Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 24, Number 6—June 2018
Perspective

Ferrets as Models for Influenza Virus Transmission Studies and Pandemic Risk Assessments

Jessica A. BelserComments to Author , Wendy Barclay, Ian Barr, Ron A.M. Fouchier, Ryota Matsuyama, Hiroshi Nishiura, Malik Peiris, Charles J. Russell, Kanta Subbarao, Huachen Zhu, and Hui-Ling YenComments to Author 
Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (J.A. Belser); Imperial College, London, UK (W. Barclay); Doherty Institute, Melbourne, Victoria, Australia (I. Barr, K. Subbarao); Erasmus Medical Center, Rotterdam, the Netherlands (R.A.M. Fouchier); Hokkaido University, Sapporo, Japan (R. Matsuyama, H. Nishiura); The University of Hong Kong, Hong Kong, China (M. Peiris, H. Zhu, H.-L. Yen); St. Jude Children's Research Hospital, Memphis, Tennessee, USA (C.J. Russell)

Main Article

Table 1

Examples of heterogeneity in experimental designs among published risk-assessment studies using ferrets as models for influenza virus transmission studies and pandemic risk assessments*

Parameter Examples of variability
Virus (before ferret introduction)
 Seed stock passage history, stock growth matrix, stock titer, wild-type vs. reverse genetics, plaque-purified vs. quasispecies, storage and propagation conditions
Ferret (before virus introduction)
 Source/genetic lineage, serostatus, age, sex, weight, neutered or intact status, hormonal treatment (females), anesthetic used, housing conditions
Virus inoculation
 Inoculation route, method, dose, and volume; buffer for dilution
Transmission experimental designs Donor:recipient ratio, number of replicates per containment, caging size and setup, perforation size and exposure area between cages, distance between cages, directional airflow, air changes per hour, temperature and humidity, timing and duration of exposure, frequency and sites for sample collection

*References for individual studies using these conditions are described in (1).

