A Two-part, Phase I, Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Safety, Tolerability and Immunogenicity of a Dose Range og Group B Streptococcus Vaccine in Healthy Female Volunteers Aged 18 to 40.
Phase: PHASE1
Conditions: Infection by Streptococcus Group B
Sponsor: Minervax ApS

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Protocol MVX13211 
 
 
A two-part, Phase I, randomised, double-blind, placebo-controlled, parallel group study 
to evaluate the safety, tolerability and immunogenicity of a dose range of Group B 
Streptococcus vaccine (GBS-NN) in healthy female volunteers aged 18 to 40. 
 
 
 
Version: 
6.0 
 
Version Date: 
30 Nov 2015 
EUDRACT Number: 
2014-004542-10 
 
Sponsor: 
Minervax ApS 
Ole Maaløes Vej 3 
DK-2200 Copenhagen N 
Denmark 
 
Phase: 
Phase I 
 
GCP Statement: 
This study is to be performed in full compliance with ICH and all 
applicable local Good Clinical Practices and regulations. 
 
Confidentiality: 
This document is confidential. It contains proprietary information 
of Minervax. Any viewing or disclosure of such information that is 
not authorised in writing by the Sponsor is  strictly  prohibited. Such 
information may be used solely for the purpose of reviewing or 
performing this study. 

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Table of Contents 
1. 
APPROVAL SIGNATURES ................................................................................................................................ 5 
2. 
PROTOCOL REVISION HISTORY .................................................................................................................... 9 
3. 
STUDY CONTACTS .......................................................................................................................................... 10 
4. 
SYNOPSIS .......................................................................................................................................................... 12 
5. 
LIST OF ABBREVIATIONS .............................................................................................................................. 19 
6. 
INTRODUCTION ............................................................................................................................................... 21 
6.1 
Background ................................................................................................................................................ 21 
6.2 
Rationale for Study .................................................................................................................................... 22 
6.2.1 Rationale for Exploratory Immunological Assessments ............................................................................. 24 
6.3 
Risk/Benefit Assessment ............................................................................................................................ 26 
7. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................................... 28 
7.1 
Primary Objective ...................................................................................................................................... 28 
7.2 
Secondary Safety Objectives ...................................................................................................................... 28 
7.3 
Secondary Immunological Objectives ........................................................................................................ 28 
 
 
 
 
 
8. 
STUDY DESIGN ................................................................................................................................................ 30 
8.1 
Overview .................................................................................................................................................... 30 
8.2 
Study Centre(s) .......................................................................................................................................... 30 
8.3 
Study Duration ........................................................................................................................................... 30 
9. 
STUDY POPULATION ...................................................................................................................................... 31 
9.1 
Inclusion Criteria ........................................................................................................................................ 31 
9.2 
Exclusion Criteria ...................................................................................................................................... 31 
9.3 
Planned Sample Size .................................................................................................................................. 32 
9.4 
Allocation of Randomisation Numbers ...................................................................................................... 32 
9.5 
Volunteer Withdrawal ................................................................................................................................ 33 
9.6 
Volunteer Replacement .............................................................................................................................. 33 
9.7 
Premature Termination of the Study .......................................................................................................... 33 
10. 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................................... 35 
10.1 
Identity and Doses of IMP.......................................................................................................................... 35 
10.2 
Randomisation ........................................................................................................................................... 36 
10.3 
IMP Administration ................................................................................................................................... 37 
10.4 
Blinding ...................................................................................................................................................... 37 
10.5 
Vacccine Accountability and Storage ........................................................................................................ 37 
11. 
PRIOR AND CONCOMITANT MEDICATION, AND OTHER RESTRICTIONS .................................... 39 
11.1 
Prior Medications ....................................................................................................................................... 39 
11.2 
Concomitant Medications .......................................................................................................................... 39 
11.3 
Other Restrictions ...................................................................................................................................... 39 
12. 
STUDY CONDUCT ...................................................................................................................................... 40 

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12.1 
Screening Period (Part A and Part B) ......................................................................................................... 40 
12.2 
Treatment Period and Post-Study Period ................................................................................................... 40 
12.2.1 
Part A................................................................................................................................................. 40 
12.2.2 
Part B ................................................................................................................................................. 43 
12.3 
Safety Assessments .................................................................................................................................... 45 
12.3.1 
Clinical Laboratory Tests .................................................................................................................. 45 
12.3.2 
ECGs and Vital Signs ........................................................................................................................ 46 
12.3.3 
Injection Site Tolerability Assessment .............................................................................................. 46 
12.4 
Time Windows for Visits ........................................................................................................................... 47 
12.5 
Safety Monitoring Board and Safety Data Review Meetings (Part A only) ............................................... 47 
12.6 
Individual Volunteer Stopping Criteria ...................................................................................................... 48 
12.7 
Study Stopping Criteria .............................................................................................................................. 48 
13. 
PHARMACODYNAMIC ANALYSIS AND EXPLORATORY ASSESSMENTS ..................................... 49 
13.1 
Pharmacodynamic blood sample – antibody response ............................................................................... 49 
13.2 
Streptococcus B swab – vaginal and rectal ................................................................................................ 49 
 
 
 
 
 
14. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND REPORTING............................................... 50 
14.1 
Adverse Events (AEs) ................................................................................................................................ 50 
14.2 
Categorisation of Adverse Events .............................................................................................................. 50 
14.2.1 
Intensity Classification ...................................................................................................................... 50 
14.2.2 
Causality Classification ..................................................................................................................... 51 
14.3 
Recording and Follow up of Adverse Events ............................................................................................. 51 
14.4 
Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions (SUSARs) .................... 52 
14.5 
Reporting Timelines ................................................................................................................................... 52 
14.5.1 
SAE Reporting .................................................................................................................................. 52 
14.5.2 
SUSAR Reporting ............................................................................................................................. 53 
14.6 
Abnormal Findings from Investigations or Assessments ........................................................................... 53 
14.7 
Pregnancy ................................................................................................................................................... 53 
15. 
STATISTICAL EVALUATION .................................................................................................................... 54 
15.1 
Statistical method description .................................................................................................................... 54 
15.1.1 
General information .......................................................................................................................... 54 
15.1.2 
Descriptive statistics for the two study parts ..................................................................................... 54 
15.1.3 
Inferential statistics ............................................................................................................................ 54 
15.2 
Studied populations for each study part ..................................................................................................... 55 
15.3 
Sample size ................................................................................................................................................ 55 
15.4 
Studied criteria for the two study parts ...................................................................................................... 55 
15.4.1 
Characteristics of included volunteers ............................................................................................... 55 
15.4.2 
Primary endpoint for the two study parts .......................................................................................... 56 
15.4.3 
Secondary Safety Endpoints .............................................................................................................. 58 

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15.4.4 
Secondary Immunological Endpoints ................................................................................................ 58 
 
 
 
 
 
16. 
ETHICS AND REGULATORY .................................................................................................................... 62 
16.1 
Conduct ...................................................................................................................................................... 62 
16.2 
Review ....................................................................................................................................................... 62 
16.3 
Volunteer Information and Informed Consent ........................................................................................... 63 
17. 
GENERAL OBLIGATIONS, AGREEMENTS AND ORGANISATION .................................................... 64 
17.1 
Data Protection and Confidentiality ........................................................................................................... 64 
17.2 
CRFs and Handling .................................................................................................................................... 64 
17.3 
Quality Control and Monitoring ................................................................................................................. 64 
17.4 
Quality Assurance, Audit and Inspection ................................................................................................... 64 
17.5 
Storage of Study Documents ...................................................................................................................... 65 
17.6 
Registration and Publication of Study and Results .................................................................................... 65 
18. 
SCHEDULE OF ASSESSMENTS................................................................................................................. 66 
19. 
REFERENCES ............................................................................................................................................... 72 
APPENDIX 1 .............................................................................................................................................................. 74 

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1. 
PROTOCOL REVISION HISTORY 
 
 
 
Date 
Description 
02 Mar 2015 
Final Protocol v1.0 
04 Mar 2015 
v2.0 protocol updated to include diary cards 
for AE collection after Day 85 in Part B and 
addition of injection site assessment at 
discharge on Days 1 and 29. 
16 April 2015 
3.0 protocol clarified regarding maximum dose 
being 250 µg and the optional cohort 7 to 
investigate doses below 250 µg 
27 May 2015 
v4.0 protocol clarified regarding drugs of 
abuse and alcohol breath test at screening 
and urinalysis tests during study. 
06 Oct 2015 
v5.0 updated to change post dose medical 
cover and in house stay on day 1 and day 29 
(if applicable) for Part B. Change in safety 
laboratory for Part B. TDL added to list of 
providers. Allocation of replacement 
randomisation numbers in Part B clarified. 
30 Nov 2015 
v6.0 updated to amend the time windows after 
Day 85 to +/- 3 weeks and to change the name 
of Huntingdon Life Sciences to Envigo. 

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SAFETY LABORATORIES 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICS, DATA MANAGEMENT AND REPORT WRITING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
ANALYSIS OF PHARMACODYNAMIC BLOOD SAMPLES AND SWABS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. 
SYNOPSIS 
 
 
Protocol Number: 
MVX13211 
Study Vaccine(s): 
Group B Streptococcus Vaccine (GBS-NN) 
Title: 
A two-part, Phase I, randomised, double-blind, placebo-controlled, 
parallel 
group 
study 
to 
evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of a dose range of Group B Streptococcus vaccine (GBS-
NN) in healthy female volunteers aged 18 to 40. 
EudraCT Number: 
2014-004542-10 
Objectives 
and Endpoints: 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of the GBS-
NN vaccine for 12 weeks after the first dose of vaccine. 
The following endpoints will be evaluated to support this objective: local 
and systemic reactogenicity; adverse events; laboratory tests; urinalysis; 
vital signs; 12-Lead ECG parameters; physical examination. 
Secondary Safety Objectives 
The secondary safety objective for Part B is to evaluate the long term 
safety profile of the GBS-NN vaccine up to 1 year following the first dose. 
The same endpoints will be evaluated as for the primary objective. 
Secondary Immunological Objectives 
The secondary immunological objectives for both parts of the study are: 
• To evaluate IgG antibody responses induced by different vaccine 
doses alone or in the presence of Alhydrogel over time in healthy 
female volunteers. 
• To determine the impact of pre-existing antibody levels on the 
vaccine-induced antibody response. 
In addition for Part A: 
• To determine the effect of Alhydrogel® adjuvant on the 
immunogenicity of GBS-NN vaccine. 
• To select the dose levels and regimens for vaccination of cohorts in 
Part B, based on the antibody levels at 8 weeks following the first dose 
(Day 57). 
In addition for Part B: 

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• To evaluate the immune response to the GBS-NN vaccine up to 1 
year following the first dose. 
The following endpoints will be evaluated by group and time-point to 
support these objectives: 
• Geometric mean antibody concentration in μg/mL. 
• Geometric mean fold increase in antibody concentration. 
• Seroconversion rate (proportion of volunteers with fold increase 
above threshold). 
• Proportion of volunteers achieving antibody concentrations above 
specific thresholds at Day 85 (for Part A these will be 0.5, 1, 2, 4, 8 
μg/mL and for Part B these may be modified based on the results from 
Part A). 
The primary immunological endpoints for both Part A and Part B will be 
the values of these endpoints at Day 85, 12 weeks after the 
administration of the first dose of vaccine. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
A Phase I, randomised, double-blind, placebo-controlled, parallel group, 
single centre study. 
All cohorts in Part A will incorporate sentinel dosing of 2 volunteers in 

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The following data (safety, immunogenicity and exploratory endpoints) 
will be described according to vaccine dose groups (and according to 
visits if relevant): 
• 
Demographic and baseline data; 
• 
Safety data including: 
 
vital signs (heart rate, blood pressure, tympanic 
temperature and respiratory rate) 
 
12-lead ECG 
 
safety laboratory tests (haematology, biochemistry) 
 
urinalysis 
 
adverse events 
 
physical examinations 
 
assessment 
results 
of 
the 
injection 
site 
(local 
reactogenicity) and systemic reactogenicity using scale 
variables; 
• 
Pharmacodynamic blood sample results (antibody response). 
. 
Descriptive statistics 
Descriptive statistics for quantitative parameters will be provided using 
number of observations (N), mean, standard deviation (SD), standard 
error of the mean (SEM), minimum, median and maximum. Descriptive 
statistics for qualitative parameters will be provided using absolute 
frequencies (n) and relative frequencies (%). 
Inferential statistics 
Statistical tests will be carried out to compare results between treatment 
groups, depending on studied variable type. These analyses will be fully 
detailed in the SAP. 
For categorical endpoints, such as local and systemic reactogenicity, a 
comparison of events intensity (scores) between vaccine dose groups 
can be performed with an adequate statistical test dealing with 
categorical variables (for example: Fisher exact test, Chi square test or 
generalized estimating equations). 
For continuous endpoints, such as immune response induced by different 
GBS-NN vaccine dosing regimens, appropriate statistical method (for 
example: ANOVA) can be used to compare pre-vaccination and post-
vaccination levels. 
Studied populations 
The following populations will be taken into account for each study part: 
• Intention to Treat Set (ITT): All included volunteers who receive at 
least one dose of the study vaccine will be taken into account in the 
description of the population  (disposition,  demographic  or  baseline 
characteristics); 
• Immunogenicity Set (IG): The subset of volunteers who will receive
at least one dose of the study vaccine with available pre- and post-
vaccination titers. 
• Per Protocol Set (PP): All volunteers who receive both doses of the 
study vaccine and provide evaluable samples for analysis of the 

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The Primary and Secondary Safety analyses will be performed on the ITT 
set. The Secondary Immunological analyses will be performed on  the IG 
set. The “primary” immunological analysis (i.e. the results on Day 85 in 
both study parts) will also be performed on the PP set. 
Sample size: 
Up to 70 healthy female volunteers in part A (7 cohorts of 10 volunteers) 
and up to 240 in part B (3 cohorts of 80 volunteers). The final number of 
volunteers to be randomized in part B will be calculated following a data 
review from part A. 

