Immunogenicity and Safety of GBS-NN/NN2 in Pregnant Women

Study Overview
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Brief Summary
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This is a phase II, multicentre, multinational, randomized, parallel group, placebo-controlled study of four vaccination regimens in healthy pregnant women. There will be 5 treatment groups; three groups of 60 participants will receive will receive two doses of GBS-NN/NN2 vaccine and one dose of placebo (saline); one group of 60 participants will receive one dose of GBS-NN/NN2 vaccine and two doses of placebo (saline), and one group of 60 participants will receive three doses of placebo (saline).

Detailed Description
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This is a phase II, multicentre, multinational, randomized, parallel group, placebo-controlled study of four vaccination regimens in healthy pregnant women. There will be 5 treatment groups; Group 1 will receive one injection of placebo at 22 (±1) weeks gestational age (GA), one injection of GBS-NN/NN2 at 26 (±1) weeks GA and one injection of GBS- NN/NN2 at 30 (±1) weeks GA. Group 2 will receive one injection of GBS-NN/NN2 at 22 (±1) weeks GA, one injection of GBS-NN/NN2 at 26 (±1) weeks GA and one injection of placebo at 30 (±1) weeks GA.Group 3 will receive one injection of GBS-NN/NN2 at 22 (±1) weeks GA, one injection of placebo at 26 (±1) weeks GA and one injection of GBS- NN/NN2 at 30 (±1) weeks GA. Group 4 will receive one injection of placebo at 22 (±1) weeks GA, one injection of GBS-NN/NN2 at 26 (±1) weeks GA and one injection of placebo at 30 (±1) weeks GA. Group 5 will receive an injection of placebo at 22, 26 and 30 weeks (±1) GA. Participants will attend the clinic for assessment visits up to delivery and for a further 3 visits at 28 (±4) days, 90 (±6) days and 180 (±14) days post delivery. Babies will be also be assessed at delivery, and 28 (±4) days, 90 (±6) days and 180 (±14) days post delivery.

Official Title
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A Multicentre, Multinational, Parallel Group, Observer-blind, Randomised, Placebo-controlled Study on the Group B Streptococcus Vaccine (GBS-NN/NN2), Investigating the Immunogenicity and Safety of Four Vaccination Regimens in Pregnant Woman, Assessing IgG Specific to AlpN Proteins in Cord Blood and Maternal Blood, and the Safety Profile in Mother and Infant up to 6 Months Post-delivery

Conditions
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Group B Streptococcal Infection

