Clin Exp Vaccine Res.  2017 Jul;6(2):83-94. 10.7774/cevr.2017.6.2.83.

The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents

• Choi WS
• Lloren KK
• Baek YH
• Song MS

• KMID: 2391568
• DOI: http://doi.org/10.7774/cevr.2017.6.2.83

Abstract

Due to the increased frequency of interspecies transmission of avian influenza viruses, studies designed to identify the molecular determinants that could lead to an expansion of the host range have been increased. A variety of mouse-based mammalian-adaptation studies of avian influenza viruses have provided insight into the genetic alterations of various avian influenza subtypes that may contribute to the generation of a pandemic virus. To date, the studies have focused on avian influenza subtypes H5, H6, H7, H9, and H10 which have recently caused human infection. Although mice cannot fully reflect the course of human infection with avian influenza, these mouse studies can be a useful method for investigating potential mammalian adaptive markers against newly emerging avian influenza viruses. In addition, due to the lack of appropriate vaccines against the diverse emerging influenza viruses, the generation of mouse-adapted lethal variants could contribute to the development of effective vaccines or therapeutic agents. Within this review, we will summarize studies that have demonstrated adaptations of avian influenza viruses that result in an altered pathogenicity in mice which may suggest the potential application of mouse-lethal strains in the development of influenza vaccines and/or therapeutics in preclinical studies.

Keyword

Influenza A virus; Mouse adaptation; Molecular determinant; Vaccination; Virulence; Serial passage

MeSH Terms

Animals
Host Specificity
Humans
Influenza A virus
Influenza in Birds*
Influenza Vaccines
Methods
Mice
Orthomyxoviridae
Pandemics
Serial Passage
Vaccination
Vaccines*
Virulence
Influenza Vaccines
Vaccines

Reference

1. Hinshaw VS, Wood JM, Webster RG, Deibel R, Turner B. Circulation of influenza viruses and paramyxoviruses in waterfowl originating from two different areas of North America. Bull World Health Organ. 1985; 63:711–719. PMID: 3878741.

2. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev. 1992; 56:152–179. PMID: 1579108.

3. Kilbourne ED. Influenza pandemics of the 20th century. Emerg Infect Dis. 2006; 12:9–14. PMID: 16494710.

4. World Health Organization. World now at the start of 2009 influenza pandemic [Internet]. Geneva: World Health Organization;2009. cited 2017 May 1. Available from: http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/.

5. Smith GJ, Vijaykrishna D, Bahl J, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009; 459:1122–1125. PMID: 19516283.

6. Centers for Disease Control and Prevention (CDC). Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep. 2009; 58:521–524. PMID: 19478718.

7. Abdelwhab EM, Veits J, Mettenleiter TC. Prevalence and control of H7 avian influenza viruses in birds and humans. Epidemiol Infect. 2014; 142:896–920. PMID: 24423384.

8. Chen H, Yuan H, Gao R, et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet. 2014; 383:714–721. PMID: 24507376.

9. Li Q, Zhou L, Zhou M, et al. Epidemiology of human infections with avian influenza A(H7N9) virus in China. N Engl J Med. 2014; 370:520–532. PMID: 23614499.

10. Malik Peiris JS. Avian influenza viruses in humans. Rev Sci Tech. 2009; 28:161–173. PMID: 19618624.

11. Yuan J, Zhang L, Kan X, et al. Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan. Clin Infect Dis. 2013; 57:1367–1368. PMID: 23881153.

12. Yang ZF, Mok CK, Peiris JS, Zhong NS. Human infection with a novel avian influenza A(H5N6) virus. N Engl J Med. 2015; 373:487–489.

13. World Health Organization. Avian influenza weekly update number 579 [Internet]. Geneva: World Health Organization;2017. cited 2017 May 1. Available from: http://www.wpro.who.int/emerging_diseases/AvianInfluenza/en/.

14. Belser JA, Katz JM, Tumpey TM. The ferret as a model organism to study influenza A virus infection. Dis Model Mech. 2011; 4:575–579. PMID: 21810904.

15. Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci U S A. 2006; 103:9988–9992. PMID: 16785447.

16. Lowen AC, Steel J, Mubareka S, Palese P. High temperature (30 degrees C) blocks aerosol but not contact transmission of influenza virus. J Virol. 2008; 82:5650–5652. PMID: 18367530.

