A Narrative Review of Norovirus Gastroenteritis: More Global Attention Is Needed

Document Type : Review Article


1 Laboratory Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

2 Key Lab of Enteric Pathogenic Microbiology, Ministry of Health, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China


Noroviruses (NoVs), an important pathogenic agent of foodborne illness, lead to acute and chronic gastroenteritis in humans of all ages and to travelers’ diarrhea. Many genotypes exist in nature; GII.4 is widely known as the most predominant. Outbreaks mostly occur in semi-closed settings. Although the disease is self-limited to person, many cases have resulted in death, which has raised more concerns. However, a lack of microbial culture techniques limits research and thus knowledge about these viruses. To date, there are no specific antiviral drugs that fight NoVs. Rehydration is the ideal approach at present for severe cases. The only way to prevent infection is to improve personal hygiene. So many variants and ambiguous evolution mechanisms make research for a vaccine much more difficult. In recent years, several vaccine candidates entered pre-clinical development. This review concentrates on summarizing the aspects of NoV structure, culture, genetic evolution, and the vaccine.


  1. Ahmed SM, Hall AJ, Robinson AE, et al. Global prevalence of norovirus in cases of gastroenteritis: a systematic review and metaanalysis. Lancet Infect Dis. 2014;14(8):725-730. doi:10.1016/S1473-3099(14)70767-4.
  2. Fischer Walker CL, Perin J, Aryee MJ, Boschi-Pinto C, Black RE. Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Public Health. 2012;12:220. doi:10.1186/1471-2458-12-220.
  3. White PA. Evolution of norovirus. Clin Microbiol Infect. 2014;20(8):741-745. doi:10.1111/1469-0691.12746.
  4. Tan M, Jiang X. Vaccine against norovirus. Hum Vaccin Immunother. 2014;10(6):1449-1456. doi:10.4161/hv.28626.
  5. Alhatlani B, Vashist S, Goodfellow I. Functions of the 5’ and 3’ ends of calicivirus genomes. Virus Res. 2015;206:134-143. doi:10.1016/j.virusres.2015.02.002.
  6. McFadden N, Bailey D, Carrara G, et al. Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4. PLoS Pathog. 2011;7(12):e1002413. doi:10.1371/journal.ppat.1002413.
  7. May J, Viswanathan P, Ng KK, Medvedev A, Korba B. The p4-p2’ amino acids surrounding human norovirus polyprotein cleavage sites define the core sequence regulating self-processing order. J Virol. 2014;88(18):10738-10747. doi:10.1128/JVI.01357-14.
  8. Hussey RJ, Coates L, Gill RS, et al. A structural study of norovirus 3C protease specificity: binding of a designed active site-directed peptide inhibitor. Biochemistry. 2011;50(2):240-249. doi:10.1021/bi1008497.
  9. Ayukekbong JA, Mesumbe HN, Oyero OG, Lindh M, Bergstrom T. Role of noroviruses as aetiological agents of diarrhoea in developing countries. J Gen Virol. 2015;96(8):1983-1999. doi:10.1099/vir.0.000194.
  10. Bertolotti-Ciarlet A, White LJ, Chen R, Prasad BV, Estes MK. Structural requirements for the assembly of Norwalk virus-like particles. J Virol. 2002;76(8):4044-4055.
  11. Bertolotti-Ciarlet A, Crawford SE, Hutson AM, Estes MK. The 3’ end of Norwalk virus mRNA contains determinants that regulate the expression and stability of the viral capsid protein VP1: a novel function for the VP2 protein. J Virol. 2003;77(21):11603-11615.
  12. Zheng DP, Ando T, Fankhauser RL, Beard RS, Glass RI, Monroe SS. Norovirus classification and proposed strain nomenclature. Virology. 2006;346(2):312-323. doi:10.1016/j.virol.2005.11.015.
  13. Hernandez JD, Silva LD, Sousa ECJ, et al. Analysis of uncommon norovirus recombinants from Manaus, Amazon region, Brazil: GII.P22/GII.5, GII.P7/GII.6 and GII.Pg/GII.1. Infect Genet Evol. 2016;39:365-371. doi:10.1016/j.meegid.2016.02.007.
  14. Caddy S, Breiman A, le Pendu J, Goodfellow I. Genogroup IV and VI canine noroviruses interact with histo-blood group antigens. J Virol. 2014;88(18):10377-10391. doi:10.1128/JVI.01008-14.
