Genome-based prediction of cross-protective, HLA-DR-presented epitopes as putative vaccine antigens for multiple Bordetella species

Abstract

ABSTRACT 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.

Keywords

• Bordetella pertussis
• epitope vaccines
• cross-protection
• immunogenicity