Intervention / Treatment
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* Biological: GBS-NN/NN2 Vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy pregnant woman above the legally defined age of consent at the time of screening Carrying a normal singleton pregnancy, and is at 21+0 to 23+6 weeks GA at the planned tme of the 1st vaccination, as established by first/second trimester ultrasound examination Properly informed about the study and has given written informed consent and parental consent (for her baby) in accordance with the International Conference on Harmonization Good Clinical Practice (ICH GCP) and local legislation prior to the first study intervention Grants access to her own and her baby's study related medical records Exclusion Criteria Previous vaccination with an investigational Group B Streptococcus (GBS) Vaccine BMI of <17 or >40 at the time of screening Human immunodeficiency virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) positive or positive for syphilis Knowingly carrying, at screening, a malformed or genetically abnormal foetus, incl. renal pelvis dilation, single umbilical artery (screening will be undertaken after the ultrasound conducted for the detection of anomalies) Chronic or pregnancy induced hypertension at screening, >1+ protein in urine regardless of blood pressure or 1+ protein in urine and hypertension Experienced a previous stillbirth prior to going into labour Gestational, type 1 or type 2 diabetes Potential placenta previa as per malformation ultrasound scan Rhesus negative and has anti-D antibodies or other potential harmful antibodies Known or suspected allergies to any components of the vaccine including to aluminium or aminoglycoside antibiotics, or an allergic reaction related to a previous vaccination Fever (temperature >37.9°C) on the day of receiving the first dose or an acute infection in the 7 days before the first dose (the first dose can be delayed if gestational age permits) Received systemic steroids in the 6 weeks before the first dose (inhaled and topical steroids are acceptable) Any lesion (including tattoos) at the planned injection site that will impair the assessment of the injection site Received immunosuppressive medication, chemotherapy or radiotherapy in the 24 weeks before the first dose Received blood, blood products, plasma derivatives or any immunoglobulin preparations in the 12 weeks before the first dose Anaemia, haemoglobin (<10 g/dL, 100 g/L, 6.2 mmol/L) Currently breast feeding Received any investigational medicinal product or vaccine in the 12 weeks or 5 half-lives before the first dose Received an approved vaccine within the 4 weeks before the first dose or expects to receive an approved vaccine during the study. Routine vaccinations recommended during pregnancy (e.g., pertussis and influenza) are permitted but every effort should be made to separate routine vaccinations from the trial vaccinations by at least 7 days. Known or suspected immunodeficiency or cancer (leukaemia, lymphoma), or a family history of congenital or hereditary immunodeficiency History or presence of uncontrolled cardiovascular disease, pulmonary, hepatic, gall bladder or biliary tract, renal, haematological, gastrointestinal, endocrine, immunologic, dermatological, neurological, psychiatric, or autoimmune disease History of, or current drug or alcohol abuse In the opinion of the investigator not suitable for inclusion in the study The pregnancy is considered high risk by treating physicians
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Participants will be randomized to one of 5 groups
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 4 week dose interval; 2 doses<br>Participants will receive one injection of placebo at 22 (±1) weeks GA, one injection of GBS-NN/NN2 at 26 (±1) weeks GA and one injection of GBS- NN/NN2 at 30 (±1) weeks GA | Biological: GBS-NN/NN2 Vaccine<br>* 0.5 mL GBS-NN/NN2 containing 50 μg of GBS-NN and 50 μg of GBS-NN2 and 0.5 mg of aluminium, given by intramuscular injection.<br>Biological: Placebo<br>* 0.5 mL normal saline given by intramuscular injection<br>* Other names: Normal saline;|
| Experimental: Group 2: early intervention; 4 week dose interval; 2 doses<br>Participants will receive one injection of GBS-NN/NN2 at 22 (±1) weeks GA, one injection of GBS-NN/NN2 at 26 (±1) weeks GA and one injection of placebo at 30 (±1) weeks GA | Biological: GBS-NN/NN2 Vaccine<br>* 0.5 mL GBS-NN/NN2 containing 50 μg of GBS-NN and 50 μg of GBS-NN2 and 0.5 mg of aluminium, given by intramuscular injection.<br>Biological: Placebo<br>* 0.5 mL normal saline given by intramuscular injection<br>* Other names: Normal saline;|
| Experimental: Group 3: early intervention; 8 week dose interval; 2 doses<br>Participants will receive one injection of GBS-NN/NN2 at 22 (±1) weeks GA, one injection of placebo at 26 (±1) weeks GA and one injection of GBS- NN/NN2 at 30 (±1) weeks GA | Biological: GBS-NN/NN2 Vaccine<br>* 0.5 mL GBS-NN/NN2 containing 50 μg of GBS-NN and 50 μg of GBS-NN2 and 0.5 mg of aluminium, given by intramuscular injection.<br>Biological: Placebo<br>* 0.5 mL normal saline given by intramuscular injection<br>* Other names: Normal saline;|
| Experimental: Group 4: single dose<br>Participants will receive one injection of placebo at 22 (±1) weeks GA, one injection of GBS-NN/NN2 at 26 (±1) weeks GA, and one injection of placebo at 30 (±1) weeks GA. | Biological: GBS-NN/NN2 Vaccine<br>* 0.5 mL GBS-NN/NN2 containing 50 μg of GBS-NN and 50 μg of GBS-NN2 and 0.5 mg of aluminium, given by intramuscular injection.<br>Biological: Placebo<br>* 0.5 mL normal saline given by intramuscular injection<br>* Other names: Normal saline;|
| Placebo Comparator: Group 5: placebo<br>Participants will receive one injection of placebo at 22, 26 and 30 weeks (±1) GA | Biological: Placebo<br>* 0.5 mL normal saline given by intramuscular injection<br>* Other names: Normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of Immunoglobulin (Ig) G antibodies specific to the AlpN proteins in μg/mL in cord blood from each baby | Concentrations of IgG antibodies specific to the AlpN proteins in μg/mL in cord blood from each baby | Delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Injection site reactions in the mother | Number of participants with solicited injection site reactions following vaccination | To Day 84 | 
| Adverse events following the vaccinations in the mother | Number of participants with solicited and other adverse events following the vaccinations | To Day 84 | 
| Clinically significant abnormal laboratory tests in the mother | Number of participants with clinically significant abnormal laboratory tests in the mother | To Day 84 | 
| Clinically significant changes in vital signs in the mother | Number of participants with clinically significant changes in vital signs (heart rate,blood pressure, oral temperature) in the mother | To Day 84 | 
| Clinically significant changes in physical examination in the mother | Number of participants with clinically significant changes in physical examination in the mother | To Day 84 | 
| Gestational weight in the baby | Gestational weight in the baby | Delivery, 28 days, 90 days and 180 days post delivery. | 
| Weight in the baby | Weight in the baby | Delivery, 28 days, 90 days and 180 days post delivery. | 
| Length in the baby | Length in the baby | Delivery, 28 days, 90 days and 180 days post delivery. | 
| Head circumference in the baby | Head circumference in the baby | Delivery, 28 days, 90 days and 180 days post delivery. | 
| Apgar score in the baby | Apgar score in the baby, range 0 to 10 where high scores are good and low scores are bad | 1, 5 and 10 minutes | 
| Developmental milestones in the baby using Ages & Stages questionnaire | Developmental milestones in the baby using Ages & Stages questionnaire | 6 months | 
| Concentrations of IgG antibodies specific to the AlpN proteins in μg/mL in maternal blood | Concentrations of IgG antibodies specific to the AlpN proteins in μg/mL in maternal blood | Delivery | 
| Concentrations of IgG antibodies specific to the AlpN proteins in μg/mL in blood from each baby | Concentrations of IgG antibodies specific to the AlpN proteins in μg/mL in blood from each baby | 1 month, 3 months |