A Phase I, Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Safety, Tolerability and Immunogenicity of Two Doses of Group B Streptococcus Vaccine (GBS-NN/NN2 With Alhydrogel®) in Healthy Female Subjects Aged 18 to 40
Phase: PHASE1
Conditions: Group B Strep Infection
Sponsor: Minervax ApS

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Protocol MVX0002 
 
 
A Phase I, randomised, double-blind, placebo-controlled, parallel group study to evaluate the 
safety, tolerability and immunogenicity of two doses of Group B Streptococcus vaccine 
(GBS-NN/NN2 with Alhydrogel®) in healthy female subjects aged 18 to 40. 
 
 
 
 
Version:  
 
 
4.0 (incorporating protocol amendments 1 and 2) 
 
Version Date:  
 
 02 January 2019 
 
EUDRACT Number:  
2017-003871-27 
 
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 
1. 
APPROVAL SIGNATURES ............................................................................................................................. 6 
- 
APPROVAL SIGNATURES ............................................................................................................................. 7 
• 
APPROVAL SIGNATURES ............................................................................................................................. 8 
2. 
PROTOCOL REVISION HISTORY ............................................................................................................... 9 
3. 
STUDY CONTACTS ................................................................................................................................... 10 
4. 
SYNOPSIS ..................................................................................................................................................... 12 
Primary Objective ............................................................................................................................................. 12 
• 
Secondary Objectives .............................................................................................................................. 12 
• 
 
 
• 
Primary Endpoints .................................................................................................................................... 12 
5. 
LIST OF ABBREVIATIONS .......................................................................................................................... 15 
6. 
INTRODUCTION ....................................................................................................................................... 17 
6.1  
Background ......................................................................................................................................... 17 
6.2 
Rationale for Study .............................................................................................................................. 18 
6.2.1 
 Summary of Non Clinical Data ...................................................................................................... 19 
6.2.2 
Summary of Clinical Data ............................................................................................................... 19 
6.3 
Risk/Benefit Assessment ..................................................................................................................... 20 
7. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................... 21 
7.1 
Primary Objective ............................................................................................................................... 21 
7.2  
Secondary Objectives .......................................................................................................................... 21 
7.3 
 
7.4 Primary Endpoints ....................................................................................................................................... 22 
7.5 Secondary Endpoints ............................................................................................................................ 22 
8. 
STUDY DESIGN ........................................................................................................................................... 22 
8.1 
Overview ............................................................................................................................................. 22 
8.2 
Study Centre(s) ................................................................................................................................... 22 
8.3 
Study Duration .................................................................................................................................... 23 
9. 
STUDY POPULATION ................................................................................................................................ 24 
9.1 
Inclusion Criteria ................................................................................................................................. 24 
9.2 
Exclusion Criteria ................................................................................................................................ 24 
9.3 
Planned Sample Size ............................................................................................................................ 25 
9.4 
Allocation of Randomisation Numbers ............................................................................................... 25 
9.5 
Subject Withdrawal ............................................................................................................................. 25 
9.6 
Subject Replacement ........................................................................................................................... 26 
9.7 
Premature Termination of the Study .................................................................................................. 26 
10. 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................................................... 27 
10.1 
Identity and Doses of IMP ................................................................................................................... 27 
10.2 
Rationale for doses ............................................................................................................................. 27 
10.3 
Randomisation ..................................................................................................................................... 27 
10.4 
IMP Administration ............................................................................................................................. 27 

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10.5 
Blinding ................................................................................................................................................ 27 
10.6 
Vaccine Accountability and Storage .................................................................................................... 28 
11. 
PRIOR AND CONCOMITANT MEDICATION, AND OTHER RESTRICTIONS ............................... 29 
11.1 
Prior Medications ................................................................................................................................ 29 
11.2 
Concomitant Medications ................................................................................................................... 29 
11.3 
Other Restrictions .............................................................................................................................. 29 
12. 
STUDY CONDUCT ............................................................................................................................... 30 
12.1 
Screening Period ................................................................................................................................. 30 
12.2 
Treatment Period and Post-Study Period ........................................................................................... 30 
12.3 
Safety Assessments ............................................................................................................................. 32 
12.3.1 
Clinical Laboratory Tests ........................................................................................................... 32 
12.3.2 
ECGs and Vital Signs .................................................................................................................. 33 
12.3.3 
Injection Site Tolerability Assessment ....................................................................................... 33 
12.4 
Time Windows for Visits .................................................................................................................... 33 
12.5 
Safety Monitoring Board and Safety Data Review Meetings ............................................................... 33 
12.6 
Individual Subject Stopping Criteria .................................................................................................... 34 
12.7 
Study Stopping Criteria ....................................................................................................................... 35 
13. 
PHARMACODYNAMIC ANALYSIS AND ASSESSMENTS ................................................................... 36 
13.1 
Pharmacodynamic blood sample – antibody response ....................................................................... 36 
14. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS ANDREPORTING ................................................. 37 
14.1 
Adverse Events (AEs) .......................................................................................................................... 37 
14.2 
Categorisation of Adverse Events ....................................................................................................... 37 
14.2.1 
Intensity Classification ................................................................................................................ 37 
14.2.2 
Causality Classification ............................................................................................................... 37 
14.3 
Recording and Follow up of Adverse Events ...................................................................................... 38 
14.4 
Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions (SUSARs) ............. 38 
14.5 
Reporting Timelines ............................................................................................................................ 39 
14.5.1 
SAE Reporting ............................................................................................................................ 39 
14.5.2 
SUSAR Reporting ....................................................................................................................... 39 
14.6 
Abnormal Findings from Investigations or Assessments .................................................................... 39 
14.7  
Pregnancy ............................................................................................................................................ 40 
15. 
STATISTICAL EVALUATION ................................................................................................................. 41 
15.1 
Statistical method description ............................................................................................................. 41 
15.1.1 
General information ................................................................................................................... 41 
15.1.2 
Descriptive statistics................................................................................................................... 41 
15.1.3 
Inferential statistics ..................................................................................................................... 41 
15.2 
Studied populations for each study part ............................................................................................. 42 
15.3 
Sample size .......................................................................................................................................... 42 
15.4 
Studied criteria .................................................................................................................................... 42 
15.4.1 
Characteristics of included subjects ........................................................................................... 42 
15.4.2 
Primary endpoint ........................................................................................................................ 43 
15.4.3 
Secondary Endpoints (Immunological Endpoints) ...................................................................... 45 

