<i>In silico</i>identification and modification of T cell epitopes in pertussis antigens associated with tolerance

Abstract

The resurgence of whooping cough since the introduction of acellular (protein) vaccines has led to a renewed interest in the development of improved pertussis vaccines; Outer Membrane Vesicles (OMVs) carrying pertussis antigens have emerged as viable candidates. An <i>in silico</i> immunogenicity screen was carried out on 49 well-known <i>Bordetella pertussis</i> proteins in order to better understand their potential role toward the efficacy of pertussis OMVs for vaccine design; seven proteins were identified as being good candidates for including in optimized cellular and acellular pertussis vaccines. We then screened these antigens for putative tolerance-inducing sequences, as proteins with reduced tolerogenicity have improved vaccine potency in preclinical models. We used specialized homology tools (JanusMatrix) to identify peptides in the proteins that were cross-reactive with human sequences. Four of the 19 identified cross-reactive peptides were detolerized <i>in silico</i> using a separate tool, OptiMatrix, which disrupted the potential of these peptides to bind to human HLA and murine MHC. Four selected cross-reactive peptides and their detolerized variants were synthesized and their binding to a set of eight common HLA class II alleles was assessed <i>in vitro</i>. Reduced binding affinity to HLA class II was observed for the detolerized variants compared to the wild-type peptides, highlighting the potential of this approach for designing more efficacious pertussis vaccines.