17. Kamal RP, Katz JM, York IA. Molecular determinants of influenza virus pathogenesis in mice. Curr Top Microbiol Immunol. 2014; 385:243–274. PMID: 25038937.

18. Lu X, Tumpey TM, Morken T, Zaki SR, Cox NJ, Katz JM. A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. J Virol. 1999; 73:5903–5911. PMID: 10364342.

19. Gambaryan AS, Boravleva EY, Matrosovich TY, et al. Polymer-bound 6′ sialyl-N-acetyllactosamine protects mice infected by influenza virus. Antiviral Res. 2005; 68:116–123. PMID: 16214231.

20. Qiu M, Fang F, Chen Y, et al. Protection against avian influenza H9N2 virus challenge by immunization with hemagglutinin- or neuraminidase-expressing DNA in BALB/c mice. Biochem Biophys Res Commun. 2006; 343:1124–1131. PMID: 16580631.

21. Leneva IA, Roberts N, Govorkova EA, Goloubeva OG, Webster RG. The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Antiviral Res. 2000; 48:101–115. PMID: 11114412.

22. Smirnov YA, Lipatov AS, Gitelman AK, Claas EC, Osterhaus AD. Prevention and treatment of bronchopneumonia in mice caused by mouse-adapted variant of avian H5N2 influenza A virus using monoclonal antibody against conserved epitope in the HA stem region. Arch Virol. 2000; 145:1733–1741. PMID: 11003481.

23. Govorkova EA, Rehg JE, Krauss S, et al. Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004. J Virol. 2005; 79:2191–2198. PMID: 15681421.

24. Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science. 2001; 293:1840–1842. PMID: 11546875.

25. Subbarao EK, London W, Murphy BR. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol. 1993; 67:1761–1764. PMID: 8445709.

26. Cheng K, Yu Z, Chai H, et al. PB2-E627K and PA-T97I substitutions enhance polymerase activity and confer a virulent phenotype to an H6N1 avian influenza virus in mice. Virology. 2014; 468-470:207–213. PMID: 25194918.

27. Li J, Ishaq M, Prudence M, et al. Single mutation at the amino acid position 627 of PB2 that leads to increased virulence of an H5N1 avian influenza virus during adaptation in mice can be compensated by multiple mutations at other sites of PB2. Virus Res. 2009; 144:123–129. PMID: 19393699.

28. Song MS, Pascua PN, Lee JH, et al. The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model. J Virol. 2009; 83:12325–12335. PMID: 19793828.

29. Claas EC, Osterhaus AD, van Beek R, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 1998; 351:472–477. PMID: 9482438.

30. Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 2008; 4:e1000115. PMID: 18670648.

31. Mase M, Tanimura N, Imada T, Okamatsu M, Tsukamoto K, Yamaguchi S. Recent H5N1 avian influenza A virus increases rapidly in virulence to mice after a single passage in mice. J Gen Virol. 2006; 87(Pt 12):3655–3659. PMID: 17098982.

32. Min JY, Santos C, Fitch A, et al. Mammalian adaptation in the PB2 gene of avian H5N1 influenza virus. J Virol. 2013; 87:10884–10888. PMID: 23864613.

33. Hatta M, Hatta Y, Kim JH, et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog. 2007; 3:1374–1379. PMID: 17922570.

34. Long JS, Howard WA, Nunez A, et al. The effect of the PB2 mutation 627K on highly pathogenic H5N1 avian influenza virus is dependent on the virus lineage. J Virol. 2013; 87:9983–9996. PMID: 23843645.

35. Choi WS, Baek YH, Kwon JJ, et al. Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse. Sci Rep. 2017; 7:40667. PMID: 28094780.

36. Han P, Hu Y, Sun W, et al. Mouse lung-adapted mutation of E190G in hemagglutinin from H5N1 influenza virus contributes to attenuation in mice. J Med Virol. 2015; 87:1816–1822. PMID: 26089289.

37. Smirnov YA, Lipatov AS, Van Beek R, Gitelman AK, Osterhaus AD, Claas EC. Characterization of adaptation of an avian influenza A (H5N2) virus to a mammalian host. Acta Virol. 2000; 44:1–8. PMID: 10989685.

38. Wu H, Peng X, Peng X, et al. Multiple amino acid substitutions involved in the adaptation of avian-origin influenza A (H10N7) virus in mice. Arch Virol. 2016; 161:977–980. PMID: 26699787.

39. Taft AS, Ozawa M, Fitch A, et al. Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus. Nat Commun. 2015; 6:7491. PMID: 26082035.

