An Encapsulated Yersinia pseudotuberculosis Is a Highly Efficient Vaccine against Pneumonic Plague

Abstract

BackgroundPlague is still a public health problem in the world and is re-emerging, but no efficient vaccine is available. We previously reported that oral inoculation of a live attenuated Yersinia pseudotuberculosis, the recent ancestor of Yersinia pestis, provided protection against bubonic plague. However, the strain poorly protected against pneumonic plague, the most deadly and contagious form of the disease, and was not genetically defined.Methodology and Principal FindingsThe sequenced Y. pseudotuberculosis IP32953 has been irreversibly attenuated by deletion of genes encoding three essential virulence factors. An encapsulated Y. pseudotuberculosis was generated by cloning the Y. pestis F1-encoding caf operon and expressing it in the attenuated strain. The new V674pF1 strain produced the F1 capsule in vitro and in vivo. Oral inoculation of V674pF1 allowed the colonization of the gut without lesions to Peyer's patches and the spleen. Vaccination induced both humoral and cellular components of immunity, at the systemic (IgG and Th1 cells) and the mucosal levels (IgA and Th17 cells). A single oral dose conferred 100% protection against a lethal pneumonic plague challenge (33×LD50 of the fully virulent Y. pestis CO92 strain) and 94% against a high challenge dose (3,300×LD50). Both F1 and other Yersinia antigens were recognized and V674pF1 efficiently protected against a F1-negative Y. pestis.Conclusions and SignificanceThe encapsulated Y. pseudotuberculosis V674pF1 is an efficient live oral vaccine against pneumonic plague, and could be developed for mass vaccination in tropical endemic areas to control pneumonic plague transmission and mortality.

LcrV Delivered via Type III Secretion System of Live Attenuated Yersinia pseudotuberculosis Enhances Immunogenicity against Pneumonic Plague

“…As we know, recombinant attenuated Salmonella vaccines (RASVs) have been used mostly to induce mucosal and systemic immunity either to Salmonella itself or to heterologous antigens delivered by RASVs (95)(96)(97). Live attenuated Y. pseudotuberculosis strains as oral vaccines against different pathogens, including those causing plague, have been explored (36)(37)(38)(39)(40).…”

“…Derbise et al indicated that introduction of the pGEN-caf plasmid (low-copy-number plasmid) expressing F1 antigen into an attenuated Y. pseudotuberculosis strain V674 to form V674 pF1 greatly enhanced protective efficacy (39). There are significant differences between our study and that by Derbise et al, such as the use of different Y. pseudotuberculosis strains (PB1ϩ versus IP32953), different mouse species (Swiss Webster versus OF1), different challenge strains [KIM6ϩ(pCD1Ap) versus CO92], and different mutations [⌬msbB868::P msbB msbB (EC) ⌬P crp21 ::TT araC P BAD crp versus ⌬HPI ⌬yopK ⌬psaA] and the harboring of different recombinant plasmids (pYA5199 versus pGEN-caf).…”

“…Recently, Derbise et al reported that a single oral immunization of the encapsulated Y. pseudotuberculosis V674pF1 strain offered great protection against a lethal pneumonic plague challenge (39). Therefore, these data demonstrated the feasibility of using modified Y. pseudotuberculosis strains to control plague transmission and induction of mortality.…”

Plague Vaccine Development: Current Research and Future Trends

“…The similar group generated an encapsulated Y. pseudotuberculosis by cloning the F1 encoding caf operon of Y. pestis . A single oral vaccination with the live attenuated Y. pseudotuberculosis V674pF1 imparted significant protection against pneumonic plague in mice (96). Later, the caf operon was manipulated into the chromosome of a genetically attenuated Y. pseudotuberculosis , yielding the VTnF1 strain.…”

Pest und Lungenpest

“…Auch ist nicht bekannt wie lange der Impfschutz anhält. Weitere, z. T. rekombinante Impfstoffe sind in der Entwicklung [48]. In Deutschland ist derzeit kein Präparat zur aktiven Immunisierung zugelassen.…”