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5. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic and Therapeutic Class 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
CA 
Competent Authority 
CPS 
Capsule Polysaccharide 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CS 
Clinically Significant 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOD 
Early Onset Disease 
EU 
European Union 
FACS 
Fluorescence-Activated Cell Sorting 
FSH 
Follicle Stimulating Hormone 
GBS 
Group B Streptococcus 
GBS-NN 
Group B Streptococcus vaccine 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMT 
Geometric Mean Titre 
HIV 
Human Immunodeficiency Virus 
IAP 
Inter Partum Antibiotic Prophylaxis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IG 
Immunogenicity Set 
IS 
Included Set 
ITT 
Intention to Treat 

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IUD 
Intra Uterine Device 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification 
LOD 
Late Onset Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
NTEAE 
Non Treatment Emergent Adverse Event 
OPA 
Opsonophagocytic Killing Assay 
PBMC 
Peripheral Blood Mononuclear Cell 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SEM 
Standard Error of the Mean 
SMB 
Safety Monitoring Board 
SOC 
System Organ Class 
SS 
Safety Set 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
Th cells 
T helper cells 
TOPS 
The Over Volunteering Prevention System 
VIS 
Volunteer Information Sheet 
WHO-DD 
World Health Organisation – Drug Dictionary 

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6. 
INTRODUCTION 
6.1 
Background 
 
Streptococcus agalactiae is a Lancefield Group B Streptococcus (GBS), first isolated in 1887, 
but was not considered a human pathogen until the 1970’s. This bacterium has now emerged 
as the leading cause of neonatal sepsis. GBS is also increasingly recognised as an important 
cause of disease in adults, especially in the elderly and those with underlying disease (Schrag 
et al., 2000, Skoff et al., 2009). In fact GBS is responsible for 50% of life- threatening 
infections in newborns, leading to severe morbidity and life-long disabilities. In particular, GBS 
is responsible for over 80% of meningitis in neonates less than 2 months of age (CDC, 2010 
Vol.59). 
 
GBS neonatal infections are associated with high morbidity and mortality and constitute a 
major public health problem affecting 0.5 to 3 new-borns per 1000 live births (CDC 2002).  In 
the UK, national surveillance during 2000-2001 identified a total of 568 cases; an incidence 
of 0.72 per 1000 live births, showing regional variation with 0.42 per 1000 live births in 
Scotland and 0.9 in Northern Ireland. GBS neonatal infections have been reported in and 
across Europe, USA, Australasia, South Africa, Kenya and Malawi confirming the global 
nature of the disease. 
 
GBS related neonatal morbidity can be classified into Early Onset Disease (EOD; occurring 
1 to 6 days after birth), and Late Onset Disease (LOD; occurring 7 to 89 days after birth). 
EOD accounts for about 60 to 70% of GBS related neonatal morbidity as a result of vertical 
transmission of GBS from mother to infant at or around the time of delivery. In over 90% of 
cases, clinical features of sepsis and pneumonia occur within 12 to 24 hours (Heath et al., 
2004, 2009). In contrast LOD, which occurs 7 to 89 days post-delivery, and is acquired 
perinatally, nosocomially or from community sources, presenting with meningitis in up to 50% 
of cases (Heath et al., 2004). 
 
GBS is a human commensal of the gastrointestinal tract and about 10 to 35% of pregnant 
women are carriers. GBS colonisation can be transient, intermittent or persistent and yet 
commonly asymptomatic (Verani and Schrag 2010). Spontaneous vaginal/rectal colonisation 
constitutes the fundamental risk factor for GBS transmission. Other recognised risk factors 
include, preterm birth (less than 37 weeks), a mother with a previous baby infected with GBS, 
presence of high temperature during labour, over 18 hours rupture of membranes, and the 
presence of GBS in urine of a pregnant woman. 
 
Introduction of inter partum antibiotic prophylaxis (IAP) in year 2000 in birthing women, who 
are at risk of transmitting GBS to the infant during childbirth due to vaginal/rectal colonisation 
with GBS or other known risk factors, has reduced the incidences of EOD by up to 80% in 
countries, like the US, where universal antenatal screening programs for GBS colonization 
during pregnancy have been implemented. Other countries rely on risk assessment based 
on the factors outlined above, rather than universal screening for GBS colonization. On 
average GBS screening or risk-assessment results in some 20 to 50% of birthing women 
receiving IAP, depending on region. 
 
Despite this widespread use of IAP, EOD has not been reduced by more than 80% at the 
most, and still affects some 4,500 new-born babies annually in Europe and the US combined; 
and the incidences have recently been on the rise again (Health Protection 

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Agency UK, 2012 Vol.6). The failure of IAP to fully eradicate EOD relates primarily to lack of 
adherence to protocol, poor implementation of protocols, premature delivery, and childbirth 
lasting less than the 4 hours required for IAP to be fully active. 
 
Importantly, the serious LOD infections (>50% meningitis) have remained unaffected by IAP, 
at 3,000 cases annually, due to the fact that nosocomial infections are unaffected by IAP 
during childbirth. Also, IAP has had no effect on the incidences of GBS induced stillbirths 
(900) and premature deliveries (7,000), which occur prior to administration of IAP. 
 
In addition to the inability of IAP to completely eradicate EOD and in any way prevent GBS- 
induced LOD, stillbirth and preterm labour, the widespread use of antibiotic prophylaxis in 
GBS prevention has resulted in the emergence of antibiotic resistance in GBS. Penicillin 
remains the preferred antibiotic prophylaxis, but clinical isolates with reduced sensitivity to 
penicillin due to mutations in penicillin-binding proteins have emerged over recent years 
(CDC, 2010 Vol.59) (Kimura, 2008 Vol.52). The alarming finding is that the emerging patterns 
of mutations are identical to those observed in S. pneumoniae prior to the breakthrough of 
widespread true penicillin resistance in that pathogen (Dahesh, 2008 Vol. 52) (Nagano, 2008 
Vol.52). Full breakthrough of penicillin resistance in GBS will lead to a dramatic increase in 
the incidences of EOD, potentially returning the world to pre-IAP levels, as well as creating a 
serious problem when having to treat such infections. In addition, wide-spread resistance to 
antibiotics other than penicillin already exists in GBS isolates (CDC, 2010 Vol.59). Finally, 
IAP has also lead to an increase in neonatal infections with antibiotic resistant strains of other 
bacteria such as E.coli. 
 
6.2 
Rationale for Study 
 
A large medical need exist for the development of an effective alternative to IAP for the 
prevention of neonatal GBS infections, as outlined above. 
 
Maternal immunization of pregnant women during the latter part of pregnancy leading to 
passive immunization of the unborn child through trans-placental transfer of protective GBS-
specific antibodies would be beneficial. Such antibodies will likely persist for 3-6 months after 
birth and likely protect both the foetus in-utero against GBS induced still birth and premature 
delivery; and the newborn baby against both EOD and LOD. A vaccine therefore seems the 
obvious choice for an alternative to IAP. 
 
A number of GBS serotypes can be distinguished based on their type-specific capsular 
polysaccharides (CPS). This capsule represents a major virulence factor, which helps 
bacterial invasion by interfering with phagocytic clearance except in the presence of type 
specific opsonophagocytic antibodies (Baker 2000, Nizer et al., 2000). To date, 10 
antigenically unique GBS serotypes have been identified (Ia, Ib, II-IX). Of these serotypes Ia, 
III and V are the most prevalent in EOD with type III accounting for 36% of EOD and 71 
% of LOD, and together, serotypes Ia, Ib, II, III and V cover approximately 95% of all isolates. 
 
Spontaneous colonization of women with GBS is the likely explanation for the existence of 
naturally occurring antibodies against several GBS antigens in pregnant women. 
Interestingly, the presence of high levels of anti-CPS antibodies in pregnant women has been 
found to correlate with protection of their off-spring against invasive GBS disease, indicating 
that vaccine-induced maternal anti-CPS antibodies would indeed be protective (Baker and 
Kasper, 1976; Lin et al., 2001; Lin et al., 2004). Indeed, CPS-based vaccines 

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Based on the results from clinical use of other protein vaccines adsorbed to Alhydrogel®, and 
other aluminium containing adjuvants transient local reactions at the injection site, including 
pain, oedema, bruising, erythema and induration, mainly of mild intensity, are likely to occur. 
In addition flu-like symptoms, such as fatigue, malaise, myalgia, and mild to moderate 
headache may occur. 
 
GBS-NN vaccination is contraindicated in volunteers known to suffer hypersensitivity 
reactions to vaccines or a known allergy to aluminium hydroxide. For the purpose of the study 
volunteers who have experienced a significant illness in the four weeks prior to check in will 
be excluded. The vaccine should not be given to volunteers with known or suspected immune 
deficiency, autoimmune diseases or who have an acute infection. 
 
GBS-NN should not currently be given to women known, or suspected to be, pregnant, or to 
nursing mothers. Currently GBS-NN should only be administered to women of  child-bearing 
potential if adequate contraceptive precautions are taken, accompanied by serum and/or 
urine pregnancy testing prior to vaccination and during follow up. 
 
All study volunteers will be monitored for potential side effects of vaccination during the entire 
course of the study, as per the protocol, and adverse events must be appropriately followed 
up. 

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7. 
STUDY OBJECTIVES AND ENDPOINTS 
 
 
7.1 
Primary Objective 
 
The primary objective is to evaluate the safety and tolerability of the GBS-NN vaccine for 12 
weeks after the first dose of vaccine. 
 
The following endpoints will be evaluated to support this objective: local and systemic 
reactogenicity; adverse events; laboratory tests; urinalysis; vital signs; 12-Lead ECG 
parameters; physical examination. 
 
7.2 
Secondary Safety Objectives 
 
The secondary safety objective for Part B is to evaluate the long term safety profile of the 
GBS-NN vaccine up to 1 year following the first dose. 
 
The same endpoints will be evaluated as for the primary objective. 
 
7.3 
Secondary Immunological Objectives 
 
The secondary immunological objectives for both parts of the study are: 
• To evaluate IgG antibody responses induced by different vaccine doses alone or in the 
presence of Alhydrogel over time in healthy female volunteers. 
• To determine the impact of pre-existing antibody levels on the vaccine-induced 
antibody response. 
 
In addition for Part A: 
• To determine the effect of Alhydrogel® adjuvant on the immunogenicity of GBS-NN 
vaccine. 
• To select the dose levels and regimens for vaccination of cohorts in Part B, based on 
the antibody levels at 8 weeks following the first dose (Day 57). 
 
In addition for Part B: 
• To evaluate the immune response to the GBS-NN vaccine up to 1 year following the 
first dose. 
 
The following endpoints will be evaluated by group and time-point to support these 
objectives: 
• Geometric mean antibody concentration in μg/mL. 
• Geometric mean fold increase in antibody concentration. 
• Seroconversion rate (proportion of volunteers with fold increase above threshold). 

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• Proportion of volunteers achieving antibody concentrations above specific thresholds at 
Day 85 (for Part A these will be 0.5, 1, 2, 4, 8 μg/mL and for Part B these may be modified 
based on the results from Part A). 
 
