Mucosal Immunization with Live Attenuated Francisella novicida U112ΔiglB Protects against Pulmonary F-tularensis SCHU S4 in the Fischer 344 Rat Model

The need for an efficacious vaccine against Francisella tularensis is a consequence of its low infectious dose and high mortality rate if left untreated. This study sought to characterize a live attenuated subspecies novicida-based vaccine strain (U112 Delta iglB) in an established second rodent model of pulmonary tularemia, namely the Fischer 344 rat using two distinct routes of vaccination ( intratracheal [i.t.] and oral). Attenuation was verified by comparing replication of U112 Delta iglB with wild type parental strain U112 in F344 primary alveolar macrophages. U112 Delta iglB exhibited an LD50> 10(7) CFU compared to the wild type (LD50 = 5 x 10(6) CFU i.t.). Immunization with 10(7) CFU U112 Delta iglB by i.t. and oral routes induced antigen-specific IFN-gamma and potent humoral responses both systemically (IgG2a>IgG1 in serum) and at the site of mucosal vaccination (respiratory/intestinal compartment). Importantly, vaccination with U112 Delta iglB by either i.t. or oral routes provided equivalent levels of protection (50% survival) in F344 rats against a subsequent pulmonary challenge with similar to 25 LD50 (1.25 x 10(4) CFU) of the highly human virulent strain SCHU S4. Collectively, these results provide further evidence on the utility of a mucosal vaccination platform with a defined subsp. novicida U112 Delta iglB vaccine strain in conferring protective immunity against pulmonary tularemia.