Study of Safety, Reactogenicity and Immunogenicity of GlaxoSmithKline's (GSK)Respiratory Syncytial Virus (RSV)Maternal Unadjuvanted Vaccine in Healthy Pregnant Women (Aged 18 to 40 Years) and Their Infants

Study of Safety, Reactogenicity and Immunogenicity of GlaxoSmithKline's (GSK)Respiratory Syncytial Virus (RSV)Maternal Unadjuvanted Vaccine in Healthy Pregnant Women (Aged 18 to 40 Years) and Their Infants

A Phase II, Randomised, Observer-blind, Placebo Controlled Multi-country Study to Assess the Safety, Reactogenicity and Immunogenicity of a Single Intramuscular Dose of GSK Biologicals' Investigational RSV Maternal Unadjuvanted Vaccine (GSK3888550A), in Healthy Pregnant Women Aged 18 to 40 Years and Infants Born to Vaccinated Mothers

The purpose of this study was to evaluate the safety and immune response to a single intramuscular (IM) dose of GSK Biologicals' investigational RSV maternal vaccine (RSVPreF3) in healthy pregnant women 18-40 years of age and in infants born to vaccinated mothers.

Data was collected in an observer-blind manner. The laboratory in charge of the sample testing was blinded to the intervention assignment, codes were used to link the subject and study (without any link to the intervention attributed to the subject) to each sample. Investigators remained blinded to each subject's assigned study intervention until the second analysis. After the second analysis, the study was not considered observer blind as the investigator brochure was updated to include safety information presented by treatment group. This led to inadvertent unblinding of investigators and site staff to some subjects' treatment assignments. The subjects themselves remained blinded throughout their participation in the study.

Maternal subjects randomized to RSV MAT 60 Group received a single dose of RSV MAT (60 µg) vaccine at Day 1, and were followed up until the study end.

Maternal subjects randomized to RSV MAT 120 group received a single dose of RSV MAT (120 µg) vaccine at Day 1, and were followed up until the study end.

Maternal subjects randomized to the Control Group received a single dose of Placebo at Day 1, and were followed up until the study end.

This group consisted of infants born to mothers (from RSV MAT 60 Group-Mother) who received a single dose of RSV MAT (60 µg) vaccine during pregnancy.

This group consisted of infants born to mothers (from RSV MAT 120 Group-Mother) who received a single dose of RSV MAT (120 µg) vaccine during pregnancy.

This group consisted of infants born to mothers (from Control Group-Mother) who received a single dose of placebo during pregnancy.

One single dose of RSV MAT 60 µg vaccine administered intramuscularly in the deltoid region of the non-dominant arm on Day 1.

One single dose of RSV MAT 120 µg vaccine administered intramuscularly in the deltoid region of the non-dominant arm on Day 1.

One single dose of placebo (NaCl solution) administered intramuscularly in the deltoid region of the non-dominant arm on Day 1.

Assessed solicited administration site events were pain, erythema and swelling. Any = occurrence of the symptom regardless of intensity grade. Any erythema and swelling symptom = symptom reported with a surface diameter greater than 0 millimeters.

Assessed solicited systemic events were fatigue, headache, nausea, vomiting, diarrhea, abdominal pain and fever [temperature equal to or above (≥) 38 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade or relation to study intervention.

Number of Maternal Subjects With Any Haematological Laboratory Abnormalities at Day 8 by Baseline Ranges

Hematological parameters assessed were Eosinophils (EOS), Erythrocytes (ERY), Hematocrit (HEM), Lymphocytes (LYMP), Mean Corpuscular Volume (MCV), Neutrophils (NEU), Platelets (PLA), and White Blood Cells (WBC) count. The increase and/or decrease of these parameters were evaluated at Day 8. Abnormal laboratory values refer to range indicator at Day 8 (D8) categorized as Missing, Below, Within and Above normal values and compared to the baseline (B) range indicator of the same parameter, at Screening (up to 15 days before vaccination) i.e. Missing, Below, Within and Above. E.g. 'WBC decrease Below (B) - Within (D8)' = WBC decrease in subjects with below normal values at baseline and within normal values at Day 8.

