Norovirus, initially known as winter vomiting disease, was identified as the cause of the outbreak in 1972 when researchers observed 27-nm-virus particles by immune electron microscopy in the infected fecal filtrate from an acute outbreak of gastroenteritis in Norwalk, Ohio, in 1968, and named “Norwalk virus” (1, 2). Norovirus is a single-stranded and unenveloped RNA virus, which can be classified into 10 genogroups (GI-GX) and 49 genotypes with most of the infections in humans caused by GI and GII genogroups, which could be further divided to 9 and 27 genotypes, respectively (3). Currently, no drugs effectively treat norovirus.

The disease burden of norovirus is becoming increasingly serious worldwide and in China, causing ~684 million cases and 212,000 deaths, annually (4). Compared with other countries, China has a higher prevalence of norovirus (19.8–21.0%) (5). The annual report of the National Statutory Infectious Diseases Reporting System, found a significant decrease in the incidence of infectious diarrhea caused by cholera, dysentery and typhoid fever between 2006 and 2016; on the other hand, the number of cases caused by viral pathogens increased from 741,809 to 1,017,962 (6). Nowadays, norovirus is replacing rotavirus as the main pathogen of viral acute gastroenteritis, which indicates that norovirus outbreaks remain an important public health problem in China. Understanding the characteristics of the disease is key to the effective implementation of disease prevention and control. Existing studies have found significant differences in the epidemiological characteristics of norovirus outbreaks between China and other countries. First, whole populations are susceptible to norovirus infection (7); however, the outbreak sites are different. In developed countries, norovirus outbreaks occur mainly in medical institutions, such as long-term care facilities and hospitals (8, 9), whereas in China, norovirus outbreaks mainly occur in school environments and nurseries (10–13). Second, different age groups face different risks of infection; particularly, one study found that the highest incidence was observed in children aged <5 years (14). Other studies have found that children younger than 12 years are more susceptible and infection is common in children under 2 years old in developing countries (15, 16). Additionally, differences were observed between the genotypes. In the past two decades, the GII.4 virus has caused norovirus outbreaks in most age groups worldwide (17). However, norovirus genotypes are constantly changing in China with the emergence of new genotypes and differences in genotypes observed in different regions.

In recent years, an increase has been observed in the incidence rate of infectious diarrhea in Jiangsu Province. In a study on norovirus and meteorological factors in Jiangsu Province, bacterial culture and viral nucleic acid testing were performed on 6,640 stool specimens collected, and 1,193 positive specimens were obtained, of which the positive rate for viruses was greater than that for bacteria; and among the positive specimens for viruses, the positive rate for norovirus was higher than that for rotavirus (18). Norovirus has a heavy disease burden in Jiangsu Province. Currently, researchers in Jiangsu Province have made significant progress in studying the molecular epidemiological characteristics of norovirus outbreaks (19–22). However, epidemiological characterization of large sample sizes is still limited for a large number of reported norovirus outbreaks in Jiangsu Province. Previous epidemiological studies on norovirus outbreaks usually calculated the total attack rate (TAR) or duration of the outbreak as the dependent variable and collected risk factors associated with the infection as independent variables for statistical analysis, and finally found the epidemiological characteristics of norovirus outbreaks and factors influencing the severity of outbreaks in a certain area during a certain period of time, providing a scientific basis for controlling norovirus outbreaks (23–25). However, we believe that studies on the TAR do not completely reflect the transmissibility of the virus, and it is necessary to construct mathematical models to quantify the transmissibility of norovirus in outbreaks. Current mathematical models used to calculate the transmissibility of infectious diseases include agent-based models and ordinary differential equation models. In our previous study, the transmissibility of norovirus in interpersonal transmission and water transmission modes was described by constructing ordinary differential equation models (26). Therefore, in order to identify as many risk factors as possible and determine the epidemiological characteristics of norovirus outbreaks in Jiangsu province, we collected all outbreak investigation reports from 2012 to 2018 in Jiangsu Province, sequenced all positive specimens eligible for sequencing to determine the genotype, determined the TAR of each outbreak, and constructed transmission dynamics models for different transmission routes to calculate the transmissibility, and performed statistical analyses of risk factors associated with the TAR and transmissibility.

In this study, we used TAR and a transmission dynamics model to explore which factors would influence the norovirus outbreaks in Jiangsu Province.