40. de Vries E, Guo H, Dai M, Rottier PJ, van Kuppeveld FJ, de Haan CA. Rapid emergence of highly pathogenic avian influenza subtypes from a subtype H5N1 hemagglutinin variant. Emerg Infect Dis. 2015; 21:842–846. PMID: 25897518.

41. Dalby AR, Iqbal M. The European and Japanese outbreaks of H5N8 derive from a single source population providing evidence for the dispersal along the long distance bird migratory flyways. PeerJ. 2015; 3:e934. PMID: 25945320.

42. Saito T, Tanikawa T, Uchida Y, Takemae N, Kanehira K, Tsunekuni R. Intracontinental and intercontinental dissemination of Asian H5 highly pathogenic avian influenza virus (clade 2.3.4.4) in the winter of 2014-2015. Rev Med Virol. 2015; 25:388–405. PMID: 26458727.

43. Gu M, Liu W, Cao Y, et al. Novel reassortant highly pathogenic avian influenza (H5N5) viruses in domestic ducks, China. Emerg Infect Dis. 2011; 17:1060–1063. PMID: 21749770.

44. Berhane Y, Kobasa D, Embury-Hyatt C, et al. Pathobiological characterization of a novel reassortant highly pathogenic H5N1 virus isolated in British Columbia, Canada, 2015. Sci Rep. 2016; 6:23380. PMID: 26988892.

45. Kim YI, Pascua PN, Kwon HI, et al. Pathobiological features of a novel, highly pathogenic avian influenza A(H5N8) virus. Emerg Microbes Infect. 2014; 3:e75. PMID: 26038499.

46. Pulit-Penaloza JA, Sun X, Creager HM, et al. Pathogenesis and transmission of novel highly pathogenic avian influenza H5N2 and H5N8 viruses in ferrets and mice. J Virol. 2015; 89:10286–10293. PMID: 26223637.

47. Li Q, Wang X, Zhong L, et al. Adaptation of a natural reassortant H5N2 avian influenza virus in mice. Vet Microbiol. 2014; 172:568–574. PMID: 25037995.

48. Peng X, Wu H, Peng X, et al. Amino acid substitutions occurring during adaptation of an emergent H5N6 avian influenza virus to mammals. Arch Virol. 2016; 161:1665–1670. PMID: 26997612.

49. Wu H, Peng X, Peng X, Wu N. Amino acid substitutions involved in the adaptation of a novel highly pathogenic H5N2 avian influenza virus in mice. Virol J. 2016; 13:159. PMID: 27663652.

50. Capua I, Mutinelli F, Bozza MA, Terregino C, Cattoli G. Highly pathogenic avian influenza (H7N1) in ostriches (Struthio camelus). Avian Pathol. 2000; 29:643–646. PMID: 19184863.

51. Pasick J, Berhane Y, Hisanaga T, et al. Diagnostic test results and pathology associated with the 2007 Canadian H7N3 highly pathogenic avian influenza outbreak. Avian Dis. 2010; 54(1 Suppl):213–219. PMID: 20521634.

52. van den Berg T, Houdart P. Avian influenza outbreak management: action at time of confirmation, depopulation and disposal methods; the ‘Belgian experience’ during the H7N7 highly pathogenic avian influenza epidemic in 2003. Zoonoses Public Health. 2008; 55:54–64. PMID: 18201328.

53. Zanin M, Kocer ZA, Poulson RL, et al. Potential for low-pathogenic avian H7 influenza A viruses to replicate and cause disease in a mammalian model. J Virol. 2017; 91:e01934–e01916. PMID: 27852855.

54. Kim YI, Kim SW, Si YJ, et al. Genetic diversity and pathogenic potential of low pathogenic H7 avian influenza viruses isolated from wild migratory birds in Korea. Infect Genet Evol. 2016; 45:268–284. PMID: 27615552.

55. Joseph T, McAuliffe J, Lu B, Jin H, Kemble G, Subbarao K. Evaluation of replication and pathogenicity of avian influenza a H7 subtype viruses in a mouse model. J Virol. 2007; 81:10558–10566. PMID: 17634234.

56. Food Agriculture Organization. Diseases Events (search criteria: disease list; H5N1 HPAI, H5N6 HPAI, H7N9 LPAI, H7N9 HPAI/animal affected; human) [Internet]. Rome: Food Agriculture Organization;2017. cited 2017 May 1. Available from: http://empres-i.fao.org/eipws3g/.

