A Phase 2, Non-Randomized, Controlled, Open-Label, Parallel-Group, Extension Study to Evaluate the Immunogenicity and Safety of the Second Dose of GBS Trivalent Vaccine in Healthy Non-pregnant Subjects.
Phase: PHASE2
Conditions: Bacterial Infection Due to Streptococcus, Group B, Streptococcus Agalactiae
Sponsor: GlaxoSmithKline

GSK 
02 JUL 15 Final Version 1 
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Protocol V98_06E1 
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CLINICAL STUDY PROTOCOL V98_06E1 Version 1 
 
 
A Phase 2, Non-Randomized, Controlled, Open-Label, Parallel-Group, Extension 
Study to Evaluate the Immunogenicity and Safety of the Second Dose of GBS 
Trivalent Vaccine in Healthy Non-pregnant Subjects 
 
 
 
 
Evaluation of a Second Dose of GBS Trivalent Vaccine in Healthy Non-Pregnant 
Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK . 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................... 2 
PROTOCOL SYNOPSIS V98_06E1 VERSION 1 ............................................................. 7 
LIST OF ABBREVIATIONS ............................................................................................ 21 
1. 
BACKGROUND AND RATIONALE .................................................................... 22 
1.1 
Background .......................................................................................................... 22 
1.2 
Rationale .............................................................................................................. 23 
2. 
OBJECTIVES ........................................................................................................... 25 
2.1 
Primary Objective(s) ............................................................................................ 25 
2.2 
Secondary Objective(s) ........................................................................................ 25 
2.3 
Exploratory Objective(s) ...................................................................................... 25 
3. 
STUDY DESIGN ..................................................................................................... 26 
3.1 
Overview of Study Design ................................................................................... 26 
3.2 
Study Period ......................................................................................................... 27 
3.3 
Blinding Procedures ............................................................................................. 27 
3.4 
Data Collection .................................................................................................... 27 
3.4.1 Data Collected from Subjects ....................................................................... 27 
3.4.2 Tools Used for Data Collection .................................................................... 28 
3.5 
Collection of Clinical Specimens......................................................................... 29 
3.6 
Stopping/Pausing Guidelines ............................................................................... 30 
3.7 
Data Monitoring Committee ................................................................................ 30 
3.8 
Premature Withdrawal from Study ...................................................................... 30 
3.9 
End of Study ........................................................................................................ 32 
4. 
SELECTION OF STUDY POPULATION .............................................................. 33 
4.1 
Inclusion Criteria ................................................................................................. 33 
4.2 
Exclusion Criteria ................................................................................................ 33 
4.3 
Criteria for Delay of Vaccination ........................................................................ 35 
5. 
STUDY PROCEDURES .......................................................................................... 36 
5.1 
Pre-vaccination Clinic Visit(s) ............................................................................. 36 
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5.1.1 Informed Consent ......................................................................................... 36 
5.1.2 Screening ...................................................................................................... 37 
5.1.3 Enrolment ..................................................................................................... 38 
5.1.4 Randomization .............................................................................................. 38 
5.2 
Vaccination Clinic Visit ....................................................................................... 39 
5.2.1 Post-vaccination Procedures ......................................................................... 39 
5.2.2 Post-vaccination Reminders ......................................................................... 40 
5.3 
Post-vaccination Visits ........................................................................................ 40 
5.3.1 Follow-up Clinic Visits ................................................................................. 40 
5.3.2 Safety Follow-up Calls ................................................................................. 41 
5.4 
Unscheduled Visits .............................................................................................. 42 
5.5 
Study Termination Visit ....................................................................................... 42 
5.5.1 Early Termination Visit ................................................................................ 43 
6. 
TREATMENT OF SUBJECTS ................................................................................ 44 
6.1 
Study Vaccine ...................................................................................................... 44 
6.2 
Non-Study Vaccines ............................................................................................ 45 
6.3 
Vaccine Preparation and Administration ............................................................. 45 
6.4 
Vaccine Administration Error or Overdose of Vaccine ....................................... 46 
6.5 
Prior and Concomitant Medications and Vaccines .............................................. 47 
6.6 
Vaccine Supply, Labeling, Storage and Tracking................................................ 48 
7. 
ASSESSMENTS ...................................................................................................... 50 
7.1 
Safety Assessment ............................................................................................... 50 
7.1.1 Solicited Adverse Events .............................................................................. 50 
7.1.2 Unsolicited Adverse Events .......................................................................... 52 
7.1.3 Evaluation of Adverse Events....................................................................... 53 
7.1.4 Serious Adverse Events ................................................................................ 54 
7.1.4.1 Adverse Events of Special Interest ........................................................ 55 
7.1.5 Methods for Recording Adverse Events and Serious Adverse Events ......... 56 
7.1.5.1 Post-Study Events .................................................................................. 56 
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7.1.6 Pregnancies ................................................................................................... 56 
7.1.7 Safety Laboratory Measurements ................................................................. 57 
7.2 
Efficacy Assessment ............................................................................................ 57 
7.3 
Immunogenicity Assessment ............................................................................... 57 
8. 
STATISTICAL CONSIDERATIONS ..................................................................... 59 
8.1 
Endpoints ............................................................................................................. 59 
8.1.1 Primary Endpoint(s) ...................................................................................... 59 
8.1.1.1 Primary Safety Endpoint(s) ................................................................... 59 
8.1.1.2 Primary Efficacy Endpoint(s) ................................................................ 59 
8.1.1.3 Primary Immunogenicity Endpoint(s) ................................................... 59 
8.1.2 Secondary Endpoint(s) .................................................................................. 59 
8.1.2.1 Secondary Safety Endpoint(s) ................................................................ 59 
8.1.2.2 Secondary Efficacy Endpoint(s) ............................................................ 59 
8.1.2.3 Secondary Immunogenicity Endpoint(s) ............................................... 60 
8.1.3 Exploratory Endpoint(s) ............................................................................... 60 
8.1.3.1 Exploratory Safety Endpoint(s) ............................................................. 60 
8.1.3.2 Exploratory Efficacy Endpoint(s) .......................................................... 60 
8.1.3.3 Exploratory Immunogenicity Endpoint(s) ............................................. 61 
8.2 
Success Criteria .................................................................................................... 61 
8.2.1 Success Criteria for Primary Objective(s) .................................................... 61 
8.2.1.1 Success Criteria for Primary Safety Objective(s) .................................. 61 
8.2.1.2 Success Criteria for Primary Efficacy Objective(s) ............................... 61 
8.2.1.3 Success Criteria for Primary Immunogenicity Objective(s) .................. 61 
8.2.2 Success Criteria for Secondary Objective(s) ................................................ 61 
8.2.2.1 Success Criteria for Secondary Safety Objective(s) .............................. 61 
8.2.2.2 Success Criteria for Secondary Efficacy Objective(s) ........................... 62 
8.2.2.3 Success Criteria for Secondary Immunogenicity Objective(s) .............. 62 
8.3 
Analysis Sets ........................................................................................................ 62 
8.3.1 All Enrolled Set ............................................................................................ 62 
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8.3.2 All Exposed Set ............................................................................................ 62 
8.3.3 Safety Set ...................................................................................................... 62 
8.3.4 Full Analysis Set (FAS) Immunogenicity Set .............................................. 63 
8.3.5 Per Protocol (PP) Set Immunogenicity Set ................................................... 63 
8.3.6 Other Analysis Sets ....................................................................................... 63 
8.3.7 Subgroups ..................................................................................................... 63 
8.3.8 Protocol Deviations ....................................................................................... 63 
8.4 
Statistical Analysis Plan ....................................................................................... 64 
8.4.1 Analysis of Demographic and Baseline Characteristics ............................... 64 
8.4.2 Analysis of Primary Objective(s).................................................................. 64 
8.4.2.1 Analysis of Primary Safety Objective(s) ........................................... 64 
8.4.2.1.1 
Analysis of Extent of Exposure ...................................................... 64 
8.4.2.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events 64 
8.4.2.1.3 
Analysis of Unsolicited Adverse Events ........................................ 65 
8.4.2.1.4 
Analysis of Safety Laboratory Values ............................................ 65 
8.4.2.2 Analysis of Primary Efficacy Objective(s) ........................................ 65 
8.4.2.2.1 
Statistical Hypotheses ..................................................................... 66 
8.4.2.2.2 
Analysis Sets .................................................................................. 66 
8.4.2.2.3 
Statistical Methods ......................................................................... 66 
8.4.2.3 Analysis of Primary Immunogenicity Objective(s) ............................... 66 
8.4.2.3.1 
Statistical Hypotheses ..................................................................... 66 
8.4.2.3.2 
Analysis Sets .................................................................................. 66 
8.4.2.3.3 
Statistical Methods ......................................................................... 67 
8.4.3 Analysis of Secondary Objective(s).............................................................. 67 
8.4.3.1 Analysis of Secondary Safety Objective(s) ....................................... 67 
8.4.3.1.1 
Statistical Methods ......................................................................... 67 
8.4.3.2 Analysis of Secondary Efficacy Objective(s) ........................................ 67 
8.4.3.3 Analysis of Secondary Immunogenicity Objective(s) ........................... 67 
8.4.3.3.1 
Statistical Hypotheses ..................................................................... 67 
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8.4.3.3.2 
Analysis Sets .................................................................................. 67 
8.4.3.3.3 
Statistical Methods ......................................................................... 67 
8.4.4 Analysis of Exploratory Objectives .............................................................. 70 
8.4.4.1 Analysis of Exploratory Safety Objective(s) ......................................... 70 
8.4.4.2 Analysis of Exploratory Efficacy Objective(s) ...................................... 70 
8.4.4.3 Analysis of Exploratory Immunogenicity Objective(s) ......................... 70 
8.5 
Sample Size and Power Considerations ............................................................... 71 
8.6 
Interim Analysis ................................................................................................... 71 
9. 
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING ...... 72 
9.1 
Source Documentation ......................................................................................... 72 
9.2 
Study Monitoring, Auditing and Source Data Verification ................................. 73 
10. 
DATA MANAGEMENT ......................................................................................... 74 
10.1 Data Entry and Management ................................................................................ 74 
10.2 Data Clarification ................................................................................................. 74 
10.3 Data Protection .................................................................................................... 74 
11. 
RECORD RETENTION .......................................................................................... 75 
12. 
USE OF INFORMATION AND PUBLICATION .................................................. 76 
13. 
ETHICAL CONSIDERATIONS ............................................................................. 77 
13.1 Regulatory and Ethical Compliance .................................................................... 77 
13.2 Informed Consent Procedures .............................................................................. 77 
13.3 Responsibilities of the Investigator and EC ......................................................... 78 
13.4 Protocol Amendments .......................................................................................... 79 
14. 
REFERENCE LIST .................................................................................................. 80 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS V98_06E1 VERSION 1 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
Title of Study: 
A Phase 2, Non-Randomized, Controlled, Open-Label, Parallel-Group Extension Study 
to Evaluate the Immunogenicity and Safety of the Second Dose of GBS Trivalent 
Vaccine in Healthy Non-Pregnant Subjects. 
Study Period: Approximately 6 months 
Clinical Phase: 2 
Background and Rationale: 
Group B Streptococcus (GBS) is a major cause of neonatal disease in developed and 
developing countries. Newborns are very susceptible to GBS disease which is known to 
manifest with bacteremia, sepsis, meningitis or pneumonia typically during the first 
three months of life. 
The infants may acquire the infection either in utero by the ascending route through the 
ruptured or intact membranes (Melin & Efstratiou 2013), by contact with the bacteria in 
the birth canal during parturition or after birth through contact with caregivers. Studies 
have shown that 25-35% of pregnant women are colonized with GBS in the lower 
genital and/or gastrointestinal tract and about 50% of colonized women transmit GBS 
vertically to the gastrointestinal tract or upper respiratory tract of neonates. One to two 
% of colonized infants develop invasive GBS disease (Baker 2013). 
Current prevention strategies of GBS disease in infants, implemented mainly in 
developed countries, focus on maternal screening for recto-vaginal GBS colonization in 
late pregnancy (35-37 weeks of gestation), with subsequent use of intrapartum antibiotic 
prophylaxis (IAP) during delivery in GBS colonized women (www.cdc.gov/mmwr 
/pdf/rr/rr5910.pdf November 19 2010). Limitations of the current standard culture for 
GBS carriage detection include the need for prolonged incubation, which require 
antenatal screening culture resulting in poor predictive value for colonization status in 
labor and in missing of GBS carriage screening in some preterm labor cases. In the 
future, advances in diagnostic molecular technologies are expected to offer rapid GBS 
intrapartum screening test with higher sensitivity, specificity and predictive values (Di 
Renzo et al. 2014). The use of IAP however has little impact on GBS infections that 
occur after the first week of life (www.cdc.gov/abcs/reportsindings/survreports/ 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
gbs08.html Accessed January 27, 2014), thus alternative strategies for prevention of 
neonatal GBS disease remain to be an unmet medical need. 
One alternative strategy is maternal vaccination against GBS. Maternal serotype-specific 
anti-capsular antibodies to GBS are transferred to the fetus trans-placentally, mainly in 
the third trimester of pregnancy, and persist in the infant throughout the first months of 
life, which is the period of high vulnerability to GBS disease (Englund et al. 1995; 
Glezon & Alpers 1999; Baker & Kasper 1977; Boyer et al. 1984). Case-control studies 
have linked higher serotype-specific maternal anti-capsular polysaccharide antibody 
concentrations to protection against neonatal GBS disease during the first week of life 
(Baker, Carey & Rench et al. 2013, Baker, Rench & McInnes 2003, Lin et al. 2004, Lin 
at el. 2001). These findings support the approach of maternal vaccination as a potential 
strategy for preventing GBS infection in the newborns and infants. 
GSK has developed a trivalent glycoconjugate vaccine against GBS that contains the 
capsular polysaccharides (CPS) of GBS serotypes Ia, Ib and III, conjugated to a protein 
carrier, CRM197, which enhances their immunogenicity. 
Single 5 µg doses of adjuvanted and unadjuvanted GBS Trivalent Vaccine demonstrated 
immunogenicity and a favorable safety profile in approximately 400 pregnant and 320 
non-pregnant subjects in Phase 1 and 2 studies (V98_06, V98_04, V98_05, V98_08). 
Single 20 µg doses of adjuvanted and unadjuvanted GBS Trivalent Vaccine were 
assessed in Phase 1and 2 (V98_06, V98_08) studies in approximately 200 non-pregnant 
subjects. The immunogenicity and safety profile of single dose of 5 µg and 20 µg doses 
were comparable. 
In the Phase 1b study (V98_06) two-injection regimens at the same dose range of 5 µg 
and 20 µg (adjuvanted and unadjuvanted) with one month interval between injections 
were evaluated in approximately 160 non-pregnant subjects per dose. The 
immunogenicity of 5 µg and 20 µg doses administered as single or two injections 
courses were comparable. Two injection regimens at the same dose range did not impact 
the immune response and no clear dose-response relationship was observed for either 
GMC or percentage of subjects reaching pre-defined antibody concentrations at day 60 
(which is approximately the mean time of delivery after vaccination in Phase 2 studies 
with pregnant subjects). The series of these concentrations was based on putative 
protective serotype-specific thresholds which corresponded with reduced risk of infant 
 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
infection in the earlier case-control studies (Lin 2001, Lin 2004). 
The candidate vaccine is intended to be administered to the pregnant woman in the third 
trimester of pregnancy to optimize antibody transfer to the fetus. The GBS antibody 
levels induced by vaccination are expected to decrease over time and re-vaccination 
during the subsequent pregnancy is likely to be required to ensure that protective levels 
of antibodies are achieved again. The repeat administration of conjugate vaccines with 
the same carrier protein (CRM197) has the potential to affect vaccine immunogenicity 
through antigen competition (Pichichero ME. Hum Vaccin Immunother. 2013). 
Considering that CRM197 is a nontoxic variant of diphtheria toxin, the impact on existing 
anti-diphtheria antibody levels has to be considered and evaluated. 
However, safety and immunogenicity of the second dose of GBS Trivalent Vaccine 
when administered after longer than one month has not been evaluated to date. The 
objective of this extension study is the initial assessment of safety and immunogenicity 
of the second dose of GBS Trivalent Vaccine following the longer time interval that is 
closer to the inter-pregnancy interval observed in the general population (Gemmill 
A, Lindberg LD. Short interpregnancy intervals in the United States. Obstet 
Gynecol. 122(1):64-71, 2013). 
To address this objective, the subjects who received a single 5µg dose of GBS Trivalent 
Vaccine or placebo as part of the V98_06 study will be vaccinated and receive a second 
dose of 5µg approximately 4-6 years after the first vaccination. As the 20 µg dose 
formulation of GBS Trivalent Vaccine is not currently available, it will not be included 
in the current re-vaccination study. The placebo group from V98_06 study is included as 
a control that provides longitudinal data both for the immunogenicity and anti-diphtheria 
antibody levels and has the advantage over naive subjects of being a group that was 
randomized as part of the original study. Naive subjects who have never received GBS 
Trivalent Vaccine will also be enrolled to ensure adequate number of controls in case of 
significant loss to follow up of the V98_06 study placebo treated subjects. 
While high levels of antibodies to GBS in a pregnant woman are predictive of lower 
incidence of infant GBS disease, (Lin 2001, Lin 2004, Baker CJ, Kasper DL NEJM, 
1976), the levels of serotype-specific IgG antibodies needed in a mother in order to 
protect her infant from GBS have not yet been established. Until these levels have been 
established, a set of increasing serotype-specific ELISA IgG cut-off levels will be used 
to attempt to bracket where the assumed protective levels may be. The study objectives 
 
