Safety and Immunogenicity of a Trivalent Group B Streptococcus Vaccine in Healthy Pregnant Women

Study Overview
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Brief Summary
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Evaluate the safety and immunogenicity of the trivalent group B streptococcus vaccine in healthy pregnant women. The study will also evaluate the levels of GBS serotype-specific antibodies in infants, placental transfer from the pregnant women to the infant and levels of antibodies in the breast milk.

Official Title
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A Phase II, Multicenter, Randomized, Observer-Blind, Controlled Study to Evaluate Safety and Immunogenicity of a Trivalent Group B Streptococcus Vaccine in Healthy Pregnant Women

Conditions
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GBS Disease, Streptococcus Agalactiae

Intervention / Treatment
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* Biological: GBS trivalent vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy pregnant women 18-40 years of age, inclusive and at 24 0/7 through 34 6/7 weeks gestation. Individuals who intend to breastfeed for at least 90 days postpartum. Individuals who have given written consent after the nature of the study has been explained according to local regulatory requirements. Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator. Individuals who can comprehend and comply with all study procedures and are available for follow-up. Exclusion Criteria: Individuals with history of illness or an ongoing illness that, in the opinion of the investigator, may pose additional risk to the subject if she participates in the study. Individuals with known hypersensitivity to any component of the vaccine. Individuals who received or plan to receive any licensed vaccine within 14 days before or after the study vaccine with the exception of inactivated influenza vaccine which may be administered up to 7 days before or after study vaccine. Individuals with an infection requiring systemic antibiotic or antiviral treatment within 7 days prior to Study Day 1. Individuals determined as high risk for serious obstetrical complication, including: Gestational hypertension, as defined by American College of Obstetricians and Gynecologists guidelines (ACOG Practice Bulletin 2012) Gestational diabetes which is not controlled by diet and exercise as per American College of Obstetricians and Gynecologists guidelines (ACOG Practice Bulletin 2013) Pre-eclampsia or eclampsia as defined by American College of Obstetricians and Gynecologists guidelines (ACOG practice bulletin, 2002) HIV infection Obesity class II or greater (pre-pregnancy BMI≥35.0) multiple pregnancy Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the study. Individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study. Individuals with known or suspected impairment of the immune system including known or suspected HIV infection or HIV-related disease, a history of or an active autoimmune disorder and receipt of immunosuppressive therapy. Long term use of glucocorticoids, including oral or parenteral prednisone ≥ 20 mg/day or equivalent for more than 2 consecutive weeks (or 2 weeks total) within 30 days prior to enrollment. Use of inhaled, intranasal, or topical corticosteroids is allowed. Individuals participating in any clinical trial with another investigational product during the pregnancy or intent to participate in another clinical study at any time during the conduct of this study. Pregnant with a fetus with a known or suspected congenital anomaly Individuals who are acting as study personnel or immediate family members (brother, sister, child, parent) or the spouse of study personnel. Individuals with a fever (oral temperature ≥ 38°C/100.4 °F) within 3 days prior to intended study vaccination. Individuals with a history of culture confirmed GBS case in the infant(s) previously born to her.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GBS Group<br>Healthy pregnant women, between and including 18-40 years of age, at 24 0/7 through 34 6/7 weeks of gestation, with the intent to breastfeed, who received a single dose of Group B Streptococcus (GBS) trivalent vaccine, injected intramuscularly. (Pregnant women are referred to as maternal subjects as the study period spans from pregnancy to Day 180 postpartum). | Biological: GBS trivalent vaccine<br>* Intramuscular injection - Liquid formulation of a vaccine containing polysaccharide capsules from serotypes Ia, Ib, and III of the Group B Streptococcus and conjugated to the Corynebacterium diphtheriae CRM197 carrier protein<br>|
| Active Comparator: Placebo Group<br>Healthy pregnant women, between and including 18-40 years of age, at 24 0/7 through 34 6/7 weeks of gestation, with the intent to breastfeed, who received a single dose of Placebo, injected intramuscularly. (Pregnant women are referred to as maternal subjects as the study period spans from pregnancy to Day 180 postpartum). | Biological: Placebo<br>* Intramuscular injection - Normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Serotype Ia GBS IgG Levels in Infant Serum at Delivery and at Days 42 and 90 of Age | To evaluate serotype-specific Ia GBS serum IgG antibody levels (anti-Ia) in infants born to maternal subjects receiving the GBS trivalent vaccine, as measured at birth, Day 42 and Day 90 of age. Antibody concentrations were measured by Enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). | At Birth, Day 42 and Day 90 | 
