Noroviruses: The Perfect Human Pathogens?Parasite manipulation of host behavior previously: Deciphering the Tools of Nature’s Zombies
Noroviruses are perhaps the perfect human pathogens. These viruses possess essentially all of the attributes of an ideal infectious agent: highly contagious, rapidly and prolifically shed, constantly evolving, evoking limited immunity, and only moderately virulent, allowing most of those infected to fully recover, thereby maintaining a large susceptible pool of hosts. These characteristics have enabled noroviruses to become the leading cause of endemic diarrheal disease across all age groups , the leading cause of foodborne disease , and the cause of half of all gastroenteritis outbreaks worldwide . In the United States alone, noroviruses are responsible for an estimated 21 million cases of acute gastroenteritis annually, including >70 000 hospitalizations and nearly 800 deaths   . In developing countries, where the greatest burden of diarrheal disease occurs, noroviruses have been estimated to cause up to 200 000 deaths each year in children < 5 years of age . Although recognition of this immense disease burden is relatively recent, it is unclear whether it has long been present and failed to be recognized because of lack of sensitive diagnostics or if, in fact, noroviruses represent a truly emergent public health issue . Regardless, attempts to address the overwhelming burden of norovirus disease first require an understanding of the complexity and efficiency with which these viruses spread.
Pathogenesis of Noroviruses, Emerging RNA Viruses
Human noroviruses in the family Caliciviridae are a major cause of epidemic gastroenteritis. They are responsible for at least 95% of viral outbreaks and over 50% of all outbreaks worldwide. Transmission of these highly infectious plus-stranded RNA viruses occurs primarily through contaminated food or water, but also through person-to-person contact and exposure to fomites. Norovirus infections are typically acute and self-limited. However, disease can be much more severe and prolonged in infants, elderly, and immunocompromised individuals. Norovirus outbreaks frequently occur in semi-closed communities such as nursing homes, military settings, schools, hospitals, cruise ships, and disaster relief situations. Noroviruses are classified as Category B biodefense agents because they are highly contagious, extremely stable in the environment, resistant to common disinfectants, and associated with debilitating illness. The number of reported norovirus outbreaks has risen sharply since 2002 suggesting the emergence of more infectious strains. There has also been increased recognition that noroviruses are important causes of childhood hospitalization. Moreover, noroviruses have recently been associated with multiple clinical outcomes other than gastroenteritis. It is unclear whether these new observations are due to improved norovirus diagnostics or to the emergence of more virulent norovirus strains. Regardless, it is clear that human noroviruses cause considerable morbidity worldwide, have significant economic impact, and are clinically important emerging pathogens. Despite the impact of human norovirus-induced disease and the potential for emergence of highly virulent strains, the pathogenic features of infection are not well understood due to the lack of a cell culture system and previous lack of animal models. This review summarizes the current understanding of norovirus pathogenesis from the histological to the molecular level, including contributions from new model systems.
Tracking Environmental Norovirus Contamination in a Pediatric Primary Immunodeficiency Unit
Norovirus strains were detected in two patients and in environmental swabs from a pediatric primary immunodeficiency unit in London, United Kingdom, during an infection control incident in November and December 2007. Detailed analyses of the gene encoding the P2 domain demonstrated that the majority of the strains were not related to the patients and that the environmental contamination was most likely due to secondary transfer by the hands of staff or visitors.
A Point-Source Norovirus Outbreak Caused by Exposure to Fomites
We investigated a norovirus outbreak (genotype GII.2) affecting 9 members of a soccer team. Illness was associated with touching a reusable grocery bag or consuming its packaged food contents (risk difference, 0.636; P < .01). By polymerase chain reaction, GII norovirus was recovered from the bag, which had been stored in a bathroom used before the outbreak by a person with norovirus-like illness. Airborne contamination of fomites can lead to subsequent point-source outbreaks. When feasible, we recommend dedicated bathrooms for sick persons and informing cleaning staff (professional or otherwise) about the need for adequate environmental sanitation of surfaces and fomites to prevent spread.
Recurring Norovirus Transmission on an Airplane
Previously reported outbreaks of norovirus gastroenteritis associated with aircraft have been limited to transmission during a single flight sector. During October 2009, an outbreak of diarrhea and vomiting occurred among different groups of flight attendants who had worked on separate flight sectors on the same airplane. We investigated the cause of the outbreak and whether the illnesses were attributable to work on the airplane. Information was obtained from flight attendants on demographic characteristics, symptoms, and possible transmission risk factors. Case patients were defined as flight attendants with diarrhea or vomiting <51 hours after the end of their first flight sector on the airplane during 13–18 October 2009. Stool samples were tested for norovirus RNA. A passenger had vomited on the Boeing 777-200 airplane on the 13 October flight sector. Sixty-three (82%) of 77 flight attendants who worked on the airplane during 13–18 October provided information, and 27 (43%) met the case definition. The attack rate among flight attendants decreased significantly over successive flight sectors from 13 October onward (P < .001). Working as a supervisor was independently associated with development of illness (adjusted odds ratio, 5.8; 95% confidence interval, 1.3–25.6). Norovirus genotype GI.6 was detected in stool samples from 2 case patients who worked on different flight sectors. Sustained transmission of norovirus is likely to have occurred because of exposures on this airplane during successive flight sectors. Airlines should make provision for adequate disinfection of airplanes with use of products effective against norovirus and other common infectious agents after vomiting has occurred.
Norovirus Vaccine against Experimental Human Norwalk Virus Illness
Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus–specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05). This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.)
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