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Norovirus Illness Is a Global Problem: Emergence and Spread of Norovirus GII.4 Variants, 2001–2007

  1. J. Joukje Siebenga1,2,
  2. Harry Vennema1,
  3. Du-Ping Zheng3,
  4. Jan Vinjé3,
  5. Bonita E. Lee4,
  6. Xiao-Li Pang4,
  7. Eric C. M. Ho5,
  8. Wilina Lim5,
  9. Avinash Choudekar7,
  10. Shobha Broor7,
  11. Tamar Halperin8,
  12. Nassar B. G. Rasool9,
  13. Joanne Hewitt10,
  14. Gail E. Greening10,
  15. Miao Jin6,
  16. Zhao-Jun Duan6,
  17. Yalda Lucero11,
  18. Miguel O’Ryan11,
  19. Marina Hoehne12,
  20. Eckart Schreier12,
  21. Rodney M. Ratcliff13,
  22. Peter A. White14,
  23. Nobuhiro Iritani15,
  24. Gábor Reuter16 and
  25. Marion Koopmans1,2
  1. 1National Institute for Public Health and the Environment, Bilthoven, and
  2. 2Erasmus Medical Centre, Rotterdam, the Netherlands;
  3. 3Centers for Disease Control and Prevention, Atlanta, Georgia, United States;
  4. 4Provincial Public Health Laboratory (Microbiology), Edmonton, Alberta, Canada;
  5. 5Centre for Health Protection, Hong Kong, and
  6. 6Department of Viral Diarrhea, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China;
  7. 7All India Institute of Medical Sciences, New Delhi, India;
  8. 8Central Laboratory, Israel Defense Force Medical Corps, Israel;
  9. 9University of Malaya, Kuala Lumpur, Malaysia;
  10. 10Institute of Environmental Science and Research, Porirua, New Zealand;
  11. 11Institute of Biomedical Sciences, University of Chile, Santiago, Chile;
  12. 12Robert Koch Institute, Berlin, Germany;
  13. 13Institute of Medical and Veterinary Science and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, and
  14. 14University of New South Wales, Sydney, Australia;
  15. 15Osaka City Institute of Public Health and Environmental Sciences, Osaka, Japan;
  16. 16ÁNTSZ Regional Institute of State Public Health Service, Pécs, Hungary
  1. Reprints or correspondence: J. Joukje Siebenga, RIVM, LIS-VIR, Postbus 1, 3720 BA Bilthoven, the Netherlands (Joukje.Siebenga{at}RIVM.nl)
 
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Abstract

BackgroundNoroviruses (NoVs) are the most common cause of viral gastroenteritis. Their high incidence and importance in health care facilities result in a great impact on public health. Studies from around the world describing increasing prevalence have been difficult to compare because of differing nomenclatures for variants of the dominant genotype, GII.4. We studied the global patterns of GII.4 epidemiology in relation to its genetic diversity

MethodsData from NoV outbreaks with dates of onset from January 2001 through March 2007 were collected from 15 institutions on 5 continents. Partial genome sequences (n=775) were collected, allowing phylogenetic comparison of data from different countries

ResultsThe 15 institutions reported 3098 GII.4 outbreaks, 62% of all reported NoV outbreaks. Eight GII.4 variants were identified. Four had a global distribution—the 1996, 2002, 2004, and 2006b variants. The 2003Asia and 2006a variants caused epidemics, but they were geographically limited. Finally, the 2001Japan and 2001Henry variants were found across the world but at low frequencies

ConclusionsNoV epidemics resulted from the global spread of GII.4 strains that evolved under the influence of population immunity. Lineages show notable (and currently unexplained) differences in geographic prevalence. Establishing a global NoV network by which data on strains with the potential to cause pandemics can be rapidly exchanged may lead to improved prevention and intervention strategies

Noroviruses (NoVs) are the leading cause of acute viral gastroenteritis worldwide. People of all ages are affected, but outbreaks are most often reported in health care settings (such as nursing homes and hospitals), where infections in high-risk groups (such as elderly and immunocompromised people) can have a serious impact by causing prolonged morbidity and mortality [1, 2]. Outbreaks are difficult to control and may lead to considerable economic costs resulting from closure of wards, increased length of hospitalization, hiring of extra personnel, and use of extra supplies [3, 4]

