Safety, Adverse Event Following Immunisation, Birth Outcomes
Conditions
Keywords
Vaccination, Safety, Birth outcomes, Flublok, Pregnant, Influenza
Brief summary
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.
Interventions
The first recombinant inactivated influenza vaccine (RIV) using an insect baculovirus expression system and recombinant DNA technology
Standard inactivated influenza vaccine (IIV) manufactured involving the use of embryonated hen eggs.
Sponsors
Children's Hospital Medical Center, Cincinnati
Boston Medical Center
Centers for Disease Control and Prevention
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pregnant Women Vaccinated With RIV4 Versus IIV4 With Adverse Birth Outcomes | Birth outcomes were monitored within postnatal day 28. | 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 gestation * Spontaneous abortion (SAB)- pregnancy loss prior to 20 weeks 0 days * Fetal death- intrauterine death of fetus at or after 20 weeks 0 days * Neonatal death- infant death within first 28 days of life |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pregnant Women With Preterm Birth After RIV4 Versus IIV4 Vaccination | Birth outcomes were monitored through 36 weeks 6 days gestation. | Preterm birth is defined as born alive at less than 37 weeks and 0 days gestation. |
| Number of Pregnant Women With Fetal or Neonatal Death After RIV4 Versus IIV4 Vaccination | Birth outcomes were monitored through postnatal day 28. | 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. |
| Number of Pregnant Women With Spontaneous Abortion After RIV4 Versus IIV4 Vaccination | Birth outcomes were monitored through 19 weeks 6 days gestation. | Spontaneous abortion (SAB) is defined as pregnancy loss prior to 20 weeks 0 days. |
| Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Reactogenicity was measured for 8 days post-vaccination. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RIV4 Subjects in this group received an intramuscular injection of 0.5mL quadrivalent Recombinant Influenza Vaccine, Flublok (RIV4) | 190 |
| IIV4 Subjects in this group received an intramuscular injection of 0.5mL standard quadrivalent Inactivated Influenza vaccine (IIV4), Flulaval. | 192 |
| Total | 382 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Elective termination | 0 | 1 |
| Overall Study | Found to be ineligible | 1 | 1 |
| Overall Study | Intrauterine fetal demise (IUFD) | 0 | 2 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Spontaneous abortion (SAB) | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | RIV4 | IIV4 |
|---|---|---|---|
| Age, Customized Maternal Age | 31 years | 31 years | 31 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 49 Participants | 24 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 329 Participants | 166 Participants | 163 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Gestational Age at Enrollment 20-34 weeks | 239 Participants | 125 Participants | 114 Participants |
| Gestational Age at Enrollment less than 20 weeks | 143 Participants | 65 Participants | 78 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 126 Participants | 63 Participants | 63 Participants |
| Race (NIH/OMB) More than one race | 22 Participants | 12 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) White | 212 Participants | 98 Participants | 114 Participants |
| Receipt of prior influenza season vaccine | 281 Participants | 143 Participants | 138 Participants |
| Region of Enrollment United States | 382 Participants | 190 Participants | 192 Participants |
| Sex: Female, Male Female | 382 Participants | 190 Participants | 192 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 190 | 0 / 192 |
| other Total, other adverse events | 22 / 190 | 22 / 192 |
| serious Total, serious adverse events | 14 / 190 | 12 / 192 |
Outcome results
Primary
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 gestation * Spontaneous abortion (SAB)- pregnancy loss prior to 20 weeks 0 days * Fetal death- intrauterine death of fetus at or after 20 weeks 0 days * Neonatal death- infant death within first 28 days of life
Time frame: Birth outcomes were monitored within postnatal day 28.
Population: mITT Population- any participant that was enrolled, randomized into the study, and received study vaccine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIV4 | Number of Pregnant Women Vaccinated With RIV4 Versus IIV4 With Adverse Birth Outcomes | 17 Participants |
| IIV4 | Number of Pregnant Women Vaccinated With RIV4 Versus IIV4 With Adverse Birth Outcomes | 21 Participants |
Comparison: The null hypothesis assumes that RIV4 is inferior (i.e., RIV4 will have a higher proportion) to IIV4 in regards to the proportion of pregnant women with adverse birth outcomes.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Birth outcomes were monitored through postnatal day 28.
