Abstract
Francisella tularensis, the causative agent of the fatal human disease known as tularemia is classified as a Category A Select Agent by the Centers for Disease Control. No licensed vaccine is currently available for prevention of tularemia in the United States. Previously, we published that a tri-antigen tobacco mosaic virus (TMV) vaccine confers 50% protection in immunized mice against respiratory tularemia caused by F. tularensis. In this study, we refined the TMV-vaccine formulation to improve the level of protection in immunized C57BL/6 mice against respiratory tularemia. We developed a tetra-antigen vaccine by conjugating OmpA, DnaK, Tul4, and SucB proteins of Francisella to TMV. CpG was also included in the vaccine formulation as an adjuvant. Primary intranasal (i.n.) immunization followed by two booster immunizations with the tetra-antigen TMV vaccine protected 100% mice against i.n. 10LD100 challenges dose of F. tularensis live vaccine strain (LVS). Mice receiving three immunization doses of tetra-antigen TMV vaccine showed only transient body weight loss, cleared the infection rapidly, and showed minimal histopathological lesions in lungs, liver, and spleen following a lethal respiratory challenge with F. tularensis LVS. Mice immunized with the tetra-antigen TMV vaccine also induced strong ex vivo recall responses and were protected against a lethal challenge as late as 163 days post-primary immunization. Three immunization with the tetra-antigen TMV vaccine also induced a stronger humoral immune response predominated by IgG1, IgG2b, and IgG2c antibodies than mice receiving only a single or two immunizations. Remarkably, a single dose protected 40% of mice, while two doses protected 80% of mice from lethal pathogen challenge. Immunization of Interferon-gamma (IFN-γ)-deficient mice with the tetra-antigen TMV vaccine demonstrated an absolute requirement of IFN-γ for the generation of protective immune response against a lethal respiratory challenge with F. tularensis LVS. Collectively, this study further demonstrates the feasibility of TMV as an efficient platform for the delivery of multiple F. tularensis antigens and that tetra-antigen TMV vaccine formulation provides complete protection, and induces long-lasting protective and memory immune responses against respiratory tularemia caused by F. tularensis LVS.
Highlights
Francisella tularensis causes the highly lethal disease known as tularemia in humans especially when the infection is acquired through the respiratory route
We have shown that tri-antigen tobacco mosaic virus (TMV) vaccine consisting of OmpA, DnaK, and Tul4 proteins of F. tularensis SchuS4 generated a TH2 predominated humoral immune response indicated by higher levels of F. tularensis-specific IgG1 antibodies and provided only 50% protection in immunized C57BL/6 mice (Banik et al, 2015)
The results from this study demonstrate that tetraantigen TMV vaccine formulation with CpG adjuvant provides 100% protection in immunized C57BL/6 mice and induces a long-term protection against respiratory tularemia caused by F. tularensis live vaccine strain (LVS)
Summary
Francisella tularensis causes the highly lethal disease known as tularemia in humans especially when the infection is acquired through the respiratory route. F. tularensis is categorized among the most prominent threats for use as a bioterror agent as it can be rapidly disseminated by aerosols and can cause widespread severe illness and death (Bossi and Bricaire, 2003; Cronquist, 2004). As F. tularensis has been used in bioweapon programs in the past and may potentially be used as a bioterror agent, it poses a clear and present threat to public health. Antibiotic resistance, either through engineering or natural occurrence, undermines all currently available therapeutic options for treatment of respiratory tularemia. No FDA approved vaccine is available in the United States for prevention of tularemia. There is an urgent need for development of safe and effective vaccines
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