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02 JUL 15 Final Version 1 
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Protocol V98_06E1 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
are non-specific as to the exact level needed to establish protection. 
It is acknowledged that due to loss to follow up the study sample size may be limited. 
Also, due to baseline heterogeneity of subjects who received different adjuvants or no 
adjuvant with first vaccination, the study will be exploratory by nature and the results 
will be interpreted as such. 
Study Objectives: 
Primary Objectives: 
Immunogenicity Objective 
To evaluate the immunogenicity of a second dose of GBS Trivalent Vaccine (5 µg 
without adjuvant) administered approximately 4-6 years after the initial GBS 
vaccination, measured by ELISA. 
Safety Objective 
To assess the safety and tolerability of a second dose of GBS Trivalent Vaccine (5 µg 
without adjuvant) administered approximately 4-6 years after the initial dose. 
Secondary Objectives: 
To further characterize the immune response following a dose of GBS Trivalent Vaccine 
(5 µg without adjuvant) in study subjects and in subgroups of subjects defined by pre- 
vaccination serotype-specific GBS antibody LLQ status in the V98_06 study or 
V98_06E1 for the naïve subjects.. 
To assess the impact of a dose of the GBS Trivalent Vaccine (5 µg without adjuvant) on 
the serum level of anti-diphtheria antibodies in subjects who received study vaccination 
(active or placebo) as part of the V98_06 and naïve subjects from V98_06E1 
Exploratory Objective: 
To assess the immunogenicity of a dose of GBS Trivalent Vaccine (5 µg without 
adjuvant) in study subjects as measured by OPK and in subgroups of subjects defined by 
pre-vaccination serotype-specific GBS ELISA antibody LLQ status in the V98_06 or 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
V98_06E1 for the naïve subjects. 
Study Design: 
This is a Phase 2, non-randomized, controlled, open-label, parallel-group, extension of 
the V98_06 Study. All eligible subjects will receive a single injection of 5 µg dose (of 
each conjugate polysaccharide - serotypes Ia, Ib, and III) of unadjuvanted GBS Trivalent 
Vaccine (Table 1). 
Table 1 
Treatment Groups and Number of Subjects 
Following screening, eligible subjects will provide a blood sample for pre-vaccination 
measurement of serotype-specific GBS antibodies and will receive a single dose of 
unadjuvanted GBS Trivalent Vaccine containing 5 µg of each polysaccharide (serotypes 
Ia, Ib, and III). On day 31 and day 61 additional blood samples will be obtained to 
 
 
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Treatment Groups 
Vaccine Dose 
(µg Ia/Ib/III 
Glycoconjugate, no 
adjuvant) 
Number of 
Subjects 
V98_06: Single vaccination 
5/5/5 no adjuvant 
5/5/5 
Up to 40 
V98_06: Single vaccination 
5/5/5 Alum 
5/5/5 
Up to 40 
V98_06: Single vaccination 
5/5/5 MF59 full dose 
5/5/5 
Up to 40 
V98_06: Single vaccination 
5/5/5 MF59 half dose 
5/5/5 
Up to 40 
V98_06: Placebo (Enrollment 
Group 1 and Enrollment Group 
2) 
5/5/5 
Up to 40 
Naive subjects (not previously 
enrolled in V98_06) 
5/5/5 
20 
Total – up to 220 subjects 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
assess serotype-specific GBS antibody responses. 
The following data will be collected for safety analysis: 
- 
Day 1 (vaccination): A 30 minute post-injection assessment for signs or 
symptoms of anaphylaxis. 
- 
Day 1 (vaccination) to day 7: Solicited local and systemic adverse events (AEs), 
body temperature and other indicators of solicited adverse events recorded daily 
using a Subject Diary. 
- 
Day 1 (vaccination) to day 31: All unsolicited AEs. 
- 
Day 1 to day 181: SAEs, Medically-attended AEs and AEs leading to 
discontinuation from the trial only. 
- 
Day 1 to day 181: All concomitant medications administered in relation to the 
reported AEs, any vaccines administered and all antibiotics and any other 
prescription or over the counter medicine(s) deemed clinically significant by the 
investigator. 
The study will include, 3 clinic visits (day 1 – vaccination, day 31 and day 61) and 3 
safety calls (day15, 121 and 181). 
Number of Subjects planned: 
The total number of subjects to be enrolled into the trial will not exceed 220, which 
includes the total number of subjects who received the 5 µg single dose of GBS 
Trivalent Vaccine or placebo in the V98_06 study and up to 20 naive subjects. 
Study Population and Subject Characteristics: 
Healthy, non-pregnant subjects who have received a single 5 µg dose of GBS Trivalent 
Vaccine or placebo in the V98_06 study and healthy non-pregnant female subjects aged 
22-46 years inclusive on the day of informed consent who have not received any GBS 
vaccine in the past. 
The list of inclusion and exclusion criteria is included in protocol section 4, Selection of 
Study Population. 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
Study Procedures: 
After signing the informed consent form (ICF), all subjects will undergo review of 
medical history and concomitant medications/vaccinations. They will have a full 
physical examination and, if required, undergo urine pregnancy test to confirm they are 
not pregnant prior to vaccination. 
Once eligibility is confirmed, subjects will receive 5 µg of unadjuvanted GBS Trivalent 
Vaccine. 
Each subject will have: 
• 3 Clinic Visits: at day 1 (day of vaccination), at day 31 and day 61 
• 2 Subject Diary Reminder calls: at day 3 and day 5 (To remind the subject to 
complete the Subject Diary) 
• 3 Safety Follow-up calls at day 15, 121 and 181 
Blood for serology assessment of serotype-specific (Ia, Ib and III) GBS IgG antibody 
concentrations will be collected as follows: 
• Approximately 20 mL of blood will be collected on day 1 (prior to vaccination), on 
day 31 and day 61. 
Safety will be evaluated in all subjects as follows: 
• Solicited local and systemic AEs occurring at the day of study vaccination (day 1) 
and the following 6 days (day 2 to day 7) will be recorded daily using a Subject 
Diary. 
• Unsolicited AEs occurring within 30 days (day 1 to day 31) after study vaccination 
will be collected by interviewing the subject during the day 15 safety calls and day 
31 clinic visits, and by review of available medical records. 
• Medically-attended AEs, AEs leading to study withdrawal and SAEs will be 
collected during the entire study period. These data will be captured by interviewing 
the subject during the site visits and phone calls and by review of available medical 
records. Subjects will be encouraged to call the site in case of any medically- 
attended AEs or any AEs which they perceive as being of concern during the entire 
 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
study period. 
Study procedures at each visit are displayed in Table 2. 
Table 2 
Study Procedures 
Vaccine 
Group 
Visit for 
Vaccination 
Subject Diary 
Reminder calls 
(To remind 
the subject to 
fill out the 
Subject Diary) 
Visits for Blood 
Sampling for 
Immunogenicity 
Safety 
Follow-up 
calls 
Lyophilized 
GBS Trivalent 
Vaccine, 
5µg of each 
glycoconjugate 
(serotype 
Ia/Ib/III), 
unadjuvanted 
Day 1 
Day 3 
Day 5 
Day 1 
(pre- 
vaccination), 
Day 31 and 
Day 61 
Day 15 
Day 121 
Day 181 
Study Vaccines: 
Lyophilized Formulation of GBS Trivalent Vaccine will be supplied by GSK. 
Vial: Each vial contains 6 μg of each capsular polysaccharides (serotype Ia, Ib and III) 
conjugated to the Corynebacterium diphtheriae CRM197 carrier protein. At the time of 
injection, the vaccine will be reconstituted at the site with 0.6 mL sterile saline. The 
sterile saline will be supplied by GSK as 2.0 mL sterile saline for IM injection at a 
concentration of 0.9% of sodium chloride. 
Dose: A dose of 5 μg of each glycoconjugate antigen administered with the single 
vaccine injection of 0.5 mL delivered by the IM route, preferably the deltoid muscle in 
the non-dominant arm. 
 
 
 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
Primary Endpoints: 
Immunogenicity Endpoints 
Percentage and frequency of subjects who reach pre-defined sequential serotype-specific 
serum antibody levels for serotypes Ia, Ib and III at day 61 post vaccination, as 
measured by ELISA. 
Safety Endpoints: 
The frequency and percentage of subjects with solicited local and systemic AEs from 
vaccination to day 7 in study V98_06E1. Time intervals after vaccination that will be 
summarized are: the first 30 minutes after vaccination, days 1-3 (excluding the first 30 
min), days 4-7 and days 1-7 (excluding the first 30 min).. 
The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (day 1 in study V98_06E1) to day 31. 
The frequency and percentage of subjects with SAEs, medically attended AEs, and AEs 
leading to study withdrawal from vaccination in study V98_06E1 to day 181 
Secondary Endpoints: 
The serotype-specific (Ia, Ib, and III) geometric mean antibody as measured by ELISA 
at days 31 and 61 post-vaccination in study V98_06E1 in all subjects and by pre- 
vaccination serotype-specific GBS antibody LLQ status in the V98_06 study or 
V98_06E1 study for the naive group. 
The percentage of subjects reaching pre-defined sequential serotype-specific serum 
antibody levels for serotypes Ia, Ib and III at day 31 post vaccination as measured by 
ELISA in all subjects 
The percentage of subjects reaching pre-defined sequential serotype-specific serum 
antibody levels for serotypes Ia, Ib and III at day 31 and 61 post vaccination as 
measured by ELISA in subjects according to pre-vaccination serotype-specific GBS 
antibody LLQ status in the V98_06 study or V98_06E1 study for the naive group. 
The within subject geometric mean ratio (GMR) of serotype-specific (Ia, Ib & III) serum 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
antibody levels as measured by ELISA at day 31 and 61. The GMRs will be determined 
relative to pre-vaccination in V98_06E1 and separately relative to pre-vaccination in 
V98_06 for groups except the naive group. The GMRs will be determined for all 
subjects and by pre-vaccination serotype-specific GBS antibody LLQ status in the 
V98_06 study or V98_06E1 study for the naive group. 
Reverse cumulative distribution function (RCDF) curves of serotype-specific (Ia, Ib and 
III) serum antibody levels, as measured by ELISA, at pre-vaccination in V98_06 study 
or V98_06E1 study for the naive group, vaccination and day 31 and 61 post-vaccination 
in all subjects and by pre-vaccination serotype-specific GBS antibody LLQ status in the 
V98_06 study or V98_06E1 study for the naive group. 
The anti-diphtheria geometric mean antibody concentrations measured by ELISA for 
samples collected before the first vaccination with GBS Trivalent Vaccine in the 
V98_06 study or V98_06E1 study for the naive group and on day 31 and day 61 post 
vaccination in V98_06E1. 
Exploratory Endpoints: 
The exploratory immunogenicity endpoints are: 
The serotype-specific (Ia, Ib, and III) geometric mean antibody titer as measured by 
OPK at days 31 and 61 post-vaccination in study V98_06E1 in all subjects and by pre- 
vaccination serotype-specific GBS antibody LLQ status in the V98_06 study or 
V98_06E1 study for the naive group. 
The serotype-specific (Ia, Ib, and III) geometric mean antibody titer as measured by 
OPK at day 1 pre-vaccination in study V98_06E1 in all subjects and by pre-vaccination 
serotype-specific GBS antibody LLQ status in the V98_06 study or V98_06E1 study for 
the naive group. 
Exploratory OPK objectives will be addressed in a randomly selected subset of up to 60 
subjects (10 subjects per arm). 
 