Population: mITT Population- any participant that was enrolled, randomized into the study, and received study vaccine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIV4 | Number of Pregnant Women With Fetal or Neonatal Death After RIV4 Versus IIV4 Vaccination | 2 Participants |
| IIV4 | Number of Pregnant Women With Fetal or Neonatal Death After RIV4 Versus IIV4 Vaccination | 0 Participants |
Comparison: Fetal or neonatal deathp-value: 0.2447Mantel Haenszel
Secondary
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.
Time frame: Reactogenicity was measured for 8 days post-vaccination.
Population: mITT Population- any participant that was enrolled, randomized into the study, and received study vaccine
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Nausea | 7 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Headache | 11 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Redness | 2 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Chills/Shivering | 3 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Vomiting | 5 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Body Rash | 0 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Swelling | 0 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Fever | 0 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Diarrhea | 6 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Malaise (Fatigue) | 11 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Tenderness | 16 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Myalgia (Body Aches) | 7 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Abdominal Pain | 4 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Joint Pain | 5 Participants |
| RIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Pain | 16 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Joint Pain | 7 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Pain | 14 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Redness | 1 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Tenderness | 22 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Injection Site Swelling | 0 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Nausea | 13 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Vomiting | 8 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Diarrhea | 6 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Abdominal Pain | 5 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Headache | 20 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Chills/Shivering | 3 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Body Rash | 1 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Fever | 0 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Malaise (Fatigue) | 12 Participants |
| IIV4 | Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 | Myalgia (Body Aches) | 8 Participants |
Comparison: Injection Site Painp-value: 0.702995% CI: [0.55, 2.5]Mantel Haenszel
Comparison: Injection Site Rednessp-value: 0.621795% CI: [0.18, 22.52]Mantel Haenszel
Comparison: Injection Site Tendernessp-value: 0.384895% CI: [0.35, 1.39]Mantel Haenszel
Comparison: Nauseap-value: 0.250495% CI: [0.21, 1.35]Mantel Haenszel
Comparison: Vomitingp-value: 0.575195% CI: [0.2, 1.93]Mantel Haenszel
Comparison: Diarrheap-value: 195% CI: [0.32, 3.19]Mantel Haenszel
Comparison: Abdominal Painp-value: 195% CI: [0.21, 3.04]Mantel Haenszel
Comparison: Headachep-value: 0.132695% CI: [0.25, 1.13]Mantel Haenszel
Comparison: Chills/Shiveringp-value: 195% CI: [0.2, 5.04]Mantel Haenszel
Comparison: Body Rashp-value: 1Mantel Haenszel
Comparison: Malaise (Fatigue)p-value: 195% CI: [0.39, 2.15]Mantel Haenszel
Comparison: Myalgia (Body Aches)p-value: 195% CI: [0.31, 2.48]Mantel Haenszel
Comparison: Joint Painp-value: 0.770495% CI: [0.22, 2.29]Mantel Haenszel
Secondary
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.
Time frame: Birth outcomes were monitored through 36 weeks 6 days gestation.
Population: mITT Population- any participant that was enrolled, randomized into the study, and received study vaccine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIV4 | Number of Pregnant Women With Preterm Birth After RIV4 Versus IIV4 Vaccination | 14 Participants |
| IIV4 | Number of Pregnant Women With Preterm Birth After RIV4 Versus IIV4 Vaccination | 19 Participants |
Comparison: Preterm birthp-value: 0.464595% CI: [0.35, 1.48]Mantel Haenszel
Secondary
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.
Time frame: Birth outcomes were monitored through 19 weeks 6 days gestation.
Population: mITT Population- any participant that was enrolled, randomized into the study, and received study vaccine. By definition, SAB can only occur in women that are at less than 20 weeks 0 days gestational age. All women that were at or over 20 weeks 0 days gestational age were removed from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIV4 | Number of Pregnant Women With Spontaneous Abortion After RIV4 Versus IIV4 Vaccination | 1 Participants |
| IIV4 | Number of Pregnant Women With Spontaneous Abortion After RIV4 Versus IIV4 Vaccination | 2 Participants |
Comparison: Spontaneous abortionp-value: 0.623595% CI: [0.04, 5.47]Mantel Haenszel