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

Study Overview
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Brief Summary
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The purpose of this study is 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 will also evaluate 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 will continue to be monitored as part of the study.

Official Title
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A Phase III, Randomized, Double-blind, Placebo-controlled Multi-country Study to Demonstrate Efficacy of a Single Dose of Unadjuvanted RSV Maternal Vaccine, Administered IM to Pregnant Women 18 to 49 Years of Age, for Prevention of RSV Associated LRTIs in Their Infants up to 6 Months of Age

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Biological: RSV MAT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RSV_MAT Group<br>Maternal participants randomized to the RSV_MAT Group will receive a single dose of RSV MAT vaccine at day 1, via the intramuscular route; the preferred injection site will be the deltoid region of the non-dominant arm. | Biological: RSV MAT<br>* One dose of RSV MAT vaccine reconstituted with NaCl solution administered intramuscularly in the non-dominant arm.<br>|
| Placebo Comparator: Control Group<br>Maternal participants randomized to the Control Group will receive a single dose of Placebo at day 1, via the intramuscular route; the preferred injection site will be the deltoid region of the non-dominant arm. | Drug: Placebo<br>* One dose of lyophilized sucrose reconstituted with NaCl solution administered intramuscularly in the non-dominant arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of infant participants with medically assessed, RSV-associated LRTIs, up to 6 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of severe and/or any medically assessed, RSV-associated LRTIs. | From birth to Day 181 post birth | 
| Number of infant participants with at least one SAE, AE leading to study termination or Medically Attended AE (MAE), from birth up to 6 months after birth | A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study participant. A MAE is an unsolicited AE such as a symptom or illness which requires a hospitalisation, or emergency room visit, or visit to/by a health care provider. | From birth to Month 6 post birth | 
| Number of infant participants with at least one SAE, AE leading to study termination or MAE, from birth up to 12 months after birth | A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study participant. A MAE is an unsolicited AE such as a symptom or illness which requires a hospitalisation, or emergency room visit, or visit to/by a health care provider. | From birth to Month 12 post birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of infant participants with RSV-associated hospitalizations | The vaccine arm will be compared to the placebo arm through the occurrence of RSV associated hospitalizations. | From birth to Day 181 post birth | 
| Number of infant participants with all-cause LRTIs | The vaccine arm will be compared to the placebo arm through the occurrence of all-cause LRTIs. | From birth to Day 181 post birth | 
| Number of infant participants with all-cause LRTIs with hospitalization | The vaccine arm will be compared to the placebo arm through the occurrence of all-cause LRTIs with hospitalization. | From birth to Day 181 post birth | 
| Number of infant participants with medically assessed, RSV-associated severe LRTIs, up to 12 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of medically assessed, RSV-associated severe LRTIs. | From birth to Day 366 post birth | 
| Number of infant participants with any medically assessed, RSV-associated LRTIs, up to 12 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of any medically assessed, RSV-associated LRTIs. | From birth to Day 366 post birth | 
| Number of infant participants with severe medically assessed, RSV-associated LRTIs for RSV subtype A and RSV subtype B separately, up to 6 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of severe medically assessed, RSV-associated LRTIs for RSV subtype A and RSV subtype B separately. | From birth to Day 181 post birth | 
| Number of infant participants with any medically assessed, RSV-associated LRTIs for RSV subtype A and RSV subtype B separately, up to 6 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of any medically assessed, RSV-associated LRTIs for RSV subtype A and RSV subtype B separately. | From birth to Day 181 post birth | 
| Number of infant participants with medically assessed, RSV-associated LRTIs, up to 4 months of age | The vaccine arm will be compared to the placebo arm through the occurrence of severe and any medically assessed, RSV-associated LRTIs. | From birth to Day 121 post birth | 
| Number of infant participants with all-cause pneumonia | The vaccine arm will be compared to the placebo arm through the occurrence of all-cause pneumonia. | From birth to Day 181 post birth | 
| Number of infant participants with RSV-associated hospitalizations | The vaccine arm will be compared to the placebo arm through the occurrence of RSV associated hospitalizations. | From birth to Day 366 post birth | 
| Number of maternal participants with RSV-associated Medically Attended RTIs (RSV-MA-RTIs) | The vaccine arm will be compared to the placebo arm through the occurrence of RSV-associated MA-RTIs. | From Day 1 (vaccination) to Day 181 post delivery | 
| Humoral immune response in terms of RSV-A neutralizing antibody Geometric Mean Titers (GMTs) in maternal participants, at specified timepoints | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At Day 1 (pre vaccination), Day 31 and at Delivery | 
| Humoral immune response in terms of RSV-A neutralizing antibody GMTs in infant participants, at specified timepoints. | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At birth, Day 43 post birth, Day 121 post birth and Day 181 post birth | 
| Geometric mean ratio between cord blood and maternal RSV MAT IgG-specific antibody concentrations | Transfer of RSV-specific antibodies from maternal participants vaccinated with RSV Mat to their infants is calculated as the ratio between cord blood* and maternal RSV MAT IgG-specific antibody concentrations. * or an infant blood sample collected within 72 hours after birth (if no cord blood sample can be obtained) | At delivery or birth | 
| Number of maternal participants with solicited adverse events (AEs) | Assessed solicited administration site events include pain, redness and swelling, at the injection site. Assessed solicited systemic events include fatigue, fever, nausea, vomiting, diarrhoea, abdominal pain and headache. | From Day 1 to Day 7 | 
| Number of maternal participants with unsolicited AEs | 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 is to be reported as an unsolicited AE. | From Day 1 to Day 30 | 
| Number of maternal participants with at least one serious adverse event (SAE), AE leading to study termination or medically attended respiratory tract illness (MA-RTI) | A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study participant. MA-RTI occurs when the maternal participant visits 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. | From Day 1 (vaccination) to Month 6 post delivery | 
| Number of maternal participants with at least one other medically attended AE | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | From Day 1 (vaccination) to Day 43 post delivery | 
| Number of maternal participants with each pregnancy outcome | These pregnancy outcomes include live birth with no congenital anomalies, live birth with minor congenital anomaly(ies) only; live birth with at least one major congenital anomaly, fetal death/still birth (antepartum or intrapartum) with no congenital anomalies, fetal death/still birth (antepartum or intrapartum) with only minor congenital anomalies, fetal death/still birth (antepartum or intrapartum) with at least 1 major congenital anomaly; elective/therapeutic termination with no congenital anomalies; elective/therapeutic termination with only minor congenital anomalies, and elective/therapeutic termination with at least 1 major congenital anomaly. | From Day 1 to Day 43 post delivery | 
| Number of maternal participants with each pregnancy-related AE of special interest (AESI) | These pregnancy-related AESIs include maternal death, hypertensive disorders of pregnancy, fetal growth restriction, pathways to preterm birth, gestational diabetes mellitus and chorioamnionitis. Worsening, post study vaccine administration, of pre-existing conditions already present at the time of enrolment. (e.g. controlled gestational hypertension or controlled gestational diabetes) are collected as (S)AEs and indicated as worsening or aggravated. These are not to be considered as AESIs. | From Day 1 (vaccination) to Day 43 post delivery | 
| Number of infant participants with each neonatal AESI | Neonatal AESIs include small for gestational age, low birth weight including very low and extremely low birth weight, congenital anomalies, neonatal death, preterm birth. | From birth to Day 43 post birth |