Tularemia - Research - Developing a Novel Tularemia Vaccine
Author:
Mark Bolanowski1, Wayne Conlan2, Petra Oyston3, Anders, Sjostedt4Summary:
Title: Developing a Novel Tularemia Vaccine Based on Rationally Attenuated Strains of F. tularensis
Company Information for Authors.
1 DynPort Vaccine Company, Frederick, MD, USA.
2 National Research Council Canada Ottawa, Canada.
3 Defence Science and Technology Laboratory, Porton Down, UK.
4 Umea University, Umea, Sweden.
Abstract.
Background: To overcome the potential liabilities of the current tularemia vaccine (LVS), we are testing the hypothesis that a rationally attenuated variant of F. tularensis SCHU S4 is superior to LVS in safety and efficacy.
Methods: Comparative genomics, RNA and protein profiling, and data from other pathogens were used to identify genes whose deletion would likely attenuate SCHU S4. Techniques were developed to delete genes in SCHU S4 via allelic replacement. We developed a mouse model of tularemia in BALB/c mice to assess the virulence and efficacy of mutants. Humoral and cellular immune responses to vaccination and challenge were characterized using immunoproteomics and T cell recall stimulation (LPA, FACS, cytokine expression).
Results: Virulence and efficacy of > 30 single gene knockouts and five double-knockouts were evaluated in vivo. The generation of additional single- and double-knockouts is ongoing as is the generation of transposon insertion mutants to more completely survey the genome for virulence factors. Six single knockouts, three double knockouts, and one insertion mutant are attenuated > 103-fold, and two of these strains are attenuated by „d 107-fold.
Each of these nine strains conferred nearly complete protection against an intradermal challenge with 100 MLD of SCHU S4. One of these strains conferred significant protection against an aerosol challenge with SCHU S4. The characteristic protective immunological response to vaccination in our models is Th1 in nature and thus consistent with published results.
Conclusions: Rationally attenuated strains of SCHU S4 confer protection against tularemia in a mouse model. These findings demonstrate the feasibility of creating an effective and safe vaccine via our approach.
This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN26620050041C.
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