A Phase III, Double-blind Study to Assess Safety and Efficacy of an RSV Maternal Unadjuvanted Vaccine, in Pregnant Women and Infants Born to Vaccinated Mothers

Phase 3TerminatedNCT04605159

GlaxoSmithKline11,194 enrolled

Overview

The purpose of this study was to evaluate the ability of a single dose of the investigational RSV Maternal vaccine, administered intramuscularly (IM) to pregnant women aged 18-49 years, in good general maternal health, in preventing medically assessed RSV associated Lower Respiratory Tract Illnesses (LRTIs) in infants born to vaccinated mothers. The study also evaluated the safety of the investigational RSV Maternal vaccine both in vaccinated mothers and in their corresponding infant. Following a recommendation from the Independent Data Monitoring Committee of NCT04605159 (RSV MAT 009), GSK made the decision to stop enrolment and vaccination in the study. Ongoing study participants at that time continued to be monitored as part of the study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

11,194

Conditions

Respiratory Syncytial Virus Infections

Interventions

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 49 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Maternal participants * Participants who, in the opinion of the investigator, can and will comply with the requirements of the protocol. * Participants who give written or witnessed/thumb printed informed consent after the study has been explained, and before any study specific procedures are performed, as per local regulations regulatory requirements. * Age 18 to 49 years, inclusive, at the time of study intervention. * Pre-pregnancy BMI 17.0 to 39.9 kg/m2, inclusive. * In good general maternal health as established by medical history and clinical examination before entering into the study. * Singleton pregnancy (including instances where the singleton pregnancy derives from a vanishing twin syndrome). * At 24\^0/7 to 34\^0/7 weeks of gestation at the time of study vaccination (Visit 1), as established by: * last menstrual period (LMP) date corroborated by first or second trimester ultrasound examination (U/S) i.e. at or before 28 weeks of gestation. * 1st or 2nd trimester U/S only, if LMP is unknown/uncertain * Certain LMP, corroborated by an U/S performed after 28 weeks of gestation is also acceptable. * No fetal genetic abnormalities (based on genetic testing, if performed). * No significant congenital malformations, as assessed by fetal anomaly ultrasound scan conducted at or beyond 18 weeks of gestation. * Willing to provide cord blood. * Who do not plan to give their child for adoption. * Who plan to reside in the study area for at least one year after delivery. * Willing to have the infant followed-up after delivery for a period of 12 months. Infant participants * Live-born from the study pregnancy. * If required per local regulations/guidelines, re-signed (confirmed) written or witnessed/thumb printed informed consent for study participation of the infant obtained from the infant's mother and/or father and/or LAR, before performing any study specific procedure. OR, if permitted by local regulation, documented verbal consent for infant's participation obtained from the parent(s)/LAR(s) at birth, followed by written consent obtained by (or before) Visit 2-newborn. Exclusion Criteria: Maternal participants Medical conditions * History of allergic disease or reactions likely to be exacerbated by any component of the RSV vaccine * Hypersensitivity to latex * Significant complications in the current pregnancy: * Gestational hypertension unless blood pressure it is controlled and maintained in the normal range (\<140mmHg and \<90mmHg) through diet and/or antihypertensive medications * Gestational diabetes not controlled by medication, diet and/or exercise * Pre-eclampsia * Eclampsia * Intrauterine Growth Restriction/Fetal Growth Restriction * Placenta previa * Placental abruption, placenta accreta/percreta/increta, chorioamnionitis or any abnormalities that can impair the maternal-fetal circulation * Polyhydramnios * Oligohydramnios * Preterm labour or history of preterm labour in the current pregnancy * Any intervention to prevent preterm delivery or medical treatment for suspected preterm delivery, including administration of systemic corticosteroids for fetal lung maturation * Cholestasis * Other pregnancy-related complications (per investigator's judgement) * Significant structural abnormalities of the uterus or cervix * History of 2 or more prior stillbirths or neonatal deaths/history of 2 or more preterm births at ≤34 weeks gestation/3 or more consecutive spontaneous abortions * Known HIV infection (as per serological