| Concentration of Serotype Ib GBS IgG Levels in Infant Serum at Delivery and at Days 42 and 90 of Age | To evaluate serotype-specific Ib GBS serum IgG antibody levels (anti-Ib) in infants born to maternal subjects receiving the GBS trivalent vaccine, as measured at birth, Day 42 and Day 90 of age. 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 Birth, Day 42 and Day 90 | 
| Concentration of Serotype III GBS IgG Levels in Infant Serum at Delivery and at Days 42 and 90 of Age | To evaluate serotype-specific III GBS serum IgG antibody levels (anti-III) in infants born to maternal subjects receiving the GBS trivalent vaccine, as measured at birth, Day 42 and Day 90 of age. 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 Birth, Day 42 and Day 90 | 
| Concentration of Serotype Ia GBS IgG Levels in Maternal Serum at Pre-vaccination, at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | To evaluate serotype-specific (Ia) GBS serum IgG antibody levels (anti-Ia) in maternal subjects. Antibody concentrations were measured by Enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). | At Day 1 (pre-vaccination), Day 31 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 
| Concentration of Serotype Ib GBS IgG Levels in Maternal Serum at Pre-vaccination, at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | To evaluate serotype-specific (Ib) GBS serum IgG antibody levels (anti-Ib) in maternal subjects. 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 (pre-vaccination), Day 31 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 
| Concentration of Serotype III GBS IgG Levels in Maternal Serum at Pre-vaccination, at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | To evaluate serotype-specific (III) GBS serum IgG antibody levels (anti-III) in maternal subjects. 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 (pre-vaccination), Day 31 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 
| Ratio Relative to Pre-vaccination Levels of Maternal Serum GBS IgG Antibody Levels - Serotype Ia, as Measured at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | Geometric Mean Ratio relative to pre-vaccination (Day 1) of serotype-specific (Ia) GBS serum IgG antibody concentrations (anti-Ia) in maternal subjects. Antibody concentrations were measured by Enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). | At Day 31 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 
| Ratio Relative to Pre-vaccination Levels of Maternal Serum GBS IgG Antibody Levels - Serotype Ib, as Measured at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | Geometric Mean Ratio relative to pre-vaccination (Day 1) of serotype-specific (Ib) GBS serum IgG antibody concentrations (anti-Ib) in maternal subjects. 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 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 
| Ratio Relative to Pre-vaccination Levels of Maternal Serum GBS IgG Antibody Levels - Serotype III, as Measured at Study Day 31, at Delivery and at Days 42 and 90 Postpartum | Geometric Mean Ratio relative to pre-vaccination (Day 1) of serotype-specific (III) GBS serum IgG antibody concentrations (anti-III) in maternal subjects. 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 (post-vaccination), Delivery, Days 42 and 90 (postpartum) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of GBS IgG Antibody Levels - Serotype Ia in Infant Serum Relative to Maternal Serum at the Time of Delivery | To evaluate the relationship of serotype-specific Ia GBS IgG antibody levels (anti-Ia) in the infant serum to the GBS IgG antibody levels in the maternal serum at the time of delivery/birth. Antibody concentrations were measured by Enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). | At Delivery | 
| Ratio of GBS IgG Antibody Levels - Serotype Ib in Infant Serum Relative to Maternal Serum at the Time of Delivery | To evaluate the relationship of serotype-specific Ib GBS IgG antibody levels (anti-Ib) in the infant serum to the GBS IgG antibody levels in the maternal serum at the time of delivery/birth. 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 Delivery | 
| Ratio of GBS IgG Antibody Levels - Serotype III in Infant Serum Relative to Maternal Serum at the Time of Delivery | To evaluate the relationship of serotype-specific III GBS IgG antibody levels (anti-III) in the infant serum to the GBS IgG antibody levels in the maternal serum at the time of delivery/birth. 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 Delivery | 
| Percentage of Maternal Subjects With Solicited Local and Solicited Systemic Adverse Events (AEs) up to 30 Minutes | Percentage and frequency of maternal subjects with solicited local and solicited systemic AEs up to Study Day 7 and calculated for four time intervals after vaccination: 30 minutes, Study Days 1-3 (without 30 min), Study Days 4-7, Study Days 1-7 (without 30 min). Threshold for Ecchymosis, Erythema, Swelling and Induration: Grade 0 (<25 mm), Any (≥ 25 mm). Systemic fever includes subjects with body temperature ≥ 38 °C irrespective of route of measurement. | Up to 30 minutes post-vaccination | 
| Percentage of Maternal Subjects With Solicited Local and Solicited Systemic AEs - Study Days 1-3 | Percentage and frequency of maternal subjects with solicited local and solicited systemic AEs up to Study Day 7 and calculated for four time intervals after vaccination: 30 minutes, Study Days 1-3 (without 30 min), Study Days 4-7, Study Days 1-7 (without 30 min). Threshold for Ecchymosis, Erythema, Swelling and Induration: Grade 0 (<25 mm), Any (≥ 25 mm). Systemic fever includes subjects with body temperature ≥ 38 °C irrespective of route of measurement. | During Study Days 1-3 (from 6 hours through Day 3 post-vaccination) | 