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15.4.4 
 
16. 
ETHICS AND REGULATORY ................................................................................................................ 47 
16.1 
Conduct .............................................................................................................................................. 47 
16.2 
Review ................................................................................................................................................. 47 
16.3 
Subject Information and Informed Consent ....................................................................................... 48 
17. 
GENERAL OBLIGATIONS, AGREEMENTS AND ORGANISATION .................................................. 49 
17.1 
Data Protection and Confidentiality ................................................................................................... 49 
17.2 
CRFs and Handling .............................................................................................................................. 49 
17.3 
Quality Control and Monitoring ......................................................................................................... 49 
17.4 
Quality Assurance, Audit and Inspection ............................................................................................ 49 
17.5 
Storage of Study Documents .............................................................................................................. 50 
17.6 
Registration and Publication of Study and Results .............................................................................. 50 
18. 
SCHEDULE OF ASSESSMENTS .............................................................................................................. 51 
19. 
REFERENCES........................................................................................................................................... 52 
APPENDIX 1 ........................................................................................................................................................ 54 
 
 
 
 
 

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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
Signature  
 
Date 
 
 
 

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1. APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor 
 
 
Signature 
 
Date 
 
 

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- APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MinervaX 
 
 
Signature 
 
 
Date 
 
 
 

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• APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biostatistician 
 
 
Signature 
 
Date 
 

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2. 
PROTOCOL REVISION HISTORY 
 
 
 
Date 
Description 
18 July 2017 
Original Draft 0.1 
30 Aug 2017 
Draft 0.2 
18 Sep 2017 
Draft 0.3 
26 Sep 2017 
Draft 0.4 
03 Oct 2017                                                     Draft 0.5 
17 Oct 2017                                                     Draft 0.6 
23 Oct 2017 
Draft 0.7 
13 Feb 2018 
Draft 0.8 
16 Feb 2018 
Final 1.0 
14 March 2018 
Version 2.0 Sections 9.1, 10, 12.7, modified in 
response to GNA letter 
12 December 2018 
Administrative changes to Sections 3, 12.1, 12.2, 
13.1, 15.4 and 18 
Change in PD laboratory and correction of 
inconsistencies. 
Transcription error in the EUDRACT number 
corrected. 
02 January 2019 
Total blood volume draw corrected, correction 
of typographical Error Section 13 
 
 
 
 
 
 

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3. 
STUDY CONTACTS 
 
 
PRINCIPAL INVESTIGATOR 
 
  
 
 
 
 
 
 
 
 
INVESTIGATIONAL SITE 
 
  
 
 
 
 
24 HOUR SPONSOR MEDICAL MONITOR 
 
 
 
 
 
 
 
  
 
 
SAFETY REPORTING 
 
 
 
 
 
 
 
 
 
   
  
 
  
 
  
 
 
 
 
 
 

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• 
Geometric mean fold increase in antibody concentration. 
• 
Seroconversion rate (proportion of subjects with fold increase above 
threshold at any time post vaccination). 
• 
Proportion of subjects achieving antibody concentrations above 
specific thresholds at Days 29 & 85 (these will be 2, 4, 8 μg/mL).  This 
will provide an assessment of the immune response to the first and 
second doses. 
Study Design: 
This is a Phase I, randomised, double-blind, placebo-controlled, parallel 
group, single centre study. 
There will be 2 cohorts of 30 subjects.  Cohort 1  will receive two 0.5 mL 
injections, 4 weeks apart, each consisting of 25 μg of GBS-NN and 25 μg of 
GBS-NN2 (24 subjects) or placebo (6 subjects).  Cohort 2 (30 subjects) will 
receive two 0.5 mL injections, 4 weeks apart, each consisting of 50 μg of 
GBS-NN and 50 μg of GBS-NN2 (24 subjects) or placebo (6 Subjects).  All 
vaccines will be adsorbed to 500 μg Al3+ as Alhydrogel®. 
 
Safety will be assessed after all subjects have completed Visit 4 (Day 8) for 
Cohort 1, at which point the decision will be made as to whether proceeding 
with administration of the doses in cohort 2 is appropriate.   
Study Duration: 
Study start is defined as check-in to the study unit on Day 1.  Each individual 
subject will be involved in the study for approximately 12 weeks (excluding 
the 28 day screening period and the 6 month safety follow up). 
Study Population: 
60 healthy female subjects aged 18 to 40 will be randomised into 2 cohorts 
of 30 subjects. 
Investigational Medicinal 
Product and mode of 
administration 
GBS-NN/NN2 vaccine will be supplied 
 
 
 
The placebo vaccine will contain Alhydrogel® mixed with sterile dilution 
buffer. 
Selection of Doses 
The GBS-NN/NN2 vaccine will be supplied a
 
  
 
The placebo vaccine will contain Alhydrogel® mixed with sterile dilution 
buffer. 
 
 
 
 
 
 
Individual subject treatments will be dispensed by the pharmacist or designee 
and labelled in accordance with Annex 13 of “The Rules Governing Medical 
Products in European Community, volume 4 Good Manufacturing Practice for 
Medicinal Products”. 
 
The following dosing strategy will be employed: 
Cohort 
Dose 
schedule 
Dose level GBS-NN/NN2 or 
placebo 
1 
Day 1, 29 
25µg of each protein or placebo 
2 
Day 1, 29 
50µg of each protein or placebo 
Treatment Schedule  
Volunteers will provide written informed consent and will be screened for 
eligibility within 28 days before first study vaccine administration (Day 1).  
Study start is defined as check-in to the study unit on Day 1.  Each individual 
subject will be involved in the study for approximately 12 weeks (excluding 

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the 28-day screening period and the 6-month safety follow up). Eligible 
Subjects will be administered the primary dose of the appropriate dose of 
GBS-NN/NN2 or placebo according to the cohort and dosing schedule 
described in section 10.1. at Visit 2 and a second dose will be administered at 
Visit 6.  All cohorts will incorporate sentinel dosing of 2 subjects in each 
cohort for the primary dose only: 1 on active treatment and 1 on placebo.  
No further subjects in that cohort will be dosed until 24 hours after dosing 
the second subject, 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 the 
subsequent cohort will be made as described in Section 12.5. 
A safety follow-up visit will be performed 6 months (±2 weeks) following 
the second study vaccine administration to check the general health collect 
blood for haematology, biochemistry and to assess the immune response. of 
the subject and to review adverse events (AEs). 
Statistical Analysis: 
Statistical analyses will be performed by 
 using SAS 9.3 or higher. 
Descriptive statistics for quantitative parameters will be provided using 
number of observations (N), mean, standard deviation (SD), minimum, median 
and maximum. Descriptive statistics for qualitative parameters will be provided 
using absolute frequencies (n) and relative frequencies (%). For immunological 
endpoints (IgG concentration and fold increase) additionally geometric means 
with corresponding 95% confidence intervals will be presented. 
 