tests performed during the current pregnancy) * Known or suspected HBV or HCV infection * Known or suspected infection during the current pregnancy with Toxoplasma, Parvovirus B19, Syphilis, Zika, Rubella, Varicella, CMV or primary genital Herpes Simplex * Active infection with tuberculosis * Known or suspected impairment of the immune system * Current autoimmune disorder for which the participant has received immune-modifying therapy within 6 months before study vaccination, or plans administration through delivery * Lymphoproliferative disorder or malignancy within 5 years before study vaccination * Acute or chronic clinically significant abnormality or poorly controlled pre-existent co-morbidities or any other clinical conditions that might pose additional risk to the participant due to participation in the study * Any conditions that may interfere with participant's ability to comply with study procedures or receipt of prenatal care * Any condition which would increase the risks of study participation to the unborn infant Prior/Concomitant therapy * Prior receipt of an RSV vaccine in the current pregnancy * Use of any investigational/non-registered product other than the study vaccine/product as described below, or planned use during the period : * For a drug, vaccine or medical device: from 29 days before the dose of study vaccine * For immunoglobulins: 3 months before the dose of study vaccine/product. The exception to this is investigational products administered in the setting of a pandemic which may be allowed following delivery * Planned administration/administration of any vaccine from 29 days before the dose of study vaccine or planned administration through delivery, except: * Seasonal influenza vaccines, tetanus vaccines, dTpa/Tdap - alone vaccines, dTpa/Tdap vaccines that also contain other antigens, Hepatitis B vaccines, and COVID-19 vaccines all of which may be administered according to standard of care ≥15 days before or after study vaccination * Administration of immunoglobulins (except anti-Rh0D IG, which may be administered at any time), blood products or plasma derivatives within 3 months before study vaccination or planned administration through delivery * Administration of immune-modifying therapy within 6 months before the study vaccination, or planned administration through delivery. This includes but is not limited to: * Azathioprine, mycophenolate mofetil, 6-mercaptopurine, cyclosporine, tacrolimus, monoclonal or polyclonal antibodies * Prednisone ≥5 mg/day or equivalent for ≥14 days; Inhaled, intra-articular/intra-bursal and topical steroids are allowed * Corticosteroids administered for fetal lung maturation Prior/Concurrent clinical study experience \- Concurrently participating in another clinical study, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product Other exclusions * Alcoholism or substance use disorder within the past 24 months based on DSM-5 criteria * A local condition that precludes injection of the study vaccine/product or precludes assessment of local reactogenicity * Consanguinity of maternal participant and her partner (second degree cousins or closer) * Any study personnel or their immediate dependants, family or household members Infant participants * Concurrently participating in another clinical study, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product * Any condition which would increase the risks of study participation to the infant * Child in care.

Locations (159)

GSK Investigational Site

Birmingham, Alabama, United States

GSK Investigational Site

Dothan, Alabama, United States

GSK Investigational Site

Mobile, Alabama, United States

GSK Investigational Site

Phoenix, Arizona, United States

GSK Investigational Site

Tucson, Arizona, United States

GSK Investigational Site

Outcomes

Primary Outcomes

Number of Infant Participants With Medically Assessed, RSV-associated Lower Respiratory Tract Illnesses (LRTIs) of Any Severity and RSV-associated Severe LRTIs From Birth to Day 181 Post-birth

An RSV-associated LRTI of any severity was characterized by a history of cough OR difficulty in breathing, AND a blood oxygen saturation by pulse oximetry (SpO2) lower than (\<) 95%, OR respiratory rate increase AND a confirmed RSV infection. An RSV-associated severe LRTI met the case definition of RSV-LRTI AND was additionally characterized by a SpO2 \<93%, OR lower chest wall in-drawing, OR inability to feed, OR failure to respond/unconscious. Medically assessed = the infant was evaluated by a healthcare professional for the LRTI.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With at Least One Serious Adverse Event (SAE) From Birth to Day 181 Post-birth