The incidence of NoV illness is high. A population study of gastroenteritis in the Netherlands estimated that 500,000 NoV cases occurred among a population of 15.7 million in 1999 (a nonepidemic year) [5]. A study from England (1993–1996) reported that NoVs were the most commonly identified pathogen in cases of intestinal infectious disease [6]. On the basis of these and historical data, the prevalence in the United States was estimated to be 23 million cases annually [7]. In developing countries, where diarrhea is a leading cause of death in young children [8], relatively little is known about the etiological role played by NoVs, but estimates indicating that >1.1 million hospitalizations and almost 220,000 deaths occur among children <5 years old each year in such countries have been published recently [9]

NoVs are extremely contagious, owing to a very low infectious dose (estimated median infectious dose, ∼18 viral particles) [10] and to levels of shedding >1×1010 RNA copies per gram of stool [11, 12]. Additionally, although patients usually recover from symptoms within 2 or 3 days, shedding may last several weeks [11]. Transmission occurs through the fecal-oral route, either by direct contact with infected individuals or via contaminated surfaces, food, or water. No or limited long-term immunity results from infection [13, 14], so one person may be repeatedly infected. Nevertheless, short-term immunity combined with the high prevalence of NoVs amounts to herd immunity [15, 16]

NoVs belong to a highly genetically and antigenically diverse genus of the family Caliciviridae. They segregate into 5 genogroups. In genogroup I, 8 genotypes are currently recognized; in genogroup II, 19 are recognized [17]. Viruses of the GII.4 genotype have been predominant during the past decade in the United States, Europe, and Oceania, causing 70%–80% of all NoV outbreaks (particularly in health care settings) [18]. In 2002, the number of reported NoV outbreaks increased sharply in many countries, followed by 4 epidemic winters in 2002–2003, 2004–2005, 2006–2007, and 2007–2008 in the Northern Hemisphere. During these seasons, incidence rates were likely much higher than reported in the previously mentioned population studies, which were all conducted before 2002. Genetic analyses showed that these epidemics coincided with the emergence of novel GII.4 variants except for the 2007–2008 epidemic, which was a continuation of the 2006–2007 epidemic [15, 19 –26]. The global molecular epidemiology of GII.4 lineages has not been systematically evaluated; reports describing the molecular epidemiology of the GII.4 variants have focused on local or regional studies. Furthermore, the lack of a unified nomenclature for GII.4 variants has hampered comparison of the available data. Thus, the extent to which reported epidemics were truly global remains unclear

The growing awareness and knowledge of both the scale and impact of NoV epidemiology raised the question as to how patterns suggested by molecular data analyses matched observations from public health surveillance across the world. We also wanted to create a common data set for NoV strains to function as a starting point for the newly established global NoV collaboration network, NoroNet. This global network aims at limiting the impact and scale of future NoV epidemics, for which monitoring of circulating strains is essential. Here, we present a global overview of the molecular epidemiology of GII.4 NoVs for the period from January 2001 through March 2007. During this period, 4 of the described GII.4 variants had a truly global distribution, whereas 4 had a different distribution or prevalence. Our results demonstrate that emergent GII.4 NoV strains spread throughout the world very rapidly and, therefore, that epidemiology needs to be assessed on a global scale in order to further the development of the basic knowledge that will underpin future research and prevention and control measures

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Methods

Epidemiologic data Data obtained from January 2001 through March 2007 were included in the present study. Institutions on 5 continents were contacted for participation. Selected institutions were included because they had structured NoV surveillance programs that included the molecular characterization of outbreak strains (n=10) or because they provided data on geographic areas that could not otherwise be evaluated (n=6)

The aggregated data set contained monthly reports describing all reported NoV outbreaks attributable to each GII.4 variant. NoV outbreaks were identified according to criteria used by each institution. Epidemiologic data describing the population covered, the number of outbreaks reported annually, the number of confirmed NoV outbreaks, and the percentage of GII.4 outbreaks were collected

