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. Author manuscript; available in PMC: 2011 Aug 5.
Published in final edited form as: Discov Med. 2010 Jul;10(50):61–70.

Noroviruses: The Principal Cause of Foodborne Disease Worldwide

Hoonmo L Koo 1,2, Nadim Ajami 1,2, Robert L Atmar 1, Herbert L DuPont 1,2,4
PMCID: PMC3150746  NIHMSID: NIHMS294945  PMID: 20670600

Abstract

Noroviruses are the leading cause of foodborne disease outbreaks worldwide, and may soon eclipse rotaviruses as the most common cause of severe pediatric gastroenteritis, as the use of rotavirus vaccines becomes more widespread. Genetic mutations and recombinations contribute to the broad heterogeneity of noroviruses and the emergence of new epidemic strains. Although typically a self-limited disease, norovirus gastroenteritis can cause significant morbidity and mortality among children, the elderly, and the immunocompromised. The lack of a cell culture or small animal model has hindered norovirus research and the development of novel therapeutic and preventative interventions. However, vaccines based on norovirus capsid protein virus-like particles are promising and may one day become widely available through transgenic expression in plants.

Introduction

Noroviruses (NoVs) are emerging as one of the foremost enteric pathogens of foodborne disease worldwide. First recognized in 1972 by Albert Kapikian and colleagues (Kapikian et al., 1972), the epidemiology of NoV infections has long been underestimated due to the limited availability of optimal detection methods. The inability to cultivate these viruses in cell culture and the lack of a small animal model have hindered NoV research and the development of diagnostic assays readily available to the majority of clinical laboratories. As more facilities gain the capacity to perform sensitive molecular diagnostic testing for NoVs, the prevalence and clinical impact of noroviruses continues to expand globally. Currently, NoVs are considered as the leading cause of foodborne disease and acute non-bacterial gastroenteritis worldwide (Atmar and Estes, 2006).

Molecular Characteristics of Noroviruses

The RNA genome of NoVs is composed of three open reading frames (ORFs). ORF1 encodes a nonstructural polyprotein that is auto-cleaved by the viral protease into 6 proteins: p48, nucleoside triphosphatase, p22, VPg, protease (Pro), and the RNA-dependent RNA polymerase (RdRp). Translation of ORF2 produces the capsid protein VP1, which is the major structural protein of NoVs. ORF3 is translated to VP2, a minor structural protein with unknown function (Belliot et al., 2003; Prasad et al., 1999). Expression of the NoV capsid protein in baculovirus recombinants in insect cells leads to the spontaneous self-assembly of virus-like particles (VLPs). The viral capsid structure contains histo-blood group antigen (HBGA) binding sites and viral antigenic determinants, allowing for NoV VLPs to be used for vaccine development. These VLPs are nonpathogenic because they lack nucleic acid and are unable to replicate.

Genetic Diversity of Noroviruses

Noroviruses are classified into five genogroups based upon the phylogenetic analysis of the viral capsid (VP1) gene, and further subdivided into genetic clusters called genotypes. Genogroups I (GI) and II (GII) are most commonly associated with human infections. The prototype strain, Norwalk virus, is classified as a GI.1 NoV. GII.4 NoVs are the predominant circulating genotype identified in NoV outbreaks worldwide (Bull et al., 2006). Significant genetic variation of the capsid amino acid sequence exists within a genogroup (< 44%) and between genogroups (>45%) (Zheng et al., 2006). Point mutations and recombination of related NoVs contribute to the great diversity of NoVs. The rapid evolution of NoV GII.4 variants or antigenic drift of NoVs has led to the emergence of novel strains associated with global epidemics, as new NoV strains are capable of infecting newly susceptible populations lacking protective immunity and are able to bind potentially new genetic carbohydrate targets (Siebenga et al., 2009).

