Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses

Judith Falloon, H Keipp Talbot, Craig Curtis, John Ervin, Diane Krieger, Filip Dubovsky, Therese Takas, Jing Yu, Li Yu, Stacie L Lambert, Tonya Villafana, Mark T Esser, Judith Falloon, H Keipp Talbot, Craig Curtis, John Ervin, Diane Krieger, Filip Dubovsky, Therese Takas, Jing Yu, Li Yu, Stacie L Lambert, Tonya Villafana, Mark T Esser

Abstract

This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this randomized, double-blind study, 261 subjects aged ≥60 years received inactivated influenza vaccine (IIV), a vaccine containing 120 μg sF with escalating doses of GLA (1, 2.5, or 5 μg) in SE, or a vaccine containing 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were also randomized to receive IIV or placebo. Immunity to RSV was assessed by detection of microneutralizing, anti-F immunoglobulin G, and palivizumab-competitive antibodies and F-specific gamma interferon enzyme-linked immunosorbent spot assay T-cell responses. Higher adjuvant doses increased injection site discomfort, but at the highest dose, the reactogenicity was similar to that of IIV. Significant humoral and cellular immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulation resulted in the highest responses in all subjects and in older subjects. These results confirm previous observations of vaccine tolerability, safety, and immunogenicity and were used to select the 120 μg sF plus 5.0 μg GLA formulation for phase 2 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT02289820.).

Keywords: TLR-4 agonist; adjuvant; adult; cell-mediated immunity; respiratory syncytial virus; vaccine.

Copyright © 2017 Falloon et al.

Figures

FIG 1
FIG 1
Immunogenicity of an RSV sF vaccine adjuvanted with GLA in 2% SE (GLA-SE) by dose. (A) RSV microneutralization antibody titer at postdose day 29; (B) anti-F IgG antibody levels (antibody units per milliliter) at postdose day 29; (C) palivizumab-competitive antibody levels (micrograms per milliliter) at postdose day 29; (D) F-specific gamma interferon ELISPOT assay results (number of spot-forming cells [SFC] per 106 peripheral blood mononuclear cells [PBMC]) at postdose day 8. Bars, medians and first and third quartiles; black dotted lines, lower limit of quantitation (LLOQ); red dotted lines, 67th percentile of baseline microneutralizing antibody titers or 90th percentile of the baseline levels for the other assays. F IgG, F-specific IgG; PCA, palivizumab-competitive antibody; RSV, respiratory syncytial virus.
FIG 2
FIG 2
Percentage of subjects with day 29 humoral immunogenicity and day 8 F-specific gamma interferon ELISPOT assay results greater than the 67th percentile of the baseline titer (microneutralization assay) or 90th percentile of the baseline levels (all other assays). Values for all subjects combined have a yellow background; values less than the values for all subjects have a gray background, and values more than the values for all subjects have a green background. By cohort, results are presented for all subjects and for subjects older than the median age (69 years). ELISPOT, F-specific gamma interferon enzyme-linked immunosorbent spot assay; F IgG, F-specific IgG; GLA, glucopyranosyl lipid A; MN, microneutralization assay; PCA, palivizumab-competitive antibodies; RSV, respiratory syncytial virus; SE, stable emulsion; sF, soluble RSV fusion protein.
FIG 3
FIG 3
Anti-F immunoglobulin G antibody level over time in subjects who received either the RSV vaccine (by dose) or the influenza vaccine. The geometric mean fold rise in the antibody level from that at the baseline is presented by day postdose. CI, confidence interval; F IgG, F-specific IgG; GLA, glucopyranosyl lipid A; RSV, respiratory syncytial virus; SE, stable emulsion; sF, soluble RSV fusion protein.
FIG 4
FIG 4
Study dosing cohorts. Subjects within each cohort were randomized to the investigational product arm and, for subjects receiving a vaccine in each arm, to the dosing arm. For analysis, all subjects receiving IIV (with or without placebo) were combined into a control group. GLA, glucopyranosyl lipid A; IIV, inactivated influenza vaccine; RSV, respiratory syncytial virus; SE, stable emulsion; sF, soluble RSV fusion protein.

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