Research article Open Access
Like 0



HAVNet is an international laboratory network sharing sequences and corresponding metadata on hepatitis A virus in an online database. We give an overview of the epidemiological and genetic data and assess the usability of the present dataset for geographical annotation, backtracing and outbreak detection. A descriptive analysis was performed on the timeliness, completeness, epidemiological data and geographic coverage of the dataset. Length and genomic region of the sequences were reviewed as well as the numerical and geographical distribution of the genotypes. The geographical signal in the sequences was assessed based on a short common nt stretch using a 100% identity analysis. The 9,211 reports were heterogeneous for completeness and timeliness, and for length and genomic region of the sequences. Some parts of the world were not represented by the sequences. Geographical differences in prevalence of HAV genotypes described previously could be confirmed with this dataset and for a third (1,075/3,124) of the included sequences, 100% identity of the short common sequence coincided with an identical country of origin. Analysis of a subset of short, shared sequences indicates that a geographical annotation on the level of individual countries is possible with the HAVNet data. If the current incompleteness and heterogeneity of the data can be improved on, HAVNet could become very useful as a worldwide reference set for geographical annotation and for backtracing and outbreak detection.


Article metrics loading...

Loading full text...

Full text loading...



  1. Robertson BH, Jansen RW, Khanna B, Totsuka A, Nainan OV, Siegl G, et al. Genetic relatedness of hepatitis A virus strains recovered from different geographical regions. J Gen Virol. 1992;73(Pt 6):1365-77.  https://doi.org/10.1099/0022-1317-73-6-1365  PMID: 1318940 
  2. Costa-Mattioli M, Cristina J, Romero H, Perez-Bercof R, Casane D, Colina R, et al. Molecular evolution of hepatitis A virus: a new classification based on the complete VP1 protein. J Virol. 2002;76(18):9516-25.  https://doi.org/10.1128/JVI.76.18.9516-9525.2002  PMID: 12186933 
  3. Fangcheng Z, Xuanyi W, Mingding C, Liming J, Jie W, Qi J, et al. Era of vaccination heralds a decline in incidence of hepatitis A in high-risk groups in China. Hepat Mon. 2012;12(2):100-5.  https://doi.org/10.5812/hepatmon.4907  PMID: 22509186 
  4. Vacchino MN. Incidence of Hepatitis A in Argentina after vaccination. J Viral Hepat. 2008;15(Suppl 2):47-50.  https://doi.org/10.1111/j.1365-2893.2008.01029.x  PMID: 18837834 
  5. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine. 2010;28(41):6653-7.  https://doi.org/10.1016/j.vaccine.2010.08.037  PMID: 20723630 
  6. World Health Organization (WHO). The Global Prevalence of Hepatitis A Virus Infection and Susceptability: a systematic review. Geneva: WHO; 2010. Available from: http://apps.who.int/iris/bitstream/handle/10665/70180/WHO_IVB_10.01_eng.pdf;jsessionid=A7F0D6907A6AD5B3BB430FDCC2F304A1?sequence=1
  7. Global Health Data Exchange. Countries. [Accessed 1 Dec 2017]. Available from: http://ghdx.healthdata.org/countries
  8. Urbanus AT, van Houdt R, van de Laar TJ, Coutinho RA. Viral hepatitis among men who have sex with men, epidemiology and public health consequences. Euro Surveill. 2009;14(47):19421.  https://doi.org/10.2807/ese.14.47.19421-en  PMID: 19941800 
