Concomitant Administration of Ad26.RSV.preF/RSV preF Protein Vaccine and High-Dose Influenza Vaccine in Adults 65 Years and Older: A Noninferiority Trial

Abstract

Background: Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults ≥65 years old.

Methods: Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively.

Results: Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration.

Conclusions: Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults ≥65 years old.

Keywords: Ad26.RSV.preF/RSV preF protein; Fluzone-HD; influenza; noninferiority; respiratory syncytial virus.

Figure 1.

Participant disposition (A) and study design (B). The 2 most common causes of study discontinuation were withdrawal of subject consent and loss to follow-up. Immunogenicity assessments were performed on the per-protocol influenza immunogenicity (PPII) and per-protocol respiratory syncytial virus (RSV) immunogenicity (PPRI) sets (A). PPII consisted of all randomized participants who received at least the first study vaccination, while PPRI encompassed those in the Coadministration (CoAd) group who received the first study vaccination and those in the Control group who received the second study vaccination. Participants included in the PPII and PPRI sets did not experience any major protocol deviations expected to impact immunogenicity outcomes, including out-of-window sample collection. Participants in the PPII and PPRI sets had data available for ≥1 of the influenza vaccine strains or RSV immunogenicity, respectively. Day 1, 29, and 57 visits were on-site visits, while month 6 follow-up was performed by phone. Besides these visits, there were also phone calls performed 7 days after each vaccination as a part of safety follow-up (B). Abbreviations: Ad26, adenovector 26; Flu, Fluzone-HD vaccine; HD, high-dose; preF, prefusion conformation-stabilized RSV F protein; QIV, quadrivalent influenza vaccine. ^aTiming relative to vaccination with Ad26.RSV.preF/RSV preF protein.

Figure 2.

Noninferiority analyses for hemagglutination inhibition (HI) antibody responses and respiratory syncytial virus (RSV) preF A immunoglobulin G (IgG) (A), geometric mean titer (GMT) of HI and RSV preF A IgG antibodies (B), and percentage of seroconversion and seroprotection rates in the Coadministration (CoAd) and Control groups (C). An analysis of HI antibody titers was conducted using the per-protocol influenza immunogenicity set, while that on RSV preF A IgG was using the per-protocol RSV immunogenicity set. Noninferiority was achieved as the 95% confidence interval (CI) upper limits of the geometric mean ratio of the HI antibody titers, and the RSV preF A IgG titers were below the predefined 1.5 margin (A). GMTs of HI and RSV preF A IgG antibodies at baseline, day 29, and day 57 were plotted. It is important to note that, in the Control group, the participants received Ad26.RSV.preF/RSV preF protein vaccine at day 29; thus, the day 29 samples of this participant were plotted at day 1 (baseline), and the day 57 samples were plotted at day 29 to allow comparison with the CoAd group. Following the study design, no samples were collected 56 days post–Ad26.RSV.preF/RSV preF protein vaccination in the Control group (B). Seroconversion is defined as an HI antibody titer at 28 days postvaccination ≥1:40 in participants with a prevaccination HI titer of <1:10 or a ≥4-fold HI titer increase in participants with a prevaccination HI titer of ≥1:10. Seroprotection was defined as HI antibody titer at 28 days postvaccination ≥1:40 (C). Abbreviations: Ad26, adenovector 26; EU, enzyme-linked immunosorbent assay units; preF, prefusion conformation-stabilized RSV F protein.

Figure 3.

The percentage of solicited local (A) and systemic (B) adverse events (AEs) reported during the 7-day postvaccination period by worst severity grade. The analysis was performed using the full analysis set (ie, all participants who received ≥1 study vaccination, regardless of protocol deviations). No grade 4 solicited local or systemic AEs were recorded. Post dose 1 represented the period after receiving the first study vaccination, while post dose 2 represented the period after receiving the second dose. Abbreviations: Ad26, adenovector 26; CoAd, Coadministration group; Ctrl, Control group; Flu, Fluzone-HD vaccine; G3, grade 3; HD, high-dose; Pbo, placebo; preF, prefusion conformation-stabilized RSV F protein; RSV, respiratory syncytial virus. ^aDenotes participants who received the Fluzone-HD vaccine. ^bDenotes participants who received the Ad26.RSV.preF/RSV preF protein vaccine.