Extension Study to Evaluate the Immunogenicity and Safety of the Second Dose of GBS Trivalent Vaccine in Healthy Non-Pregnant Subjects.

Study Overview
=================
Brief Summary
-----------------
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.

Official 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.

Conditions
-----------------
Bacterial Infection Due to Streptococcus, Group B

Intervention / Treatment
-----------------
* Biological: GBS Trivalent Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator Females of childbearing potential who are using an effective birth control method which they intend to use until the end of the study (day 181 visit) or females of non-childbearing potential Exclusion Criteria: Progressive, unstable or uncontrolled clinical conditions, or clinical conditions representing a contraindication to intramuscular vaccination and blood draws Abnormal function of the immune system Received immunoglobulins or any blood products within 180 days prior to informed consent Received an investigational or non-registered medicinal product within 30 days prior to informed consent 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 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 Individuals who anticipate becoming pregnant prior to the end of the study, or individuals who are breastfeeding Individuals who have had a previous immunization with a vaccine containing Group B Streptococcus antigens that was not part of V98_06 study 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 Individuals with acute or chronic infection(s) that require systemic antibiotic treatment or antiviral therapy, within 7 days prior to day 1

Ages Eligible for Study
-----------------
Minimum Age: 22 Years
Maximum Age: 46 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GBS NoAdj/GBS NoAdj<br>Subjects who had received unadjuvanted GBS Trivalent Vaccine in parent study V98_06 (205468 - NCT01150123) and received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|
| Experimental: GBS Alum/GBS NoAdj<br>Subjects who had received GBS Trivalent Vaccine with alum adjuvant in parent study V98_06 (205468 - NCT01150123) and received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|
| Experimental: GBS MF59 Full/GBS NoAdj<br>Subjects who had received GBS Trivalent Vaccine with full dose of MF59 in parent study V98_06 (205468 - NCT01150123) and received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|
| Experimental: GBS MF59 Half/GBS NoAdj<br>Subjects who had received GBS Trivalent Vaccine with half dose of MF59 in parent study V98_06 (205468 - NCT01150123) and received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|
| Experimental: Placebo/GBS NoAdj<br>Subjects who had received placebo in parent study V98_06 (205468 - NCT01150123) and received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|
| Experimental: Naive/GBS NoAdj<br>Healthy non-pregnant female subjects aged 22 through 46 years inclusive on the day of informed consent who had not received any GBS vaccine in the past and who received a single dose of unadjuvanted GBS Trivalent Vaccine in V98_06E1 (205421 - NCT02690181). | Biological: GBS Trivalent Vaccine<br>* Administration of lyophilized formulation of a GBS trivalent vaccine containing 5 µg of each polysaccharide capsules from serotypes Ia, Ib, and III of Group B Streptococcus conjugated to CRM-197 .<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With ELISA Antibody Concentrations of GBS Serotype Ia Above Pre-specified Thresholds - Day 61 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype Ia at Day 61 post-vaccination, as measured by Enzyme-linked immunosorbent Assay (ELISA). | At Day 61 | 
| Percentage of Subjects With Antibody Concentrations of GBS Serotype Ib Above Pre-specified Thresholds - Day 61 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype Ib at day 61 post-vaccination. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 61 | 
| Percentage of All Subjects With Antibody Concentrations of GBS Serotype III Above Pre-specified Thresholds - Day 61 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype III at day 61 post-vaccination. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 61 | 
| Numbers of Subjects With Solicited Local and Systemic Adverse Events (AEs) | Threshold for Erythema, Swelling and Induration: None (0 mm), Any (>= 1 mm). | Day 1 to Day 7 | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | The number of subjects with any unsolicited AEs from the day of vaccination in study V98_06E1 to Day 31. 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. Possibly Related AE definition: 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. Probably Related AE definition: exposure to the investigational vaccine and AE are reasonably related in time and no alternative explanation has been identified. | Day 1 to Day 31 | 