The primary immunological endpoints for both Part A and Part B will be the values of 
these endpoints at Day 85, 12 weeks after the administration of the first dose of vaccine. 
 
7.4 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. 
STUDY DESIGN 
 
8.1 
Overview 
This is a Phase I, randomised, double-blind, placebo-controlled, parallel group, single centre 
study. 
The study comprises 2 parts. All cohorts in Part A will incorporate sentinel dosing of 2 
volunteers in each cohort for the primary dose only: 1 on active treatment and 1 on placebo. 
No further volunteers in that cohort will be dosed until at least 24 hours after dosing the 
second volunteer, provided that there are no serious or unexplained safety issues as 
determined by the Investigator. 
In Part A, the decision to proceed with administration of the primary dose in subsequent 
cohorts will be made as follows: 
• Safety will be assessed after at least 7 evaluable volunteers in cohort 1 (sentinel and 
main) have completed Visit 4 (Day 8), at which point the decision will be made whether 
to proceed with administration of the primary dose in cohorts 2 and 3. 
• Safety will be assessed after at least 7 evaluable volunteers in each of cohorts 2 and 3 
have completed Visit 4 (Day 8), at which point the decision will be made whether to 
proceed with administration of the primary dose in both cohorts 4 and 5 or just one of 
these cohorts. 
• Safety will be assessed after at least 7 evaluable volunteers in each of cohorts 4 and 5 
have completed Visit 4 (Day 8), at which point the decision will be made whether to 
proceed with administration of the primary dose in cohort 6. 
In Part B, sentinel dosing is not required, and volunteers in all groups may be randomised 
and dosed concurrently. 
 
8.2 
Study Centre(s) 
 
The study will be performed at a single centre based in the United Kingdom. 
8.3 
Study Duration 
 
Study start is defined as check-in to the study unit on Day 1. In Part A, each individual 
volunteer will be involved in the study for approximately 12 weeks (excluding the 28 day 
screening period and the 6 month safety follow up phone call). In Part B, each individual 
volunteer will be involved in the study for approximately 1 year (excluding the 28 day 
screening period). 

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9. 
STUDY POPULATION 
 
9.1 
Inclusion Criteria 
 
1. 
Healthy adult female volunteers (as determined by medical history, physical 
examination, laboratory test values, vital signs and electrocardiograms [ECGs] at 
screening) aged 18 – 40 years. 
2. 
Body mass index (BMI) ≥ 18 and ≤ 30 kg/m2. 
3. 
Volunteers weight ≥ 50kg and ≤100kg at screening. 
4. 
Able to voluntarily provide written informed consent to participate in the study. 
5. 
Must understand the purposes and risks of the study and agree to follow the 
restrictions and schedule of procedures as defined in the protocol. 
6. 
Volunteers must be pre-menopausal. Volunteers who have had a hysterectomy will 
have pre-menopausal status confirmed by a FSH and oestradiol test. 
7. 
Females of childbearing potential must have a negative pregnancy test at screening 
(β HCG) and prior to each dose and must be willing to use an adequate and highly 
effective method of contraception until at least Day 85 of the study. A highly effective 
method of birth control is defined as one which results in a low failure rate (i.e. less 
than 1% per year) when used consistently and correctly such as sterilisation, implants, 
injectables, combined oral contraceptives, IUDs (Intrauterine Device), condoms, 
occlusive caps (cervical/vault caps) with spermicidal foam/gel/ film/cream/suppository. 
True sexual abstinence is acceptable when this is in line  with the preferred and usual 
lifestyle of the volunteer (periodic abstinence e.g. calendar, ovulation, symptothermal, 
post-ovulation methods, declaration of abstinence for the duration of the trial, and 
withdrawal are not acceptable methods of contraception) 
8. 
In Part A: Volunteers must be non-smokers for at least 3 months prior to first 
studyvaccine administration. In Part B: Volunteers may be light smokers i.e. up to a 
maximum of 5 cigarettes per day or nicotine equivalent. 
9. 
Must be willing to consent to have data entered into The Over Volunteering Prevention 
System (TOPS). 
10. The volunteer’s primary care physician has confirmed within the last 12 months that 
there is nothing in their medical history that would preclude their enrolment into a 
clinical trial. 
9.2 
Exclusion Criteria 
 
1. 
Volunteers with history or presence of significant cardiovascular disease, pulmonary, 
hepatic, gallbladder or biliary tract, renal, haematological, gastrointestinal, endocrine, 
immunologic, dermatological, neurological, psychiatric, autoimmune disease or 
current infection. 
2. 
Pregnant or lactating females. 
3. 
Laboratory values at screening which are deemed to be clinically significant, unless 
agreed in advance by the Sponsor’s Responsible Medic and Principal Investigator. 

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4. 
Current or history of drug or alcohol abuse, or a positive urine drugs of abuse test or 
alcohol breath test at screening or prior to first dosing (note that a positive drugs of 
abuse result for a regular medication allowed by this protocol will be permitted). 
5. 
Positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C. 
 
6. 
Participation in a clinical drug study during the 90 days preceding the initial dose in 
this study. 
7. 
Any significant illness during the 4 weeks preceding check-in for this study (Day 1). 
8. 
Volunteers with a history of severe allergic reactions after previous vaccination. 
9. 
Volunteers who have received any vaccine within 30 days of screening, or who are 
planning to receive a vaccine up to Day 85 of the study. 
10. Volunteers receiving immunosuppressive therapy (e.g. systemic steroids, cancer 
therapies, methotrexate, azathioprine) in the 6 months prior to screening, antibiotics 
within 10 days of receiving the first dose or taking any short-term medications 
including over-the-counter preparations, vitamins, herbal and/or mineral supplements 
within 7 days of the first dose. Chronic medications such as antihypertensives, 
bronchodilators, oral contraceptives or statins that do not affect the immune system, 
will be permitted and allowed to continue during the study at the discretion of the 
Investigator. Paracetamol will be permitted for the treatment of headache or other 
symptoms. 
11. Volunteers with tattoos at the proposed site of vaccine administration. 
12. Donation of blood or blood products within 90 days prior to vaccine administration. 
13. Volunteers who, in the opinion of the Investigator, are unsuitable for participation in 
the study. 
 
 
9.3 
Planned Sample Size 
 
In Part A, up to 70 healthy female volunteers aged 18 to 40 will be randomised (i.e. up to 7 
cohorts of 10 volunteers). 
In Part B, up to 240 healthy female volunteers aged 18 to 40 will be randomised (i.e. 3 cohorts 
of 80 volunteers). The final number of volunteers to be randomised in Part B will be calculated 
following a review of the data from Part A, and will not exceed 240 volunteers. 
 
At least 7 evaluable volunteers in Part A are required to attend through visit 4 in each cohort 
in order to provide sufficient data for a decision to dose escalate. If the required number of 
evaluable volunteers are not obtained in a cohort, then replacement volunteers must be 
dosed for that cohort, prior to considering dose escalation. 
 
9.4 
Allocation of Randomisation Numbers 
 
Each randomised volunteer will be allocated a four digit randomisation number. The 
randomisation numbers for Part A will be 1001 to 1070, and for Part B will be 2001 to 2240. 
 
In Part A, replacement volunteers will be allocated a randomisation number which is equal to 
the randomisation number of the volunteer they are replacing plus 100, and they will 

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receive the same treatment as the volunteer they are replacing, e.g. if randomisation number 
1003 is replaced, the replacement volunteer will be allocated the randomisation number 
1103. 
 
In Part B, replacement volunteers will be allocated a randomisation number which is equal to 
the randomisation number of the volunteer they are replacing plus 500, and they will receive 
the same treatment as the volunteer they are replacing, e.g. if randomisation number 2003 is 
replaced, the replacement volunteer will be allocated the randomisation number 2503. 
 
9.5 
Volunteer Withdrawal 
 
The volunteer has the right to abstain from participation in the study or to withdraw consent 
to participate at any time without penalty. The Sponsor or the Investigator also holds the 
responsibility to withdraw a randomised volunteer from the study prematurely if it is 
considered in the best interest of the volunteer. The entire study may be stopped if there are 
unpredicted safety concerns. 
 
A volunteer’s participation may be discontinued at any point during the study without 
implications on further medical care if: 
• 
They no longer wish to participate. 
• 
The physician feels it is in their best interest to withdraw. 
• 
The volunteer deviates from the treatment plan specified in the protocol (e.g. failure 
to attend study visits). 
• 
The volunteer is no longer willing to comply with the requirements of the study 
protocol. 
• 
The study is prematurely terminated, see Section 9.7. 
If the participation of any volunteer ceases prematurely, the reasons leading to withdrawal 
from the study should be described in detail. A post-study medical should be performed as 
described in Section 12.2. The case report form (CRF) must be completed as fully as possible 
giving reasons for withdrawal when available. 
9.6 
Volunteer Replacement 
 
At least 7 evaluable volunteers in Part A are required to attend through visit 4 in each cohort 
in order to provide sufficient data for a decision to dose escalate. If the required number of 
evaluable volunteers are not obtained in a cohort, then replacement volunteers must be 
dosed for that cohort, prior to considering dose escalation. 
9.7 
Premature Termination of the Study 
 
Following review by the Sponsor and the Investigator, the study may be terminated prematurely if: 
• 
There are new toxicological or pharmacological findings, serious adverse events (AEs) 
or frequent severe AEs likely to be related to the vaccine that invalidate the positive 
benefit-risk assessment. 
• 
AEs occur in such prominence (i.e. severity and frequency) that the proposed schedule 
can no longer be adhered to. 

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• 
Significant protocol deviations occur at a frequency implicating the valid and safe 
conduct of the study. 
• 
The Sponsor decides to discontinue the study. 
The individual stopping criteria and study stopping criteria are described in Sections 12.6 
and 12.7. 

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It is anticipated that each cohort will receive the following dose regimen as described in the 
table below. 
Note that cohort 7 is an optional cohort, and will proceed if deemed necessary to test an 
additional dosing regimen at a dose level below 250 µg, which will be determined following 
an ongoing review of the data. 
 
 
Cohort 
Dose 
schedule 
Dose level 
Adjuvant 
1 
Day 1, 29 
10µg (A) 
None 
2 
Day 1, 29 
50µg (B) 
None 
3 
Day 1, 29 
10µg (A) 
Alhydrogel® 
4 
Day 1, 29 
250µg (C) 
None 
5 
Day 1, 29 
50µg (B) 
Alhydrogel® 
6 
Day 1, 29 
250µg (C) 
Alhydrogel® 
7 
TBD 
TBD, not 
exceeding 
250 µg 
TBD 
Anticipated dose regimens in Part A 
 
 
The aim of the dose finding overall is to identify the minimum dose level which provides the 
maximum immune response in terms of seroconversion rate, level of specific IgG reached 
and shortest time to peak level, whilst maintaining an acceptable safety profile. 
It is anticipated that the results from Part A will indicate whether the optimal dose level lies 
between 10µg and 50µg, or between 50µg and 250µg. The effect of Alhydrogel® on these 
parameters will guide the decision on whether to include it in one or  more  cohorts  in  Part 
B. 
 
Part B: 
The levels of GBS-NN specific IgG observed in Part A at Day 57, along with the safety 
profile, will be used to define a narrower range of dose levels to explore in Part B, where the 
group sizes are larger and the significance of any observed differences in immune 
responses will be measurable. 
It is currently anticipated that three dose regimens will be selected for evaluation in Part B. 
At least two dose levels will be evaluated, which may be the same or different to those 
administered in Part A, but will not exceed the highest dose administered in Part A. It is 
anticipated that the regimens in Part B will comprise two doses of Alhydrogel® adjuvanted 
vaccine with the second being administered after a variable interval, not exceeding four 
weeks. It is, however, possible that a single dose of vaccine may be evaluated in Part B. 
 
10.2 Randomisation 
 
Volunteers will be randomised pre-dose on the morning of Day 1, once all eligibility criteria 
have been verified. A randomisation list will be held on site, which will be accessible only to 
unblinded study personnel. 

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10.3 IMP Administration 
 
Administration will be by intramuscular injection, preferably into the non-dominant arm. The 
dominant arm may be used if it is not possible to administer into the non-dominant arm e.g. 
due to an ongoing injection site reaction, or tattoo. 
 
