The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK A, GSK A, GSK A, GSK A, GSK A, GSK A Study Number: (RSV F-001) Title: An observer-blind study to evaluate the safety, reactogenicity and immunogenicity of GSK Biologicals Respiratory Syncytial Virus (RSV) investigational vaccine (GSK A) in healthy men. GSK A (RSV): GlaxoSmithKline (GSK) Biologicals RSV investigational vaccine. Rationale: The purpose of this first-time-in-humans study was to evaluate the safety and immunogenicity of 6 investigational RSV vaccine formulations, when administered as a single intramuscular dose to healthy men aged 18 to 44 years. 3 different concentrations of the active compound were evaluated: low-dose (LD), medium-dose (MD) and -high-dose (HD); each one administered either non-adjuvanted or adjuvanted with aluminium. A placebo was used as control. The subjects were followed-up for approximately 1 year after vaccination, starting from Day 0 up to, and including, Day 360. Epoch 001: Primary starting at Day 0 and ending at, and including Day 60 and Epoch 002 : follow-up starting at Day 180 and ending at, and including Day 360)). GSK A (RSV-LD): GSK Biologicals RSV vaccine, in a LD formulation, non-adjuvanted. GSK A (RSV-LD alum): GSK Biologicals RSV vaccine, LD formulation, aluminium-adjuvanted. GSK A (RSV-MD): GSK Biologicals RSV vaccine, MD formulation, non-adjuvanted. GSK A (RSV-MD alum): GSK Biologicals RSV vaccine, MD formulation, aluminium-adjuvanted. GSK A (RSV-HD): GSK Biologicals RSV vaccine, HD formulation, non-adjuvanted. GSK A (RSV-HD alum): GSK Biologicals RSV vaccine, HD formulation, aluminium-adjuvanted. Phase: I Study Period: 22 July 2013 to 9 April 2014 (Day 60 time point) to 16 march 2015 (Day 360 time point) Study Design: Randomized, observer-blind, single-country, placebo-controlled, dose-escalation* study with 2 steps and 8 groups; 5 in Step 1 (randomization ratio 1:1:1:1:1) and 3 in Step 2 (randomization ratio 1:1:1) *Refer to the Treatment Section below for details on dose-escalation procedures in this study. Centers: 3 centers in Canada Indication: Administration of RSV investigational vaccine in healthy men aged 18 to 44 years Treatment: Study groups were as follows: RSV-LD (Step 1): Subjects received one dose of non-adjuvanted RSV-LD vaccine. RSV-LD alum (Step 1): Subjects received one dose of aluminium-adjuvanted RSV-LD vaccine. RSV-MD (Step 1): Subjects received one dose of non-adjuvanted RSV-MD vaccine. RSV-MD alum (Step 1): Subjects received one dose of aluminium-adjuvanted RSV-MD vaccine. RSV-HD (Step 2): Subjects received one dose of non-adjuvanted RSV-HD vaccine. RSV-HD alum (Step 2): Subjects received one dose of aluminium-adjuvanted RSV-HD vaccine. Control-1 (Step 1): Subjects received one dose of placebo solution. Conrol-2 (Step 2): Subjects received one dose of placebo solution. The RSV vaccine and placebo solution were administered intramuscularly in the deltoid. Enrolment in this study was conducted in a staggered manner, including 2 steps. During Step 1, the LD and MD formulations of the RSV vaccine, non-adjuvanted or adjuvanted with alum, were evaluated. Thereafter, during Step 2, the HD formulations of the RSV vaccine, non-adjuvanted or adjuvanted with alum, were evaluated. Enrolment for this Step 2 was conditional on the favorable outcome of the evaluation of safety data collected from subjects enrolled in Step 1, up to 7 days after vaccination. The safety evaluation was performed by an Internal Safety Review Committee Objectives: To evaluate the safety and tolerability of a single intramuscular dose of the RSV investigational vaccines, up to 60 days after vaccination. Primary Outcome Variable: Occurrence of adverse events (AEs) from vaccination to Day 60, in all subjects, in all groups: o Occurrence of each solicited local and general AE, during a 7-day follow-up period after vaccination (i.e. the day of vaccination and 6 subsequent days). o Occurrence of any hematological (hemoglobin level, white blood cell [WBC], lymphocyte, neutrophil, eosinophil and platelet count) and biochemical (alanine amino-transferase [ALT], aspartate amino-transferase [AST] and creatinine) laboratory abnormality at Day 0, Day 7, Day 30 and Day 60. o Occurrence of any unsolicited AE, during a 30-day follow-up period after vaccination (i.e. the day of vaccination