The Expanding Epidemiology of Noroviruses

NoVs are the most common cause of foodborne disease worldwide. In the U.S., NoV infections attribute for more than two-thirds of all foodborne gastroenteritis outbreaks (Bresee et al., 2002) and cause approximately 23 million cases each year (Mead et al., 1999). Norovirus outbreaks are commonly identified in populations including restaurant patrons (Centers for Disease Control and Prevention, 2007; Daniels et al., 2000), children (Centers for Disease Control and Prevention, 2008; Patel et al., 2008), the elderly (Green et al., 2002), the immunocompromised (Roddie et al., 2009), military personnel (Hyams et al., 1993; Sharp et al., 1995), travelers to developing countries (Ajami et al., 2010; Koo et al., 2010), passengers of cruise ships (Widdowson et al., 2004), residents of healthcare facilities such as nursing homes (Calderon-Margalit et al., 2005; Green et al., 2002) and hospitals (Johnston et al., 2007), and other populations housed in close quarters (Yee et al., 2007) (Table 1). NoVs have also been associated with Clostridium difficile infections (CDI) in limited studies. However, increased rates of C. difficile detection during NoV outbreaks may simply reflect false positives related to increased testing of stool specimens for C. difficile or the detection of C. difficile colonization in a healthcare setting (Koo et al., 2009b). NoVs were identified as an uncommon cause of non-CDI antibiotic-associated diarrhea in a tertiary hospital in Houston, Texas (Koo et al., 2009a).

Table 1.

Populations at Risk for Norovirus Gastroenteritis

Restaurant patrons
Children in developing and industrialized nations
Elderly
Immunocompromised
Travelers to developing nations, cruise ship passengers
Military personnel
Residents of healthcare facilities (e.g., nursing homes, hospitals)
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Noroviruses are the second most common cause of severe gastroenteritis in children less than five years of age in both developing and industrialized nations, preceded only by rotaviruses. NoVs are responsible for ~12 % children less than 5 years of age hospitalized for severe gastroenteritis worldwide. Each year, NoVs cause approximately 900,000 cases of pediatric gastroenteritis in industrialized nations and at least 1.1 million episodes and 218,000 deaths in developing nations (Patel et al., 2008). As rotavirus vaccines become more widely distributed and routinely administered in countries like the U.S., significant decreases in the prevalence of rotavirus infections have been noted (Curns et al., 2010). With the success of the rotavirus vaccine, NoVs may soon become the most important enteric pathogen in pediatric populations worldwide.

Travelers to developing nations, where greater fecal contamination of food and water supplies may be encountered, are at risk for developing norovirus gastroenteritis. We have demonstrated that NoVs were the second most common enteric pathogen identified among travelers who acquired diarrhea in Mexico, India, or Guatemala, following diarrheagenic Escherichia coli (Koo et al., 2010). In the United States, numerous NoV outbreaks have been documented among travelers on cruise ships, and noroviruses have gained notoriety as the “cruise ship virus” (Widdowson et al., 2004). Close living quarters and difficulty in eradicating this infectious agent with traditional cleaning agents likely contribute to these recurrent NoV outbreaks on cruise ships.

Transmission

With their low infectious dose (18-1,000 virus particles) (Teunis et al., 2008), stability on inanimate surfaces, and resistance to conventional cleaning agents, NoVs have ideal properties as enteric outbreak pathogens and are considered as Category B potential bioterrorism agents, according to the National Institute of Allergy and Infectious Diseases classification of pathogens important for biodefense (NIAID Biodefense Research). NoVs are primarily transmitted in a fecal-oral fashion including person-person and fomite contamination. Airborne transmission via aerosolization with vomiting has been implicated in a restaurant and emergency room outbreak based on epidemiologic surveillance studies (Marks et al., 2000; Sawyer et al., 1988). Widespread dissemination of NoV gastroenteritis is facilitated by close living quarters and decreased sanitary conditions, leading to NoV outbreaks in daycare centers, nursing homes, and a large outbreak among Hurricane Katrina refugees housed in the Reliant Stadium in Houston, Texas (Yee et al., 2007). Persistence of NoV shedding for up to 8 weeks even after clinical resolution of symptoms may also contribute to NoV transmission (Atmar et al., 2008), although studies are needed to confirm whether these persistently shed virus particles are infectious.

Genetic Susceptibility

Genetic susceptibility to norovirus infections is related to the expression of histo-blood group antigens (HBGAs) on the mucosal surface of intestinal epithelial cells. HBGAs are blood group carbohydrates including ABO, Lewis, and precursor antigens expressed on epithelial cells, which are putative receptors or co-receptors for NoVs. Host genetic susceptibility and HBGA binding patterns appear to be NoV strain-specific, with different NoV strains preferentially binding to different HBGA carbohydrates. The most important HBGA related to susceptibility to NoV gastroenteritis is the H1 antigen encoded by the secretor gene (FUT2 gene). Hosts with homozygous null mutant alleles are described as nonsecretors (Figure 1). Nonsecretors have been shown to be resistant to infection with GI NoVs, including Norwalk virus strains, and to GII.4 NoVs, the predominant NoV genotype associated with outbreaks worldwide (Le Pendu et al., 2006; Lindesmith et al., 2003). However, one nonsecretor individual developed gastroenteritis in a recent GII.4 NoV outbreak (Carlsson et al., 2009).