10.4 Blinding 
 
This is a double-blind study. The study vaccine will be prepared at the study site by an 
unblinded pharmacy team as detailed in a separate instruction manual. The Investigator  will 
have access to emergency envelopes at all times. In case of an emergency or any finding 
that requires unblinding to determine the identification of the treatment administered for the 
appropriate management of a volunteervolunteer on the study, the Investigator may break 
the blinding code for an individual volunteer. If the blind is broken the Investigator will inform 
the Sponsor, within 24 hours of breaking the blind, that the blind has been broken (but not 
necessarily the outcome of the breaking of the blind), and record the date, time and reason 
for breaking the blind. 
 
Following database soft lock after visit 10 at 12 weeks for both Part A and Part B, dedicated 
members of the Data Management and Statistical teams will be unblinded. Study volunteers 
and clinical staff at the study site will remain blinded until after completion of the final follow-
up visit in Week 52. 
 
For the analysis of IgG concentration data up to Day 57 in Part A, to enable dose selection 
for Part B, a separate statistician will be unblinded to perform the analysis. 
 
10.5 Vacccine Accountability and Storage 
 
The Investigator and study staff will be responsible for the accountability of all study vaccines 
(dispensing, inventory and record keeping) and adherence to GCP guidelines as well as 
appropriate regulations. Studyvaccines will be stored according to the instructions on the 
label as received by the manufacturer. 
 
The Investigator will not allow the study vaccine to be used other than as directed by this 
protocol. Study vaccines will not be dispensed to any individual who is not randomised in the 
study. 
 
An accurate and timely record of the receipt of all study vaccines, dispensing to volunteers, 
collection of unused study vaccines returned, and subsequent return of unused study 
vaccines to the Sponsor (or designated distributor) must be maintained. This includes, but 
may not be limited to, receipt of study vaccines, IMP accountability logs, IMP return 
documentation and shipping receipts. 
 
The supplies and inventory records must be made available, upon request, for inspection by 
the designated representative of the Sponsor or a representative of a regulatory authority. All 
unused study vaccines will be reconciled and handled in agreement with the Sponsor. 

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The Investigator must ensure the availability of an appropriate storage location and the 
recording and evaluation of storage conditions. The responsible pharmacist will keep an 
inventory. This will include a description of the formulation and the quantity of investigational 
materials received for the study and a record of the materials that are dispensed, to whom 
and when. 
 
Upon termination of the study the pharmacist will conduct a final inventory of the medication 
supply and will record the results of this inventory in the Drug Accountability Form. Unused 
medication will be returned to the Sponsor (or designated distributor) or destroyed at the end 
of the study according to instructions provided by the Sponsor. 

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11. PRIOR AND CONCOMITANT MEDICATION, AND OTHER 
RESTRICTIONS 
 
11.1 Prior Medications 
 
Medications which are not permitted prior to study start are detailed in the exclusion criteria. 
11.2 Concomitant Medications 
 
Chronic medications such as antihypertensives, bronchodilators, oral contraceptives or 
statins that do not affect the immune system, will be permitted and allowed to continue during 
the study at the discretion of the Investigator. Paracetamol will be permitted for the treatment 
of headache or other symptoms. 
 
Any medication the volunteer takes other than study vaccine, including herbal and other non-
traditional remedies, is considered a concomitant medication. All concomitant medications 
taken during the study must be recorded in the CRF. 
 
11.3 Other Restrictions 
 
The Investigator or designee will request that volunteers abstain from: 
• 
Donation of blood or blood products for 90 days after the last dose of trial medication. 
• 
Consumption of alcoholic beverages within 24 hours prior to dosing. 
• 
Use of cosmetics or creams at the site of vaccination within 24 hours prior to dosing. 
• 
Excessive exercise or a significant change in usual exercise habit within 7 days prior 
to dosing and for 7 days post dosing. 

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12. STUDY CONDUCT 
 
12.1 Screening Period (Part A and Part B) 
 
Screening assessments for Part A and Part B will be performed within 28 days prior to the 
first study vaccine administration (Day 1). The following assessments will be carried out at 
the screening visit (Visit 1) after written informed consent has been obtained: 
• 
Inclusion/Exclusion 
• 
Demography 
• 
Medical history 
• 
Physical examination 
• 
Height, weight, body mass index (BMI) 
• 
Vital signs (heart rate, blood pressure, tympanic temperature and respiration rate) 
• 
12-lead electrocardiogram (ECG) 
• 
Urinalysis 
• 
Blood samples for haematology and biochemistry 
• 
Blood samples for HIV, hepatitis B and hepatitis C 
• 
Serum pregnancy test for females of child-bearing potential 
• 
Alcohol breath test 
• 
Urine drugs of abuse test (methadone, methamphetamine, cannabis, phencyclidine, 
benzodiazepines, cocaine, opiates, tricyclic antidepressants, barbiturates and 
amphetamines) 
• 
A review of all medications taken in the previous month 
 
 
12.2 Treatment Period and Post-Study Period 
12.2.1 Part A 
Volunteers will receive one of up to 7 dosing regimens of GBS-NN or placebo on 1 or 2 
occasions – a primary dose will be administered at Visit 2 and volunteers will remain in the 
study unit for at least 8 hours post-dose, and if a booster dose is required, this will be 
administered at Visit 6. There will be a time interval of 4 weeks between Visit 2 and Visit  6, 
although this time interval may change if the dosing regimen is changed. There will be 10 
volunteers in each group, 8 randomised to active and 2 to placebo. All cohorts in Part A will 
incorporate sentinel dosing of 2 volunteers in each cohort for the primary dose only: 1 on 
active treatment and 1 on placebo. No further volunteers in that cohort will be dosed until at 
least 24 hours after dosing the second volunteer, provided that there are no serious or 
unexplained safety issues as determined by the Investigator. 
The decision to proceed with administration of the primary dose in subsequent cohorts will 
be made as described in Section 12.5. 

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The following assessments will be carried out at these visits: 
Visit 2 
A urine pregnancy test, brief physical examination, urine drugs of abuse test and alcohol 
breath test will be performed to confirm eligibility.  Eligible volunteers will be randomised  to 
receive active or placebo on 1 or 2 occasions (all volunteers will receive a primary dose at 
Visit 2 and a booster dose of the same medication (active or placebo) will be administered 
at Visit 6 if required). The dose administered, the number of doses and the time interval 
between doses will be dependent on the data generated from the preceding cohort and will 
be decided by the Safety Review Committee. A pharmacodynamic blood sample will be 
taken to measure pre-existing antibody levels prior to dosing. The primary dose will be 
administered at Visit 2 and volunteers will remain in the study unit for at least 8 hours post-
dose.  Vital signs will be recorded pre-dose and at 2 and 6 hours post-dose  A brief medical 
examination (including an assessment of the injection site) will be performed prior to 
discharge to ensure the volunteer is fit for discharge. 
Visit 3 
Visit 3 will be performed 24 hours (± 2 hours) after administration of the primary dose and 
an assessment of the injection site will be performed, vital signs will be recorded and AEs 
and concomitant medications will be reviewed. 
Visit 4 
Visit 4 will be performed 1 week after administration of the primary dose. An assessment of 
the injection site will be performed, vital signs will be recorded, safety blood samples for 
haematology and biochemistry will be collected, urinalysis will be performed and AEs and 
concomitant medications will be reviewed. 
Visit 5 
Visit 5 will be performed 2 weeks after administration of the primary dose. This visit will be 
performed via telephone and a review of AEs and concomitant medications will be 
performed. 
Visit 6 
Visit 6 will be performed 4 weeks after Visit 2. A booster dose will or will not be administered 
at this visit depending on the decision made by the Safety Review Committee for each 
cohort. 
If a booster dose is administered at this visit, the following assessments will be performed: 
an assessment of the injection site and a pharmacodynamic blood sample will be taken to 
measure antibody response prior to dosing. A urine pregnancy test will be performed prior 
to dosing. A booster dose will be administered. Volunteers will remain in the study unit for 
at least 4 hours post-dose. Vital signs will be recorded pre-dose and at 2 hours post-dose. 
A brief medical examination (including an assessment of the injection sites) will be 
performed prior to discharge to ensure the volunteer is fit for discharge. 
If a booster dose is not administered at this visit, the following assessments will be 
performed: an assessment of the injection site and a pharmacodynamic blood sample will 
be taken to measure antibody response. 
AEs and concomitant medications will be reviewed whether a booster dose is administered 
or not. 

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Visit 7 (Only if a booster dose is administered) 
Visit 7 will be performed 24 hours (± 2 hours) after administration of the booster dose and 
an assessment of the injection sites will be performed, vital signs will be recorded and AEs 
and concomitant medications will be reviewed. If a booster dose is not administered, this 
visit will not be performed. 
Visit 8 
Visit 8 will be performed 2 weeks following Visit 6 and the following assessments will be 
performed: an assessment of the injection sites, vital signs will be recorded, safety blood 
samples for haematology and biochemistry will be collected, urinalysis will be performed, a 
pharmacodynamic blood sample will be taken to measure antibody response and AEs and 
concomitant medications will be reviewed. 
Visit 9 
Visit 9 will be performed 8 weeks following the first study vaccine administration and the 
following assessments will be performed: an assessment of the injection site and a 
pharmacodynamic blood sample will be taken to measure antibody response and AEs and 
concomitant medications will be reviewed. 
Post-Study Medical (Visit 10) 
A post-study medical will be performed 12 weeks following the first study vaccine 
administration and the following assessments will be carried out: an assessment of the 
injection site, a pharmacodynamic blood sample will be taken to measure antibody 
response, physical examination, vital signs, 12-lead ECG, urinalysis, blood samples for 
haematology and biochemistry, serum pregnancy test (if applicable) and a review of AEs 
and concomitant medications. 
Safety Follow-Up (Visit 11) 
A safety follow-up phone call will be performed 3 months after the end of the study (Visit 10) 
i.e. 6 months following the first study vaccine administration to check the general health of 
the volunteer and to review significant AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
In both Part A and Part B, following the primary dose volunteers will remain in the study unit 
for 8 hours post-dose to ensure that no significant AEs occur and the medicinal product is 
well tolerated. No additional acute safety concerns are considered likely to occur following 
8 hours of observation. Following the booster dose volunteers will remain 

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in the clinic for at least 4 hours post-dose, as the volunteer has tolerated the initial dose, 
and therefore, tolerability should be consistent. The concern is for an acute systemic 
reaction following the booster dose. It is not considered necessary to keep the volunteers in 
the study unit overnight as no samples are being taken and the time intervals are considered 
appropriate to assess the safety and tolerability prior to discharge. 
12.2.2 Part B 
 
Volunteers will receive one of 3 dosing regimens (X, Y or Z) of GBS-NN or placebo on 1 or 
2 occasions – a primary dose will be administered at Visit 2, and if a booster dose is required, 
this will be administered at Visit 6. There will be up to 80 volunteers in each group, up to 60 
randomised to active vaccine and up to 20 to placebo. 
The following assessments will be carried out at the visits during the Treatment Period: 
Visit 2 
A urine pregnancy test, brief physical examination, urine drugs of abuse test and alcohol 
breath test will be performed to confirm eligibility. Eligible volunteers will be randomised to 
receive active or placebo on 1 or 2 occasions (all volunteers will receive a primary dose at 
Visit 2 and a booster dose will be administered at Visit 6 if required). The dose administered 
and the number of doses will be decided based on the results of Part A. Vaginal and rectal 
swabs will be taken to assess colonisation by Group B streptococcus (GBS) and a 
pharmacodynamic blood sample will be taken to measure pre-existing antibody levels prior 
to dosing. 
The primary dose will be administered at Visit 2 and volunteers will remain in the study unit 
for at least 2 hours post-dose. Vital signs will be recorded pre-dose and at 2 hours post-
dose. A brief medical examination (including an assessment of the injection site) will be 
performed prior to discharge to ensure the volunteer is fit for discharge. 
Visit 3 
Visit 3 will be performed 24 hours (± 2 hours) after administration of the primary dose and 
an assessment of the injection site will be performed, and vital signs will be recorded and 
AEs and concomitant medications will be reviewed. 
Visit 4 
Visit 4 will be a performed 1 week after administration of the primary dose by telephone to 
review AEs and concomitant medications. 
Visit 5 
Visit 5 will be performed 2 weeks after after administration of the primary dose and the 
following assessments will be performed: an assessment of the injection site, and AEs and 
concomitant medications will be reviewed, a pharmacodynamic blood sample will be taken 
to measure antibody response. Vital signs will be recorded, safety blood samples for 
haematology and biochemistry will be collected and urinalysis will be performed. 
Visit 6 
Visit 6 will be performed 4 weeks after Visit 2, although this time interval may change 
depending on the dose regime chosen. A booster dose will or will not be administered at 
this visit depending on the dose regime chosen. 
If a booster dose is administered at this visit, the following assessments will be performed: 
an assessment of the injection site, vaginal and rectal swabs will be taken to assess 
colonisation by GBS and a pharmacodynamic blood sample will be taken to measure 

