Of the average 57 million annual deaths over the past ten years, more than 20 million are directly due to infectious diseases with millions more due to secondary effects of infections. The numbers of annual deaths due to infections by Salmonella Typhi, Streptococcus pneumoniae and Mycobacterium tuberculosis (Mtb) vary widely but may account for about 13 per cent of the total deaths with an even greater cost due to the severe morbidity associated with these diseases. In the belief that improving health, nutrition and economic well being (the latter dependent on the first two) provide the best means to enhance the quality of life globally, we propose a vaccine development program based on our recent technical developments in using recombinant attenuated Salmonella vaccines (RASV).
Our Specific Aims are: (1) to evaluate S. Typhimurium RASVs with recently perfected and improved genotypes to deliver five different S. pneumoniae protective protein antigens and compare antigen delivery by a mixture of three strains versus a single strain delivering all five antigens o maximize induction of mucosal and systemic antibody responses and to evaluate (i) antibody affinity to a diversity of S. pneumoniae strains representing the major serotypes distributed globally and (ii) induction of protective immunity to intranasal colonization and lethal challenge with mouse-adapted S. pneumoniae strains, (2) to conduct all needed preclinical studies with the optimal S. Typhimurium RASV and with the S. Typhi RASV of essentially the same genotype to validate the S. Typhi RASV for evaluation in future human clinical trials and to then support such clinical trials by providing strains and reagents and assisting in evaluations and verifications, as necessary, (3) to perfect the improved RASV regulated delayed lysis system for delivery of Mtb antigens by T2SS, T3SS and lysis in eukaryotic cell cytosol to generate both CD4- and CD8-dependent immunities against Mtb infection and to evaluate protection conferred by immunization by RASV-Mtb vaccines alone and following initial immunization with M. bovis BCG, and (4) to design, construct and evaluate recombinant attenuated S. Typhi regulated delayed lysis systems producing the optimal combination of Mtb antigens (determined from Specific Aim 3 and delivered by T2SS, T3SS and lysis in the eukaryotic cell cytosol to confer protection against Mtb infection. We will add to our Master File (filed with FDA), 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 future studies.

Public Health Relevance

Infectious diseases, particularly respiratory tract infections like pneumonia and tuberculosis, continue to have profound adverse effects on humankind, accounting for some 6 to 7 million deaths annually. We have developed recombinant attenuated Salmonella vaccine (RASV) systems that utilize Salmonella's ability to trigger mucosal, systemic and cellular immune responses to deliver antigens of Streptococcus pneumoniae and Mycobacterium tuberculosis to elicit protective immune responses to infections by these two pathogens. We propose to improve and perfect these RASV systems to provide safe, efficacious vaccines that will provide long-lasting protection against pneumonia and TB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI056289-13
Application #
8867121
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Lu, Kristina
Project Start
2003-07-01
Project End
2019-05-31
Budget Start
2015-08-01
Budget End
2016-05-31
Support Year
13
Fiscal Year
2015
Total Cost
$444,683
Indirect Cost
$148,228
Name
University of Florida
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Xin, Wei; Wanda, Soo-Young; Zhang, Xiangmin et al. (2012) The Asd(+)-DadB(+) dual-plasmid system offers a novel means to deliver multiple protective antigens by a recombinant attenuated Salmonella vaccine. Infect Immun 80:3621-33
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

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