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• Infectious disease topics
• Norovirus infection

Facts about norovirus

Norovirus cause gastrointestinal illness to humans. Norovirus infection can cause vomiting, diarrhoea, and stomach pain. Less common symptoms are low fever, chills and headache. Vomiting can be sudden and frequent resulting in remarkable fluid loss. Death is rare but remains as a risk especially for elderly or persons with weakened immune system. Recovery occurs usually in one or two days. The incubation period ranges between 12 and 48 hours. Sometimes, symptoms can be milder and last for a week but no long-term adverse health effects have been reported.

Noroviruses belong to the Caliciviridae family and they are well known as causing “winter-vomiting disease” or “stomach-flu” referring to their rapid spread in human populations especially during winter months. Noroviruses are relatively resistant in the environment: they can survive freezing as well as high temperatures (up to 60°C). The viruses survive long periods on different surfaces. Steam cooking of shellfish may allow them to survive. It is important to notice that the viruses can survive in up to 10 ppm chlorine, well in excess of levels routinely present in public drinking water systems (less that 2 ppm).

Transmission

Noroviruses are highly contagious and 10-100 viral particles may be sufficient to infect an individual. They are transmitted primarily through the faecal-oral route, either by consumption of contaminated food or water, or by spreading directly from person to person. Vomiting creates effectively aerosols with high content of virus particles, which enter the oral mucosa or contaminate surfaces. The virus survives long on different surfaces and thus, environment may serve as a source of new infections.  During one single outbreak of norovirus gastroenteritis, several modes of transmission usually occur. Even though the incubation period is relatively short (15-50h), since the infective dose is very small, and asympomatic shedding does occur, the origin of the outbreak is often difficult to confirm. For example, initially food or water borne transmission is often followed by secondary person-to-person transmissions to close contacts. Virus shedding usually starts with the onset of symptoms (mainly vomiting and diarrhoea) and may continue for 2 weeks after recovery.

As the immunity may only last a few months and is strain-specific, and given their genetic variability, infection can happen several times in a lifetime and affects individuals of all ages.  Susceptibility to infection is probably genetically determined. According to recent studies, persons of blood group 0 are at greatest risk for infection.

Many different food items have been associated with norovirus outbreaks. Raspberries and oysters have caused several national and international outbreaks. In principle, any food item may become contaminated if handled by infected person or if washed or humidified with contaminated water. Norovirus infections spread effectively from person to person in community settings like hospitals, schools, day care centers and nursing homes. Several outbreaks have been recorded in cruise ships, which provide an ideal closed setting for the spread of infection.

Preventive measures 

• Proper hand washing after using the bathroom/toilet and always before start of food preparation;
• Isolation of sick patients, if possible;
• Careful environmental cleaning and disinfection of public places, including toilets, where vomiting has occurred. Disinfectants should have high virucidal effect;
• While cleaning up vomits it is advisable to use light masks to prevent infection through aerosols. Gloves should be used when cleaning and disinfecting the environment;
• Avoiding food handling when having gastrointestinal symptoms and staying away for at least 48 hours after the end of symptoms. For health care workers, intensified hand disinfection for 14 days with virucidal disinfectant is recommended after the end of symptoms.

Norovirus infection

On this page, when to see a doctor, risk factors, complications.

Norovirus infection can cause severe vomiting and diarrhea that start suddenly. Noroviruses are highly contagious. They commonly spread through food or water that is contaminated during preparation or through contaminated surfaces. Noroviruses can also spread through close contact with a person who has norovirus infection.

Diarrhea, stomach pain and vomiting typically begin 12 to 48 hours after exposure. Norovirus infection symptoms usually last 1 to 3 days. Most people recover completely without treatment. However, for some people — especially young children, older adults and people with other medical conditions — vomiting and diarrhea can be severely dehydrating and require medical attention.

Norovirus infection occurs most frequently in closed and crowded environments. Examples include hospitals, nursing homes, child care centers, schools and cruise ships.

Signs and symptoms of norovirus infection may start suddenly and include:

• Stomach pain or cramps
• Watery or loose diarrhea
• Feeling ill
• Low-grade fever
• Muscle pain

Signs and symptoms usually begin 12 to 48 hours after your first exposure to a norovirus and last 1 to 3 days. You can continue to shed virus in your stool for several weeks after recovery. This shedding can last weeks to months if you have another medical condition.

Some people with norovirus infection may show no signs or symptoms. However, they're still contagious and can spread the virus to others.

Seek medical attention if you develop diarrhea that doesn't go away within several days. Also call your health care provider if you experience severe vomiting, bloody stools, stomach pain or dehydration.

Noroviruses are highly contagious. That means the norovirus infection can easily spread to others. The virus is shed in stool and vomit. You can spread the virus from the time you first have symptoms of illness until several days after you recover. Noroviruses can stay on surfaces and objects for days or weeks.

You can get norovirus infection by:

• Eating contaminated food
• Drinking contaminated water
• Touching your hand to your mouth after your hand has been in contact with a contaminated surface or object
• Being in close contact with a person who has norovirus infection

Noroviruses are difficult to kill because they can withstand hot and cold temperatures and many disinfectants.

