Promiscuous Coxiella burnetii CD4 Epitope Clusters Associated With Human Recall Responses Are Candidates for a Novel T-Cell Targeted Multi-Epitope Q Fever Vaccine

Front Immunol. 2019 Feb 15;10:207. doi: 10.3389/fimmu.2019.00207. eCollection 2019.

Abstract

Coxiella burnetii, the causative agent of Q fever, is a Gram-negative intracellular bacterium transmitted via aerosol. Regulatory approval of the Australian whole-cell vaccine Q-VAX® in the US and Europe is hindered by reactogenicity in previously exposed individuals. The aim of this study was to identify and rationally select C. burnetii epitopes for design of a safe, effective, and less reactogenic T-cell targeted human Q fever vaccine. Immunoinformatic methods were used to predict 65 HLA class I epitopes and 50 promiscuous HLA class II C. burnetii epitope clusters, which are conserved across strains of C. burnetii. HLA binding assays confirmed 89% of class I and 75% of class II predictions, and 11 HLA class II epitopes elicited IFNγ responses following heterologous DNA/DNA/peptide/peptide prime-boost immunizations of HLA-DR3 transgenic mice. Human immune responses to the predicted epitopes were characterized in individuals naturally exposed to C. burnetii during the 2007-2010 Dutch Q fever outbreak. Subjects were divided into three groups: controls with no immunological evidence of previous infection and individuals with responses to heat-killed C. burnetii in a whole blood IFNγ release assay (IGRA) who remained asymptomatic or who experienced clinical Q fever during the outbreak. Recall responses to C. burnetii epitopes were assessed by cultured IFNγ ELISpot. While HLA class I epitope responses were sparse in this cohort, we identified 21 HLA class II epitopes that recalled T-cell IFNγ responses in 10-28% of IGRA+ subjects. IGRA+ individuals with past asymptomatic and symptomatic C. burnetii infection showed a comparable response pattern and cumulative peptide response which correlated with IGRA responses. None of the peptides elicited reactogenicity in a C. burnetii exposure-primed guinea pig model. These data demonstrate that a substantial proportion of immunoinformatically identified HLA class II epitopes show long-lived immunoreactivity in naturally infected individuals, making them desirable candidates for a novel human multi-epitope Q fever vaccine.

Keywords: Coxiella burnetii; IFNγ; Q fever; T cell; immunoinformatics; multi-epitope vaccine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bacterial Vaccines / immunology
  • Biomarkers
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Coxiella burnetii / immunology*
  • Cytokines / metabolism
  • Enzyme-Linked Immunospot Assay
  • Epitopes, T-Lymphocyte / immunology*
  • Guinea Pigs
  • HLA Antigens / immunology
  • HLA Antigens / metabolism
  • Humans
  • Immunization
  • Immunogenicity, Vaccine
  • Immunologic Memory*
  • Interferon-gamma / biosynthesis
  • Q Fever / immunology*
  • Q Fever / metabolism
  • Q Fever / prevention & control

Substances

  • Bacterial Vaccines
  • Biomarkers
  • Cytokines
  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Interferon-gamma