IntroductionSequence-based typing of hepatitis A virus (HAV) is important for outbreak detection, investigation and surveillance. In 2013, sequencing was central to resolving a large European Union (EU)-wide outbreak related to frozen berries. However, as the sequenced HAV genome regions were only partly comparable between countries, results were not always conclusive.AimThe objective was to gather information on HAV surveillance and sequencing in EU/European Economic Area (EEA) countries to find ways to harmonise their procedures, for improvement of cross-border outbreak responses.MethodsIn 2014, the European Centre for Disease Prevention and Control (ECDC) conducted a survey on HAV surveillance practices in EU/EEA countries. The survey enquired whether a referral system for confirming primary diagnostics of hepatitis A existed as well as a central collection/storage of hepatitis A cases' samples for typing. Questions on HAV sequencing procedures were also asked. Based on the results, an expert consultation proposed harmonised procedures for cross-border outbreak response, in particular regarding sequencing. In 2016, a follow-up survey assessed uptake of suggested methods.ResultsOf 31 EU/EEA countries, 23 (2014) and 27 (2016) participated. Numbers of countries with central collection and storage of HAV positive samples and of those performing sequencing increased from 12 to 15 and 12 to 14 respectively in 2016, with all countries typing an overlapping fragment of 218 nt. However, variation existed in the sequenced genomic regions and their lengths.ConclusionsWhile HAV sequences in EU/EEA countries are comparable for surveillance, collaboration in sharing and comparing these can be further strengthened.

Carlos 3 Institute of Health Madrid Spain

Center for Virology Medical University of Vienna Vienna Austria

Centre for Disease Prevention and Control Riga Latvia

Croatian Institute of Public Health Zagreb Croatia

Department of Infectious Diseases and Global Health University of Southern Denmark Odense Denmark

European Centre for Disease Prevention and Control Solna Sweden

European Programme for Public Health Microbiology Training Solna Sweden

Health Board Tallinn Estonia

Hellenic Centre for Disease Control and Prevention Athens Greece

HSE Health Protection Surveillance Centre Dublin Ireland

Institute of Microbiology and Immunology Ljubljana Slovenia

Karolinska Institutet Stockholm Sweden

Landspitali National University Hospital Reykjavik Iceland

Ministry of Health Msida Malta

National Center of Infectious and Parasitic Diseases Sofia Bulgaria

National Institute for Health and Welfare Helsinki Finland

National Institute for Public Health and the Environment Bilthoven the Netherlands

National Institute of Health Dr Ricardo Jorge Lisbon Portugal

National Institute of Health Rome Italy

National Institute of Public Health Bucharest Romania

National Institute of Public Health Prague Czech Republic

National Public Health Institute Budapest Hungary

National Reference Centre for Hepatitis A Villejuif France

National Reference Laboratory for HAV Regensburg University Medical Center Regensburg Germany

National Virus Reference Laboratory Dublin Ireland

Norwegian institute of Public Health Oslo Norway

Public Health Agency of Sweden Solna Sweden

Public Health England London United Kingdom

Robert Koch Institute Berlin Germany

Sciensano Directorate Infectious diseases in humans Brussels Belgium

Scientific Institute of Public Health Brussels Belgium

Statens Serum Institut Copenhagen Denmark

Euro Surveill. 2019 Nov;24(47). doi: 10.2807/1560-7917.ES.2019.24.47.1900695. PubMed

See more in PubMed

World Health Organization (WHO) WHO position paper on hepatitis A vaccines – June 2012. Wkly Epidemiol Rec. 2012;87(28/29):261-76. PubMed

Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-602. 10.1016/S0140-6736(16)31678-6 PubMed DOI PMC

Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine. 2010;28(41):6653-7. 10.1016/j.vaccine.2010.08.037 PubMed DOI

Jeong SH, Lee HS. Hepatitis A: clinical manifestations and management. Intervirology. 2010;53(1):15-9. 10.1159/000252779 PubMed DOI

European Centre for Disease Prevention and Control (ECDC). Hepatitis A. In: ECDC. Annual epidemiological report for 2016. Stockholm: ECDC; 2019. Available from: https://ecdc.europa.eu/sites/portal/files/documents/AER_for_2016-hepatitis-A_0.pdf

European Centre for Disease Prevention and Control (ECDC). Surveillance Atlas of Infectious Diseases. Stockholm: ECDC; 2019. Available from: https://ecdc.europa.eu/en/surveillance-atlas-infectious-diseases