Sequence data Each participating institution provided sequences from representative strains detected during the beginning, middle, and end of the circulation periods of each variant for genotyping; sequences obtained were from the preferred genomic regions of the strains (regions A, C, D, and E) (figure 1) [27]. These data enabled comparison of the nomenclature used by the participating institutions and in the literature (table 1), standardization of assignment of variant names, a check of the quality of the submitted data, and phylogenetic comparison of sequences detected in different geographic regions of the world. As the basis for variant assignment, we used the recently published amino acid sequences of the complete VP1 [15]. This method defines variants on the basis of phylogenetic clustering combined with epidemiologic patterns. Variant names include the first reported year of detection supplemented by a geographic region or suffix when necessary. Table 1 summarizes these names in addition to names used in other publications

Figure 1
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Figure 1

Schematic representation of the locations of the genomic regions of norovirus used for genotyping. Adapted from Vinjé et al [27]. Region B was not used for the analyses in the present study because it does not enable discrimination between GII.4 variants. ORF, open reading frame; RdRp, RNA-dependent RNA polymerase

Data analyses Variant assignment was done by the participating institutions, using either their own referencing systems, a tool offered by the Netherlands National Institute for Public Health and the Environment (RIVM) for regions A and C (Norovirus Quicktyping; available at: http://www.rivm.nl/bnwww), or a set of reference sequences compiled for this purpose that spanned the continuous genomic region covering regions A, C, E, and D

Epidemiologic and sequence data were stored and analyzed in Microsoft Excel and BioNumerics software (version 4.61; Applied Maths). Additional reference sequences were obtained from GenBank. At RIVM, phylogenetic analysis of all sequences was performed using PhyML software (version 2.4.4) [33]

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Results

Participants Table 2 lists the participants of the present study and outlines their surveillance methods. Overall, most reported outbreaks occurred in health care settings. In the countries of most participating institutions, it was mandatory to report outbreaks caused by any pathogen in health care settings. Ten institutions had an ongoing passive NoV surveillance program (table 2, top section). The Provincial Public Health Laboratory, Canada, had limited surveillance data for 2001; therefore, this year was not included. Five additional institutions, plus a targeted population study from the University of Chile, that did not have a structured NoV surveillance program provided target-study data and sequences with detection dates (table 2, bottom section). The University of Malaya, Malaysia, had different target studies mainly involving hospitalized children. The Israel Defense Force Medical Corps Central Laboratory provided data on NoV outbreaks in military units in Israel [42]. The Institute of Biomedical Sciences, University of Chile, submitted data from intermittent population surveillance and targeted population studies but usually without genotyping data [38]. The All India Institute of Medical Sciences provided data from a study comprising 4 different study groups [41]

Epidemiology of NoV outbreaks, by geographic area In total, 4988 NoV outbreaks were reported, of which 3089 (62%) were confirmed to be GII.4 outbreaks (figure 2). Winter seasonality was seen in almost all geographic areas analyzed and was largely associated with elevated numbers of GII.4 outbreaks

Figure 2
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Figure 2

Monthly numbers of reported norovirus outbreaks (thick line) and GII.4 outbreaks (thin line), by geographic area. Note the different scales for the Y-axes. The total numbers of reported norovirus outbreaks (left of virgule) and the total numbers of GII.4 outbreaks (right of virgule) for each area are given above the graphs

Data were comparable among the European countries, although the 2002–2003 and 2004–2005 seasons in Hungary were not as pronounced as those in Germany and the Netherlands. Germany and the Netherlands reported an off-seasonal peak in April and May 2002 that preceded the epidemic winter of 2002–2003 [32]