  15. Wang QH, Costantini V, Saif LJ. Porcine enteric caliciviruses: genetic and antigenic relatedness to human caliciviruses, diagnosis and epidemiology. Vaccine. 2007;25(30):5453-5466. doi:10.1016/j.vaccine.2006.12.032.
  16. Shen Q, Zhang W, Yang S, Cui L, Hua X. Complete genome sequence of a new-genotype porcine norovirus isolated from piglets with diarrhea. J Virol. 2012;86(12):7015-7016. doi:10.1128/JVI.00757-12.
  17. Martella V, Lorusso E, Decaro N, et al. Detection and molecular characterization of a canine norovirus. Emerg Infect Dis. 2008;14(8):1306-1308. doi:10.3201/eid1408.080062.
  18. Moore MD, Goulter RM, Jaykus LA. Human norovirus as a foodborne pathogen: challenges and developments. Annu Rev Food Sci Technol. 2015;6:411-433. doi:10.1146/annurevfood-022814-015643.
  19. Wobus CE, Karst SM, Thackray LB, et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2004;2(12):e432. doi:10.1371/journal.pbio.0020432.
  20. Lay MK, Atmar RL, Guix S, et al. Norwalk virus does not replicate in human macrophages or dendritic cells derived from the peripheral blood of susceptible humans. Virology. 2010;406(1):1-11. doi:10.1016/j.virol.2010.07.001.
  21. Takanashi S, Saif LJ, Hughes JH, et al. Failure of propagation of human norovirus in intestinal epithelial cells with microvilli grown in three-dimensional cultures. Arch Virol. 2014;159(2):257-266. doi:10.1007/s00705-013-1806-4.
  22. Ettayebi K, Crawford SE, Murakami K, et al. Replication of human noroviruses in stem cell-derived human enteroids. Science. 2016. doi:10.1126/science.aaf5211.
  23. Bok K, Parra GI, Mitra T, et al. Chimpanzees as an animal model for human norovirus infection and vaccine development. Proc Natl Acad Sci U S A. 2011;108(1):325-330. doi:10.1073/pnas.1014577107.
  24. Bui T, Kocher J, Li Y, et al. Median infectious dose of human norovirus GII.4 in gnotobiotic pigs is decreased by simvastatin treatment and increased by age. J Gen Virol. 2013;94(Pt 9):2005-2016. doi:10.1099/vir.0.054080-0.
  25. Souza M, Azevedo MS, Jung K, Cheetham S, Saif LJ. Pathogenesis and immune responses in gnotobiotic calves after infection with the genogroup II.4-HS66 strain of human norovirus. J Virol. 2008;82(4):1777-1786. doi:10.1128/JVI.01347-07.
  26. Hsu CC, Piotrowski SL, Meeker SM, Smith KD, Maggio-Price L, Treuting PM. Histologic lesions induced by murine norovirus infection in laboratory mice. Vet Pathol. 2016. doi:10.1177/0300985815618439.
  27. Zonta W, Mauroy A, Farnir F, Thiry E. Comparative virucidal efficacy of seven disinfectants against murine norovirus and feline calicivirus, surrogates of human norovirus. Food Environ Virol. 2016;8(1):1-12. doi:10.1007/s12560-015-9216-2.
  28. Arthur SE, Gibson KE. Environmental persistence of Tulane virus - a surrogate for human norovirus. Can J Microbiol. 2016;62(5):449-454. doi:10.1139/cjm-2015-0756.
  29. Richards GP. Critical review of norovirus surrogates in food safety research: rationale for considering volunteer studies. Food Environ Virol. 2012;4(1):6-13. doi:10.1007/s12560-011-9072-7.
  30. Kapikian AZ, Wyatt RG, Dolin R, Thornhill TS, Kalica AR, Chanock RM. Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol. 1972;10(5):1075-1081.
  31. Division of Viral Diseases NCfI, Respiratory Diseases CfDC, 

    Prevention. Updated norovirus outbreak management and disease 

    prevention guidelines. MMWR Recomm Rep. 2011;60(RR-3):1-

  32. Hall AJ, Lopman BA, Payne DC, et al. Norovirus disease in 

    the United States. Emerg Infect Dis. 2013;19(8):1198-1205. 


  33. Ajami NJ, Kavanagh OV, Ramani S, et al. Seroepidemiology 

    of norovirus-associated travelers’ diarrhea. J Travel Med. 

    2014;21(1):6-11. doi:10.1111/jtm.12092.
  34. Lindesmith LC, Beltramello M, Donaldson EF, et al. Immunogenetic 

    mechanisms driving norovirus GII.4 antigenic variation. PLoS 

    Pathog. 2012;8(5):e1002705. doi:10.1371/journal.ppat.1002705. 

