: Yersinia pestis, the causative agent of plague, secretes LcrV (low calcium response V or V antigen) during infection. LcrV triggers release of interleukin 10 (IL-10) by host immune cells and suppresses pro- inflammatory cytokines such as tumor necrosis factor alpha (TNF-a) and interferon-gamma (IFN-Q) as well as innate defense mechanisms required to combat the pathogenesis of plague. Further, LcrV plays an important role in the type III secretion machinery-dependent delivery of Yop virulence factors into host cells as a bacterial means to combat innate immune responses. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of full length LcrV as a human plague vaccine. Herein we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271-300 (rV10) elicited immune responses that protected mice against a lethal challenge with fully virulent Y. pestis strain CO92. When compared to full-length LcrV, rV10 immunization afforded greater levels of vaccine protection in a murine model of pneumonic plague. In contrast to full length LcrV, rV10 displayed reduced ability to release IL-10 from mouse and human macrophages. Further, LPS-stimulated release of pro-inflammatory cytokines by human or mouse macrophages was inhibited by full length LcrV but not by the rV10 variant. Thus, because the rV10 variant displays significantly reduced immune-modulatory properties and superior immunogenicity, rV10 can likely be used as a safe human vaccine to generate protective immunity against plague. This hypothesis will be pursued by an inter-disciplinary team of scientists at the University of Chicago, the Great Lakes RCE for Biodefense & Emerging Infectious Diseases, Cambrex Inc. and SRI International. Product development research is structured to achieve four successive milestones. Following development of GLP large scale production of rV10 (Milestone 1) and GMP grade vaccine preparation (Milestone 2), rV10 vaccine immune responses and safety will be determined (Milestone 3). Using plague challenge of immunized animals, FDA-CBER Animal Rule regulations will be followed to examine vaccine efficacy (Milestone 4). Research protocols will be designed in close collaboration with FDA-CBER and the entire body of acquired information will be used to develop rV10 vaccine as an Investigative New Drug, permitting its future use in human clinical trials. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (M2))
Program Officer
Zou, Lanling
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Miller, Nathan C; Quenee, Lauriane E; Elli, Derek et al. (2012) Polymorphisms in the lcrV gene of Yersinia enterocolitica and their effect on plague protective immunity. Infect Immun 80:1572-82
Quenee, Lauriane E; Ciletti, Nancy A; Elli, Derek et al. (2011) Prevention of pneumonic plague in mice, rats, guinea pigs and non-human primates with clinical grade rV10, rV10-2 or F1-V vaccines. Vaccine 29:6572-83
Quenee, Lauriane E; Ciletti, Nancy; Berube, Bryan et al. (2011) Plague in Guinea pigs and its prevention by subunit vaccines. Am J Pathol 178:1689-700
Quenee, Lauriane E; Berube, Bryan J; Segal, Joshua et al. (2010) Amino acid residues 196-225 of LcrV represent a plague protective epitope. Vaccine 28:1870-6
Cornelius, Claire A; Quenee, Lauriane E; Elli, Derek et al. (2009) Yersinia pestis IS1541 transposition provides for escape from plague immunity. Infect Immun 77:1807-16
Quenee, Lauriane E; Schneewind, Olaf (2009) Plague vaccines and the molecular basis of immunity against Yersinia pestis. Hum Vaccin 5:817-23
Anderson, Deborah M; Ciletti, Nancy A; Lee-Lewis, Hanni et al. (2009) Pneumonic plague pathogenesis and immunity in Brown Norway rats. Am J Pathol 174:910-21
Cornelius, Claire A; Quenee, Lauriane E; Overheim, Katie A et al. (2008) Immunization with recombinant V10 protects cynomolgus macaques from lethal pneumonic plague. Infect Immun 76:5588-97