Risk factors for becoming infected with a norovirus include:

• Eating in a place where food has been handled by someone with norovirus infection or the food has been in contact with contaminated water or surfaces
• Attending preschool or a child care center
• Living in close quarters, such as in nursing homes
• Staying in hotels, resorts, cruise ships or other destinations with many people in close quarters
• Having contact with someone who has norovirus infection

For most people, norovirus infection usually clears up within a few days and isn't life-threatening. But in some people — especially young children; older adults; and people with weakened immune systems or other medical conditions or who are pregnant — norovirus infection can be severe. Norovirus infection can cause severe dehydration and even death.

Warning signs of dehydration include:

• Dry mouth and throat
• Listlessness
• Decreased urine output

Children who are dehydrated might cry with few or no tears. They might be unusually sleepy or fussy.

Norovirus infection is highly contagious. There are many types of noroviruses. Anyone can get norovirus infection more than once.

To prevent norovirus infection:

• Wash your hands thoroughly with soap and water for at least 20 seconds, especially after using the toilet or changing a diaper and before you prepare food and eat or drink. Alcohol-based hand sanitizers aren't as effective against noroviruses as using soap and water.
• Avoid contaminated food and water, including food that could have been prepared by someone who was sick.
• Wash fruits and vegetables before eating.
• Cook seafood thoroughly.
• Disinfect surfaces that might have been contaminated. Wear gloves and use a chlorine bleach solution or a disinfectant that is effective against noroviruses.
• Use caution when traveling. If you're traveling to areas with a high risk of norovirus infection, consider eating only cooked foods, drinking only hot or carbonated beverages, and avoiding food sold by street vendors.

To help prevent norovirus infection spread, during illness and for 2 to 3 days after your symptoms end:

• Avoid contact with others as much as possible.
• Wash your hands thoroughly with soap and water.
• Stay home from work. Children should stay home from school or child care.
• Avoid handling food and items to be used by other people. Disinfect contaminated surfaces with a disinfectant effective against noroviruses.
• Dispose of vomit and stool carefully. Wearing disposable gloves, soak up material with disposable towels. Disturb soiled material as little as possible to avoid spreading noroviruses by air. Place soiled items in plastic bags and place them in the trash. Remove and wash clothes and linens that may be contaminated.
• Avoid traveling until 2 to 3 days after your symptoms are gone.

Mar 04, 2022

• Norovirus illness: Key facts. Centers for Disease Control and Prevention. https://www.cdc.gov/norovirus/index.html. Accessed Oct. 29, 2021.
• AskMayoExpert. Norovirus. Mayo Clinic; 2021.
• Feldman M, et al., eds. Infectious enteritis and proctocolitis. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 29, 2021.
• O'Ryan MG. Norovirus. https://www.uptodate.com/contents/search. Accessed Oct. 29, 2021.
• How you treat norovirus. Centers for Disease Control and Prevention. https://www.cdc.gov/norovirus/about/treatment.html. Accessed Oct. 29, 2021.
• Preventing norovirus. Centers for Disease Control and Prevention. https://www.cdc.gov/norovirus/about/prevention.html. Accessed Oct. 29, 2021.
• The symptoms of norovirus. Centers for Disease Control and Prevention. https://www.cdc.gov/norovirus/about/symptoms.html. Accessed Oct. 29, 2021.
• Ferri FF. Gastroenteritis. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed Nov. 1, 2021.
• Viral gastroenteritis ("stomach flu"). National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/digestive-diseases/viral-gastroenteritis/all-content. Accessed Nov. 1, 2021.
• How norovirus spreads. Centers for Disease Control and Prevention. https://www.cdc.gov/norovirus/about/transmission.html. Accessed Nov. 1, 2021.
• When and how to wash your hands. Centers for Disease Control and Prevention. https://www.cdc.gov/handwashing/when-how-handwashing.html. Accessed Nov. 1, 2021.
• Tosh PK (expert opinion). Mayo Clinic. Nov. 2, 2021.
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Update on Epidemiology and Management of Norovirus

Aug 17, 2014

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Update on Epidemiology and Management of Norovirus. Aron J. Hall, DVM, MSPH Viral Gastroenteritis Team Centers for Disease Control and Prevention [email protected] Presented at American College Health Association Annual Meeting Philadelphia, PA June 3, 2010

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• ill food service workers
• enzyme immunoassays
• appropriate hand hygiene
• norovirus outbreaks
• diarrhea viral shedding

Presentation Transcript

Update on Epidemiology and Management of Norovirus Aron J. Hall, DVM, MSPH Viral Gastroenteritis Team Centers for Disease Control and Prevention [email protected] Presented at American College Health Association Annual Meeting Philadelphia, PA June 3, 2010 “I have NO actual or potential conflict of interest in relation to this educational activity or presentation”

History • 1929: “Winter vomiting disease” first described • 1940s-1960s: 75% of gastroenteritis episodes of unknown etiology • 1968: Outbreak of acute gastroenteritis (AGE) at elementary school in Norwalk, Ohio • 1972: Viral particle seen by electron microscopy • 1973-1992: Electron microscopy and serology used to confirm outbreaks • 1992-1994: Reverse transcription-polymerase chain reaction (RT-PCR) developed

