Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination

J Clin Invest. 2019 Mar 7;129(5):1960-1971. doi: 10.1172/JCI125372. Print 2019 May 1.

Abstract

Background: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies 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, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1.

Results: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while 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 two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and 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 nine genes and serum levels of CXCL10 (D1/D0) best foreseen 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: ClinicalTrials.gov NCT01707602.

Keywords: Clinical practice; Immunology; Influenza; Innate immunity; Vaccines.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Viral / immunology
  • Antibody Formation
  • CD8-Positive T-Lymphocytes / cytology
  • Chemokine CXCL10 / metabolism
  • Female
  • Gene Expression Profiling
  • Granzymes / metabolism
  • Humans
  • Immunity, Cellular
  • Immunity, Humoral*
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H3N2 Subtype / immunology
  • Influenza Vaccines / immunology*
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control
  • Male
  • Middle Aged
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcriptome
  • Vaccination
  • Young Adult

Substances

  • Antibodies, Viral
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Influenza Vaccines
  • Granzymes

Associated data

  • ClinicalTrials.gov/NCT01707602

Grant support

INSERM-DGOSThe Fondation pour la recherche médicale (FRM)Société Française de Dermatologie