Number of Maternal Subjects With Any Biochemical Laboratory Abnormalities at Day 8 by Baseline Ranges

Biochemical parameters assessed were Alanine Amino-Transferase (ALT), Aspartate Amino-Transferase (AST), Creatinine (CRE) and Urea nitrogen (URN). The increase was evaluated only for AST and ALT parameters at Day 8. Abnormal laboratory values refer to range indicator at Day 8 (D8) categorized as Missing, Below, Within and Above normal values and compared to the baseline (B) range indicator of the same parameter, at Screening (up to 15 days before vaccination) i.e. Missing, Below, Within and Above. E.g. 'AST increase Below (B) - Within (D8)' = AST increase in subjects with below normal values at baseline and within normal values at Day 8.

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Unsolicited AE is any AE reported in addition to those solicited during the clinical study and that was spontaneously communicated by a maternal subject. Also, any solicited symptom with onset outside the specified period of follow-up for solicited symptoms is to be reported as an unsolicited AE. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

During 30-day follow-up period after vaccination (i.e. the day of vaccination and 29 subsequent days)

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity, was a congenital anomaly/birth defect in the offspring of a study subject or abnormal pregnancy outcomes (spontaneous abortion, foetal death, stillbirth, congenital anomalies, ectopic pregnancy), other situations (medical events that might jeopardize the participant or required medical/surgical intervention to prevent one of the other SAEs listed above: e.g. invasive/malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization). Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs leading to study withdrawal = AEs identified by investigators to cause subject(s) withdrawal until the resolution of the event. These subject withdrawals were considered different from subject withdrawals for other reasons.

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Also, for instances where, due to the special circumstances, the subject could not seek medical advice for symptoms/an illness by visiting a medical facility or arranging for a home visit, the subject sought this advice instead via telephone, SMS, email, videotelephony or telemedicine, or other means. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

Pregnancy outcomes were: live birth with no congenital anomalies, live birth with congenital anomalies, Fetal death/still birth with no Congenital Anomalies (CA) - Antepartum and Unknown (Subjects withdrew from the study before delivery and pregnancy outcome information was not available for them).

Pregnancy-related AESIs were: Non-Reassuring Fetal Status, Hypertensive Disorders of Pregnancy (HDP), Oligohydramnios, Pathways to Preterm Birth (PPB), Chorioamnionitis, Fetal Growth Restriction, Gestational Liver Disease (GLD), Postpartum Haemorrhage and Gestational Diabetes Mellitus.

Neonatal AESIs, reported up to 6 weeks after birth were: Respiratory Distress In The Neonate, Macrosomia, Low Birth Weight, Small For Gestational Age, Preterm Birth, Large For Gestational Age, Neonatal Invasive Blood Stream Infections (NIBSI) and Congenital Anomalies (CA).

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity or is a congenital anomaly/birth defect, other situations (medical events that might jeopardize the participant or required medical/surgical intervention to prevent one of the other SAEs listed above: e.g. invasive/malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization). Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs leading to study withdrawal = AEs identified by investigators to cause subject(s) withdrawal until the resolution of the event. These subject withdrawals were considered different from subject withdrawals for other reasons.

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Also, for instances where, due to the special circumstances, the subject could not seek medical advice for symptoms/an illness by visiting a medical facility or arranging for a home visit, the subject sought this advice instead via telephone, SMS, email, videotelephony or telemedicine, or other means. Any = occurrence of the symptom regardless of intensity grade.

RSV MAT Immunoglobulin G (IgG)-Specific Antibody Concentrations in Terms of Geometric Mean Concentrations (GMCs) in Maternal Subjects

Serological assays for the determination of IgG antibodies against RSV MAT were performed by Enzyme-linked immunosorbent assay (ELISA). The corresponding antibody concentrations were expressed in ELISA units per milliliter (EU/mL) and were measured on blood samples collected from vaccinated maternal subjects.

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed in Estimated Dilution 60 (ED60) and were measured on blood samples collected from vaccinated maternal subjects.

Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA. The corresponding antibody concentrations were expressed in EU/mL. The antibodies were measured on the cord blood sample collected at delivery, or on a blood sample collected from the infant within 3 days after birth (if no cord blood sample could be obtained).

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were presented as GMTs, expressed in ED60. The antibodies were measured on the cord blood sample collected at delivery, or on a blood sample collected from the infant within 3 days after birth (if no cord blood sample could be obtained).

The placental transfer ratio of IgG specific antibody concentration was determined from cord blood (or blood sample collected within 3 days after birth from infants if cord blood was not collected) over that of the blood sample from mother at delivery if blood sample was not collected during delivery). Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA.