 
 
 
 
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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V98_06E1 
Generic name of study vaccine: 
GBS Trivalent Vaccine 
Statistical Analyses: Statistical Analyses: 
The percentages of subjects with serotype-specific concentrations above a set of pre- 
defined sequential serotype-specific serum antibody levels and associated two-sided 
95% CIs will be computed for each study group on day 1 before vaccination in 
V98_06E1, and on day 31 and day 61 post-vaccination (primary endpoint). These 
percentages will be graphically displayed as RCDFs. 
Additionally, the data will be logarithmically transformed (base 10) before estimating 
the serotype-specific GMCs at day 1 before vaccination and at day 31 and day 61 post- 
vaccination. The GMRs, relative to the original baseline and separately relative to the 
pre-vaccination baseline in V98_06E1 and their associated 95% confidence intervals 
(CIs) will be computed for each study group. 
Analyses will be performed for the following groups of subjects: 
• All subjects 
• Subjects determined by their serotype-specific LLQ status prior to initial vaccination 
in study V98_06 or V98_06E1 for the naive group 
• Subjects who received no adjuvant in study V98_06 
• Subjects who received alum adjuvant in study V98_06 
• Subjects who received half dose of MF59 in study V98_06 
• Subjects who received full dose of MF59 in study V98_06 
• Subjects who received placebo in study V98_06 
• Subjects who are naive and were not vaccinated as a part of V98_06 
Safety analyses will be performed on the appropriate safety sets. 
Interim Analysis: 
There will be no interim analysis included in this study. 
Data Monitoring Committee: 
No DMC will be established for this study. 
 
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Table 3 
Time and Events Table 
 
Visit Type 
Day 
Visit Window 
(Days) 
Events 
Visit Number 
Clinic Visit 
Clinic 
Visit 
Subject 
Diary 
Reminder 
Call 
Safety 
Follow-up 
Call 
Clinic 
Visit 
Clinic 
Visit 
Safety 
Follow-up 
Call 
Safety 
Follow- 
up 
Call 
1 
3, 5 
15 
31 
61 
121 
181 
-5 to 1 
n/a 
(-1/+1)/(- 
1/+2) 
-3 to +3 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
Pre- 
vaccination 
1 
2 
3 
4 
5 
6 
Study Event 
References 
Screening 
Informed Consent a 
Section 5.1.1 
X 
Medical History 
Section 5.1.2 
X 
X b 
Physical Exam 
Sections 5.1.2 
and 5.3.1 
X b 
Pregnancy Testc 
Sections 3.5 and 
5.1.2 
X b 
Exclusion/Inclusion 
Criteria 
Section 4 
X 
X b 
30 Minutes Post Injection 
Assessment 
Section 5.2.1 
X 
Subject Diary Dispensed 
with Training 
Section 5.2.1 
X 
Immunogenicity 
 
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Visit Type 
Day 
Visit Window 
(Days) 
Events 
Visit Number 
Clinic Visit 
Clinic 
Visit 
Subject 
Diary 
Reminder 
Call 
Safety 
Follow-up 
Call 
Clinic 
Visit 
Clinic 
Visit 
Safety 
Follow-up 
Call 
Safety 
Follow- 
up 
Call 
1 
3, 5 
15 
31 
61 
121 
181 
-5 to 1 
n/a 
(-1/+1)/(- 
1/+2) 
-3 to +3 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
Pre- 
vaccination 
1 
2 
3 
4 
5 
6 
Study Event 
References 
Serology Blood Draw 
Section 3.5 
X b 
X 
X 
Study Treatment 
Vaccination 
Section 5.2 
X 
Safety 
Subject Diary Reminder 
Call 
Section 5.2.2 
X 
Symptom Directed 
Physical Exam 
Sections 5.1.2 
and 5.3.1 
X 
X 
Subject Diary Reviewed 
and Collected 
Section 5.3.1 
X 
Assess all AEs 
Section 7.1 
X 
X 
X 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess for medically 
attended AEs and AEs 
leading to withdrawal 
Sections 7.1.4.1 
and 7.1.3 
X 
X 
X 
X 
X 
X 
 
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Visit Type 
Day 
Visit Window 
(Days) 
Events 
Visit Number 
Clinic Visit 
Clinic 
Visit 
Subject 
Diary 
Reminder 
Call 
Safety 
Follow-up 
Call 
Clinic 
Visit 
Clinic 
Visit 
Safety 
Follow-up 
Call 
Safety 
Follow- 
up 
Call 
1 
3, 5 
15 
31 
61 
121 
181 
-5 to 1 
n/a 
(-1/+1)/(- 
1/+2) 
-3 to +3 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
Pre- 
vaccination 
1 
2 
3 
4 
5 
6 
Study Event 
References 
Assess relevant 
medications 
Sections 5.1.2 
and 6.5 
X 
X 
X 
X 
X 
X 
X 
Study Completion Procedures 
Study Termination 
Section 5.5 
X 
Notes: 
a Confirm consent form(s) signed prior to any procedures. 
b Procedure to be performed prior to vaccination 
c Only for women of child bearing potential 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCDM 
Biostatistics and Clinical Data Management 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMI 
Cell Mediated Immunity 
CPS 
Capsular Polysaccharides 
CRF 
Case Report Form 
CRM 
Cross Reactive material 
CRO 
Contract Research Organization 
DCF 
Data Clarification Form 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDT 
Electronic Data Transfer 
ELISA 
Enzyme-linked Immunosorbent Assay 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GBS 
Group B Streptococcus 
GCP 
Good Clinical Practices 
GMC 
Geometric Mean Concentration 
IAP 
Intrapartum Antibiotic Prophylaxis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activit ies 
PCR 
Polymerase Chain Reaction 
PPS 
Per Protocol Set 
SAE 
Serious Adverse Event 
SDA 
Source Data Agreement 
SOC 
System Organ Class 
 
 
 
 
 
 
 
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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Background 
Group B Streptococcus (GBS) is a major cause of neonatal disease in developed and 
developing countries. Newborns are very susceptible to GBS disease which is known to 
manifest with bacteremia, sepsis, meningitis, or pneumonia, typically during the first 
three months of life. 
 
Infants may acquire the infection either in utero by the ascending route through the 
ruptured or intact membranes (Melin & Efstratiou 2013), by contact with the bacteria in 
the birth canal during parturition, or after birth through contact with caregivers. Studies 
have shown that 25-35% of pregnant women are colonized with GBS in the lower genital 
and/or gastrointestinal tract and about 50% of colonized women transmit GBS vertically 
to the gastrointestinal tract or upper respiratory tract of neonates. One to two % of 
colonized infants develop invasive GBS disease (Baker 2013). 
 
Current prevention strategies of GBS disease in infants, implemented mainly in 
developed countries, focus on maternal screening for recto-vaginal GBS colonization in 
late pregnancy (35-37 weeks of gestation), with subsequent use of intrapartum antibiotic 
prophylaxis (IAP) during delivery in GBS colonized women (www.cdc.gov/mmwr 
/pdf/rr/rr5910.pdf November 19 2010). Limitations of the current standard culture for 
GBS carriage detection include the need for prolonged incubation, which require 
antenatal screening culture resulting in poor predictive value for colonization status in 
labor and in missing of GBS carriage screening in some preterm labor cases. In the future, 
advances in diagnostic molecular technologies are expected to offer rapid GBS 
intrapartum screening test with higher sensitivity, specificity and predictive values (Di 
Renzo et al. 2014). The use of IAP however has little impact on GBS infections that occur 
after the first week of life (www.cdc.gov/abcs/reportsindings/survreports/ gbs08.html 
Accessed January 27, 2014), thus alternative strategies for prevention of neonatal GBS 
disease remain to be an unmet medical need. 
 
One alternative strategy is maternal vaccination against GBS. Maternal serotype-specific 
anti-capsular antibodies to GBS are transferred to the fetus trans-placentally, mainly in 
the third trimester of pregnancy, and persist in the infant throughout the first months of 
life, which is the period of high vulnerability to GBS disease (Englund et al. 1995;  
Glezon & Alpers 1999; Baker & Kasper 1977; Boyer et al. 1984). Case-control studies 
have linked higher serotype-specific maternal anti-capsular polysaccharide antibody 
concentrations to protection against neonatal GBS disease during the first week of life 
(Baker, Carey & Rench et al. 2013, Baker, Rench & McInnes 2003, Lin et al. 2004, Lin at 
el. 2001). These findings support the approach of maternal vaccination as a potential 
strategy for preventing GBS infection in the newborns and infants. 
 
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GSK has developed a trivalent glycoconjugate vaccine against GBS that contains the 
capsular polysaccharides (CPS) of GBS serotypes Ia, Ib and III, conjugated to a protein 
carrier, CRM197, which enhances their immunogenicity. 
Single 5 µg doses of adjuvanted and unadjuvanted GBS Trivalent Vaccine demonstrated 
immunogenicity and a favorable safety profile in approximately 400 pregnant and 320 
non-pregnant subjects in Phase 1 and 2 studies (V98_06, V98_04, V98_05, V98_08). 
Single 20 µg doses of adjuvanted and unadjuvanted GBS Trivalent Vaccine were assessed 
in Phase 1and 2 (V98_06, V98_08) studies in approximately 200 non-pregnant subjects. 
The immunogenicity and safety profile of single dose of 5 µg and 20 µg doses were 
comparable. 
 
In the Phase 1b study (V98_06) two-injection regimens at the same dose range of 5 µg 
and 20 µg (adjuvanted and unadjuvanted) with one month interval between injections 
were evaluated in approximately 160 non-pregnant subjects per dose. The 
immunogenicity of 5 µg and 20 µg doses administered as single or two injections courses 
were comparable. Two injection regimens at the same dose range did not impact the 
immune response and no clear dose-response relationship was observed for either GMC 
or percentage of subjects reaching pre-defined antibody concentrations at day 60 (which 
is approximately the mean time of delivery after vaccination in Phase 2 studies with 
pregnant subjects). The series of these concentrations was based on putative protective 
serotype-specific thresholds which corresponded with reduced risk of infant infection in 
the earlier case-control studies (Lin 2001, Lin 2004). 
 
The candidate vaccine is intended to be administered to the pregnant woman in the third 
trimester of pregnancy to optimize antibody transfer to the fetus. The GBS antibody 
levels induced by vaccination are expected to decrease over time and re-vaccination 
during the subsequent pregnancy is likely to be required to ensure that protective levels of 
antibodies are achieved again. The repeat administration of conjugate vaccines with the 
same carrier protein (CRM197) has the potential to affect vaccine immunogenicity through 
antigen competition (Pichichero ME. Hum Vaccin Immunother. 2013). Considering that 
CRM197 is a nontoxic variant of diphtheria toxin, the impact on existing anti-diphtheria 
antibody levels has to be considered and evaluated. However, the safety and 
immunogenicity of the second dose of GBS Trivalent Vaccine when administered after 
longer than one month has not been evaluated to date. 
 
1.2 
Rationale 
The objective of this extension study is the initial assessment of safety and 
immunogenicity of the second dose of GBS Trivalent Vaccine following the time interval 
that is close to the inter-pregnancy interval observed in the general population (Gemmill 
 
 
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A, Lindberg LD. Short interpregnancy intervals in the United States. Obstet 
Gynecol. 122(1):64-71, 2013). 
 
To address this objective, the subjects who received a single 5µg dose of GBS Trivalent 
Vaccine or placebo as part of the V98_06 study, will be vaccinated and receive a second 
dose of 5µg approximately 4-6 years after the first vaccination. The placebo group from 
V98_06 study is included as a control that provides longitudinal data both for the 
immunogenicity and anti-diphtheria antibodies levels and has the advantage over naive 
subjects of being a group that was randomized as part of the original study. Naive 
subjects who have never received GBS Trivalent vaccine will also be enrolled to ensure 
adequate number of controls in case of significant loss to follow up of the V98_06 study 
placebo treated subjects. 
 
While high levels of antibodies to GBS in a pregnant woman are predictive of lower 
incidence of infant GBS disease, (Lin 2001, Lin 2004, Baker CJ, Kasper DL NEJM, 
1976), the levels of serotype-specific IgG antibodies needed in a mother in order to 
protect her infant from GBS have not yet been established. Until these levels have been 
established, a set of increasing serotype-specific ELISA IgG cut-off levels will be used to 
attempt to bracket where the assumed protective levels may be. The study objectives are 
non-specific as to the exact level needed to establish protection. 
 
It is acknowledged that due to loss to follow up the study sample size may be limited. 
Also, due to baseline heterogeneity of subjects who received different adjuvants or no 
adjuvant with first vaccination, the study will be exploratory by nature and the results will 
be interpreted as such. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. 
OBJECTIVES 
 
2.1 
Primary Objective(s) 
Immunogenicity Objective 
 
To evaluate the immunogenicity of a second dose of GBS Trivalent Vaccine (5 µg 
without adjuvant) administered approximately 4-6 years after the initial GBS vaccination, 
measured by ELISA. 
 
Safety Objective 
 
To assess the safety and tolerability of a second dose of GBS Trivalent Vaccine (5 µg 
without adjuvant) administered approximately 4-6 years after the initial dose. 
 
