A Study to Assess the Safety, Reactogenicity and Immune Response of GlaxoSmithKline (GSK) Biologicals' Investigational Respiratory Syncytial Virus (RSV) Vaccine (GSK3844766A) in Older Adults

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, reactogenicity and immune responses of two doses of the investigational RSV vaccines (with different formulations), when administered intramuscularly (IM) according to a 0, 2 month schedule, in older adults aged 60 to 80 years. As the investigational vaccines have not yet been tested in humans before, the study will first assess the safety, reactogenicity and immune responses in young adults aged 18 to 40 years. The study will thus be conducted in 2 parts (Part A and Part B).

Official Title
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Phase I/II, Observer-blind, Safety, Reactogenicity and Immunogenicity Study of GSK Biologicals' Respiratory Syncytial Virus (RSV) Vaccine GSK3844766A in Subjects Aged 18-40 or 60-80 Years

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Biological: RSV Vaccine (GSK3844766A) unadjuvanted low dose
* Biological: RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01E
* Biological: RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01B
* Biological: RSV Vaccine (GSK3844766A) unadjuvanted medium dose
* Biological: RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01E
* Biological: RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01B
* Biological: RSV Vaccine (GSK3844766A) unadjuvanted high dose
* Biological: RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01E
* Biological: RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01B
* Drug: Placebo (Saline solution)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all subjects: 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 performing any study specific procedure. For Part A: • A male or female between, and including, 18 and 40 years of age at the time of the first vaccination. For Part B: A male or female between, and including, 60 and 80 years of age at the time of the first vaccination. Subjects with residence status allowing free mixing with general community or in an assisted-living facility that provides minimal assistance, such that the subject is primarily responsible for self-care and activities of daily living. Exclusion Criteria: For all subjects: Use of any investigational or non-registered product other than the study vaccine during the period starting 30 days before the first dose of study vaccine, or planned use during the study period. Any medical condition that in the judgment of the investigator would make IM injection unsafe. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting 6 months prior to the first vaccine dose. For corticosteroids, this will mean prednisone (≥ 20 mg/day, or equivalent). Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs or planned administration at any time during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose and ending 30 days after the last dose of study vaccine administration, with the exception of inactivated and subunit influenza vaccines which can be administered up to 14 days before or from 30 days after each study vaccination. Concurrently participating in 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. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. Hypersensitivity to latex. Serious or unstable chronic illness. Patients with chronic stable conditions with or without specific treatment, such as diabetes, hypertension or cardiac disease, are allowed to participate in this study. Any other condition (e.g. chronic obstructive pulmonary disease or severe respiratory condition) that, in the opinion of the investigator, might interfere with the evaluations required by the study. History of any neurological disorders or seizures. Acute disease and/or fever at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by the investigator based on medical history, physical examination or laboratory screening tests. Hepatomegaly, right upper quadrant abdominal pain or tenderness. Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccine or planned administration during the study period. History of chronic alcohol consumption and/or drug abuse as deemed by the investigator to render the potential subject unable/unlikely to provide accurate safety reports. Significant underlying illness that in the opinion of the investigator would be expected to prevent completion of the study. Previous vaccination with an RSV vaccine. Lymphoproliferative disorder and malignancy within 5 years. Body mass index > 40 kg/m². Planned move to a location that will prohibit participating in the trial until study end. At screening: Hematology parameters (complete blood cell count [red blood cells, white blood cells], white blood cells differential count [lymphocytes, neutrophils and eosinophils], platelets count or hemoglobin level) and/or biochemistry parameters (creatinine, blood urea nitrogen or liver enzymes [alanine aminotransferase or aspartate aminotransferase]) outside the normal laboratory ranges, unless the laboratory abnormalities are considered not clinically significant by the investigator. For Part A: Pregnant or lactating female. Female subjects of childbearing potential, except if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. For Part B: Known previous administration of a vaccine containing MPL, QS-21 and/or MF59 (e.g. GSK Biologicals' vaccine against human papillomavirus infection marketed as Cervarix, GSK Biologicals' Herpes Zoster vaccine marketed as Shingrix, an adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine [HZ/su], or MF59 adjuvanted influenza vaccines [e.g. Fluad]). Planned administration of GSK Biologicals' Herpes Zoster vaccine marketed as Shingrix or an adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine [HZ/su] within 180 days after the second dose of the study vaccine. Bedridden subjects.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

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: Group Low Dose_PLAIN_A<br>Subjects in Part A, aged 18-40 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted low dose on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted low dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm<br>|