57. de Jong RM, Stockhofe-Zurwieden N, Verheij ES, et al. Rapid emergence of a virulent PB2 E627K variant during adaptation of highly pathogenic avian influenza H7N7 virus to mice. Virol J. 2013; 10:276. PMID: 24007444.

58. Gabriel G, Dauber B, Wolff T, Planz O, Klenk HD, Stech J. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005; 102:18590–18595. PMID: 16339318.

59. Yu Z, Sun W, Li X, et al. Adaptive amino acid substitutions enhance the virulence of a reassortant H7N1 avian influenza virus isolated from wild waterfowl in mice. Virology. 2015; 476:233–239. PMID: 25555151.

60. Chen Q, Yu Z, Sun W, et al. Adaptive amino acid substitutions enhance the virulence of an H7N7 avian influenza virus isolated from wild waterfowl in mice. Vet Microbiol. 2015; 177:18–24. PMID: 25769645.

61. Zhao Y, Yu Z, Liu L, et al. Adaptive amino acid substitutions enhance the virulence of a novel human H7N9 influenza virus in mice. Vet Microbiol. 2016; 187:8–14. PMID: 27066703.

62. Shinya K, Watanabe S, Ito T, Kasai N, Kawaoka Y. Adaptation of an H7N7 equine influenza A virus in mice. J Gen Virol. 2007; 88(Pt 2):547–553. PMID: 17251573.

63. Brown EG, Liu H, Kit LC, Baird S, Nesrallah M. Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: identification of functional themes. Proc Natl Acad Sci U S A. 2001; 98:6883–6888. PMID: 11371620.

64. Homme PJ, Easterday BC. Avian influenza virus infections. I. Characteristics of influenza A-turkey-Wisconsin-1966 virus. Avian Dis. 1970; 14:66–74. PMID: 4314007.

65. Guo YJ, Krauss S, Senne DA, et al. Characterization of the pathogenicity of members of the newly established H9N2 influenza virus lineages in Asia. Virology. 2000; 267:279–288. PMID: 10662623.

66. Peiris M, Yuen KY, Leung CW, et al. Human infection with influenza H9N2. Lancet. 1999; 354:916–917. PMID: 10489954.

67. Khan SU, Anderson BD, Heil GL, Liang S, Gray GC. A systematic review and meta-analysis of the seroprevalence of influenza A(H9N2) infection among humans. J Infect Dis. 2015; 212:562–569. PMID: 25712969.

68. Guan Y, Shortridge KF, Krauss S, Webster RG. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong? Proc Natl Acad Sci U S A. 1999; 96:9363–9367. PMID: 10430948.

69. Yang L, Zhu W, Li X, et al. Genesis and dissemination of highly pathogenic H5N6 avian influenza viruses. J Virol. 2017; 91:e02199–e02116. PMID: 28003485.

70. Wu A, Su C, Wang D, et al. Sequential reassortments underlie diverse influenza H7N9 genotypes in China. Cell Host Microbe. 2013; 14:446–452. PMID: 24055604.

71. Liu D, Shi W, Gao GF. Poultry carrying H9N2 act as incubators for novel human avian influenza viruses. Lancet. 2014; 383:869. PMID: 24581684.

72. Lee YJ, Shin JY, Song MS, et al. Continuing evolution of H9 influenza viruses in Korean poultry. Virology. 2007; 359:313–323. PMID: 17056087.

73. Choi YK, Seo SH, Kim JA, Webby RJ, Webster RG. Avian influenza viruses in Korean live poultry markets and their pathogenic potential. Virology. 2005; 332:529–537. PMID: 15680418.

74. Zhang H, Xu B, Chen Q, Chen Z. Characterization of H9N2 influenza viruses isolated from Dongting Lake wetland in 2007. Arch Virol. 2011; 156:95–105. PMID: 21053033.

75. Wu R, Zhang H, Yang K, et al. Multiple amino acid substitutions are involved in the adaptation of H9N2 avian influenza virus to mice. Vet Microbiol. 2009; 138:85–91. PMID: 19342184.

76. Zhang Z, Hu S, Li Z, et al. Multiple amino acid substitutions involved in enhanced pathogenicity of LPAI H9N2 in mice. Infect Genet Evol. 2011; 11:1790–1797. PMID: 21896338.

