Safety and Immunogenicity of Simultaneous Tdap and IIV in Pregnant Women

Study Overview
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Brief Summary
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This is a pilot, prospective, randomized, open-label clinical trial. During the study, pregnant women will be randomized (1:1) to receive co-administration of a single intramuscular (IM) 0.5 mL dose of US-licensed inactivated influenza vaccine (IIV) and a single intramuscular (IM) 0.5 mL dose of US-licensed Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap) or sequential administration of the vaccines (IIV followed by Tdap   21 days later). Vaccines will be administered by licensed study personnel. Prior Tdap/Td/TT and influenza vaccine history will be verified by medical record review when possible. Injection-site (local) and systemic reaction data will be assessed on vaccination day and during the 7 days following vaccination using either identical web-based or paper diaries, depending on study participant preference. Maternal serum samples will be collected for antibody titers relevant to the Tdap and Influenza at time points that include: prior to vaccination(s),  21 days post vaccination(s), and at delivery. Additionally, cord blood serum will be analyzed for the same antibody titers. Pregnant women will be followed with comprehensive obstetric and neonatal outcomes obtained from medical record review.

Official Title
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A Prospective, Randomized, Open-label Clinical Trial to Assess the Safety and Immunogenicity of Simultaneous vs Sequential Administration of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine and Inactivated Influenza Vaccine in Pregnant Women - Pilot