2.2 
Secondary Objective(s) 
Immunogenicity Objectives 
 
To further characterize the immune response following a dose of GBS Trivalent Vaccine 
(5 µg without adjuvant) in study subjects and in subgroups of subjects defined by pre- 
vaccination serotype-specific GBS antibody LLQ status in the V98_06 study or 
V98_06E1 for the naïve subjects. 
 
To assess the impact of a dose of the GBS Trivalent Vaccine (5 µg without adjuvant) on 
the serum level of anti-diphtheria antibodies in subjects who received study vaccination 
(active or placebo) as part of the V98_06 and naïve subjects from V98_06E1. 
 
2.3 
Exploratory Objective(s) 
To assess the immunogenicity of a dose of GBS Trivalent Vaccine (5 µg without 
adjuvant) in study subjects as measured by OPK and in subgroups of subjects defined by 
pre-vaccination serotype-specific GBS ELISA antibody LLQ status in the V98_06 or 
V98_06E1 for the naïve subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
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3. 
STUDY DESIGN 
 
3.1 
Overview of Study Design 
This is a Phase 2, non-randomized, controlled, open-label, parallel-group, extension of the 
V98_06 Study. All eligible subjects will receive a single injection of 5 µg dose (of each 
glycoconjugated polysaccharide - serotypes Ia, Ib, and III) of unadjuvanted GBS 
Trivalent Vaccine (Table 3-1). 
 
Table 3-1 
Treatment Groups and Number of Subjects 
 
Treatment Groups 
Vaccine Dose 
(µg Ia/Ib/III Glycoconjugate, 
no adjuvant) 
Number of 
Subjects 
V98_06: Single vaccination 5/5/5 
no adjuvant 
5/5/5 
Up to 40 
V98_06: Single vaccination 5/5/5 
Alum 
5/5/5 
Up to 40 
V98_06: Single vaccination 5/5/5 
MF59 full dose 
5/5/5 
Up to 40 
V98_06: Single vaccination 5/5/5 
MF59 half dose 
5/5/5 
Up to 40 
V98_06: Placebo (Enrollment 
Group 1 and Enrollment Group 
2) 
5/5/5 
Up to 40 
Naive* subjects (not previously 
enrolled in V98_06) 
5/5/5 
20 
Total – up to 220 subjects 
 
*The naive group will be healthy non-pregnant female subjects aged 22-46 years 
inclusive on the day of informed consent who did not participate in the V98_06 study, 
who have not received any GBS vaccine in the past and who meet all of the 
inclusion/exclusion criteria for the current V98_06E1 study. 
 
Following screening and the giving of consent, eligible subjects will provide a blood 
sample for pre-vaccination measurement of serotype-specific GBS antibodies and will 
receive a single dose of unadjuvanted GBS Trivalent Vaccine containing 5 µg of each 
polysaccharide (serotypes Ia, Ib, and III). On day 31 and day 61 additional blood samples 
will be obtained to assess serotype-specific GBS antibody responses. 
 
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The following data will be collected for safety analysis: 
- 
Day 1 (vaccination): A 30 minute post-injection assessment for signs or symptoms 
of anaphylaxis. 
- 
Day 1 (vaccination) to day 7: Solicited local and systemic adverse events (AEs), 
body temperature and other indicators of solicited adverse events recorded daily 
using a Subject Diary. 
- 
Day 1 (vaccination) to day 31: All unsolicited AEs. 
- 
Day 1 to day 181: SAEs, Medically-attended AEs and AEs leading to 
discontinuation from the trial only. 
- 
Day 1 to day 181: All concomitant medications administered in relation to the 
reported AEs, any vaccines administered and all antibiotics and any other 
prescription or over the counter medicine(s) deemed clinically significant by the 
investigator. 
 
The study will include 2 subject diary reminder calls (day 3 and day 5), 3 clinic visits 
(day 1 – vaccination, day 31 and day 61) and 3 safety calls (day15, day 121 and day 181). 
 
All site staff will be properly trained on the study protocol and procedures. 
 
3.2 
Study Period 
Each subject should expect to participate in the study for approximately 6 months, from 
the time of enrolment through the last study visit. 
 
3.3 
Blinding Procedures 
 
This study is an Open-Label study. There is no blinding of the study treatment either to 
the Investigator, subject and site or sponsor staff. All persons involved in the conduct of 
the study will be aware of the vaccine allocation to each subject which will be a 5 µg dose 
of unadjuvanted GBS Trivalent Vaccine. 
 
3.4 
Data Collection 
 
3.4.1 Data Collected from Subjects 
 
The following data will be collected from each subject over the duration of their study 
participation: 
• Demographic Information 
• Adverse Events 
 
 
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• Medical History 
• Concomitant Medications 
All data collected must only be identified using the GSK Subject ID, as described in 
section 5.1.4, Randomization. 
 
3.4.2 Tools Used for Data Collection 
 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
 
Subject Diary 
 
Paper Diaries (pDiaries) hereafter referred to as Subject Diaries will be the only source 
document allowed for solicited local and systemic adverse events (including body 
temperature measurements (preferably orally)), starting after the initial 30 minute post- 
vaccination period at the clinic. The following additional rules apply to documentation of 
safety information collected in the Subject Diary. 
 
1. No corrections or additions to the information recorded by the subject within the 
Subject Diary will be allowed after it is delivered to the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
 
Case Report Forms 
 
This study utilizes Case Report Forms (CRFs) to collect study-related data from each 
subject. A qualified site staff member(s) is required to enter subject data in the CRFs in 
English based on the medical information available in each subject’s source record. 
 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a GSK-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
 
The following additional rules apply to documentation of Subject Diary information 
collected in the CRFs: 
 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
 
 
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subject, this should be described in the source document and reported as an 
unsolicited adverse event in the Adverse Event CRF (e.g., if the subject above 
confirms body temperature of 40°C on the day in which body temperature: 400°C was 
written into her Subject Diary, this fever of 40°C should be recorded in the Adverse 
Event CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore entered on the Adverse Event CRF. 
 
3.5 
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject (urine 
will only be collected for women of child bearing potential and those of non-child bearing 
potential who do not have available medical records to support non-child bearing potential 
status) in this study: 
• Blood 
• Urine 
Processing of each specimen should be completed by a qualified site member and in 
accordance with the study-specific Clinical Specimen Laboratory Manual. Testing of 
clinical blood specimens will be performed by a GSK or designated laboratory. Refer to 
the study-specific Clinical Specimen Laboratory Manual for additional details. 
 
Blood Specimens 
 
Approximately of 20 mL sample of blood will be drawn from all subjects at visit 1 before 
vaccination, and at visit 3 and 4. The blood volume will not exceed 25 mL at each time 
point in order to provide the necessary serum volume (approximately half of the blood 
draw volume) for the serology assays. 
 
The blood will be used for immunological assays. See section 7, Assessments for 
additional details. 
 
The total amount of blood collected over the study period per subject will not exceed 75 
mL. 
 
Urine Specimens 
Urine will be collected for pregnancy testing in females of child bearing potential (and 
those of non-child bearing potential who do not have available medical records to support 
 
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non-child bearing potential status). Urine will be collected at visit 1 before vaccination 
and the results recorded in the source document and CRF. 
 
3.6 
Stopping/Pausing Guidelines 
 
There are no predetermined stopping rules in this study. Subjects may be withdrawn from 
the study according to investigator discretion as described in section 3.8, Premature 
Withdrawal from Study. 
 
3.7 
Data Monitoring Committee 
 
No DMC will be established for this study. 
 
3.8 
Premature Withdrawal from Study 
 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if she violates the study plan 
or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study before all doses are administered or prior to the 
last planned study visit, the subject will be asked to be followed for safety for the duration 
of the study. When a subject withdraws, or is withdrawn, from the study, the procedures 
described in section 5.5.1, Early Termination Visit should be completed if possible. 
 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
 
Adverse Event 
 
For any subject withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. Any ongoing AEs at the time of study withdrawal 
must be followed until resolution or stabilization. 
 
 
 
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Death 
 
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination CRF page and the associated SAE that led to the death must be 
reported. 
 
Withdrawal of consent 
 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
 
Lost to Follow-Up 
 
For subjects who fail to show up for scheduled visits (clinic or telephone contacts), or for 
three consecutive visits, study staff are encouraged to make at least three documented 
attempts to contact the subject by telephone and at least one documented written attempt 
to contact the subject to encourage the completion of study termination procedures. These 
efforts to contact the subject should be recorded in the source document. The termination 
date for the subject to be captured on the Study Termination CRF page is the date of the 
last successful contact (clinic visit or telephone) with the subject. 
 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Termination CRF page and any ongoing AEs at the time of 
study withdrawal must be followed until resolution/stabilization. 
 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC and should assure appropriate therapy 
and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
 
 
 
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For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination CRF page. 
 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the EC and health authorities it cannot be 
implemented. 
 
Any subject who becomes pregnant during the study, despite the protocol requirement for 
adequate contraception, should be encouraged to continue participating in the study for 
safety follow-up. The site must complete a Pregnancy Report CRF (initial report) as soon 
as possible after learning of pregnancy occurrence (see section 7.1.6, Pregnancies for 
further details). If the subject withdraws from the study for any of the above categories 
except death, the site will obtain permission from the subject to continue to remain in 
contact with her until the outcome of the pregnancy is known, even if the outcome is not 
known until after the subject reaches the end of follow-up period. 
 
3.9 
End of Study 
 
For the purpose of this protocol, end of study is defined as the completion of the Last 
Subject Last Visit (LSLV). 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. 
SELECTION OF STUDY POPULATION 
 
4.1 
Inclusion Criteria 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
 
1. Healthy, non-pregnant subjects who have received a single 5 µg dose of GBS 
Trivalent Vaccine or placebo in the V98_06 study and healthy non-pregnant female 
subjects aged 22-46 years inclusive on the day of informed consent who have not 
received any GBS vaccine in the past. 
2. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
3. Individuals in good health as determined by the outcome of medical history, physical 
examination and clinical judgment of the investigator. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Females of childbearing potential who are using an effective birth control method2 
which they intend to use until the end of the study (day 181 visit) or females of non- 
childbearing potential3. 
4.2 
Exclusion Criteria 
 
1. Progressive, unstable or uncontrolled clinical conditions. 
 
 
 
 
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the 
Subject Diary/ return for all the follow-up visits/ be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Abstinence 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 
- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3 A female is considered to be of non-childbearing potential only after hysterectomy, bilateral 
oophorectomy, or iatrogenic ablation of ovarian function. 
 
 
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2. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
3. Abnormal function of the immune system resulting from: 
a. Clinical conditions, including but not limited to known or suspected HIV infection 
or HIV-related disease, a history of or an active autoimmune disorder (as per the 
judgment of the Investigator) 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent. 
d. Receipt of immunosuppressive therapy within 90 days prior to informed consent 
4. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
5. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent. 
6. Study personnel as an immediate family or household member. 
7. Any other clinical condition that, in the opinion of the investigator, might interfere 
with the results of the study or pose additional risk to the subject due to participation 
in the study. 
8. Individuals who received any other vaccines within 14 days for inactivated vaccines 
or 28 days for live vaccines prior to enrolment in this study or who are planning to 
receive any vaccine within 28 days from the study vaccination. Exception - an 
inactivated influenza vaccine may be administered up to 7 days prior to study 
vaccination or 7 days after study vaccination. 
9. Individuals who anticipate becoming pregnant prior to the end of the study, Day 181 
Visit. 
10. Individuals who are nursing (breastfeeding). 
11. Individuals who have had a previous immunization with a vaccine containing Group 
B Streptococcus antigens that was not part of V98_06 study. 
12. Individuals with a fever (oral temperature ≥ 38°C) within 3 days prior to day 1 or use 
of antipyretics and/or analgesic medications within 24 hours prior to day 1. 
13. Individuals with acute or chronic infection(s) that require systemic antibiotic 
treatment or antiviral therapy, within 7 days prior to day 1. 
 
 
 
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14. Individuals with a history of severe allergic reactions after previous vaccinations or 
medications, such as anaphylactic shock, asthma, urticaria, or other allergic reaction 
or hypersensitivity to any vaccine component or medical equipment including latex 
used in this study. 
15. Individuals with any progressive or severe neurologic disorder, seizure disorder, 
epilepsy or Guillain-Barré syndrome. 
16. Individuals with history of substance or alcohol abuse within the past 2 years. 
 
4.3 
Criteria for Delay of Vaccination 
There may be instances when individuals meet all eligibility criteria for vaccination yet 
have a transient clinical circumstance which may warrant delay of vaccination: body 
temperature elevation (≥38.0° C) within 3 days prior to intended study vaccination, or use 
of antipyretics and/or analgesic medications within 24 hours prior to vaccination. Under 
such circumstances, a subject may be considered eligible for study enrolment after the 
appropriate window for delay has passed and inclusion/exclusion criteria have been 
rechecked, and if the subject is confirmed to be eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. 
STUDY PROCEDURES 
 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Table 3 
 
Table 5-1 
Study Procedures 
 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit(s) 
Section 5.1 describes procedures to be 
followed prior to study vaccination: 
informed consent, screening, enrolment, 
and randomization 
Vaccination Clinic Visit(s) 
Section 5.2 describes procedures to be 
followed during each clinic visit involving 
vaccination: vaccination, post-vaccination 
procedures, and post-vaccination reminders 
Post-vaccination Visit(s) 
Section 5.3 describes follow-up clinic visits 
and safety follow-up calls 
Unscheduled Visit(s) 
Section 5.4 describes possible procedures 
to be followed at unscheduled clinic visit 
Study Termination Visit 
Section 5.5 describes procedures to be 
followed at the last study visit for a subject 
(may include early termination visit) 
 
5.1 
Pre-vaccination Clinic Visit(s) 
 
This section describes the procedures that must be performed for each potential subject 
prior to vaccination, including obtaining informed consent, screening and enrolment. 
 