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antibody response prior to dosing. A urine pregnancy test will be performed prior to dosing. 
A booster dose will be administered. Volunteers will remain in the study unit for at least 2 
hours post-dose. Vital signs will be recorded pre-dose and at 2 hours post-dose. A brief 
medical examination (including an assessment of the injection sites) will be performed prior 
to discharge to ensure the volunteer is fit for discharge. 
If a booster dose is not administered at this visit, the following assessments will be 
performed: an assessment of the injection site, vaginal and rectal swabs will be taken to 
assess colonisation by GBS and a pharmacodynamic blood sample will be taken to measure 
antibody response. 
AEs and concomitant medications will be reviewed whether a booster vaccination is 
administered or not. 
Visit 7 (To be conducted only if a booster dose is administered) 
Visit 7 will be performed 24 hours (± 2 hours) after administration of the booster dose and 
an assessment of the injection sites will be performed, vital signs will be recorded and AEs 
and concomitant medications will be reviewed. If a booster dose is not administered, this 
visit will not be performed. 
Visit 8 
Visit 8 will be performed 2 weeks after Visit 6 and the following assessments will be 
performed: an assessment of the injection sites, vital signs will be recorded, safety blood 
samples for haematology and biochemistry will be collected, urinalysis will be performed, a 
pharmacodynamic blood sample will be taken to measure antibody response and AEs and 
concomitant medications will be reviewed. 
Visits 9 and 10 
These are follow-up visits for the assessment of pharmacodynamic markers and/or safety 
up to the timing of the primary endpoint (Visit 10 i.e. Week 12). 
Visit 9 (week 8) and Visit 10 (week 12, timing of primary endpoint) will take place at the 
study unit and the following assessments will be performed: vaginal and rectal swabs will 
be taken to assess colonisation by GBS, a pharmacodynamic blood sample will be taken to 
measure antibody response, vital signs will be recorded, an assessment of the injection 
sites will be performed and AEs and concomitant medications will be reviewed. At Visit 10 
(week 12) a urine pregnancy test will also be performed. 
Visits 11, 12, 13, 14, 15, 16, 17, 18 and 19 
Visit 11 (week 16), Visit 13 (week 24), Visit 15 (week 32) and Visit 17 (week 40) will take 
place at the study unit and the following assessments will be performed: vaginal and  rectal 
swabs will be taken to assess colonisation by GBS, a pharmacodynamic blood sample will 
be taken to measure antibody response, vital signs will be recorded, an assessment of the 
injection site will be performed and significant AEs and concomitant medications will be 
reviewed. 
The remaining visits [Visit 12 (week 20), Visit 14 (week 28), Visit 16 (week 36), Visit 18 
(week 44) and Visit 19 (week 48)] will be conducted via a phone call and AE’s and 
concomitant medications will be reviewed. 
Post-Study Medical (Visit 20) 
A post-study medical will be performed 12 months following the first injection and the 
following assessments will be carried out: an assessment of the injection site, vaginal and 
rectal swabs will be taken to assess colonisation, a pharmacodynamic blood sample will 

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be taken to measure antibody response, physical examination, vital signs (heart rate and 
blood pressure, including tympanic temperature and respiration rate), 12-lead 
electrocardiogram (ECG), urinalysis, blood samples for haematology and biochemistry, 
serum pregnancy test (if applicable) and a review of AEs and concomitant medications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Phenotypic and genetic analyses may be performed on GBS strains isolated from 
volunteers’ vaginal and rectal swabs. 
12.3 Safety Assessments 
 
The description of safety assessments is given below, and the timings of these assessments 
is given in the Schedule of Assessments. The time points of the safety assessments may 
change depending on information gained throughout the study, however the total number of 
safety assessments per volunteer will not be reduced, although unscheduled assessments 
may be performed at the discretion of the Investigator. 
 
12.3.1 Clinical Laboratory Tests 
 
The following parameters will be measured: 
Haematology 
Red blood cell count 
Haemoglobin 
Haematocrit 
Platelet count 
White blood cell count with absolute differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
 
Biochemistry 
 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea 

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Creatinine 
Creatine Kinase 
Glucose (in a fasting state at screening) 
Calcium 
Albumin 
Cholesterol 
Triglycerides 
Phosphorus (inorganic phosphate) 
Lactate dehydrogenase (LDH) 
Total protein 
Globulin 
Uric acid 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyl-transferase (GGT) 
Total bilirubin 
Direct bilirubin 
Urinalysis  
Specific gravity 
pH 
Protein 
Glucose 
Ketone 
Occult blood 
Leukocyte esterase 
Nitrites 
 
Additional urine microscopy analysis will be undertaken, if any abnormalities are detected, 
to analyse for red blood cells, white blood cells, epithelial cells, bacteria, casts, and crystals. 
12.3.2 ECGs and Vital Signs 
 
ECGs will be recorded after the volunteer has been lying for at least 5 minutes. 
 
Vital signs will be recorded in the supine position, after the volunteer has been lying for at 
least 5 minutes. The normal ranges for vital signs are: 
 
Systolic blood pressure 
90-140 mmHg 
Diastolic blood pressure 
40-90 mmHg 
Pulse rate 
40-100 bpm 
Respiration rate 
10-20 breaths per minute 
Temperature 
≥ 35.8oC and ≤ 38oC 
 
12.3.3 Injection Site Tolerability Assessment 
 
Injection site tolerability assessments will be performed as described in Appendix 1. 

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12.4 Time Windows for Visits 
 
Vital signs will be performed within ±10 minutes of the scheduled time. 
The time window for Visits 3 and 7 is ± 2 hours. 
The time window for Visits 4, 5, 6, 8, 9 and 10 is +/- 1 day. 
The time window for Visit 11 in Part A is +/- 1 week. 
The time window for visits from Visit 11 in Part B onwards is +/- 3 weeks. 
 
 
12.5 Safety Monitoring Board and Safety Data Review Meetings (Part A only) 
 
All cohorts in Part A will incorporate sentinel dosing of 2 volunteers in each cohort for the 
primary dose only: 1 on active treatment and 1 on placebo. No further volunteers in that 
cohort will be dosed until at least 24 hours after dosing the second volunteer, provided that 
there are no serious or unexplained safety issues as determined by the Investigator. 
In Part A, the decision to proceed with administration of the primary dose in subsequent 
cohorts will be made as follows: 
• Safety will be assessed after at least 7 evaluable volunteers in cohort 1 (sentinel and 
main) have completed Visit 4 (Day 8), at which point the decision will be made to proceed 
with administration of the primary dose in cohorts 2 and 3. 
• Safety will be assessed after at least 7 evaluable volunteers in each of cohorts 2 and 3 
have completed Visit 4 (Day 8), at which point the decision will be made to proceed with 
administration of the primary dose in both cohorts 4 and 5 or just one of these cohorts. 
• Safety will be assessed after at least 7 evaluable volunteers in each of cohorts 4 and 5 
have completed Visit 4 (Day 8), at which point the decision will be made to proceed with 
administration of the primary dose in cohort 6. 
The following safety data will be reviewed: 
• Clinical Laboratory Tests 
• ECGs 
• Vital signs 
• Physical examinations 
• Assessment of injection site reactions 
• AEs 
 
The Safety Monitoring Board will include two voting members - the Principal Investigator 
and Sponsor’s Medical Monitor. If a voting member is unable to attend a Safety Data Review 
Meeting, a designated back-up can attend on their behalf and act as a voting member. 
Designated back-ups must be agreed and documented in advance. Non-voting members 
may also be part of the Safety Monitoring Board. 
 
The Safety Monitoring Board will meet in person or by teleconference at scheduled Safety 
Data Review Meetings at which the safety data will be reviewed. A summary of safety  data 
will be provided for review, including safety data entered on to the electronic CRF 

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(eCRF) by the site and clinical laboratory test results transferred to the Data Management 
provider from the safety laboratory. 
 
After review and discussion of all the data, the decision will be made on dose escalation 
and documented by signature of the Dose Escalation Approval Form by the voting members 
of the Safety Monitoring Board. Minutes documenting the main points  discussed and 
decisions made regarding dose escalation will be produced. The minutes will be agreed by 
all parties and filed in the site Trial Master File. 
 
At least 7 evaluable volunteers in Part A are required to complete through visit 4 in each 
cohort in order to provide sufficient data for a decision to dose escalate. If the required 
number of evaluable volunteers are not obtained in a cohort, then replacement volunteers 
must be dosed for that cohort, prior to considering dose escalation. The Safety Monitoring 
Board may also decide to repeat a dose level or choose an intermediate dose. 
 
Progression to the next higher dose level will be stopped if any of the study stopping criteria 
are met as described in Section 12.7. Individual volunteers will be discontinued from the 
study if they meet any of the individual volunteer stopping criteria as described in Section 
12.6. 
 
In Part B, sentinel dosing is not required, and volunteers in all groups may be randomised 
and dosed concurrently. 
 
12.6 Individual Volunteer Stopping Criteria 
 
Volunteers who meet one or more of the following stopping criteria will receive no further 
doses of study vaccine but will be followed up for safety: 
• 
Severe injection site reaction, see Appendix 1 
• 
Severe systemic reaction, e.g. anaphylaxis, see section 14.2.1 
• 
Persistent febrile reaction (>38.9oC and >24 hours) at the Investigator’s discretion 
• 
SAE related to the study agent 
The medical safety of the volunteer is of paramount importance when discussing study 
continuation. 
12.7 Study Stopping Criteria 
 
A Safety Review Meeting will be convened to determine the progression of the study if any 
of the following scenarios occur: 
• 
If one of the sentinel group or more than 20% of the volunteers in a cohort experience 
a severe site reaction. 
• 
If one of the sentinel group or more than 20% of the volunteers in a cohort experience 
a severe systemic reaction. 
• 
If one of the sentinel group or more than 20% of the volunteers in a cohort experience 
a persistent febrile reaction (>38.9oC and >24 hours) 
• 
1 or more volunteers experience a SAE related to the study agent. 

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13. PHARMACODYNAMIC ANALYSIS AND EXPLORATORY 
ASSESSMENTS 
 
13.1 Pharmacodynamic blood sample – antibody response 
 
Each blood sample will be approximately 20 mL in volume, to yield 2 aliquots each comprising 
approximately 5mL of serum. Five samples will be collected during Part A  which represents 
approximately 100 mL of blood and 11 samples will be collected during Part B which 
represents approximately 220 mL of blood. 
 
Detailed processing instructions will be included in a separate lab manual. 
 
13.2 Streptococcus B swab – vaginal and rectal 
 
Vaginal and rectal swabs will be performed during Part B of the study to assess colonisation 
by Group B streptococcus. 
 
The vaginal swab will be performed of the lower vagina (vaginal introitus), and this will be 
followed by a separate swab of the rectum (by insertion of the swab through the anal 
sphincter). The vaginal swab will be performed without a speculum. Swabs will be kept, 
shipped and analysed separately. 
 
Detailed processing instructions will be included in a separate lab manual. 
13.3 Exploratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 

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14. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND 
REPORTING 
 
14.1 Adverse Events (AEs) 
 
An AE is any untoward medical occurrence in a volunteer to whom a medicinal product has 
been administered, including occurrences which are not necessarily caused by or related to 
that product. 
 
An AE can be: 
 
• 
Any unfavourable and unintended sign (including reactions from overdose, abuse, 
incorrect use of any treatment, or interaction) 
• 
Any new disease or exacerbation of an existing disease (e.g. increase in frequency or 
worsening in nature) 
• 
Any deterioration in measurements of laboratory values or other clinical tests (e.g. 
ECG, vital signs or X-ray) that results in symptoms, a change in treatment, or 
discontinuation from the IMP 
• 
Recurrence of an intermittent medical condition (e.g. headache) not present at baseline 
• 
Other medical events regardless of their relationship to the IMP, such as accidents, 
falls and any injuries resulting from them. 
AEs will be recorded from the start of the study, i.e. from the first visit to the study unit on Day 
1, until the post-study medical visit. 
 
After completion of the 12 week period following the first vaccination in Part B (i.e. after  Visit 
10), AEs will be recorded by the volunteer in a diary card, and only those deemed to be 
relevant or significant by the Investigator will be recorded in the eCRF. A relevant or 
significant AE will be any event that caused the patient to visit any health care professional. 
These events will be recorded and the Investigator will determine if the event was possibly 
related to the investigational product. Any event deemed serious will be processed as a SAE 
in the normal way and if considered related reported as a SUSAR. 
 