Disease Burden • #1 cause of acute gastroenteritis in U.S. • 23 million cases annually • 1 in 13 Americans become ill each year • Affects all ages, though greatest burden in children and elderly • 63,000 children hospitalized annually in U.S. • 80 deaths annually among elderly in U.K. • Occurs year round, though seasonal peak activity during winter • Found worldwide Mead 1999 EID Patel 2008 EID Harris 2008 EID

Norovirus Detection in Outpatients,British Infectious Intestinal Disease Study Amar 2007 Eur J Clin Micro

Clinical Disease • Incubation period: 12-48 hours • Acute-onset vomiting and/or diarrhea • Watery, non-bloody stools • Abdominal cramps, nausea, low-grade fever • Most recover after 12-72 hours • Up to 10% seek medical attention; some require hospitalization and fluid therapy • More severe illness and death possible in elderly and those with other illnesses

Laboratory Diagnostics • No cell culture or animal model available • Polymerase chain reaction (PCR) • Gold standard: Quantitative real-time assay • Conventional RT-PCR used for genetic sequencing • Enzyme Immunoassays (EIA) • Recent use of virus-like particles (VLP) • Inadequate sensitivity (<50%) for clinical use • Electron Microscopy (EM) • Resource intensive • Poor sensitivity

Viral Shedding • Primarily in stool, but also vomitus • Occurs for at least 2-3 weeks • Peaks 4 days after exposure • Greater in those with symptoms • May occur after resolution of symptoms • Infectivity of shed virus unknown • Infectious dose: 10-100 viral particles

Asymptomatic Vomiting and Diarrhea Viral Shedding After Experimental Infection Atmar 2008 EID

Immunity • Short-term homologous immunity • No persistent cross-protective immunity • 30% infections asymptomatic • Genetic susceptibility • Histo-blood group antigens • Secretor status (FUT2 gene)

Treatment • No specific antiviral agents or vaccines currently available • Supportive care for dehydration, primarily oral or IV fluid therapy • Antibiotics, antiemetics, antimotility agents generally not recommended

Transmission • Person to person • Direct fecal-oral • Ingestion of aerosolized vomitus • Indirect via fomites or contaminated environment • Food • Contamination by infected food handlers • Point of service or source (raspberries, oysters) • Recreational and Drinking Water • Well contamination from septic tank • Chlorination system breakdown

Intestinal Pathology Symptomatic (70%) Asymptomatic (30%) A B Infected Viral Shedding Present (40%) Protected Absent (60%) Susceptible to Infection Stool Vomit Previously Acquired Immunity Transmission Vehicles Person-to-Person Environment& Fomites Water Food Non-secretor (20%) Innately Resistant Secretor (80%) Susceptible to infection Exposed Population Norovirus Transmission Cycle

Foodborne Burden • Causes 67% of all foodborne illness in U.S. from known agents • Annual foodborne norovirus estimates (rank among known agents) • 9,200,000 cases of disease (#1) • 20,000 hospitalizations (#1) • 120 deaths (#4) Mead 1999 EID

Confirmed and Suspected Etiology of 1270 Foodborne Outbreaks Reported to CDC, 2006 CDC 2009 MMWR

Etiology of Foodborne Outbreaks Reported to CDC CDC 2009 MMWR

Single Food Commodities Involved in Norovirus Outbreaks, 1998-2007 Preliminary CDC Data

Norovirus Classification • Genogroups • >60% amino acid similarity • 3 affect humans (GI, GII, GIV) • Genotypes • >80% amino acid similarity • 8 GI genotypes, 17 GII genotypes • Strains (variants, clusters) • >95% amino acid similarity • 11 GII.4 strains identified Broad Specific

Norovirus Classification Tree Patel 2009 J Clin Virol

Norovirus GII.4 Pandemics

GII.4 Strain Prevalence in Outbreaks Tested at CDC Siebenga 2009 JID

Setting of Norovirus Outbreaks Reported to CDC, 1994-2006 Zheng 2010 JCM

Seasonality of Norovirus Outbreaks Reported to CDC, 1994-2006 Zheng 2010 JCM

Dynamics of Strain Evolution and Population Immunity Variant 1 Variant 2 Estimated population immunity to circulating variant Cases

Challenges • Asymptomatic infections • Persistent in the environment • Resistant to common disinfectants • Very low infectious dose • Recurrent infections

College Campus Outbreaks: Recent Examples

Outbreak 1:California, 2008 • Large university (enrollment 32,000) • Oct 3: Initial report of >30 students at emergency dept or student health center (SHC) with AGE • L.A. County Dept of Public Health (LACDPH) • Conducted site visits for interviews with ill students and environmental inspection • Monitored daily GI reports from hospitals, SHC, and residence hall advisors • Campus administration sent mass email to all students to complete web-based survey • case ascertainment • risk factor analysis

Outbreak 1:Investigation Findings • 5,227 (16%) students completed web-based survey • 478 (1.5%) total cases identified via survey or reported directly LACDPH • 185 (39%) sought medical care at SHC • 35 (7.3%) visited ED • 10 (2.1%) hospitalized for dehydration • 10 stool specimens tested • 6 positive for norovirus GII by qRT-PCR • All identical GII.6 Seacroft strain • No single event, residence hall, eating venue, or ill food handler were implicated