Demographic, baseline characteristics and data recorded during the study will 
be summarized using descriptive statistics by treatment (placebo or vaccine) 
and dose group, unless otherwise specified. 
Individual data 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. 
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/NN2 vaccine dosing regimens, appropriate statistical method (for 
example: ANOVA or ANCOVA) can be used to compare pre-vaccination and 
post-vaccination levels as well as post-vaccination levels between groups. 
 
 

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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 component no 1 
GBS-NN2  
Group B Streptococcus vaccine component no 2 
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 
IUD 
 
Intra Uterine Device 
LDH 
 
Lactate Dehydrogenase  
LLOQ 
 
Lower Limit of Quantification 
LOD 
 
Late Onset Disease 

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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 
PP  
 
Per Protocol Set 
PT  
 
Preferred Term 
SAE 
 
Serious Adverse Event 
SAF 
 
Safety Set 
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 Subjecting Prevention System 
VIS 
 
Subject Information Sheet 
 
 
 

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6. 
INTRODUCTION 
6.1  Background 
 
Group B Streptococcus (GBS) has now emerged as the leading cause of neonatal sepsis and 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).  There is also an association with GBS urinary tract infection and the 
occurrence of chorioamnionitis, and premature labour (Anderson et al., 2007; Thomsen et al., 
1987). 
 
Introduction of inter partum antibiotic prophylaxis (IAP) in the 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 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 anyway 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) 

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(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 led 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 exists for the development of an effective alternative to IAP for the 
prevention of neonatal GBS infections, as outlined above and a maternal vaccine would be the 
appropriate solution. 
 
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 
potentially protect 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 (Madhi et al 2016, Donders et al 2016, Heyderman et al 2016). 
 
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). 
 
MinervaX has developed a novel GBS vaccine candidate, GBS-NN, based on the N-terminals of 
the Rib and AlphaC surface proteins of GBS. Rib and AlphaC, and cross-reactive Alpha-like 
proteins (Alp 1 and Alp2/3; Alp2 and Alp3 have an identical N-terminal domains) that are found 
on most isolates of serotypes Ia, Ib, II, III, IV, V, VI, VII and VIII, and antibodies directed against 
the vaccine were found to recognize 80-100% of 154 clinical isolates of serotypes Ia, Ib, II, III 
and V tested for antibody binding. Naturally occurring antibodies against the full-length Rib and 
AlphaC proteins are found in pregnant women, likely due to exposure to GBS from 
colonization, and such antibodies are efficiently transferred to their babies in-utero. Antibodies 
to Rib and AlphaC elicit protective immunity in animal models when administered with the 
standard adjuvant alum (Larsson et al., 1999). 
 
The first clinical trial with GBS-NN, in healthy non-pregnant women, has shown the potential 
vaccine to be highly immunogenic well tolerated with a good safety profile.  Investigations into 
the breadth of coverage of the GBS-NN vaccine against all GBS strains have identified the need 
for the additional antigens, Alp1, Alp2, and Alp3 to be included in a vaccine.  GBS-NN2 contains 
the Alp1, Alp2 and Alp3 N-terminal proteins (Alp2 N and Alp3 N are identical) and has been 
added to GBS-NN.  Hence, of the four different members of the targeted surface proteins that 
are found on different GBS bacteria, two are represented in GBS-NN and the remaining two in 
GBS-NN2.  MinervaX has completed toxicology studies on the GBS-NN/NN2 vaccine, which is 

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now ready to move into clinical trials, in a population of healthy, non-pregnant female subjects.  
 
6.2.1  Summary of Non Clinical Data 
 
Mice have been dosed with GBS-NN with and without alum at doses ranging from 2µg to 64µg 
 immune responses were elicited at all doses, with the 
antibody responses at doses of 4µg to 64µg in the presence of Alhydrogel® being 
indistinguishable from each other and showing a trend towards being higher than responses to 2 
µg 
. The addition of alum reduced the time taken for the peak 
immune response to be achieved, increased the magnitude of the immune response and 
increased the number of responders. 
 
The local and systemic toxicity studies with GBS-NN/NN2 in rabbits and rats, respectively, did 
not identify any unexpected findings.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
r. 
 
The findings of the studies are in line with the findings GBS-NN alone and the changes seen in 
the animals were considered to be the pharmacological responses to the vaccine inducing an 
immune response.  
 
 
 
 
 
Overall the data indicate that it is appropriate to continue development and administer the 
GBS-NN/NN2 vaccine to healthy subjects. 
 
Reproductive toxicology studies are being completed, preliminary data has not identified any 
adverse effect on foetuses or foetal development. 
 
Immunogenicity studies with GBS-NN/NN2 have been undertaken in mice 
.  
Immunisation with either GBS-NN or GBS-NN2 induces significant cross-reactivity with the 
heterologous antigen.  Primary immunization with the combination of GBS-NN and GBS-NN2 
gives similar responses to all four domains and the responses to homologous antigens are 
equivalent to those induced by immunizing with the single molecules. 
6.2.2 Summary of Clinical Data 
 
Study MVX13211 with GBS-NN alone, has shown that GBS-NN is well tolerated in healthy 
female subjects.  The study concluded that GBS-NN has an appropriate safety profile for a 
vaccine with the primary adverse reaction of pain at injection site was mild and reported at an 
incidence comparable to other intramuscularly administered vaccines that contain Alhydrogel®.  
Healthy subjects developed high concentrations of antibodies against the N-terminal proteins 
AlphaC and Rib 
. 
, if 
the antibodies are protective, it is anticipated that the foetus will be passively immunized from 
the mother. 
 
The first clinical trial with GBS-NN, in healthy non-pregnant women, has shown the potential 

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This is a new investigational product; therefore, there are currently no expected AEs related to 
the product. However, following injection of GBS-NN alone, approximately 30% of the subjects 
in the study experienced mild pain. Pain post-injection that is worse that mild would be 
considered to be unexpected. It is not anticipated that adding the two additional antigenic 
proteins, to GBS-NN, bound to Alum will significantly alter the safety profile. The Investigator is 
responsible for reporting adverse events (AEs) that occur during the course of the study.  
Serious adverse reactions that are deemed to be related to the investigational product in the 
proposed study will be reported as suspected unexpected serious adverse events (SUSAR). 
 
