Yersinia pestis, in three pandemics, resulted in some 200 million plague deaths and is still endemic throughout the world resulting in sporadic infections. Due to its inability to lead a saprophytic life and its residence in many rodent populations, plague is one of the most feared of zoonotic diseases caused by an obligate animal-human pathogen. The plague bacillus began to be used as a biological weapon at least 800 years ago and is today one of the more likely biological threats. Because of these considerations, we propose to: (i) Construct and evaluate recombinant attenuated Salmonella Typhimurium vaccines (RASV) synthesizing Y. pestis KIM antigens in vivo after oral immunization of mice to identify antigens or combinations of antigens that stimulate protective immunity against all three human pathogenic Yersinia species, including virulent Y. pestis CO92. (ii) Construct and evaluate a recombinant attenuated S. Paratyphi A to deliver multiple protective Y. pestis KIM antigens. If it is found that different antigen delivery modes are required to induce protective immunity to Y. pestis challenge, we will construct all deemed necessary recombinant vaccines to be administered as a cocktail. (iii) Conduct experiments to establish all safety, efficacy and immunogenicity features and provide data to secure an IND license from the FDA, make Master Seeds and validate their stability. We will also develop our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines be clinically evaluated in human volunteers. We will provide research support during the proposed clinical trials.

Public Health Relevance

There is currently no licensed vaccine to protect against plague in the United States. We are developing live recombinant attenuated Salmonella vaccines for delivery of multiple antigens to protect against all pathogenic species of Yersinia, including Yersinia pestis, the causative agent of plague. We will identify the optimal vaccine candidate and prepare all necessary materials and data to support testing it in a Phase I clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057885-09
Application #
8278020
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Zou, Lanling
Project Start
2004-01-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$377,438
Indirect Cost
$129,938
Name
Arizona State University-Tempe Campus
Department
Other Health Professions
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
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Sun, Wei; Six, David A; Reynolds, C Michael et al. (2013) Pathogenicity of Yersinia pestis synthesis of 1-dephosphorylated lipid A. Infect Immun 81:1172-85
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Sun, Wei; Curtiss, Roy (2013) Rational considerations about development of live attenuated Yersinia pestis vaccines. Curr Pharm Biotechnol 14:878-86
Wang, Shifeng; Li, Yuhua; Shi, Huoying et al. (2011) Comparison of a regulated delayed antigen synthesis system with in vivo-inducible promoters for antigen delivery by live attenuated Salmonella vaccines. Infect Immun 79:937-49
Sun, Wei; Six, David; Kuang, Xiaoying et al. (2011) A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. Vaccine 29:2986-98
Wang, Shifeng; Li, Yuhua; Shi, Huoying et al. (2010) Immune responses to recombinant pneumococcal PsaA antigen delivered by a live attenuated Salmonella vaccine. Infect Immun 78:3258-71
Sun, Wei; Roland, Kenneth L; Kuang, Xiaoying et al. (2010) Yersinia pestis with regulated delayed attenuation as a vaccine candidate to induce protective immunity against plague. Infect Immun 78:1304-13
Torres-Escobar, Ascencion; Juarez-Rodriguez, Maria Dolores; Curtiss 3rd, Roy (2010) Biogenesis of Yersinia pestis PsaA in recombinant attenuated Salmonella Typhimurium vaccine (RASV) strain. FEMS Microbiol Lett 302:106-13

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