A Study on the Safety and Immune Response to an Unadjuvanted RSV Maternal Vaccine, in High Risk Pregnant Women Aged 15 to 49 Years and Infants Born to the Vaccinated Mothers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, reactogenicity and immune response of a single intramuscular dose of the respiratory syncytial virus (RSV) maternal vaccine compared to placebo, when administered in the second or third trimester of pregnancy in women, 15 to 49 years of age (YOA), with high risk pregnancies and in the infants born to the vaccinated mothers. 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, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety, Reactogenicity and Immune Response of a Single Intramuscular Dose of Unadjuvanted RSV Maternal Vaccine, in High Risk Pregnant Women Aged 15 to 49 Years and Infants Born to the Vaccinated Mothers

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 can and will comply with the requirements of the protocol. Participants and LARs who give written or witnessed/thumb printed informed consent after the study has been explained according to local regulatory requirements, and before any study specific procedures are performed. The informed consent given at screening should either: include consent for both the maternal participant's participation* and participation of the infant after the infant's birth, or include consent for the maternal participant's participation* and expressed willingness to consider permitting the infant to take part after the infant's birth (if local regulations/guidelines require parent(s) to provide an additional informed consent after the infant's birth). both mother and father should consent if local regulations / guidelines require it. Pre-pregnancy Body Mass Index (based on participant's report) 18.5 to 39.9 kg/m^2, inclusive. Healthy adolescent pregnant women, 15 to 17 YOA, inclusive, at the time of study intervention administration. OR Pregnant women, 18 to 49 YOA, inclusive, at the time of study intervention administration with: HIV infection AND/OR Obstetric complications or risk factors during the current pregnancy, where the expectant management of the pregnancy is possible and without evidence of non-reassuring fetal status (only cases for which fetal heart rate can be ascertained) as follows: Gestational diabetes, well-controlled on medications (with or without diet or exercise) Gestational hypertension, well-controlled on diet or medications below 160/110 mmHg. Pre-eclampsia without severe features (i.e. eclampsia, severe hypertension [>160/110 mmHg], organ dysfunction, unstable or complicated by [HELLP] syndrome). Fetal Growth Restriction in singleton pregnancies, with normal umbilical artery Doppler and estimated fetal weight 3 to 10th percentile for gestational age. History of threatened preterm labor in the current pregnancy, with no cervical dilation greater than 2 cm or effacement exceeding 50%, and/or no progressive change in cervical dilation or effacement detected by serial examinations, when maternal participant is asymptomatic Uncomplicated twin gestation. Pregnant females at 24^0/7 to 36^0/7 weeks of gestation at the time of study intervention administration (Day 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). First or second 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. The level of diagnostic certainty of the gestational age should be established by using the Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) gestation age assessment tool Participants who are willing to provide cord blood. Willing to have their offspring followed-up after delivery for a period of 12 months. Participants who do not plan to give their offspring for adoption or place the child in care. Note that women whose pregnancies resulted from Assisted Reproductive Technologies may be enrolled if they meet all inclusion criteria and none of the exclusion criteria. 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 infant study specific procedure. To comply with RTI surveillance and other protocol required procedures that begin immediately after birth: if written consent cannot be provided by the parent(s)/LAR(s) readily post-birth, verbal consent - if permitted per local regulation -- may be sought from the parent(s) / LAR(s) instead. Verbal consent should be documented in the source data by the investigator or delegate. The parent(s) / LAR(s) will provide additional, written informed consent by (or before) Visit 2-NB. Exclusion Criteria: Maternal participants Medical conditions History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention. Hypersensitivity to latex. Any pre-existing medical conditions or obstetric complications in the current pregnancy that, are poorly controlled and/or with clinical evidence of a non-reassuring fetal status and/or are likely to result in delivery within 7 days after study intervention administration and/or when the timing of planned delivery is within 7 days after study intervention administration and/or acute conditions requiring immediate medical attention for maternal stabilization