Modifications of Alphavirus Replicon Vaccine Platforms: A Literature Review

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Austin, Riley
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McGill, Jodi
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Blitvitch, Bradley
Verhoeven, David
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With the ever-evolving emergence of novel pathogens in the animal health space, it is key that we can respond rapidly with antigen-delivery vehicles and other therapeutics. One category of vaccines that can be developed and deployed promptly is the alphavirus-based replicon vaccine. Alphaviruses are enveloped, positive sense (+) single-stranded RNA (ssRNA) viruses in the family Togaviridae with 12Kb genomes. They are classically divided into two subfamilies, Old World Alphaviruses, and New World Alphaviruses. Alphavirus replicon-based vaccine platforms utilize the natural genome of the virus, replacing the genes that typically encode the capsid and glycoproteins with a transgene for the expression of an antigen. Packaged replicon particles derived from an attenuated strain of VEE have been used for the development of vaccines for infectious diseases as well as cancer therapy. This allows for the generation of a virus-like particle (VLP) that contains the genomic mRNA with added transgene. This packaged VLP is denoted as a virus-like replicon particle (VRP). Due to the 26s sub-genomic (sg) promoter located in the modified genome, the transgene is capable of replication once penetration into target cells occurs, designated as a self-amplifying mRNA or replicon. Capsid and E1-E2 glycoprotein genes that are required for initial VLP formation and packaging are utilized as unique, separate mRNA transcripts that are not incorporated into the nucleocapsid structure, leading to a replication-defective, single cycle virus (Pushko et al., 1997). Replicon, capsid, and glycoprotein mRNAs are introduced into an expression cell line for replication and packaging of RPs. Inside the expression cell line, replicon, capsid and glycoprotein E1-E2 trimers self-assemble into functional replicon particle VRPs. These newly generated RPs are then collected and delivered into target cells via intramuscular (IM) injection. RPs then penetrate host cells and unpackage, exposing genomic mRNA. Replicon VRPs do exhibit a tropism for dendritic cells (MacDonalad, 2000). Viral replication machinery as well as the antigenic transgene are expressed. Antigens are then presented on the cell surface where they activate cell-mediated immunity which leads to the eventual generation of protective antibodies, effectively protecting the host from the desired pathogen. Because of their inherent antigenic nature, alphavirus-based replicon vaccines due induce strong innate host immune system responses which can limit the intensity and duration of the transgene expression (Ballesteros-Briones, 2020). Due to the broad host range of alphaviruses, they make for an excellent potential antigen delivery system as they can replicate in most vertebrate cells. Sources for this chosen based on relevance to VEEV-based replicon vector expression and studies that showed significant modifications to this system that resulted in a novel application or advancement of the platform. This review aims to describe literature exploring the development and applications of the alphavirus replicon vector system as well as modifications to the traditional platform to modulate sub-genomic mRNA and transgene expression for potential clinical applications.
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