The anthrax bioterror attacks in the US in 2001, led to an awareness of the potentially devastating effects of attack with a bioweapon and the recognition of the need to prepare against possible future nefarious events. F. tularensis is a highly virulent organism that can cause severe and fatal disease in humans following inhalation of as few as 10-100 organisms. It has a history of weaponization by several countries and is a Category A select agent, one of six pathogens that are of highest priority for countermeasure development. One live vaccine strain, LVS, based on a type B strain, was developed and tested in the 1960's and conferred partial protection against exposure to aerosols containing virulent type A F. tularensis. While providing proof of principle that a live attenuated F. tularensis vaccine can protect, LVS is not licensed by the FDA and suffers from several notable drawbacks that render it a sub-optimal tularemia vaccine. The literature supports the superior protective capacity of type A strains against type A challenge. We have engineered a vaccine candidate based on type A strain SchuS4, that contains an unmarked precisely defined deletion in the aroD gene encoding a critical enzyme in microbial metabolic processes. This vaccine is highly attenuated in the mouse model and was protective against a very high challenge dose (1,000 CFU) of wild type (WT) type A strain SchuS4. This is the first report of a live attenuated F. tularensis vaccine capable of protecting against a type A challenge of this magnitude. Furthermore, in preliminary rabbit studies SchuS4?aroD provided partial protection against a lethal aerosol challenge with SchuS4;this level of protection was superior to that conferred by LVS in this model. The fact that this vaccine strain, SchuS4?aroD, is more attenuated and more protective than LVS in the mouse model and more protective in the rabbit model supports its potential for success as a human vaccine. We are proposing to perform a set of focused studies to confirm the safety, stability, and protective capacity of the candidate vaccine, SchuS4?aroD, using the mouse and rabbit models. Parallel studies in the laboratories of collaborating investigators at 3 institutions, with specific expertise in the evaluation of Francisella strains i animal models, will accelerate progress. Our goal is to accumulate sufficient data to support transition of this candidate to advanced development. Advanced development will require a substantial commitment of resources that cannot be justified without the preliminary studies outlined within this proposal to substantiate the potential of this candidate as an efficacious human vaccine.

Public Health Relevance

There is currently no licensed vaccine for use against Francisella tularensis, a highly virulent pathogen which can cause disease and death following inhalation of as few as 10-100 organisms. This pathogen has been used as a bioweapon in the past and is a Category A select agent, one of 6 pathogens that are the highest priority for countermeasure development in the US. This proposal aims advance the development of a highly protective and defined live attenuated vaccine candidate that could be used to prevent tularemia.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases (VMD)
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Zou, Lanling
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Balzano, Phillip M; Cunningham, Aimee L; Grassel, Christen et al. (2018) Deletion of the Major Facilitator Superfamily Transporter fptB Alters Host Cell Interactions and Attenuates Virulence of Type A Francisella tularensis. Infect Immun 86:
Richard, Katharina; Mann, Barbara J; Qin, Aiping et al. (2017) Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity. Clin Vaccine Immunol 24:
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:
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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