and/or treatment. A multiple pregnancy with 3 or more fetuses. Complicated twin gestation. Placenta Accreta Spectrum, including placenta increta, percreta, and accreta. Fetal structural defects or genetic abnormalities that affect (or are likely to affect) fetal health or survival during the first year of life. Known or suspected impairment of the immune system or immunodeficiency syndrome other than HIV. Lymphoproliferative disorder or malignancy within 5 years before study dose administration. Any illness of the mother or conditions of the fetus that, may substantially interfere with the maternal participant's ability to comply with study procedures, or could increase the risks to the mother or the fetus, or could preclude the evaluation of the participant's data. Any other clinical condition that, might pose additional risk to the participant due to participation in the study, as determined by medical history, physical examination or laboratory screening tests. Women with any diagnosis, condition, treatment, or other factor that, has the potential to affect or confound assessments of immunogenicity or safety Any conditions which, in the investigator's opinion, would increase the risks of study participation to the unborn infant. Prior/Concomitant therapy Prior receipt of an RSV maternal vaccine. Use of any investigational or non-registered product other than the study intervention(s) during the period beginning: For a drug, vaccine or medical device: 29 days before the dose of study intervention(s) (Day -28 to Day 1), or their planned use during the study period. For immunoglobulins: 90 days before the dose of study intervention(s), or their planned use during the study period. The exception to this is investigational products administered in the setting of a pandemic. Administration in this case should respect the same period outlined above prior to study intervention administration, but may be allowed following delivery. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 29 days before the study Day 1 and ending at delivery, with the exception of seasonal influenza vaccines, tetanus vaccines, dTpa/Tdap - alone vaccines, dTpa/Tdap vaccines that also contain other antigens and Hepatitis B vaccines, all of which may be administered according to standard of care ≥ 15 days before or after study intervention (Day 1). Receipt of blood or plasma products or immunoglobulin, from 90 days before study intervention administration, or planned receipt through delivery, with the exception of Rho(D) immunoglobulin, which can be given at any time. In that sense, COVID-19 vaccines may be allowed, when administered ≥ 15 days before or after study vaccination. Administration of immune-modifying therapy within 6 months before study intervention administration, or planned administration through delivery, except if it is part of management of HIV infection. Prior/Concurrent clinical study experience • Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational intervention. Other exclusions Alcoholism or substance use disorder within the past 24 months based on the presence of 2 or more of the following abuse criteria: hazardous use, social/interpersonal problems related to use, neglect of major roles to use, withdrawal, tolerance, use of larger amounts or longer, repeated attempts to quit or control use, much time spent using, physical or psychological problems related to use, activities given up to use, craving. A local condition that precludes injection of the study vaccine/product or precludes assessment of local (administration site) reactogenicity. Consanguinity of maternal participant and her partner. Any study personnel or their immediate dependents, family, or household members. Infant participants Concurrently participating in another clinical trial, at any time during the study period, 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: 15 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RSV_MAT Group<br>Maternal participants randomized to the RSV_MAT Group receive a single dose of the RSV MAT vaccine administered intramuscularly between 24 and 36 weeks of gestation (Day 1) and are followed up until 180 days post-delivery. | Biological: RSV MAT<br>* Single dose of the RSV MAT vaccine reconstituted with NaCl solution, administered intramuscularly in the non-dominant arm, at Day 1.<br>|
| Placebo Comparator: Control Group<br>Maternal participants randomized to the Control Group receive a single dose of placebo administered intramuscularly between 24 and 36 weeks of gestation (Day 1) and are followed up until 180 days post-delivery. | Drug: Placebo<br>* Single dose of placebo, administered intramuscularly in the non-dominant arm, at Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of maternal participants reporting solicited administration site events | Assessed solicited administration site events include injection site pain, redness and swelling. | From Day 1 to Day 7 included | 
| Percentage of maternal participants reporting solicited systemic events | Assessed solicited systemic events include fatigue, fever, nausea, vomiting, diarrhea, abdominal pain and headache. | From Day 1 to Day 7 included | 
