Department of Medicine, Division of Infectious Diseases and Immunology; Program in Molecular Medicine
Bacterial Infections and Mycoses | Immunity | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Therapeutics
Francisella tularensis is an intracellular pathogen causing the disease tularemia, and an organism of concern to biodefence. There is no licensed vaccine available. Subunit approaches have failed to induce protection, which requires both humoral and cellular immune memory responses, and have been hampered by a lack of understanding as to which antigens are immunoprotective. We undertook a preliminary in silico analysis to identify candidate protein antigens. These antigens were then recombinantly expressed and encapsulated into glucan particles (GPs), purified Saccharomyces cerevisiae cell walls composed primarily of beta-1,3-glucans. Immunological profiling in the mouse was used to down-selection to seven lead antigens: FTT1043 (Mip), IglC, FTT0814, FTT0438, FTT0071 (GltA), FTT0289, FTT0890 (PilA) prior to transitioning their evaluation to a Fischer 344 rat model for efficacy evaluation. F344 rats were vaccinated with the GP protein antigens co-delivered with GP-loaded with Francisella LPS. Measurement of cell mediated immune responses and computational epitope analysis allowed down-selection to three promising candidates: FTT0438, FTT1043 and FTT0814. Of these, a GP vaccine delivering Francisella LPS and the FTT0814 protein was able to induce protection in rats against an aerosol challenge of F. tularensis SchuS4, and reduced organ colonisation and clinical signs below that which immunisation with a GP-LPS alone vaccine provided. This is the first report of a protein supplementing protection induced by LPS in a Francisella vaccine. This paves the way for developing an effective, safe subunit vaccine for the prevention of inhalational tularemia, and validates the GP platform for vaccine delivery where complex immune responses are required for prevention of infections by intracellular pathogens.
Vaccines, Antigen encapsulation, Francisella tularensis, Immune response, Mouse models, Antigen isotypes, Enzyme-linked immunoassays, Vaccination and immunization
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Copyright: © 2018 Crown Copyright. This is an open access article distributed under the terms of the Creative Commons CC BY 4.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS One. 2018 Oct 8;13(10):e0200213. doi: 10.1371/journal.pone.0200213. eCollection 2018. Link to article on publisher's site
Whelan AO, Flick-Smith HC, Homan J, Shen ZT, Carpenter Z, Khoshkenar P, Abraham A, Walker NJ, Levitz SM, Ostroff GR, Oyston PC. (2018). Protection induced by a Francisella tularensis subunit vaccine delivered by glucan particles. Open Access Articles. https://doi.org/10.1371/journal.pone.0200213. Retrieved from https://escholarship.umassmed.edu/oapubs/3631
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