| Experimental: Group Medium Dose_PLAIN_A<br>Subjects in Part A aged 18-40 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted medium dose, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted medium dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group High Dose_PLAIN_A<br>Subjects in Part A aged 18-40 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted high dose, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted high dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Placebo Comparator: Group Placebo_A<br>Subjects in Part A aged 18-40 years, receiving 2 doses of placebo (saline solution) control, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Drug: Placebo (Saline solution)<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group Low Dose_PLAIN_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted low dose, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted low dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm<br>|
| Experimental: Group Low Dose_AS01E_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01E, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01E<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group Low Dose_AS01B_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01B, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) low dose adjuvanted with AS01B<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm<br>|
| Experimental: Group Medium Dose_PLAIN_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted medium dose, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted medium dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group Medium Dose_AS01E_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01E, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01E<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group Medium Dose_AS01B_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01B, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) medium dose adjuvanted with AS01B<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group High Dose_PLAIN_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of RSV Vaccine (GSK3844766A) unadjuvanted high dose, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) unadjuvanted high dose<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Experimental: Group High Dose_AS01E_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01E, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01E<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm<br>|
| Experimental: Group High Dose_AS01B_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of the RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01B, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Biological: RSV Vaccine (GSK3844766A) high dose adjuvanted with AS01B<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the arm.<br>|
| Placebo Comparator: Group Placebo_B<br>Subjects in Part B aged 60-80 years, receiving 2 doses of placebo (saline solution) control, on a 0, 2 Months schedule, by IM injection into the deltoid region of the arm. | Drug: Placebo (Saline solution)<br>* Two doses administered intramuscularly at Days 1 and 61 in the deltoid region of the 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 Solicited Local Symptoms After First Vaccination Dose | Assessed solicited local AEs at injection site are pain, erythema and swelling. Any erythema/swelling was scored as injection site erythema/swelling with a diameter larger than (>) 20 millimeters (mm) | During a 7-day follow-up period after first vaccination dose (i.e., on the day of vaccination [at Day 1] and 6 subsequent days) | 
| Number of Subjects With Any Solicited Local Symptoms After Second Vaccination Dose | Assessed solicited local AEs at injection site are pain, erythema and swelling. Any erythema/swelling was scored as injection site erythema/swelling with a diameter larger than (>) 20 millimeters (mm) | During a 7-day follow-up period after second vaccination dose (i.e., on the day of vaccination [at Day 61] and 6 subsequent days) | 
| Number of Subjects With Any Solicited General Symptom After First Vaccination Dose | Assessed solicited general symptoms include arthralgia, fatigue, fever [defined as temperature equal to or above 38.0 degrees Celsius (°C)], gastrointestinal symptoms [nausea, vomiting, diarrhea and/or abdominal pain], headache, myalgia and shivering. | During a 7-day follow-up period after the first vaccination dose (i.e., on the day of vaccination [at Day 1] and 6 subsequent days) | 
| Number of Subjects With Any Solicited General Symptom After Second Vaccination Dose | Assessed solicited general symptoms include arthralgia, fatigue, fever [defined as temperature equal to or above 38.0 degrees Celsius (°C)], gastrointestinal symptoms [nausea, vomiting, diarrhea and/or abdominal pain], headache, myalgia and shivering. | During a 7-day follow-up period after the second vaccination dose (i.e., on the day of vaccination [at Day 61] and 6 subsequent days) | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) After Any Vaccination Dose | 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/or any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any is defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During a 30-day follow-up period (i.e., on the day of vaccination and 29 subsequent days) after any vaccination dose (across doses) | 
| Number of Subjects Presenting Change From Baseline in Hematology and Biochemistry With Respect of Normal Laboratory Ranges, After First Vaccine Dose (Part A Groups) | Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, lymphocytes, monocytes, neutrophils, platelets, white blood cells. Biochemical laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, urea nitrogen and uric acid. Categories reported when comparing Day 1 (pre-vaccination dose 1=baseline) and Day 8 hematological and biochemical laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Ranges level being classified as unknown, below, within or above the normal ranges. | At baseline and at 7 days after the first vaccine dose (Day 8) | 