GBS-NN/NN2, like other protein-based vaccines, may theoretically be associated with a 
transient febrile reaction (body temperature greater than 38.0°C but not greater than 38.7°C) 
following vaccination.  Immune complex-mediated reactions are unlikely given the recombinant 
nature of GBS-NN/NN2, however, it is still possible that hypersensitivity may occur. 
 
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. 
 
The protocol requires that subjects are monitored after vaccine administration (vital signs and 
general signs and symptoms), with regular follow-up visits for physician assessment and 
questioning regarding AEs will be conducted for all subjects in the study. All study subjects 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. 
 
GBS-NN/NN2 vaccination is contraindicated in subjects known to suffer hypersensitivity 
reactions to vaccines or a known allergy to aluminium hydroxide. For the purpose of the study 
subjects who have experienced a significant illness in the four weeks prior to check in will be 
excluded. The vaccine should not be given to subjects with known or suspected immune 
deficiency, autoimmune diseases or who have an acute infection.  
 
GBS-NN/NN2 should not currently be given to women known, or suspected to be, pregnant, 
or to nursing mothers.  Currently GBS-NN/NN2 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.  
7. STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary Objective 
• 
The primary objective is to evaluate the safety and tolerability of the GBS-NN/NN2 
vaccine for 12 weeks (up to Day 85) after the first dose of vaccine. 
7.2  Secondary Objectives 
• 
To evaluate IgG antibody responses induced by the two vaccine doses of GBS-
NN/NN2 up to Day 85 in healthy female subjects. 
• 
To assess whether pre-existing antibody levels affect the vaccine-induced antibody 
response.  
7.3 
 
 
 
 
 
pregnancy. 

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• 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 Primary Endpoints 
• 
Local and systemic reactogenicity; adverse events; laboratory tests; urinalysis; vital 
signs; physical examination. 
7.5 Secondary Endpoints 
• 
Local and systemic reactogenicity; adverse events; laboratory tests if undertaken for 
cause; urinalysis if undertaken for cause; vital signs; physical examination; the outcome 
of any pregnancies. 
• 
Geometric mean antibody concentration in μg/mL. 
• 
Geometric mean fold increase in antibody concentration. 
• 
Seroconversion rate (proportion of subjects with fold increase above threshold at any 
time post vaccination). 
• 
Proportion of subjects achieving antibody concentrations above specific thresholds at 
Days 29 & 85 (these will be 2, 4, 8 μg/mL).  This will provide an assessment of the 
immune response to the first and second doses. 
8. STUDY DESIGN 
8.1 
Overview 
This is a Phase I, randomised, double-blind, placebo-controlled, parallel group, single centre 
study. 
There will be 2 cohorts of 30 subjects.  Cohort 1 will receive two 0.5 mL injections, 4 weeks 
apart, each consisting of 25 μg of GBS-NN and 25 μg of GBS-NN2 (24 subjects) or placebo (6 
subjects).  Cohort 2 (30 subjects) will receive two 0.5 mL injections, 4 weeks apart, each 
consisting of 50 μg of GBS-NN and 50 μg of GBS-NN2 (24 subjects) or placebo (6 Subjects). 
All vaccines will be adsorbed to 500 μg Al3+ as Alhydrogel®. 
 
Safety will be assessed in a blinded fashion after all subjects have completed Visit 4 (Day 8) for 
Cohort 1 , at which point the decision will be made as to whether proceeding with 
administration of the doses in cohort 2 is appropriate.   
8.2 
Study Centre(s) 
The study will be performed at a single centre based in the United Kingdom. 

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8.3 
Study Duration 
Study start is defined as check-in to the study unit on Day 1.  Each individual subject will be 
involved in the study for approximately 12 weeks (excluding the 28 day screening period and 
the 6 month safety follow up). 
 
 
 

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9. 
STUDY POPULATION 
9.1 
Inclusion Criteria 
1. 
Healthy female subjects aged 18 – 40 years.  
2. 
Body mass index (BMI) ≥18 and ≤30 kg/m2. 
3. 
Subjects weight ≥50kg and ≤100kg at screening. 
4. 
Able to voluntarily provide written informed consent to participate in the study. 
5. 
Subjects are pre-menopausal.   
6. 
Females of childbearing potential must have a negative pregnancy test at screening (β 
HCG) and prior to each dose.  To prevent pregnancy female subjects of childbearing 
potential must take adequate contraceptive precautions for the entire duration of study 
participation (up to Day 85). Adequate and highly effective contraceptive precautions 
include: 
• 
Established use of oral, injected or implanted hormonal methods of 
contraception. 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
• 
Barrier methods of contraception: Condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.  
• 
Male sterilisation (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female subjects, the vasectomised male 
partner should be the sole partner for that subject]. 
• 
True abstinence, when this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception]. 
• 
The chosen contraception method(s) must be followed from the first dose until 
at least Day 85 of the study. 
 
7. 
Non-smokers for at least 3 months prior to first study vaccine administration. 
9.2 
Exclusion Criteria 
1. 
Subjects who have received GBS-NN vaccine previously.   
2. 
Subjects 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. 
3. 
Pregnant or lactating females. 
4. 
Laboratory values at screening which are deemed by the investigator to be clinically 
significantly abnormal. 
5. 
Positive drug screen for drugs of abuse or a positive alcohol urine test prior to first 
dosing unless there is a documented medical explanation for the positive result other 
than drugs of abuse (e.g., the subject has been prescribed opioids for pain). 
6. 
Positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C. 
7. 
Participation in a clinical drug study during the 90 days preceding the initial dose in this 
study. 

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8. 
Any significant illness during the 4 weeks preceding check-in for this study (Day 1). 
9. 
Subjects with a history of allergic reactions after previous vaccination.   
10. Subjects 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. 
11. Subjects receiving immunosuppressive therapy in the 6 months prior to screening, 
taking any short-term medications including over-the-counter (OTC) preparations, 
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. Use of OTC vitamins and dietary supplements is allowed 
12. Subjects with tattoos at the proposed site of vaccine administration. 
13. Donation of blood or blood products within 90 days prior to vaccine administration or 
intending to donate blood or blood products within 90 days of the last visit. 
14. Subjects who, in the opinion of the Investigator, are unsuitable for participation in the 
study. 
9.3 
Planned Sample Size 
60 healthy female subjects aged 18 to 40 will be randomised into 2 cohorts of 30 subjects. 
 At least 24 evaluable subjects in cohort 1 will be required to attend through to visit 4 in order 
to provide sufficient data for a decision to dose escalate in cohort 2. If the required number of 
evaluable subjects are not obtained in a cohort, then the safety review committee (SRC) must 
decide whether there is enough safety information available to make a decision or whether 
further subjects should replace the dropped subjects or if sufficient information exists to 
determine if the dosing of cohort 2 is appropriate. 
9.4 
Allocation of Randomisation Numbers 
 
Subjects will be allocated to treatment groups according to a randomisation code produced by 
using the PROC PLAN procedure of SAS® version 9.3.  
Subjects will be numbered sequentially from 001 (i.e. 001, 002 etc.).  Replacement subjects will 
be assigned the same randomisation as the subject they are replacing, however, 100 will be added 
to the number (i.e. 101 would replace 001 etc.). 
 
