title: Type III interferon attenuates a vesicular stomatitis virus-based vaccine vector.
abstract: Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture. In vivo, IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications.
  
  
  OBJECTIVE
  Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ryann C
authors.initials: RC
authors.lastname: Guayasamin
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Reynolds
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA michael.robek@yale.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Robek
mesh_terms: D000818:Animals; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D050130:Oncolytic Virotherapy / Q000295:instrumentation; D054243:Vesicular Stomatitis / Q000276:immunology* / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication; D000095022:Interferon Lambda
chemical_list: D007378:Interleukins; C000594666:IL28A protein, mouse; D000095022:Interferon Lambda