2 and 29 subsequent days). o Occurrence of any Serious Adverse Events (SAEs) from Day 0 to Day 60. Secondary Outcome Variable(s): Humoral immune response to the investigational RSV vaccines, pre-vaccination (Day 0) and post-vaccination (Day 7, Day 30 and Day 60), in all subjects, in all groups: Neutralizing antibody titers against RSV subgroup A. Neutralizing antibody titers against RSV subgroup B. Enzyme-linked Immunosorbent Assay (ELISA) antibody titers against RSV. Occurrence of AEs, in all subjects, in all groups: Occurrence of any hematological (hemoglobin level, WBC, lymphocyte, neutrophil, eosinophil and platelet count) and biochemical (ALT, AST and creatinine) laboratory abnormality at Day 180 and Day 360. Occurrence of any SAE from Day 60 to the study conclusion. Persistence of the humoral immune response to the investigational RSV vaccines, at Day 180 and Day 360, in all subjects, in all groups: Neutralizing antibody titers against RSV subgroup A. Neutralizing antibody titers against RSV subgroup B. ELISA antibody titers against RSV. Statistical Methods: The analysis was performed on the Total Vaccinated cohort and the Adapted ATP cohort for immunogenicity : - The Total Vaccinated cohort included all subjects with study vaccine administration documented. o The Adapted ATP cohort for immunogenicity used for each time point the corresponding ATP cohort for immunogenicity/persistence.the ATP cohort for immunogenicity - Epoch 001: included all subjects from the Total Vaccinated cohort, meeting all eligibility criteria and for whom the administration route and site of the vaccine was according the protocol, who did not have received a vaccine not specified or forbidden in the protocol up to Day 30 visit and who, up to the Day 60 visit, did not receive a concomitant medication/ product or present with a medical condition leading to exclusion from the ATP analysis, who complied with the protocol-specified timing of the 30 days and 60 days post-vaccination blood sample and for whom postvaccination immunogenicity results were available for at least 1 anti-rsv assay for at least one time point. o The ATP cohort for persistence at Day Epoch 002 included all subjects from the Total Vaccinated cohort, meeting all eligibility criteria and for whom the administration route and site of the vaccine was according the protocol, who did not have received a vaccine not specified or forbidden in the protocol up to Day 30 visit and who, up to the Day 180 visit, did not receive a concomitant medication/ product or present with a medical condition leading to exclusion from the ATP analysis, who complied with the protocolspecified timing of blood sample for persistence of immunogenicity at Day 180 and for whom postvaccination results were available at Day 180 for at least 1 anti-rsv assay. o The ATP cohort for persistence at Day Epoch 002 included all subjects from the Total Vaccinated cohort, meeting all eligibility criteria and for whom the administration route and site of the vaccine was according the protocol, who did not have received a vaccine not specified or forbidden in the protocol up to Day 30 visit and who, up to the Day 360 visit, did not receive a concomitant medication/ product or present with a medical condition leading to exclusion from the ATP analysis, who complied with the protocolspecified timing of blood sample for persistence of immunogenicity at Day 360 and for whom postvaccination results were available at Day 360 for at least 1 anti-rsv assay. Analysis of Safety The analysis was performed on Total Vaccinated cohort. The percentage of subjects with solicited local and general symptoms during the 7-day follow-up period after vaccination was tabulated for each group with exact 95% confidence interval (CI). The same tabulation was performed for Grade 3 solicited local and general symptoms and for solicited general symptoms assessed by the investigator as related to the study vaccination. For each group and for each hematology and biochemistry parameter, the percentage of subjects having hematology and biochemistry results below or above or within the local laboratory normal ranges with reference to baseline was tabulated by time point. The percentage of subjects reporting the occurrence of unsolicited AE during the 30-day follow-up period after vaccination was classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and tabulated by group. The percentages of subjects with SAEs as well as the number of subjects with SAEs assessed by the investigator as related to study vaccination, from study start up to Day 60 and up to study end were classified by MedDRA preferred term and tabulated by group.

