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Review
. 2015 Nov 10;3(4):940-72.
doi: 10.3390/vaccines3040940.

Live-Attenuated Bacterial Vectors: Tools for Vaccine and Therapeutic Agent Delivery

Ivan Y C Lin  1 , Thi Thu Hao Van  2 , Peter M Smooker  3
Affiliations
Review

Live-Attenuated Bacterial Vectors: Tools for Vaccine and Therapeutic Agent Delivery

Ivan Y C Lin et al. Vaccines (Basel). .

Abstract

Genetically attenuated microorganisms, including pathogenic and commensal bacteria, can be engineered to carry and deliver heterologous antigens to elicit host immunity against both the vector as well as the pathogen from which the donor gene is derived. These live attenuated bacterial vectors have been given much attention due to their capacity to induce a broad range of immune responses including localized mucosal, as well as systemic humoral and/or cell-mediated immunity. In addition, the unique tumor-homing characteristics of these bacterial vectors has also been exploited for alternative anti-tumor vaccines and therapies. In such approach, tumor-associated antigen, immunostimulatory molecules, anti-tumor drugs, or nucleotides (DNA or RNA) are delivered. Different potential vectors are appropriate for specific applications, depending on their pathogenic routes. In this review, we survey and summarize the main features of the different types of live bacterial vectors and discussed the clinical applications in the field of vaccinology. In addition, different approaches for using live attenuated bacterial vectors for anti-cancer therapy is discussed, and some promising pre-clinical and clinical studies in this field are outlined.

Keywords: Salmonella; attenuated vector; cancer; infectious disease; vaccine.

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Figures

Figure 1
Figure 1
The use of bacterial vectors to vaccinate against pathogens. (I–IV) Cloning of heterologous gene and insertion into bacterial vector, either carried on a plasmid or inserted into the chromosome; (V) Expression of the heterologous antigen; (VI) Elicitation of immune responses; (VII) protection against pathogens.
Figure 2
Figure 2
Tumor-targeting ability of bacterial vectors. (I) The hypoxic microenvironment in necrotic areas of solid tumor favours the colonization and proliferation of facultative anaerobes and obligate anaerobes; (II) Increased entrapment in the organisationally compromised and leaky vasculature, caused by neo-angiogenesis; (III) Chemo-attracting compounds present in necrotic areas (e.g., aspartate, serine, citrate, ribose or galactose) allow bacterial vectors to taxi toward tumors; (IV) Compromised pathogen clearance due to the presence of myeloid-derived immune suppressor cells and the accumulation of ligands of immunosuppressive receptors in the tumor micro-environment.
Figure 3
Figure 3
Bactofection into tumors. (A) Bacteria are used as a vector to deliver the genetic information into the eukaryotic cell. Bacterial vectors that possess plasmid (each bacterial vector can carry multiple copies of transgenic plasmid) carrying a transgene are administered into the target tissue, I.: The vectors penetrate into the cells. II: Vectors undergo lysis and the plasmids are released into the cytoplasm, III: The released plasmids enter the nuclei and the therapeutic transgene is expressed by eukaryotic transcription and translation mechanisms; (B) Alternative gene therapy: recombinant bacterial vectors express the recombinant therapeutic protein in situ intracellularly or in the intercellular space. Recombinant bacterial vector that possess plasmid carrying the transgene are administered into the target tissue and either enter the cells or stay in the intercellular space; I: The transgene is expressed and secreted after entering the cell, or; II: Bacteria do not enter the eukaryotic cell, but express the therapeutic transgene in the intercellular space.
Figure 4
Figure 4
Tumor therapy using RNA interference: Bacterial vectors are transformed with an shRNA-encoding vector for intra-bacterial transcription. shRNA are expressed inside the vectors before release into the target tumour cell’s cytoplasm. Following bacterial lysis, the shRNA molecules are cleaved by Dicer into the corresponding siRNA molecules. The anti-sense strand of the siRNA specifically binds with its target mRNA, which is then degraded by the RNA-induced silencing (RISC) complex resulting to a post-transcriptional gene silencing or suppression.
Figure 5
Figure 5
Tumor therapy with cell death inducer or pro-drug activating enzymes. (I) Cancer cells transfected with apoptosis inducers such as Fas ligand could lead to apoptosis in Fas-sensitive cells; (II) Cells transfected with pro-drug activating enzyme allow more specific and localised cell destruction, even upon systemic pro-drug administration.
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