9.5 
Subject Withdrawal 
 
The subject has the right to abstain from participation in the study or to withdraw consent to 
participate at any time.  The Sponsor or the Investigator also holds the responsibility to 
withdraw a randomised subject from the study prematurely if it is considered in the best 
interest of the subject.  The entire study may be stopped if there are unpredicted safety 
concerns. 
 
A subject’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 subject deviates from the treatment plan specified in the protocol (e.g. failure to 
attend essential or significant amount of study visits). 

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• 
The subject 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 subject 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.  If a subject become pregnant between Day 1 (first dose) 
and Day 85, she will not receive any further vaccinations (if conception occurs between the first 
and second dose) but will undergo all follow-up visits and the pregnancy will be followed to 
term to determine the outcome unless the subject withdraws consent. 
 
9.6 
Subject Replacement 
 
If the required number of evaluable subjects are not obtained in a cohort, then replacement 
subjects may be recruited as per section 9.3. 
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. 
 
• 
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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administered for the appropriate management of a subject on the study, the Investigator may 
break the blinding code for an individual subject. If the blind is broken the Investigator will 
inform the Sponsor within 24 hours of breaking the blind, that the blind has been broken and 
the reason for breaking the blind (but not necessarily the outcome of the breaking of the blind) 
and record the date/time and reason for breaking the blind. 
10.6 Vaccine 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 Good Clinical Practice (GCP) 
guidelines as well as appropriate regulations. Study vaccines will be stored according to the 
instructions on the label as received by the manufacturer. Storage of GBS-NN and GBS-NN2 
will be 
  Alhydrogel® and diluents buffer will be stored at 2 to 8°C. 
 
 
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 subjects, 
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. 
 
The Investigator must ensure the availability of an appropriate storage location and the 
recording and evaluation of storage conditions. The Pharmacy Department 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 or designee 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 
 
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. 
 
Non-permitted medications are provided in the exclusion criteria Section 9.2. 
11.2 Concomitant Medications 
 
Paracetamol will be permitted for the treatment of headache or other symptomatic pains. 
 
Any medication the subject takes, other than study vaccine and approved medications approved 
by the PI will be considered a concomitant medication; this will include herbal and other 
remedies.  All concomitant medications taken during the study must be recorded in the CRF.   
11.3 Other Restrictions 
 
The Investigator or designee will request that subjects 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 and post dosing and scheduled 
clinic visits.  
• 
Use of cosmetics or creams at the site of vaccination that are known to cause irritation 
within 24 hours prior to dosing and for the duration of the study. 
• 
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 
Please refer to the schedule of assessments (Table 1, section 18) for a detailed overview of the 
study conduct. 
12.1 Screening Period 
 
Screening assessments 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, oral 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 urine  test 
• 
Urine drugs of abuse test Cannabinoids, amphetamines, cocaine, benzodiazepines, opiates 
and cotinine. 
• 
A review of all medications taken in the previous month 
12.2 Treatment Period and Post-Study Period 
Subjects will be administered the primary dose of the appropriate dose of GBS-NN/NN2 or 
placebo according to the cohort and dosing schedule described in section 10.1 at Visit 2 and a 
second dose will be administered at Visit 6.All cohorts will incorporate sentinel dosing of 2 
subjects in each cohort for the primary dose only: 1 on active treatment and 1 on placebo.  
No further subjects in that cohort will be dosed until 24 hours after dosing the second 
subject, 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 the subsequent cohort will 
be made as described in Section 12.5. 
 
The following assessments will be carried out at these visits: 
Visit 2 
A general medical review, vital signs, urine pregnancy test, urine drugs of abuse test and 
alcohol urine test will be performed to re-confirm eligibility.   Eligible subjects will then be 
randomised to receive the appropriate treatment as per the randomisation list for the cohort. 
A pharmacodynamic blood sample will be taken to measure pre-existing antibody levels and to 
obtain Peripheral Blood Mononuclear Cells (PBMCs) to assess cellular responses, prior to 

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dosing.  Blood sample for haematology and serum biochemistry will be taken.  Vital signs will 
be recorded at pre-dose (within 60 minutes of dosing), 2 (±0.25) and 4 (±0.25) hours post-
dose.  A general medical examination (including an assessment of the injection site) will be 
performed prior to discharge to ensure the subject is fit for discharge.  At discharge subjects 
will be provided with oral temperature kit and instructed to record a temperature if they feel 
unwell in the seven days post dose.   
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 (±1 day) 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 (±2 days) after administration of the primary dose.  This 
visit will review of AEs and concomitant medications. An assessment of the injection site will 
be performed, vital signs will be recorded, safety blood samples for haematology and 
biochemistry will be collected and a pharmacodynamic blood sample will be taken to measure 
the antibody response. 
Visit 6 
Visit 6 will be performed 4 weeks (±3 days) after Visit 2.  An assessment of the injection site, 
AEs and concomitant medications review, urine pregnancy test, and a pharmacodynamic blood 
sample will be taken to measure the antibody response prior to administering the second 
dose.  Vital signs will be recorded pre-dose and at 2 (±0.25) and 4 (±0.25) hours post-dose.  A 
brief medical examination (including an assessment of the injection sites) will be performed 
prior to discharge to ensure the subject is fit for discharge.    At discharge subjects will be 
provided with oral temperature kit and instructed to record a temperature if they feel unwell 
in the 7 days post dose.   
Visit 7 
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. 
Visit 8 
Visit 8 will be performed 2 weeks (±2 days) 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 
to obtain PBMCs to asses cellular responses, and AEs and concomitant medications will be 
reviewed.   
Visit 9 
Visit 9 will be performed 8 weeks (±2 days) 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.   