5.1.1 Informed Consent 
"Informed consent" is the voluntary agreement of an individual or her legal guardian(s) to 
participate in research. Consent must be given with free will of choice, and without undue 
inducement. The individual must have sufficient knowledge and understanding of the 
nature of the proposed research, the anticipated risks and potential benefits, and the 
requirements of the research to be able to make an informed decision. 
 
 
 
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Informed consent following local EC guidance must be obtained before conducting any 
study-specific procedure (i.e., all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent. 
 
If a subject is unable to read, an impartial witness should be present during the entire 
informed consent discussion. An impartial witness is defined as a person who is 
independent from study conduct, who cannot be unfairly influenced by those involved 
with the study, who attends the informed consent process if the subject or the subject's 
legally acceptable representative cannot read, and who reads the informed consent form 
and any other written information supplied to the subject. After the written informed 
consent form and any other written information to be provided to subjects, is read and 
explained to the subject and after the subject has verbally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
informed consent form, the witness should sign and personally date the consent form. By 
signing the consent form, the witness attests that the information in the consent form and 
any other written information was accurately explained to, and apparently understood by, 
the subject and that informed consent was freely given by the subject. 
 
5.1.2 Screening 
 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number manually created by the 
investigator. The subject’s unique Screening Number will be documented in the 
Screening and Enrolment log. The eligibility of the subject will be determined based on 
the inclusion and exclusion criteria listed in section 4, Selection of Study Population and 
evaluated during this screening procedure. 
 
Prior to study enrolment, demographic data will be collected from the subject, including: 
race, receipt of diphtheria containing vaccine up to 5 years prior to vaccination in the 
V98_06 study (if applicable), receipt of diphtheria containing vaccine between 
vaccination in the V98_06 study and enrolment into the V98_06E1 study (if applicable), 
receipt of diphtheria containing vaccine up to 5 years prior to the V98_06E1 study (naive 
subjects only), whether or not they participated in the parent V98_06 study and if 
applicable the Subject ID they were assigned in the parent V98_06 study. 
 
Medical history will also be collected, including but not limited to any medical history 
that may be relevant to subject eligibility for study participation such as prior 
vaccinations, concomitant medications, and previous and ongoing illnesses or injuries. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it represents 
an exacerbation of an underlying disease/pre-existing problem. 
 
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If a subject reports they are of non-childbearing potential, the medical history in the form 
of medical records (verbal medical history only is not sufficient in this case) must be 
collected prior to vaccination or the subject will have to undergo a urine pregnancy test. 
 
If applicable, prior and concomitant medications or vaccinations taken prior to start of 
study should be collected (refer to section 6.5, Prior and Concomitant Medications and 
Vaccines for further details). 
 
Collect vital signs. Measure height and weight. 
 
Perform pregnancy testing in women of childbearing potential (refer to section 3.5, 
Collection of Clinical Specimens for guidance regarding the procedure). 
 
A general physical examination is to be performed by a qualified health care practitioner. 
“Qualified health care practitioner” refers to any licensed health care professional who is 
permitted by institutional policy to perform physical examinations and who is identified 
within the Study Staff Signature Log. 
 
These data will be written in the source document (see section 9.1, Source 
Documentation). Should the physical assessment reveal any abnormal values or events, 
these must be documented in the CRF Adverse Events Form. 
 
Prior to vaccination, approximately 20 mL of blood will be drawn from all subjects for 
the following testing: serology testing. Refer to section 3.5, Collection of Clinical 
Specimens. 
 
In the event that the individual is determined ineligible for study participation, she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. If the individual is determined to be eligible for the study, 
she will be enrolled into the study. 
 
5.1.3 Enrolment 
 
After signing the informed consent form, if an individual is determined to be eligible for 
study participation, the investigator will enroll the subject and enter the manually created 
Subject ID and Subject Code into the EDC system. The Screening Number ceases to be 
used and remains in the Screening and Enrolment Log only. 
 
5.1.4 Randomization 
This is a single treatment open label study therefore no randomization will be carried out. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for duration of the study. 
 
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If for any reason, after enrolment the subject fails to undergo treatment this is an Early 
Termination and the reason should be recorded in source document as specified in the 
Source Data Agreement (SDA). The information on these Early Termination subjects 
should be kept distinct in the source documentation from subjects who are screen failures, 
as described in section 5.1.2, Screening. 
 
5.2 
Vaccination Clinic Visit 
Vaccination will be performed on day 1. 
 
Ensure all serology samples are taken prior to each vaccination. 
 
After completing the pre-vaccination procedures on day 1, administer the vaccine to the 
subject according to the procedures described in section 6.3, Vaccine Preparation and 
Administration. 
 
5.2.1 Post-vaccination Procedures 
The following post-vaccination procedures will be performed on day 1. 
 
After vaccination, the subject will be observed for at least 30 minutes including 
observation for unsolicited adverse events, solicited adverse events, and body temperature 
measurement. Record all safety data collected during this time in the subject’s source 
document. 
 
A Subject Diary will be used in this study to document solicited adverse events. The 
Subject Diary is the only source for collection of these data; therefore, it is critical that the 
subject completes the Subject Diary correctly. The subject should be trained on how and 
when to complete each field of the Subject Diary. 
 
The subject should be trained on how to self-measure local solicited adverse events and 
body temperature (preferably orally). The measurement of solicited local adverse events 
is to be performed using the ruler provided by the site. 
 
The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during the 
day, the subject should check body temperature. If the subject has fever, the highest body 
temperature observed that day should be recorded in the Subject Diary. 
 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
 
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Subject Diary and/or subject’s source record. Any individual that makes entries into the 
Subject Diary must receive training on completion of the Subject Diary at the time of the 
visit. This training must be documented in the subject’s source record. 
 
The same individual should complete the Subject Diary throughout the course of the 
study. 
 
The site should schedule the subject diary reminder calls and the next study safety follow- 
up call with the subject. 
 
The subject should be reminded of the next planned study activity. The subject will be 
reminded to complete the Subject Diary and to contact the site if there are any questions, 
and to contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room visit 
or to a visit to/by a doctor or is of concern. 
 
5.2.2 Post-vaccination Reminders 
 
Reminder calls or alerts are not intended to be an interview for collection of safety data. If 
the subject wishes to describe safety information, this information should only be 
collected by a healthcare professional at the site, and the safety data described must be 
written down in the subject’s medical chart. 
 
Subject Diary Reminder Calls 
 
Subject Diary reminder calls will be performed on day 3 and day 5. The purpose of these 
calls is to remind the subject about completion of the Subject Diary. The call follows the 
Subject Diary Reminder Telephone Call Script provided to the site. The subject should be 
reminded to contact the site via the telephone number provided in the informed 
 
5.3 
Post-vaccination Visits 
Post-vaccination visits will be performed on day 15, day 31, day 61, day 121 and day 181. 
 
5.3.1 Follow-up Clinic Visits 
Safety follow-up clinic visits will be performed on day 31 and day 61. 
 
During the follow-up clinic visit at day 31, the Subject Diary will be reviewed. No 
changes to the information recorded within the Subject Diary are permissible. For details 
on the Subject Diary see sections 3.4.2, Tools Used for Data Collection and 5.2.1, Post- 
vaccination Procedures. 
 
 
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The subject will be interviewed to determine if unsolicited adverse events occurred (all 
unsolicited AEs up to day 31 and SAEs, medically attended AEs and AEs leading to 
withdrawal only up to day 61) and if any concomitant medications in relation to the 
reported AEs, and/or vaccines and/or antibiotics/other prescription or over the counter 
medicine(s) deemed clinically significant by the investigator were taken/received in the 
time since the last clinic visit. 
 
This interview will follow a script which will facilitate the collection of relevant safety 
information. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. Adverse events reported by the subject at this follow-up clinic 
visit must be recorded in the subject's source document and on an Adverse Events CRF, 
as specified in section 7.1, Safety Assessment, and not written on the script used for the 
interview. 
 
Perform a brief symptom-directed physical examination, according to symptoms the 
subject has reported. This physical examination will include an examination of organ 
systems that are relevant to the investigator based on review of the subject’s concurrent 
medical conditions, reported adverse events, concomitant medication use. The physical 
assessment must be performed by the investigator or designee of the investigator, who is 
qualified to perform a physical assessment in accordance with their institutional policy. 
Corresponding information is documented in the subject’s source document and CRF(s). 
 
Approximately 20 mL of blood will be drawn from all subjects for the following testing: 
serology testing. Refer to section 3.5, Collection of Clinical Specimens. 
 
The site should schedule the next study clinic visit or safety call with the subject. 
 
The subject will be reminded of the next planned study activity. The subject will be 
reminded to contact the site if there are any questions and to contact the site immediately 
(or as soon as the subject is medically stable) if the subject has a medical condition that 
leads to a hospitalization or an emergency room visit. 
 
5.3.2 Safety Follow-up Calls 
 
Safety follow-up calls will be performed on day 15, day 121 and day 181. 
 
Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to the 
script. 
 
 
 
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At day 15 information relating to all unsolicited adverse events and all concomitant 
medications administered in relation to them, any vaccines administered and all 
antibiotics and any other prescription or over the counter medicine(s) deemed clinically 
significant by the investigator will be collected. 
 
At days 121 and 181 information relating to only SAEs, medically attended adverse 
events, AEs leading to withdrawal and all concomitant medications administered in 
relation to them, any vaccines administered and all antibiotics and any other prescription 
or over the counter medicine(s) deemed clinically significant by the investigator will be 
collected. 
 
All safety information described by the subject must be written down in a designated 
location within the source document and not written on the script used for the telephone 
call. 
 
The site should schedule the next study activity clinic visit or safety call with the subject. 
 
The subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
 
5.4 
Unscheduled Visits 
Not applicable for this study. 
 
5.5 
Study Termination Visit 
The study termination visit will occur on day 181. The termination visit will be a 
telephone call. The date of termination is the day 181 visit or the last contact (clinic visit 
or telephone call) in which the subject’s health status was assessed or, in cases where the 
subject does not agree to any further safety follow-up, it is the date consent is withdrawn. 
This date should be recorded on the termination CRF page. For visit procedures to be 
performed for a subject whose planned study participation ends prematurely, please see 
section 5.5.1, Early Termination Visit. 
 
During the telephone call, the following procedures will be performed: interview of 
subject to collect medically attended adverse events, AEs leading to withdrawal, SAEs 
and concomitant medications/ vaccinations including concomitant medications 
administered in relation to the reported AEs, all antibiotics and any other prescription or 
over the counter medicine(s) deemed clinically significant by the investigator. 
 
The site will review with the subject the plan of when information relating to the subject’s 
participation in the study may be available (e.g., study results). It will also be discussed 
 
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how information relating to the subject’s participation in the study will be shared with the 
subject’s healthcare provider, if the subject chooses to share this information. 
 
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study. 
 
5.5.1 Early Termination Visit 
 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures as outlined 
below. The reason(s) for the early termination will be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were enrolled but 
not treated. 
 
At the clinic visit or during the telephone call, procedures should be carried out according 
to the next closest scheduled visit. I.e., if the subject terminates early at clinic visit day 31 
then all procedures outlined for the day 31 visit should be carried out. Similarly if they 
terminate early between day 121 and day 181 safety telephone calls all procedures as 
according to the day 181 safety call should be carried out. 
 
The site will review with the subject the plan of when information relating to the subject’s 
participation in the study may be available (e.g., study results). It will also be discussed 
how information relating to the subject’s participation in the study will be shared with the 
subject’s healthcare provider, if the subject chooses to share this information. 
 
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. 
TREATMENT OF SUBJECTS 
 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
 
6.1 
Study Vaccine 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccine specific to this study is 
described below. 
 
GroupB streptococcus (GBS) TrivalentVaccine 
Lyophilized Formulation of GBS trivalent vaccine will be supplied by GSK. 
 
• Vial 
Each vial contains 6 µg of each glycoconjugate (i.e. serotype Ia, Ib and III). Each of 
the three capsular polysaccharides is conjugated to the Corynebacterium diptheriae 
CRM197 carrier protein. At the time of injection, the vaccine will be reconstituted at 
the site with 0.6 mL sterile saline. The sterile saline will be supplied by GSK as 2.0 
mL sterile saline for intramuscular (IM) injection at a concentration of 0.9% of 
sodium chloride. 
 
• Dose 
A dose of 5 µg of each antigen with the single vaccine injection of 0.5 mL delivered 
by the IM route, preferably the deltoid muscle in the non-dominant-arm. 
 
Vaccine lots to be used in this study have been produced via Good Manufacturing 
Practices. Different lots of Group B streptococcus glycoconjugate vaccine that may be 
used in this study are comparable based on product and process specifications. 
 
The vaccine handling and preparation, including reconstitution, instructions will be 
developed and provided to the site prior to study start, placed in the investigator site file 
and the investigator should be referred here to review these materials prior to study start. 
The vaccine must be stored between 2°C to 8°C (in a refrigerator) and protected from 
light. DO NOT FREEZE. 
 
 
 
 
 
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Table 6.1-1 
Group B Streptococcus Trivalent Vaccine Composition – 
Lyophilized Supplied as lyophilized product with 6 µg of each 
antigen per vial, to be reconstituted with 0.6mL of sterile normal 
saline (NaCl 9 mg/ml) to provide for a single dose as 0.5 mL of 
injectable suspension. 
 
Active substances (active ingredient / antigen carrier protein) 
Unit per dose 
(1 dose = 0.5mL) 
GBS. CPS-Ia CRM197 
5 µg 
GBS. CPS-Ib CRM197 
5 µg 
GBS.CPS-III CRM197 
5 µg 
Sodium chloride (tonicity modifying agent) 
4.5 mg 
Potassium dihydrogen phosphate (pH buffering agent) 
0.34 mg 
Mannitol (lyophilization bulking and tonicity modifying agent 
7.5 mg 
Water for injection (solvent) 
Qs to 0.5 mL 
Vaccine presentation 
Vial 
 
Saline solution (diluent) 
GSK will provide commercially available sterile saline solution, supplied as 0.9% 
Sodium Chloride in 2.0 mL glass ampoules, for use at the site to reconstitute the 
lyophilized formulation of GBS Trivalent Vaccine. Only the saline solution provided by 
GSK is to be used for study vaccine preparation of the lyophilized formulation. 
 
