Genome-based prediction of cross-protective, HLA-DR-presented epitopes as putative vaccine antigens for multiple
Bordetella
species
Authors: Natrajan Muktha S. , Hall Jesse M. , Weigand Michael R. , Peng Yanhui , Williams Margaret M. , Momin Mohamed , Damron Frederick Heath , Dubey Purnima , Tondella Maria Lucia , Pawloski Lucia C. 
Published: December 2023

Acellular pertussis vaccines protect against severe pertussis, but vaccine-induced immunity wanes over time. Prior animal studies showed that T-cell responses are integral to long-lasting immunity. Current pertussis vaccines also do not provide considerable protection against other species that cause pertussis-like illness, such as
Bordetella parapertussis
and
Bordetella holmesii
. We aimed to identify potential vaccine antigens from conserved orthologs that are predicted to engage CD4 T cells and provide cross-protective immunity against multiple
Bordetella
pathogens. Whole-genome sequence data were previously collected for
Bordetella pertussis
,
B. parapertussis
, and
B. holmesii
isolates. Immunoinformatics and comparative genomics were used to predict immunogenicity, cross-reactive proteins, and protein homology for a set of
Bordetella
isolates. Expression and production levels of homologous, immunogenic targets were screened using transcriptomic and proteomic data, and detectable genes were analyzed by reverse transcription quantitative PCR. Computational prediction methods identified putative human leukocyte antigen-DR-binding epitopes. Recognition of targets by T cells from individuals immunized with whole-cell pertussis vaccines was confirmed
ex vivo
. From the
B. pertussis
genome, 408 genes exhibited high sequence conservation with orthologs in
B. parapertussis
and
B. holmesii
, and a select group had high immunogenicity scores. A subset of detectable proteins were also
Bordetella
-specific and non-cross-reactive. Epitope mapping predicted 36 conserved, immunogenic, and naturally processed epitopes. Of these 36 targets, six epitopes upregulated markers of T-cell activation, and three elicited cytokine production. Our findings identified a list of peptides specific to
Bordetella
respiratory pathogens that may confer long-lasting, cross-protective T-cell immunity.

IMPORTANCE

Pertussis, caused by
Bordetella pertussis
, can cause debilitating respiratory symptoms, so whole-cell pertussis vaccines (wPVs) were introduced in the 1940s. However, reactogenicity of wPV necessitated the development of acellular pertussis vaccines (aPVs) that were introduced in the 1990s. Since then, until the COVID-19 pandemic began, reported pertussis incidence was increasing, suggesting that aPVs do not induce long-lasting immunity and may not effectively prevent transmission. Additionally, aPVs do not provide protection against other
Bordetella
species that are observed during outbreaks. The significance of this work is in determining potential new vaccine antigens for multiple
Bordetella
species that are predicted to elicit long-term immune responses. Genome-based approaches have aided the development of novel vaccines; here, these methods identified
Bordetella
vaccine candidates that may be cross-protective and predicted to induce strong memory responses. These targets can lead to an improved vaccine with a strong safety profile while also strengthening the longevity of the immune response.