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Visit 10 
A full medical examination will be performed 12 weeks (Day 85±2 days) 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, urinalysis, blood samples for haematology and 
biochemistry, serum pregnancy test and a review of AEs and concomitant medications.  This 
visit signifies the endpoint for the primary endpoint for the study. 
Safety Follow-Up (Visit 11) 
A safety follow-up visit will be performed 6months (±2 weeks) following the second study 
vaccine administration to check the general health, measure vital signs, collect blood for 
haematology, biochemistry and to assess the immune response of the subject and to review 
adverse events (AEs). 
Subjects do not have to use highly effective contraception following the Day 85 visit, should 
any subject become pregnant between Day 85 and Day 210, permission will be sought to 
follow the pregnancy, to obtain data on the outcome of the pregnancy. 
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 subject 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) counts 
 
 
Biochemistry 
 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Blood urea 
Creatinine 
Creatine Kinase 
Glucose  
Calcium 
Albumin 
Cholesterol 
C- reactive protein CRP 
Triglycerides 
Phosphorus (inorganic phosphate)  
Lactate dehydrogenase (LDH) 

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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 
 
Screening ECGs will be recorded after the subject has been lying for at least 5 minutes. 
 
Vital signs will be recorded in the supine position, after the subject 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 ≤37.5oC  
 
12.3.3 
Injection Site Tolerability Assessment 
 
Injection site tolerability assessments will be performed as described in Appendix 1. 
12.4 Time Windows for Visits 
 
Vital signs will be performed within ±15 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 ± 2 days. 
The time window for Visit 11 is ±2 weeks. 
12.5 Safety Monitoring Board and Safety Data Review Meetings 
Both cohorts will incorporate sentinel dosing of 2 subjects in each cohort for the primary 
dose only: 1 on active treatment and 1 on placebo.  No further subjects in that cohort will be 

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dosed until 24 hours after dosing the second subject, 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 the subsequent cohort will 
be made as follows: 
• It is intended that safety will be assessed after at least 24 evaluable subjects in cohort 1 
(sentinel and main dose groups) have completed Visit 4 (Day 8), at which point the decision 
will be made to proceed with administration of the primary dose in cohort 2. 
 At least 24 evaluable subjects are required to complete through to visit 4 in cohort 1, in 
order to provide sufficient data for a decision to dose escalate.  If the required number of 
evaluable subjects is not obtained in cohort 1, then the safety review committee (SRC) must 
decide whether there is enough information present to make a decision or whether further 
subjects should replace the dropped subjects or if sufficient information exists to determine if 
the dosing of cohort 2 is appropriate. The decision of the safety monitoring board and the 
output of the safety review must be clearly documented after the meeting.   
The following safety data will be reviewed: 
• Clinical Laboratory Tests  
• Vital signs  
• Assessment of injection site reactions 
• AEs 
 
The SRC will include at least 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 SRC. 
 
The SRC 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 
prior to these meetings for the SRC to review. 
 
After review and discussion of all the data, the decision will be made on dose escalation and 
documented by signature of a Dose Escalation Approval Form by the voting members of the 
SRC.  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. 
 
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 subjects will be discontinued from the study if 
they meet any of the individual subject stopping criteria as described in Section 12.6.  
12.6 Individual Subject Stopping Criteria 
 
Subjects who meet one or more of the following stopping criteria will receive no further doses 
of the 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 (≥38.5°C for ≥12 hours) at the Investigator’s discretion 
• 
SAE related to the study agent 

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The medical safety of the subject 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 subjects in a cohort experience a 
severe site reaction related to the GBS-NN/NN2 vaccine (study agent). 
• 
If one of the sentinel group or more than 20% of the subjects in a cohort experience a 
severe systemic reaction related to the study agent. 
• 
If one of the sentinel group or more than 20% of the subjects in a cohort experience a 
persistent febrile reaction (>38.5°C for ≥12hours) related to (study agent). 
• 
If one or more subjects experience a SAE related to the study agent. 
• 
If two or more subjects in the same cohort, experience 'severe' non-serious adverse 
reactions (i.e. severe non-serious adverse events, independent of system-organ-class, 
considered at least possibly related, to the IMP administration). 
 
 
 

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13. 
PHARMACODYNAMIC ANALYSIS AND 
ASSESSMENTS 
 
13.1 
 
Pharmacodynamic blood sample – antibody response 
 
Each blood sample will be approximately 20 mL in volume, to yield approximately 10 mL of 
sera.  The sera will be divided into aliquots, as described in the laboratory manual.  Seven 
samples will be collected during the study which represents approximately 140 mL of blood. 
 
The total blood volume taken over the study will be approximately 300 mL, which represents 
seven of approximately 20 mL pharmacodynamic samples, two of approximately 40 mL PBMC’s 
and seven of approximately 9 mL clinical laboratory blood samples. 
 
Pharmacodynamic samples will be collected at the following timepoints; Day 1, Day 15, Day 29, 
Day 43, Day 57, Day 85 and Day 210 
 
Detailed processing instructions will be included in a separate lab manual. 
 
 
 
 
Serum samples for PD antibody response analysis will be performed at 
 at 
 and 
 
 
 
Serum samples will be assayed in a validated ELISA to measure the concentrations of IgG 
specific for GBS-NN and GBS-NN2. Raw data from the assay will be inspected by the QC/QA 
scientists at the analytical lab to identify any samples which give unexpected results based on 
the normal kinetics of IgG induction following vaccination. Such unexpected values may 
indicate a problem with sample identification or with the assay performance. Potentially 
anomalous results will be discussed with the sponsor, without revealing the identity of the 
subjects, and if necessary samples will be re-analysed and corrected if the result fits with 
expectation. If the re-analysis returns essentially the same result a decision will be taken on 
whether to exclude the samples from the IG population analysis. Prior to formal statistical 
analysis of the results a standard test for outliers (e.g. the ROUT function in Grpahpad Prizm 
or equivalent) will be performed and any data points identified will be excluded from the 
analysis. In parallel the analysis will be performed on all data points including outliers to reveal 
the magnitude of the effect of excluding them. 
 
 
 

 
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14. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS 
ANDREPORTING 
 
14.1 Adverse Events (AEs) 
 
An AE is any untoward medical occurrence in a subject 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. 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 (i.e. after Visit 10), AEs 
will be recorded by the subject 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. 
14.2.2 
Causality Classification 
 
The relationship of an AE to the study vaccine will be classified according to the following: 
 

 
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Related:  
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 subject's clinical state and, if necessary, the reaction 
returns on re-starting the vaccine (re-challenge). 
 
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. 
 
14.3 Recording and Follow up of Adverse Events 
 
Up to Day 85 (Visit 10), the subjects 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 subject 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. Following Day 85 (Visit 10) AEs 
will be recorded by the subject 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, however the Investigator will 
continue to follow up ongoing related AEs and record information in the source documents. 
Related SAEs will be followed until the event resolves or the event or sequelae stabilise and this 
information will be reported to the Sponsor using the SAE reporting forms. 
 
