In silico 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 in silico immunogenicity screen was carried out on 49 well-known Bordetella pertussis 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 in silico 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 in vitro. 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.

KEYWORDS:

• Pertussis
• OMV
• vaccine
• HLA class II
• T cell epitopes
• tolerance
• immunoinformatics
• EpiMatrix
• JanusMatrix

Acknowledgments

The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. We would like to acknowledge Sundos Khan for her help in reviewing this manuscript, and the EpiVax laboratory team for performing the HLA Binding assays.

Disclosure of potential conflicts of interest

ADG and WM are senior officers and majority shareholders, and GR and PH were employees, at the time this research was conducted, of EpiVax, Inc., a company specializing in the immunoinformatic analysis. These authors recognize the presence of a potential conflict of interest and affirm that the information represented in this paper is original and based on unbiased observations.

Supplementary Material

Supplemental data for this article can be accessed online at http://dx.doi.org/10.1080/21645515.2019.1703453.

Additional information

Funding

This work was supported by the Health Holland [LSHM16019].