Student AGE Cases by Onset Date, California, 2008

Outbreak 2:Michigan, 2008 • Small college (enrollment 3,000) • Nov 6: 60 AGE cases at campus medical clinic • State and County health depts sent health alert • local schools • healthcare providers • medical facilities • Nov 7: total increased to 130 cases, suggesting point source exposure • One primary dining facility on campus • Parents’ day activities began following day

Outbreak 2:Actions Taken • County health dept closed campus • Curtail transmission and facilitate disinfection • Only take-out and delivery available on campus • Email & text messages sent to students • Stay in residence unless required medical attention • Completed electronic questionnaire if ill • Disinfect dorm room with dilute bleach, wash soiled linens and clothing, and wash hands frequently • Ill faculty and staff advised to stay home until 72 hours after symptoms resolved • Parents and media sent outbreak updates via email and announcements on college website

Outbreak 2:Investigation Findings • 418 (13%) of 3,238 students ill • 205 via electronic reporting • 213 via direct reporting to medical clinic • 33 (5.2%) of 630 faculty/staff ill • 5 stool specimens tested • All positive for norovirus GI by qRT-PCR • All identical GI.4 strain • 3 ill food service workers with vomiting and diarrhea at work on Nov 4

Student/Faculty/Staff AGE Cases by Onset Date, Michigan, 2008 Ill food workers

Outbreak 3:Wisconsin, 2008 • Large university (enrollment 42,000) • Nov 6: 2 students from residence Hall A (population 1,150) with AGE • Students reported additional residents in Hall A with similar symptoms • AGE reported during following week from other residence halls and a sorority house

Outbreak 3:Actions Taken • Campus health services led investigation • Daily reports of ill residents from Hall A staff • Email sent to all residence hall residents (3,480) and fraternity/sorority members (2,700) • If AGE during preceding 2 weeks, asked to complete online questionnaire • Students educated on hand washing • Dormitories, public restrooms, communal areas cleaned with approved disinfectants

Outbreak 3:Investigation Findings • 156 total student cases reported • 138 identified online, 18 through campus health • 36 (23%) sought healthcare, none hospitalized • Symptoms included: • diarrhea (92%) • chills (80%), • vomiting (88%) • body aches (81%), • cramps (88%) • subjective fever (65%) • 93 cases among Hall A residents (8% attack rate) • 5 stool specimens tested • 2 positive for norovirus GII by qRT-PCR • Sequencing not performed

Student AGE Cases by Residence and Onset Date, Wisconsin, 2008 Index cases reported Email sent

Outbreak Examples Summary • 1,000 reported cases of illness, including at least 10 hospitalizations • Median outbreak duration: 19 days (range: 16-20) • Minimum attack rates ranged from 1.5% to 12.9% • College campuses at high risk for norovirus outbreaks • Extensive opportunities for transmission • Numerous shared exposures and living areas • Access to healthcare encourages illness reporting and facilitates outbreak recognition

Prevention and Control Recommendations • Promote appropriate hand hygiene • Wash with soap and water ≥ 20 seconds • Alcohol-based hand sanitizers as adjunct • Prompt and thorough environmental disinfection • Bleach solution for contaminated surfaces (1000-5000 ppm) • Other EPA-approved disinfectants? • Exclude ill students/staff from food preparation for ≥48-72 hrs after symptom resolution • Encourage ill students to seek medical care and limit social activities • Consider facility closure and/or event cancellation • Disseminate recommendations promptly during outbreak, including via electronic media

Acknowledgments • University of Southern California • University of Wisconsin-Madison • Craig Roberts • Hope College • Tom Renner • Ottawa County Health Dept • Paul Heidel • Debra VandeBunte • Los Angeles County Dept of Public Health • Curtis Croker • Roshan Reporter • Shikari Nakagawa-Ota • Michigan Dept of Community Health • Brenda Brennan • Wisconsin Div of Public Health • John Archer

Thank You… Questions? Disclaimer: The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.

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Collection Review

Collection Review articles synthesize in narrative form the best available evidence on a topic. Submission of Collection Review articles is by invitation only, and they are only published as part of a PLOS Collection as agreed in advance by the PLOS Medicine Editors.

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The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control

* E-mail: [email protected]

Affiliation Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America

Affiliation Enteric & Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, Washington, United States of America

• Benjamin A. Lopman, 
• Duncan Steele, 
• Carl D. Kirkwood, 
• Umesh D. Parashar

Published: April 26, 2016

• https://doi.org/10.1371/journal.pmed.1001999
• Reader Comments

Globally, norovirus is associated with approximately one-fifth of all diarrhea cases, with similar prevalence in both children and adults, and is estimated to cause over 200,000 deaths annually in developing countries. Norovirus is an important pathogen in a number of high-priority domains: it is the most common cause of diarrheal episodes globally, the principal cause of foodborne disease outbreaks in the United States, a key health care–acquired infection, a common cause of travel-associated diarrhea, and a bane for deployed military troops. Partly as a result of this ubiquity and burden across a range of different populations, identifying target groups and strategies for intervention has been challenging. And, on top of the breadth of this public health problem, there remain important gaps in scientific knowledge regarding norovirus, especially with respect to disease in low-income settings.