Conditions
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Pregnancy

Intervention / Treatment
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* Biological: Tetanus, Diphtheria, and Pertussis Vaccine
* Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine
* Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant, as determined by medical history; 18 - 45 years of age inclusive Intention of receiving Tdap and IIV vaccines based on Advisory Committee on Immunization Practices (ACIP) recommendations Willing to provide written informed consent prior to initiation of any study procedures Singleton gestation ≥ 26 weeks 0 days gestation - ≤32 weeks 0 days gestation at the time of Visit 1 vaccination based on reconciliation of last menstrual period and ultrasound dating. Estimated due date (EDD) and Gestational Age (GA) - EDD will be based on reconciliation of a sure first day of the last menstrual period (LMP) and earliest dating ultrasound. If the LMP is uncertain, then the earliest dating ultrasound will be used to determine EDD and GA. If the ultrasound derived-EDD is in agreement with sure-LMP derived EDD, then the LMP-derived EDD is used to determine GA. If the ultrasound derived EDD is not in agreement with the LMP-derived EDD, the ultrasound-derived EDD is used to determine GA. English or Spanish literate Intention of being available for entire study period and complete all relevant study procedures, including follow-up phone calls and collection of delivery information. Exclusion Criteria: For subjects enrolling during the 2016-2017 influenza season: IIV/LAIV receipt during 2016-2017 influenza season prior to study enrollment For subjects enrolling during the 2017-2018 influenza season: IIV/LAIV receipt during 2017-2018 influenza season prior to study enrollment 2. Tdap/Td/TT receipt during current pregnancy prior to study enrollment 3. Has immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months. 4. Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (daily low dose aspirin may be acceptable). 5. Has a history of receiving immunoglobulin or other blood product (with exception of Rhogam) within the 3 months prior to enrollment in this study. 6. Known to have pre-existing diabetes mellitus or an autoimmune disorder. 7. Febrile illness within the last 24 hours or an oral temperature >/= 100.4°F (>/= 38.0°C) prior to IIV or Tdap administration 8. Contraindication to IIV receipt including history of severe allergic reaction after a previous dose of any influenza vaccine; or to a vaccine component, including egg protein 9. Contraindication to Tdap receipt including history of severe allergic reaction after a previous dose of any tetanus toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine or encephalopathy within 7 days of administration of a previous dose of a pertussis antigen-containing vaccine that is not attributable to another identifiable cause 10. Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoid-containing vaccine within the last 10 years 11. Any condition that may interfere with assessment of local injection site reactions, e.g. lymphadenectomy or obscuring tattoos 12. History of Guillain-Barré syndrome within 6 weeks of a prior dose of any tetanus toxoid-, diphtheria toxoid- or pertussis antigen-containing vaccine or influenza vaccine 13. Known or suspected impairment of immunologic function including infection with HIV, hepatitis B or C 14. Use of immunosuppressive or cytotoxic drugs except receipt of oral or parenteral (intravenous, subcutaneous or intramuscular) corticosteroids 30 or more days prior to enrollment. Persons who have used oral or parenteral corticosteroids within 12 months prior to enrollment may be enrolled if the longest course of therapy was less than 14 consecutive days and no dose was given within 30 days of enrollment. Intraarticular, bursal, tendon, or epidural injections of corticosteroids are permissible if the most recent injection was 30 or more days prior to enrolment. Persons applying topically corticosteroid in either upper arm (i.e. injection site) may be enrolled 1 or more days after their therapy is completed. Corticosteroids administered topically at non-injection sites, by inhalation or intranasally are permissible 15. Receipt of any licensed vaccine within 14 days prior to study vaccination or planning receipt of any vaccines (except study vaccines) prior to Visit 7 follow up. 16. Receipt of live vaccine during current pregnancy. 17. High risk for preterm birth (active preterm labor, short cervix, cervical cerclage, receipt of antenatal corticosteroids for fetal lung maturity prior to Visit 1) 18. Antenatal ultrasound diagnosis of fetal growth restriction, defined as < 10th percentile estimated fetal weight for gestational age 19. Known fetal congenital anomaly, e.g. genetic abnormality or malformation based on antenatal ultrasound 20. Any condition which, in the opinion of the investigators, may pose a health risk to the subject or interfere with the evaluation of the study objectives. 21. Anyone who is a relative of any research study personnel 22. Anyone who is an employee of any research study personnel 23. Anyone who is already enrolled or plans to enroll in another clinical trial with an investigational product. Co-enrollment in observational or behavioral intervention studies are allowed at any time. 24. Previous participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Simultaneous vaccination arm<br>In the study arm,subjects will receive both Tdap and IIV vaccines during study visit 1. | Biological: Tetanus, Diphtheria, and Pertussis Vaccine<br> <br> * Other names: Tdap;Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine<br> <br> * Other names: 2016-2017 Flu vaccine;Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine<br> <br> * Other names: 2017-2018 Flu vaccine;|
| Other: Sequential vaccination arm<br>In this study arm, subjects will receive the IIV vaccine during study visit 1. Approximately 3 weeks later, they will receive the Tdap vaccine during study visit 4. | Biological: Tetanus, Diphtheria, and Pertussis Vaccine<br> <br> * Other names: Tdap;Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine<br> <br> * Other names: 2016-2017 Flu vaccine;Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine<br> <br> * Other names: 2017-2018 Flu vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Injection-site Reactions Post Tdap and IIV4 Administration | Percentage of injection-site reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid | 8 days post vaccine administration | 
| Percentage of Participants With Systemic Reactions Post Tdap and IIV4 Administration - Visit 1 | Percentage of systemic reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid | 8 days post vaccine administration | 
| Percentage of Participants With Systemic Reactions Post Tdap and IIV4 Administration - Visit 4 | Percentage of systemic reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid | 8 days post vaccine administration | 
| Pertussis Serum Antibody Levels, as Measured by Geometric Mean Titers | Measurement of serum antibody levels to pertussis antigens, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery | Pre-vaccination and approximately 21 days post vaccination and at Delivery | 
| Percentage of Subjects With Seroprotection as Determined by Diphtheria Serum Antibody Levels (Defined as ≥ 0.1 IU/mL) | Measurement of serum antibody levels to diphtheria toxoids, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery | Pre vaccination and approximately 21 days post vaccination and at Delivery | 
| Percentage of Subjects With Seroprotection as Determined by Tetanus Serum Antibody Levels (Defined as ≥ 0.1 IU/mL) | Measurement of serum antibody levels to tetanus toxoids, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery | 21 days post vaccination | 
| Percentage of Subjects With Seroprotection as Determined by Influenza Serum Antibody Levels (≥1:40) (Pre- and Post-immunization) and Seroconversion (4-fold Rise From Baseline or a Change From <1:10 to ≥1:40) ) | Measurement of serum antibody levels to influenza antigens in maternal blood and infant cord blood obtained at delivery | Pre and 21 days post vaccination and at Delivery | 
| Percentage of Subjects Recruited Enrollment Period | Percentage of subjects recruited during 4 month enrollment period | Approximately 1 year | 
| Feasibility as Measured by Participant Retention (Percentage of Participants Who Complete All Visits) | Percentage of participants that completed all in-person and delivery visits | Approximately 1 year | 
| Feasibility Reported as Percentage of Reactogenicity Data Collected | Percentage of reactogenicity data days reported (days reported / total possible days) | Approximately 1 year | 
| Feasibility Reported as Percentage of Adequate Biospecimens Collected | Percentage of samples collected (sample timepoints collected / total possible sample timepoints) | Approximately 1 year | 
| Feasibility Reported as Percentage of Timely Collected Biospecimens | Timeliness is defined as collected within the visit window | Approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Maternal Outcomes | The number of participants with adverse maternal outcomes at delivery. Missing data is data not collected or unavailable. | Up to the 6-week postpartum visit | 
| Number of Participants With Adverse Infant Outcomes Based on Medical Record Review | Number of participants with adverse infant outcomes. Missing data is data not collected or unavailable. | approximately 2 months | 
| Percentage of Participants With Clinical Chorioamnionitis | Percentage of participants with clinical chorioamnionitis | at the time of delivery | 
| Percentage of Participants With Histologic Chorioamnionitis on Surgical Pathology Examination of Placental Tissue | Percentage of participants with histologic chorioamnionitis on surgical pathology examination of placental tissue | after delivery, approximately up to 2 weeks | 
| Feasibility as Measured by Percentage of Blood Samples in Testable Condition | Percentage of blood samples received in testable condition (sufficient volume and quality) | Approximately 1 year | 
| Feasibility as Measured by Percentage of Blood Samples in With Sufficient Volume for Testing | Percentage of blood samples received with sufficient volume for testing | Approximately 1 year | 
| Feasibility as Measured by Percentage of Testable Blood Samples Completed | Percentage of testable (sufficient volume and quality) blood samples completed | Approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tdap vaccine, Flu vaccine, vaccines in pregnancy, immunizations in pregnancy, Whooping Cough, Pertussis, Influenza