  9. Sánchez G, Pintó RM, Vanaclocha H, Bosch A. Molecular characterization of hepatitis a virus isolates from a transcontinental shellfish-borne outbreak. J Clin Microbiol. 2002;40(11):4148-55.  https://doi.org/10.1128/JCM.40.11.4148-4155.2002  PMID: 12409389 
  10. Petrignani M, Verhoef L, Vennema H, van Hunen R, Baas D, van Steenbergen JE, et al. Underdiagnosis of foodborne hepatitis A, The Netherlands, 2008-2010(1.). Emerg Infect Dis. 2014;20(4):596-602.  https://doi.org/10.3201/eid2004.130753  PMID: 24655539 
  11. Severi E, Verhoef L, Thornton L, Guzman-Herrador BR, Faber M, Sundqvist L, et al. Large and prolonged food-borne multistate hepatitis A outbreak in Europe associated with consumption of frozen berries, 2013 to 2014. Euro Surveill. 2015;20(29):21192.  https://doi.org/10.2807/1560-7917.ES2015.20.29.21192  PMID: 26227370 
  12. Koopmans M, Vennema H, Heersma H, van Strien E, van Duynhoven Y, Brown D, et al. European Consortium on Foodborne Viruses. Early identification of common-source foodborne virus outbreaks in Europe. Emerg Infect Dis. 2003;9(9):1136-42.  https://doi.org/10.3201/eid0909.020766  PMID: 14519252 
  13. FAO/WHO Food and Agriculture Organization of the United Nations/World Health Organization. Viruses in food: scientific advice to support risk management activities: meeting report.; 2008. Microbiological Risk Assessment Series No. 13. Rome. 79pp.
  14. Gossner CM, Severi E. Three simultaneous, food-borne, multi-country outbreaks of hepatitis A virus infection reported in EPIS-FWD in 2013: what does it mean for the European Union? Euro Surveill. 2014;19(43):20941.  https://doi.org/10.2807/1560-7917.ES2014.19.43.20941  PMID: 25375903 
  15. Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, et al. GenBank. Nucleic Acids Res. 2017;45(D1):D37-42.  https://doi.org/10.1093/nar/gkw1070  PMID: 27899564 
  16. Duizer E, Kroneman A, Siebenga J, Verhoef L, Vennema H, Koopmans MFBVE network. Typing database for noroviruses. Euro Surveill. 2008;13(19):18867. PMID: 18761977 
  17. Kroneman A, Verhoef L, Harris J, Vennema H, Duizer E, van Duynhoven Y, et al. Analysis of integrated virological and epidemiological reports of norovirus outbreaks collected within the Foodborne Viruses in Europe network from 1 July 2001 to 30 June 2006. J Clin Microbiol. 2008;46(9):2959-65.  https://doi.org/10.1128/JCM.00499-08  PMID: 18650354 
  18. Koopmans M, Vennema H, Heersma H, van Strien E, van Duynhoven Y, Brown D, et al. Early identification of common-source foodborne virus outbreaks in Europe. Emerg Infect Dis. 2003;9(9):1136-42.  https://doi.org/10.3201/eid0909.020766  PMID: 14519252 
  19. National Institute for Public Health and the Environment (RIVM). HAVNet. Bilthoven: RIVM. [Accessed 1 Dec 2017]. Available from: www.havnet.nl
  20. National Institute for Public Health and the Environment (RIVM). Hepatitis A Virus Genotyping Tool Version 1.0. [Accessed 1 Dec 2017]. Available from: http://www.rivm.nl/mpf/hav/typingtool
  21. de Oliveira T, Deforche K, Cassol S, Salminen M, Paraskevis D, Seebregts C, et al. An automated genotyping system for analysis of HIV-1 and other microbial sequences. Bioinformatics. 2005;21(19):3797-800.  https://doi.org/10.1093/bioinformatics/bti607  PMID: 16076886 
  22. Kroneman A, Vennema H, Deforche K, v d Avoort H, Peñaranda S, Oberste MS, et al. An automated genotyping tool for enteroviruses and noroviruses. J Clin Virol. 2011;51(2):121-5.  https://doi.org/10.1016/j.jcv.2011.03.006  PMID: 21514213 
