Utilizing previously identified in vitro correlates of protection to predict the efficacy of a novel vaccine candidate against the intracellular bacterium Francisella tularensis

Abstract

Abstract Francisella tularensis (Ft) is an intracellular bacterium that causes tularemia, a disease with a low incidence in US. The only available vaccine, the Live Vaccine Strain (LVS), is investigational and is derived from Type B Ft, not the more virulent Type A Ft. Previous work produced potential correlates to predict successful vaccination. These were determined by in vitro stimulation of murine Ft LVS-immune cells and analyses of their gene expression. We used this approach to investigate correlates of protection for the novel ΔclpB vaccine, derived from Type A Ft SchuS4. Mice were vaccinated with ΔclpB as well as LVS-derived vaccines and subsequently challenged with a lethal dose of LVS, after which all mice vaccinated with ΔclpB and LVS survived. The in vivo survival data was compared with in vitro data obtained from PBLs and splenocytes from vaccinated mice. In general, the in vitro functions of leukocytes from ΔclpB-vaccinated mice were comparable or exceeded those of leukocytes from LVS-vaccinated mice, including control of LVS intramacrophage replication, IFN-gamma secretion, and NO production. Correlates up-regulated in cells from mice vaccinated with ΔclpB included IFN-gamma, IL-21, Nos2, LTA, T-bet, IL-12rbeta2, CCL5 and GzmB; in some cases up-regulation was higher than that from LVS-derived PBLs. Other genes were up-regulated in ΔclpB-derived but not LVS-derived leukocytes, suggesting that improved protection stimulated by the ΔclpB vaccine may be related to the change in strain and/or to stronger immune responses. Hence, this panel of correlates could contribute to the screening of new vaccine candidates, bridging from animal models to humans, and augmenting clinical trials.