Abstract
The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.
Highlights
From the discovery of a new pathogen, it can be many years before a vaccine that is specific to the organism is developed
We used an opsonizing Ab that was specific for the surface of Francisella tularensis (Ft) to target Ft Live Vaccine Strain (LVS) vaccines to Fc receptors (FcRs) [17,18]
Yersinia enterolitica adhesion protein A (YadA) is an autotransporter with a N-terminal signal sequence, a collagen-binding domain (CBD), helical stalk, and a C-terminal β-barrel that anchors the protein into the outer membrane (OM) (Figure 1b)
Summary
From the discovery of a new pathogen, it can be many years before a vaccine that is specific to the organism is developed. Inactivated whole cell vaccines are often non-stimulatory and require the addition of adjuvant for production of an effective immune response [1]. Mucosal administration has become an appealing needle-free method of vaccination and several labs are developing new immunostimulatory adjuvants for this route, some of which are reviewed here [3,4]. Efforts to increase specificity and amplitude of the immune response to an Ag include targeting vaccines or other therapies to specific cells. Dendritic cells (DCs) present Ag via MHCI and MHCII, inducing both the cellular and humoral arms of adaptive immunity, which is an appealing feature in vaccine development [5,6]. Targeting receptors on DCs via the fusion of peptide Ags to either α-Clec9A antibody (Ab) [7], α-CD11c Ab, or DC-specific cytokines, results in increased Ag-specific
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