Abstract

Francisella tularensis (Ft) is a category A biothreat agent for which there is no Food and Drug Administration-approved vaccine. Ft can survive in a variety of habitats with a remarkable ability to adapt to changing environmental conditions. Furthermore, Ft expresses distinct sets of antigens (Ags) when inside of macrophages (its in vivo host) as compared to those grown in vitro with Mueller Hinton Broth (MHB). However, in contrast to MHB-grown Ft, Ft grown in Brain-Heart Infusion (BHI) more closely mimics the antigenic profile of macrophage-grown Ft. Thus, we anticipated that when used as a vaccine, BHI-grown Ft would provide better protection compared to MHB-grown Ft, primarily due to its greater antigenic similarity to Ft circulating inside the host (macrophages) during natural infection. Our investigation, however, revealed that inactivated Ft (iFt) grown in MHB (iFt-MHB) exhibited superior protective activity when used as a vaccine, as compared to iFt grown in BHI (iFt-BHI). The superior protection afforded by iFt-MHB compared to that of iFt-BHI was associated with significantly lower bacterial burden and inflammation in the lungs and spleens of vaccinated mice. Moreover, iFt-MHB also induced increased levels of Ft-specific IgG. Further evaluation of early immunological cues also revealed that iFt-MHB exhibits increased engagement of Ag-presenting cells including increased iFt binding to dendritic cells, increased expression of costimulatory markers, and increased secretion of pro-inflammatory cytokines. Importantly, these studies directly demonstrate that Ft growth conditions strongly impact Ft vaccine efficacy and that the growth medium used to produce whole cell vaccines to Ft must be a key consideration in the development of a tularemia vaccine.

Highlights

  • Whole cell-based vaccines are preferred in the absence of well-defined protective immunogens

  • While we initially hypothesized that Brain-Heart Infusion (BHI)-grown inactivated Ft (iFt), which more closely mimics the antigenic repertoire of in vivo macrophagegrown Francisella tularensis (Ft), would provide the superior vaccine immunogen, we found that iFt-Mueller Hinton Broth (MHB) generates superior protection compared to iFt grown in BHI (iFt-BHI)

  • Following the above observation of differential protection afforded by iFt-MHB versus iFt-BHI, we investigated the ability of the two iFt immunogens to protect against bacterial replication and tissue damage exerted by Ft LVS infection

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Summary

Introduction

Whole cell-based vaccines are preferred in the absence of well-defined protective immunogens. In the absence of an identified protective Ag, Differential Cultivation Impacts Vaccine Efficacy directing the immune response toward an array of Ags that the host is likely to encounter during a natural infection maximizes the potential for a protective immune response to be generated upon vaccination. In this regard, the composition of the antigenic repertoire expressed by the constituent whole cell vaccine becomes very important, while PAMPs can provide molecular components required for the activation of Ag-presenting cells (APCs). The mechanism responsible for this apparent difference has not been well established

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