3 Analysis of Immunogenicity The analysis was performed on the Adapted ATP cohort for immunogenicity. For the anti-rsv humoral immune response, for each group, at each time point that blood samples were collected for the anti- RSV-A and anti-rsv-b neutralization assay (cut-off = 8 and 6 ED60 respectively) and for the anti-rsv PreF ELISA assay (cutoff =10 EU/mL), the following was performed: -The percentage of subjects above the cut-off and their 95% CI was tabulated. -Geometric mean concentrations/titers (GMCs/GMTs) and their 95% CI were calculated. Study Population: Healthy males between, and including, 18 and 44 years of age at the time of vaccination were enrolled in the study. Subjects were excluded from the study if they had had previous vaccination against RSV, any confirmed or suspected immunosuppressive or immunodeficient condition, a family history of congenital or hereditary immunodeficiency, history of or current autoimmune disease, history of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines, any clinically significant hematological (hemoglobin level, WBC, lymphocyte, neutrophil, eosinophil and platelet count) and biochemical (ALT, AST and creatinine) abnormality, as per the opinion of the investigator based on the local laboratory normal ranges. Subjects with a minor illness (such as mild diarrhea) without fever could be enrolled at the discretion of the investigator. Written informed consent was obtained from subjects prior to any stud procedure. Number of Subjects: RSV-LD RSV-LD alum RSV-MD RSV-MD alum RSV-HD RSV-HD alum Control 1 Control 2 Planned, N Randomized, N (Total Vaccinated cohort) Completed to Day 60, n (%) 16 (100) 15 (93.8) 15 (100) 15 (93.8) 16 (100) 16 (100) 17 (100) 16 (100) Completed to Day 360, n (%) 16 (100) 15 (93.8) 15 (100) 13 (81.2) 16 (100) 14 (87.5) 16 (94.1) 16 (100) Total Number of subjects withdrawn, n (%) 0 (0.0) 1 (6.3) 0 (0.0) 3 (18.8) 0 (0.0) 2 (12.5) 1 (5.9) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 1 (6.2) 0 (0.0) 3 (18.8) 0 (0.0) 2 (12.5) 1 (5.9) 0 (0.0) Demographics RSV-LD RSV-LD RSV-MD RSV-MD RSV-HD RSV-HD Control alum alum alum 1 Control 2 N (Total Vaccinated cohort) Males, n (%) 16 (100) 16 (100) 15 (100) 16 (100) 16 (100) 16 (100) 17 (100) 16 (100) Mean Age, years (SD) (8.7) (7.8) (7.4) (6.6) (7.2) (7.9) (6.2) (7.5) Median Minimum, Maximum 20, 43 20, 41 21, 43 22, 44 20, 43 21, 42 18, 45 20, 44 White - Caucasian / European Heritage, n (%) 11(68.8) 11 (68.8) 13 (86.7) 10 (62.5) 6 (37.5) 7 (43.8) 12 (70.6) 8 (50.0) Asian - South East Asian Heritage, n (%) 3 (18.8) 1 (6.3) 2 (13.3) 2 (12.5) 5 (31.3) 8 (50.0) 2 (11.8) 6 (37.5) African Heritage / African American, n (%) 1 (6.3) 2 (12.5) 0 (0.0) 2 (12.5) 4 (25.0) 1 (6.3) 0 (0.0) 1 (6.3) Primary Outcome Results: Incidence of solicited local symptoms reported during the 7-day (Days 0-6) post-vaccination period (Total Vaccinated cohort) RSV-LD RSV-LD alum RSV-MD RSV-MD alum 95 % CI 95 % CI 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL N n % LL UL N n % LL UL Pain Redness Any Grade Any >100 mm

