Abstract
In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.
Highlights
Most vaccines against infectious diseases in clinical use today act by stimulating the production of antibodies, which block virus entry, neutralize toxins, or otherwise limit infection through a variety of mechanisms
To further uncover T cell effector mechanisms, we have previously developed an in vitro tissue culture system to mimic in vivo immune responses [25,26], in which Live Vaccine Strain (LVS)-immune lymphocytes are co-cultured with LVSinfected bone marrow derived macrophages and intramacrophage bacterial replication is measured
We found that the relative activity of Francisella-immune lymphocytes in vitro in the co-culture assay, as well as the relative expression of a group of immunologicallyrelated genes in cells recovered from this assay, correlated with the degree of protection observed in vivo
Summary
Most vaccines against infectious diseases in clinical use today act by stimulating the production of antibodies, which block virus entry, neutralize toxins, or otherwise limit infection through a variety of mechanisms. Understanding T cell effector functions that control intracellular infections, and developing clinically useful predictive correlates, would greatly facilitate evaluation of new vaccines for intracellular pathogens of major public health importance such as Mycobacteria, Chlamydia, Salmonella, and Leishmania. To address these questions, we have exploited experimental infection models that use the Live Vaccine Strain (LVS) of Francisella tularensis, a Gram-negative intracellular bacterium that causes tularemia. The sporadic nature of disease likely means that vaccine field trials for efficacy are impractical
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