Figure 1.

Figure 1

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Synthesis for Type 1 Histo-blood Group Antigens

Abbreviations: FT, fucosyltransferase; Le, Lewis

The Host Immune Response to NoV Infections

The human host immune response, in terms of protective immunity and clearance of NoV infections, is not well-characterized. Antibody neutralization assays are currently not available because of the lack of cell culture or small animal model. Seroprevalence studies have shown that up to 90% individuals develop antibodies against NoVs by adulthood (Gray et al., 1993; O'Ryan et al., 1998). However, the humoral protection provided by these NoV antibodies against subsequent NoV exposure remains unclear. Some challenge studies have reported short-term (< 6 months) antibody-mediated immunity against re-exposure to NoV strains, but long-term protection has not been demonstrated even for hosts re-challenged with the same NoV strain (Parrino et al., 1977; Wyatt et al., 1974). The antigenic diversity of NoVs likely plays an important role in evasion of host immune responses and limits antibody protection, and may also allow for hosts to be susceptible with new NoV strain-specific host receptor binding patterns (Lindesmith et al., 2008; Siebenga et al., 2007).

Cell-mediated immunity may be important for clearance of NoV infections. A predominant Th1 immune response, with increased IFN-γ and IL-2 cytokine production, has been demonstrated in human hosts infected with NoVs. CD4+ T-cell depletion prior to stimulation of peripheral blood mononuclear cells (PBMCs) with NoV virus-like particles led to a significant decrease in IFN-γ production in in vitro studies (Lindesmith et al., 2005). Allogeneic hematopoietic stem cell transplantation (HSCT) recipients with both cellular and humoral immunosuppression have been reported to suffer chronic NoV gastroenteritis and severe complications including death (Roddie et al., 2009).

Clinical Manifestations

Described as the “winter-vomiting” disease, norovirus gastroenteritis often presents with nausea, vomiting, and watery diarrhea, following an incubation period of 1–2 days. Other associated symptoms include abdominal pain or cramps, anorexia, malaise, and low-grade fever. NoVs are not invasive pathogens, and dysenteric symptoms including bloody or mucoid diarrhea or high fever are uncommon (Koo et al., 2009a). Up to one-third of persons exposed to noroviruses may develop an asymptomatic infection (Graham et al., 1994). NoV gastroenteritis is a self-limited disease lasting 24–60 hours in the majority of cases. However, infected persons may continue to shed NoVs up to approximately 8 weeks with high viral loads (up to 1012 NoV copies/g feces) after clinical resolution of symptoms (Atmar et al., 2008). Post-infectious irritable bowel syndrome has been described as a sequela of NoV infection (Marshall et al., 2007). Immunocompromised individuals, children, and the elderly can experience a more persistent and severe disease course including dehydration, weight loss, renal failure, disseminated intravascular coagulation (DIC), chronic diarrhea for months to years, malnutrition, and even death (Atmar and Estes, 2006; Dolin, 2007). In one case series describing adult allogeneic hematopoietic stem cell transplant (HSCT) recipients (n=12), ten patients developed chronic diarrhea for a median duration of 3 months. Two HSCT recipients died, with one being related to complications of malnutrition and chronic NoV gastroenteritis. Supplemental nutrition was required for six patients due to persistent diarrheal illness. These NoV-infected patients were hospitalized for a median of 73 days during their gastroenteritis (Roddie et al., 2009).