The saline solution may be stored at room temperature with temperatures at < 25°C or in 
a refrigerator. DO NOT FREEZE. 
 
The package insert (or the summary of product characteristics) for the commercial saline 
solution will be included in the investigator site file and the investigator will be instructed 
to refer to these materials prior to study start. 
 
6.2 
Non-Study Vaccines 
Not applicable for this study. 
 
6.3 
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
 
 
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study protocol. All vaccines will be administered only by personnel who are qualified to 
perform that function under applicable local laws and regulations for the specific study 
site. 
 
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the Protocol Ancillary Document prior to study start. The lyophilized 
vaccine must be used immediately after reconstitution, in accordance with the vaccine 
instructions. 
 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and 
it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.1, Inclusion Criteria and 4.2, 
Exclusion Criteria. 
 
Study vaccines should not be administered to individuals with known hypersensitivity to 
any component of the vaccines. 
 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. 
DO NOT inject intravascularly or intragluteally. 
 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available. 
 
6.4 
Vaccine Administration Error or Overdose of Vaccine 
 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
 
 
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6.5 
Prior and Concomitant Medications and Vaccines 
 
All medications (excluding vitamins, minerals and nutritional supplements), vaccines and 
blood products taken or received by the subject within 30 days prior to administration of 
study vaccine are to be recorded on the Prior and Concomitant Medications CRF. 
 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
 
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in section 4, Selection of Study Population to ensure 
that the subject should be enrolled in the study. 
 
The use of the following concomitant medications may interfere with the interpretation of 
the study objectives and therefore, are prohibited: 
- 
use of antipyretics and/or analgesic medications within 24 hours prior to day 1 
- 
any live vaccine 28 days prior to study vaccination 
- 
any inactivated vaccines 14 days prior to study vaccination 
- 
any vaccines within 28 days after study vaccination 
- 
exception: an inactivated influenza vaccine may be administered up to 7 days prior 
to study vaccination or 7 days after study vaccination 
- 
blood, blood products or a parenteral immunoglobulin preparation (except Rho(D) 
Immunoglobulin); 
- 
immunoglobulins or any blood products within 180 days prior to informed consent 
- 
antineoplastic and immunomodulating agents or radiotherapy within 90 days prior 
to informed consent. 
- 
immunosuppressive therapy within 90 days prior to informed consent 
- 
investigational or non-registered medicinal product within 30 days prior to 
informed consent 
- 
Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent 
 
Concomitant medications that include all medications administered in relation to reported 
AEs, any vaccines administered and all antibiotics and any other prescription or over the 
counter medicine(s) deemed clinically significant by the Investigator taken 
 
 
 
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by/administered to the subject at and after enrolment and must be documented on the 
Concomitant Medications CRF. 
 
6.6 
Vaccine Supply, Labeling, Storage and Tracking 
 
The Sponsor will ensure the following: 
• Supply of the study vaccine 
• Appropriate labeling of all study vaccine provided that complies with the legal 
requirements of each country where the study is to be performed. 
 
The investigator must ensure the following: 
• Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the 
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
• Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
• Appropriate use of the study vaccines, including: 
- 
Not use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying numbers 
assigned to subjects and study vaccines, and time of vaccine administration. 
This information will be maintained in an administration log that will be 
reviewed by the site monitor. 
 
 
 
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▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines were 
destroyed at the site, and which vaccines were returned to the Sponsor, as 
applicable. 
• Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
• Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. 
ASSESSMENTS 
 
7.1 
Safety Assessment 
The measures of safety used in this study are routine clinical procedures. They include a 
close vigilance for, and stringent reporting of, selected local and systemic adverse events 
routinely monitored in vaccine clinical studies as indicators of reactogenicity. 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
 
The period of observation for AEs (or sub-set of AEs as according to the Time and Events 
Table 3) extends from the time the subject signs informed consent until he or she 
completes the specified safety follow-up period (until day 181 visit) or terminates the 
study early (whichever comes first). AEs occurring after the informed consent form is 
signed but prior to receiving study vaccine/product will be documented as an adverse 
event and recorded within source document. However, any AEs occurring prior to receipt 
of any study vaccine will be analyzed separately from “treatment emergent” AEs (AEs 
occurring after administration of the first study vaccine). 
 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries. 
 
7.1.1 Solicited Adverse Events 
 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject for 7 consecutive days, using a pre-defined Subject Diary. 
 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported in parentheses below: 
 
Solicited local adverse events: 
 
The list of solicited local (injection site) adverse events is: 
• Pain 
 
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• Erythema (mm) 
• Swelling (mm) 
• Warmth 
• Induration (mm) 
• Ecchymosis (mm) 
Injection site erythema, swelling, induration and ecchymosis will be categorized based on 
the linear measurement of these events. 
 
Injection site pain and warmth will be summarized according to none, mild (transient with 
no interference in normal daily activity), moderate (some interference in normal daily 
activity) or severe (unable to perform normal daily activity). 
 
Solicited systemic adverse events: 
The list of solicited systemic adverse events is: 
 
• Chills 
• Generalized myalgia 
• Malaise 
• Nausea 
• Headache 
• Fatigue 
• Body rash 
• Generalized arthralgia 
Systemic events (except body rash) occurring up to day 7 after vaccination will be 
summarized according to: none, mild (transient with no interference in normal daily 
activity), moderate (some interference in normal daily activity) or severe (unable to 
perform normal daily activity). Body rash occurring up to day 7 after vaccination will be 
summarized according to: none (no rash), mild (localized area of the skin, or only one 
extremity), moderate (moderate area of the skin, or two or more body regions, without 
whole body involvement), or severe (most of the skin). 
 
 
 
 
 
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Other solicited reactions: 
 
• Body temperature for fever (preferably oral, captured daily as measurements in 
degrees Celsius) 
• Use of analgesics/antipyretics 
Body temperature will be summarized based on the measurement and grade. 
 
Use of analgesics/antipyretics will be summarized as “for treatment” or “for prophylaxis”. 
Each local and systemic reaction will also be categorized as none vs. present. 
 
The study staff must review the data entered into the Subject Diary as described in section 
3.4.2, Tools Used for Data Collection and section 5.3.1, Follow-up Clinic Visit(s). 
 
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see section 9.1, Source Documentation) and also as an 
adverse event on the Adverse Event CRF: 
• Solicited local or systemic adverse event that continues beyond day 7 after 
vaccination. 
• Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3, Evaluation of Adverse Events). 
• Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse 
event leading to withdrawal, see section 7.1.3, Evaluation of Adverse Events). 
• Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4, Serious Adverse Events). 
 
7.1.2 Unsolicited Adverse Events 
 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
 
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subject. In case of such events, subjects will be instructed to 
contact the site as soon as possible to report the event(s). The detailed information about 
the reported unsolicited AEs will be collected by the qualified site personnel during the 
interview and will be documented in the subject’s records. 
 
 
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Unsolicited AEs that are not medically attended nor perceived as a concern by subjects 
will be collected during interview with the subject and by review of available medical 
records at the next visit (see section 5.3, Post-vaccination Visit(s)). 
 
7.1.3 Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported 
by a subject for an underlying diagnosis and to capture this diagnosis as the event in the 
AE page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
 
The severity of events reported on the Adverse Events CRF will be determined by the 
investigator as: 
 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: 
unable to perform normal daily activity. 
 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
 
2. Possibly Related 
 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
 
3. Probably Related 
 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. 
 
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Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in section 7.1.1, Solicited 
Adverse Events. 
 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
• “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
• AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. The investigator’s assessment of 
ongoing Adverse Events at the time of each subject’s last visit should be documented in 
the subject’s medical chart. 
 
7.1.4 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
• Death. 
• Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• Required or prolonged hospitalization. 
• Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
• Congenital anomaly/or birth defect. 
• An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
 
Adverse events which do not fall into these categories are defined as non-serious. 
 
 
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It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the AE CRF. All SAEs will be evaluated by the investigator 
for relationship of the event to study vaccine. SAEs that are judged to be possibly or 
probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
 
1. Related/suspected 
 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 7.1.3, Evaluation of Adverse Events). 
 
2. Not Related 
 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
 
7.1.4.1 
Adverse Events of Special Interest 
 
AESIs are not assessed during the study. 
 
 
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7.1.5 Methods for Recording Adverse Events and Serious Adverse Events 
 
Findings regarding Adverse Events must be reported on an Adverse Events CRF, as 
specified in section 7.1.1, Solicited Adverse Events, and on the VSAE form, if applicable, 
which is part of the Investigator Site File. All findings in subjects experiencing AEs must 
be reported also in the subject's source document. 
 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to GSK or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to GSK will be provided to the investigator. 
 
All SAEs are also to be documented on the Adverse Events CRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
 
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
 
All SAEs must be reported by the investigator to her corresponding EC and applicable 
regulatory authority in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
 
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority and the EC. If a SUSAR or other safety 
signal relating to use of one of the study vaccines is reported to GSK or its designee, the 
Sponsor will communicate the information to the investigator and the investigator will be 
responsible for submitting this information to the EC and other relevant authorities. 
 
7.1.5.1 
Post-Study Events 
 
Any SAE that occurs outside of the protocol-specified follow-up period and considered to 
be caused by the study vaccine must be reported to GSK or its designee. These SAEs will 
be processed by GSK or its designee as during the course of the study, until 6 months post 
LSLV. Instructions and contact details for collecting and reporting these suspected SAEs 
will be provided to the investigator. 
 
7.1.6 Pregnancies 
 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to GSK or delegate within 72 hours of the site learning of its occurrence. If the 
subject agrees to submit this information, the pregnancy must be followed to determine 
 
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outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. This follow-up should occur even if intended duration of safety 
follow-up for the study has ended. 
 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report) and reported to GSK or delegate. 
Instructions and contact details for submitting the Pregnancy CRFs will be provided to 
the investigator. 
Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4, Serious 
Adverse Events) must also be reported on the VSAE Report Form. 
 
7.1.7 Safety Laboratory Measurements 
 
This study has no safety laboratory measurements. 
 
7.2 
Efficacy Assessment 
 
This study has no efficacy measurements. 
 
7.3 
Immunogenicity Assessment 
 
For the primary and secondary immunogenicity objectives, the GBS serotype–specific 
(Ia, Ib, III) IgG antibody responses in the serum will be determined by ELISA. 
 
Original samples from subjects who participated in the V98_06 study who are also 
participating in this V98_06E1 study may be re-tested for the purposes of consistency in 
the ELISA assay being used to analyze the samples collected in this extension study. 
 
The GBS serotype-specific IgG ELISAs in sera will be carried out by Clinical Laboratory 
Sciences, GlaxoSmithKline, Marburg, Germany. 
 
The diphtheria-specific IgG antibody levels will be measured by ELISA. Testing will be 
conducted by a designated, qualified external laboratory. 
 
Functional activities of anti-GBS antibodies will be measured by opsonophagocytic 
killing assay (OPK). Testing will be conducted by a designated qualified external 
laboratory. 
 
Technical details (or instructions) for specimen collection, processing and shipment will 
be described in Clinical Specimen Lab Manual which will be made available to site 
 
 
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personnel after site initiation (e.g. refer to the Clinical Specimen Lab Manual in the 
investigator site file). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. 
STATISTICAL CONSIDERATIONS 
 
8.1 
Endpoints 
 
8.1.1 Primary Endpoint(s) 
 
8.1.1.1 
Primary Safety Endpoint(s) 
The frequency and percentage of subjects with solicited local and systemic AEs from 
vaccination to day 7 in study V98_06E1. Time intervals after vaccination that will be 
summarized are: the first 30 minutes after vaccination, days 1-3 (excluding the first 30 
min), days 4-7 and days 1-7 (excluding the first 30 min).. 
 
The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (day 1 in study V98_06E1) to day 31. 
 
The frequency and percentage of subjects with SAEs, medically attended AEs, and AEs 
leading to study withdrawal from vaccination in study V98_06E1 to day 181. 
 
8.1.1.2 
Primary Efficacy Endpoint(s) 
 
This study has no efficacy endpoints. 
 
8.1.1.3 
Primary Immunogenicity Endpoint(s) 
 
The primary immunogenicity endpoints are the percentages of subjects who reach pre- 
defined sequential serotype-specific (Ia, Ib and III) serum antibody levels at day 61 post 
vaccination, as measured by ELISA. 
 
8.1.2 Secondary Endpoint(s) 
 
8.1.2.1 
Secondary Safety Endpoint(s) 
 
This study has no secondary safety endpoints. 
 
8.1.2.2 
Secondary Efficacy Endpoint(s) 
 
This study has no efficacy endpoints. 
 
 
 
 
 
 
 
 
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8.1.2.3 
Secondary Immunogenicity Endpoint(s) 
 
The secondary immunogenicity endpoints are: 
 
The percentage of subjects reaching pre-defined sequential serotype-specific (Ia, Ib and 
III) serum antibody levels as measured by ELISA at other time points and in subgroups of 
subjects defined by their pre-vaccination serotype-specific GBS antibody LLQ status in 
the V98_06 study (or the V98_06E1 study for the naive group). 
 
The serotype-specific (Ia, Ib, and III) geometric mean concentrations (GMCs) as 
measured by ELISA at days 31 and 61 post-vaccination in study V98_06E1 and in the 
subgroups of subjects defined according to their pre-vaccination serotype-specific GBS 
antibody LLQ status in the V98_06 study (or V98_06E1 study for the naive group). 
 
The within subject geometric mean ratio (GMR) of serotype-specific (Ia, Ib & III) serum 
antibody levels as measured by ELISA at day 31 and 61. The GMRs will be determined 
relative to pre-vaccination in V98_06E1 and separately relative to pre-vaccination in 
V98_06 for all groups except the naive group. The GMRs will also be determined for 
subgroups of subjects defined according to their pre-vaccination serotype-specific GBS 
antibody LLQ status in the V98_06 study or V98_06E1 study for the naive group. 
 