  23. Brister JR, Ako-Adjei D, Bao Y, Blinkova O. NCBI viral genomes resource. Nucleic Acids Res. 2015;43(Database issue):D571-7.  https://doi.org/10.1093/nar/gku1207  PMID: 25428358 
  24. Costa-Mattioli M, Monpoeho S, Schvoerer C, Besse B, Aleman MH, Billaudel S, et al. Genetic analysis of hepatitis A virus outbreak in France confirms the co-circulation of subgenotypes Ia, Ib and reveals a new genetic lineage. J Med Virol. 2001;65(2):233-40.  https://doi.org/10.1002/jmv.2025  PMID: 11536228 
  25. Severi E, Vennema H, Takkinen J, Lopalco PL, Coulombier D. Hepatitis A outbreaks. Lancet Infect Dis. 2015;15(6):632-4.  https://doi.org/10.1016/S1473-3099(15)00021-3  PMID: 26008835 
  26. Freidl GS, Sonder GJ, Bovée LP, Friesema IH, van Rijckevorsel GG, Ruijs WL, et al. Hepatitis A outbreak among men who have sex with men (MSM) predominantly linked with the EuroPride, the Netherlands, July 2016 to February 2017. Euro Surveill. 2017;22(8):30468.  https://doi.org/10.2807/1560-7917.ES.2017.22.8.30468  PMID: 28251892 
  27. MacDonald E, Steens A, Stene-Johansen K, Gillesberg Lassen S, Midgley S, Lawrence J, et al. Increase in hepatitis A in tourists from Denmark, England, Germany, the Netherlands, Norway and Sweden returning from Egypt, November 2012 to March 2013. Euro Surveill. 2013;18(17):20468. PMID: 23647624 
  28. Petrignani M, Harms M, Verhoef L, van Hunen R, Swaan C, van Steenbergen J, et al. Update: a food-borne outbreak of hepatitis A in the Netherlands related to semi-dried tomatoes in oil, January-February 2010. Euro Surveill. 2010;15(20):19572. Available from: https://www.eurosurveillance.org/content/10.2807/ese.15.20.19572-en PMID: 20504389 
  29. Kiyohara T, Sato T, Totsuka A, Miyamura T, Ito T, Yoneyama T. Shifting seroepidemiology of hepatitis A in Japan, 1973-2003. Microbiol Immunol. 2007;51(2):185-91.  https://doi.org/10.1111/j.1348-0421.2007.tb03900.x  PMID: 17310086 
  30. Aarestrup FM, Brown EW, Detter C, Gerner-Smidt P, Gilmour MW, Harmsen D, et al. Integrating genome-based informatics to modernize global disease monitoring, information sharing, and response. Emerg Infect Dis. 2012;18(11):e1.  https://doi.org/10.3201/eid1811.120453  PMID: 23092707 
  31. Greninger AL, Waghmare A, Adler A, Qin X, Crowley JL, Englund JA, et al. Rule-Out Outbreak: 24-Hour Metagenomic Next-Generation Sequencing for Characterizing Respiratory Virus Source for Infection Prevention. J Pediatric Infect Dis Soc. 2017;6(2):168-72.  https://doi.org/10.1093/jpids/pix019  PMID: 28379561 
  32. Parker J, Chen J. Application of next generation sequencing for the detection of human viral pathogens in clinical specimens. J Clin Virol. 2017;86:20-6.  https://doi.org/10.1016/j.jcv.2016.11.010  PMID: 27902961 
  33. Tang P, Croxen MA, Hasan MR, Hsiao WWL, Hoang LM. Infection control in the new age of genomic epidemiology. Am J Infect Control. 2017;45(2):170-9.  https://doi.org/10.1016/j.ajic.2016.05.015  PMID: 28159067 
  34. Mulyanto M, Wibawa IDN, Suparyatmo JB, Amirudin R, Ohnishi H, Takahashi M, et al. The complete genomes of subgenotype IA hepatitis A virus strains from four different islands in Indonesia form a phylogenetic cluster. Arch Virol. 2014;159(5):935-45.  https://doi.org/10.1007/s00705-013-1874-5  PMID: 24212885 
  35. Wang H, Wang X, Cao J, Gao Y, Zhou W, Bi S. Full-length genome characterization and quasispecies distribution of hepatitis A virus isolates in China. Virol Rep. 2015;5:29-46.  https://doi.org/10.1016/j.virep.2015.03.001 

Data & Media loading...

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error