Regarding time, the number of reported cases increased sharply in 2017 and 2018. Jiangsu Province began to establish a norovirus surveillance system in 2012, using a unified case definition, outbreak determination principles, and laboratory testing methods for surveillance, so we consider our description that the number of norovirus outbreaks is increasing is consistent with the real epidemiologic characteristics. Meanwhile, we observed that the GII.2 [P16] genotype caused more than half of the norovirus outbreaks in Jiangsu province in 2017 and 2018. Previously, a study on norovirus outbreak surveillance in China had already found that the number of norovirus outbreaks increased substantially at the end of 2016, greatly exceeding the number reported in the same month in the previous 4 years, and the majority of these outbreaks were associated with GII.2 [P16] (53). The researchers analyzed this finding and concluded that the GII.2 [P16] genotype evolved extremely fast, which most likely led to a sudden increase of this virus (54). We, therefore, considered that the prevalence of the GII.2 [P16] genotype is responsible for the surge in the number of norovirus outbreaks in Jiangsu Province between 2017 and 2018.

Regarding the season, in our study, TAR was significantly lower during summer, and norovirus outbreaks in Jiangsu Province mainly occurred in the colder weather in spring, autumn, and winter, which is consistent with the results of previous studies (55, 56). Regarding the regional distribution, the increased outbreaks in southern Jiangsu despite the higher TAR in central Jiangsu may be attributed to the increased sensitivity to disease surveillance and more timely detection and reporting of the outbreaks in southern Jiangsu. Regarding rural and urban sites, the mean TAR in rural areas was higher compared to urban areas, which may be related to poor sanitation in rural areas and the untimely adoption of control measures.

Consistent with previous studies (8–13), the outbreaks we monitored occurred more often in schools than in hospitals and long-term care facilities, this phenomenon is largely due to the fact that: (1) In China (56), schools have a more standard outbreak screening system in which the government requires schools to check and screen students for symptoms of fever, vomiting, or diarrhea every morning. In contrast, hospitals or long-term care facilities do not see similar mechanisms for disease detection and reporting. (2) Long-term care facilities are important health care settings outside China. In the United States (57), long-term care facilities serve more than 2 million Americans each year, and local health units often provide infection control courses to facility staff. Ontario requires by law that each health unit must provide in-service training to long-term care facilities at least once a year. In France (58), epidemiological surveillance of acute gastroenteritis outbreaks in various types of nursing homes has been conducted since November 2010. Well-established facilities and systematic services make such settings capable of detecting and reporting norovirus outbreaks.

Most outbreaks occurred in primary schools, which is consistent with a previous study on norovirus outbreaks in China in 2014–2017 (13). Kindergarten has a higher TAR and transmissibility than other types of schools for the following reasons: (1) Studies have found that students in kindergartens and primary schools are more likely to vomit when infected with norovirus (59), and some children in kindergartens may become infected with the virus by going around when vomiting occurs due to poor hygiene awareness. (2) Kindergartens are small and therefore have a high population density and higher exposure among younger children. We found that the mean TAR of norovirus outbreaks was highest in outbreaks with <1,000 susceptible people, and of the 61 outbreaks reported in Jiangsu Province, each with <1,000 susceptible people, the highest proportion of outbreaks occurred in kindergartens, so it can be assumed that small crowded places such as kindergartens are more likely to cause the spread of the outbreak. (3) Different types of schools are composed of students of different ages. Since children under 5 years of age are most susceptible (60), and most of the students in kindergartens in China are children aged 3–6 years old, norovirus outbreaks are more likely to occur in kindergartens.

Jiangsu Provincial Center for Disease Control and Prevention has undertaken a national foodborne and waterborne norovirus outbreak surveillance program. Once an outbreak of norovirus occurs, the corresponding outbreak investigation will be started, the cases, water and food will be sampled, and the prevention and control measures will be implemented. However, due to the high economic level and satisfactory sanitary conditions in Jiangsu Province, norovirus outbreaks caused by water or food are rare, accounting for only eight (3.9%) of all reported outbreaks. Among them, water source outbreaks are caused by barreled water contamination rather than pipe network contamination, and foodborne outbreaks are caused by a small number of kitchen workers infecting and polluting the food, and not from the food itself. These conditions led to a small significant difference in TAR among outbreaks of different transmission routes.