14.4 Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 
 
A SAE is any AE that: 
 
• 
results in death 
• 
is life-threatening  
• 
requires inpatient hospitalization or prolongation of existing hospitalization  
• 
results in persistent or significant disability or incapacity 
• 
consists of a congenital anomaly or birth defect. 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardise the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above should also be considered serious. 
 
A SUSAR is an adverse reaction, which is both serious and unexpected. 

 
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14.5 Reporting Timelines 
14.5.1 
SAE Reporting 
 
An SAE must be reported immediately (within 24 hours), independent of the circumstances or 
suspected cause, if it occurs or comes to the attention of the Investigator at any time during the 
study period.  Any SAE with a suspected causal relationship to the IMP occurring at any other 
time after completion of the study must be promptly reported. 
 
Contact Details for SAE Reporting: 
 
 
  
 
 
 
 
 
 
The following mandatory information must be provided to the Sponsor pharmacovigilance 
contact within 24 hours for each SAE:  
 
• Protocol number 
• Subject number 
• AE 
• IMP 
• Investigator's name and contact details 
Causality assessment should be completed as soon as possible. 
 
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. 
 
The 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 and vital sign 

 
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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 6 month follow up it is possible that one or more subjects may become 
pregnant after day 85.  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 
, and will inform the Sponsor.  
 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 subject.   
 
 

 
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15.2 Studied populations for each study part 
 
The following populations will be taken into account for each study part: 
 
• 
Randomized Set (RAN): All included subjects who are randomized at V2 to one of 
the two cohorts; 
• 
Safety Set (SAF): All subjects from the SAF set who receive at least one dose of the 
study vaccine (or placebo) will be taken into account in the description of the population 
(demographic or baseline characteristics); 
• 
Immunogenicity Set (IG): The subset of subjects from the SAF set who will receive 
at least one dose of the study vaccine (or placebo) with available pre- and post-
vaccination titres.  
• 
Per Protocol Set (PP): All subjects from the IG set who receive both doses of the 
study vaccine (or placebo) and provide evaluable samples for analysis of the IgG antibody 
response to the GBS-NN/NN2 vaccine at Day 85 (most important immunological 
endpoint) and do not violate the protocol. 
 
The safety analyses will be performed on the SAF set. The immunological analyses will be 
performed on the IG set. The most important immunological endpoint (immune response 
on Day 85) will also be performed on the PP set if the number of subjects in the PP set 
differs by more than 5% from the number of subjects in the IG 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 60 healthy female subjects will be included in 2cohorts of 30 subjects respectively.   
 
15.4 Studied criteria 
15.4.1 
Characteristics of included subjects 
 
• Subject disposition 
Subject disposition will be presented for the RAN set and will include the number enrolled, 
the number in each subject population for analysis (RAN, SAF, IG and PP), the number who 
withdrew prior to completing the study and primary reason for withdrawal (if applicable). 
 
• Subject demographic characteristics 
 
 For demography, continuous variables (for example: age, height, weight, BMI) and 
 qualitative variables (for example: ethnic origin) will be summarized using descriptive 
 statistics on the SAF population. Demographic characteristics will be also presented for 
other study populations (IG and/or PP) if they are different from SAF. 
 
• Medical history events 
Medical and surgical history events will be coded using MedDRA (latest version) and will be 
summarized by System Organ Class (SOC) and Preferred Term (PT). Subjects will 
contribute only once per SOC and 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 
subject. 
 
• Physical examination 
 
 Abnormal physical findings at screening period or at V2 pre-dose (study baseline) will be 
 listed by treatment/dose group, subject and visit. 

 
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• Pregnancy test 
 
Serum pregnancy test will be performed at screening and post-study medical visit and 
 
urine pregnancy test will be performed prior to each administered dose (primary and 
 
booster doses at Visit 2 and Visit 6 respectively). A listing of positive results will be 
 
presented by treatment/dose group, subject and visit. 
 
• Previous medications 
Previous medications will be listed and will be presented by treatment/dose group and 
subject. 
 
• Concomitant medication 
Concomitant treatments will be  listed by treatment/dose group. 
 
15.4.2 Primary endpoint 
 
The primary objective is to evaluate the safety and tolerability of the GBS-NN/NN2 vaccine 
for 12 weeks after the first dose of vaccine.  
 
All the subjects included in the SAF set (including the withdrawal and dropout subjects) will 
be evaluated for safety analysis. 
 
The following endpoints will be evaluated: 
 
• 
Local and systemic reactogenicity 
 
Assessment results will be described according to treatment/dose group and visit. 
 
• 
Adverse events 
 
Adverse events will be coded according to the Medical Dictionary for Regulatory 
Activity (MedDRA, latest version). They will be classified into pre-defined  standard 
categories according to chronological criteria: 
 
Treatment Emergent Adverse Events (TEAEs): AEs which occur for the first time after 
the first administration or present before and worsened during vaccine exposure. 
 
Non-Treatment Emergent Adverse Events (NTEAEs): AEs which occur before the first 
study vaccine administration (also called “pre-dose event”). 
 
TEAEs will be described by relation to study vaccine (for example: related or 
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 subjects with at least one TEAE (based on SAF). 
In case of few TEAEs (≤5 per study part for example), only a listing will be 
performed. 
 
If descriptive statistics are performed, vaccine relation of TEAEs (i.e. related or not 
related to study vaccine) will be summarized by MedDRA codes (SOC and PT) and 
treatment/dose group. 
 
Two distinct listings of TEAEs and NTEAEs will be presented by treatment/dose 
group, subject and MedDRA codes in order to provide more information about 
adverse events (example: description, duration, time since last administration if 

 
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applicable, seriousness, relation to study vaccine, any actions taken as concomitant 
medication or hospitalization). 
 
• 
Laboratory tests 
 
 Biochemistry and haematology tests will be performed at V1 (screening), V2, V4, V5, 
V8, post-study medical V10 and V11.  
 
Parameter values, position according to laboratory ranges (if available) and 
investigator assessment will be listed according to visit for each treatment/dose 
group. In order to assess study evolution of parameters after vaccination, parameter 
values changes from pre- to post-dose visits (baseline to pre second dose Day 29 
(effect of first dose) and baseline and pre second dose to 28 days after second dose 
(Day 57) then base line to Day 85).  will be calculated. Emergent values (for 
parameters with available laboratory ranges; values not within this range) with their 
corresponding position according to ranges will be listed by treatment/dose group 
and subject. 
 
