MicroRNA reduction of neuronal West Nile virus replication attenuates and affords a protective immune response in mice

Details

• Alternative Title:
  Vaccine
• Personal Author:
  Brostoff, Terza ; Pesavento, Patricia A. ; Barker, Christopher M. ; Kenney, Joan L. ; Dietrich, Elizabeth A. ; Duggal, Nisha K. ; Bosco-Lauth, Angela M. ; Brault, Aaron C.
• Description:
  West Nile virus (WNV) is an important agent of human encephalitis that has quickly become endemic across much of the United States since its identification in North America in 1999. While the majority (∼75%) of infections are subclinical, neurologic disease can occur in a subset of cases, with outcomes including permanent neurologic damage and death. Currently, there are no WNV vaccines approved for use in humans. This study introduces a novel vaccine platform for WNV to reduce viral replication in the central nervous system while maintaining peripheral replication to elicit strong neutralizing antibody titers. Vaccine candidates were engineered to incorporate microRNA (miRNA) target sequences for a cognate miRNA expressed only in neurons, allowing the host miRNAs to target viral transcription through endogenous RNA silencing. To maintain stability, these targets were incorporated in multiple locations within the 3'-untranslated region, flanking sequences essential for viral replication without affecting the viral open reading frame. All candidates replicated comparably to wild type WNV in vitro within cells that did not express the cognate miRNA. Insertional control viruses were also capable of neuroinvasion and neurovirulence in vivo in CD-1 mice. Vaccine viruses were safe at all doses tested and did not demonstrate mutations associated with a reversion to virulence when serially passaged in mice. All vaccine constructs were protective from lethal challenge in mice, producing 93-100% protection at the highest dose tested. Overall, this is a safe and effective attenuation strategy with broad potential application for vaccine development.
• Subjects:
  3' Untranslated Regions Animals Antibodies, Neutralizing Antibodies, Viral Article Attenuation Brain Disease Models, Animal DNA Replication Immunogenicity Mice MicroRNAs MiRNA Mutagenesis, Insertional Neuroinvasive Neurons Neurovirulence Open Reading Frames RNA Interference Vaccines, Attenuated Virus Replication West Nile Fever West Nile Virus West Nile Virus Vaccines WNV

  More +
• Source:
  Vaccine. 34(44):5366-5375
• Pubmed ID:
  27637937
• Pubmed Central ID:
  PMC5683167
• Document Type:
  Journal Article
• Funding:
  CC999999/Intramural CDC HHSUnited States/ ; U54 AI065359/AI/NIAID NIH HHSUnited States/
• Volume:
  34
• Issue:
  44
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:a46de5991e52ca94b38ff1b533ecf48ab16dde2668c35dc5028fd9616c670448
• Download URL:
  https://stacks.cdc.gov/view/cdc/49796/cdc_49796_DS1.pdf
• File Type:
  [PDF - 870.17 KB ]