Carrillo-Santisteve P, Tavoschi L, Severi E, Bonfigli S, Edelstein M, Byström E, et al. ECDC HAV Expert Panel Seroprevalence and susceptibility to hepatitis A in the European Union and European Economic Area: a systematic review. Lancet Infect Dis. 2017;17(10):e306-19. 10.1016/S1473-3099(17)30392-4 PubMed DOI

Beauté J, Westrell T, Schmid D, Müller L, Epstein J, Kontio M, et al. Travel-associated hepatitis A in Europe, 2009 to 2015. Euro Surveill. 2018;23(22):1700583. 10.2807/1560-7917.ES.2018.23.22.1700583 PubMed DOI PMC

Sane J, MacDonald E, Vold L, Gossner C, Severi E, on behalf of the International , Outbreak Investigation Team Multistate foodborne hepatitis A outbreak among European tourists returning from Egypt--need for reinforced vaccination recommendations, November 2012 to April 2013. Euro Surveill. 2015;20(4):21018. 10.2807/1560-7917.ES2015.20.4.21018 PubMed DOI

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. PubMed

Werber D, Michaelis K, Hausner M, Sissolak D, Wenzel J, Bitzegeio J, et al. Ongoing outbreaks of hepatitis A among men who have sex with men (MSM), Berlin, November 2016 to January 2017 - linked to other German cities and European countries. Euro Surveill. 2017;22(5):30457. 10.2807/1560-7917.ES.2017.22.5.30457 PubMed DOI PMC

Beebeejaun K, Degala S, Balogun K, Simms I, Woodhall SC, Heinsbroek E, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January 2017. Euro Surveill. 2017;22(5):30454. 10.2807/1560-7917.ES.2017.22.5.30454 PubMed DOI PMC

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. 10.2807/1560-7917.ES.2017.22.8.30468 PubMed DOI PMC

European Centre for Disease Prevention and Control (ECDC). Hepatitis A outbreaks in the EU/EEA mostly affecting men who have sex with men - third update, 28 June 2017. Stockholm: ECDC. 2017. Available from: https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-hepatitis-outbreak-eueea-mostly-affecting-men-who-have-sex

Ndumbi P, Freidl GS, Williams CJ, Mårdh O, Varela C, Avellón A, et al. Hepatitis A outbreak disproportionately affecting men who have sex with men (MSM) in the European Union and European Economic Area, June 2016 to May 2017. Euro Surveill. 2018;23(33):1700641. 10.2807/1560-7917.ES.2018.23.33.1700641 PubMed DOI PMC

Latash J, Dorsinville M, Del Rosso P, Antwi M, Reddy V, Waechter H, et al. Notes from the Field: Increase in Reported Hepatitis A Infections Among Men Who Have Sex with Men - New York City, January-August 2017. MMWR Morb Mortal Wkly Rep. 2017;66(37):999-1000. 10.15585/mmwr.mm6637a7 PubMed DOI PMC

Rivas V, Barrera A, Pino K, Núñez R, Caceres CJ, Lopez-Lastra M, et al. Hepatitis A outbreak since November 2016 affecting men who have sex with men (MSM) in Chile connected to the current outbreak in MSM in Europe, situation up to October 2017. Euro Surveill. 2018;23(9):1800060. 10.2807/1560-7917.ES.2018.23.9.18-00060 PubMed DOI PMC

Gozlan Y, Bar-Or I, Rakovsky A, Savion M, Amitai Z, Sheffer R, et al. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016 - June 2017. Euro Surveill. 2017;22(29):30575. 10.2807/1560-7917.ES.2017.22.29.30575 PubMed DOI PMC

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. 10.2807/1560-7917.ES2015.20.29.21192 PubMed DOI

Bruni R, Taffon S, Equestre M, Chionne P, Madonna E, Rizzo C, et al. Key Role of Sequencing to Trace Hepatitis A Viruses Circulating in Italy During a Large Multi-Country European Foodborne Outbreak in 2013. PLoS One. 2016;11(2):e0149642. 10.1371/journal.pone.0149642 PubMed DOI PMC

Costa-Mattioli M, Di Napoli A, Ferré V, Billaudel S, Perez-Bercoff R, Cristina J. Genetic variability of hepatitis A virus. J Gen Virol. 2003;84(Pt 12):3191-201. 10.1099/vir.0.19532-0 PubMed DOI

Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and biological differences between strains of hepatitis A virus. Vaccine. 1992;10(Suppl 1):S40-4. 10.1016/0264-410X(92)90540-Z PubMed DOI

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. 10.1099/0022-1317-73-6-1365 PubMed DOI