Similar summer peaks were seen more widely in 2006, caused by 2 emerging variants: 2006a and 2006b. These peaks were observed in the Netherlands; Germany; Hungary [23]; Australia; Alberta, Canada; Japan; and Hong Kong. In Japan and Hong Kong, the peaks were caused by the 2006b variant only. In Hong Kong, winter peaks started earlier (September–October) than in the other analyzed regions of the Northern Hemisphere (November–December), and the year 2006 in Hong Kong was marked by many outbreaks, with those occurring during the 2005–2006 winter being only partly related to GII.4 outbreaks. In Japan, the number of reported NoV outbreaks increased gradually, and, especially during the 2006–2007 winter, the proportion of GII.4 viruses was very high (almost 100%). Unlike most other countries, the United States reported many GII.4 outbreaks during the 2003–2004 winter

The Southern Hemisphere countries Australia and New Zealand had different pictures. Interestingly, winter seasonality was absent from New Zealand. In the Adelaide area of Australia, the frequency of NoV outbreaks increased 5–10-fold during the 2006 epidemic, compared with that during the previous outbreak years of 2002 and 2004. This increase did not coincide with alterations in the surveillance scheme

Sequence analysis and phylogeny A total of 781 sequences were analyzed, including sequences of 19 strains from the public databases of Brazil (n=12), Malawi (n=1), and Ghana (n=6) (to represent geographic areas that were not covered by surveillance) and 11 reference sequences. Twenty-four of the submitted sequences were too short for reliable analysis and were excluded from further analysis

Full capsid sequences and partial sequences from regions A, C, E, and D (figure 1) were phylogenetically analyzed (figure 3A and 3B ). Discriminatory power was not sufficient to distinguish different variants in region B; therefore, sequences from region B were not collected. Partial genome sequences were assigned a variant type on the basis of similarity with complete capsid sequences and associated partial polymerase sequences. Clustering into variants was consistent, as illustrated for region C sequences in figure 3B , except for the 2001Henry variant. Although the capsid sequence for this variant was clearly distinct, partial sequences clustered with other variants. As a result, discrimination of this strain may not have been accurate, and assessing its prevalence was difficult. Geographic trends within variant clusters were not identified. Analyses of regions A, E, and D resulted in identical clustering (data not shown)

Figure 3
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Figure 3

A, Phylogenetic tree of complete capsid sequences, constructed by means of PhyML software (49 sequences, 1623 nt, SYM+I+Γ4 [symmetric, with allowance for invariant sites and gamma substitution rate variation], 1000 bootstraps). Reference strains (first complete capsid sequences submitted to the public databases) are shown in boldface type. The model was selected using MrAIC software (J. A. A. Nylander, 2004. MrAIC.pl. Program distributed by author. Evolutionary Biology Centre, Uppsala University). B, Phylogenetic tree of all available region C sequences, constructed by means of PhyML software (301 sequences, 266 nt, SYM+I+Γ4). Strains detected in Australia, China, Germany, Ghana, Hong Kong, Hungary, Japan, the Netherlands, New Zealand, and the United States were included in this tree

Eight GII.4 variants were identified (table 1 and figure 3A ); the 5 main variants were 1996, 2002, 2004, 2006a, and 2006b, and the 3 minor variants were 2003Asia, 2001Japan, and 2001Henry. The minor variants were detected at multiple geographic locations but at low frequencies. The variant 2003Asia is a recombinant, with an open reading frame 1 sequence belonging to GII.12 (Wortley-like) and open reading frame 2 and 3 sequences belonging to GII.4. This strain caused many outbreaks in Asia; however, in Hong Kong it was detected only among sporadic NoV cases, not in outbreaks. In Hong Kong, 993 sporadic NoV cases were analyzed, of which 58 (6%) were 2003Asia strains detected from late 2002 through 2005. The peak prevalence of 2003Asia in sporadic cases in Hong Kong was observed between January 2004 and January 2005 (15% [33/223] of cases; data not shown). The 2001Japan sublineage showed the most genetic resemblance to the Bristol and Lordsdale reference strains. The 2001Henry variant was identified in the United States and China (DQ364459), but prevalence was low

All variants from the 2002 variant onward (ie, the 2001Henry, 2003Asia, 2002, 2004, 2006a, and 2006b variants) had a 1-aa insertion (at position 393) in the P2 domain of the capsid