Reverse cumulative distribution function (RCDF) curves of serotype-specific (Ia, Ib and 
III) serum antibody levels, as measured by ELISA, at pre-vaccination in V98_06 study or 
V98_06E1 study for the naive group, vaccination, day 31 and day 61 post-vaccination in 
all subjects and by pre-vaccination serotype-specific GBS antibody LLQ status in the 
V98_06 study or V98_06E1 study for the naive group. 
 
The anti-diphtheria geometric mean antibody concentrations measured by ELISA for 
samples collected before the first vaccination with GBS Trivalent Vaccine in the V98_06 
study or V98_06E1 study for the naive group and on day 61 post-vaccination in 
V98_06E1. 
 
8.1.3 Exploratory Endpoint(s) 
 
8.1.3.1 
Exploratory Safety Endpoint(s) 
This study has no exploratory safety endpoints. 
 
8.1.3.2 
Exploratory Efficacy Endpoint(s) 
This study has no efficacy endpoints. 
 
 
 
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8.1.3.3 
Exploratory Immunogenicity Endpoint(s) 
 
The exploratory immunogenicity endpoints are: 
 
The serotype-specific (Ia, Ib, and III) geometric mean titer (GMT) as measured by OPK 
at day 1 pre-vaccination and at days 31 and 61 post-vaccination in study V98_06E1 in 
study subjects and in subgroups of subjects defined by pre-vaccination ELISA serotype- 
specific GBS antibody LLQ status in the V98_06 study or V98_06E1 study for the naive 
group. 
 
The within subject GMR of serotype-specific (Ia, Ib & III) serum titers as measured by 
OPK at day 31 and 61. The GMRs will be determined relative to pre-vaccination in 
V98_06E1. The GMRs will also be determined for subgroups of subjects defined 
according to their pre-vaccination ELISA serotype-specific GBS antibody LLQ status in 
the V98_06 study, or V98_06E1 study for the naive group. 
 
Exploratory OPK objectives will be addressed in a randomly selected subset of up to 60 
subjects (10 subjects per arm). 
 
8.2 
Success Criteria 
 
There is no pre-defined success criterion for this study. 
 
8.2.1 Success Criteria for Primary Objective(s) 
 
8.2.1.1 
Success Criteria for Primary Safety Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.2.1.2 
Success Criteria for Primary Efficacy Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.2.1.3 
Success Criteria for Primary Immunogenicity Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.2.2 Success Criteria for Secondary Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.2.2.1 
Success Criteria for Secondary Safety Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
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8.2.2.2 
Success Criteria for Secondary Efficacy Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.2.2.3 
Success Criteria for Secondary Immunogenicity Objective(s) 
 
There is no pre-defined success criterion for this study. 
 
8.3 
Analysis Sets 
 
The analysis sets described below are specific to study V98_06E1. Similar analysis sets 
have already been defined in study V98_06 for subjects receiving a second vaccination in 
this study. 
 
8.3.1 All Enrolled Set 
 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s treatment status in this study. 
 
8.3.2 All Exposed Set 
All subjects in the enrolled set who receive a study vaccination in study V98_06E1. 
 
8.3.3 Safety Set 
 
Solicited Safety Set (solicited local and systemic adverse events and other solicited 
adverse events) 
All subjects in the Exposed Set with any solicited adverse event data and/or indicators of 
solicited adverse events (e.g., use of analgesics/antipyretics) reported in this study. 
 
Unsolicited Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set with unsolicited adverse event data reported in this study. 
 
Overall Safety Set 
All subjects who are in the Solicited Safety Set and/or Unsolicited Safety Set. 
 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received). 
 
 
 
 
 
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8.3.4 Full Analysis Set (FAS) Immunogenicity Set 
Full Analysis Set Immunogenicity 
All subjects in the All Enrolled Set who receive at least one study vaccination in study 
V98_06E1 and provide immunogenicity data at day 1 (pre-vaccination), day 31 or day 61 
in V98_06E1. 
 
8.3.5 Per Protocol (PP) Set Immunogenicity Set 
All subjects in the FAS Immunogenicity set who: 
• Correctly receive the vaccine (i.e., receive the vaccine to which the subject was 
randomized and at the scheduled time points) in V98_06 (for non-naïve subjects). 
• Have no protocol deviations leading to exclusion (see section 8.3.8, Protocol 
Deviations) as defined prior to analysis. 
• Are not excluded due to other reasons defined prior to analysis (see section 8.3.8, 
Protocol Deviations) 
 
Examples for subjects excluded due to reasons other than protocol deviations are: 
- 
Subjects who withdrew informed consent 
- 
Premature withdrawal due to an adverse event. 
 
8.3.6 Other Analysis Sets 
There are no additional analysis sets. 
 
8.3.7 Subgroups 
Subgroups of subjects will be created based on the ELISA serotype-specific (Ia, Ib, III) 
antibody LLQ status prior to initial vaccination in study V98_06 (or V98_06E1 for the 
naive group). 
 
8.3.8 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. CSR-reportable protocol deviations will be defined 
as exclusionary from the analysis according to protocol objectives and endpoints, which 
will be specified in the statistical analysis plan. In some cases exclusion of data may be 
due to a reason other than a protocol deviation, e.g. early termination. 
 
 
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8.4 
Statistical Analysis Plan 
 
8.4.1 Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight at enrolment will be calculated overall and by vaccine group. 
 
Distributions of subjects by sex, race, ethnic origin, V98_06 vaccine formulation group 
(or naïve) and pre-vaccination LLQ status will be summarized overall and by vaccine 
group. 
 
8.4.2 Analysis of Primary Objective(s) 
 
8.4.2.1 
Analysis of Primary Safety Objective(s) 
 
8.4.2.1.1 Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations in V98_06E1 will be 
summarized by vaccine group and overall for the Enrolled Set. 
 
8.4.2.1.2 Analysis of Solicited Local, Systemic and Other Adverse Events 
 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
 
Post-vaccination solicited adverse events reported from day 1 to day 7 will be 
summarized for the intervals day 1-3, day 4-7, day 1-7 by maximal severity and by 
vaccine group, excluding the 30 minute measurement, which will be summarized 
separately. The severity of solicited local adverse events, including injection-site 
erythema, swelling and induration will be summarized according to categories based on 
linear measurement: 0 mm, <25 mm, 25 to 50 mm, 51-100 mm, > 100 mm. 
 
Injection site pain/tenderness and systemic adverse events (except fever) occurring up to 
day 7 after each vaccination will be summarized according to “mild”, “moderate” or 
“severe”. 
 
Each solicited local and systemic adverse event will also be further summarized as 
“none” versus “any”. 
 
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Implausible measurements (for further definition see statistical analysis plan) will be left 
out of the analysis. 
 
Use of antipyretics and analgesics will be summarized by frequency, by type of use 
(prophylactic versus treatment), and percentage of subjects reporting use. 
 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C and will be broken down according by route of measurement. 
 
8.4.2.1.3 Analysis of Unsolicited Adverse Events 
 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
 
Separate summaries will be produced for the following categories: 
• Serious adverse events. 
• Adverse events that are possibly or probably related to vaccine. 
• Adverse event leading to withdrawal. 
• Adverse events leading to a medically attended visit. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
 
8.4.2.1.4 Analysis of Safety Laboratory Values 
 
This study has no safety laboratory values. 
8.4.2.2 
Analysis of Primary Efficacy Objective(s) 
 
This study has no efficacy objectives. 
 
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8.4.2.2.1 Statistical Hypotheses 
 
Not applicable 
 
8.4.2.2.2 Analysis Sets 
 
Not applicable. 
 
8.4.2.2.3 Statistical Methods 
 
Not applicable. 
 
8.4.2.3 
Analysis of Primary Immunogenicity Objective(s) 
 
The frequency and percentages of subjects with serotype-specific (Ia, Ib, and III) antibody 
concentrations above a set of pre-defined sequential serotype-specific serum antibody 
levels and associated two-sided 95% Clopper-Pearson CIs will be computed for each 
study group, for the MF59 study groups combined, for the unadjuvanted and Alum 
adjuvanted study groups combined, and the placebo and naive groups combined for 
concentrations at day 61 post-vaccination. 
 
Differences in percentages between study groups will be computed and two-sided 95% 
confidence intervals for the difference constructed using the method of Miettinen and 
Nurminen. The following treatment group comparisons will be examined: each 5 µg 
group compared to the placebo group from study V98_06 and separately to the naïve 
group; the combined MF59 groups compared to the combined placebo and naïve groups; 
and, the combined unadjuvanted and Alum groups compared to the combined placebo 
and naïve groups. 
 
8.4.2.3.1 Statistical Hypotheses 
There are no statistical hypotheses. All analyses are descriptive. 
 
8.4.2.3.2 Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at day 
61. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
 
 
 
 
 
 
 
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8.4.2.3.3 Statistical Methods 
 
8.4.3 Analysis of Secondary Objective(s) 
 
8.4.3.1 
Analysis of Secondary Safety Objective(s) 
 
There are no secondary safety objectives. 
 
8.4.3.1.1 Statistical Methods 
 
8.4.3.2 
Analysis of Secondary Efficacy Objective(s) 
This study has no efficacy objectives. 
 
8.4.3.3 
Analysis of Secondary Immunogenicity Objective(s) 
 
8.4.3.3.1 Statistical Hypotheses 
 
There are no statistical hypotheses. All analyses are descriptive. 
 
8.4.3.3.2 Analysis Sets 
 
The secondary immunogenicity analyses will be based on the per-protocol set (PPS). 
 
8.4.3.3.3 Statistical Methods 
 
GBS 
 
Percentages at Day 31 and RCDFs 
 
The frequency and percentages of subjects with serotype-specific concentrations above a 
set of pre-defined sequential serotype-specific (Ia, Ib and III) serum antibody levels and 
associated two-sided 95% Clopper-Pearson CIs will be computed for each study group, 
for the MF59 study groups combined, for the unadjuvanted and Alum adjuvanted study 
groups combined, and the placebo and naive groups combined for concentrations at day 
31 post-vaccination. Differences in percentages between study groups will computed and 
two-sided 95% confidence intervals for the difference constructed using the method of 
Miettinen and Nurminen. Differences in percentages between study groups will be 
computed and two-sided 95% confidence intervals for the difference constructed using 
the method of Miettinen and Nurminen. The following treatment group comparisons will 
be examined: each 5µg group compared to the placebo group from study V98_06 and 
separately to the naïve group; the combined MF59 groups compared to the combined 
 
 
 
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placebo and naïve groups; and, the combined unadjuvanted and Alum groups compared 
to the combined placebo and naïve groups. 
 
Similar analyses will be performed for the subset of subjects defined by the pre 
vaccination serotype-specific GBS antibody LLQ status in the V98_06 study or 
V98_06E1 study for the naive group. 
 
The percentages of subjects with serotype-specific concentrations above a set of pre- 
defined sequential serotype-specific serum antibody levels will be graphically displayed 
as RCDFs. 
 
Geometric Mean Concentrations 
 
Before any statistical analysis that assumes normally distributed observations, antibody 
concentrations will be log10-transformed. Individual concentrations below the limit of 
quantitation (LLQ) will be set to half that limit. 
 
The logarithmically (base 10) transformed antibody concentrations will be modeled using 
an analysis of covariance (ANCOVA) model with a qualitative factor for vaccine group 
and log (base 10) pre-vaccination concentration in study V98_06, or V98_06E1 for the 
naive group, as a covariate. As this is a single-center study, site is not included as a 
covariate. Response in the V98_06 study was different in those with a pre-vaccination 
concentration below the LLQ, so pre-vaccination concentration is included. The adjusted 
GMC and the two-sided, 95%, confidence intervals (CIs) of the GMC will be calculated 
based on this model. The ratio of GMCs and the corresponding two-sided, 95% CI will 
also be calculated based on this model. The adjusted GMC and two-sided 95% CIs will 
be constructed by exponentiation (base 10) of the least square means of the 
logarithmically transformed (base 10) antibody concentration. The model can be written 
as: 
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the vaccine group i effect 
(where vaccine group is either the V98_06 vaccine group, or naïve), β represents the 
common slope for the log10 prevaccination concentration, xik for subject k in vaccine 
group i, and εik represents random error for subject k in vaccine group i. A similar 
approach will be used in the subgroups based on pre-vaccination LLQ status. 
 
Geometric Mean Ratios 
 
The logarithmically (base 10) transformed within subject ratio of antibody concentrations 
(post vaccination / baseline) will be modeled using an analysis of variance model with a 
qualitative factor for vaccine group (vaccine received in study V98_06 or naïve). The 
 
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adjusted GMR and the two-sided, 95% CIs of the GMR will be calculated based on this 
model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the vaccine group i effect and 
εik represents random error for subject k in vaccine group i. The baseline value is either 
the pre-vaccination concentration in study V98_06 or the pre-vaccination concentration in 
study V98_06E1 as both are to be used in separate analyses. A similar approach will be 
used in the subgroups based on pre-vaccination LLQ status. 
 
Anti-diphtheria 
 
Geometric Mean Concentrations 
 
The logarithmically (base 10) transformed antibody concentrations will be modeled using 
an analysis of covariance (ANCOVA) model with a qualitative factor for vaccine group 
and log (base 10) pre-vaccination concentration in study V98_06, or V98_06E1 for the 
naive group, as a covariate. The adjusted GMC and the two-sided, 95%, confidence 
intervals (CIs) of the GMC will be calculated based on this model. The ratio of GMCs 
and the corresponding two-sided, 95% CI will also be calculated based on this model. 
The adjusted GMC and two-sided 95% CIs will be constructed by exponentiation (base 
10) of the least square means of the logarithmically transformed (base 10) antibody 
concentration. The model can be written as: 
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the vaccine group i effect 
(where vaccine group is either the V98_06 vaccine group, or naïve), β represents the 
common slope for the log10 prevaccination concentration, xik for subject k in vaccine 
group i, and εik represents random error for subject k in vaccine group i. 
Geometric Mean Ratios 
 
The logarithmically (base 10) transformed within subject ratio of antibody concentrations 
(post vaccination / baseline) will be modeled using an analysis of variance model with a 
qualitative factor for vaccine group (vaccine received in study V98_06 or naïve). The 
adjusted GMR and the two-sided, 95% CIs of the GMR will be calculated based on this 
model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the vaccine group i effect and 
εik represents random error for subject k in vaccine group i. The baseline value is either 
 
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the pre-vaccination concentration in study V98_06 or the pre-vaccination concentration in 
study V98_06E1 for the naïve subjects. 
 