Diagnosis of NoV gastroenteritis

Reverse-transcription polymerase chain reaction of diarrheal stools or emesis for NoVs is the diagnostic test of choice (Koopmans, 2008). Unfortunately, many clinical laboratories are still unable to perform this test. The sensitivity of the RT-PCR assay is dependent upon the primers used, with certain primers capable of amplifying a broader array of NoV genotypes. However, no primer set detects all NoVs because of the broad genetic diversity of NoVs. RT-PCR may be limited by the presence of inhibitors of amplification, inefficient RNA extraction, and degradation of NoV RNA with specimen storage at suboptimal conditions. Some studies indicate that real-time RT-PCR may be more sensitive for NoV detection than conventional RT-PCR (Kageyama et al., 2003; Scipioni et al., 2008). Real-time PCR may also be less time-consuming because subsequent confirmation of NoV genogroups by separate probe hybridization or nucleic acid sequencing is often required for conventional RT-PCR. Electron microscopy was used originally to identify NoVs but is relatively insensitive (<25%) compared to RT-PCR (Richards et al., 2003). An ideal NoV detection method would be a rapid yet sensitive assay such as an enzyme-linked immunosorbent assay (ELISA). Unfortunately, despite improvements in both sensitivity and specificity of NoV detection with ELISA assays, the sensitivities of these diagnostic tests are still inferior to RT-PCR (Atmar and Estes, 2006; Khamrin et al., 2008).

In an outbreak setting where microbiological evaluation is not possible, the Kaplan criteria have been used successfully to identify a likely NoV outbreak (Table 2). These epidemiologic and clinical criteria were established by Kaplan and colleagues based upon an in-depth analysis of 38 Norwalk virus acute gastroenteritis outbreaks between 1976-1980 (Kaplan et al., 1982b). Application of these criteria to distinguish NoV acute gastroenteritis outbreaks from other enteric pathogens has been associated with a sensitivity of ~70% and a specificity of up to 99% (Kaplan et al., 1982a; Turcios et al., 2006). Given the relative insensitivity of these diagnostic criteria, NoVs cannot be excluded as the etiologic agent if outbreak characteristics fail to meet the Kaplan criteria and there is suspicion for a viral enteropathogen.

Table 2.

Kaplan Criteria for Norovirus Gastroenteritis Outbreaks

  1. Duration of illness (mean or median) of 12–60 hours

  2. Incubation period (mean or median) of 24–48 hours

  3. Greater than 50% affected persons with vomiting

  4. No bacterial cause identified

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Evaluating food for NoV contamination can be difficult. The optimal method for NoV detection is unknown because inhibitors of amplification appear to vary for different food groups. We investigated food items from a wedding reception in Houston, Texas in August 2007, which was implicated in an acute gastroenteritis outbreak involving more than 100 wedding guests. Seven food items were tested for NoV contamination -- frosted white cake, uncooked salad vegetables, uncooked spinach, cooked white rice, cooked mixed vegetables (carrots, broccoli, cauliflower), uncooked tomatoes, and chicken florentine hand-stuffed with spinach. Using TRIzol for RNA extraction (Table 3) (Schwab et al., 2000), followed by serial dilutions for potential inhibitors in the food samples and RT-PCR, we were able to demonstrate GI NoV contamination of the chicken florentine spinach stuffing. Although we were successful in demonstrating NoV contamination of a food item in this outbreak, detection of NoV contamination has been performed in relatively few outbreaks with no current standardized method for testing food items. Failure to detect NoV contamination is insufficient to assume a food is unrelated to a NoV outbreak.

Table 3.

