Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve

J Infect Dis. 2016 Aug 15;214(4):516-24. doi: 10.1093/infdis/jiw123. Epub 2016 Apr 1.


Background: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model.

Methods: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology.

Results: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis.

Conclusions: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.

Keywords: H5N1; encephalitis; ferret; influenza; olfactory mucosa; olfactory nerve; oseltamivir; vaccine; virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Chemoprevention / methods
  • Disease Models, Animal
  • Female
  • Ferrets
  • Influenza A Virus, H5N1 Subtype / drug effects
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / isolation & purification*
  • Influenza Vaccines / administration & dosage*
  • Injections, Intramuscular
  • Meningoencephalitis / prevention & control*
  • Olfactory Nerve / virology
  • Orthomyxoviridae Infections / complications*
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Oseltamivir / administration & dosage*
  • Treatment Outcome


  • Antiviral Agents
  • Influenza Vaccines
  • Oseltamivir