Development of Antiviral Vaccine Utilizing Self-Destructing Salmonella for Antigen and DNA Vaccine Delivery
Vaccines are the most effective means to prevent infectious diseases, especially for viral infection. The key to an excellent antiviral vaccine is the ability to induce long-term protective immunity against a specific virus. Bacterial vaccine vectors have
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Introduction Geneticallymodified Salmonella strains that harbor a plasmid to synthesize protective antigens or DNA vaccine vectors have been, and are currently, being developed to provide novel needle-free and low-cost protection against various diseases. Oral administration of GMSs enables Salmonella to attach to and invade mucosal associated lymphoid tissues (see Notes 1–3). The use of Salmonella GMS leads to the induction of mucosal, systemic, and cellular immune responses, which result in long-term protective immunity [1–6]. The methodology of antiviral vaccine delivery described in this chapter is to use a biological containment system designed to cause programmed bacterial cell lysis with no survivors. The system is composed of two parts. The first component is Salmonella strain
Alexandra R. Lucas (ed.), Viruses as Therapeutics: Methods and Protocols, Methods in Molecular Biology, vol. 2225, https://doi.org/10.1007/978-1-0716-1012-1_3, © Springer Science+Business Media, LLC, part of Springer Nature 2021
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with deletions of two genes required for peptidoglycan synthesis and additional mutations to enhance complete lysis and antigen delivery. The second component is a plasmid, which encodes arabinose-regulated peptidoglycan synthesis. These GMS strains are attenuated yet capable of synthesizing protective antigens. The regulated delayed attenuation and programmed selfdestructing features are designed into these GMS strains to enable them to efficiently colonize host tissues and allow the release of the bacterial cell contents after lysis [2]. To turn such an antigendelivering GMS strain into a universal DNA vaccine-delivery vehicle, the approach is to enable GMS strain to display a hyperinvasive phenotype to maximize Salmonella host entry and host cell internalization, to enable Salmonella endosomal escape to release a DNA vaccine into the cytosol and to decrease Salmonella-induced pyroptosis/apoptosis that allows the DNA vaccine time to traffic to the nucleus for efficient synthesis of encoded protective antigens [3]. The development and application of the GMS strains are described in detail in the following sections. 1.1 Self-Destructing GMS for Antigen Delivery
To eliminate the use of plasmid vectors with non-permitted drug resistance genes and to stabilize plasmid vectors in Salmonella strains in vivo, a balanced lethal Salmonella host-vector system with deletion of the aspartate-semialdehyde dehydrogenase (asdA) gene is developed to impose an obligate requirement for diaminopimelic acid (DAP) [7] and a plasmid vector with the wildtype asdA gene [8, 9]. Muramic acid is another essential constituent of peptidoglycan. The UDP-N-acetylglucosamine enolpyruvyl transferase (murA) gene encodes the first enzyme in muramic acid synthesis [10]. The asdA and murA genetic modifications are combined, which provides redundant mechanisms to ensure Salmonella cell lysis. A regulated delayed lysis system is devised for antigen delivery after colonization of host lymphoid tissues that rely on using a m
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