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity, was a congenital anomaly/birth defect in the offspring of a study subject or abnormal pregnancy outcomes (spontaneous abortion, foetal death, stillbirth, congenital anomalies, ectopic pregnancy), other situations (medical events that might jeopardize the participant or required medical/surgical intervention to prevent one of the other SAEs listed above: e.g. invasive/malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization). Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Also, for instances where, due to the special circumstances, the subject could not seek medical advice for symptoms/an illness by visiting a medical facility or arranging for a home visit, the subject sought this advice instead via telephone, SMS, email, videotelephony or telemedicine, or other means. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

Percentage of Maternal Subjects With AE Leading to Study Withdrawal From Day 1 to Day 181 Post Delivery

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs leading to study withdrawal = AEs identified by investigators to cause subject(s) withdrawal until the resolution of the event. These subject withdrawals were considered different from subject withdrawals for other reasons.

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject, other situations (medical events that might jeopardize the participant or required medical/surgical intervention to prevent one of the other SAEs listed above: e.g. invasive/malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization). Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs leading to study withdrawal = AEs identified by investigators to cause subject(s) withdrawal until the resolution of the event. These subject withdrawals were considered different from subject withdrawals for other reasons.

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Also, for instances where, due to the special circumstances, the subject could not seek medical advice for symptoms/an illness by visiting a medical facility or arranging for a home visit, the subject sought this advice instead via telephone, SMS, email, videotelephony or telemedicine, or other means. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject, other situations (medical events that might jeopardize the participant or required medical/surgical intervention to prevent one of the other SAEs listed above: e.g. invasive/malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization). Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

Percentage of Infant Subjects With Any AE Leading to Study Withdrawal From Birth to Month 12 Post-birth

An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs leading to study withdrawal = AEs identified by investigators to cause subject(s) withdrawal until the resolution of the event. These subject withdrawals were considered different from subject withdrawals for other reasons.

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Also, for instances where, due to the special circumstances, the subject could not seek medical advice for symptoms/an illness by visiting a medical facility or arranging for a home visit, the subject sought this advice instead via telephone, SMS, email, videotelephony or telemedicine, or other means. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination.

Percentage of Maternal Subjects With RSV-associated Medically Attended Respiratory Tract Illnesses (MA-RTI)

A maternal MA-RTI occurs when the maternal subject visits a healthcare professional for any respiratory symptom, including cough, sputum production and difficulty breathing. An RSV associated MA-RTI is characterised by a medically attended visit for RTI symptoms (runny nose or blocked nose or cough) and a confirmed RSV infection.

An RSV-associated LRTI is characterised by a history of cough or difficulty in breathing, a blood oxygen saturation by pulse oximetry (SpO2) lesser than (<) 95% or respiratory rate increase and a confirmed RSV infection.

A RSV-associated severe LRTI is characterised by a history of cough or difficulty in breathing, a SpO2 < 93% or lower chest wall in-drawing and a confirmed RSV infection.

A RSV-associated very severe LRTI is characterised by a history of cough or difficulty in breathing, a SpO2 < 90% or inability to feed or failure to respond/unconscious and a confirmed RSV infection.

An RSV-associated hospitalisation is characterised by a confirmed RSV infection and a hospitalisation for an acute medical condition.

Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA. The corresponding antibody concentration were expressed in EU/mL.

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-B are performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA. The corresponding antibody concentration were expressed in EU/mL.

Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA. The corresponding antibody concentration were expressed in EU/mL.

Serological assays for the determination of IgG antibodies against RSV MAT were performed by ELISA. The corresponding antibody concentration were expressed in EU/mL.

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-B were performed by neutralization assay. The corresponding antibody titers were expressed in ED60. The antibodies were measured on the cord blood sample collected at delivery, or on a blood sample collected from the infant within 3 days after birth (if no cord blood sample could be obtained).

Serological assays for the determination of antibodies against RSV-B were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-B were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Serological assays for the determination of antibodies against RSV-B were performed by neutralization assay. The corresponding antibody titers were expressed in ED60.

