Use of Bacteroides thetaiotaomicron derived extracellular vesicles as vaccine delivery vehicles for mucosal vaccines against respiratory pathogens

Miquel Clopes, Ariadna (2023) Use of Bacteroides thetaiotaomicron derived extracellular vesicles as vaccine delivery vehicles for mucosal vaccines against respiratory pathogens. Doctoral thesis, University of East Anglia.

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Abstract

Most infectious pathogens enter the body via mucosal sites, yet very few mucosal vaccines have been licensed. Major hurdles in mucosal vaccine development, such as stability, mucosal barriers and immune tolerance, hinder delivery of antigens to mucosa-immune cells. New vaccine delivery systems are therefore needed to provide broad and long-term protection against respiratory viruses. To address these issues Bacteroides thetaiotaomicron (Bt), a human commensal gut bacterium, has been engineered to export into their bacterial extracellular vesicles (BEVs) Yersinia pestis, influenza virus (IV), or SARS-CoV-2 antigens. In addition, two means of decorating Bt BEVs with antigens have also been explored, using highly expressed vitamin B12 receptors and chemical conjugation. Pre-clinical studies using non-human primates (Y. pestis) or murine models (IAV and SARS-CoV-2) were used to determine the immunogenicity of Bt BEV vaccines and their ability to induce protective immune responses.

Native Bt BEVs displayed inherent adjuvanticity after intranasal administration, as shown by their ability to elicit mobilisation of immune cells and the development of organised lymphoid structures in the upper and lower respiratory tract. BEV vaccines were safe with no signs of any adverse effects in immunised animals. Bt BEVs vaccine formulations induced antigen-specific local and systemic humoral (IgA/IgG) and cellular (IFN- and/or TNF- producing CD4/8 T cells) immune responses. For Y. pestis BEV vaccines correlates of protection were obtained from serum antibody mediated neutralisation and cytotoxicity assays using live plague bacteria. BEV-IAV vaccines provided heterotypic protection against a lethal dose of H1N1 IAV. Initial pre-clinical studies of SARS-CoV-2 BEV vaccines showed them to be capable of inducing low levels of antigen-specific mucosal and systemic IgA and IgG antibodies. Additional studies to optimise antigen expression, dose and frequency refinements are needed. The results obtained showed that Bt BEV could be used as a platform to produce mucosal vaccines against respiratory pathogens.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	19 Jun 2023 09:43
Last Modified:	19 Jun 2023 09:43
URI:	https://ueaeprints.uea.ac.uk/id/eprint/92423
DOI:

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