  35. Fu JG, Ai J, Qi X, Zhang J, Tang FY, Zhu YF. Emergence of two 

    novel norovirus genotype II.4 variants associated with viral 

    gastroenteritis in China. J Med Virol. 2014;86(7):1226-1234. 


  36. Green KY. Norovirus infection in immunocompromised hosts. 

    Clin Microbiol Infect. 2014;20(8):717-723. doi:10.1111/1469-

  37. Cummins M, Ready D. Role of the Hospital Environment in 

    Norovirus Containment. J Infect Dis. 2016;213 Suppl 1:S12-14. 


  38. Wikswo ME, Cortes J, Hall AJ, et al. Disease transmission and 

    passenger behaviors during a high morbidity Norovirus outbreak 

    on a cruise ship, January 2009. Clin Infect Dis. 2011;52(9):1116- 

    1122. doi:10.1093/cid/cir144.

  39. Vega E, Barclay L, Gregoricus N, Shirley SH, Lee D, Vinje J. 

    Genotypic and epidemiologic trends of norovirus outbreaks in the 

    United States, 2009 to 2013. J Clin Microbiol. 2014;52(1):147-

    155. doi:10.1128/JCM.02680-13.

  40. Leshem E, Gastanaduy PA, Trivedi T, et al. Norovirus in a United 

    States virgin islands resort: outbreak investigation, response, and 

    costs. J Travel Med. 2016;23(5). doi:10.1093/jtm/taw040.
  41. Widdowson MA, Glass R, Monroe S, et al. Probable transmission 

    of norovirus on an airplane. JAMA. 2005;293(15):1859-1860. 


  42. Marks PJ, Vipond IB, Regan FM, Wedgwood K, Fey RE, Caul EO. 

    A school outbreak of Norwalk-like virus: evidence for airborne 

    transmission. Epidemiol Infect. 2003;131(1):727-736.
  43. Atmar RL, Opekun AR, Gilger MA, et al. Determination of the 

    50% human infectious dose for Norwalk virus. J Infect Dis. 

    2014;209(7):1016-1022. doi:10.1093/infdis/jit620.

  44. Roth AN, Karst SM. Norovirus mechanisms of immune 

    antagonism. Curr Opin Virol. 2016;16:24-30. doi:10.1016/j.

  45. Lee RM, Lessler J, Lee RA, et al. Incubation periods of viral 

    gastroenteritis: a systematic review. BMC Infect Dis. 2013;13:446. 


  46. Teunis PF, Sukhrie FH, Vennema H, Bogerman J, Beersma MF, 

    Koopmans MP. Shedding of norovirus in symptomatic and 

    asymptomatic infections. Epidemiol Infect. 2015;143(8):1710-

    1717. doi:10.1017/S095026881400274X.

  47. Donaldson EF, Lindesmith LC, Lobue AD, Baric RS. Norovirus 

    pathogenesis: mechanisms of persistence and immune evasion in 

    human populations. Immunol Rev. 2008;225:190-211. 
  48. Eden JS, Hewitt J, Lim KL, et al. The emergence and evolution of 

    the novel epidemic norovirus GII.4 variant Sydney 2012. Virology. 

    2014;450-451:106-113. doi:10.1016/j.virol.2013.12.005.

  49. Debbink K, Donaldson EF, Lindesmith LC, Baric RS. Genetic 

    mapping of a highly variable norovirus GII.4 blockade epitope: 

    potential role in escape from human herd immunity. J Virol. 

    2012;86(2):1214-1226. doi:10.1128/JVI.06189-11.

  50. Novella IS, Presloid JB, Taylor RT. RNA replication errors and the 

    evolution of virus pathogenicity and virulence. Curr Opin Virol. 

    2014;9:143-147. doi:10.1016/j.coviro.2014.09.017.
  51. Bull RA, White PA. Mechanisms of GII.4 norovirus evolution. Trends 

    Microbiol. 2011;19(5):233-240. doi:10.1016/j.tim.2011.01.002.
  52. Copper PD, Steiner-Pryor A, Scotti PD, Delong D. On the nature 

    of poliovirus genetic recombinants. J Gen Virol. 1974;23(1):41-49. 


  53. Fu JG, Ai J, Zhang J, et al. Molecular epidemiology of genogroup 

    II norovirus infection among hospitalized children with acute 

    gastroenteritis in Suzhou (Jiangsu, China) from 2010 to 2013. J 

    Med Virol. 2016;88(6):954-960. doi:10.1002/jmv.24429.