An SAE is defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect or resulted in other situations that were considered serious per medical or scientific judgment. At least one SAE = occurrence of at least one SAE regardless of intensity grade or relation to vaccination.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With at Least One Adverse Event (AE) Leading to Study Withdrawal From Birth to Day 181 Post-birth

A participant was considered a 'withdrawal' from the study when no study procedure has occurred, no follow-up has been performed and no further information has been collected for this participant from the date of withdrawal/last contact. Participants who were withdrawn from the study because of AEs were clearly distinguished from participants who were withdrawn for other reasons. Investigators followed participants who were withdrawn from the study as a result of an AE until the event was resolved. At least one AE leading to study withdrawal = occurrence of at least one AE leading to study withdrawal regardless of intensity grade or relation to vaccination.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With at Least One Medically Attended AE (MAE) From Birth to Day 181 Post-birth

An MAE is defined as an unsolicited AE, such as a symptom or illness, which required hospitalization, or emergency room visit, or visit to/by a health care provider. At least one MAE = occurrence of at least one MAE regardless of intensity grade or relation to vaccination.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With at Least One SAE From Birth to Day 366 Post-birth

Time frame: From birth to Day 366 post-birth

Number of Infant Participants With at Least One AE Leading to Study Withdrawal From Birth to Day 366 Post-birth

Time frame: From birth to Day 366 post-birth

Number of Infant Participants With at Least One MAE From Birth to Day 366 Post-birth

Time frame: From birth to Day 366 post-birth

Secondary Outcomes

Number of Infant Participants With RSV-associated Hospitalizations From Birth to Day 181 Post-birth

RSV-associated hospitalization is defined as a confirmed RSV infection and hospitalized for acute medical condition. Hospitalization is defined as admission for observation or treatment based on the judgment of a health care provider.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With All-cause LRTIs From Birth to Day 181 Post-birth

All-cause LRTI was characterized by history of cough OR difficulty in breathing, AND SpO2 \< 95%, OR respiratory rate increase.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With All-cause LRTIs With Hospitalization From Birth to Day 181 Post-birth

All-cause LRTI was characterized by history of cough OR difficulty in breathing, AND SpO2 \< 95%, OR respiratory rate increase. Hospitalization is defined as admission for observation or treatment based on the judgment of a health care provider.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With Medically Assessed, RSV-associated Severe LRTIs From Birth to Day 366 Post-birth

An RSV-associated LRTI of any severity was characterized by a history of cough OR difficulty in breathing, AND an SpO2 \<95%, OR respiratory rate increase AND a confirmed RSV infection. An RSV-associated severe LRTI met the case definition of RSV-LRTI AND was additionally characterized by an SpO2 \<93%, OR lower chest wall in-drawing, OR inability to feed, OR failure to respond/unconscious. Medically assessed = the infant was evaluated by a healthcare professional for the LRTI.

Time frame: From birth to Day 366 post-birth

Number of Infant Participants With Medically Assessed, RSV-associated LRTIs of Any Severity From Birth to Day 366 Post-birth

Number of Infant Participants With Medically Assessed, RSV-associated Severe LRTIs for RSV Subtype A and RSV Subtype B Separately From Birth to Day 181 Post-birth

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With Medically Assessed, RSV-associated LRTIs of Any Severity for RSV Subtype A and RSV Subtype B Separately From Birth to Day 181 Post-birth

An RSV-associated LRTI of any severity was characterized by a history of cough OR difficulty in breathing, AND an SpO2 \<95%, OR respiratory rate increase AND a confirmed RSV infection. Medically assessed = the infant was evaluated by a healthcare professional for the LRTI. The RSV subtypes assessed for this analysis were RSV subtype A and RSV subtype B.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With Medically Assessed, RSV-associated Severe LRTIs From Birth to Day 121 Post-birth

Time frame: From birth to Day 121 post-birth

Number of Infant Participants With Medically Assessed, RSV-associated LRTIs of Any Severity From Birth to Day 121 Post-birth

Time frame: From birth to Day 121 post-birth

Number of Infant Participants With All-cause Pneumonia From Birth to Day 181 Post-birth

The number of infant participants with all-cause pneumonia is presented in this outcome measure.

