Safety of RIV4 Versus IIV4 in Pregnant Women

A Prospective, Randomized, Clinical Trial to Compare Adverse Birth Outcomes in Pregnant Women Receiving Quadrivalent Recombinant Influenza Vaccine (RIV4) Versus Quadrivalent Inactivated Influenza Vaccine (IIV4)

This is a prospective, randomized clinical trial. During the study, pregnant women will be randomized (1:1) to receive RIV4 or IIV4. Vaccines will be administered by licensed providers.

Prior 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 8 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 Influenza at time points that include: prior to vaccination and ~29 days post vaccination. When feasible, maternal blood at delivery and cord blood serum will be analyzed for the same antibody titers.

Pregnant women will be followed through delivery with comprehensive obstetric and neonatal outcomes obtained from medical record review for 90 days of life.

Study Overview

• Status: Completed
• Conditions: Safety; Birth Outcomes; Adverse Event Following Immunisation
• Intervention / Treatment: Biological: Quadrivalent Recombinant Influenza Vaccine; Biological: Quadrivalent Inactivated Influenza Vaccine

• Study Type: Interventional
• Enrollment (Actual): 384
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Pregnant, as determined by medical history
2. Age ≥ 18 years of age at enrollment
3. Intention of receiving influenza vaccine based on ACIP-CDC guidelines
4. Willing to provide written informed consent prior to initiation of any study procedures
5. Gestational age at vaccination ≤ 34 weeks 0 days 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 "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.
6. English or Spanish literate
7. 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:

1. Influenza vaccine receipt during 2019-2020 or 2020-2021 influenza season prior to study enrollment.
2. Participation in this study in 2019-2020 influenza season
3. Any condition that may interfere with assessment of local injection site reactions, e.g. obscuring tattoos
4. Known or suspected immunosuppression as a result of an underlying illness or treatment
5. Use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months
6. Use of oral or parenteral corticosteroids (≥ 20mg/day prednisone equivalent) or high-dose inhaled glucocorticoid for ≥ 14 consecutive days within the preceding 30 days
7. Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (a daily aspirin is acceptable)
8. Has a history of receiving immunoglobulin or other blood product (with exception of Rh immunoglobulin) within the 3 months prior to study vaccination.
9. History of febrile illness (> 100.4°F or 38°C) within the past 24 hours prior to study vaccination
10. Contraindication to IIV or RIV receipt including history of severe allergic reaction after a previous dose of any influenza vaccine; or to a vaccine component, including egg protein
11. History of Guillain-Barré syndrome within 6 weeks of a prior dose of any influenza vaccine
12. Receipt of any licensed vaccine within 7 days prior to study vaccination or intention of receiving any vaccines during 8-day post-vaccination period
13. Receipt of live vaccine during current pregnancy
14. Signs or symptoms of active preterm labor, defined as regular uterine contractions with cervical change (dilation/effacement)
15. Known multi-fetal gestation or fetal congenital anomaly, e.g. genetic abnormality or major congenital malformation based on antenatal ultrasound
16. Anyone who is already enrolled or plans to enroll in another randomized clinical trial with any drug, vaccine or medical device. Co-enrollment in observational or behavioral intervention studies are allowed at any time
17. Any condition which, in the opinion of the investigators, may pose a health risk to the participant or interfere with the evaluation of the study objectives.
18. Anyone who is a relative of any research study personnel or is an employee supervised by study staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RIV4; The first recombinant inactivated influenza vaccine (RIV) using an insect baculovirus expression system and recombinant DNA technology	Biological: Quadrivalent Recombinant Influenza Vaccine; The first recombinant inactivated influenza vaccine (RIV) using an insect baculovirus expression system and recombinant DNA technology; Other Names: Flublok Quadrivalent
Active Comparator: IIV4; Standard inactivated influenza vaccine (IIV) manufactured involving the use of embryonated hen eggs.	Biological: Quadrivalent Inactivated Influenza Vaccine; Standard inactivated influenza vaccine (IIV) manufactured involving the use of embryonated hen eggs.; Other Names: Flulaval

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Pregnant Women Vaccinated With RIV4 Versus IIV4 With Adverse Birth Outcomes	As measured by the number of women experiencing one of the following: Adverse birth outcome is a composite of occurrence of at least one of the following: preterm birth, spontaneous abortion, fetal death, or neonatal death.Preterm birth- born alive at less than 37 weeks and 0 days gestationSpontaneous abortion (SAB)- pregnancy loss prior to 20 weeks 0 daysFetal death- intrauterine death of fetus at or after 20 weeks 0 daysNeonatal death- infant death within first 28 days of life	Birth outcomes were monitored within postnatal day 28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Pregnant Women With Preterm Birth After RIV4 Versus IIV4 Vaccination	Preterm birth is defined as born alive at less than 37 weeks and 0 days gestation.	Birth outcomes were monitored through 36 weeks 6 days gestation.
Number of Pregnant Women With Fetal or Neonatal Death After RIV4 Versus IIV4 Vaccination	Fetal death is defined as intrauterine death of fetus at or after 20 weeks 0 days. Neonatal death is defined as infant death within first 28 days of life.	Birth outcomes were monitored through postnatal day 28.
Number of Pregnant Women With Spontaneous Abortion After RIV4 Versus IIV4 Vaccination	Spontaneous abortion (SAB) is defined as pregnancy loss prior to 20 weeks 0 days.	Birth outcomes were monitored through 19 weeks 6 days gestation.
Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4	Reactogenicity events include Injection Site Pain, Injection Site Redness, Injection Site Tenderness, Injection Site Swelling, Nausea, Vomiting, Diarrhea, Abdominal Pain, Headache, Chills/Shivering, Body Rash, Fever, Malaise (Fatigue), Myalgia (Body Aches), and Joint Pain.	Reactogenicity was measured for 8 days post-vaccination.

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Boston Medical Center; Centers for Disease Control and Prevention; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Geeta K Swamy, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Actual): September 29, 2021
• Study Completion (Actual): September 29, 2021

Study Registration Dates

• First Submitted: May 28, 2019
• First Submitted That Met QC Criteria: May 28, 2019
• First Posted (Actual): May 31, 2019

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Safety; Influenza; Vaccination; Pregnant; Birth outcomes; Flublok
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: Pro00101707

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No