Handling of missing values 
 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
analysis will comprise a complete case analysis only, without introducing any bias. 
Imputation methods will not be used. 
 
8.4.4 Analysis of Exploratory Objectives 
 
8.4.4.1 
Analysis of Exploratory Safety Objective(s) 
 
This study has no exploratory safety objectives. 
 
8.4.4.2 
Analysis of Exploratory Efficacy Objective(s) 
 
This study has no efficacy objectives. 
 
8.4.4.3 
Analysis of Exploratory Immunogenicity Objective(s) 
 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
 
Geometric Mean OPK Titers 
 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for vaccine group and 
log (base 10) pre-vaccination titer in study V98_06E1 as a covariate. The adjusted GMT 
and the two-sided, 95%, confidence intervals (CIs) of the GMT will be calculated based 
on this model. The adjusted GMT and two-sided 95% CIs will be constructed by 
exponentiation (base 10) of the least square means of the logarithmically transformed 
(base 10) antibody titer. The ratio of GMTs and the corresponding two-sided, 95% CI will 
also be calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the vaccine group i effect, β 
represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
vaccine group i, and εik represents random error for subject k in vaccine group i. 
 
 
 
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8.5 
Sample Size and Power Considerations 
 
Sample size for this study is not based on power considerations. The sample size is 
determined by the number of subjects from study V98_06 agreeing to participate in this 
study, plus 20 subjects not previously participating in V98_06. 
 
8.6 
Interim Analysis 
 
There will be no interim analysis included in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. 
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING 
 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enrolled subject (see section 8.3.1, All Enrolled Set for definition 
of enrolled subject). Documentation of screened but not enrolled subjects must be 
maintained at the site and made available for review by the site monitor. Data and 
documents will be checked by the Sponsor and/or monitor. 
 
9.1 
Source Documentation 
 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA prior to subject 
enrolment. 
 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, medical 
records to support non child bearing potential if applicable dates of visits, adherence to 
protocol procedures, adequate reporting and follow-up of adverse events, documentation 
of prior/concomitant medication/vaccines, study vaccine receipt/dispensing/return 
records, study vaccine administration information, any data collected by a telephone 
conversation with the subject and date of completion and reason. 
 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
 
All safety data reported by subjects must be written down in source documents prior to 
entry of the data into CRFs. If there are multiple sources of information (e.g., Subject 
Diary, verbal report of the subject, telephone contact details, medical chart) supporting 
the diagnosis of an adverse event, these sources must be identified in the source 
documents, discrepancies between sources clarified, the ultimate diagnosis must be 
justified and written in the source documents, and this diagnosis must be captured in the 
Adverse Event CRF (AE CRF). 
 
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9.2 
Study Monitoring, Auditing and Source Data Verification 
 
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored by GSK or its designee as frequently as necessary to ensure: 
• that the rights and well-being of human subjects are protected, 
• the reported study data are accurate, complete, and verifiable from the source 
documents and 
• the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
 
Contact details for the GSK team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on CRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol. 
 
Data verification may also be performed through a centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency. 
 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by GSK or its representative at the time of each monitoring 
visit and Sponsor audits, when applicable. These documents must also be available for 
inspection, verification and copying, as required by regulations, by officials of the 
regulatory health authorities (e.g., FDA, EMA and others) and/or ECs. The investigator 
and study site staff must comply with applicable privacy, data protection and medical 
confidentiality laws for use and disclosure of information related to the study and enrolled 
subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
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10. 
DATA MANAGEMENT 
 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered onto case report forms (CRFs) in a timely fashion by the investigator 
and/or the investigator’s dedicated site staff. Data entered onto CRFs are stored on a 
secure website. The data collected on this secure website are assimilated into an 
electronic data capture (EDC) system, which is compliant with Title 21 Part 11 policies of 
the Code of Federal Regulations (FDA 1997). The data system includes password 
protection and internal quality checks. The EDC system will be designed and validated by 
the Sponsor prior to activation for data entry by sites. The investigator or designated 
delegate must review data entered and electronically sign the CRFs to verify their 
accuracy. 
 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
 
10.2 
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes. 
 
10.3 
Data Protection 
 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 
 
 
 
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11. 
RECORD RETENTION 
 
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements. 
 
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12. 
USE OF INFORMATION AND PUBLICATION 
 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
 
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the end of study as defined in 
section 3.9, End of Study. 
 
In accordance with standard editorial, ethical practices and current guidelines of Good 
Publication Practice (Graf 2009), GSK will generally support publication of multicenter 
studies only in their entirety and not as individual center data. In this case, a coordinating 
investigator will be designated by mutual agreement prior to the start of the study. The 
coordinating investigator will also sign the clinical study report on behalf of the principal 
investigators (CPMP/EWP/2747/00). Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors authorship 
requirements. Any formal publication of the study in which contribution of GSK 
personnel exceeded that of conventional monitoring will be considered as a joint 
publication by the investigator and the appropriate GSK personnel. 
 
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13. 
ETHICAL CONSIDERATIONS 
 
13.1 
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirements. 
 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare, GSK 
codes on protection of human rights, and with the ethical principles laid down in the 
Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 
1997). 
 
13.2 
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent, as described in section 5.1.1, Informed Consent/Assent. Before the start of the 
study, the investigator will have the informed consent and any other materials that will be 
provided to the subjects reviewed and approved by the EC. This review and approval will 
be documented and stored with other study documents. The investigator or designee must 
fully inform the subject of all pertinent aspects of the study. A copy of the written 
informed consent will be given to the subject or the designee. The subject/designee must 
be allowed ample time to ask about the details of the study and to make a decision as to 
whether or not to participate in the study. The subject must sign the consent form 
indicating their agreement to participate in the study before any study-related procedures 
are conducted. The informed consent process may be conducted up to 5 days prior to 
vaccination on day 1. If the subject is unable to read and write, a witness must be present 
during the informed consent discussion and at the time of informed consent signature. 
 
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the EC and 
a copy of the approved version must be provided to the GSK monitor after EC approval. 
 
Women of childbearing potential (and women of non-childbearing potential who do not 
provide medical records as evidence of the procedures) should be informed that taking the 
study medication may involve unknown risks to the fetus if pregnancy were to occur 
during the study and agree that in order to participate in the study they must adhere to the 
contraception requirements indicated in the protocol for the duration of the study. 
 
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13.3 
Responsibilities of the Investigator and EC 
 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted EC before study start. Properly constituted EC is defined in ICH 
Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated 
statement that the protocol and informed consent have been approved by the EC must be 
given to GSK before study initiation. Prior to study start and at any time the protocol is 
amended during study conduct, the investigator is required to sign a protocol signature 
page confirming her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to GSK monitors, auditors, GSK Clinical Quality Assurance 
representatives, designated agents of GSK, ECs, and regulatory authorities as required. If 
an inspection of the clinical site is requested by a regulatory authority, the investigator 
must inform GSK immediately that this request has been made. 
 
The investigator also responsible for the following: 
 
• Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
• Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
• Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
• Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational products, and their study-related duties and functions 
• Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
• If permission to do so is given by the subject ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the EC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
 
 
 
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The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior EC approval/favorable 
opinion. As soon as possible, the implemented deviation or change, the reasons for it, 
and, if appropriate, the proposed protocol amendment(s) should be submitted: 
(a) to the EC for review and approval/favorable opinion, 
 
(b) to the Sponsor for agreement and, if required, 
 
(c) to the regulatory authority(ies). 
 
13.4 
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by GSK, health authorities where required, and 
the EC. In cases when the amendment is required in order to protect the subject safety, the 
amendment can be implemented prior to EC approval. Notwithstanding, the need for 
formal approval of a protocol amendment, the investigator is expected to take any 
immediate action required for the safety of any subject included in this study, even if this 
action represents a deviation from the protocol. In such cases, GSK should be notified of 
this action, the EC at the study site, and, if required by local regulations, the relevant 
health authority) should be informed within 10 working days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. 
REFERENCE LIST 
 
Baker, C.J., Kasper, D.L. (1977). Immunological investigation of infants with septicemia 
or meningitis due to group B Streptococcus. J Infect Dis 136, S98-S104. 
 
Baker, C.J., Carey, V.J., Rench, M.A., et al. (2004) Maternal Antibody at Delivery 
Protects Neonates From Early Onset Group B. Streptococcal Disease. J Infect Dis 209(5): 
781-788. 
 
Baker, C.J., Kasper, D.L., (1976). Correlation of maternal antibody deficiency with 
susceptibility to neonatal group B streptococcal infection. N Engl J Med 294, 753-756. 
 
Baker CJ, Rench MA, McInnes P. (2003). Immunization of pregnant women with group 
B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine. 21(24): 
3468-72. 
 
Boyer KM, Papierniak CK, Gadzala CA, Parvin JD, Gotoff SP. J Pediatr. (1984). 104(4):618-20 
 
Centers for Disease Control and Prevention. 
Prevention of Perinatal Group B Streptococcal Disease. MMWR 2010;59(No. RR-10). 
 
Cockcroft DW, Gault MJ. (1976) Prediction of creatinine clearance from serum 
creatinine. Nephron; 16: 31-41. 
 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
 
Committee for proprietary medicinal products (CPMP), European Agency for the 
Evaluation of Medicinal Products. (1998) Points to consider on clinical investigation of 
medicinal products used in the treatment of osteoarthritis. London, UK. 
 
Committee for proprietary medicinal products (CPMP), European Agency for the 
Evaluation of Medicinal Products. (2001) Note for guidance on coordinating investigator 
signature of clinical study reports. London, UK. 
 
Eisen HN. (1974) Immunology: An introduction to molecular and cellular principles of 
the immune response. 5th ed; New York: Harper and Row. 
 
Englund JA, Anderson EL, Reed GF, Decker MD, Edwards KM, Pichichero ME, Steinhoff MC, 
Rennels MB, Deforest A, Meade BD. (1995). Pediatrics. 96(3 Pt 2):580-4. 
 
 
 
 
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Englund JA, Glezen WP, Turner C, Harvey J, Thompson C, Siber GR. (1995). J Infect Dis. 
171(1):99-105 
 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of 
the Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
 
Gemmill A, Lindberg LD. (2013) Short interpregnancy intervals in the United States. 
Obstet Gynecol. 122(1):64-71. 
 
Glezen WP, Alpers M. (1999) Maternal Immunization. 28(2):219-24. 
 
Graf C, Battisti WP, Bridges D. (2009). Good publication practice for communicating 
company Sponsored medical research: the GPP2 guidelines. BMJ; 339: b4330 
 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 
(R1). Federal Register, 62 (90): 25691-25709 
 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 
 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
 
Lin FY, Philips JB 3rd, Azimi PH, Weisman LE, Clark P, Rhoads GG, Regan J, Concepcion NF, 
Frasch CE, Troendle J, Brenner RA, Gray BM, Bhushan R, Fitzgerald G, Moyer P, Clemens JD. 
(2001) J Infect Dis. 184(8):1022-8. 
 
Lin FY, Weisman LE, Azimi PH, Philips JB 3rd, Clark P, Regan J, Rhoads GG, Frasch CE, Gray 
BM, Troendle J, Brenner RA, Moyer P, Clemens JD. (2004) J Infect Dis. 190(5):928-34. 
 
Melin P, Efstratiou A. (2013) Group B. Streptococcal Epidemiology and Vaccine Needs 
in Developed Countries. Vaccine. 31 Suppl 4:D31-42. 
 
Pichichero ME. (2013) Hum Vaccin Immunother. 2013 
 
US Department of Health and Human Services, Food and Drug Administration (2007) 
Guidance for Industry: toxicity grading scale for healthy adult and adolescent volunteers 
enrolled in preventive vaccine clinical. Rockville, MD. 
 
 
 
 
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U.S. Department of Health and Human Services, Food and Drug Administration, CBER 
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. / 
 
 
 
 
UserName: PPD 
PPD 
 
Title: Cluster Physician 
Date: Monday, 06 July 2015, 18:54 GMT 
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Clinical Study Protocol V98_06E1 Amendment 1 
Confidential 
Page 1  of 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
 
Study Number: V98_06E1 
 
Protocol Title: A Phase 2, Non-Randomized, Controlled, Open-Label, Parallel-Group 
Extension Study to Evaluate the Immunogenicity and Safety of the Second Dose of GBS 
Trivalent Vaccine in Healthy Non-Pregnant Subjects. 
 
 
Amendment Number 1 
 
Revised Protocol version 2 issued on 24 SEP 15 
 
The present amendment reflects changes to the Protocol version 1 
issued on 02 JUL 15 
 
 
 
 
 
 
 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK 
 
 
 
 
 
 
 
 
 
 
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DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
CHANGE 1 (Page 16, Paragraph 3): 
 
Previously read: The anti-diphtheria geometric mean antibody concentrations measured 
by ELISA for samples collected before the first vaccination with GBS Trivalent Vaccine 
in the V98_06 study or V98_06E1 study for the naive group and on day 31 and day 61 
post vaccination in V98_06E1. 
 
 
Now reads: The anti-diphtheria geometric mean antibody concentrations measured by 
ELISA for samples collected before the first vaccination with GBS Trivalent Vaccine in 
the V98_06 study or V98_06E1 study for the naive group and on day 61 post vaccination 
in V98_06E1. 
 
 
Rationale for Change: This is being removed due to an inconsistency error. When the 
body of the protocol was changed prior to finalization, the synopsis was not updated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD 
Document Approval Certificate / 
PPD 
/ 
 
The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. / 
 
. 
 
 
 
UserName: PPD 
PPD 
 
Title: Cluster Physician 
Date: Wednesday, 30 September 2015, 15:45 GMT 
Meaning: As an approver, I agree with the content and format of this document. 
================================================ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This signature certificate is only valid when accompanied by all the pages of the document. / 
PPD 
 
Doc Number: 75314293