| Number of Subjects With Serious Adverse Events (SAEs), Medically Attended AEs, and AEs Leading to Study Withdrawal | An SAE is defined as any untoward medical occurrence that at any dose results in one or more of the following: Death; life-threatening; that 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; congenital anomaly/or birth defect; any important and significant medical event that may not be immediately life-threatening or resulting in death or hospitalization but, based upon appropriate medical judgement, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above. Medically attended adverse event is defined as an adverse event that leads to a visit to a healthcare provider and AEs leading to withdrawal are defined as adverse events leading to study or vaccine withdrawal. | Day 1 to Day 181 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With ELISA Antibody Concentrations of GBS Serotype Ia Above Pre-specified Thresholds - Day 31 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype Ia at Day 31 post-vaccination, as measured by ELISA. | At Day 31 | 
| Percentage of Subjects With Antibody Concentrations of GBS Serotype Ib Above Pre-specified Thresholds - Day 31 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype Ib at day 31 post-vaccination. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 31 | 
| Percentage of Subjects With Antibody Concentrations of GBS Serotype III Above Pre-specified Thresholds - Day 31 | Percentage of subjects who reach pre-defined sequential serotype-specific serum antibody levels for serotype III at day 31 post-vaccination. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 31 | 
| Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia | The Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia in All Subjects were estimated for at Day 1, Day 31 and Day 61. | At Day 1, Day 31 and Day 61. | 
| Geometric Mean Antibody Concentrations of GBS Serotype Ib | The Geometric Mean Antibody Concentrations of GBS Serotype Ib in All Subjects were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean Antibody Concentrations of GBS Serotype III | The Geometric Mean Antibody Concentrations of GBS Serotype III in All Subjects were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia in Subjects With Prevaccination Serotype-specific GBS Antibody Less Than the Lower Limit of Quantitation (LLQ) | The Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia in subjects with prevaccination serotype-specific GBS antibody less than LLQ were estimated for at Day 1, Day 31 and Day 61. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean Antibody Concentrations of GBS Serotype Ib in Subjects With Prevaccination Serotype-specific GBS Antibody Less Than LLQ | The Geometric Mean Antibody Concentrations of GBS Serotype Ib in subjects with prevaccination serotype-specific GBS antibody less than LLQ were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean Antibody Concentrations of GBS Serotype III in Subjects With Prevaccination Serotype-specific GBS Antibody Less Than LLQ | The Geometric Mean Antibody Concentrations of GBS Serotype III in subjects with prevaccination serotype-specific GBS antibody less than LLQ were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia in Subjects With Prevaccination Serotype-specific GBS Antibody Equal or Greater Than LLQ | The Geometric Mean ELISA Antibody Concentrations of GBS Serotype Ia in subjects with prevaccination serotype-specific GBS antibody equal or greater than LLQ were estimated for at Day 1, Day 31 and Day 61. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean Antibody Concentrations of GBS Serotype Ib in Subjects With Prevaccination Serotype-specific GBS Antibody Equal or Greater Than LLQ | The Geometric Mean Antibody Concentrations of GBS Serotype Ib in subjects with prevaccination serotype-specific GBS antibody equal or greater than LLQ were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean Antibody Concentrations of GBS Serotype III in Subjects With Prevaccination Serotype-specific GBS Antibody Equal or Greater Than LLQ | The Geometric Mean Antibody Concentrations of GBS Serotype III in subjects with prevaccination serotype-specific GBS antibody equal or greater than LLQ were estimated for at Day 1, Day 31 and Day 61. As the singleton ELISA was no longer in use at the time of serotypes Ib and III testing, results for both serotypes were tested using multiplex immunoassay. | At Day 1, Day 31 and Day 61 | 
| Geometric Mean ELISA Anti-Diphtheria Antibody Concentrations in All Subjects | Geometric Mean ELISA Anti-Diphtheria Antibody Concentrations (95%CI) in All Subjects at Day 1 Pre-vaccination in the V98_06 study or V98_06E1 for the Naive Group and at Day 61 Post-vaccination in Study V98_06E1. Anti-diphtheria antibody testing was not performed in this study because no diphtheria vaccine was administered in the study and also because data from other Cross Reactive Material(CRM)-based vaccines demonstrate that administration has not resulted in a decline in anti-diphtheria antibody concentrations. | At Day 1 (V98_06 or V98_06E1) and Day 61 |