Background The aim was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3). Methods This phase I/II, randomized, controlled, observer-blind study enrolled 48 young adults (YA; 18–40 years) and 1005 older adults (OA; 60–80 years) between January and August 2019. Participants were randomized into equally sized groups to receive two doses of unadjuvanted (YA and OA) or AS01-adjuvanted (OA) vaccine or placebo two months apart. Vaccine safety and immunogenicity were assessed until one (YA) or 12 months (OA) after second vaccination. Results The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific IgG and RSV-A neutralizing antibody) responses, which increased in an antigen-concentration-dependent manner and were highest post-dose one. Compared to pre-vaccination, the geometric mean frequencies of polyfunctional CD4+ T-cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Post-vaccination immune responses persisted until end of follow-up. Solicited adverse events (AEs) were mostly mild-to-moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation. Conclusions Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development. Trial registration ClinicalTrials.gov NCT03814590; URL: https://clinicaltrials.gov/ct2/show/NCT03814590

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Lay Summary Respiratory syncytial virus (RSV) causes respiratory illnesses, which can lead to serious complications in older adults. We estimated how common infections due to RSV are in adults living in the community or long-term care facilities. For 2 years, we followed approximately 2000 adults 50 years and older in Europe and the United States. Between October 2019 and March 2020, about 2 in 100 adults in this study had RSV infections; of these, fewer than one fifth had complications and there were no hospitalizations or deaths. Other viruses were present for less than one fifth of RSV infections. Between October 2020 and June 2021, during COVID-19 restrictions, we detected RSV infection in one adult, living in a long-term care facility, with no complications. RSV causes respiratory disease among adults 50 years and older and therefore programs to prevent RSV infection are needed in this age group.

Background RSV is a common cause of respiratory acute illness in older adults (OA). We evaluated safety and reactogenicity of RSVPreF3 candidate vaccine in young adults (YA) and OA. Methods In this phase I/II, placebo-controlled, multi-country trial (NCT03814590), YA aged 18–40 years were randomized 1:1:1:1 and received 2 doses of Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted vaccine, or placebo, 2 months apart. Following favorable safety evaluation, a staggered enrolment with 2 steps followed in OA aged 60–80 years, who were randomized 1:1:1:1:1:1:1:1:1:1 to receive 1 of the 9 RSV vaccine formulations containing Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo (same schedule). Safety/reactogenicity up to 1 month post-dose 1 are reported here. Results Exposed set was comprised of 48 YA and 1005 OA. Within 7 days post-dose 1, any solicited/unsolicited adverse event (AE) ranged from 58.3% to 83.3% across YA vaccinees (placebo YA: 58.3%) and from 29.9% to 84.2% across OA vaccinees (placebo OA: 33.7%) (Fig 1). Pain was the most common solicited local AE, being reported in ≤ 58.3% of YA (placebo YA: 0.0%) and at higher rates in the adjuvanted groups (≤ 75.7%) vs non-adjuvanted groups of OA (≤ 14.1%) and placebo OA (4.1%) (Fig 2A). Of solicited general AEs, fatigue (YA: ≤ 41.7% in vaccinees vs 50.0% in placebo; OA: ≤ 48.5% in vaccinees vs 16.3% in placebo) and headache (YA: ≤ 33.3% in vaccinees vs 16.7% in placebo; OA: ≤ 27.7% in vaccinees vs 8.2% in placebo) were most commonly reported (Fig 2B), while fever ≥ 38.0 °C was observed in ≤ 3.0% of OA vaccinees (placebo OA: 0.0%). Grade 3 solicited local and general AEs were observed in OA only, with erythema (≤ 4.9% in vaccinees vs 0.0% in placebo) and fatigue (≤ 2.0% in vaccinees vs 1.0% in placebo) being most common (Fig 2). No serious AEs (SAEs) were reported in YA. A number of 11 OA reported a SAE within 1 month post-dose 1, but none was fatal or assessed as vaccine-related. No clinically significant abnormalities occurred in hematological/biochemical parameters in any group. Figure 1. Percentage of participants presenting at least one type of solicited/unsolicited adverse event (AE) within 7 days post-dose 1 Figure 2. Percentage of participants with at least one type of solicited adverse event (AE) within 7 days post-dose 1 Conclusion First dose of RSVPreF3 candidate vaccine is well tolerated. AE rates tended to be higher after AS01B-adjuvanted formulations compared to other vaccine formulations. No safety concerns were raised. Funding GlaxoSmithKline Biologicals SA Disclosures Jelena Tica, PhD, GSK group of companies (Employee, Shareholder) Javier Ruiz Guiñazú, MD MSc, GSK group of companies (Employee, Shareholder) Charles P. Andrews, MD, GSK group of companies (Scientific Research Study Investigator) Charles Fogarty, MD, GSK group of companies (Grant/Research Support) Edward Kerwin, MD, Amphastar (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)AstraZeneca (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Boehringer Ingelheim (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Chiesi (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Cipla (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)GSK group of companies (Employee, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Mylan (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Novartis (Employee, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)other around 40 pharmaceutical companies (Other Financial or Material Support, conducted multicenter clinical research trials)Pearl (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Sunovion (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Theravance (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Isabel Leroux-Roels, MD PhD, GSK group of companies (Scientific Research Study Investigator) Corinne Vandermeulen, MD PhD, GSK group of companies (Other Financial or Material Support, My university only received Grant/Research Support) Marie-Pierre David, MSc, GSK group of companies (Employee, Shareholder) Nancy Dezutter, PhD, PharmD, RPh, GSK group of companies (Employee, Shareholder) Laurence Fissette, MSc, GSK group of companies (Employee) Juliane Koch, MD, GSK group of companies (Employee, Shareholder) Narcisa Mesaros, MD, MSc, GSK group of companies (Employee)