  54. Bull RA, Tanaka MM, White PA. Norovirus recombination. J Gen 

    Virol. 2007;88(Pt 12):3347-3359. doi:10.1099/vir.0.83321-0.

  55. Eden JS, Tanaka MM, Boni MF, Rawlinson WD, White PA. 

    Recombination within the pandemic norovirus GII.4 lineage. J 

    Virol. 2013;87(11):6270-6282. doi:10.1128/JVI.03464-12.
  56. Puustinen L, Blazevic V, Huhti L, et al. Norovirus genotypes in 

    endemic acute gastroenteritis of infants and children in Finland 

    between 1994 and 2007. Epidemiol Infect. 2012;140(2):268-275. 

  57. Kaplan JE, Feldman R, Campbell DS, Lookabaugh C, Gary GW. 

    The frequency of a Norwalk-like pattern of illness in outbreaks of 

    acute gastroenteritis. Am J Public Health. 1982;72(12):1329-1332.

  58. Turcios RM, Widdowson MA, Sulka AC, Mead PS, Glass RI. 

    Reevaluation of epidemiological criteria for identifying outbreaks 

    of acute gastroenteritis due to norovirus: United States, 1998-

    2000. Clin Infect Dis. 2006;42(7):964-969. doi:10.1086/500940.

  59. Oshiro LS, Haley CE, Roberto RR, et al. A 27-nm virus isolated 

    during an outbreak of acute infectious nonbacterial gastroenteritis 

    in a convalescent hospital: a possible new serotype. J Infect Dis. 


  60. Vyas K, Atkinson C, Clark DA, Irish D. Comparison of five 

    commercially available immunochromatographic tests for 

    the detection of norovirus in faecal specimens. J Hosp Infect. 

    2015;91(2):176-178. doi:10.1016/j.jhin.2015.06.013.

  61. Thery L, Bidalot M, Pothier P, Ambert-Balay K. Evaluation 

    of immunochromatographic tests for the rapid detection 

    of the emerging GII.17 norovirus in stool samples, January 

    2016. Euro Surveill. 2016;21(4). doi:10.2807/1560-7917. 

  62. Xia M, Farkas T, Jiang X. Norovirus capsid protein expressed 

    in yeast forms virus-like particles and stimulates systemic and 

    mucosal immunity in mice following an oral administration of 

    raw yeast extracts. J Med Virol. 2007;79(1):74-83. doi:10.1002/


  63. Jiang X, Wang M, Graham DY, Estes MK. Expression, self-assembly, 

    and antigenicity of the Norwalk virus capsid protein. J Virol. 

  64. Lai H, Chen Q. Bioprocessing of plant-derived virus-like particles 

    of Norwalk virus capsid protein under current Good Manufacture 

    Practice regulations. Plant Cell Rep. 2012;31(3):573-584. 

  65. Santi L, Batchelor L, Huang Z, et al. An efficient plant viral 

    expression system generating orally immunogenic Norwalk viruslike 

    particles. Vaccine. 2008;26(15):1846-1854. doi:10.1016/j.

  66. Tan M, Jiang X. The p domain of norovirus capsid protein forms a 

    subviral particle that binds to histo-blood group antigen receptors. 

    J Virol. 2005;79(22):14017-14030. doi:10.1128/JVI.79.22.14017-

  67. Atmar RL, Bernstein DI, Harro CD, et al. Norovirus vaccine 

    against experimental human Norwalk Virus illness. N Engl J Med. 

    2011;365(23):2178-2187. doi:10.1056/NEJMoa1101245.

  68. LoBue AD, Lindesmith L, Yount B, et al. Multivalent norovirus 

    vaccines induce strong mucosal and systemic blocking antibodies 

    against multiple strains. Vaccine. 2006;24(24):5220-5234. 


  69. El-Kamary SS, Pasetti MF, Mendelman PM, et al. Adjuvanted 

    intranasal Norwalk virus-like particle vaccine elicits antibodies and 

    antibody-secreting cells that express homing receptors for mucosal 

    and peripheral lymphoid tissues. J Infect Dis. 2010;202(11):1649-

    1658. doi:10.1086/657087.
  70. Tacket CO, Sztein MB, Losonsky GA, Wasserman SS, Estes MK. 

    Humoral, mucosal, and cellular immune responses to oral Norwalk 

    virus-like particles in volunteers. Clin Immunol. 2003;108(3):241-