 
Proband #: _________  
 
 
 
OUTER LABEL  
 
Prüfer: Prof. Dr. Bernd Jilma 
Prüfplan Code: BioMed 0515 
Eudra CT: 2015-003714-24 
 
Sponsor: Biomedizinische Forschungund Bio-Produkte AG 
Lazarettgasse 19, A 1090 Wien 
 
rTSST-1 Variant Vakzine  
10 µg rTSST-1 Variant in 0,5 ml, adjuvantiert mit 1 mg Al(OH)3 
 
eine Einzeldosis (0,5 ml) enthält 10 µg rTSST-1 Variant adjuvantiert mit 1 mg Al(OH)3 
 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
 
Ch. Bez.: 01XYYYZ 
 
verwendbar bis: XX.YY.ZZZZ 
 
Lagertemperatur: 2-8°C 
NICHT EINFRIEREN 
VOR GEBRAUCH SCHÜTTELN 
 
Nur zur klinischen Prüfung 
 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 46 of 47 
 
TEST PREPARATION (Treatment Groups 4-6): 
 
100.0 µg rTSST-1 Variant Vaccine 
 
INNER LABEL 
 
Prüfer: Prof. Dr. Bernd Jilma 
Prüfplan Code: BioMed 0515 
Sponsor: Biomedizinische Forschungund Bio-Produkte AG 
Lazarettgasse 19, A 1090 Wien 
 
rTSST-1 Variant Vakzine  
100 µg rTSST-1 Variant in 0,5 ml, adjuvantiert mit 1 mg Al(OH)3 
 
eine Einzeldosis (0,5 ml) enthält 100 µg rTSST-1 Variant adjuvantiert mit 1 mg Al(OH)3 
 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
Ch. Bez.: 01XYYYZ 
Lagertemperatur: 2-8°C 
 
Proband #: _________  
 
 
 
OUTER LABEL  
 
Prüfer: Prof. Dr. Bernd Jilma 
Prüfplan Code: BioMed 0515 
Eudra CT: 2015-003714-24 
 
Sponsor: Biomedizinische Forschungund Bio-Produkte AG 
Lazarettgasse 19, A 1090 Wien 
 
rTSST-1 Variant Vakzine  
100 µg rTSST-1 Variant in 0,5 ml, adjuvantiert mit 1 mg Al(OH)3 
 
eine Einzeldosis (0,5 ml) enthält 100 µg rTSST-1 Variant adjuvantiert mit 1 mg Al(OH)3 
 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
 
Ch. Bez.: 01XYYYZ 
verwendbar bis: XX.YY.ZZZZ 
Lagertemperatur: 2-8°C 
NICHT EINFRIEREN 
VOR GEBRAUCH SCHÜTTELN 
 
Nur zur klinischen Prüfung 
 
 

rTSST-1 Variant Vaccine Phase 2/ BioMED 0515     Biomedizinische Forschung und Bio-Produkte AG 
 
EUDRACT Nr  2015-003714-24 
 
Date   March 20, 2020 
Version 1.6 
 
Page 47 of 47 
 
REFERENCE PREPARATION (Control Group 7): 
 
1.0 mg Aluminium Hydroxide 
 
Prüfer: Prof. Dr. Bernd Jilma  
Prüfplan Code: BioMed 0515 
Sponsor: Biomedizinische Forschungund Bio-Produkte AG 
Lazarettgasse 19, A 1090 Wien 
 
Placebo 
1 mg Al(OH)3 in 0,5 ml 
eine Dosis (0,5 ml) enthält 1 mg Al(OH)3 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
 
Ch. Bez.: 51XYYYZ 
Lagertemperatur: 2-8°C 
 
Proband #: _________  
 
 
 
 
OUTER LABEL  
 
Prüfer: Prof. Dr. Bernd Jilma 
Prüfplan Code: BioMed 0515 
Eudra CT 2015-003714-24 
 
Sponsor: Biomedizinische ForschungH 
Lazarettgasse 19, A 1090 Wien 
 
Placebo 
1 mg Al(OH)3 in 0,5 ml 
eine Dosis (0,5 ml) enthält 1 mg Al(OH)3 
 
 
Suspension zur i.m. Injektion 
Nur zur einmaligen Entnahme 
 
Ch. Bez.: 51XYYYZ 
verwendbar bis: XX.YY.ZZZZ 
 
Lagertemperatur: 2-8°C 
NICHT EINFRIEREN 
VOR GEBRAUCH SCHÜTTELN 
 
Nur zur klinischen Prüfung