4 Swelling Any >100 mm RSV-HD RSV-HD alum Control 1 Control 2 95 % CI 95 % CI 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL N n % LL UL N n % LL UL Pain Any Redness Swelling Grade Any >100 mm Any >100 mm N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of grade. Grade 3 pain = significant pain at rest. Symptom which prevented normal everyday activities Primary Outcome Results: Incidence of solicited general symptoms reported during the 7-day (Days 0-6) post-vaccination period (Total Vaccinated cohort) RSV-LD RSV-LD alum RSV-MD RSV-MD alum 95 % CI 95 % CI 95 % CI 95 % CI Symptom Intensity /Relation ship N n % LL UL N n % LL UL N n % LL UL N n % LL UL Fatigue Any Grade Related Gastrointestinal symptoms Any Grade Related Headache Any Grade Related Temperature (Oral) Symptom 37.5 C >39.5 C Related RSV-HD RSV-HD alum Control 1 Control 2 95 % CI 95 % CI 95 % CI 95 % CI Intensity/ Relations hip N n % LL UL N n % LL UL N n % LL UL N n % LL UL Fatigue Any Grade Related Gastrointestin Any al symptoms Grade Related Headache Any

5 Temperature (Oral) Grade Related C >39.5 C Related N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of grade or relationship to vaccination Grade 3 = symptom which prevented normal everyday activities Related = symptom assessed by the investigator(s) to be causally related to study vaccination. Primary Outcome Results: Distribution of change from baseline in hematology and biochemistry parameters up to Day 360 with respect to normal laboratory ranges (Total Vaccinated cohort) RSV-LD RSV-LD alum Below Within Above Below Within Above N n % n % n % N n % n % n % Laboratory parameter Timing Baseline (PRE)* ALT PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above AST PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above Creatinine PI(D7)* Below Within PI(D30)* Below Within PI(D60)* Below Within

6 PI(D180) Below Within PI(D360) Below Within Eosinophils PI(D7)* Unknown Within Above Within Above PI(D60)* Unknown Within Above Within PI(D360) Unknown Within Hemoglobin PI(D7)* Unknown Within Above Within Above PI(D60)* Unknown Within Above Within Above PI(D360) Unknown Within Above WBC PI(D7)* Unknown Within Within PI(D60)* Unknown

7 Within Within PI(D360) Unknown Within Lymphocytes PI(D7)* Unknown Below Within Below Within PI(D60)* Unknown Below Within Below Within PI(D360) Unknown Below Within Neutrophils PI(D7)* Unknown Below Within Below Within PI(D60)* Unknown Below Within Below Within PI(D360) Unknown Below Within Platelets PI(D7)* Unknown Below Within Below

8 Within PI(D60)* Unknown Below Within Below Within PI(D360) Unknown Below Within RSV-MD RSV-MD alum Below Within Above Below Within Above Laboratory Baseline N n % n % n % N n % n % n % parameter Timing (PRE)* ALT PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above AST PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above Creatinine PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within

9 Above PI(D180) Within Above PI(D360) Within Above Eosinophils PI(D7)* Unknown Within Above PI(D30)* Unknown Within Above PI(D60)* Unknown Within Above Within Above Within Above Hemoglobin PI(D7)* Unknown Within Above PI(D30)* Unknown Within Above PI(D60)* Unknown Within Above Within Above Within Above WBC PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within PI(D60)* Unknown

10 Below Within Below Within Below Within Lymphocytes PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within PI(D60)* Unknown Below Within Below Within Below Within Neutrophils PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within PI(D60)* Unknown Below Within Below Within Below Within Platelets PI(D7)* Unknown Below Within PI(D30)* Unknown

11 Below Within PI(D60)* Unknown Below Within Below Within Below Within RSV-HD RSV-HD alum Below Within Above Below Within Above Laboratory Baseline N n % n % n % N n % n % n % parameter Timing (PRE)* ALT PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above AST PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above Creatinine PI(D7)* Within PI(D30)* Within PI(D60)*