Main Article

References
  1. Belser  JA, Eckert  AM, Tumpey  TM, Maines  TR. Complexities in ferret influenza virus pathogenesis and transmission models. Microbiol Mol Biol Rev. 2016;80:733–44. DOIPubMedGoogle Scholar
  2. Herfst  S, Schrauwen  EJ, Linster  M, Chutinimitkul  S, de Wit  E, Munster  VJ, et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science. 2012;336:1534–41. DOIPubMedGoogle Scholar
  3. Zhu  H, Wang  D, Kelvin  DJ, Li  L, Zheng  Z, Yoon  SW, et al. Infectivity, transmission, and pathology of human-isolated H7N9 influenza virus in ferrets and pigs. Science. 2013;341:183–6. DOIPubMedGoogle Scholar
  4. Tumpey  TM, Maines  TR, Van Hoeven  N, Glaser  L, Solórzano  A, Pappas  C, et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science. 2007;315:655–9. DOIPubMedGoogle Scholar
  5. Yen  HL, Lipatov  AS, Ilyushina  NA, Govorkova  EA, Franks  J, Yilmaz  N, et al. Inefficient transmission of H5N1 influenza viruses in a ferret contact model. J Virol. 2007;81:6890–8. DOIPubMedGoogle Scholar
  6. Maines  TR, Chen  LM, Matsuoka  Y, Chen  H, Rowe  T, Ortin  J, et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc Natl Acad Sci U S A. 2006;103:12121–6. DOIPubMedGoogle Scholar
  7. Munster  VJ, de Wit  E, van den Brand  JM, Herfst  S, Schrauwen  EJ, Bestebroer  TM, et al. Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science. 2009;325:481–3.PubMedGoogle Scholar
  8. Cox  NJ, Trock  SC, Burke  SA. Pandemic preparedness and the Influenza Risk Assessment Tool (IRAT). Curr Top Microbiol Immunol. 2014;385:119–36. DOIPubMedGoogle Scholar
  9. World Health Organization. Tool for Influenza Pandemic Risk Assessment (TIPRA). Geneva: The Organization; 2016.
  10. Imai  M, Watanabe  T, Hatta  M, Das  SC, Ozawa  M, Shinya  K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 2012;486:420–8. DOIPubMedGoogle Scholar
  11. Maines  TR, Belser  JA, Gustin  KM, van Hoeven  N, Zeng  H, Svitek  N, et al. Local innate immune responses and influenza virus transmission and virulence in ferrets. J Infect Dis. 2012;205:474–85. DOIPubMedGoogle Scholar
  12. Oh  DY, Lowther  S, McCaw  JM, Sullivan  SG, Leang  SK, Haining  J, et al. Evaluation of oseltamivir prophylaxis regimens for reducing influenza virus infection, transmission and disease severity in a ferret model of household contact. J Antimicrob Chemother. 2014;69:2458–69. DOIPubMedGoogle Scholar
  13. Houser  KV, Pearce  MB, Katz  JM, Tumpey  TM. Impact of prior seasonal H3N2 influenza vaccination or infection on protection and transmission of emerging variants of influenza A(H3N2)v virus in ferrets. J Virol. 2013;87:13480–9. DOIPubMedGoogle Scholar
  14. Linster  M, van Boheemen  S, de Graaf  M, Schrauwen  EJA, Lexmond  P, Mänz  B, et al. Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus. Cell. 2014;157:329–39. DOIPubMedGoogle Scholar
  15. Russier  M, Yang  G, Rehg  JE, Wong  SS, Mostafa  HH, Fabrizio  TP, et al. Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein. Proc Natl Acad Sci U S A. 2016;113:1636–41. DOIPubMedGoogle Scholar
  16. Yen  HL, Liang  CH, Wu  CY, Forrest  HL, Ferguson  A, Choy  KT, et al. Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. Proc Natl Acad Sci U S A. 2011;108:14264–9. DOIPubMedGoogle Scholar
  17. Blumenkrantz  D, Roberts  KL, Shelton  H, Lycett  S, Barclay  WS. The short stalk length of highly pathogenic avian influenza H5N1 virus neuraminidase limits transmission of pandemic H1N1 virus in ferrets. J Virol. 2013;87:10539–51. DOIPubMedGoogle Scholar
  18. Paules  CI, Lakdawala  S, McAuliffe  JM, Paskel  M, Vogel  L, Kallewaard  NL, et al. The hemagglutinin A stem antibody MEDI8852 prevents and controls disease and limits transmission of pandemic influenza viruses. J Infect Dis. 2017;216:356–65. DOIPubMedGoogle Scholar
  19. Baz  M, Boonnak  K, Paskel  M, Santos  C, Powell  T, Townsend  A, et al. Nonreplicating influenza A virus vaccines confer broad protection against lethal challenge. MBio. 2015;6:e01487–15. DOIPubMedGoogle Scholar
  20. Cowling  BJ, Lam  TT-Y, Yen  HL, Poon  LLM, Peiris  M. Evidence-based options for controlling respiratory virus transmission. [cited 2018 Feb 20]. Emerg Infect Dis. 2017;23. DOIGoogle Scholar
  21. Moore  IN, Lamirande  EW, Paskel  M, Donahue  D, Kenney  H, Qin  J, et al. Severity of clinical disease and pathology in ferrets experimentally infected with influenza viruses is influenced by inoculum volume. J Virol. 2014;88:13879–91. DOIPubMedGoogle Scholar
  22. Gustin  KM, Belser  JA, Wadford  DA, Pearce  MB, Katz  JM, Tumpey  TM, et al. Influenza virus aerosol exposure and analytical system for ferrets. Proc Natl Acad Sci U S A. 2011;108:8432–7. DOIPubMedGoogle Scholar
  23. Belser  JA, Gustin  KM, Maines  TR, Pantin-Jackwood  MJ, Katz  JM, Tumpey  TM. Influenza virus respiratory infection and transmission following ocular inoculation in ferrets. PLoS Pathog. 2012;8:e1002569. DOIPubMedGoogle Scholar
  24. Nishiura  H, Yen  HL, Cowling  BJ. Sample size considerations for one-to-one animal transmission studies of the influenza A viruses. PLoS One. 2013;8:e55358. DOIPubMedGoogle Scholar
  25. Belser  JA, Maines  TR, Katz  JM, Tumpey  TM. Considerations regarding appropriate sample size for conducting ferret transmission experiments. Future Microbiol. 2013;8:961–5. DOIPubMedGoogle Scholar
  26. Frise  R, Bradley  K, van Doremalen  N, Galiano  M, Elderfield  RA, Stilwell  P, et al. Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance. Sci Rep. 2016;6:29793. DOIPubMedGoogle Scholar
  27. Varble  A, Albrecht  RA, Backes  S, Crumiller  M, Bouvier  NM, Sachs  D, et al. Influenza A virus transmission bottlenecks are defined by infection route and recipient host. Cell Host Microbe. 2014;16:691–700. DOIPubMedGoogle Scholar
  28. Lakdawala  SS, Jayaraman  A, Halpin  RA, Lamirande  EW, Shih  AR, Stockwell  TB, et al. The soft palate is an important site of adaptation for transmissible influenza viruses. Nature. 2015;526:122–5. DOIPubMedGoogle Scholar
  29. Lakdawala  SS, Lamirande  EW, Suguitan  AL Jr, Wang  W, Santos  CP, Vogel  L, et al. Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. PLoS Pathog. 2011;7:e1002443. DOIPubMedGoogle Scholar
  30. Gustin  KM, Katz  JM, Tumpey  TM, Maines  TR. Comparison of the levels of infectious virus in respirable aerosols exhaled by ferrets infected with influenza viruses exhibiting diverse transmissibility phenotypes. J Virol. 2013;87:7864–73. DOIPubMedGoogle Scholar
  31. Koster  F, Gouveia  K, Zhou  Y, Lowery  K, Russell  R, MacInnes  H, et al. Exhaled aerosol transmission of pandemic and seasonal H1N1 influenza viruses in the ferret. PLoS One. 2012;7:e33118. DOIPubMedGoogle Scholar
  32. Lowen  AC, Steel  J. Roles of humidity and temperature in shaping influenza seasonality. J Virol. 2014;88:7692–5. DOIPubMedGoogle Scholar
  33. Gustin  KM, Belser  JA, Veguilla  V, Zeng  H, Katz  JM, Tumpey  TM, et al. Environmental conditions affect exhalation of H3N2 seasonal and variant influenza viruses and respiratory droplet transmission in ferrets. PLoS One. 2015;10:e0125874. DOIPubMedGoogle Scholar
  34. Roberts  KL, Shelton  H, Stilwell  P, Barclay  WS. Transmission of a 2009 H1N1 pandemic influenza virus occurs before fever is detected, in the ferret model. PLoS One. 2012;7:e43303. DOIPubMedGoogle Scholar
  35. Lipsitch  M, Barclay  W, Raman  R, Russell  CJ, Belser  JA, Cobey  S, et al. Viral factors in influenza pandemic risk assessment. eLife. 2016;5:5. DOIPubMedGoogle Scholar

Main Article

Page created: May 18, 2018
Page updated: May 18, 2018
Page reviewed: May 18, 2018
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external