Time frame: From birth to Day 181 post-birth

Number of Infant Participants With RSV-associated Hospitalizations From Birth to Day 366 Post-birth

Time frame: From birth to Day 366 post-birth

Number of Maternal Participants With RSV-associated Medically Attended RTIs (RSV-MA-RTIs) From Study Intervention Administration (Day 1) to Day 181 Post-delivery

RSV-associated MA-RTI is defined as a medically attended visit for RTI symptoms and confirmed RSV infection.

Time frame: From study intervention administration (Day 1) to Day 181 post-delivery

RSV-A Neutralizing Antibody Titers for Maternal Participants at Day 1, at Day 31 and at Delivery

RSV-A neutralizing titers were determined by neutralization assay and expressed as geometric mean titers (GMTs).

Time frame: At Day 1 (before study intervention administration), at Day 31 and at delivery

RSV-A Neutralizing Antibody Titers for Infant Participants at Delivery or Within 72 Hours After Birth

RSV-A neutralizing titers were determined by neutralization assay and expressed as GMTs. The titers were measured on the cord blood sample collected at delivery, or on a blood sample collected from the infant within 72 hours after birth (if no cord blood sample could be obtained).

Time frame: At delivery or within 72 hours after birth

RSV-A Neutralizing Antibody Titers for Infant Participants at Day 43 Post-birth

RSV-A neutralizing titers were determined by neutralization assay and expressed as GMTs.

Time frame: At Day 43 post-birth

RSV-A Neutralizing Antibody Titers for Infant Participants at Day 121 Post-birth

RSV-A neutralizing titers were determined by neutralization assay and expressed as GMTs.

Time frame: At Day 121 post-birth

RSV-A Neutralizing Antibody Titers for Infant Participants at Day 181 Post-birth

RSV-A neutralizing titers were determined by neutralization assay and expressed as GMTs.

Time frame: At Day 181 post-birth

RSV MAT Immunoglobulin G (IgG)-Specific Antibody Concentrations for Maternal Participants at Delivery

RSV MAT IgG-specific antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per milliliter (ELU/mL).

Time frame: At delivery

RSV MAT IgG-specific Antibody Concentrations for Infant Participants at Delivery or Within 72 Hours After Birth

RSV MAT IgG-specific antibody concentrations were determined by ELISA and expressed as GMCs in ELU/mL. The antibody concentrations were measured on the cord blood sample collected at delivery, or on a blood sample collected from the infant within 72 hours after birth (only if no cord blood sample could be obtained at delivery).

Time frame: At delivery or within 72 hours after birth (only if no cord blood sample could be obtained at delivery)

Geometric Mean Ratio (GMR) Between Cord Blood and Maternal RSV MAT Immunoglobulin G (IgG)-Specific Antibody Concentrations

The placental transfer ratio of RSV-MAT IgG-specific antibody concentration was determined from cord blood over that of the blood sample from mother at delivery. If no cord blood could be obtained, an infant blood sample was collected 72 hours after birth.

Time frame: At delivery (for maternal participants) or within 72 hours after birth (for infant participants, only if no cord blood could be obtained)

Number of Maternal Participants With Any Solicited Administration Site Events From Day 1 to Day 7 Included

Assessed solicited administration site events included erythema, pain and swelling at the injection site. Any pain = occurrence of the symptom regardless of intensity grade. Any erythema and swelling = symptom reported with a surface diameter greater than or equal to 20 millimeters.