Quality assurance The accuracy of variant assignment by participants was independently verified by phylogenetic analysis of submitted sequences. Of the 775 submitted sequences, 767 (99%) had been assigned to the correct variant. Furthermore, sequences of 2 separate genomic regions had been submitted for a subset of 81 outbreaks, and, with the exception of 5 (6%), they consistently belonged to the same variant in both regions. The 5 remaining strains may have been recombinants, or 2 different viruses may have been present in 1 outbreak

Epidemiology of GII.4 variants Epidemiologic analysis of the GII.4 variants was done using the 3089 submissions for which collection dates had been provided (figure 4). In 2001–2002, the 1996 variant caused significant numbers of outbreaks in Europe and Hong Kong but was rare in other geographic areas. The 2002, 2004, and 2006b variants caused epidemics in all areas with population surveillance, but there was a marked difference in the magnitude of the seasonal peaks. The 2002 variant heavily affected Europe, the United States, and Canada [32] but was observed less frequently in Asia and Oceania, despite significant numbers of reported outbreaks. During the same period, high numbers of GII.4 strains were reported in New Zealand, but they could not be assigned to a GII.4 variant because they were sequenced in region B only. Variants 2004 and 2006b were truly global and were prevalent in all analyzed geographic areas; 2006a is closely related phylogenetically to the 2004 variant, but both the complete capsid sequence and its distinct epidemiology (with clearly discernible epidemic peaks in 2004–2005 and 2006–2007) justify its classification as a separate variant [15]. Interestingly, 2006a was rarely reported by participants in Asia—1 outbreak was reported in Japan, and no sequences belonging to the 2006a variant were submitted by other participants in Asia (China, Japan, Hong Kong, India, and Malaysia [not all data shown])

Figure 4
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Figure 4

Prevalence of GII.4 variants, by geographic area. All data are from areas where ongoing population surveillance is being conducted; data from China are from sporadic diarrhea cases occurring in children <5 years old (derived from sequence data submitted for this study). The number of reported outbreaks is indicated for each area. Note the different scales for the Y-axes. The large number of unclassified (UC) strains reported by New Zealand were sequenced in region B only. In Hong Kong, 2003Asia strains were detected only in sporadic cases (especially between January 2004 and January 2005) but not in outbreaks

The minor variants were not confined to a single geographic area. For example, the 2001Japan variant has been detected in Japan, the Netherlands, Malawi (GenBank), and Chile, and the 2003Asia variant has been detected in China, Japan [1, 43], Hong Kong, New Zealand, and the United Kingdom [29]—although rarely in the latter two and, interestingly, only in sporadic cases but not in outbreaks in Hong Kong

Pilot studies in geographic areas with no structured outbreak surveillance data Data from participants with targeted population studies—including participants in Australia, China, India, Chile, Israel, and Malaysia (table 2, bottom section), as well as GenBank sequences detected in Brazil, Malawi, and Ghana—were included to establish a more comprehensive overview of the global GII.4 variant distribution. The data thus obtained fit the overall picture of common GII.4 variants except for the data from Chile and China. Seven of 10 Chilean strains belonged to the 2001Japan variant. The sequences from China (n=97) (figure 4) represented studies of children <5 years old and showed no evidence of epidemics caused by the 2002, 2004, or 2006a variants. However, a high number of 2003Asia strains were identified, especially in 2004 and 2005, and a high number of 2006b strains were identified in 2006

Figure 5
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Figure 5

Timeline of reported outbreaks accumulated on each continent, by GII.4 variant. Dark blue indicates Europe (the Netherlands, Hungary, and Germany); red, Asia (Hong Kong and Japan); green, North America (United States and Canada); and light blue, Oceania (New Zealand and Australia [the Adelaide area]). Note that absolute numbers are depicted and that they vary by continent because of different sizes of reporting areas and populations

Table 1
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Table 1

Nomenclature for GII.4 Variants

Table 2
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Table 2

Participating Institutions and Brief Description of Their Surveillance Setup

Timeline of GII.4 variant emergence and spread over different continents Figure 5 shows accumulated outbreaks per variant per continent. For the 2002 variant, the off-seasonal peak in Europe was seen first, followed by the epidemic winter in Oceania (although the latter is difficult to observe in the graphs because of the low numbers relative to those for the other continents). Three variants emerged first in Oceania or Asia—the 2004 and 2006a variants clearly first emerged in Oceania, and the 2006b lineage caused high numbers of outbreaks first in Asia (Hong Kong), followed by an off-seasonal peak in Europe and then Oceania