14.2 Categorisation of Adverse Events 
14.2.1 Intensity Classification 
 
AEs will be classified as mild, moderate or severe according to the following criteria: 
Mild: 
Awareness of sign, symptom, or event, but easily tolerated. 
Moderate: 
Discomfort enough to cause interference with usual activity and may 
warrant intervention. 
Severe: 
Incapacitating with inability to do usual activities or significantly affects 
clinical status and warrants intervention. 

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14.2.2 Causality Classification 
 
The relationship of an AE to the study vaccine will be classified according to the following: 
 
Definite: 
A reaction that: follows a reasonable temporal sequence from 
administration of the vaccine, follows a known or expected response 
pattern to the suspected vaccine, could not be reasonably explained by the 
known characteristics of the volunteer's clinical state and, if necessary, the 
reaction returns on re-starting the vaccine (re-challenge). 
 
Probable: 
A reaction that: follows a reasonable temporal sequence from 
administration of the vaccine, follows a known or expected response 
pattern to the suspected vaccine and could not be reasonably explained by 
the known characteristics of the volunteer's clinical state. 
 
Possible: 
A reaction that: follows a reasonable temporal sequence from 
administration of the vaccine and that follows a known or expected 
response pattern to the suspected vaccine but that could readily have been 
produced by a number of other factors. 
 
Unlikely: 
A reaction that: follows a reasonable temporal sequence from 
administration of the vaccine, does not follow a known or expected 
response pattern of the suspected vaccine and could readily have been 
produced by a number of other factors. 
 
Unrelated: 
A reaction that: does not follow a reasonable temporal sequence from 
administration of the vaccine and for which there is sufficient and 
conclusive information that the event is not related to the study vaccine. 
 
AEs defined as definite, probable or possible will be reportable. AEs defined as unlikely or 
unrelated will not be reported. The output from the statistical analysis will be binary, related 
or not related. 
14.3 Recording and Follow up of Adverse Events 
 
Up to Day 85 (Visit 10), the volunteers will be instructed to spontaneously report all AEs to the 
site staff or Investigator as soon as possible. Any AEs observed or reported by a volunteer and/or 
staff up to Day 85 (Visit 10) will also be recorded in the eCRF. The Investigator will review results 
from the physical examinations. All new and aggravated findings, as compared with baseline, 
must be identified and recorded as AEs in the eCRF. In Part B, following Day 85 (Visit 10) AEs 
will be recorded by the volunteer in a diary card, and only relevant or significant AEs will be 
recorded in the eCRF. 
AEs already recorded and designated as ‘continuing’ should be reviewed at each subsequent 
assessment. 
 
For all AEs, the Investigator must obtain adequate information to determine the outcome of 
the AE and to assess whether it meets the criteria for classification as an SAE. For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the 
AE (i.e. study vaccine or other illness). The Investigator is required to assess causality and 
record that assessment on the eCRF. Follow-up of the AE, after the date of therapy 
discontinuation, is required if the AE or its sequelae persist. Any AE that is still ongoing at the 
post-study medical visit will have an outcome of ‘ongoing‘ recorded in the eCRF, 

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Follow-up information should be actively sought until the SAE has resolved or sequelae have 
stabilised. Additional information e.g. hospital reports or death certificates, may be requested 
by the Sponsor and should be anonymised/pseudonymised before transmission and 
subsequently filed in the Investigator Site File. 
 
The expectedness of an SAE shall be determined by the Sponsor according to the most 
recent version of the Investigator’s Brochure. 
14.5.2 SUSAR Reporting 
 
The Sponsor shall ensure that all relevant information about a suspected unexpected serious 
adverse reaction (SUSAR), which occurs during the course of a clinical trial in the United 
Kingdom and is fatal or life-threatening is reported as soon as possible to the  MHRA, the 
competent authorities of any EEA State, other than the United Kingdom, in which the trial is 
being conducted, and the relevant Ethics Committee. This needs to be done not later than 
seven days after the sponsor was first aware of the reaction. Any additional relevant 
information should be sent within eight days of the report. 
 
A sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as soon 
as possible and in any event not later than 15 days after the sponsor is first aware of the 
reaction. 
14.6 Abnormal Findings from Investigations or Assessments 
 
Abnormal findings from investigations or assessments will be recorded as AEs if the 
Investigator considers they are clinically significant and/or result in medical intervention. This 
may include but is not limited to abnormal laboratory results, physical examination findings, 
ECG values/changes and vital sign values/changes. 
14.7 Pregnancy 
 
Pregnancy is not an adverse event but the outcome of a pregnancy might be an adverse 
event. Over the course of the 1 year follow up period in Part B it is possible that one or more 
volunteers may become pregnant. It is important that any pregnancy is followed up. On being 
notified of a pregnancy the Investigator will complete a pregnancy notification form, which will 
be submitted to Diamond Pharma Services, and will inform the Sponsor. Diamond Pharma 
Services will seek permission to follow up the pregnancy and at the time of the estimated 
date of delivery will contact the Investigator to remind the Investigator to determine the 
outcome of the pregnancy with the volunteer. 
 
In the event of a pregnancy occurring during the course of the study, and with the written 
consent of the pregnant woman (under a separate consent form), matched serum samples 
from the mother and cord blood will be collected and relevant serum analyses will be 
performed at the University of Lund as described under the exploratory assessments. 

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15. STATISTICAL EVALUATION 
Details of the planned statistical analyses will be described in the Statistical Analysis Plan 
(SAP) and some important features are presented in this protocol. Statistical analyses will be 
performed by Eurofins Optimed using SAS statistical software. 
15.1 Statistical method description 
15.1.1 General information 
 
Statistical results will be separately presented for parts A and B. 
 
Demographic, baseline characteristics and data recorded during the study will be 
summarised using descriptive statistics by treatment (placebo, vaccine taken alone or 
vaccine combined with adjuvant) and dose group, unless otherwise specified. If relevant 
additional descriptive graphs can be provided. 
 
Individual data for all included volunteers will be presented as a data listing, sorted by 
treatment and administered dose level. 
 
For parameters with evaluation before vaccination and in case of re-checked value(s), only 
the last observation prior to dosing will be used in descriptive and inferential statistics and 
derivations of other parameter values. After vaccination, only values of scheduled 
assessments (planned in the protocol) will be used. 
 
For laboratory/clinical parameters for which laboratory/reference ranges will be available, 
position of parameter values according to ranges will be flagged with the following rule: 
- “L” for values lower than laboratory/reference ranges; 
- “H” for values higher than laboratory/reference ranges. 
In addition, parameter values can be assessed by investigator and flagged as follows in 
order to determine clinical relevance: 
- Normal; 
- Abnormal and NCS (Not clinically Significant); 
- Abnormal and CS (Clinically Significant). 
 
15.1.2 Descriptive statistics for the two study parts 
 
Descriptive statistics for quantitative parameters will be provided using number of 
observations (N), mean, standard deviation (SD), standard error of the mean (SEM), 
minimum, median and maximum. Descriptive statistics for qualitative parameters will be 
provided using absolute frequencies (n) and relative frequencies (%). 
 
15.1.3 Inferential statistics 
 
Adequate statistical tests will be used to carry out comparison between treatment/dose 
groups performed on primary, secondary or exploratory endpoints, even though it is accepted 
that the power of these tests for groups in Part A will be low due to small numbers of 
volunteers. 

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For categorical endpoints, such as local and systemic reactogenicity, a comparison of 
events intensity (scores) between vaccine dose groups will be performed with an adequate 
statistical test dealing with categorical variables (for example: Fisher exact test, Chi square 
test or generalized estimating equations). 
For continuous endpoints, such as immune response induced by different GBS-NN vaccine 
dosing regimens, appropriate statistical method (for example: ANOVA) will be used to 
compare pre-vaccination and post-vaccination levels. 
 
 
15.2 Studied populations for each study part 
 
The following populations will be taken into account for each study part: 
 
• Intention to Treat Set (ITT): All included volunteers who receive at least one dose of the 
study vaccine will be taken into account in the description of the population (disposition, 
demographic or baseline characteristics); 
• Immunogenicity Set (IG): The subset of volunteers who will receive at least one dose of 
the study vaccine with available pre- and post-vaccination titers. 
• Per Protocol Set (PP): All volunteers who receive both doses of the study vaccine and 
provide evaluable samples for analysis of the primary immunological endpoint and do not 
violate the protocol. 
 
The Primary and Secondary Safety analyses will be performed on the ITT set. The Secondary 
Immunological analyses will be performed on the IG set. The “primary” immunological 
analysis (i.e. the results on Day 85 in both study parts) will also be performed on the PP set. 
 
Missing or incomplete data will not be replaced, unless otherwise specified (example: values 
strictly under the LLOQ for immunogenicity data). 
15.3 Sample size 
 
Up to 70 healthy female volunteers will be included in part A (7 cohorts of 10 volunteers) and 
up to 240 in part B (3 cohorts of 80 volunteers). The final number of volunteers to be 
randomized in part B will be calculated following a data review from part A. 
15.4 Studied criteria for the two study parts 
15.4.1 Characteristics of included volunteers 
 
• Volunteer demographic characteristics 
For demography, continuous variables (for example: age, height, weight, BMI) and 
qualitative variables (for example: ethnical origin) will be summarised using descriptive 
statistics on all included volunteers. Demographic characteristics will be also presented 
for other study populations (IG and/or PP) if they are different from ITT. 
 
• Medical history events 
Medical and surgical history events will summarised by System Organ Class (SOC) and 
Preferred Term (PT). In case of few relevant history events (≤5 per study part for example), 
only a listing will be provided according to treatment/dose group and volunteer. 

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TEAEs will be described by relation to study vaccine (for example: definite / probable / 
possible / unlikely / unrelated) and maximum intensity (for example: mild / moderate / 
severe) according to treatment/dose group. Descriptive statistics will be characterised by 
number of TEAEs, number and percentage of volunteers with at least one TEAE (based 
on ITT). In case of few TEAEs (≤ 5 per study part for example), only a listing will be 
performed. 
 
Vaccine related TEAEs (i.e. definite, probable or possible relationship to study vaccine) 
will be summarised by MedDRA codes (SOC and PT) and treatment/dose group. In case 
of few vaccine related TEAEs (≤ 5 per study part for example), only a listing will be 
performed. TEAEs not related to study vaccine (i.e. unlikely or unrelated relationship to 
study vaccine) will also be summarized by MedDRA codes. 
 
Two distinct listings of TEAEs and NTEAEs will be presented by treatment/dose group, 
volunteer and MedDRA codes in order to provide more information about adverse events 
(example: description, duration, time since last administration if applicable, seriousness, 
any actions taken as concomitant medication or hospitalization). 
 
• Laboratory tests 
Biochemistry and haematology tests will be performed at V1 (screening), V4 (part A), V5 
(part B), V8 (parts A and B) and post-study medical visit (V10 for part A and V20 for part 
B). 
 
Parameter values, position according to laboratory ranges (if available) and investigator 
assessment will be described according to visit for each treatment/dose group. In order to 
study evolution of parameters after vaccination, parameter values changes from pre- to 
post-dose visits will be performed. Emergent values (for parameters with available 
laboratory ranges) with their corresponding position according to ranges will be listed by 
treatment/dose group and volunteer. 
 
• Urinalysis 
Urinalysis will be performed at V1 (screening), V4 (part A), V5 (part B), V8 (parts A and B) 
and post-study medical visit (V10 for part A and V20 for part B). 
 
Parameter values (quantitative or binary results, i.e. positive/negative), position according 
to laboratory ranges (if available) and investigator assessment will be described according 
to visit for each treatment/dose group. In order to study evolution of continuous parameters 
after vaccination, parameter values changes from screening to post-study medical visit will 
be performed. Emergent values (for parameters with available laboratory ranges or with 
binary results) will be listed by treatment/dose group and volunteer. 
 
• Vital signs 
Vitals signs will be characterised by heart rate, blood pressure, tympanic temperature and 
respiratory rate. Vital signs will be assessed at V1 (screening), V2 (pre-dose, T2h and T3h 
post-dose), V3, V4 (part A only), V6 (pre-dose and T2h post-dose for volunteers receiving 
booster dose), V7 (only if administered booster dose), V8, and post-study medical visit 
(V10 for part A and V20 for part B). For study part B, additional vital signs assessments 
will be performed at V5, V8, V9, V10, V11, V13, V15 and V17. 

