We propose to conduct experiments to establish all safety, efficacy and immunogenicity features and provide data to secure IND licenses from FDA for Phase I clinical trials to test recombinant attenuated Salmonella Typhimurium, Paratyphi A and Typhi vaccines to prevent Salmonella-induced gastroenteritis, enteric fever and typhoid fever, respectively, and using these same attenuated vectors to deliver additional protective antigens to protect against all pathogenic Yersinia species, all Shigella species and serotypes and most Escherichia coli EPEC and ExPEC pathovars. We also propose to conduct the same series of studies to enable use of a recently developed Salmonella vaccine to deliver influenza antigens to induce long-term protective cellular immunity and antibody responses to all influenza virus types and type-specific immunity against HA antigens delivered by a newly constructed efficacious DNA vaccine delivery system. The means of attenuation and antigen delivery are based on many innovative newly discovered/developed strategies that are present in three different recombinant attenuated S. Typhi vaccine vectors currently being evaluated in a comparative Phase I clinical trial. In this double-blinded trial, there have been no adverse events, no positive blood cultures and no shedding of vaccine in stools after doses of up to 109 CGU. These Salmonella vectors constitute a most effective adjuvant due to display and delivery of engineered ligands to various innate immunity external and internal receptors and stimulate mucosal immunity in all secretory glands and on all mucosal surfaces. These vaccine constructions can be rapidly altered and verified to deliver or cause synthesis of new protective antigens in two to three weeks and can be cost effectively rapidly manufactured in millions or billions of doses as a thermostable vaccine that can be stockpiled for rapid deployment in any emergency. We will make Master Seeds of all candidate vaccines, validate their potency, safety, genetic purity and stability and amend our Master File with FDA to include all information on the construction and properties of these new vaccine constructions.

Public Health Relevance

We propose to collect all the preclinical research information needed to justify securing government approval to further evaluate the safety and efficacy of these vaccines in human clinical trials. These innovative new vaccines are designed and constructed to protect against infections by a diversity of bacterial pathogens and to validate a newly discovered novel means to immunize against viral pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-NLE-M (J1))
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Alexander, William A
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Arizona State University-Tempe Campus
Other Health Professions
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United States
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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
Brenneman, Karen E; Willingham, Crystal; Kilbourne, Jacquelyn A et al. (2014) A low gastric pH mouse model to evaluate live attenuated bacterial vaccines. PLoS One 9:e87411
Sun, Wei; Sanapala, Shilpa; Henderson, Jeremy C et al. (2014) LcrV delivered via type III secretion system of live attenuated Yersinia pseudotuberculosis enhances immunogenicity against pneumonic plague. Infect Immun 82:4390-404
Wang, Shifeng; Kong, Qingke; Curtiss 3rd, Roy (2013) New technologies in developing recombinant attenuated Salmonella vaccine vectors. Microb Pathog 58:17-28
Sun, Wei; Curtiss, Roy (2013) Rational considerations about development of live attenuated Yersinia pestis vaccines. Curr Pharm Biotechnol 14:878-86
Brenneman, Karen E; Willingham, Crystal; Kong, Wei et al. (2013) Low-pH rescue of acid-sensitive Salmonella enterica Serovar Typhi Strains by a Rhamnose-regulated arginine decarboxylase system. J Bacteriol 195:3062-72
Kong, Wei; Clark-Curtiss, Josephine; Curtiss 3rd, Roy (2013) Utilizing Salmonella for antigen delivery: the aims and benefits of bacterial delivered vaccination. Expert Rev Vaccines 12:345-7
Roland, Kenneth L; Brenneman, Karen E (2013) Salmonella as a vaccine delivery vehicle. Expert Rev Vaccines 12:1033-45
Kong, Wei; Brovold, Matthew; Koeneman, Brian A et al. (2012) Turning self-destructing Salmonella into a universal DNA vaccine delivery platform. Proc Natl Acad Sci U S A 109:19414-9
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

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