Desbois D, Couturier E, Mackiewicz V, Graube A, Letort MJ, Dussaix E, et al. Epidemiology and genetic characterization of hepatitis A virus genotype IIA. J Clin Microbiol. 2010;48(9):3306-15. 10.1128/JCM.00667-10 PubMed DOI PMC

Kroneman A, de Sousa R, Verhoef L, Koopmans MPG, Vennema H, On Behalf Of The HAVNet Network Usability of the international HAVNet hepatitis A virus database for geographical annotation, backtracing and outbreak detection. Euro Surveill. 2018;23(37):1700802. 10.2807/1560-7917.ES.2018.23.37.1700802 PubMed DOI PMC

Aragonès L, Bosch A, Pintó RM. Hepatitis A virus mutant spectra under the selective pressure of monoclonal antibodies: codon usage constraints limit capsid variability. J Virol. 2008;82(4):1688-700. 10.1128/JVI.01842-07 PubMed DOI PMC

National Institute for Public Health and the Environment (RIVM). HAVNet. Bilthoven: RIVM. Available from: https://www.rivm.nl/documenten/typing-protocol-havnet-vp1p2a.

European Commission. Commission Regulation (EC) No 2018/945 of 22 June 2018 on the communicable diseases and related special health issues to be covered by epidemiological surveillance as well as relevant case definitions under Decision No 1082/2013/EU of the European Parliament and of the Council of 22 October 2013. Official Journal of the European Union. Luxembourg: Publications Office of the European Union. 06/072018: L 170. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32018D0945&from=EN#page=22

European Centre for Disease Control and Prevention (ECDC). ECDC Map Maker (EMMa). Stockhom: ECDC. [Accessed 18 Jan 2018]. Available from: https://emma.ecdc.europa.eu/

Nordic Outbreak Investigation Team C. Joint analysis by the Nordic countries of a hepatitis A outbreak, October 2012 to June 2013: frozen strawberries suspected. Euro Surveill. 2013;18(27):20520. 10.2807/1560-7917.ES2013.18.27.20520 PubMed DOI

Mellou K, Chrisostomou A, Sideroglou T, Georgakopoulou T, Kyritsi M, Hadjichristodoulou C, et al. Hepatitis A among refugees, asylum seekers and migrants living in hosting facilities, Greece, April to December 2016. Euro Surveill. 2017;22(4):30448. 10.2807/1560-7917.ES.2017.22.4.30448 PubMed DOI PMC

Enkirch T, Eriksson R, Persson S, Schmid D, Aberle SW, Löf E, et al. Hepatitis A outbreak linked to imported frozen strawberries by sequencing, Sweden and Austria, June to September 2018. Euro Surveill. 2018;23(41):1800528. 10.2807/1560-7917.ES.2018.23.41.1800528 PubMed DOI PMC

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. 10.3201/eid2004.130753 PubMed DOI PMC

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. 10.1128/JVI.76.18.9516-9525.2002 PubMed DOI PMC

Brown EA, Jansen RW, Lemon SM. Characterization of a simian hepatitis A virus (HAV): antigenic and genetic comparison with human HAV. J Virol. 1989;63(11):4932-7. PubMed PMC

Wang H, Zheng H, Cao J, Zhou W, Yi Y, Jia Z, et al. Genetic diversity of hepatitis A virus in China: VP3-VP1-2A genes and evidence of quasispecies distribution in the isolates. PLoS One. 2013;8(9):e74752. 10.1371/journal.pone.0074752 PubMed DOI PMC

Vaughan G, Xia G, Forbi JC, Purdy MA, Rossi LM, Spradling PR, et al. Genetic relatedness among hepatitis A virus strains associated with food-borne outbreaks. PLoS One. 2013;8(11):e74546. 10.1371/journal.pone.0074546 PubMed DOI PMC

Food and Drug Administration bacteriological analytical manual (BAM). Detection of hepatitis A in foods. BAM; [Accessed 08 Jan 2018]. Available from: http://www.fda.gov/Food/FoodScienceResearch/LaboratoryMethods/ucm374006.htm

Bruni R, Taffon S, Equestre M, Cella E, Lo Presti A, Costantino A, et al. Hepatitis a virus genotypes and strains from an endemic area of Europe, Bulgaria 2012-2014. BMC Infect Dis. 2017;17(1):497. 10.1186/s12879-017-2596-1 PubMed DOI PMC

European Centre for Disease Prevention and Control (ECDC). Expert opinion on whole genome sequencing for public health surveillance. Stockholm: ECDC; 2016. Available from: https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/whole-genome-sequencing-for-public-health-surveillance.pdf