Maternal Determinants of Infant Immunity to Pertussis

Study Overview
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Brief Summary
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The overall objective of the project is to identify the determinants of antibody-mediated immunity in infants born to mothers immunized during pregnancy. Using maternal pertussis immunization as a model, the project will identify key predictors and potential determinants of vaccine responses in pregnant women, of the transfer of maternal antibodies to the newborn and of vaccine responses in infants. A systems biology approach will be used to delineate pre-vaccination and post-vaccination cellular and molecular correlates of the immune response to pertussis immunization in peripheral blood and in breastmilk.

Detailed Description
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The overall objective of the project is to identify the determinants of antibody-mediated immunity to pertussis in infants born to mothers immunized during pregnancy. Three specific objectives will be targeted: Determine the impact of pregnancy on the quality of antibody response to pertussis immunization and identify immune predictors of vaccine responses in pregnant and non-pregnant women. Identify immune predictors of the transfer of maternal antibodies to the newborn and the presence of antibody in breastmilk following pertussis immunization during pregnancy. Determine the impact of maternal antibodies on the quality of antibody response to pertussis immunization in infants born to mothers immunized or not immunized during pregnancy and identify immune predictors of vaccine responses in the first months of life. To reach these objectives, 40 non-pregnant and 80 pregnant women will be recruited into the study and vaccinated with a single dose of a pertussis containing vaccine (Boostrix). Blood samples will be collected from: non-pregnant women: before vaccination, and day 1/7/28 and month 5 post-vaccination. pregnant women: before vaccination, day 1/7/28 post-vaccination, at delivery, and week 6/12 post-delivery. At week 6/12 post-delivery, breast milk samples will be collected as well. In addition, infants 2-3 months old born either from mothers who were not vaccinated against pertussis during pregnancy (n=40) or born from mothers who were vaccinated against pertussis during pregnancy (n=80) will be recruited in the study. Infants will be vaccinated with three doses of a pertussis containing vaccine (Hexyon), each one month apart starting from 2-3 months of age. Blood samples will be collected from: infants from vaccinated mothers: cord blood, before 1st vaccine dose, day 1 post 1st vaccine dose, before 3rd vaccine dose, and day 28 post 3rd vaccine dose. infants from unvaccinated mothers: before 1st vaccine dose, day 1 post 1st vaccine dose, before 3rd vaccine dose, and day 28 post 3rd vaccine dose.

Official Title
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Maternal Determinants of Infant Immunity to Pertussis

Conditions
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Vaccination; Infection, Maternal-Fetal Relations, Pertussis, Immunoglobulins

Intervention / Treatment
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* Biological: Boostrix® (Pertussis-containing vaccine)
* Biological: Hexyon® (Pertussis-containing vaccine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For non-pregnant & pregnant women Age between 18 and 45 years Eligible for Tdap vaccination For infants Born to mothers vaccinated or not with Tdap Vaccinated with hexavalent vaccine Age between 2 and 3 months Exclusion Criteria: For pregnant and non-pregnant women Inability to understand the nature and extent of the study and the procedures required Grade III/IV anemia, Acute infection at the time of immunization Chronic infections such as Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) infection, acute toxoplasmosis Current or recent use of immunosuppressive drugs Active neoplasia Other vaccine(s) administered at the same time as Tdap vaccination (wash out of 3 weeks after others vaccinations and 28 days after Tdap vaccination ) For pregnant women Risk of premature delivery or intrauterine growth retardation Twin or triplet pregnancies For non-pregnant women Last Tdap vaccination < 12 months before For infants: Infants born before 35 weeks of gestation Birthweight below 2.5 kg, Severe neonatal distress Serious congenital abnormalities or congenital infection.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Non pregnant and pregnant women will be recruited in parallel Infants born to Tdap vaccinated-mothers (enrolled or not in the study) or not vaccinated mothers will be recruited
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pregnant women<br>Pregnant women will receive one dose of Pertussis-containing vaccine during pregnancy. | Biological: Boostrix® (Pertussis-containing vaccine)<br>* Boostrix® (Pertussis-containing vaccine) will be administered: in non-pregnant women presenting to the Travel and Vaccine clinic for pertussis immunization only or hospital member staff requiring Tetanus Toxoid (TT)-booster immunisation in Pregnant women between 16 and 29 weeks of gestation.<br>|
| Active Comparator: Non pregnant women<br>Non-Pregnant women will receive one dose of Pertussis-containing vaccine. | Biological: Boostrix® (Pertussis-containing vaccine)<br>* Boostrix® (Pertussis-containing vaccine) will be administered: in non-pregnant women presenting to the Travel and Vaccine clinic for pertussis immunization only or hospital member staff requiring Tetanus Toxoid (TT)-booster immunisation in Pregnant women between 16 and 29 weeks of gestation.<br>|
| Active Comparator: Infants born to Tdap-vaccinated mothers<br>Infants whose mothers have been immunized during pregnancy with Tdap vaccine. Infants will receive three doses of Pertussis-containing vaccine (with 28 days interval starting at two months of age). | Biological: Hexyon® (Pertussis-containing vaccine)<br>* Hexyon ® (Hexavalent vaccine) will be proposed in infants at 8, 12 and 16 weeks of life.<br>|
| Active Comparator: Infants born to non Tdap-vaccinated mothers<br>Infants whose mothers have not been immunized during pregnancy with Tdap vaccine. Infants will receive three doses of Pertussis-containing vaccine (with 28 days interval starting at two months of age). | Biological: Hexyon® (Pertussis-containing vaccine)<br>* Hexyon ® (Hexavalent vaccine) will be proposed in infants at 8, 12 and 16 weeks of life.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG titers specific to Bordetella Pertussis Antigens by Enzyme-linked immunosorbent assay (ELISA) | IgG titers specific to Bordetella Pertussis Antigens will be assessed by ELISA: in women (pregnant and non-pregnant) at 28 days post vaccination in infants (from unvaccinated mothers and mothers vaccinated during pregnancy) at 28 days post third vaccine dose | Day 28 post-vaccination | 
| IgG titers specific to Bordetella Pertussis Antigens by Enzyme-linked immunosorbent assay (ELISA) | IgG titers specific to Bordetella Pertussis Antigens will be assessed by ELISA: in women vaccinated during pregnancy, at delivery in umbilical cord blood of infants born to mothers vaccinated during pregnancy | At delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG titers specific to Bordetella Pertussis Antigens by Enzyme-linked immunosorbent assay (ELISA) | IgG titers specific to Bordetella Pertussis Antigens will be assessed by ELISA: in pregnant women (PW): at day of vaccination , day 7 post-vaccination, week 6 and 12 post-delivery in non-pregnant women (non PW): at day of vaccination, day 7 and Month 5 post-vaccination in infants (from unvaccinated mothers and mothers vaccinated during pregnancy) at day of first and third vaccine dose | up to 9 month after vaccination | 
| CD4+ T cell frequencies specific to Bordetella Pertussis Antigens by flow cytometry | The percentage of CD4+ T cells expressing any of the following biomarkers (CD154, Interferon gamma, IL-2) in response to in vitro stimulation with Bordetella Pertussis Antigens will be measured by flow cytometry: i. in pregnant and non-pregnant women: at day of vaccination, and day 28 post vaccination ii. in infants (from unvaccinated mothers and mothers vaccinated during pregnancy) at day of first vaccine dose and 28 days after third vaccine dose | up to 9 month after vaccination |