Many pathogens can cause acute gastroenteritis. Historically, rotavirus was the most common cause of severe disease in young children globally. Now, vaccines are available for rotavirus and are universally recommended by the World Health Organization. In countries with effective rotavirus vaccination programs, disease due to that pathogen has decreased markedly, but norovirus persists and is now the most common cause of pediatric gastroenteritis requiring medical attention. However, the data supporting the precise role of norovirus in low- and middle-income settings are sparse. With vaccines in the pipeline, addressing these and other important knowledge gaps is increasingly pressing.

We assembled an expert group to assess the evidence for the global burden of norovirus and to consider the prospects for norovirus vaccine development. The group assessed the evidence in the areas of burden of disease, epidemiology, diagnostics, disease attribution, acquired immunity, and innate susceptibility, and the group considered how to bring norovirus vaccines from their current state of development to a viable product that will benefit global health.

Citation: Lopman BA, Steele D, Kirkwood CD, Parashar UD (2016) The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control. PLoS Med 13(4): e1001999. https://doi.org/10.1371/journal.pmed.1001999

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Funding: This work was supported by the Bill & Melinda Gates Foundation by a grant to the National Foundation for Center for Disease Control and Prevention (Grant ID: OPP1110771).

Competing interests: The authors have no competing interests to declare.

Abbreviations: AGE, acute gastroenteritis; BMGF, the Bill & Melinda Gates Foundation; CDC, Centers for Disease Control and Prevention; DALYs, disability-adjusted life years; EPI, Expanded Program on Immunization; G, genogroup; GEMS, Global Enterics Multi-Center Study; HBGAs, histo-blood group antigens; MAL-ED, Malnutrition and Enteric Disease Study; RT-qPCR, real-time quantitative PCR; TPP, target product profile; VLPs, virus like particles

Provenance: Commissioned; part of a Collection; externally peer reviewed

Summary Points

• Diagnostic improvements have fundamentally changed our understanding of norovirus. The current evidence suggests that disease burden of norovirus is high, second only to rotavirus as a cause of severe acute gastroenteritis in children in developed countries, and that it is a key cause of diarrhea-associated morbidity and mortality worldwide.
• Young children experience the highest incidence of disease; severe outcomes are most common among young children and the elderly.
• Immunity is of limited duration and is strain- or genotype-specific, with little or no protection conferred across genogroups.
• Innate susceptibility to noroviruses is determined by the host’s genetics of glycan expression; individuals with a functional FUT2 gene (known as secretors) have greater susceptibility to certain common viruses.
• Recent progress has been made in the development of in vitro cell culture for norovirus as well as in the identification of candidate immune correlates of protection.
• Norovirus vaccines are steadily moving through the development pipeline. All of these products are based on the production of virus like particles (VLPs) or P particle subunit in expression systems. Initial human challenge studies have demonstrated safety, immunogenicity, and efficacy.
• One of the challenges for developing targeted interventions, including a norovirus vaccine, is that many distinct population groups, based on demographics (e.g., children, elderly) or risk (e.g., food handlers, military, travelers, health care workers), are affected.

Introduction

Significant progress has been made towards the control of diarrheal diseases. Global diarrheal deaths for all ages have declined dramatically, from an estimated 2.6 million annually in 1990 to approximately 1.3 million in 2013 [ 1 ]. Over the same period, improvements specifically for children under 5 years of age have been most impressive, with rates of decline in diarrheal deaths at around 5% per year, in absolute numbers, to an estimate of 578,000 deaths in 2013 [ 2 ]. Diarrheal disease is now the fourth most common cause of mortality overall, but morbidity has not changed at the same pace, with diarrheal disease remaining the second most common cause of morbidity worldwide in children under the age of 5 years [ 3 ]. Many bacterial and parasitic pathogens are controllable through improvements in water, sanitation, and hygiene, facilitated by economic development, as is evidenced by the rapid declines in mortality; rotavirus disease has been significantly impacted through vaccination in virtually every setting where it has been introduced, and can be further impacted with additional introduction of rotavirus vaccines in countries [ 4 ].

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. It is estimated to cause 212,000 deaths annually worldwide; approximately 99% of these are estimated to occur in middle- and high-mortality countries [ 5 ]. According to these estimates, norovirus is the most common cause of diarrheal cases across for all ages, the second most common cause of diarrheal death in children under the age of 5 years, and the most common cause of diarrheal death over 5 years of age, with similar patterns across WHO regions. So while the overall mortality risks are likely to be much lower in high-income settings, high incidence of disease appears universal. For example, the Malnutrition and Enteric Disease Study (MAL-ED), conducted in eight low- and middle-income countries, found norovirus to be the first and second most common cause of diarrheal disease in the first and second year of life, respectively [ 6 ]. And in high- and middle-income countries with successful rotavirus vaccination programs, norovirus is the most common cause of pediatric gastroenteritis [ 7 , 8 ].

