Venezuelan equine encephalitis virus replicon particles: mucosal vaccine vectors and biological adjuvants Public Deposited

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  • March 22, 2019
Creator
  • Thompson, Joseph Michael
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Vaccination is the most effective control measure in the fight against infectious diseases, and represents an opportunity to intercede in the spread of dangerous organisms through prophylactic intervention. Viral vectors, including alphavirus vectors, have proven to be powerful vaccine delivery vehicles and a promising platform for vaccines against multiple pathogens. Specifically, as demonstrated here, Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) induced strong humoral, cell-mediated, and mucosal immune responses directed against heterologous antigens expressed from the viral genome, as well as against antigens simply mixed with VRP. These observations established a dual function of VRP as both vaccine expression vectors and vaccine adjuvants, demonstrating that VRP possess intrinsic immunostimulatory properties. When utilized as adjuvants, VRP systemic humoral adjuvant activity was as strong as the activity of CpG DNA. In addition, the mucosal responses induced by VRP adjuvants were superior to those induced by CpG, an effect that was dependent upon VRP RNA replication. The induction of mucosal immune responses is critical for vaccine-mediated protection following challenge with mucosal pathogens. Delivery of antigens directly to mucosal lymphoid tissues, as occurs following mucosal delivery, results in the strongest mucosal immune responses. While this has revealed the components of the natural mucosal inductive pathway, little is known regarding the lymphoid structures responsible for mucosal immune induction following nonmucosal delivery. Here we demonstrate that following nonmucosal VRP vaccination, several markers of mucosal lymphoid tissues were present in the draining lymph node (DLN). This included the presence of antigen-specific polymeric IgA antibodies, upregulated expression of the α4β7 integrin on DLN lymphocytes, expression of the mucosal addressin, MAdCAM-1, and the production of IL-6 and other mucosal cytokines. The presence of these markers is consistent with a model in which the DLN is converted by VRP infection into the functional equivalent of a mucosal inductive site. Furthermore, while type I interferon (IFN) signaling was not required for VRP adjuvant activity, it was critical for the induction of mucosal IgA responses induced by VRP expression vectors. Together, these findings may significantly improve both our knowledge of viral immunology and the efficacy of viral-based vaccines.
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  • Johnston, Robert E.
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