| Percentage of maternal participants reporting unsolicited adverse events (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 included | 
| Percentage of maternal participants reporting serious adverse events (SAEs), (S)AEs leading to study withdrawal, and medically attended adverse events (MAEs) | 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, is a congenital anomaly/birth defect in the offspring of a study participant or results in abnormal pregnancy outcomes. A MAE is an unsolicited AE for which the participants received medical attention defined as symptoms or illnesses requiring a hospitalization, or an emergency room visit, or visit to/by a health care provider. | From Day 1 up to 42 days post-delivery | 
| Percentage of maternal participants reporting pregnancy outcomes | Pregnancy outcomes include live birth with no congenital anomalies, live birth with minor congenital anomaly(ies) only; live birth with at least 1 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 up to 42 days post-delivery | 
| Percentage of maternal participants reporting pregnancy-related adverse events of special interest (AESIs) | Pregnancy-related AESIs include maternal death, hypertensive disorders of pregnancy (gestational hypertension, pre-eclampsia, pre-eclampsia with severe features including eclampsia), fetal growth restriction, gestational diabetes mellitus, pathways to preterm birth (premature preterm rupture of membranes, preterm labor, provider-initiated preterm birth) and chorioamnionitis. | From Day 1 up to 42 days post-delivery | 
| Percentage of maternal participants reporting worsening of pre-existing medical conditions and/or obstetric complications from Day 1 up to 42 days post-delivery | Worsening of pre-existing medical condition and/or obstetric complication is considered by the investigator, using clinical judgement and the following criteria: Change in medication and/or medication dose Medically attended event in relation to pre-existing condition and/or obstetric complication that are outside the routine management of the condition/complication SAE and/or hospitalization in relation to pre-existing condition and/or obstetric complication. | From Day 1 up to 42 days post-delivery | 
| Percentage of infant participants reporting neonatal / infant AESIs | Neonatal / infant AESIs include small for gestational age, low birth weight including very low and extremely low birth weight, congenital anomalies, neonatal death and preterm birth. | From birth up to 42 days post-birth | 
| Percentage of infant participants reporting SAEs, (S)AEs leading to study withdrawal, and MAEs | 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, is a congenital anomaly/birth defect in the offspring of a study participant or results in abnormal pregnancy outcomes. A MAE is an unsolicited AE for which the participants received medical attention defined as symptoms or illnesses requiring a hospitalization, or an emergency room visit, or visit to/by a health care provider. | From birth up to 42 days post-birth | 
| Percentage of infant participants reporting SAEs, (S)AEs leading to study withdrawal, and MAEs | 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, is a congenital anomaly/birth defect in the offspring of a study participant or results in abnormal pregnancy outcomes. A MAE is an unsolicited AE for which the participants received medical attention defined as symptoms or illnesses requiring a hospitalization, or an emergency room visit, or visit to/by a health care provider. | From birth up to 180 days post-birth | 
| Percentage of infant participants reporting SAEs, (S)AEs leading to study withdrawal, and MAEs | 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, is a congenital anomaly/birth defect in the offspring of a study participant or results in abnormal pregnancy outcomes. A MAE is an unsolicited AE for which the participants received medical attention defined as symptoms or illnesses requiring a hospitalization, or an emergency room visit, or visit to/by a health care provider. | From birth up to 365 days post-birth | 
| Humoral immune response in terms of RSV MAT immunoglobulin G (IgG)-specific antibody concentrations at pre-dosing (Day 1) for maternal participants | Serological assays for the determination of IgG antibodies against RSV MAT are performed by Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 1 (pre-dosing) | 
| Humoral immune response in terms of RSV MAT IgG-specific antibody concentrations at delivery for maternal participants | Serological assays for the determination of IgG antibodies against RSV MAT are performed by Enzyme-Linked Immunosorbent Assay (ELISA). | At delivery | 
| Humoral immune response in terms of RSV-A neutralizing antibody titers at pre-dosing (Day 1) for maternal participants | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At Day 1 (pre-dosing) | 
| Humoral immune response in terms of RSV-A neutralizing antibody titers at delivery for maternal participants | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At delivery | 
