Respiratory and oral vaccination improves protection conferred by the live vaccine strain against pneumonic tularemia in the rabbit model

Abstract

Tularemia is a severe, zoonotic disease caused by a gram-negative bacterium, Francisella tularensis We have previously shown that rabbits are a good model of human pneumonic tularemia when exposed to aerosols containing a virulent, type A strain, SCHU S4. We further demonstrated that the live vaccine strain (LVS), an attenuated type B strain, extended time to death when given by scarification. Oral or aerosol vaccination has been previously shown in humans to offer superior protection to parenteral vaccination against respiratory tularemia challenge. Both oral and aerosol vaccination with LVS were well tolerated in the rabbit with only minimal fever and no weight loss after inoculation. Plasma antibody titers against F. tularensis were higher in rabbits that were vaccinated by either oral or aerosol routes compared to scarification. Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4. LVS given by scarification extended time to death compared to mock-vaccinated controls. One orally vaccinated rabbit did survive aerosol challenge, however, only aerosol vaccination extended time to death significantly compared to scarification. These results further demonstrate the utility of the rabbit model of pneumonic tularemia in replicating what has been reported in humans and macaques as well as demonstrating the utility of vaccination by oral and respiratory routes against an aerosol tularemia challenge.

Development, Characterization, and Standardization of a Nose-Only Inhalation Exposure System for Exposure of Rabbits to Small-Particle Aerosols Containing Francisella tularensis

“…These data suggest that BHI-grown SCHU S4 is a more rigorous challenge for demonstrating protection in vaccine studies than MHB-grown SCHU S4. Considering that we have previously shown that attenuated derivatives of SCHU S4 outperform LVS and protect rabbits well against both morbidity and mortality at even higher challenge doses of SCHU S4 grown in BHI, this further illustrates the superior performance of these attenuated derivatives as potential vaccine candidates (4)(5)(6). Both the survival of LVS-vaccinated rabbits and the consistent/higher SF from the aerosol characterization studies argue that BHI-grown F. tularensis should be used in pivotal F. tularensis efficacy studies to achieve a rigorous, reproducible aerosol challenge sufficient to demonstrate the efficacy of potential vaccine candidates in animals.…”

“…One argument against using the rabbit for tularemia vaccine studies had been that vaccination with LVS extended the time to death but not survival (5,6,10,21). Our own prior studies are included in those findings, including the observation that oral inoculation or inhalation of LVS did extend the rabbit time to death more than subcutaneous inoculation, with one oral LVS-vaccinated rabbit surviving challenge (5). These data do fit with what has been reported in humans and monkeys, where oral and aerosol LVS vaccination offered better protection against subsequent respiratory challenge (17,20,34,35).…”

“…The cause of death in the rabbits appeared to be severe septic shock and/or acute respiratory distress syndrome. Additionally, we have shown that attenuated strains of F. tularensis can protect rabbits against aerosol challenge with virulent SCHU S4 (4)(5)(6). The degree of protection against morbidity and mortality is a function of the attenuated strain used, the number of vaccinations, and the route of vaccination.…”

Development, characterization and standardization of a nose-only inhalation exposure system for exposure of rabbits to small particle aerosols containingFrancisella tularensis

“…One argument against using the rabbit for tularemia vaccine studies had been that vaccination with LVS extended time to death but not survival (5, 6, 10, 21). Our own prior studies are included in those findings, including the observation that oral inoculation or inhalation of LVS did extend rabbit time to death more than subcutaneous inoculation (5).…”

“…One argument against using the rabbit for tularemia vaccine studies had been that vaccination with LVS extended time to death but not survival (5, 6, 10, 21). Our own prior studies are included in those findings, including the observation that oral inoculation or inhalation of LVS did extend rabbit time to death more than subcutaneous inoculation (5). This data does fit with what has been reported in humans and monkeys where oral and aerosol LVS vaccination offered better protection against subsequent respiratory challenge (17, 20, 35, 36).…”