| Number of Subjects Presenting Change From Baseline in Hematology and Biochemistry With Respect of Normal Laboratory Ranges, After First Vaccine Dose (Part B Groups) | Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, lymphocytes, monocytes, neutrophils, platelets, white blood cells. Biochemical laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, urea nitrogen and uric acid. Categories reported when comparing Day 1 (pre-vaccination dose 1=baseline) and Day 8 hematological and biochemical laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Ranges level being classified as unknown, below, within or above the normal ranges. | At baseline and at 7 days after the first vaccine dose (Day 8) | 
| Number of Subjects Presenting Change From Baseline in Hematology and Biochemistry With Respect of Normal Laboratory Ranges, After Second Vaccine Dose (Part A Groups) | Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, lymphocytes, monocytes, neutrophils, platelets, white blood cells. Biochemical laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, urea nitrogen and uric acid. Categories reported when comparing Day 61 (pre-vaccination dose 2=baseline) and Day 68 hematological and biochemical laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Ranges level being classified as unknown, below, within or above the normal ranges. | At baseline and at 7 days after the second vaccine dose (Day 68) | 
| Number of Subjects Presenting Change From Baseline in Hematology and Biochemistry With Respect of Normal Laboratory Ranges, After Second Vaccine Dose (Part B Groups) | Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, lymphocytes, monocytes, neutrophils, platelets, white blood cells. Biochemical laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, urea nitrogen and uric acid. Categories reported when comparing Day 61 (pre-vaccination dose 2=baseline) and Day 68 hematological and biochemical laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Ranges level being classified as unknown, below, within or above the normal ranges. | At baseline and at 7 days after the second vaccine dose (Day 68) | 
| Number of Subjects With Any Grade 3 Non-serious AEs (Solicited and Unsolicited) After First Dose of Vaccination | A Grade 3 AE is any AE assessed as severe, i.e. which prevents normal, everyday activities. In adults, such an AE would, for example, prevent attendance at work and would necessitate the administration of corrective therapy. | During a 30-day follow-up period (i.e., on the day of vaccination at Day 1, and 29 subsequent days) after first dose of vaccination | 
| Number of Subjects With Any Grade 3 Non-serious AEs (Solicited and Unsolicited) After Second Dose of Vaccination | A Grade 3 AE is any AE assessed as severe, i.e. which prevents normal, everyday activities. In adults, such an AE would, for example, prevent attendance at work and would necessitate the administration of corrective therapy. | During a 30-day follow-up period (i.e., on the day of vaccination at Day 61, and 29 subsequent days) after second dose of vaccination | 
| Number of Subjects With Any Serious Adverse Events (SAEs) up to 30 Days After the Second Vaccination | A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization or results in disability/incapacity. | From first vaccination (Day 1) up to 30 days post second vaccination (Day 91) | 
| Number of Subjects With Any Potential Immune-mediated Diseases (pIMDs) up to 30 Days After the Second Vaccination (Part B Groups) | pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. | From first vaccination (Day 1) up to 30 days post second vaccination (Day 91) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any SAEs, up the End of Follow-up Period (Month 14) - Part B Groups | A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization or results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study subject. | From Day 1 up to the end of follow-up period (Month 14) | 
| Number of Subjects Reporting pIMDs up to the End of Follow-up Period (Month 14) - Part B Groups | pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. | From Day 1 up to the end of follow-up period (Month 14) | 
| Number of Subjects With at Least One RSV-confirmed Respiratory Tract Infection (RTI) Episode Post-vaccination Reported During RTI Surveillance - Part B Groups | The number of subjects with at least one RTI case was provided by group. Reported categories are RSV+ (= RTI episode tested as RSV positive by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on nasal/throat swab) and RSV- (= RTI episode tested as RSV negative by qRT-PCR on nasal/throat swab). | During the RSV season (from October 2019 to March 2020) | 
| Humoral Immune Response With Respect to Components of the Investigational Vaccine in Terms of Neutralizing Antibody Titers Against RSV-serotype A | Serological assays for the determination of functional antibodies against RSV-A were performed by neutralization assay. Anti RSV-A neutralizing antibody titers are given as geometric mean titers (GMTs) and expressed as Estimated Dose: serum dilution giving a 60% reduction of the signal compared to a control without serum (ED60). | At pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), on the day of second vaccination (Day 61) and 30 days post-Dose 2 (Day 91) | 
| Humoral Immune Response With Respect to Components of the Investigational Vaccine in Terms of RSVPreF3-specific Immunoglobulin G (IgG) Antibody Concentrations | The detection and the quantification of total IgG antibodies directed against RSVPreF3 in human serum samples were based on an indirect enzyme-linked immunosorbent assay (ELISA). Anti RSVPreF3 antibody concentration is given in geometric mean concentration (GMC) and is expressed in ELISA Laboratory Units per milliliter (ELU/mL). | At pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), on the day of second vaccination (Day 61) and 30 days post-Dose 2 (Day 91) | 
| Descriptive Statistics of the Frequency of RSVPreF3 Specific Cluster of Differentiation 4+ (CD4+) T Cells Expressing at Least 2 Markers | Among markers expressed were interleukin-2 (IL2), cluster of 40 ligand (CD40L), tumor necrosis factor alpha (TNF α) and interferon gamma (IFN γ), in vitro upon stimulation with RSVPreF3 peptide preparations. Reported statistics at each time point during which blood sample were collected for cell-mediated immunity, are geometric mean and inter-quartile range. | At pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), on the day of second vaccination (Day 61) and 30 days post-Dose 2 (Day 91) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory syncytial virus (RSV), Vaccine, Safety, Reactogenicity, Immunogenicity