The increase in norovirus-related research over the last 15 years has been tremendous, concurrent with improvements in and more widespread availability of diagnostic methods. Included in this body of work are fundamental advances in our understanding, ranging from better burden-of-disease estimates [ 5 , 9 , 10 ], to the first demonstration of in vitro cell culture [ 11 ], to elucidation of key interactions that noroviruses have with other agents in the microbiome [ 11 – 13 ], to the demonstration that vaccination against human norovirus infection and disease is possible [ 14 , 15 ]. While many challenges remain before norovirus can be considered “controllable,” the confluence of recent advances gives us optimism. To this end, in February 2015, Centers for Disease Control and Prevention (CDC) and the Bill & Melinda Gates Foundation (BMGF), led by a scientific organizing committee from the areas of government, academia, and philanthropy, convened a symposium in Atlanta, Georgia, United States, with representatives from all these sectors in addition to vaccine developers. Our charge was to review the most up-to-date knowledge on norovirus with the aim of identifying key gaps and detailing the most critical studies to address them, all with the ultimate goal of guiding the development of a norovirus vaccine for the populations that stand to benefit most: children in the developing world. The full report from the convening can be found at http://www.cdc.gov/norovirus/downloads/global-burden-report.pdf . Many of the papers in this PLOS Collection were either presented at or inspired by the meeting.

Critical Knowledge Gaps

• Basic epidemiological and disease burden data are lacking, especially from developing countries. There remains uncertainty and some scientific controversy in defining the norovirus disease burden.
• With sensitive real-time quantitative PCR (RT-qPCR) assays, norovirus is frequently detected in stool of healthy individuals, complicating the interpretation of diagnostic results and disease attribution.
• Understanding of natural immunity to norovirus remains incomplete.
• The implications of genetic susceptibility for population health, viral evolution, and vaccines remains unclear.
• Genotype-specific immune responses and antigenic variation of norovirus suggest that a polyvalent vaccine will be needed and may require updating when new pandemic strains emerge.
• There is limited understanding of the relative roles that different age groups play in virus transmission. Better data coupled with appropriate models could help to devise vaccination strategies that lead to the greatest benefits at the population level.

Insights from this Collection

Global economic burden.

In a recent PLOS Collection, the World Health Organization’s Global Estimates of the Burden of Foodborne Disease in 2010 were published. These estimates position norovirus as the most common cause of cases of and deaths from foodborne diarrhea disease and the fourth greatest burden in terms of disability-adjusted life years (DALYs). Norovirus was estimated to cause 684 million (95% Uncertainty Interval 491–1,112 million) episodes of diarrheal disease and 212,000 deaths, annually, for all ages and from all modes of transmission [ 5 , 10 ].

In our current Collection, Bartsch et al. extend those findings to consider global economic impacts of norovirus [ 16 ]. They estimate that globally, norovirus results in an economic burden of US$4.2 billion (95% UI: US$3.2–US$5.7 billion) in direct health system costs and US$60.3 billion (95% UI: US$44.4–US$83.4 billion) in societal costs annually. Two-thirds of that burden is a result of disease in children under the age of five years. Low-, middle-, and high-income countries all have a considerable economic burden, indicating that norovirus gastroenteritis is a truly global economic problem.

Local Burden Data

While there is clearly a lack of local, national, and regional studies from developing countries on the epidemiology and molecular diversity of norovirus, those gaps are beginning to be filled. In their systematic review, Mans et al. included data on 19 studies from 14 African countries. Overall, in these studies, norovirus was associated with 13.5% of diarrheal disease in children, and GII.4 strains predominated in the majority of studies. The authors identified lack of data in older children and adults as a critical gap in Africa [ 17 ]; the same gap exists for low- and middle-income settings globally [ 9 ].

A number of papers in this collection also offer new epidemiological data from specific populations from Asia, Africa, and North and South America. Shioda et al. present some of the first age-specific community and outpatient incidence rates of diarrheal disease associated with norovirus (as well as sapovirus and astrovirus) in Kenya [ 18 ]. Their community-based incidence estimate is about twice that of estimates from the US, United Kingdom, and the Netherlands, suggesting higher overall incidence in this developing country.

Grytdal et al. provide some of the first estimates of age-specific incidence rates for norovirus-associated acute gastroenteritis (AGE) in outpatient and community settings for the US [ 19 ]. In a population served by a managed care organization, norovirus gastroenteritis incidence in the community was estimated at 6% per year, with substantially higher rates among children under 5 years of age, particularly in outpatient settings (i.e., medically attended disease). Also for the US, Rha et al. estimated medically attended norovirus AGE rates for active-duty military personnel and their beneficiaries [ 20 ]. Like Grytdal et al., they reported that outpatient rates were approximately five times higher among children under 5 years of age compared to the rest of the population. Overall, rates of medically attended norovirus in this military population were considerably higher than estimates for the civilian population from Grytdal et al. [ 19 ] or previously published estimates [ 21 – 24 ], perhaps owing to more frequent exposure for military personnel.

Molecular Epidemiology

A signature biological feature of norovirus is its genetic diversity and rapid, immune selection-driven evolution. A number of papers in this collection highlight this diversity and give insight into its mechanistic underpinnings and implications for health and disease. Most of our understanding of the molecular epidemiology of norovirus comes from outbreak samples. However, Allen et al. examined samples from sporadic cases in diverse settings: the UK and Malawi [ 25 ]. Certain GII.4 strains that caused global increases in outbreak activity could be found in sporadic samples in both of these settings many years before becoming globally predominant. Based on this, the authors suggest the importance of surveillance of sporadic disease. Such data, especially from high incidence settings in the developing world, may be crucial for understanding and anticipating strain emergence and for predicting the potential strains for vaccines.