The genetic diversity of noroviruses can be reflected by differences in epidemiology (61). Surveillance of norovirus genotypes in our study showed that the major genotypes of noroviruses in Jiangsu province change every 2–3 years. The following characteristics of the changes in the genotypes causing norovirus outbreaks have been noted: since 2002, GII.4 has been the predominant genotype in norovirus outbreaks in many countries. In the winter of 2014, the predominant norovirus strain in China changed to GII.17. Subsequently, in the winter of 2016 (2016–17), GII.2 [P16] became the predominant genotype causing norovirus outbreaks (56). Norovirus outbreaks caused by the GII.2 [P16] genotype were also found in other regions and countries outside mainland China, such as Hong Kong, Taiwan, Germany, Japan, France, the United States, and Australia. This genotype has also become the major genotype causing norovirus outbreaks in Hong Kong, Taiwan, and Germany (54). The changes in genotypes we observed in Jiangsu province are temporally consistent with the changes in genotypes throughout China. Epidemiological surveillance and vaccines are essential to control human pathogens (62). However, it has been found that different genotypes show different evolutionary patterns, and the production of new variants of GII.4 genotype every 2–3 years will always lead to a population that is always susceptible to GII.4 genotype of norovirus. Once an immune barrier is established, individuals will no longer be susceptible to the GII.2 virus, which is classified as a static virus (63, 64). Based on this view, our future studies intend to observe this through continuous monitoring of genotypes and changes in population incidence levels in combination with other factors.

The mean R_unc of norovirus outbreaks in Jiangsu Province was 12.2, which was close to the data from a previous study on outbreaks (2 to >14) (65). In our previous study, we used the model fitting method to adjust the value of κ (interpersonal transmission coefficient) to be closer to 0. Finally, we obtained transmissibility of 1.94 for norovirus outbreaks in the community, 3.44 for transmissibility in schools and 4.91 for transmissibility by water (26); these results were all smaller compared to the values obtained in the current study. This difference can be explained by another study in which researchers found that the transmissibility of norovirus was largely influenced by the structure of the model and the weight of asymptomatic infections (66). We, therefore, considered that differences in parameter values in the model and differences in sample size could be responsible for the higher transmissibility of norovirus outbreaks in Jiangsu Province.

According to our research, further improvements are required in the sensitivity monitoring in northern Jiangsu. According to the epidemiological characteristics of norovirus in Jiangsu Province, the surveillance of norovirus outbreaks should be strengthened in all seasons of the year. Furthermore, health education and health promotion should be accomplished before autumn and winter where the incidence of norovirus is high, especially in rural areas. For schools, kindergartens have the highest transmissibility, followed by primary schools. This phenomenon mainly considers the immunological differences between age groups and health habits. Older students who are not in kindergartens and primary schools, as well as teachers, should be more aware of norovirus and need to know how to handle vomit properly to prevent the spread of aerosols. Also, students who have gathered should be evacuated promptly and kept away from the vomit. Furthermore, suspected cases of norovirus infection should be isolated, especially kitchen staff. Finding out changes of dominant genotype has occurred is important for exploring the epidemiological characteristics of norovirus outbreaks in Jiangsu Province, however, not every positive specimen collected in an outbreak met the criteria for genetic sequencing and could be used to determine the genotype of the norovirus causing the outbreak. Therefore, tracking changes in the major genotypes causing outbreaks requires further surveillance.

The number of norovirus outbreaks in Jiangsu Province has generally been on the rise during the follow-up period, so prevention and control remain an important issue. Currently, factors such as year, month, season, region, urban and rural type, place type, the population of outbreak sites, route of transmission, and virus genotype significantly impact the TAR of norovirus outbreaks; notably, different types of schools influence transmissibility. The dominant genotype of the virus will change every 3 years and surveillance of norovirus genotypes should be further strengthened to explore the transmissibility of different genotypes. Our study explored how these factors affect the TAR and transmissibility of norovirus outbreaks in Jiangsu Province, suggesting current priorities for the prevention and control of norovirus outbreaks in Jiangsu Province and future issues to be addressed in the surveillance of outbreaks.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

CB, QL, TC, JA, YZ, JF, and XC contributed to conception and design of the study. JA, JF, XC, XZ, HJ, and WL collected data. TC, QL, YZ, JA, JR, TY, YW, JX, XL, MY, SL, and XG analyzed the data. CB, TC, JA, YZ, JF, and XC wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.

This study was partly supported by the Key Medical Discipline of Epidemiology (No. ZDXK A2016008), the National Major S&T Projects (No. 2018ZX10714-002), the Jiangsu Provincial Medical Youth Talent (No. QNRC2016542), the Project of Jiangsu Commission of health (Z2019006), the NHC Key Laboratory of Echinococcosis Prevention and Control (No. 2020WZK2001), and project S202110384382 supported by XMU Training Program of Innovation and Entrepreneurship for Undergraduates.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.