title: Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants.
abstract: BACKGROUND
  In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the etiological agent of severe acute respiratory syndrome, a disease characterized by severe pneumonia that sometimes results in death. SARS-CoV is a zoonotic virus that crossed the species barrier, most likely originating from bats or from other species including civets, raccoon dogs, domestic cats, swine, and rodents. A SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. We report the comprehensive investigation of SARS vaccine efficacy in young and senescent mice following homologous and heterologous challenge.
  
  
  RESULTS
  Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N), we demonstrate that VRP-S, but not VRP-N vaccines provide complete short- and long-term protection against homologous strain challenge in young and senescent mice. To test VRP vaccine efficacy against a heterologous SARS-CoV, we used phylogenetic analyses, synthetic biology, and reverse genetics to construct a chimeric virus (icGDO3-S) encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV. icGD03-S replicated efficiently in human airway epithelial cells and in the lungs of young and senescent mice, and was highly resistant to neutralization with antisera directed against the Urbani strain. Although VRP-S vaccines provided complete short-term protection against heterologous icGD03-S challenge in young mice, only limited protection was seen in vaccinated senescent animals. VRP-N vaccines not only failed to protect from homologous or heterologous challenge, but resulted in enhanced immunopathology with eosinophilic infiltrates within the lungs of SARS-CoV-challenged mice. VRP-N-induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses.
  
  
  CONCLUSIONS
  This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Damon
authors.initials: D
authors.lastname: Deming
authors.forename: Timothy
authors.initials: T
authors.lastname: Sheahan
authors.forename: Mark
authors.initials: M
authors.lastname: Heise
authors.forename: Boyd
authors.initials: B
authors.lastname: Yount
authors.forename: Nancy
authors.initials: N
authors.lastname: Davis
authors.forename: Amy
authors.initials: A
authors.lastname: Sims
authors.forename: Mehul
authors.initials: M
authors.lastname: Suthar
authors.forename: Jack
authors.initials: J
authors.lastname: Harkema
authors.forename: Alan
authors.initials: A
authors.lastname: Whitmore
authors.forename: Raymond
authors.initials: R
authors.lastname: Pickles
authors.forename: Ande
authors.initials: A
authors.lastname: West
authors.forename: Eric
authors.initials: E
authors.lastname: Donaldson
authors.forename: Kristopher
authors.initials: K
authors.lastname: Curtis
authors.forename: Robert
authors.initials: R
authors.lastname: Johnston
authors.forename: Ralph
authors.initials: R
authors.lastname: Baric
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004196:Disease Outbreaks; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006389:Hemagglutinins, Viral / Q000276:immunology*; D007111:Immunity, Cellular / Q000502:physiology; D008168:Lung / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019590:Nucleocapsid Proteins / Q000276:immunology; D012093:Replicon; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D064370:Spike Glycoprotein, Coronavirus; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000276:immunology*; D014765:Viral Vaccines; D015047:Zoonoses / Q000821:virology
chemical_list: D006389:Hemagglutinins, Viral; D008562:Membrane Glycoproteins; D019590:Nucleocapsid Proteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D014765:Viral Vaccines