Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination
Eléna Gonçalves, … , Odile Launay, Behazine Combadière
Eléna Gonçalves, … , Odile Launay, Behazine Combadière
Published March 7, 2019
Citation Information: J Clin Invest. 2019;129(5):1960-1971. https://doi.org/10.1172/JCI125372.
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Clinical Medicine Immunology Vaccines

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination

Abstract

BACKGROUND. Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We explored a strategy to shape the adaptive immune response by targeting innate immune cells through novel immunization routes. METHODS. This randomized phase I/II clinical study (n = 60 healthy subjects aged 18–45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV, season 2012–2013, 1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition [HI], microneutralization [MN] antibodies, and CD4+ and CD8+ effector T cells) were measured at baseline day 0 (d0) and at d21. Blood transcriptome was analyzed at d0 and d1. RESULTS. TIV-specific CD8+ granzyme B+ (GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, whereas immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating 2 clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy and confirmed that 9 genes and the serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T cell or antibody responses. A logistic regression analysis demonstrated that these 9 genes and the serum levels of CXCL10 at d1/d0 best predicted TIV-specific CD8+GRZ+ T cell and antibody responses at d21. CONCLUSION. This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses. TRIAL REGISTRATION. This study has been registered at ClinicalTrials.gov (NCT01707602). FUNDING. This work was supported by grants from the French Ministry of Health PHRCN 2012 – RCT 12061, INSERM-DGOS, the Fondation pour la Recherche Médicale, and the Société Française de Dermatologie (to AS). These funding sources had no direct role in any aspect of the research or article.

Authors

Eléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, Behazine Combadière

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Figure 4

Minimal innate signature correlates with immunological outcome independently of route of immunization.

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Minimal innate signature correlates with immunological outcome independe...
(A) Box-and-whisker plots (minimum to maximum) are depicted for 9 gene expression ratios between d1 and d0 in nonresponders (NR; gray) and responders (R; brown) (d21/d0 ratio ≥ 4 for A/H3N2 or A/H1N1 MN titers [left panel] and ratio ≥ 2 for TIV-specific CD8+GRZ+ T cell responses [right panel]). The Mann-Whitney t test compares responders and nonresponders (*P < 0.05; **P < 0.01; ***P < 0.001). (B) Gene and sample hierarchical clustering of 9 gene expression profiles revealed 2 clusters of subjects: S1 (purple, n = 33), with 3/17 t.c., 13/18 i.d., and all i.m. subjects (n = 17/17), and S2 (yellow, n = 19), with 14/17 t.c. and 5/18 i.d. subjects. Samples are color-coded according to vaccination route: t.c. (blue), i.d. (green), and i.m. (black). The color gradient from green (–0.4, low) to red (0.4, high) indicates the intensity of gene expression. Box-and-whisker plots with the minimum to maximum points of d21/d0 immune responses (from the bottom up: the minimum 25th percentile Q1, median, 75th percentile Q3, and maximum values) for (C) A/H1N1 MN titers, (D) A/H3N2 MN titers, and (E) TIV-specific CD8+GRZ+ T cell responses in the S1 (purple) and S2 (yellow) clusters (left panels). The Mann-Whitney t test compared the S1 and S2 clusters (***P < 0.001). Respective histograms show immune response intensities for each individual in the S1 (purple) and S2 (yellow) clusters (right panels). t.c., blue; i.d., green; and i.m., black.