• 
Urinalysis 
 
Urinalysis will be performed at V1 (screening), V4, V8 and post-study medical visit 
V10.  
 
 Parameter values (quantitative or binary results, i.e. positive/negative), position 
according to laboratory ranges (if available) and investigator assessment will be listed 
according to visit for each treatment/dose group. In order to assess 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 subject. 
 
• 
Vital signs 
 
 Vitals signs will be characterised by heart rate, blood pressure, oral temperature and 
respiratory rate. Vital signs will be assessed at V1 (screening), V2 (pre-dose, T2h and 
T4h post-dose), V3, V4, V5, V6 (pre-dose and T2h post-dose), V7, V8, and post-
study medical V10 and V11. 
 
 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 assess 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; 
values not within this range) with their corresponding position according to 
reference ranges will be listed by treatment/dose group and subject. 
 
 
• 
12-lead ECG parameters 
 
 ECGs will be assessed at V1 (screening). 
 
 
Parameter values, position according to reference ranges and investigator 
assessment (if available) will be described according to visit for each treatment/dose 
group. Emergent values (for parameters with available reference ranges; values not 

 
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within this range) with their corresponding position according to reference ranges 
will be listed by treatment/dose group and subject. 
 
• 
Physical examination 
 
Abnormal physical examinations recorded at post-study medical visit V10 andV11 
will be listed according to treatment/dose group and subject. 
15.4.3 
Secondary Endpoints (Immunological Endpoints) 
 
The secondary objectives are: 
• 
To evaluate the IgG antibody response to the GBS-NN/NN2 vaccine at Day 85 (most 
important immunological endpoint).  
• 
To assess whether pre-existing antibody levels affect the vaccine-induced antibody 
response.  
 
Immunological parameters measured to evaluate objectives 
 
In order to evaluate these objectives, GBS-NN and GBS-NN2 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 subject: 
 
- Antibody concentrations specific for GBS-NN and GBS-NN2 at each sample point (μg/mL) 
- Fold increases over pre-immunisation level (Day 1) in antibody concentrations 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 concentrations specific for GBS-NN and GBS-NN2inμg/mL 
(with 95% CI). 
- Geometric mean fold increase in antibody concentration (with 95% CI). 
- 
 Seroconversion rate (proportion of subjects with fold increase above threshold at any 
time point post vaccination up to Day 85). 
- Proportion of subjects achieving antibody concentrations above specific thresholds at Days 
29 & 85 (these will be 2, 4, 8 μg/mL).  This will provide an assessment of the immune 
response to the first and second doses. 
The most important immunological end point will be the values of these end points at Day85, 
12weeks after the administration of the first dose of vaccine. 
 
 

 
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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 Contract Research Organisation(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, subject information sheet (VIS), informed consent 
form (ICF) and any study related information or documents issued to subjects will be reviewed 
and approved along with other required documents by the Ethics Committee (EC) and each 
study site’s local EC before subjects 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. 
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 subject in the study.  The Sponsor will always 
also provide the EC/CA with a summary of the study’s outcome. 

 
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16.3 Subject Information and Informed Consent 
 
Informed consent should be obtained by means of a VIS and ICF, prepared in accordance with 
ICH E6 (R2) Section 4.8.10 and applicable local regulations, written in non-technical language. 
All subjects will be provided with oral and written information describing the nature and 
duration of the study and the procedures to be performed.  The subject will be asked to sign 
and date an ICF prior to any study-specific procedures being performed.  No subject can enter 
the study before his/her informed consent has been obtained.  A sample subject ICF used in the 
study will be included in the clinical study report for this protocol. 
 
Prior to study start, the subjects 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 subject 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 subject should understand the VIS and ICF before signing and dating the ICF.  
The Investigator or qualified person obtaining consent must also sign and date the form.  Each 
subject will be given a copy of the signed informed consent and written information.   
 
The original signed ICF for each subject 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 General Data 
Protection Regulation.  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.  Risk based monitoring will be 
used. For further specifications please refer to the monitoring plan. 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 subject 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 subject’s source data records. SDV will be performed with due regard for subject 
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 subject 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 
• 
Audit of Clinical Study Report 

 
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• 
Audit of selected study sites, requiring access to subject 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 subject 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 
Table 1. 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 
15 
Day 
29 
Day 
30, 
Day 
43 
Day 
57 
Day 85 
Day 210 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
X 
X 
 
 
 
Xd 
 
 
 
X 
 
Height, Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsa 
X 
Xb 
X 
X 
X 
Xb 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
Safety laboratory tests 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
HIV, Hep B and Hep C 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
X 
 
 
 
X 
 
Alcohol urine test 
X 
X 
 
 
 
 
 
 
 
 
 
Drugs of abuse test 
X 
X 
 
 
 
 
 
 
 
 
 
Review of subject 
eligibility 
 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Administration 
Investigational vaccine 
 
X 
 
 
 
X 
 
 
 
 
 
PD blood sample – 
antibody response 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
PD blood sample –
PBMCs 
 
X 
 
 
 
 
 
X 
 
 
 
Assessment of 
injection site 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE check 
 
X 
X 
X 
Con med check 
X 
X 
X 
X 
Footnotes 
a. 
Heart rate, blood pressure, oral temperature and respiration rate. 
b. 
Vital signs at dosing Visit will be recorded pre-dose and at 2 and 4 hours post-dose. 
c. 
Serum pregnancy test at screening and post-study medical.  Urine pregnancy test prior to each dose. 
d. 
Targeted medical examination (including assessment of the injection site(s) to determine eligibility for discharge at least 4 
hours post-dose 
e. 
Photographs may be taken of injection site reactions as required. 
 
 

 
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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. Madhi SA, Cutland CL, Jose L et al (2016) 'Safety and immunogenicity of an investigational 
maternal trivalent group B streptococcus vaccine in healthy women and their infants: a 
randomised phase 1b/2 trial.', Lancet Infect Dis, 16(8), pp. 923-934. 
3. Donders GG, Halperin SA, Devlieger R et al (2016) 'Maternal Immunization With an 
Investigational Trivalent Group B Streptococcal Vaccine: A Randomized Controlled 
Trial.', Obstet Gynecol., 127(2), pp. 213-221. 
4. Heyderman RS, Madhi SA, French N et al (2016) 'Group B streptococcus vaccination in 
pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, 
multicentre trial.', Lancet Infect Dis., 16(5), pp. 546-555. 
5. Centre for Disease Control and Prevention (2002). Prevention of perinatal Group B 
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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  
 
Subjects 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