A Study to Rank Different Dosages of Antigen of GlaxoSmithKline (GSK) Biologicals' Investigational Respiratory Syncytial Virus (RSV) Vaccine (GSK3003891A), Based on Their Immune Response and Safety, When Administered to Healthy Adult Women

Study Overview
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Brief Summary
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The purpose of this study is to rank different RSV vaccine dosages of antigen (or formulations) based on safety/reactogenicity and immune response data. The formulations eliciting strong immune responses while maintaining an acceptable safety profile will be considered for further evaluation, including in studies vaccinating pregnant women.

Detailed Description
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The purpose of the RSV F-021 study that will be conducted in an observer-blind manner during Epoch 1 and single blinded during Epoch 2, is to rank the 3 different doses of the non-adjuvanted investigational RSV PreF-vaccine (30, 60 and 120 μg) based on safety/reactogenicity and immunogenicity data up to 1 month post-vaccination (Day 30). Non-pregnant women aged 18-45 years will be randomized in a 1:1:1:1 ratio to receive one of three dose levels (30, 60, 120 μg) of the RSV PreF vaccine or placebo. The doses eliciting strong immune responses while maintaining an acceptable safety profile will be considered for further evaluation, including in studies vaccinating pregnant women. This will allow evaluation of a wider antigen dose range to determine if there is a dose response relationship in terms of antibody response at the higher dose range that was not present at the lower range. Since in RSV F-021 the 120ug dosage of the PreF-based investigational RSV vaccine will be tested for the first time in humans, appropriate safety monitoring is planned for this study, including pausing enrolment when the first 25% of subjects from each study group have been vaccinated until review of day 7 post-vaccination safety data by an unblinded GSK internal Safety Review Committee (iSRC) has been completed. The enrolment/vaccination of the remaining subjects can only start following the favourable outcome of this iSRC safety review. In addition to study visits at Day 0, Day 7 and Day 30 to evaluate primary objective of the study, additional study visits are planned at Day 60 and 90 for further investigation of the immunogenicity and safety/reactogenicity profile of the formulations. A follow-up period has been set up in which the subjects will be contacted at Day 180, 270 and 360. During these contacts, the investigator (or delegate) will ask the subject if she has experienced any serious adverse events and/or any AEs leading to study withdrawal since Day 90/last contact (as applicable), as well as if she has become pregnant during the post-vaccination period. The investigator (or delegate) will also ask the subject about concomitant vaccinations/products/medications that she has received since Day 90/last contact (as applicable) and whether the she had a respiratory tract infection that needed medical attention. Contact should be preferably performed via telephone, or alternatively, if phone contact is not possible, through email/other means where the information can be fully collected. Healthy, non-pregnant women aged 18 - 45 years will be enrolled in this study: Women aged 18 - 45 years are selected to match the vaccine's target population, i.e. pregnant women, as closely as possible (gender, age). Non-pregnant women are selected to avoid unnecessarily exposing a vulnerable population (pregnant women and the foetuses/children) to a higher dose of the vaccine that has not previously been studied in non-pregnant women.