| Geometric Mean Ratio between cord blood and maternal RSV MAT IgG-specific antibody concentrations. | Transfer of RSV-specific antibodies from maternal participants vaccinated with the RSV MAT vaccine to their infants is calculated as the ratio between cord blood and maternal RSV MAT IgG-specific antibody concentrations. Cord blood or infant blood sample is collected within 72 hours after birth (if no cord blood sample can be obtained). | At delivery | 
| Humoral immune response in terms of RSV MAT IgG-specific antibody concentrations at delivery for infant participants | Serological assays for the determination of IgG antibodies against RSV MAT are performed by Enzyme-Linked Immunosorbent Assay (ELISA). | At delivery | 
| Humoral immune response in terms of RSV-A neutralizing antibody titers at delivery for infant participants | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of maternal participants reporting SAEs, (S)AEs leading to study withdrawal, and MAEs | 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, is a congenital anomaly/birth defect in the offspring of a study participant or results in abnormal pregnancy outcomes. A MAE is an unsolicited AE for which the participants received medical attention defined as symptoms or illnesses requiring a hospitalization, or an emergency room visit, or visit to/by a health care provider. | From Day 1 up to 180 days post-delivery | 
| Percentage of maternal participants reporting worsening of pre-existing medical conditions and/or obstetric complications from Day 1 post-dosing up to 180 days post-delivery | Worsening of pre-existing medical condition and/or obstetric complication is considered by the investigator, using clinical judgement and the following criteria: Change in medication and/or medication dose. Medically attended event in relation to pre-existing condition and/or obstetric complication that are outside the routine management of the condition/complication. SAE and/or hospitalization in relation to pre-existing condition and/or obstetric complication. | From Day 1 post-dosing up to 180 days post-delivery | 
| Percentage of maternal participants reporting RSV-associated medically attended respiratory tract illnesses (MA-RTIs) | RSV-associated MA-RTI is defined as a medically attended visit for RTI symptoms and confirmed RSV infection. | From Day 1 up to 180 days post-delivery | 
| Percentage of infant participants reporting medically assessed, RSV-associated LRTIs | Infant participants reporting at least one medically assessed, RSV-associated LRTIs of any severity and severe RSV-associated LRTIs. | From birth up to 365 days post-birth | 
| Percentage of infant participants reporting medically assessed, RSV-associated hospitalizations | RSV-associated hospitalization is defined as 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. | From birth up to 365 days post-birth | 
| Humoral immune response in terms of RSV MAT IgG-specific antibody concentrations at Day 31 post-dosing for maternal participants | Serological assays for the determination of IgG antibodies against RSV MAT are performed by Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 31 post-dosing | 
| Humoral immune response in terms of RSV-A neutralizing antibody titers at Day 31 post-dosing for maternal participants | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At Day 31 post-dosing | 
| Humoral immune response in terms of RSV-B neutralizing antibody titers at pre-dosing (Day 1), Day 31 post-dosing and delivery for maternal participants | Serological assays for the determination of antibodies against RSV-B are performed by neutralization assay. | At pre-dosing (Day 1), Day 31 post-dosing and delivery | 
| Humoral immune response in terms of RSV-B neutralizing antibody titers at delivery for infant participants | Serological assays for the determination of antibodies against RSV-B are performed by neutralization assay. | At delivery | 
| Humoral immune response in terms of RSV MAT IgG-specific antibody concentrations at Day 43, Day 121 and Day 181 post-birth for infant participants | Serological assays for the determination of IgG antibodies against RSV MAT are performed by Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 43, Day 121 and Day 181 post-birth | 
| Humoral immune response in terms of RSV-A neutralizing antibody titers at Day 43, Day 121 and Day 181 post-birth for infant participants | Serological assays for the determination of antibodies against RSV-A are performed by neutralization assay. | At Day 43, Day 121 and Day 181 post-birth | 
| Humoral immune response in terms of RSV-B neutralizing antibody titers at Day 43, Day 121 and Day 181 post-birth for infant participants | Serological assays for the determination of antibodies against RSV-B are performed by neutralization assay. | At Day 43, Day 121 and Day 181 post-birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory Syncytial Virus Maternal vaccine, Safety, Reactogenicity, Immune response, High risk pregnant women, Teenage girls