77. Wang J, Sun Y, Xu Q, et al. Mouse-adapted H9N2 influenza A virus PB2 protein M147L and E627K mutations are critical for high virulence. PLoS One. 2012; 7:e40752. PMID: 22808250.

78. Liu Q, Huang J, Chen Y, et al. Virulence determinants in the PB2 gene of a mouse-adapted H9N2 virus. J Virol. 2015; 89:877–882. PMID: 25339773.

79. Liu Q, Chen H, Huang J, et al. A nonpathogenic duck-origin H9N2 influenza A virus adapts to high pathogenicity in mice. Arch Virol. 2014; 159:2243–2252. PMID: 24696271.

80. Sang X, Wang A, Chai T, et al. Rapid emergence of a PB2-E627K substitution confers a virulent phenotype to an H9N2 avian influenza virus during adoption in mice. Arch Virol. 2015; 160:1267–1277. PMID: 25782865.

81. Park KJ, Song MS, Kim EH, et al. Molecular characterization of mammalian-adapted Korean-type avian H9N2 virus and evaluation of its virulence in mice. J Microbiol. 2015; 53:570–577. PMID: 26224460.

82. Li Q, Wang X, Sun Z, et al. Adaptive mutations in PB2 gene contribute to the high virulence of a natural reassortant H5N2 avian influenza virus in mice. Virus Res. 2015; 210:255–263. PMID: 26315686.

83. Yu Z, Cheng K, Xin Y, et al. Multiple amino acid substitutions involved in the adaptation of H6N1 avian influenza virus in mice. Vet Microbiol. 2014; 174:316–321. PMID: 25457364.

84. Tan L, Su S, Smith DK, et al. A combination of HA and PA mutations enhances virulence in a mouse-adapted H6N6 influenza A virus. J Virol. 2014; 88:14116–14125. PMID: 25275121.

85. Yao Y, Wang H, Chen Q, et al. Characterization of low-pathogenic H6N6 avian influenza viruses in central China. Arch Virol. 2013; 158:367–377. PMID: 23053524.

86. Mei K, Liu G, Chen Z, et al. Deep sequencing reveals the viral adaptation process of environment-derived H10N8 in mice. Infect Genet Evol. 2016; 37:8–13. PMID: 26477933.

87. Tian J, Qi W, Li X, et al. A single E627K mutation in the PB2 protein of H9N2 avian influenza virus increases virulence by inducing higher glucocorticoids (GCs) level. PLoS One. 2012; 7:e38233. PMID: 22719870.

88. Su S, Bi Y, Wong G, Gray GC, Gao GF, Li S. Epidemiology, evolution, and recent outbreaks of avian influenza virus in China. J Virol. 2015; 89:8671–8676. PMID: 26063419.

89. Liu M, Li X, Yuan H, et al. Genetic diversity of avian influenza A (H10N8) virus in live poultry markets and its association with human infections in China. Sci Rep. 2015; 5:7632. PMID: 25591167.

90. Shi W, Shi Y, Wu Y, Liu D, Gao GF. Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan. Protein Cell. 2013; 4:846–853. PMID: 24136722.

91. Tzarum N, de Vries RP, Zhu X, et al. Structure and receptor binding of the hemagglutinin from a human H6N1 influenza virus. Cell Host Microbe. 2015; 17:369–376. PMID: 25766295.

92. Wang G, Deng G, Shi J, et al. H6 influenza viruses pose a potential threat to human health. J Virol. 2014; 88:3953–3964. PMID: 24501418.

93. Nam JH, Kim EH, Song D, Choi YK, Kim JK, Poo H. Emergence of mammalian species-infectious and -pathogenic avian influenza H6N5 virus with no evidence of adaptation. J Virol. 2011; 85:13271–13277. PMID: 21994462.

94. Gillim-Ross L, Santos C, Chen Z, et al. Avian influenza h6 viruses productively infect and cause illness in mice and ferrets. J Virol. 2008; 82:10854–10863. PMID: 18715930.

95. Kim HR, Lee YJ, Lee KK, et al. Genetic relatedness of H6 subtype avian influenza viruses isolated from wild birds and domestic ducks in Korea and their pathogenicity in animals. J Gen Virol. 2010; 91(Pt 1):208–219. PMID: 19812266.

96. Wu H, Lu R, Wu X, et al. Isolation and characterization of a novel H10N2 avian influenza virus from a domestic duck in Eastern China. Infect Genet Evol. 2015; 29:1–5. PMID: 25445651.

