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

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

Author information

1
InnatOss Laboratories B.V., Oss, Netherlands.
2
EpiVax, Inc., Providence, RI, United States.
3
Department of Cell and Molecular Biology, Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States.
4
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
5
Vaccine and Immunotherapy Center, Massachusetts General Hospital, Boston, MA, United States.
6
Department of Medicine, Yale University School of Medicine, New Haven, CT, United States.

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

PMID:
30828331
PMCID:
PMC6384241
DOI:
10.3389/fimmu.2019.00207
[Indexed for MEDLINE]
Free PMC Article

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