12 Within PI(D180) Within PI(D360) Within Eosinophils PI(D7)* Unknown Within Above PI(D30)* Unknown Within Above PI(D60)* Unknown Within Above Within Above Within Above Hemoglobin PI(D7)* Unknown Below Within Above PI(D30)* Unknown Below Within Above PI(D60)* Unknown Below Within Above Below Within Above Below Within Above WBC PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within

13 PI(D60)* Unknown Below Within Below Within Below Within Lymphocytes PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within PI(D60)* Unknown Below Within Below Within Below Within Neutrophils PI(D7)* Unknown Below Within PI(D30)* Unknown Below Within PI(D60)* Unknown Below Within Below Within Below Within Platelets PI(D7)* Unknown Within

14 PI(D30)* Unknown Within PI(D60)* Unknown Within Within Within Control 1 Control 2 Below Within Above Below Within Above Laboratory Baseline N n % n % n % N n % n % n % parameter Timing (PRE)* ALT PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above AST PI(D7)* Within Above PI(D30)* Within Above PI(D60)* Within Above PI(D180) Within Above PI(D360) Within Above Creatinine PI(D7)* Below Within Above PI(D30)* Below Within Above

15 PI(D60)* Below Within Above PI(D180) Below Within Above PI(D360) Below Within Above Eosinophils PI(D7)* Unknown Within Above Within Above PI(D60)* Unknown Within Above Within Above Within Above Hemoglobin PI(D7)* Unknown Within Above Within Above PI(D60)* Unknown Within Above Within Above Within Above WBC PI(D7)* Unknown Below Within Below Within

16 PI(D60)* Unknown Below Within Below Within Below Within Lymphocytes PI(D7)* Unknown Below Within Below Within PI(D60)* Unknown Below Within Below Within Below Within Neutrophils PI(D7)* Unknown Below Within Below Within PI(D60)* Unknown Below Within Below Within Below Within Platelets PI(D7)* Unknown Below Within

17 Below Within PI(D60)* Unknown Below Within Below Within Below Within N = number of subjects with available results for the specified laboratory parameter and timing in a given baseline category n/% = number/percentage of subjects in the specified category Unknown = missing normal laboratory range for the specified laboratory parameter Below = below the normal laboratory range defined for the specified laboratory parameter Within = within the normal laboratory range defined for the specified laboratory parameter Above = above the normal laboratory range defined for the specified laboratory parameter ALT=Alanine Aminotransferase AST = Aspartate Aminotransferase WBC = White Blood Cells PI(D7) = Post-vaccination at Day 7 PI(D30) = Post-vaccination at Day 30 PI(D60) = Post-vaccination at Day 60 PI(D180) = Post-vaccination at Day 180 PI(D360) = Post-vaccination at Day 360 *Primary outcome variables Primary Outcome Results: For results about unsolicited AEs and SAEs, please refer to the safety section of the document. Secondary Outcome Results: Number and percentage of subjects with Anti-RSV-A neutralizing antibody titer equal to or above the seropositivity threshold and GMTs, up to Day 360 (Adapted ATP cohort for immunogenicity) 8 ED60 GMT 95% CI 95% CI Antibody Timing N n % LL UL value LL UL Anti-RSV A Neutralizing Antibody RSV-LD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-LD alum PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-MD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360)

18 RSV-MD alum PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD alum PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) Control 1 PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) Control 2 PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0 PI(D7) = Post-vaccination at Day 7 PI(D30) = Post-vaccination at Day 30 PI(D60) = Post-vaccination at Day 60 PI(D180) = Post-vaccination at Day 180 PI(D360) = Post-vaccination at Day 360 Secondary Outcome Results: Number and percentage of subjects with Anti-RSV-B neutralizing antibody titer equal to or above the seropositivity threshold and GMTs, up to Day 360 (Adapted ATP cohort for immunogenicity) 6 ED60 GMT 95% CI 95% CI Antibody Timing N n % LL UL value LL UL Anti-RSV B Neutralizing Antibody RSV-LD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-LD alum PRE PI(D7) PI(D30) PI(D60) PI(D180)