Official Title
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An Observer-blind Study to Rank Different Formulations of GSK Biologicals' Investigational RSV Vaccine (GSK3003891A) Administered to Healthy Women

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Biological: RSV Vaccine (GSK3003891A) formulation 1
* Biological: RSV Vaccine (GSK3003891A) formulation 2
* Biological: RSV Vaccine (GSK3003891A) formulation 3
* Drug: Placebo (Formulation buffer S9b)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent obtained from the subject prior to performance of any study specific procedure. Non-pregnant female between, and including, 18 and 45 years of age at the time of study vaccination. Healthy subjects as established by medical history and clinical examination before entering into the study. Female subjects of non-childbearing potential may be enrolled in the study Non-childbearing potential is defined as pre-menarche, hysterectomy, ovariectomy or post-menopause. Female subjects of childbearing potential may be enrolled in the study, if the subject: Has practiced adequate contraception for 30 days prior to study vaccination, and Has a negative pregnancy test on the day of study vaccination, and Has agreed to continue adequate contraception up to 90 days after vaccination. Exclusion Criteria: Use of any investigational or non-registered product other than the study vaccines within 30 days prior to study vaccination, or planned use during the study period. Concurrently participating in the active phase of another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product. Chronic administration of immunosuppressants or other immune-modifying drugs, as well as administration of long-acting immune-modifying drugs, within 6 months prior to study vaccination, or planned administration until 90 days post-vaccination. For corticosteroids, this will mean prednisone ≥ 10 mg/day, or equivalent. Inhaled and topical steroids are allowed. Administration of immunoglobulins and/or any blood products during the period starting 3 months before the study vaccination, or planned administration until 90 days post-vaccination. Planned administration/administration of a vaccine not foreseen by the study protocol within the period starting 30 days before and ending 30 days after study vaccination, with the exception of any licensed influenza vaccine which may be administered ≥ 15 days before or after study vaccination. Previous experimental vaccination against RSV. History of any neurological disorders or seizures. Family history of congenital or hereditary immunodeficiency. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination History of or current autoimmune disease Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality as determined by physical examination and/or Medical History. Lymphoproliferative disorder or malignancy within previous 5 years. History of any reaction or hypersensitivity likely to be exacerbated by any component of the study vaccine. Hypersensitivity to latex. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Current alcohol and/or drug abuse. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥37.5°C for oral, axillary or tympanic route, or ≥ 38.0°C for rectal route. Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. For subjects with acute disease and/or fever at the time of enrolment, Visit 1/Day 0 will be rescheduled within the allowed recruitment period. Body mass index (BMI) > 40 kg/m². Pregnant or lactating female. Planned move to a location that will prohibit participating in the trial until study conclusion. Any other condition that the investigator judges may interfere with study procedures or findings.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3003891A vaccine formulation 1 Group<br>Subjects in this group received a single 30 micrograms (µg) dose injection of the investigational GSK3003891A vaccine at Day 0. | Biological: RSV Vaccine (GSK3003891A) formulation 1<br>* Single dose administered intramuscularly at Day 0 in the deltoid region of the non-dominant arm.<br>|
| Experimental: GSK3003891A vaccine formulation 2 Group<br>Subjects in this group received a single 60µg dose injection of the investigational GSK3003891A vaccine at Day 0. | Biological: RSV Vaccine (GSK3003891A) formulation 2<br>* Single dose administered intramuscularly at Day 0 in the deltoid region of the non-dominant arm.<br>|
| Experimental: GSK3003891A vaccine formulation 3 Group<br>Subjects in this group received a single 120µg dose injection of the investigational GSK3003891A vaccine at Day 0. | Biological: RSV Vaccine (GSK3003891A) formulation 3<br>* Single dose administered intramuscularly at Day 0 in the deltoid region of the non-dominant arm.<br>|
