Plague caused by the Gram-negative bacterium, Yersinia pestis, is still endemic in parts of the world today. Protection against pneumonic plague is essential to prevent the development and spread of epidemics. Despite this, there are currently no licensed plague vaccines in the western world. Here we describe the means of delivering biologically active plague vaccine antigens directly to mucosal sites of plague infection using highly stable microvesicles (outer membrane vesicles; OMVs) that are naturally produced by the abundant and harmless human commensal gut bacterium Bacteroides thetaiotaomicron (Bt). Bt was engineered to express major plague protective antigens in its OMVs, specifically Fraction 1 (F1) in the outer membrane and LcrV (V antigen) in the lumen, for targeted delivery to the gastrointestinal (GI) and respiratory tracts in a non-human primate (NHP) host. Our key findings were that Bt OMVs stably expresses F1 and V plague antigens, particularly the V antigen, in the correct, immunogenic form. When delivered intranasally V-OMVs elicited substantive and specific immune and antibody responses, both in the serum [immunoglobulin (Ig)G] and in the upper and lower respiratory tract (IgA); this included the generation of serum antibodies able to kill plague bacteria. Our results also showed that Bt OMV-based vaccines had many desirable characteristics, including: biosafety and an absence of any adverse effects, pathology or gross alteration of resident microbial communities (microbiotas); high stability and thermo-tolerance; needle-free delivery; intrinsic adjuvanticity; the ability to stimulate both humoral and cell-mediated immune responses; and targeting of primary sites of plague infection.
Bibliographical noteFunding Information:
This work was supported by SBRI/Innovate UK under the award 971525 (to S. R. C.) and by the UK Biotechnology and Biological Sciences Research Council (BBSRC) under grant numbers BB/L004291/1 and BB/J004529/1 (S. R. C.). The funders had no role in study design, data collection and interpretation nor the decision to submit the work for publication. The authors would like to thank Laura Hunter and Javier Salguero and the PHE Histology unit for their extensive tissue processing and analysis. The authors also acknowledge the support provided by Dr Phil Nugent, Kerry Godwin, Dr Andrew Gorringe, Dr Steven Taylor, Steve Thomas, Dr Francis Alexander, Dr Caroline Cruttwell and Dr Julia Vipond for technical and operational aspects of the PHE elements of the study, as well as the various staff involved in the humane treatment and husbandry of all animals used in the project. The authors also thank the National Institutes of Allergy and Infectious Disease for permission to use Y. pestis strain CO92, and Dr Judith Pell for proof reading and editing the manuscript.
© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology
- gut bacteria
- humoral immunity
- mucosal vaccine
- non-human primates
- outer membrane vesicles