Time frame: From Day 1 to Day 7 included

Number of Maternal Participants With Any Solicited Systemic Events From Day 1 to Day 7 Included

Assessed solicited systemic events included abdominal pain, diarrhea, fatigue, headache, nausea, fever \[temperature equal to or above (\>=) 38 degrees Celsius (°C)/100.4 degrees Fahrenheit (°F), regardless of the location of measurement\] and vomiting. Any = occurrence of the adverse event regardless of intensity grade or relation to study vaccination.

Time frame: From Day 1 to Day 7 included

Number of Maternal Participants With Any Unsolicited AEs From Day 1 to Day 30 Included

An unsolicited AE is defined as any AE reported in addition to those solicited during the clinical study. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE. Any = occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

Time frame: From Day 1 to Day 30 included

Number of Maternal Participants With at Least One SAE From Day 1 to Day 181 Post-delivery

An SAE is defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect in the offspring of a study participant or resulted in abnormal pregnancy outcomes or in other situations that were considered serious per medical or scientific judgment. At least one SAE = occurrence of at least one SAE regardless of intensity grade or relation to vaccination.

Time frame: From Day 1 to Day 181 post-delivery

Number of Maternal Participants With at Least One AE Leading to Study Withdrawal From Day 1 to Day 181 Post-delivery

Time frame: From Day 1 to Day 181 post-delivery

Number of Maternal Participants With at Least One All-cause MA-RTI From Day 1 to Day 181 Post-delivery

All-cause MA-RTI occurred when the maternal participant visited a healthcare professional (e.g., a General Practitioner) for any respiratory symptom, including (but not limited to) cough, sore throat, sputum production and difficulty breathing. At least one all-cause MA-RTI = occurrence of at least one all-cause MA-RTI regardless of intensity grade or relation to vaccination.

Time frame: From Day 1 to Day 181 post-delivery

Number of Maternal Participants With at Least One MAE From Day 1 to Day 42 Post-delivery

Time frame: From Day 1 to Day 42 post-delivery, an average of 2 months

Number of Maternal Participants With Pregnancy Outcomes From Day 1 to Day 42 Post-delivery

Assessed pregnancy outcomes included live birth with no congenital anomalies, live birth with minor congenital anomaly(ies), live birth with at least 1 major congenital anomaly, fetal death/still birth with no congenital anomalies, fetal death/still birth with at least 1 major congenital anomaly and unknown outcome (includes participants withdrawn before/at delivery with no available data of pregnancy outcomes).

Time frame: From Day 1 to Day 42 post-delivery, an average of 2 months

Number of Maternal Participants With Pregnancy-related Adverse Events of Special Interest (AESIs) From Day 1 to Day 42 Post-delivery

Pregnancy-related AESIs included chorioamnionitis, fetal growth restriction, gestational diabetes mellitus, gestational hypertension, pre-eclampsia, pre-eclampsia with severe features including eclampsia, maternal death, premature preterm rupture of membranes, preterm labor, provider-initiated preterm birth.

Time frame: From Day 1 to Day 42 post-delivery, an average of 2 months

Number of Infant Participants With Neonatal AESIs From Birth to Day 42 Post-birth

Neonatal/infant AESIs included congenital anomalies with functional defects, congenital anomalies with internal structural defects, congenital anomalies with major external structural defects, extremely low birth weight (\<1000 grams), low birth weight (\<2500 grams), very low birth weight (\<1500 grams), neonatal death in a preterm live birth (gestational age \>=28 and \<37 weeks), neonatal death in a term live birth (\>=37 weeks of gestational age), neonatal death in an extremely pre-term birth (gestational age \>=22 and \<28 weeks), preterm birth (\<37 weeks of gestational age), small for gestational age.

Time frame: From birth to Day 42 post-birth, an average of 2 months