Background: Adults with diabetes and other conditions are at increased risk of severe RSV disease and hospitalization. In a phase 3 placebo-controlled study (NCT04886596) in adults ≥60 years, RSVPreF3 OA showed 82.6% vaccine efficacy (VE) against RSV-related lower respiratory tract disease (RSV-LRTD) and 71.7% against RSV-related acute respiratory infection (RSV-ARI). We assessed VE among participants with different BMI and with selected pre-existing metabolic or endocrine conditions (eg, diabetes) that increase the risk of severe RSV disease. Methods: Adults ≥60 years were 1:1 randomized to receive 1 dose of RSVPreF3 OA or placebo before the RSV season. VE against first occurrence of RSV-LRTD and RSV-ARI was calculated for different subgroups (Table). Results: In total, 24,966 participants received RSVPreF3 OA (12,467) or placebo (12,499). Of these, 25.7% (RSVPreF3 OA) and 25.9% (placebo) had ≥1 metabolic or endocrine condition (22.9% diabetes). Mean BMI in both groups was 29.1 kg/m2. In participants with overweight/obesity, VE was 85.6% (RSV-LRTD) and 76.3% (RSV-ARI). In those with ≥1 metabolic or endocrine condition, VE was 100% (RSV-LRTD) and 79.4% (RSV-ARI) (Table). Conclusion: RSVPreF3 OA is highly efficacious against RSV-LRTD and RSV-ARI in adults ≥60 years with overweight/obesity and in those with ≥1 metabolic or endocrine condition. Disclosure R. G. Feldman: Research Support; GSK, Speaker's Bureau; Amgen Inc., GSK. V. Hulstroem: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. R. Antonelli incalzi: None. K. Steenackers: Employee; Johnson & Johnson Medical Devices Companies. D. Lee: None. L. Fissette: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. M. David: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. C. Maréchal: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. L. Kostanyan: None. M. Van der wielen: Employee; GlaxoSmithKline plc. Funding GlaxoSmithKline Biologicals SA