Fumian et al. and Lee Kim et al. present data on the molecular epidemiology of norovirus outbreaks from Brazil and Australia/New Zealand, respectively [ 26 , 27 ]. Despite their obvious geographical differences, the observations are remarkably consistent. GII.4 viruses were identified in 72% and 63% of outbreaks in Brazil and Australia/New Zealand, respectively. Of the non-GII.4 outbreaks, the majority in both settings were inter-genotype recombinant viruses, highlighting this important evolutionary mechanism, especially for less common strains.

Natural History, Host–Pathogen Interactions

Vomiting is a cardinal symptom of norovirus and key to its transmission, but it has also been a challenge to study directly. Using data from a collection of intentional-exposure volunteer studies, Kirby et al. show that over two-thirds of participants experience vomiting and that virus can be detected in most emesis samples from these participants [ 28 ]. Cases with vomiting but without diarrhea are typically excluded from studies of acute gastroenteritis; Kirby et al.’s study reminds us that in doing so, we exclude an important syndrome caused by norovirus infection and therefore underestimate its disease burden.

It is from these and other volunteer studies that much of our knowledge of norovirus immunity is derived. More recently, clinical trials using virus-like particles (VLPs) as candidate vaccines have further advanced our knowledge. Ramani et al. highlight two recently identified potential correlates of protection against norovirus gastroenteritis: norovirus-specific salivary IgA and norovirus-specific memory IgG cells [ 29 ]. Currently, however, serum antibody that blocks the binding of norovirus VLPs to histo-blood group antigens (HBGAs) is the best-studied and leading candidate correlate of protection.

In their Pearls article, Nordgren et al. discuss the implications of heterogeneity in innate susceptibility to norovirus in terms of burden of disease, viral genetic diversity as a function of human host diversity, and what the implications of this might be for norovirus vaccines and clinical trial design [ 30 ].

Quantifying Disease Burden and the Need for a Vaccine

The current evidence suggests that norovirus disease burden is great, but there remains considerable uncertainty and some scientific controversy in defining the precise role of norovirus in severe pediatric gastroenteritis. Epidemiological and etiological data are lacking, especially from developing countries. Routine testing is rarely performed in ongoing surveillance platforms, in part because molecular diagnostics are the standard reference for norovirus detection, and have only recently been widely available. Real-time quantitative reverse-transcription PCR (RT-qPCR) is the most sensitive and specific diagnostic for noroviruses, but use of these assays is mainly restricted to public health and research laboratories in middle- and high-income settings.

A robust estimate of the disease burden is critical to establishing a public health case to guide interventions and norovirus vaccine development. A vexing problem is how to identify when norovirus is disease-causing and then to attribute a fraction of the acute gastroenteritis disease “envelope” to norovirus. For norovirus, attribution has been particularly challenging since detection is based on highly sensitive RT-qPCR and virus is frequently detected in stool of individuals with gastroenteritis, but also in stool of healthy controls. Reinfection is common and sometimes asymptomatic; viral shedding can persist for weeks or months after symptoms and, fundamentally, we lack a diagnostic that readily discriminates between disease-causing and asymptomatic infection.

The recent Global Enterics Multi-Center Study (GEMS) is the largest systematic assessment for understanding the etiology of childhood diarrhea in developing countries [ 31 ]. GEMS and other case-control studies use the odds ratio of a microbe being present in cases versus healthy controls to calculate an attributable or etiologic fraction. When detected as frequently in healthy controls as in cases, some study authors have concluded that norovirus is a minor pathogen. We think that the conclusion is inaccurate for a virus that commonly causes reinfection and has long excretion patterns. An alternative explanation is that high levels of asymptomatic infection are a result of frequent exposure, some of which will result in asymptomatic infection because of acquired immunity [ 32 ]. Therefore, high prevalence of norovirus detection in healthy controls may be characteristic of “hyper-endemicity” where burden is higher, not lower. Quantitative and multiplex diagnostics may be important tools for ascribing etiological fractions for norovirus and other enteric pathogens, especially when coupled with rigorous field studies, such as the multi-center MAL-ED study [ 33 ]. Indeed, in that study, norovirus was identified as the pathogen with the first- and second-highest attributable fraction for diarrhea in the first and second year of life, respectively, but still only about 5% of disease could be attributed to norovirus [ 6 ].

Developing a Vaccine and Addressing Biological Challenges

Noroviruses are a genetically and antigenically diverse group of ssRNA viruses, which presents serious challenges both for creating broadly reactive diagnostics and eliciting a broadly protective immune response, following either natural infection or vaccination. The norovirus strains that infect humans are found among 29 genotypes among genogroup (G) I ( n = 9), GII ( n = 19), and GIV ( n = 1) [ 34 ]. Among this array of different noroviruses are the GII.4 strains, which rapidly evolve in a boom-and-bust cycle, with novel viruses emerging every 2–4 years and replacing previous dominant ones, a process driven by evasion of immunity in the human population [ 35 ]. In addition to their evolutionary dynamics, there are public health reasons that a successful norovirus vaccine must provide protection against GII.4 viruses: they are the predominant cause of pediatric infections worldwide [ 36 ], they predominate overwhelmingly as a cause of disease amongst the elderly in health care–associated outbreaks, and they result in more severe illness and death [ 37 ]. Studies published in this Collection are consistent with the view that GII.4 viruses predominate globally [ 17 , 25 , 26 ], with rare exception in the last 20 years [ 38 ].