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Discussion

This article represents the first effort to describe the molecular epidemiology of GII.4 NoVs on a global scale. We have demonstrated that GII.4 strains have been dominant all over the world during the past 7 years and were responsible for an increased number of reported NoV outbreaks globally. The impact of epidemic seasons was reflected in the outbreak-based surveillance, which focused on health care settings, although outbreaks also occurred in other places where close human contact occurs (such as military establishments, cruise ships, a hurricane Katrina refugee complex, and schools) [42, 44, 45]

Although the emergence of the 1996 variant falls outside the time range of this study, it was reported on all continents and likely had global coverage [20]. From the 1996 variant onward 8 distinct variants were identified, of which the 2002, 2004, and 2006b variants caused global epidemics. They displaced their predecessors rapidly and completely, although the 2006b variant initially cocirculated with the 2006a variant before continuing to cause the majority of outbreaks during the winter of 2007–2008, whereas the 2006a variant decreased in incidence but remained present (data not shown; personal communication with participating institutions). The 2006a and 2003Asia variants did cause epidemics but not in all analyzed geographic areas, whereas outbreaks of 2001Japan and 2001Henry occurred sporadically although at multiple geographic locations. Additional minor variants may have circulated but not been identified because of low frequencies. We have not proposed a nomenclature system for future variant naming here because a proposal for NoV nomenclature is currently being prepared

Successive GII.4 variants differ antigenically and in their patterns of host cell binding, as shown by detailed molecular characterization of systematically collected outbreak data, the elucidated structure of the capsid protein, and binding experiments [15, 16]. The data presented here suggest that NoV GII.4 strains evolved and spread in a manner similar to that of influenza A virus, with a rapid global spread of emerging variants. The limited information available from Africa and South America fits this general pattern, although the available data are very patchy. Clearly, more (and more-thorough) surveillance in these areas would improve our understanding of NoV epidemiology. Unlike what could be concluded from regional surveillance data alone, the present study of epidemiologic and virologic data from NoV outbreaks on 5 continents has shown that the dominant NoV genotype, GII.4, has a global impact. Additional studies, particularly in developing countries, are needed to further elucidate the burden of disease due to NoV in various communities. Although it remains possible that the increased number of reported NoV outbreaks resulted from improved diagnostics and reporting, this does not diminish our finding that the spread of the GII.4 variants was rapid and global and was unseen before the 1996 variant. Given that the incidence of NoV infection is high among young children and that diarrhea is one of the leading causes of death in children <5 years old, it is critical that studies be conducted to assess the role played by NoVs in childhood diarrhea [8, 9]

That some variants became epidemic only within a limited geographic region leads to interesting speculation as to what determines the success of different lineages (or the apparent lack thereof). The 2003Asia variant was observed in Asia but was rarely seen on other continents; conversely, the 2006a variant was rare in Asia. This was seen in our aggregated data and is substantiated in the literature, including in a recent article in which the Norovirus Surveillance Group of Japan reported a large cluster of 2003Asia and very low numbers of 2006a strains [43]. One possible explanation is that the 2006a variant shares neutralizing epitopes with the 2003Asia variant and, therefore, encountered an immune population in Asia but not in other regions. However, although the capsid of the 2003Asia variant does share 12 informative sites with that of the 2006a variant (data not shown), the same amino acid motifs are also present in the 2004 and 2006b variants, which were geographically unrestricted. Thus, prior population immunity appears to be an unlikely explanation