| Percentage of Maternal Subjects With Solicited Local and Solicited Systemic AEs - Study Days 4-7 | Percentage and frequency of maternal subjects with solicited local and solicited systemic AEs up to Study Day 7 and calculated for four time intervals after vaccination: 30 minutes, Study Days 1-3 (without 30 min), Study Days 4-7, Study Days 1-7 (without 30 min). Threshold for Ecchymosis, Erythema, Swelling and Induration: Grade 0 (<25 mm), Any (≥ 25 mm). Systemic fever includes subjects with body temperature ≥ 38 °C irrespective of route of measurement. | During Study Days 4-7 | 
| Percentage of Maternal Subjects With Solicited Local and Solicited Systemic AEs - Study Days 1-7 | Percentage and frequency of maternal subjects with solicited local and solicited systemic adverse events up to Study Day 7 and calculated for four time intervals after vaccination: 30 minutes, Study Days 1-3 (without 30 min), Study Days 4-7, Study Days 1-7 (without 30 min). Threshold for Ecchymosis, Erythema, Swelling and Induration: Grade 0 (<25 mm), Any (≥ 25 mm). Systemic fever includes subjects with body temperature ≥ 38 °C irrespective of route of measurement. | During Study Days 1-7 (from 6 hours through Day 7 post-vaccination) | 
| Percentage of Maternal Subjects With Any Unsolicited AEs | An 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 inter-current illnesses or injuries and exacerbation of pre-existing conditions. | From Study Day 1 through Study Day 31 | 
| Percentage of Maternal Subjects With Serious Adverse Events (SAEs), Unsolicited Medically Attended AEs (MAEs) and Unsolicited AEs Leading to Study Withdrawal (AEs Lead. Wthwal) | 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. An MAE is defined as an adverse event that leads to an unscheduled visit to a healthcare practitioner. | From Study Day 1 through Study Day 31 | 
| Percentage of Maternal Subjects With SAEs, Unsolicited MAEs and Unsolicited AEs Leading to Study Withdrawal (AEs Lead. Wthwal) | 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. An MAE is defined as an adverse event that leads to an unscheduled visit to a healthcare practitioner. | From Study Day 32 through Day 180 postpartum | 
| Percentage of Infants With SAEs, Unsolicited MAEs 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. An MAE is defined as an adverse event that leads to an unscheduled visit to a healthcare practitioner. | From Birth through Day 180 of age | 
| Birth Weight of Infants (Mean-Standard Deviation) | Weight at birth was summarized by reporting the mean and standard deviation, | At Birth | 
| Birth Weight of Infants (Median, Minimum and Maximum) | Weight at birth was summarized by reporting the median and the minimum and maximum. | At Birth | 
| Birth Length and Head Circumference of Infants (Mean - Standard Deviation) | Length and head circumference at birth were summarized by reporting the mean and standard deviation. | At Birth | 
| Birth Length and Head Circumference of Infants (Median - Minimum and Maximum) | Length and head circumference at birth were summarized by reporting the median and minimum and maximum | At birth | 
| Infants Apgar Scores (Mean - Standard Deviation) | Apgar (Appearance, Pulse, Grimace response, Activity and Respiration) test to evaluate the new-born's physical condition. Apgar score between 0 and 10 (highest score possible). If 1 and 5 minutes Apgar score were normal, 10 minutes Apgar score might not be required. | At 1, 5 and 10 minutes | 
| Infants Apgar Scores (Median, Minimum and Maximum) | Apgar (Appearance, Pulse, Grimace response, Activity and Respiration) test to evaluate the new-born's physical condition. Apgar scores between 0 and 10 (highest score possible). If 1 and 5 minutes Apgar score were normal, 10 minutes Apgar score might not be required. | At 1, 5 and 10 minutes | 
| Descriptive Statistics for the Score for the Long-term Developmental Outcome Assessed by Bayley Scales of Infant and Toddler Development 3rd Edition Screening Test (PsychCorp) in Infants (Mean - Standard Deviation) | Long-term developmental outcome assessed by Bayley Scales of Infant and Toddler Development 3rd edition Screening Test (PsychCorp). The screening test measured three domains: cognitive, language (receptive vs expressive communication), and motor (fine vs gross). Scaled scores range from 1 to 19 with a mean of 10 and a standard deviation of 3. The scores were summarized by reporting the mean and standard deviation. | At Day 180 of age | 
| Descriptive Statistics for the Score for the Long-term Developmental Outcome Assessed by Bayley Scales of Infant and Toddler Development 3rd Edition Screening Test (PsychCorp) in Infants (Median, Minimum and Maximum) | Long-term developmental outcome assessed by Bayley Scales of Infant and Toddler Development 3rd edition Screening Test (PsychCorp). The screening test measured three domains: cognitive, language (receptive vs expressive communication), and motor (fine vs gross). Scaled scores range from 1 to 19 with a mean of 10 and a standard deviation of 3. The scores were summarized by reporting the median, minimum and maximum. | At Day 180 of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IgG, Maternal vaccine, IgA, GBS, pregnant women