| Placebo Comparator: Control Group<br>Subjects in this group received a single placebo injection at Day 0. | Drug: Placebo (Formulation buffer S9b)<br>* A single dose of placebo is administered intramuscularly at Day 0 in the deltoid region of 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 Subjects With Any Grade 2 and Grade 3 General Adverse Events (AEs) - Solicited and Unsolicited | Assessed solicited general AEs were fatigue, gastrointestinal symptoms [nausea, vomiting, diarrhea and/or abdominal pain], fever and headache. 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 and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.Grade 2 symptoms = occurrence of symptoms discomforting enough to interfere with daily activities. Grade 3 symptoms = symptoms that prevented normal activities. This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | During the 7-day (Days 0-6) post-vaccination period | 
| Number of Subjects With Grade 2 and Grade 3 Fever | Grade 2 Fever was defined as oral temperature above (>) 38.5 degrees Celsius (°C) to less than or equal to (≤) 39.5°C. Grade 3 Fever was defined as oral temperature > 39.5°C. This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | During the 7-day (Days 0-6) post-vaccination period | 
| Number of Subjects With Related Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Related SAEs = SAEs assessed by the investigator as related to the vaccination. This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | During the 7-day (Days 0-6) post-vaccination period | 
| Neutralizing Antibody Titers Against RSV-A Subtype | RSV-A is one of the two antigenically distinct subgroups of the Respiratory Synctial Virus (RSV). Antibody titers were determined by neutralization assay and presented as geometric mean titers (GMTs), for a seropositivity cut-off value greater than or equal to (≥) 8 ED60 (Estimated Dilution 60). This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | At Day 0 | 
| Neutralizing Antibody Titers Against RSV-A Subtype | RSV-A is one of the two antigenically distinct subgroups of the Respiratory Synctial Virus (RSV). Antibody titers were determined by neutralization assay and presented as geometric mean titers (GMTs), for a seropositivity cut-off value ≥ 8 ED60 (Estimated Dilution 60). This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | At Day 30 | 
| Palivizumab Competing Antibody (PCA) Concentrations | PCA concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA), presented as geometric mean concentrations (GMCs) and expressed in micrograms per milliliter (µg/mL), for a seropositivity cut-off ≥ 9.6 µg/mL. This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | At Day 0 | 
| Pavilizumab Competing Antibody (PCA) Concentrations | PCA concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA), presented as geometric mean concentrations (GMCs) and expressed in micrograms per milliliter (µg/mL), for a seropositivity cut-off ≥ 9.6 µg/mL. This primary objective focused only on subjects from the investigational GSK3003891A vaccine groups (GSK3003891A vaccine formulation 1 Group, GSK3003891A vaccine formulation 2 Group and GSK3003891A vaccine formulation 3 Group). | At Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any, Grade 2, Grade 3 and Medically Attended Solicited Local AEs | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 2 pain = painful when limb was moved and that interfered with every day activities.Grade 3 pain = significant pain at rest, pain that prevented normal every day activity. Grade 2 redness/swelling = redness/swelling spreading beyond (>) 50 millimeters (mm) and up to (and including) 100 mm of injection site.Grade 3 redness/swelling = redness/swelling > 100 mm of injection site. Medically attended symptoms = occurrence of symptoms that required medical advice. | During the 7-day (Days 0-6) post-vaccination period | 
| Number of Subjects With Any, Grade 2, Grade 3, Related and Medically Attended Solicited General AEs | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (which include nausea, vomiting, diarrhoea and/or abdominal pain), headache, fever [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 2 symptoms = occurrence of symptoms discomforting enough to interfere with daily activities. Grade 3 symptoms = symptoms that prevented normal activities.Related = symptom assessed by the investigator as related to the vaccination. Medically attended symptom = occurrence of symptom that required medical advice. | During the 7-day (Days 0-6) post-vaccination period | 
| Number of Subjects With Any Unsolicited AEs | 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 and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 30-day (Days 0-29) post-vaccination period | 
| Number of Subjects With Any SAEs | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Day 0 up to study end, at Day 360 | 
