Yersinia

An Encapsulated Yersinia pseudotuberculosis Is a Highly
Efficient Vaccine against Pneumonic Plague
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Anne Derbise1, Alba Cerda Marın1, Patrick Ave2¤a, Thierry Blisnick1¤b, Michel Huerre2¤c, Elisabeth
Carniel1, Christian E. Demeure1*
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1 Unite de Recherche Yersinia, Institut Pasteur, Paris, France, 2 Unite Histotechnologie et Pathologie, Institut Pasteur, Paris, France

AbstractBackground: Plague 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 contagiousform of the disease, and was not genetically defined.
Methodology and Principal Findings: The 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 strainproduced
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 plaguechallenge (336LD50 of the fully virulent Y. pestis CO92 strain) and 94% against a high challenge dose
(3,3006LD50). Both F1 and other Yersinia antigens were recognized and V674pF1 efficiently protected against a F1-negative
Y. pestis.
Conclusions and Significance: The encapsulated Y. pseudotuberculosis V674pF1 is an efficient live oral vaccine against
pneumonic plague, and could be developed formass vaccination in tropical endemic areas to control pneumonic plague
transmission and mortality.
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Citation: Derbise A, Cerda Marın A, Ave P, Blisnick T, Huerre M, et al. (2012) An Encapsulated Yersinia pseudotuberculosis Is a Highly Efficient Vaccine against
Pneumonic Plague. PLoS Negl Trop Dis 6(2): e1528. doi:10.1371/journal.pntd.0001528
Editor: Pamela L. C. Small, University ofTennessee, United States of America
Received July 22, 2011; Accepted December 29, 2011; Published February 14, 2012
Copyright: ß 2012 Derbise et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Funding: Thisstudy was funded in part by an ‘‘Action Concerte Incitative Microbiologie’’ grant from the French Ministry of Health (ACIM-5-3). The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: cdemeure@pasteur.fr
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¤a Current address:Unite d’Histopathologie Humaine et Mode Animaux, Institut Pasteur, Paris, France
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¤b Current address: Unite de Biologie Cellulaire des Trypanosomes, Institut Pasteur, Paris, France
¤c Current address: Service de Pathologie, Institut Curie, Paris, France

migrate to the draining lymph nodes, causing the bubonic form of
plague, which evolves toward septicemia and death within one
week iftreatment is not rapidly started. When the bacteria reach
the lungs, an acute pneumonia develops. Patients become highly
contagious through the emission of infected aerosols that cause
primary pneumonic plague. The disease is then generally fatal
within 3 days or less. Human-to-human transmission of pneumonic plague favors a rapid spread of the disease in heavily
populated areas, as occurred...