97. Wu H, Lu R, Wu X, et al. Novel reassortant H10N7 avian influenza viruses isolated from chickens in Eastern China. J Clin Virol. 2015; 65:58–61. PMID: 25766990.

98. Zhang M, Zhang X, Xu K, et al. Characterization of the pathogenesis of H10N3, H10N7, and H10N8 subtype avian influenza viruses circulating in ducks. Sci Rep. 2016; 6:34489. PMID: 27678170.

99. Chen H, Huang L, Li H, et al. High pathogenicity of influenza A (H10N8) virus in mice. Am J Trop Med Hyg. 2015; 93:1360–1363. PMID: 26350451.

100. Francis T, Magill TP. Immunological studies with the virus of influenza. J Exp Med. 1935; 62:505–516. PMID: 19870430.

101. Lee YT, Kim KH, Ko EJ, et al. New vaccines against influenza virus. Clin Exp Vaccine Res. 2014; 3:12–28. PMID: 24427759.

102. Jang YH, Byun YH, Lee YJ, Lee YH, Lee KH, Seong BL. Cold-adapted pandemic 2009 H1N1 influenza virus live vaccine elicits cross-reactive immune responses against seasonal and H5 influenza A viruses. J Virol. 2012; 86:5953–5958. PMID: 22438541.

103. Kim SM, Kim YI, Park SJ, et al. Vaccine efficacy of inactivated, chimeric hemagglutinin H9/H5N2 avian influenza virus and its suitability for the marker vaccine strategy. J Virol. 2017; 91:e01693–e01616. PMID: 28077631.

104. Choi EH, Song MS, Park SJ, et al. Development of a dual-protective live attenuated vaccine against H5N1 and H9N2 avian influenza viruses by modifying the NS1 gene. Arch Virol. 2015; 160:1729–1740. PMID: 25959557.

105. Song MS, Moon HJ, Kwon HI, et al. Evaluation of the efficacy of a pre-pandemic H5N1 vaccine (MG1109) in mouse and ferret models. J Microbiol. 2012; 50:478–488. PMID: 22752912.

106. Shim BS, Choi YK, Yun CH, et al. Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza. PLoS One. 2011; 6:e27953. PMID: 22140491.

107. Park KS, Lee J, Ahn SS, et al. Mucosal immunity induced by adenovirus-based H5N1 HPAI vaccine confers protection against a lethal H5N2 avian influenza virus challenge. Virology. 2009; 395:182–189. PMID: 19836045.

108. Park KS, Seo YB, Lee JY, et al. Complete protection against a H5N2 avian influenza virus by a DNA vaccine expressing a fusion protein of H1N1 HA and M2e. Vaccine. 2011; 29:5481–5487. PMID: 21664216.

109. Kim EH, Lee JH, Pascua PN, et al. Prokaryote-expressed M2e protein improves H9N2 influenza vaccine efficacy and protection against lethal influenza A virus in mice. Virol J. 2013; 10:104. PMID: 23551908.

110. Takahashi K, Moyo P, Chigweshe L, Chang WC, White MR, Hartshorn KL. Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study. Virus Res. 2013; 178:495–501. PMID: 24140629.

111. D'Agostini C, Palamara AT, Favalli C, et al. Efficacy of combination therapy with amantadine, thymosin alpha 1 and alpha/beta interferon in mice infected with influenza A virus. Int J Immunopharmacol. 1996; 18:95–102. PMID: 8799359.

112. Sidwell RW, Huffman JH, Barnard DL, et al. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res. 1998; 37:107–120. PMID: 9588843.

113. Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother. 2001; 45:2723–2732. PMID: 11557461.

114. Lipatov AS, Gitelman AK, Smirnov YA. Differences between original strains and their mouse-adapted variants of human (H1) and avian (H2) influenza A viruses in the reaction with cross-neutralizing monoclonal antibody recognizing conformational epitope. Acta Virol. 1996; 40:227–230. PMID: 9014015.

115. Gitelman AK, Kaverin NV, Kharitonenkov IG, Rudneva IA, Zhdanov VM. Changes in the antigenic specificity of influenza hemagglutinin in the course of adaptation to mice. Virology. 1984; 134:230–232. PMID: 6200993.

116. World Health Oranization. Cumulative number of confirmed human cases of avian influenza A(H5N1) reported to WHO [Internet]. Geneva: World Health Organization;cited 2017 May 1. Available from: http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/.