Protocol of RNA Extraction from Food Samples

  1. Collect 25 – 50 grams of food sample.

  2. Add 8 mL of TRIzol LS reagent and centrifuge for 20 minutes at 8,000 g.

  3. Discard lipid layer and residual food pellet.

  4. Add 1.6 mL of chloroform to the remaining fluid and mix for 15 seconds.

  5. Incubate 10 minutes at room temperature. Centrifuge for 20 minutes at 8,000 g.

  6. Add 4 mL of Isopropanol to the supernatant and mix for 30 seconds.

  7. Incubate 10 minutes at room temperature. Centrifuge for 20 minutes at 8,000 g at 4°C. Discard the supernatant.

  8. Wash the RNA pellet with 8 mL of 75% ethanol. Centrifuge for 5 minutes at 7,000 g at 4°C. Discard the supernatant.

  9. Allow for the ethanol to evaporate at room temperature. Resuspend the extracted RNA in 100 μL of RNase-free water.

  10. Prepare serial dilutions of the RNA extract for possible inhibitors of RT-PCR.

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Therapy

Currently, there is no specific therapy for NoV gastroenteritis. The lack of a cell-culture model is a significant barrier to the development of antiviral agents for NoVs. The mainstay of treatment for NoV gastroenteritis involves symptomatic interventions including oral rehydration with electrolytes. Bismuth subsalicylate was shown to significantly reduce the duration of gastrointestinal symptoms compared to placebo among volunteers experimentally challenged with Norwalk virus in a small randomized, double-blind trial (n=32). However, bismuth subsalicylate had no impact on the number or weight of stools passed, the rate of viral excretion between the two groups, or the overall duration of Norwalk virus illness (Steinhoff et al., 1980). Anti-diarrheal agents such as loperamide may also provide some benefit, but no clinical trials have directly studied their effectiveness for treating NoV gastroenteritis. In a subanalysis of a small randomized, double-blind, placebo-controlled clinical trial (n=13), 3-days of nitazoxanide 500 mg twice daily (n=6) appeared to shorten the median time to resolution of illness compared to placebo (n=7) (1.5 versus 2.5 days, respectively; p=0.0295) among children and adults presenting with NoV diarrhea to Egyptian outpatient clinics. In this study, NoVs were diagnosed by ELISA (Rossignol and El-Gohary, 2006). Further clinical trials are needed to evaluate nitazoxanide for treatment of NoV gastroenteritis and to better understand the mechanism of nitazoxanide’s anti-viral activity.

Human serum immunoglobulins appear to be effective in shortening the duration of rotavirus gastroenteritis (Guarino et al., 1994) and may be a future therapeutic option for patients suffering persistent or recurrent NoV gastroenteritis. Oral administration of immunoglobulins appears to be associated with few adverse events because it is minimally absorbed from the gastrointestinal tract (Dattani and Connelly, 1996; Losonsky et al., 1985). Unfortunately, very little clinical evidence exists supporting the use of immunoglobulin therapy for NoV diarrhea. Oral immunoglobulin therapy (25 mg/kg every 6 hours for 48 hours) was given to two children who developed refractory Norwalk virus diarrhea following small intestinal transplantation. One combined liver, small bowel, and pancreas transplant infant developed recurrent, severe NoV diarrhea requiring multiple hospitalizations for dehydration and high ileostomy output. After receiving oral immunoglobulin therapy, the patient’s stool output decreased and his cycle of recurrent NoV gastroenteritis was interrupted. The second patient was a combined liver and small bowel transplant recipient, who presented with persistent increased ileostomy output, despite tapering off of his immunosuppressive regimen that prevents immune rejection of the transplants. After receiving oral immunoglobulin therapy, a transient decrease in stool output for 24 hours was observed. However, the ileostomy output subsequently increased again presumably due to the development of enterocutaneous fistulas (Florescu et al., 2008). Immunocompromised patients with NoV gastroenteritis are likely to benefit most from reconstitution of their immune system or a decrease in immunosuppression if possible. Distinguishing NoV infection from intestinal graft-versus-host disease is essential for management of transplant recipients because this complication can present similarly but requires an increase in immunosuppression (Ferrara and Deeg, 1991).

Infection Control–The Key to Controlling a NoV Outbreak

Implementation of appropriate infection control measures is critical to controlling an ongoing NoV outbreak. Unfortunately, our understanding of this important area is significantly deficient and requires further study. Stringent infection control practices are necessary for closed facilities including healthcare facilities where the close proximity of residents may facilitate rapid spread of NoVs. The Centers for Disease Control and Prevention endorses standard precautions with an emphasis on adequate hand hygiene for suspected NoV cases. Contact precautions with isolation gowns and gloves are recommended when contact with incontinent persons is anticipated, in outbreak settings, and when there is risk of contamination with infected vomitus or feces. Use of private rooms or cohorting to segregate suspected NoV cases is encouraged in outbreak settings. NoV resistance to multiple chemical agents requires cleaning methods similar to those used for C. difficile infections. Contaminated surfaces should be cleaned with sodium hypochlorite at a minimum concentration of 1,000 ppm (Centers for Disease Control and Prevention, please add the year) The effectiveness of alcohol-based hand sanitizers as NoV disinfectants is unclear (Gehrke et al., 2004). As a result, handwashing with soap and water should be performed during NoV outbreaks.

The CDC recommends for NoV-infected individuals to be excluded from work for at least 48 hours after symptomatic resolution (LeBaron et al., 1990). However, there are no formal studies evaluating the optimal time period at which ill children or adults can safely return to school or work to support these recommendations. Relatively short work furloughs for only forty-eight hours after NoV gastroenteritis symptoms have resolved may not be sufficient, particularly for special working populations such as food-handlers and healthcare workers, who are capable of exposing large numbers of people to NoVs. Previous studies have demonstrated persistent NoV shedding for weeks after clinical resolution.