A second possibility is that variants may differ in their affinity for host ligands involved in virus attachment before entry into host cells. NoVs are known to exhibit different strain-specific host-ligand-binding patterns [46]. Recently, shifts in the binding patterns of ensuing GII.4 variants were reported [16]. The lack of a receptor for the 2006a variant in Asian populations might explain why epidemics of this variant were not noted in Asia. In a similar manner, the 2003Asia variant was rarely detected outside Asia. Therefore, we compared the predicted receptor-binding interface published by Cao et al [47] in sequences of different variants, especially the 2003Asia and 2006a variants. No variation between the 2003Asia and 2006a variants could be identified at the loci involved in ligand binding other than the previously reported aa 393, which is highly polymorphic among NoV strains ([47] and X. Jiang, personal communication). Similar results indicating that more-detailed molecular characterization is needed to verify the hypotheses on binding have been reported by Lindesmith et al [16]

A third possible explanation for the differing success of GII.4 variants is the occurrence of seeding events (ie, efficient initial large-scale introduction and subsequent transmission of viruses). Diffuse, large-scale, food-related outbreaks have been described, such as the seeding of a specific strain across Europe during the winter of 2000–2001 through contaminated shellfish [48]. Such outbreaks are extremely difficult to detect given the current state of surveillance for NoVs but are estimated to be common [49]

We looked for a pattern of emergence that could be used in a global early-detection system for new epidemic strains. The date of the first reported detection is too strongly dependent on the intensity of surveillance and chance to be a reliable indicator. However, when the first epidemic peak observed in each participant’s region was considered, 3 of 4 high-impact variants were first reported in Asia and Oceania. This may indicate that these antigenic variants arose in Asia and then spread throughout the world, as has been suggested for influenza A virus [50]. Additionally, the data imply that international communication of surveillance results could help prepare health care settings for “hot seasons.” Oceania appeared to be ahead of countries in the Northern Hemisphere for the epidemic peaks of at least 2 variants, possibly resulting from its inverted seasons compared with the Northern Hemisphere. Epidemic peaks caused by emerging variants were preceded by off-seasonal peaks during spring and summer in the Northern Hemisphere [23, 32, 45]. As the number of outbreaks in Northern Hemisphere countries decreased during summer before becoming fully epidemic the following winter, winter started in Oceania, creating opportunities for the emerging variant there

Our study demonstrates that NoV epidemics result from the rapid and global spread of successful GII.4 strains. These strains have been shown to evolve under the pressure of population immunity. Notable differences in the prevalence of certain lineages have been observed that cannot be explained by our current knowledge of NoVs. This highlights that joint surveillance will increase our understanding of NoV infection and epidemiology. The participants of this retrospective study will continue to collaborate and have initiated a global NoV surveillance network, NoroNet, that has already expanded to include more institutions. Through this global network, more-timely identification of unusual activity and new variants will improve efforts to limit the scale of epidemics

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Acknowledgments

We thank Dr Jutta Preiksaitits (Provincial Public Health Laboratory, Canada) for her support and Sallene Wong (Provincial Public Health Laboratory, Canada), J. K. R. Thomas, M. A. C. Hamat, H. Kamyon, and M. R. Idid (University of Malaya, Malaysia) for practical assistance. J.J.S. kindly thanks all coauthors for generously sharing their data and answering queries

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Footnotes

  • ↵Potential conflicts of interest: none reported

    Presented in part: Third International Calicivirus Meeting, Cancun, Mexico, 10–13 November 2007 (abstract S3-6)

    Financial support: European Commission, Directorate General Research Quality of Life program (EVENT [Enteric Virus Emergence, New Tools] grant SP22-CT-2004-502571 to J.J.S.); Indian Council of Medical Research, New Delhi, India (support to S.B. and A.C.); New Zealand Ministry of Health (funding for the New Zealand studies); Hungarian Scientific Research Fund (grant F048433 to G.R.); 973 National Key Basic Research Program of China (grant 2007CB310500 to the Chinese Center for Disease Control and Prevention); Chilean National Science and Technology Research Fund (grants 10210583 and 1061079 to Y.L. and M.O.); Alberta Health and Wellness (support to B.E.L. and X.-L.P.); Ministry of Science, Technology, and Innovation, Malaysia (grant 06-02-05-001 BTK/ER/002 to N.B.G.R.)

  • Received February 16, 2009.
  • Accepted April 10, 2009.
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