Inclusion Criteria: Maternal subjects Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Subjects 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 (consistent with local regulations / guidelines) either: include consent for both the maternal subject's participation and participation of the infant after the infant's birth, or include consent for the maternal subject's participation and expressed willingness to consider permitting the infant to take part after the infant's birth. Both mother and father should consent if local regulations/guidelines require it. Age 18 to 40 years, inclusive, when informed consent is given. Pre-pregnancy BMI 18.5 to 34.9, inclusive Healthy as established by medical history and clinical examination before entering into the study. At 28^0/7 to 33^6/7 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). * If LMP and U/S do not correlate, default to U/S gestational age assessment. The level of diagnostic certainty of the gestational age should be established by using the Global Alignment of Immunisation safety Assessment in pregnancy gestation age assessment tool Subject satisfying screening requirements Singleton pregnancy HIV negative, as assessed by local standard of care serologic tests conducted during the current pregnancy and before enrolment (Visit 1). No fetal genetic abnormalities. No significant congenital malformations, as assessed by level 2 ultrasound (also known as a fetal anomaly ultrasound scan or fetal morphology assessment) conducted after 18 weeks of gestation Willing to provide cord blood Willing to have the infant followed-up after delivery for a period of 12 months Does not plan after delivery to give the infant for adoption or place the infant 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 subjects Live-born from the study pregnancy. 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 legally authorized representative, as applicable by local law, before performing any study specific procedure. Exclusion Criteria: Maternal subjects 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 such as: Gestational hypertension at ≥20 weeks of gestation in the absence of proteinuria in a woman with a previously normal blood pressure Gestational diabetes which is not controlled by diet and exercise Pre-eclampsia Eclampsia during current pregnancy Intrauterine growth restriction Placenta previa Placental abruption, placenta accreta/percreta/increta, chorioamnionitis or any abnormalities that in the opinion of Investigator can impair the maternal-fetal circulation Polyhydramnios Oligohydramnios Cervical suture in place Preterm labour or history of preterm labour in the current pregnancy Ongoing medical intervention to prevent preterm delivery or medical treatment for suspected preterm delivery Cholestasis Other pregnancy-related complications that in the Investigator's judgement would preclude participation of the subjects in an investigational vaccine trial or might pose risk to the subject due to participation in the study Significant structural abnormalities of the uterus or cervix History of prior stillbirth or neonatal death History of preterm birth History of ≥2 spontaneous abortions Known or suspected HBV or HCV infection, based on medical history and clinical presentation Known or suspected infection during the current pregnancy with Toxoplasma, Parvovirus B19, Syphilis, Zika, Rubella, Varicella, CMV or primary genital Herpes Simplex, based on medical history and clinical presentation Active infection with tuberculosis, based on medical history and clinical presentation Known or suspected impairment of the immune system or autoimmune disorder (based on medical history and physical examination; no laboratory testing required) Lymphoproliferative disorder or malignancy within 5 years before vaccination (excluding effectively treated non-melanoma skin cancer) Any clinically significant grade 1 hematological and/or biochemical laboratory abnormalities identified at screening, which are clinically significant for pregnant women in the second and third trimester Grade ≥ 2 hematological and/or biochemical laboratory abnormalities identified at screening being clinically significant for pregnant women in the second and third trimester Acute or chronic clinically significant conditions, that might pose additional risk to the subject due to participation in the study Any conditions that, may interfere with subject'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 a COVID-19 vaccine. Prior receipt of an RSV vaccine Use of any investigational or non-registered product other than the study vaccine(s)/product(s) during the period beginning 29 days before the dose of study vaccine/product or planned use during the study period Planned administration/administration of any vaccine within 29 days before study vaccine administration and through Day 43 post-delivery, except seasonal influenza vaccines and dTpa/Tdap or tetanus, which may be administered according to standard of care ≥ 15 days before or after study vaccination Administration of immunoglobulins, blood products or plasma derivatives within 3 months before study vaccination or planned administration through Visit 5 Administration of immune-modifying therapy within 6 months before the study vaccine/product dose, 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. Topical, steroids are allowed. Inhaled steroids are allowed if ≤ 500µg/day of beclomethasone or fluticasone, or ≤ 800µg/day of budesonide. Prior/Concomitant clinical study experience Previous participation in a clinical trial of an RSV vaccine Concurrently participating in another clinical study, in which the subject 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 the presence of two or more abuse criteria A local condition that precludes injection of the study drug or precludes assessment of local reactogenicity Consanguinity of maternal subject and her partner (second degree cousins or closer) Any study personnel or their immediate dependants, family, or household members Infant subjects Concurrently participating in another clinical study, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product Child in care

IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.