Francisella tularensis is a Category A select agent that can cause severe and fatal disease in humans if an aerosol containing as few as 10-100 CFU is inhaled. It is a category A select agent and is a priority for countermeasure development. The ability of the Type B derived live vaccine strain, LVS, to confer partial protection against aerosol Type A challenge in men provided proof of principle that a live attenuated F. tularensis vaccine could offer partial protection. However, LVS is not licensed by the FDA and suffers from several drawbacks that render it a sub-optimal tularemia vaccine. An optimal live vaccine will be based on introducing precisely defined attenuating mutations into a Type A parent strain and will confer strong protection against exposure to aerosolized virulent Type A F. tularensis. We have developed genetic tools that facilitated engineering of specifically targeted mutations in Type A F. tularensis. Six of the candidate strains from this series tested thus far, demonstrated attenuation in the mouse and/or macrophage survival assays. One of our most advanced candidates, FTT1103, has been shown to confer protection against wild type, Type A challenge in the stringent C57BL/6 mouse model. No other vaccine published in the literature has shown this protective capacity. In this grant application we will make use of the data produced and expertise acquired from the initial Mid Atlantic RCE funding investment to advance promising vaccine candidates to preclinical studies that will confirm their immunogenic and protective potential. Parallel studies using the rabbit and mouse models will allow accelerated progress towards the identification of lead vaccine candidates. These studies will validate the use of these two animal species as relevant models for evaluation of live Francisella vaccine strains, information that is not yet verified. In addition, in vitro assessment of vaccine strain interaction and cytokine induction in infected macrophages will be performed. Our previous studies demonstrated that mutations in Type A strains had significant effects on these critical processes and we hypothesize that a correlation could be made between macrophage data and animal model immunogenicity/efficacy that could suggest a correlate of protection or at the least, essential in vitro responses. Finally, the vaccine candidate that demonstrates protective capacity in the rabbit model will undergo expanded safety studies investigating dose ranges that will be important for advancement. This concerted effort by the assembled experts will allow identification of a promising live attenuated Francisella vaccine strain.

Public Health Relevance

No licensed vaccine is available for the prevention of Francisella tularensis, a Category A bioterror agent. This work will advance the development of a safe and efficacious live vaccine strain that will be protective against the most virulent form of this pathogen and which could be used for high risk groups including first responders and military personnel as well as in the general population in the event of a bioterror attack.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI077909-02
Application #
7933918
Study Section
Special Emphasis Panel (ZAI1-TP-M (J1))
Program Officer
Zou, Lanling
Project Start
2009-09-22
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$570,316
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Holland, Kristen M; Rosa, Sarah J; Kristjansdottir, Kolbrun et al. (2017) Differential Growth of Francisella tularensis, Which Alters Expression of Virulence Factors, Dominant Antigens, and Surface-Carbohydrate Synthases, Governs the Apparent Virulence of Ft SchuS4 to Immunized Animals. Front Microbiol 8:1158
Stinson, Elizabeth; Smith, Le'Kneitah P; Cole, Kelly Stefano et al. (2016) Respiratory and oral vaccination improves protection conferred by the live vaccine strain against pneumonic tularemia in the rabbit model. Pathog Dis 74:
Santiago, Araceli E; Mann, Barbara J; Qin, Aiping et al. (2015) Characterization of Francisella tularensis Schu S4 defined mutants as live-attenuated vaccine candidates. Pathog Dis 73:ftv036
Reed, Douglas S; Smith, Le'kneitah P; Cole, Kelly Stefano et al. (2014) Live attenuated mutants of Francisella tularensis protect rabbits against aerosol challenge with a virulent type A strain. Infect Immun 82:2098-105
Richard, Katharina; Mann, Barbara J; Stocker, Lenea et al. (2014) Novel catanionic surfactant vesicle vaccines protect against Francisella tularensis LVS and confer significant partial protection against F. tularensis Schu S4 strain. Clin Vaccine Immunol 21:212-26
Marohn, Mark E; Barry, Eileen M (2013) Live attenuated tularemia vaccines: recent developments and future goals. Vaccine 31:3485-91
Marohn, Mark E; Santiago, Araceli E; Shirey, Kari Ann et al. (2012) Members of the Francisella tularensis phagosomal transporter subfamily of major facilitator superfamily transporters are critical for pathogenesis. Infect Immun 80:2390-401
Reed, Douglas S; Smith, Le'kneitah; Dunsmore, Tammy et al. (2011) Pneumonic tularemia in rabbits resembles the human disease as illustrated by radiographic and hematological changes after infection. PLoS One 6:e24654
Ohtake, Satoshi; Martin, Russell A; Saxena, Atul et al. (2011) Formulation and stabilization of Francisella tularensis live vaccine strain. J Pharm Sci 100:3076-3087
Cole, Leah E; Laird, Michelle H W; Seekatz, Anna et al. (2010) Phagosomal retention of Francisella tularensis results in TIRAP/Mal-independent TLR2 signaling. J Leukoc Biol 87:275-81

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