Table 1.

Summary of epidemiology and potential indirect public health impact.

Feature	Summary and evidence
Epidemiology
Reservoir	Reservoir is human. Transmission is primarily through person-to-person and an estimated 10–15 % through contaminated food (e.g., grown or harvested from contaminated water (individual, municipal, recreational), or infected by preparer/handler, water, infected people and contaminated surfaces. Despite the ability of noroviruses to infect and cause disease in a broad range of animal species, to date there is no evidence that supports the transmission of norovirus from animals to humans. A few studies report evidence of human serological exposure to bovine and canine norovirus, but cross-reactivity might explain observations [7,8].
At-risk populations	Norovirus is ubiquitous, associated with 18 % (95 % CI: 17 %–20 %) of diarrheal disease worldwide, with significant burden of disease in high-, middle-, and low-income settings. Norovirus affects individuals across all age groups; however, the highest rates have been identified among young children. For a person with an average life expectancy of 80 years, norovirus will cause illness three to eight times [9–12].
Mortality	Globally, norovirus is estimated to cause a median number of 219,000 deaths each year (95 % Uncertainty Interval [UI]: 171,000–277,000) across all ages [6] 97 % of mortality is attributed in LMIC [6]. Its case fatality has been estimated to be 0.25 per 1000 cases (95 % CI 0.03–8.99), which is higher than rotavirus disease [13].
Morbidity	Globally, norovirus is estimated to cause a median number of 699 million illnesses each year (95 % Uncertainty Interval [UI]: 489–1,086 million) across all ages [6,14–16]. Norovirus is a leading cause of medically attended pediatric acute infectious GI illness, particularly in areas where rotavirus vaccine has been introduced [2–5]. 82 % of all illnesses are in LMIC countries [6]. There are research studies that indicate an increased risk of functional gastrointestinal disorders (e.g. functional dyspepsia, irritable bowel syndrome) among HIC populations. No data exists on such post-infectious sequelae in the LMIC populations.
Geographical and seasonal distribution	Norovirus has a world-wide distribution. In the northern hemisphere, seasonal trends have well established norovirus as a wintertime phenomenon, whereas seasonal patterns for norovirus in the southern hemisphere are less established, and it remains unclear if the lack of an observed trend is due to differences in epidemiologic factors or a lack of adequate data [17].
Gender distribution	Norovirus infections demonstrate a sex-switch preponderance at puberty (Male:Female IRR = 1.10, 95 % CI 1.02–1.19 in age = 5–14 years; Male:Female IRR = 0.75, 95 % CI 0.71–0.79, age 15–59 years). Adult women have higher exposure to foodborne infection due to the frequency in which they visit hospitals and day cares, and more frequently cook and prepare meals. It is likely that women of reproductive age represent more secondary cases than men due to infection directly from their children [18,19].
Socio-economic status vulnerability(ies) (equity/wealth quintile)	In LMICs limited access to potable water, access to health care, rotavirus vaccination coverage, poor sanitation, inadequate hygiene, and food contamination represent key drivers for norovirus infections. Household density may place a disproportionate burden of norovirus infections among households where there are more than 1 person living in a single room per room. Within HICs, children living in high income households had higher norovirus antibody titers at age 3 years compared to those in lower income households [20–22].
Natural immunity	In LMICs, children < 6 months of age are less frequently infected by norovirus than infants and older adults due to antibodies passed through breastmilk and limited opportunities for person-to-person and foodborne exposure. While the data are limited and reliant on outbreaks which may not represent sporadic infections, mathematical modelling estimates suggest that the duration of norovirus gastroenteritis immunity is 4.1 (95 % CI 3.2–5.1) to 8.7 (95 % CI 6.8–11.3) years [19–23].
Pathogenic types, strains, and serotypes	Noroviruses have been classified into ten genogroups (GI-GX) and 48 genotypes, though only viruses from GI (n = 9), GII (n = 23), GIV (n = 1), GVIII (n = 1) and GIX (n = 1) are causing infections in humans. GII.4 noroviruses are associated with higher frequency and more severity in all age groups, while in children GII.3 viruses are the most frequent genotype second to GII.4 viruses. GI.1 noroviruses have been identified as important in some settings, but overall is a rare genotype. Other genotypes may be important in other settings, particularly in LMIC, where few studies have been conducted Repeat infections with norovirus are common, but repeat infections with the same genotype are rare, suggesting that genotype-specific immunity is important [24,25].
Potential indirect impacts
Anti-microbial resistance (AMR) threat	There are no antiviral treatments for norovirus, though this is an area of active development (Netzler et al. 2019) Many viral infections are inappropriately treated with antibiotics. Therefore, prevention of norovirus infections with vaccination could reduce antibiotic use and the development of attendant AMR (theoretical). There is an important proportion of norovirus-positive AGE episodes where other enteropathogens are also present (mixed infections), including bacterial agents like ETEC or Shigella sp, where antibiotic treatment may be needed. There is a need to identify which organism is the cause of AGE in episodes where more than one enteropathogen is present, to reduce un-needed antibiotic treatments.
Epidemic and outbreak potential	Outbreaks are commonly found in settings involving semi-closed populations and are particularly common in health care settings such as long term care facilities (LTCF) as well as school settings among young children of primary school and kindergarten ages. Additional studies have indicated outbreaks on ships and military camps Impacts on hospitals operations in many countries have been described [20,26–28].
Transmission route/potential	Noroviruses are transmitted through the fecal-oral route but can also spread through fomites and airborne vomitus droplets. Noroviruses are highly contagious, and outbreaks occur from direct person-to-person contact but can also be transmitted through contaminated food or water. Typically, transmission occurs from humans to foods which can then act as vehicles of infection [26,29–35].
Acquired/herd immunity	Compelling data on acquisition of natural immunity comes from volunteer challenge studies and observational birth cohorts. Natural infection appears to confer short term protection against similar strains, lasting on the order of months to a few years. Observational data from birth cohort studies demonstrate decreasing attack rates with age as well as lower rates of infection and/or gastroenteritis following one or more infections. Empirical data on the duration of immunity is lacking; a modelling study estimated a range from about 3 to 9 years. [19,23,25,36–38]
Co-associated mortality	Estimates on the proportion of childhood death associated with noroviruses are extrapolated from proportions of norovirus identified in more severe AGE episodes requiring hospital treatment. The true role of norovirus on childhood mortality will be obtained by vaccine-introduction studies, as seen with rotavirus vaccine introduction.
Economic burden
Health facility costs/out of pocket costs/ productivity costs	Globally, norovirus accounts for an estimated $4.2 billion dollars (95 % UI: $3.2–5.7 billion) in direct health systems cost and approximately $60.3 billion in societal cost each year (including productivity loses). Children < 5 years old account for the majority of societal cost at 39.8 billion per year compared to 20.4 billion in societal cost for all other age groups combined. Productivity losses associated with norovirus resulted in an annual economic burden of 56.2 billion dollars per year; half of which were due to mortality(Bartsch et al. 2016) There is a need to do cost-effectiveness analyses of norovirus vaccines including cost to society, which may have important variations by regions/countries in the world. Such cost-effectiveness analyses should consider all relevant and important outcomes comprehensively. These could include studies of different (older) age groups, vulnerable populations, and the impact of prolonging or deteriorating underlying conditions in immunocompromised individuals. Other important considerations may be the indirect effects for society including education and military readiness impacts. Traditional cost-effective studies without these indicators in countries with low infant mortality may make the vaccine too costly for DALY averted [6,39].