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Parameter values, position according to reference ranges (if available) and investigator 
assessment will be described according to visit and assessment time for each 
treatment/dose group. In order to study evolution of parameters after vaccination, 
parameter values changes from pre-dose to post-dose assessments will be performed. 
Emergent values (for parameters with available reference ranges) with their corresponding 
position according to reference ranges will be listed by treatment/dose group and 
volunteer. 
 
• 12-lead ECG parameters 
ECG will be assessed at V1 (screening) and post-study medical visit (V10 for part A and 
V20 for part B). 
 
Parameter values, position according to reference ranges and investigator assessment (if 
available) will be described according to visit for each treatment/dose group. In order to 
study evolution of parameters after vaccination, parameter values changes from screening 
to post-study medical visit will be performed. Emergent values (for parameters with 
available reference ranges) with their corresponding position according to reference 
ranges will be listed by treatment/dose group and volunteer. 
 
• Physical examination 
Abnormal physical examinations recorded at post-study medical visit (V10 for part A and 
V20 for part B) will be listed according to treatment/dose group and volunteer. 
 
15.4.3 Secondary Safety Endpoints 
 
The safety secondary objective for part B is to evaluate the long term safety profile of the 
GBS-NN vaccine up to 1 year following the first dose. 
 
The same endpoints will be evaluated as for the primary objective. 
 
15.4.4 Secondary Immunological Endpoints 
 
The secondary immunological objectives for both parts of the study are: 
 
• To evaluate IgG antibody responses induced by different vaccine doses alone or in the 
presence of Alhydrogel over time in healthy female volunteers: 
• To determine the impact of pre-existing antibody levels on the vaccine-induced 
antibody response: 
 
In addition for Part A: 
• To determine the effect of Alhydrogel® adjuvant on the immunogenicity of GBS-NN 
vaccine 
• To select the dose levels and regimens for vaccination of cohorts in Part B, based on the 
antibody levels at 8 weeks following the first dose (Day 57) 
 
In addition for Part B: 

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• To evaluate the immune response to the GBS-NN vaccine up to 1 year following the first 
dose 
 
Immunological parameters measured to evaluate objectives 
 
In order to evaluate these objectives, GBS-NN specific IgG concentrations will be determined 
by ELISA against a reference standard human antibody preparation of known concentration 
as described in the laboratory protocol and used to derive the following parameters for each 
volunteer: 
 
- Antibody concentration at each sample point (μg/mL) 
- Fold increase over pre-immunisation level (Day 1) in antibody concentration at each 
sample point (ratio) 
 
Specific Endpoints calculated from immunological parameters 
These parameters will be used to derive the following endpoints at all time-points 
according to the treatment group: 
- Geometric mean antibody concentration (with 95% c.i.) 
- Geometric mean fold increase in antibody concentration (with 95% c.i.) 
- Seroconversion rate at each sample point (proportion of volunteers with fold increase 
above threshold (*see below) 
- At the primary immunological endpoint (Day 85) all groups in Part A will be analysed 
according to the proportion of volunteers whose specific antibody level (μg/mL) exceeds 
the following thresholds: 0.5; 1.0; 2.0; 4.0; 8.0 μg/mL. The analysis will be repeated for 
Part B, where the threshold values may be adjusted based on the results of Part A. 
 
* For Part A the threshold to define a positive response will be set arbitrarily to 2.5-fold rise 
above base-line, as is common practice in FIM vaccine studies. For Part B, the threshold 
will be set based upon the data derived from Part A. The fold increase for all 12 placebo 
recipients at Days 29, 43, 57 & 85 will be considered. The mean and standard deviation will 
be calculated and the cut-off defined as two standard deviations above the mean. 
The primary immunological endpoints (still secondary study endpoint) for both Part A and 
Part B will be the values of these endpoints at Day 85, 12 weeks after the administration of 
the first dose of vaccine). 
In Part A, the immunological endpoints at Days 1, 29 and 57 will be reported separately by 
group in a blinded fashion to enable the dose selection for Part B 
Additional analyses to address objectives 
For each group the individual data will be presented as scatter plots and cumulative 
frequency distributions at each time-point 
Correlation plots will be generated to compare the specific antibody concentrations before 
vaccination and at 12 weeks after the first dose to evaluate the influence of pre-existing 
antibody levels on responses. 
 
Statistical significance of differences in endpoint values 

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Statistical tests will be carried out to compare results between treatment groups, depending 
on studied variable type (see section inferential statistics). These analyses will be fully 
detailed in the SAP. In brief the following comparisons between groups will be made at Day 
29 and Day 84 (and at Day 57 in Part A only): 
 
Part A: 
- Placebo group (total 12 volunteers, 6 with buffer only and 6 with alhydrogel) against all 
other dose groups 
- Each dose level with and without Alhydrogel® 
- 10μg vs 50μg, 10μg vs 250μg, 50μg vs 250μg in volunteers vaccinated with GBS-NN 
alone 
- 10μg vs 50μg, 10μg vs 250μg, 50μg vs 250μg in volunteers vaccinated with GBS-NN in 
the presence of Alhydrogel 
- For all groups and parameters Day 29 vs Day 85 
Part B: 
- Placebo group against all other dose groups (regimens to be decided) 
- Group A vs Group B; Group A vs Group C; Group B vs GroupC 
- For all groups and parameters Day 29 vs Day 85 
 
 
15.4.5 Exploratory endpoints 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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16. ETHICS AND REGULATORY 
 
16.1 Conduct 
 
This study will be conducted in accordance with the standard operating practices of the 
Sponsor and CRO, which are designed to ensure adherence to Good Clinical Practice (GCP) 
guidelines as required by the following: 
 
1. 
Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”), and all its accepted amendments to date 
concerning medical research in humans. 
2. 
ICH E6 Guideline for GCP and subsequent notes for guidance (CPMP/ICH/135/95) 
European Agency for the Evaluation of Medicinal Products, Committee for Proprietary 
Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for 
Human Use. (Note for Guidance on Good Clinical Practice, 2002). 
3. 
European Union (EU) Clinical Trials Directive 2001/20/EC on the regulation of clinical 
trials in the EU and the implementation of GCP. 
4. 
GCP Directive 2005/28/EC. 
 
This study will be conducted in accordance with national and local laws (e.g. drug and 
narcotics laws) of the countries where study sites are located. 
 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in the protocol and to adhere to the principles of ICH Good Clinical 
Practice to which the protocol conforms as well as all governing local regulations and 
principles for medical research. 
16.2 Review 
 
The protocol, any protocol amendments, volunteer information sheet (VIS), informed consent 
form (ICF) and any study related information or documents issued to volunteers will be 
reviewed and approved along with other required documents by the Ethics Committee (EC) 
and each study site’s local EC before volunteers are screened for entry. The ECs should be 
constituted and functioning in accordance with ICH E6, Section 3.2, and any local regulations. 
The EC that provides a positive opinion for this study will be included in the clinical study 
report for this protocol. 
 
A signed letter of positive opinion regarding the study from the EC Chairman must be sent to 
the Investigator who will provide the Sponsor with a copy. The Investigators or Sponsor will 
submit, depending on local regulations, periodic reports and inform the EC of any reportable 
AEs per ICH guidelines and local EC standards of practice. 
 
SAEs should be reported to the EC in accordance with local regulatory requirements. 
 
In the case of early termination/temporary halt of the study, the Investigator should notify the 
EC and the Sponsor should notify the Competent Authority (CA) within 15 days and a detailed 
written explanation of the reasons for the termination/halt should be given. If the EC decides 
to suspend or terminate the study, the Investigator will immediately send the notice of study 
suspension or termination by the EC to the Sponsor. 

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At the end of the study, the EC and CA will be notified within 90 days. The end of the study 
will be the date of the last study visit for the last volunteer in the study. The Sponsor will 
always also provide the EC/CA with a summary of the study’s outcome. 
 
16.3 Volunteer Information and Informed Consent 
 
Informed consent should be obtained by means of a VIS and ICF, prepared in accordance 
with ICH E6 Section 4.8.10 and applicable local regulations, written in non-technical 
language. All volunteers will be provided with oral and written information describing the 
nature and duration of the study and the procedures to be performed. The volunteer will be 
asked to sign and date an ICF prior to any study-specific procedures being performed. No 
volunteer can enter the study before his/her informed consent has been obtained. A  sample 
volunteer ICF used in the study will be included in the clinical study report for this protocol. 
 
Prior to study start, the volunteers will receive a full explanation of the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any potential discomfort. Each volunteer must be informed that participation  in 
the study is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician. The volunteer should understand the VIS and ICF before  signing and 
dating the ICF. The Investigator or person obtaining consent must also sign  and date the 
form. Each volunteer will be given a copy of the signed informed consent and written 
information. 
 
The original signed ICF for each volunteer will be verified by the Sponsor monitors and kept 
in the study centre investigational site files. 

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17. GENERAL OBLIGATIONS, AGREEMENTS AND 
ORGANISATION 
17.1 Data Protection and Confidentiality 
 
Data protection will be carried out in accordance with the Principles of the Data Protection 
Act (1998) 95/46/EC. This will apply to all study data in whatever format it is collected and 
recorded. 
17.2 CRFs and Handling 
 
Electronic CRFs will be used in this trial. Should any corrections or amendments be 
necessary, data clarification requests will be forwarded to the Investigator or designee. 
17.3 Quality Control and Monitoring 
 
The conduct of the study will be monitored by appropriately qualified staff from the Sponsor and/or 
an organisation authorised to conduct activities on the Sponsor’s behalf. The Sponsor will retain the 
responsibility for monitoring and may delegate this responsibility via a contract and/or Monitoring 
Manual. 
 
The study will be monitored at regular intervals and the frequency of monitoring visits will be 
determined by the rate of volunteer recruitment. The following will be reviewed at these visits: 
• 
Responsibilities of the Investigator and the study site under GCP requirements 
• 
Compliance with the protocol 
• 
Consent procedure 
• 
Source Data Verification (SDV) 
• 
Procedures for AEs 
• 
Storage and accountability of study vaccine 
The purpose of SDV is to verify, so far as is possible, that the information in the CRF reflects the 
data recorded in the volunteer’s source data records. SDV will be performed with due regard for 
volunteer confidentiality. SDV will be undertaken on an ongoing basis as part of the monitoring visits. 
Direct access to the source documents will be required. The monitor will make a direct comparison 
with data entered in the volunteer CRFs and the source data. 
 
The Investigator must permit the monitor, the Sponsor’s internal auditors and representatives from 
the Regulatory Authorities to inspect all study-related documents and pertinent source data records 
for confirmation of data contained within the CRFs. 
17.4 Quality Assurance, Audit and Inspection 
 
This study may be subject to audit by the CRO, Sponsor or their representatives and 
Regulatory Authorities. These audits may be undertaken to check compliance with the 
requirements of GCP and can include: 
• 
In-house study file audit 
• 
Audit of computer database 

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• 
Audit of Clinical Study Report 
• 
Audit of selected study sites, requiring access to volunteer medical records, study 
documentation and facilities, laboratories or pharmacies used for the study. 
The study site, facilities and all data (including source data) and documentation will be made 
available for audit by the Investigator according to the ICH-GCP guidelines. The Investigator 
agrees to co-operate with the auditor during his/her visit and will be available to supply the 
auditor with CRFs or other files necessary to conduct that audit.  Any findings  will be strictly 
confidential. 
 
In the event that a Regulatory Authority informs the Investigator that it intends to conduct an 
inspection, the Sponsor must be notified immediately. 
17.5 Storage of Study Documents 
 
The circumstances of completion or termination of the study notwithstanding, the Investigator 
has the responsibility to retain all study documents, including but not limited to the protocol, 
copies of CRFs, Investigator's Brochure, regulatory agency registration documents, ICFs, 
and EC correspondence. 
 
The site will retain study documents for 15 years after completion of the study. This will 
include copies of the CRF. At the end of the 15 year period the site will contact  the  Sponsor 
who will determine any future arrangements for the storage of the study documents. 
 
All CRFs and clinical trial data will be stored by the Sponsor or designee for a period of at 
least 15 years after termination of the study. The volunteer consent forms and re- 
identification lists will be archived with the Investigator for at least 15 years after termination 
of the study. 
17.6 Registration and Publication of Study and Results 
 
The trial will be registered by the Sponsor on a publicly accessible database e.g. 
http://www.controlled-trials.com. 
 
The trial results will not be published without written consent by the Sponsor. Any oral or 
written communications /publications concerning the trial results will be reviewed and 
approved in writing by the Sponsor, which has a 60-day period to respond after receipt of the 
proposed communication/publication. 