| Number of Subjects With Any Biochemical and Hematological Laboratory Abnormalities | Biochemical parameters assessed included alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine. Hematological parameters assessed included eosinophils, hemoglobin level, lymphocytes, neutrophils, platelet count and White Blood Cells [WBC]. Abnormal laboratory values at Day 7 were Below, Within and Above normal ranges, as compared to the baseline status of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALT Below - Within = ALT with below normal value at baseline and within normal values at Day 7]. | At Day 7 | 
| Number of Subjects With Any Biochemical and Hematological Laboratory Abnormalities | Biochemical parameters assessed included alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine. Hematological parameters assessed included eosinophils, hemoglobin level, lymphocytes, neutrophils, platelet count and White Blood Cells [WBC]. Abnormal laboratory values at Day 30 were Below, Within and Above normal ranges, as compared to the baseline values of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALT Below - Within = ALT with below normal value at baseline and within normal values at Day 30]. | At Day 30 | 
| Number of Subjects With Any Biochemical and Hematological Laboratory Abnormalities | Biochemical parameters assessed included alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine. Hematological parameters assessed included eosinophils, hemoglobin level, lymphocytes, neutrophils, platelet count and White Blood Cells [WBC]. Abnormal laboratory values at Day 60 were Below, Within and Above normal ranges, as compared to the baseline status of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALT Below - Within = ALT with below normal value at baseline and within normal values at Day 60]. | At Day 60 | 
| Number of Subjects With Any Biochemical and Hematological Laboratory Abnormalities | Biochemical parameters assessed included alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine. Hematological parameters assessed included eosinophils, hemoglobin level, lymphocytes, neutrophils, platelet count and White Blood Cells [WBC]. Abnormal laboratory values at Day 90 were Below, Within and Above normal ranges, as compared to the baseline status of the same parameter, at Day 0 (Unknown, Below, Within and Above normal ranges) [e.g. ALT Below - Within = ALT with below normal value at baseline and within normal values at Day 90]. | At Day 90 | 
| Number of Subjects With Any Biochemical and Hematological Laboratory Abnormalities, by Maximum Grading | The biochemical and hematological parameters analyzed were ALT, AST, creatinine, eosinophils increase, hemoglobin decrease, lymphocytes decrease, neutrophils decrease, platelet count decrease, WBC decrease and WBC increase, which were graded by FDA Toxicity Grading Scale. Assessed grades over the Day 7- Day 90 period were Unknown, Grade 0 (=no grade), Grade 1 (=mild), Grade 2 (=moderate), Grade 3 (=severe) and Grade 4 (=potentially life-threatening), as compared to the baseline status of the same parameters, at Day 0 (Unknown, Grade 1, Grade 2, Grade 3) [e.g. ALT Grade 0 - Unknown = ALT Grade 0 at baseline versus Unknown grade from Day 7 up to Day 90]. | From Day 7 up to Day 90 | 
| Neutralizing Antibody Titers Against RSV-A Subtype | RSV-A is one of the two antigenically distinct subgroups of the Respiratory Synctial Virus (RSV). Antibody titers were determined by neutralization assay and presented as geometric mean titers (GMTs), for a seropositivity cut-off value ≥ 8 ED60. | At Day 60 and Day 90 | 
| Neutralizing Antibody Titers Against RSV-B Subtype | RSV-B is one of the two antigenically distinct subgroups of the Respiratory Synctial Virus (RSV). Antibody titers were determined by neutralization assay and presented as geometric mean titers (GMTs), for a seropositivity cut-off value ≥ 6 ED60. | At Day 0, Day 30, Day 60 and Day 90 | 
| Palivizumab Competing Antibody (PCA) Concentrations | PCA concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA), presented as geometric mean concentrations (GMCs) and expressed in micrograms per milliliter (µg/mL), for a seropositivity cut-off value ≥ 9.6 µg/mL. | At Day 60 and Day 90 | 
| Antibody Concentrations Against Neogenin (NEO) Residual Host Cell Protein | Anti-neogenin (anti-NEO) antibody concentrations were determined by ELISA, presented as geometric mean concentrations (GMCs) and expressed in nanograms per milliliter (ng/mL), for a seropositivity cut-off value ≥ 55 ng/mL. | At Day 0 and Day 30 | 
| Number of Subjects With Any Medically Attended (MA) Respiratory Tract Infections (RTIs) Associated With RSV | MA-RSV-RTIs were defined as a visit to a health care provider for respiratory symptoms including but not limited to cough, sputum production, difficulty breathing. | From Day 0 up to study end, at Day 360 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Vaccines, Respiratory Syncytial Viruses, Reactogenicity, Ranking of Formulations, Immunogenicity