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.
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.
|Sanapala, Shilpa; Rahav, Hannah; Patel, Hetal et al. (2016) Multiple antigens of Yersinia pestis delivered by live recombinant attenuated Salmonella vaccine strains elicit protective immunity against plague. Vaccine 34:2410-2416|
|Sun, Wei; Sanapala, Shilpa; Rahav, Hannah et al. (2015) Oral administration of a recombinant attenuated Yersinia pseudotuberculosis strain elicits protective immunity against plague. Vaccine 33:6727-35|
|Fisher, Michael L; Sun, Wei; Curtiss 3rd, Roy (2014) The route less taken: pulmonary models of enteric Gram-negative infection. Pathog Dis 70:99-109|
|Sun, Wei; Olinzock, Joseph; Wang, Shifeng et al. (2014) Evaluation of YadC protein delivered by live attenuated Salmonella as a vaccine against plague. Pathog Dis 70:119-31|
|Wang, Shifeng; Shi, Huoying; Li, Yuhua et al. (2013) A colanic acid operon deletion mutation enhances induction of early antibody responses by live attenuated Salmonella vaccine strains. Infect Immun 81:3148-62|
|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|
|Sun, Wei; Curtiss, Roy (2013) Rational considerations about development of live attenuated Yersinia pestis vaccines. Curr Pharm Biotechnol 14:878-86|
|Sun, Wei; Curtiss 3rd, Roy (2012) Amino acid substitutions in LcrV at putative sites of interaction with Toll-like receptor 2 do not affect the virulence of Yersinia pestis. Microb Pathog 53:198-206|
|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|
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