Type A-derived genetically modified live attenuated Francisella tularensis is immunogenic and efficacious in rabbits (VAC7P.965)

Abstract

Francisella tularensis is a gram negative non-motile coccobacillus that is the causative agent of tularemia. There is concern that F. tularensis could be used as a biological weapon and development of vaccines is a high priority. Type A strains are highly virulent but the current live vaccine strain (LVS) is based on a type B strain and is only partially protective against aerosol challenge with SCHU S4, a type A strain. A series of live attenuated vaccine candidates were derived from the SCHU S4 strain containing specific deletion mutations in target genes. After initial studies in mice, these attenuated strains were evaluated in rabbits. Rabbits were vaccinated by scarification which induced a mild fever and eschar formation at the inoculation site but no other clinical signs of disease. Serum IgG responses could be detected in all vaccinated rabbits as early as day 7 and continued to increase through day 21 before declining slightly on day 28. CD4+ T cells but not CD8+ T cells proliferated when cultured in vitro with heat-killed SCHU S4. Three of the vaccine strains conferred partial protection against death (ranging from 27-40%) and prolonged time to death in animals that did succumb. Vaccination with LVS prolonged survival by 1-2 days but did not protect against death. Type A-derived vaccines are immunogenic and provide better protection than LVS in the rabbit model against a robust aerosol challenge. These candidates warrant further study and evaluation.