title: Development of a Multivalent Subunit Vaccine against Tularemia Using Tobacco Mosaic Virus (TMV) Based Delivery System.
abstract: Francisella tularensis is a facultative intracellular pathogen, and is the causative agent of a fatal human disease known as tularemia. F. tularensis is classified as a Category A Biothreat agent by the CDC based on its use in bioweapon programs by several countries in the past and its potential to be used as an agent of bioterrorism. No licensed vaccine is currently available for prevention of tularemia. In this study, we used a novel approach for development of a multivalent subunit vaccine against tularemia by using an efficient tobacco mosaic virus (TMV) based delivery platform. The multivalent subunit vaccine was formulated to contain a combination of F. tularensis protective antigens: OmpA-like protein (OmpA), chaperone protein DnaK and lipoprotein Tul4 from the highly virulent F. tularensis SchuS4 strain. Two different vaccine formulations and immunization schedules were used. The immunized mice were challenged with lethal (10xLD100) doses of F. tularensis LVS on day 28 of the primary immunization and observed daily for morbidity and mortality. Results from this study demonstrate that TMV can be used as a carrier for effective delivery of multiple F. tularensis antigens. TMV-conjugate vaccine formulations are safe and multiple doses can be administered without causing any adverse reactions in immunized mice. Immunization with TMV-conjugated F. tularensis proteins induced a strong humoral immune response and protected mice against respiratory challenges with very high doses of F. tularensis LVS. This study provides a proof-of-concept that TMV can serve as a suitable platform for simultaneous delivery of multiple protective antigens of F. tularensis. Refinement of vaccine formulations coupled with TMV-targeting strategies developed in this study will provide a platform for development of an effective tularemia subunit vaccine as well as a vaccination approach that may broadly be applicable to many other bacterial pathogens.
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Sukalyani
authors.initials: S
authors.lastname: Banik
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Ahd Ahmed
authors.initials: AA
authors.lastname: Mansour
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Ragavan Varadharajan
authors.initials: RV
authors.lastname: Suresh
authors.affiliation: College of Pharmacy, Touro University California, Mare Island, Vallejo, California, United States of America.
authors.forename: Sherri
authors.initials: S
authors.lastname: Wykoff-Clary
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York, United States of America.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.affiliation: College of Pharmacy, Touro University California, Mare Island, Vallejo, California, United States of America.
authors.forename: Alison A
authors.initials: AA
authors.lastname: McCormick
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001428:Bacterial Vaccines / Q000096:biosynthesis* / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods*; D004926:Escherichia coli; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D014027:Tobacco Mosaic Virus / Q000235:genetics* / Q000378:metabolism; D014406:Tularemia / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D022223:Vaccines, Subunit