Francisella tularensis is the causitive agent of tularemia, a severe zoonotic disease in humans with fatality rates exceeding 30% in untreated subjects. Infection following inhalation causes the most severe form of disease and combind with its high virulence and history of weaponization makes this pathogen a concern for use as a biological weapon. Development of a vaccine that protects against aerosol infection is a priority. We have engineered a series of live attenuated vaccine candidates based on the highly virulent Schu S4 strain that exhibit a range of protective capacities in the mouse and rabbit models of respiratory challenge. Our studies have confirmed that rabbits are an excellent model of human pneumonic tularemia and a highly relevant model for evaluating tularemia vaccines as they display similar resistance to attenuated strains and susceptibility to virulent strains as humans. We hypothesize that the outbred human-relevant, rabbit model will allow us to identify correlates of protection using the collection of vaccine strains that confer a range (0% to 83%) of protective efficacies against lethal aerosol challenge. This grant seeks to understand the mechanism(s) underlying this protection. Our hypothesis is that effective vaccination in the rabbit model is a product of i) induction of particular, Ag-specific responses and/or ii) the immunogen's persistence and immuno-stimulatory properties.
The first aim will identify the bacterial Ag(s) recognized specifically by protective immune responses.
The second aim will explore the humoral and cellular immune response as well as the role of persistence and immune stimulation by F. tularensis derivatives in protection against challenge.
The third aim will evaluate the efficacy of a subunit vaccine and an optimized live attenuated vaccine against inhalation of F. tularensis. The information gained under this proposal will expand our understanding of the humoral and cellular immune response to tularemia vaccines, the importance of these responses in protection against tularemia in the rabbit and the relevance to protection in humans.

Public Health Relevance

Inhalation of Francisella tularensis causes significant morbidity and mortality in humans - an outbred population. The studies proposed in this application will greatly improve our knowledge of the immunological responses elicited by tularemia vaccines and responses important for protection in an outbred model against pneumonic tularemia. This information will be useful in the design and evaluation of vaccines that protect outbred species against inhalation of F. tularensis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Zou, Lanling
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Albany Medical College
Schools of Medicine
United States
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Sunagar, Raju; Kumar, Sudeep; Rosa, Sarah J et al. (2018) Differential In Vitro Cultivation of Francisella tularensis Influences Live Vaccine Protective Efficacy by Altering the Immune Response. Front Immunol 9:1594
O'Malley, Katherine J; Bowling, Jennifer L; Stinson, Elizabeth et al. (2018) Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis. PLoS One 13:e0205928
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:
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
Kumar, Sudeep; Sunagar, Raju; Pham, Giang et al. (2016) Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines. Front Immunol 7:677
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