Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination
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
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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Clinical Research and Public Health Immunology

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 3

Early innate signature discriminates immunological outcome, rather than route of immunization.

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Early innate signature discriminates immunological outcome, rather than ...
(A) Venn diagram of the genes differentially expressed between paired d1 and d0 for t.c. (blue, n = 17), i.d. (green, n = 18), and i.m. (black, n = 17). Significance for the Bayesian t test was set at a corrected P less than 0.1. The number of genes differentially expressed between d1 and d0 is indicated for each arm. (B) PCA of these 496 genes differentially expressed between d1 and d0. Vaccine administration routes are indicated. (C) Gene and sample hierarchical clustering is based on the expression profiles of these 496 genes. Two sample clusters named C1 (gray) and C2 (red) are observed. For C1, n = 28: t.c. n = 2, i.d. n = 16, i.m. n = 10. For C2, n = 24: t.c. n = 15, i.d. n = 2, i.m. n = 7. The color-gradient from green (–1, low) to red (1, high) indicates fold change d1/d0 gene expression (log2). (D) A major cluster of gene expression, with expression significantly different between C1 and C2, corresponds to the IFN-signaling pathway. Of note, IPA analysis indicated master genes (IRF7 and STAT1) at the center of the network. The red gradient indicates the differential expression between C1 and C2 (1.08- to 4.5-fold change gene expression C1/C2). And the box-and-whisker plot (from the bottom up: the minimum 25th percentile Q1, median, 75th percentile Q3, and maximum values) with minimum to maximum showing all sample points (y axis of graph in log10 scale). It represents the d1/d0 ratio of the CXCL10 serum level from the C1 (gray) and C2 (red) samples. Box-and-whisker plots represent (E) H1N1-specific MN antibody titers (d21/d0 ratios) and (F) TIV-specific CD8+GRZ+ T cells (d21/d0 ratios) according to C1 and C2 clusters (left panels). Respective histograms in E and F show immune response intensities for each individual in C1 (gray) and C2 (red) clusters (right panels). The Mann-Whitney t test compares C1 and C2 for these responses; *P < 0.05; **P < 0.01; ****P < 0.0001.