19 PI(D360) RSV-MD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-MD alum PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD alum PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) Control 1 PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) Control 2 PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0 PI(D7) = Post-vaccination at Day 7 PI(D30) = Post-vaccination at Day 30 PI(D60) = Post-vaccination at Day 60 PI(D180) = Post-vaccination at Day 180 PI(D360) = Post-vaccination at Day 360 Secondary Outcome Results: Number and percentage of subjects with ELISA Anti-RSV PreF antibody concentration equal to or above the seropositivity threshold and GMCs up to Day 360 (Adapted ATP cohort for immunogenicity) 10 EU/mL GMC (EU/mL) 95% CI 95% CI Antibody Timing N n % LL UL value LL UL Anti-RSV PreF antibody RSV-LD PRE PI(D7) PI(D30) PI(D60)

20 RSV-LD alum RSV-MD RSV-MD alum PI(D180) PI(D360) PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) RSV-HD alum Control 1 Control 2 PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) PRE PI(D7) PI(D30) PI(D60) PI(D180) PI(D360) GMC= geometric mean antibody concentration calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0 PI(D7) = Post-vaccination at Day 7 PI(D30) = Post-vaccination at Day 30 PI(D60) = Post-vaccination at Day 60 PI(D180) = Post-vaccination at Day 180 PI(D360) = Post-vaccination at Day 360 Safety Results: Percentage of subjects reporting the occurrence of unsolicited AEs within the 30-day (Days 0-29) postvaccination period (Total Vaccinated cohort)

21 Most frequent adverse events - On-Therapy (occurring within Days 0-29 following vaccination) RSV-LD RSV-LD alum RSV-MD RSV-MD alum RSV-HD RSV-HD alum Control 1 Control 2 N = 15 N = 17 Subjects with any AE(s), n (%) 4 (25.0) 6 (37.5) 5 (33.3) 5 (31.3)) 6 (37.5) 4 (25.0) 4 (23.5) 3 (18.8) Headache - 2 (12.5) (18.8) - 2 (11.8) - Cough 1 (6.3) 2 (12.5) (6.3) - - Injection site bruising 1 (6.3) (12.5) (6.3) Upper respiratory tract infection 1 (6.3) 1 (6.3) (11.8) - Nasopharyngitis (6.7) 1 (6.3) - 1 (6.3) - - Rhinorrhoea 1 (6.3) (5.9) 1 (6.3) Aspartate aminotransferase increased (6.3) (6.3) Diarrhoea 1 (6.3) 1 (6.3) Myalgia (6.7) 1 (6.3) Oropharyngeal pain (6.3) 1 (6.3) - - Sinus headache - 1 (6.3) 1 (6.7) Asthenia (6.3) Back pain (6.7) Constipation (5.9) - Dizziness (6.7) Feeling hot (6.3) Gastroenteritis (6.3) Gastroenteritis viral (6.3) Laceration - 1 (6.3) Lymphadenopathy (6.3) Nasal congestion - 1 (6.3) Nausea 1 (6.3) Pain in extremity - 1 (6.3) Pulmonary congestion - 1 (6.3) Pyrexia (6.3) - - Respiratory tract infection (6.7) Rhinitis (6.7) Sinus congestion (5.9) - Sinusitis 1 (6.3) Throat irritation - 1 (6.3) Throat tightness (6.7) Viral infection (6.3) - - -: Adverse event absent Safety Results: Number (%) of subjects with SAEs up to Day 60 (Total Vaccinated cohort) Serious Adverse Event, n (%) [n assessed by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator as related] Fatal SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator as related] RSV-LD RSV-LD alum RSV-MD N = 15 RSV-MD alum RSV-HD RSV-HD alum Control 1 N = 17 Control 2 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 RSV-LD RSV-LD alum RSV-MD N = 15 RSV-MD alum RSV-HD RSV-HD alum Control 1 N = 17 Control 2 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 Safety Results: Number (%) of subjects with SAEs up to study end.at Day 360 (Total Vaccinated cohort) Serious Adverse Event, n (%) [n assessed by the investigator to be related to study medication] All SAEs RSV-LD RSV-LD alum RSV-MD RSV-MD alum RSV-HD RSV-HD alum Control 1 Control 2