Understanding of natural immunity to norovirus is far from complete, but the current view is that immunity is strain- or genotype-specific, with little or no protection conferred across genogroups. Immunity is not lifelong, with estimates of duration ranging from 6 months to 9 years [ 32 , 39 – 42 ]. Accordingly, genotype-specific immune responses and antigenic variation suggest that a polyvalent vaccine will be needed and may require updating when new strains emerge. To date, vaccine trials and challenge studies have been conducted among adults, leaving much to learn about how “unprimed” children who have not experienced (as many) norovirus exposures develop immunity and therefore respond to vaccination.

The lack of a robust in vitro cell culture system for human norovirus has hampered the development of assays to measure protective neutralizing antibodies conferred by either natural or vaccine-induced immunity. However, important progress has been achieved very recently in this area [ 11 ] as has identification of candidate immune correlates of protection (e.g., [ 43 ]). These are important breakthroughs that may accelerate vaccine development.

Overcoming Logistical and Programmatic Challenges

Many distinct population groups are affected by norovirus, which could complicate the formulation of a research agenda and clinical development plan for specific products (Tables 1 and 2 ). But, if harnessed, this diversity in disease burden could also serve to stimulate development and generate demand from difference sources. A development plan for a target population of young children will look quite different than for older adults, or for a specific risk group, such as travelers, military personnel, or health care workers. From a public health perspective, it is clear that young children experience the highest overall incidence of disease [ 21 ], and severe disease outcomes are most common among young children and, at least in developed countries, the elderly [ 24 ]. Young children also seem to be the most important group in driving transmission in the community [ 44 ]. Accordingly, vaccinating young children would likely be most efficient for directly preventing disease burden, and would offer the greatest potential for impact at the population level through indirect benefits resulting from reduced transmission. Defining the relative roles of different age groups in transmission is challenging and may well differ in high- and low-income settings, but a combination of empirical (e.g., household) studies and mathematical modeling analysis may help to optimize the direct and population-level effect of vaccinating through targeting different groups.

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In the absence of an outside stimulus, such as major global public health donors, developed world markets are likely to provide the initial economic impetus for private industry to develop norovirus vaccines. To date, early-phase trials have been conducted among adults in high-income settings, and there have been no clinical studies in children, so we see a need for a targeted pediatric development plan. Such a plan should include studies to generate data on the compatibility of a norovirus vaccine with current routine childhood immunizations, and in particular the Expanded Program on Immunization (EPI). Adding a vaccine to the EPI schedule involves great effort to demonstrate the added value of the vaccine, on both economic and health grounds. The economics of a norovirus vaccine requiring multiple doses and/or periodic reformulation will be scrutinized carefully by policy makers. At the earliest stage, clinical development plans should define a target product profile (TPP) that will maximize public health gains by focusing on young children, with the aim of developing a vaccine that can be incorporated into the logistical arrangements of current immunization programs.

Future Directions

Norovirus as a target for vaccination is unique in many ways. First, the public health need is not restricted to a specific region, income level, or even age range, so the groups with a stake in vaccine development are many and diverse. Second, much of the totality of economic and health burden results from relatively mild disease. But even if the proportion of cases with severe outcomes is relatively low, the sheer incidence of norovirus still results in a considerable severe disease burden. Third, given the current state of knowledge, we expect that progress in understanding of disease burden and epidemiology, human–virus interactions, and vaccine development will be interdependent. More robust estimates of the disease burden of children in low-income settings should stimulate more research in vaccines that will benefit those populations; vaccine trials themselves can be used to better characterize the disease burden and also to identify correlates of protection, which have the potential to make subsequent vaccine evaluations faster and less costly; mathematical modeling studies can serve as a framework to integrate this variety of data and to predict the impact of vaccination strategies, and to objectively identify the most critical gaps in our knowledge ( Table 3 ). Addressing these key issues will be vital to accelerate and achieve the development and implementation of interventions such as vaccines to control and prevent the tremendous global morbidity and mortality from norovirus.

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Acknowledgments

We thank the Scientific Organizing Committee and all attendees of the “Global Burden of Norovirus and Prospects for Vaccine Development” symposium held in Atlanta, Georgia, 23–25 February 2015. Members included Robert Atmar (Baylor College of Medicine), Ralph Baric (University of North Carolina at Chapel Hill), Mary Estes (Baylor College of Medicine), Kim Green (NIH; National Institute of Allergy and Infectious Diseases), Roger Glass (NIH; Fogarty International Center), Aron Hall (Centers for Disease Control and Prevention), Miren Iturriza-Gómara (University of Liverpool), Gagandeep Kang (Christian Medical College), Bruce Lee (Johns Hopkins University), Ben Lopman (Centers for Disease Control and Prevention), Umesh Parashar (Centers for Disease Control and Prevention), Mark Riddle (Naval Medical Research Center), and Jan Vinjé (Centers for Disease Control and Prevention)

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, or the US Department of Health and Human Services, or the Bill & Melinda Gates Foundation.

Author Contributions

Wrote the first draft of the manuscript: BAL. Contributed to the writing of the manuscript: DS CDK UDP. Agree with the manuscript’s results and conclusions: BAL DS CDK UDP. All authors have read, and confirm that they meet, ICMJE criteria for authorship.

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