Successful Vaccination Strategies That Protect Aged Mice from Lethal Challenge from Influenza Virus and Heterologous Severe Acute Respiratory Syndrome Coronavirus

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  • Timothy Sheahan
    • Other Affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Alan Whitmore
    • Other Affiliation: Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Kristin Long
    • Other Affiliation: Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Martin Ferris
    • Other Affiliation: Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Barry Rockx
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana
  • William Funkhouser
    • Other Affiliation: Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
  • Eric Donaldson
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Lisa Gralinski
    • Other Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Martha Collier
    • Other Affiliation: Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Mark Heise
    • Other Affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Nancy Davis
    • Other Affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Robert Johnston
    • Other Affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Ralph S. Baric
    • Other Affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Abstract
  • Newly emerging viruses often circulate as a heterogeneous swarm in wild animal reservoirs prior to their emergence in humans, and their antigenic identities are often unknown until an outbreak situation. The newly emerging severe acute respiratory syndrome coronavirus (SARS-CoV) and reemerging influenza virus cause disproportionate disease in the aged, who are also notoriously difficult to successfully vaccinate, likely due to immunosenescence. To protect against future emerging strains, vaccine platforms should induce broad cross-reactive immunity that is sufficient to protect from homologous and heterologous challenge in all ages. From initial studies, we hypothesized that attenuated Venezuelan equine encephalitis virus (VEE) replicon particle (VRP) vaccine glycoproteins mediated vaccine failure in the aged. We then compared the efficacies of vaccines bearing attenuated (VRP3014) or wild-type VEE glycoproteins (VRP3000) in young and aged mice within novel models of severe SARS-CoV pathogenesis. Aged animals receiving VRP3000-based vaccines were protected from SARS-CoV disease, while animals receiving the VRP3014-based vaccines were not. The superior protection for the aged observed with VRP3000-based vaccines was confirmed in a lethal influenza virus challenge model. While the VRP3000 vaccine's immune responses in the aged were sufficient to protect against lethal homologous and heterologous challenge, our data suggest that innate defects within the VRP3014 platform mediate vaccine failure. Exploration into the mechanism(s) of successful vaccination in the immunosenescent should aid in the development of successful vaccine strategies for other viral diseases disproportionately affecting the elderly, like West Nile virus, influenza virus, norovirus, or other emerging viruses of the future.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Journal of Virology
Journal volume
  • 85
Journal issue
  • 1
Page start
  • 217
Page end
  • 230
Language
  • English
ISSN
  • 1098-5514
  • 0022-538X
  • 1070-6321
Publisher
  • American Society for Microbiology

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