Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F (RSVPreF3) Candidate Vaccine in Older Adults: Phase 1/2 Randomized Clinical Trial

Abstract

Background: The aim of this study 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 1/2, randomized controlled, observer-blind study enrolled 48 young adults (YAs; aged 18-40 years) and 1005 older adults (OAs; aged 60-80 years) between January and August 2019. Participants were randomized into equally sized groups to receive 2 doses of unadjuvanted (YAs and OAs) or AS01-adjuvanted (OAs) vaccine or placebo 2 months apart. Vaccine safety and immunogenicity were assessed until 1 month (YAs) or 12 months (OAs) after second vaccination.

Results: The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific immunoglobulin G [IgG] and RSV-A neutralizing antibody) responses, which increased in an antigen concentration-dependent manner and were highest after dose 1. Compared to prevaccination, the geometric mean frequencies of polyfunctional CD4+ T cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Postvaccination immune responses persisted until end of follow-up. Solicited adverse events 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.

Clinical trials registration: NCT03814590.

Keywords: AS01 adjuvant; F protein; RSV neutralizing antibodies; cell-mediated immunity; respiratory syncytial virus.

Figure 1.

Study design. Relevant points in the study timeline are designated as day (D) and month (M). N indicates number of participants in each study part/group. Dose 1 and 2 indicate vaccine and placebo administration timepoints. Blood sample S was the blood sample drawn for analysis of hematological (blood cell counts and hemoglobin levels) and biochemical (alanine and aspartate aminotransferases, creatinine, blood urea nitrogen, and uric acid) laboratory parameters. Blood sample H was the blood sample collected to measure concentrations of RSVPreF3-specific immunoglobulin and titers of respiratory syncytial virus-specific neutralizing antibodies. Blood sample C was the blood sample collected for analysis of polyfunctional T-cell responses. 30 μg, 60 μg, and 120 μg indicate RSVPreF3 antigen concentration. Abbreviations: AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; IDMC, independent data monitoring committee; Plain, unadjuvanted vaccine formulations; RSVPreF3, prefusion conformation of the respiratory syncytial virus F protein.

Figure 2.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram of participant cohorts in study parts A and B. Abbreviations: AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; pIMD, potential immune-mediated disease; Plain, unadjuvanted vaccine formulations; RSVPreF3, prefusion conformation of the respiratory syncytial virus F protein; SAE, serious adverse event.

Figure 3.

Summary of solicited adverse events (AEs) reported within 7 days after any dose (A) and unsolicited AEs (any within 30 days after any dose, serious AE [SAE], or fatality until study end) (B) in part B (older adults [60–80 years of age]) (exposed set). B, Percentages of participants experiencing at least 1 AE from the following categories and periods: any unsolicited AE within 30 days after any vaccination; an SAE until study end; fatal outcome until study end. 30 µg, 60 µg, and 120 µg indicate prefusion conformation of the respiratory syncytial virus F protein antigen concentration. Abbreviations: AE, adverse event; AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; CI, confidence interval; EoS, end of study; Plain, unadjuvanted vaccine formulation; SAE, serious adverse event.

Figure 4.

Solicited administration-site (A) and systemic adverse events (B) reported within 7 days after any vaccination in part B (older adults [60–80 years of age]) (exposed set). 30 µg, 60 µg, and 120 µg indicate prefusion conformation of the respiratory syncytial virus F protein antigen concentration. Abbreviations: AE, adverse event; AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; CI, confidence interval; GI, gastrointestinal; Plain, unadjuvanted vaccine formulation.

Figure 5.

Prefusion conformation of the respiratory syncytial virus F protein (RSVPreF3)-specific immunoglobulin G geometric mean concentration (A), respiratory syncytial virus (RSV) A-specific neutralizing antibody (nAb) geometric mean titer (GMT) (B), and RSV-B-specific nAb GMT values (C) in part B (older adults [60–80 years of age]) (per-protocol set). *The timepoints in months (0, 1, 2, and 3) reflect days 1 (vaccination 1), 31, 61 (vaccination 2), and 91, respectively. Month 14 data derive from the long-term evaluation subset. C, The data at timepoint month 1 (day 31) were only tested for formulations with the selected concentration of the RSVPreF3 antigen (120 μg) and placebo; the participants were also vaccinated twice and at same timepoints, but the blood samples were not analyzed on day 61. Error bars represent 95% confidence intervals. The syringe symbols above the x-axis designate vaccination timepoints. 30 µg, 60 µg, and 120 µg indicate prefusion conformation of the respiratory syncytial virus F protein antigen concentration. Abbreviations: AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; ED₆₀, estimated dilution 60; ELU, enzyme-linked immunosorbent assay unit; GMC, geometric mean concentration; GMT, geometric mean titer; IgG, immunoglobulin G; nAb, neutralizing antibody; Plain, unadjuvanted vaccine formulations; RSV, respiratory syncytial virus; RSVPreF3, prefusion conformation of the respiratory syncytial virus F protein.

Figure 6.

Geometric mean frequency (GMF) (A) and fold increase (calculated as the ratio of T-cell concentration relative to day 1 values for the corresponding vaccine formulation) (B) in prefusion conformation of the respiratory syncytial virus F protein (RSVPreF3)-specific CD4⁺ T cells expressing at least 2 markers^a and geometric mean frequency of RSVPreF3-specific CD4⁺ T cells expressing at least interferon gamma (IFN-γ)^b (C) in part B (older adults [60–80 years of age]) (per-protocol set). ^aAt least 2 of the following in vitro markers: interleukin (IL) 2, CD40 ligand, tumor necrosis factor-α, IFN-γ. ^bAt least IFN-γ among IFN-γ, IL-13, and IL-17. *The timepoints in months (0, 1, 2, and 3) reflect days 1 (vaccination 1), 31, 61 (vaccination 2), and 91, respectively. Month 14 data derive from the long-term evaluation subset. A and C, The syringe symbols above the x-axis designate vaccination timepoints; dotted lines represent the assay cutoff of 590. GMF values are plotted as the median; error bars denote the range (min, max). 30 µg, 60 µg, and 120 µg indicate RSVPreF3 antigen concentration. Abbreviations: AS01_B and AS01_E, adjuvanted vaccine formulations with the corresponding vaccine adjuvant systems; GMF, geometric mean frequency; IFN-γ, interferon gamma; Plain, unadjuvanted vaccine formulations; RSVPreF3, prefusion conformation of the respiratory syncytial virus F protein.