Immunogenicity and safety of a respiratory syncytial virus fusion protein (RSV F) nanoparticle vaccine in older adults

Abstract

Background: A preventative strategy for Respiratory Syncytial Virus (RSV) infection constitutes an under-recognized unmet medical need among older adults. Four formulations of a novel recombinant RSV F nanoparticle vaccine (60 or 90 μg RSV F protein, with or without aluminum phosphate adjuvant) administered concurrently with a licensed inactivated trivalent influenza vaccine (TIV) in older adult subjects were evaluated for safety and immunogenicity in this randomized, observer-blinded study.

Results: A total of 220 healthy males and females ≥ 60 years of age, without symptomatic cardiopulmonary disease, were vaccinated concurrently with TIV and RSV F vaccine or placebo. All vaccine formulations produced an acceptable safety profile, with no vaccine-related serious adverse events or evidence of systemic toxicity. Vaccine-induced immune responses were rapid, rising as early as 7 days post-vaccination; and were comparable in all formulations in terms of magnitude, with maximal levels attained within 28 (unadjuvanted) or 56 (adjuvanted) days post-vaccination. Peak anti-F protein IgG antibody levels rose 3.6- to 5.6-fold, with an adjuvant effect observed at the 60 μg dose, and a dose-effect observed between the unadjuvanted 60 and 90 μg regimens. The anti-F response persisted through 12 months post-vaccination. Palivizumab-competitive antibodies were below quantifiable levels (<33 μg/mL) at day 0. The rise of antibodies with specificity for Site II peptide, and the palivizumab-competitive binding activity, denoting antibodies binding at, or in proximity to, antigenic Site II on the F protein, closely paralleled the anti-F response. However, a larger proportion of antibodies in adjuvanted vaccine recipients bound to the Site II peptide at high avidity. Day 0 neutralizing antibodies were high in all subjects and rose 1.3- to 1.7-fold in response to vaccination. Importantly, the RSV F vaccine co-administered with TIV did not impact the serum hemagglutination inhibition antibody responses to a standard-dose TIV, and TIV did not impact the immune response to the RSV F vaccine.

Conclusions: RSV F protein nanoparticle vaccine induced increases in measures of functional immunity to RSV in older adults and demonstrated an acceptable safety profile. Adjuvanted formulations provided additional immunogenicity benefit as compared to increasing antigen dose alone. This trial was registered with ClinicalTrials.gov number NCT01709019.

Keywords: Anti-F IgG; Avidity; F or fusion protein; Microneutralization; Nanoparticle vaccine; Palivizumab-competitive antibody (PCA); Recombinant; Respiratory syncytial virus (RSV).

Figures

Fig. 1

Subject disposition

Fig. 2

Anti-F IgG response summary and comparative analysis to assess for an adjuvant and antigen dose-effect. a Anti-F IgG response kinetics in active vaccine and placebo recipients co-administered TIV. Data are represented by the GMEU and 95% CIs, calculated as the antilog of the mean and 95% confidence limits of log10-transformed anti-F IgG EU values. EU values below the assay lower limit of quantitation (LLOQ) of 400 were set to half LLOQ for the purposes of calculation. b Demonstration of an adjuvant effect based on the GMRAdjuvant/Unadjuvanted analysis of anti-F IgG EUs on days 28 and 56 in individual groups administered 60 (red bars) or 90 μg (black bars) RSV F doses or pooled groups (60 and 90 μg, hatched gray bars), with or without adjuvant. Results indicated as significant by single (p = 0.016) or double (p = 0.005) asterisks allow rejection of the null hypothesis of GMRAdjuvant/Unadjuvanted = 1. c Antigen dose-effect analysis based on the GMR90 μg/60 μg of anti-F IgG GMEUs on days 28 and 56 of 90 or 60 μg RSV F recipients of adjuvanted (black bars) or unadjuvanted (black striped bars), or adjuvanted and unadjuvanted (pooled, white bars) vaccines. Results indicated as significant by single (p = 0.05), double (p = 0.022), or triple (p = 0.002) asterisks allow rejection of the null hypothesis of GMR90 μg/60 μg = 1

Fig. 3

Antibody responses to the antigenic Site II epitope of the RSV F protein. Antibody response kinetics based on PCA (μg/mL with 95% CIs, a) and Site II Peptide (GMT with 95% CIs, c) ELISAs in active vaccine and placebo recipients co-administered TIV. Scatter plots (b) of anti-F IgG EU versus PCA concentration on pre-immune sera (baseline, day 0) from all groups and on day 28 sera from placebo recipients (squares, both figures) and pooled unadjuvanted (triangles, top figure) or adjuvanted (triangles, bottom figure) RSV F vaccine recipients. The hatched blue line denotes the perfect concordance, while the solid red line denotes the observed concordance. Surface plasmon resonance with antigenic Site II peptide (d) using days 0 and 56 sera obtained from unadjuvanted or aluminum phosphate adjuvanted, 90 μg RSV F vaccine recipients, or placebo recipients (N = 15 subjects per group); or using a palivizumab control (n = 8 replicates). All data points in the entire group were used to calculate the geometric mean koff

Fig. 4

Summary of RSV/A and RSV/B Microneutralization Responses. RSV/A (a) and RSV/B (b) microneutralization antibody response kinetics in active vaccine and placebo recipients co-administered TIV based on the fold-rise in post-vaccination GMTs relative to baseline (GMRPost/Pre). Data are represented by the GMT and associated 95% CIs. The pooled day 0 GMT was log2 8.2 or GMT 294 (258–334 95% CI) for RSV/A MN and log2 8.1 or GMT 284 (239–336, 95% CI) for RSV/B MN

Fig. 5

Influenza HAI titers in TIV co-administered RSV F vaccine and placebo recipients. HAI GMTs (left axis) with associated 95% CIs to the A/California (a), A/Victoria (b), and A/Wisconsin (c) vaccine strains in each treatment group at day 0 (black bars) or day 28 (gray bars). Point estimates of day 28 HAI seroconversion (red triangles) and seroprotection (blue squares) rates by treatment group are also shown (right axis)