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18. 
SCHEDULE OF ASSESSMENTS 
Part A Schedule of Assessments 
 
 
Screening 
Period 
Treatment Period 
Post- 
Study 
Medical 
Safety 
Follow 
-Up 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 10 
Visit 
11 
Assessment 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 8 
Day 
15a 
Day 
29b 
Day 
30b,c 
Day 
43b 
Day 
57b 
Day 85 
Day 
183a 
Informed 
Consent 
X 
Inclusion/ 
Exclusion 
Criteria 
X 
Demography 
X 
Medical History 
X 
Physical 
Examinationd 
X 
X 
X 
Height, Weight, 
BMI 
X 
Vital signse 
X 
Xf 
X 
X 
Xg,h 
X 
X 
X 
12-lead ECG 
X 
X 
Urinalysis 
X 
X 
X 
X 
Safety 
laboratory tests 
X 
X 
X 
X 
HIV, Hep B 
and Hep C 
X 
Pregnancy testi 
X 
X 
Xh 
X 
Alcohol breath 
test 
X 
X 
Urine drugs of 
abuse test 
X 
X 
Review of 
volunteer 
eligibility 
X 
Randomisation 
X 
Administration 
of primary dosej 
X 
Administration 
of booster dose 
Xh 
PD blood 
sample – 
antibody 
response 
X 
X 
X 
X 
X 
Brief medical 
examinationk 
X 
X 
Assessment of 
injection site(s)l 
X 
X 
Xm 
X 
X 
X 
X 
AE check 
X 
X 
X 
Con med check 
X 
X 
X 

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Footnotes 
a. 
Visit performed by telephone. 
b. 
Day numbers of Visits 6, 7, 8 and 9 may change if the dosing regimen is changed. 
c. 
Visit 7 not required if booster dose not administered. 
d. 
Full physical examination at screening and post-study medical. Brief physical examination prior to first 
dose. 
e. 
Heart rate, blood pressure, tympanic temperature and respiration rate. 
f. 
Vital signs at Visit 2 will be recorded pre-dose and at 2 and 6 hours post-dose. 
g. 
Vital signs at Visit 6 will be recorded pre-dose and at 2 hours post-dose. 
h. 
Administration of booster dose only if applicable to this cohort. If booster dose not administered, vital 
signs and pregnancy test are not to be performed. 
i. 
Serum pregnancy test at screening and post-study medical. Urine pregnancy test prior to each dose. 
j. 
Sentinel dosing for all cohorts for the primary dose only. 
k. 
Brief medical examination (including assessment of the injection site(s) to determine eligibility for 
discharge at least 8 hours post-dose on Day 1 and at least 4 hours post-dose on Day 29. 
l. 
Photographs may be taken of injection site reactions as required. 
m. 
Assessment of first injection site, to be assessed pre-dose. 

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Part A Schedule of Assessments – Exploratory Assessments 
 
 
Treatment Period 
Post-Study 
Medical 
Visit 2 
Visit 6 
Visit 8 
Visit 9 
Visit 10 
Assessment 
Day 1 
Day 29 
Day 43 
Day 57 
Day 85 
Ig ELISA 
C1-C6 
C1-C6 
C1-C6 
C1-C6 
C1-C6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
(C = cohort) 

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Part B Schedule of Assessments 
 
 
Screening 
Period 
Treatment Period 
Post- 
Study 
Medical 
 
Visit 1 
Visit 2 Visit 
3 
Visit 
4a 
Visit 
5 
Visit 
6 
Visit 
7b 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12a 
Visit 
13 
Visit 
14a 
Visit 
15 
Visit 
16a 
Visit 
17 
Visit 
18a 
Visit 
19a 
Visit 20 
 
Day -28 
to Day -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
29 
Day 
30 
Day 
43 
Day 
57 
Day 
85 
Day 
113 
Day 
141 
Day 
169 
Day 
197 
Day 
225 
Day 
253 
Day 
281 
Day 
309 
Day 
337 
Day 365 
Assessment 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52 
Informed Consent 
X 
Inclusion/ 
Exclusion Criteria 
X 
Demography 
X 
Medical History 
X 
Physical Examinationc 
X 
X 
X 
Height, Weight, BMI 
X 
Vital signsd 
X 
Xe 
X 
X 
Xf g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
Urinalysis 
X 
X 
X 
X 
Safety laboratory tests 
X 
X 
X 
X 
HIV, Hep B and Hep C 
X 
Pregnancy testh 
X 
X 
Xg 
X 
X 
Alcohol breath test 
X 
X 
Urine drugs of abuse test 
X 
X 
Review of volunteer eligibility 
X 
Randomisation 
X 
Administration of primary dose 
X 
Administration of booster dose 
Xg 
Streptococcus B swab – vaginal 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Streptococcus B swab – rectal 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sample – antibody 
response 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief medical examinationi 
X 
X 
Assessment of injection site(s)j 
X 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE check 
X 
X 
Con med check 
X 
X 
X 
 
Footnotes 
a. 
Visits 4, 12, 14, 16, 18 and 19 conducted by telephone. 
b. 
Visit 7 not required if booster dose not administered. 
c. 
Full physical examination at screening and post-study medical. Brief physical examination prior to first dose. 

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d. 
Heart rate, blood pressure, tympanic temperature and respiration rate. 
e. 
Vital signs at Visit 2 will be recorded pre-dose and at 2 hours post-dose. 
f. 
Vital signs at Visit 6 will be recorded pre-dose and at 2 hours post-dose. 
g. 
Administration of booster dose only if applicable to this cohort, If booster dose not administered, vital signs, and pregnancy test are not to be performed. 
h. 
Serum pregnancy test at screening and post-study medical. Urine pregnancy test prior to each dose and at Visit 10. 
i. 
Brief medical examination (including assessment of the injection site(s)) to determine eligibility for discharge at least 2hours post-dose on Day 1 and at 
least 2 hours post-dose on Day 29. 
j. 
Photographs may be taken of injection site reactions as required. 
k. 
Assessment of first injection site, to be assessed pre-dose. 

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Part B Schedule of Assessments – Exploratory Assessments 
 
Treatment Period 
Post-Study 
Medical 
Visit 2 
Visit 5 
Visit 6 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 13 
Visit 20 
Day 1 
Day 15 
Day 29 
Day 43 
Day 57 
Day 85 
Day 113 
Day 169 
Day 365 
Assessment 
Week 2 
Week 4 
Week 6 
Week 8 
Week 12 
Week 16 
Week 24 
Week 52 
Ig ELISA 
C1 or C2 
C1 or C2 
C1 or C2 
C1 or C2 
C1 or C2 
C1 or C2 
C1 or C2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C = cohort) 
 
Note: Cohort 1 or 2 to be selected based on results from Part A. Timepoints for sample collection may be altered based on results from Part A. 
a) Time point not entirely fixed and dependent on results obtained in Part A. 

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19. REFERENCES 
 
1. 
Baker C (2000) Group B streptococcal infections In Stevens DL, Kaplan EL eds. 
Streptococcal infections. NEW York (NY) Oxford University Press. 2000: 222-37 
2. 
Center for Disease Control and Prevention (2002). Prevention of perinatal Group B 
streptococcal disease MMWR , 51:1-22 
3. 
El Helali N, Nguyen JC, Ly A. et al., (2009) Diagnostic accuracy of a rapid real-time 
polymerase chain reaction assay for universal intrapartum group B streptococcus 
screening. Clin. Infect. Dis. Aug 1, 49: 417-23 
4. Gravekamp et al., (1996), 64,3576 
5. Gravekamp et al., (1997) 65,5216 
6. 
Heath PT, Balfour GF, Tighe H, Verlander NQ, Lamagni TL, Efstratiou A (2009).  Group 
B streptococcal disease in infants: a case control study. Arch. Dis. Child. 94(9) 674-680. 
7. 
Heath PT, Balfour GF, Weisner AM et al., (2004) Group B streptococcal disease in UK 
and Irish infants younger than 90 days. Lancet 363 (9405), 292-294. 
8. 
Jordan HT, Farley MM, Craig A et al., (2008) Revisiting the need for vaccine prevention 
of late onset neonatal group B streptococcal disease: a multistate, population-based 
analysis. Pediatr. Infect. Dis. J. 27(12): 1057-1064. 
9. 
KWS BioTest: MNV008-4-AM1. Evaluation of magnitude and kinetics of responses to 
“human doses” in mice and the need for alum. 28 Aug 2014. 
10. KWS BioTest MNV002-4. Evaluation of NN protein as a putative vaccine for Group B 
streptococcal infection: protection from neonatal infection. 22 Oct 2012. 
11. KWS BioTest: MNV003-5. Evaluation of NN protein as a putative vaccine for Group B 
streptococcal infection: neutrophil killing assessment. 28 Mar 2013. 
12. KWS BioTest: MNV007-4. Evaluation of NN protein as a putative vaccine for A909 Group 
B streptococcal infection: protection from neonatal infection. 22 Oct 2012 
13. Larsson, CE (2006) Association between low concentrations of antibodies to protein 
alpha and Rib and invasive neonatal group B streptococcal infection. Arch Dis. Child 
Fetal Neonatal, F403-F408 
14. Lin et al. Level Of Maternal IgG Anti–Group B Streptococcus Type III Antibody correlated 
with protection of neonates against Early--‐Onset Disease caused by this 
pathogen.J.Infect.Dis.2004;190:928 
15. Melin P, Schmitz M, Tsobo C et al.,(2000). Rapid intrapartum test (Stept B OIA) and 
prenatal cultures for identification of group B streptococcal carriers at delivery: a 
prospective study. In American Society of Microbiology(Ed) Program and Abstracts of 
the 40th Intersciences Conference on Antimicrobial Agents and Chemotherapy (p145 No 
357 session 30) Washington. USA: American Society for Microbiology (ASM). 
http://hdl.handle.net/2268/36477 
16. Nizet V Ferrieri P, Reubens CE (2000) Molecular pathogenesis of group B streptococcal 
disease in newborns. In Stevens DL, Kaplan EL eds. Streptococcal infections. NEW York 
(NY) Oxford University Press. 2000: 180-221. 
17. Schrag SJ, Zywicki S, Farley MM et al.,(2000). Group B Streptococcal disease in the era 
of intrapartum antibiotics. N. Engl. J. Med. 342(1), 15-20. 
18. Skoff TH, Farley MM, Petit S et al., (2009). Increasing burden of invasive group B 
streptococcal disease in non-pregnant adults 1990-2007. Clin. Infect. Dis. , 49(1), 85- 92. 
19. Stahlhammar-Carlemalm (2007) Cell Host and Microbe, 427-434. 

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20. Verani JR, Schrag SJ (2010) Group B streptococcal disease in infants: progress in 
prevention and continued challenges. Clin. Perinatol, 37: 375-92. 
21. Zangwill KM, Schuchar A, Wenger JD (1992) Group B streptococcal disease in the 
United States, 1990, report from a multistate active surveillance system. MMWR CDC 
Surveil. Summ ., 41(6):25-32 

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APPENDIX 1 
 
 
INJECTION SITE TOLERABILITY ASSESSMENT 
 
Tolerability assessments will be performed by a member of the clinical staff. An additional 
assessment by a physician will be made in the event of a local reaction being evaluated as 
moderate or severe. All measurements (in cm) refer to the longest dimension. 
 
Redness 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 
Description: 
0 NONE 
No visible redness 
1 MILD 
Greater than 0 to 2 cm (incl.) redness 
2 MODERATE Greater than 2 to 5 cm (incl.) redness 
3 SEVERE 
Greater than 5 cm redness 
Bruising 
 
 
 
 
 
 
 
 
 
Grade 
Description: 
0 NONE 
No visible bruising 
1 MILD 
Greater than 0 to 2cm (incl.) bruising 
2 MODERATE Greater than 2 to 5cm (incl.) bruising 
3 SEVERE 
Greater than 5cm bruising 

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Induration 
 
 
 
 
 
 
 
 
Grade 
Description: 
0 NONE 
No swelling detected 
1 MILD 
Palpable “firmness” only 
2 MODERATE Less than or equal to 4 cm swelling 
3 SEVERE 
Greater than 4 cm swelling 
 
 
Itching 
 
Grade 
Description: 
N: ABSENT 
Y: PRESENT 
 
 
Pain 
 
Volunteers will be asked if they experience any pain. If the answer is yes, they will be 
asked to rate the level of pain on a scale of 1-10. Assessment of pain will commence after 
first injection. 
 
Any other local reaction (for example: necrosis or ulceration)? Please specify