Prevention

The stability of NoV VLPs at acidic pH (such as gastric pH) following lyophilization allow for their oral administration (Jiang et al., 1992). In mice, Norwalk virus VLPs have been shown to be immunogenic by parenteral (Jiang et al., 1992), intranasal (Guerrero et al., 2001), and oral administration (Ball et al., 1998). Two small volunteer challenge studies have shown that Norwalk virus VLPs may be immunogenic in humans as well, with seroconversion rates up to 90–100%, when subjects were given 250 μg of Norwalk virus VLPs at enrollment and 21 days later. However, serum IgG antibody production with NoV VLPs was significantly lower than IgG titers elicited by live Norwalk virus stool filtrates. Co-administration of the NoV VLPs with adjuvants may be necessary to elicit a successful immunogenic protective response. The NoV VLPs were well-tolerated compared to placebos in these studies (Ball et al., 1999; Tacket et al., 2003).

Transgenic expression of NoV VLPs in plants such as tobacco, potatoes, and tomatoes has been successfully performed. Potential benefits from NoV VLP expression in plants include improvements and simplification of the manufacturing, packaging, storage, transportation, administration, and safety of the NoV vaccine. These advantages may translate into lower costs and greater distribution of the future vaccine to developing regions of the world (Tacket, 2005; Zhang et al., 2006).

The immunogenicity of Norwalk virus VLPs expressed in transgenic potatoes was evaluated in a randomized, double-blind, placebo-controlled volunteer study (n=24) (Tacket et al., 2000). Subjects were randomized to one of the following regimens: (1) one dose (150 g) of transgenic potatoes on days 0, 7, and 21 (n=10); (2) one dose of transgenic potatoes on days 0 and 21 and placebo potatoes on day 7 (n=10); (3) placebo potatoes on days 0, 7, and 21 (n=4). Each dose of transgenic potato contained 215–751 μg of Norwalk capsid protein. Although 19 of 20 (95%) subjects who ingested transgenic potatoes demonstrated significant increases in specific IgA antibody-secreting cells, only 4 of 20 (20%) subjects developed a 4-fold rise in serum NoV IgG titers following immunization. The lower seroconversion rate in this study may have been related to the low percentage of capsid protein assembling into VLPs (25–50%). No difference in adverse events compared to wild-type potatoes was noted. NoV VLPs expressed in tomatoes may be a more potent immunogen in mice compared to VLPs expressed in potatoes. Air-dried tomatoes led to a more robust immune response in mice compared to freeze-dried tomato powder in a recent study (Zhang et al., 2006).

Current efforts to produce an effective NoV vaccine are hindered by our lack of knowledge of the measurable correlate of immunity that corresponds with human protection against NoV infections. In addition, previous studies have shown that antibody-mediated immunity may be short-lived. Cross-protection between different genogroups or genotypes may be limited, given the significant genetic heterogeneity that exists among NoVs. Constant NoV antigenic drift may also limit widespread protection with NoV vaccines, and their success may be dependent upon vigilant surveillance for the predominant circulating NoV genotypes for which vaccinations should be prepared, similar to current influenza vaccinations.

Conclusions

Noroviruses are the leading cause of foodborne disease outbreaks worldwide, and may soon eclipse rotaviruses as the most common cause of severe pediatric gastroenteritis. Recurrent emergence of new epidemic NoV strains can be expected with NoV antigenic drift, which allows for NoVs to evade the host immune response and to possibly bind new genetic carbohydrate receptors. NoV virus-like particles composed of the virus capsid protein are promising as a vaccine candidate, which may be transgenically expressed in plants for easier administration and greater distribution. More research is needed to optimize current infection control policies and to develop new and more effective therapeutic and preventative strategies.

Acknowledgments

The authors thank Diana Koo for her invaluable assistance with sample collection and processing in the epidemiologic investigation of the norovirus outbreak in Houston, Texas. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK084513-02 to HLK) and the National Institutes of Health (P01-AI-057788, P30-DK-56338, and U54-AI-057156 to RLA).

Footnotes

Potential Financial Conflicts of Interest: None

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