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Tropical and travel-associated norovirus

current concepts

Ballard, Sarah-Blythea; Saito, Mayukob,c; Mirelman, Andrew J.d; Bern, Caryne; Gilman, Robert H.a,f

Current Opinion in Infectious Diseases: October 2015 - Volume 28 - Issue 5 - p 408–416
doi: 10.1097/QCO.0000000000000197
TROPICAL AND TRAVEL-ASSOCIATED DISEASES: Edited by Joseph M. Vinetz and Yukari C. Manabe
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Purpose of review We highlight recent advances relevant to understanding norovirus infections in the tropics, both in populations living in developing settings and travelers to these regions.

Recent findings Because of the decrease in diarrheal disease associated with the global rollout of vaccines against rotavirus, norovirus is emerging as the predominant cause of diarrhea morbidity among children in the tropics, and evidence suggests that it contributes to adult disease in endemic populations and travelers. In addition to identifying potential target populations for preventive measures, we provide an update on norovirus vaccine development and concepts related to their implementation in low-income and middle-income countries.

Summary These current concepts related to norovirus-attributable disease burden, clinical significance, and economic impact can potentially be applied to tailoring efforts to prevent and mitigate the effects of this important enteropathogen.

aDepartment of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

bDepartment of Virology, Tohoku University Graduate School of Medicine, Sendai, Japan

cAsociación Benéfica PRISMA, Lima, Peru

dCentre for Health Economics, University of York, Heslington, UK

eDepartment of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, California, USA

fLaboratorios de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Lima, Peru

Correspondence to Sarah-Blythe Ballard, MD, MPH, 615 N. Wolfe St., Rm. W5515, Baltimore, MD 21205, USA. Tel: +1 410 614 3959; fax: +1 410 510 1284; e-mail: sballar3@jhu.edu

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INTRODUCTION

Globally, norovirus is the most common cause of acute sporadic gastroenteritis in adults and the second leading cause of severe diarrhea in children, after rotavirus. In countries with mature rotavirus immunization programs, norovirus is emerging as the predominant diarrhea-associated pathogen in young children [1]. This review covers the latest scientific insights into norovirus infections in the tropics while addressing the challenges of controlling this disease in low-income and middle-income country (LMIC) populations and travelers to these regions.

Box 1

Box 1

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ASSESSING NOROVIRUS DISEASE BURDEN IN THE TROPICS

Norovirus detection in symptomatic cases

Ahmed et al. [2▪] estimated a global norovirus prevalence of 18% among acute gastroenteritis cases in a meta-analysis of 175 studies published between 2008 and 2014. The pooled prevalences among hospitalized and community cases were 17 and 24%, respectively [2▪]. When stratified by WHO mortality category [3], norovirus was more prevalent in diarrhea stools from low mortality than high mortality developing settings (19 versus 14%, respectively) [2▪]. This likely represents a more diverse enteropathogen landscape in the context of higher overall diarrhea incidence in high-mortality settings [2▪]. Prior to rotavirus vaccine implementation, norovirus was the most frequently identified pathogen in ambulatory [4] and community [5▪▪] diarrhea cases in certain LMIC settings. Rotavirus was usually reported more frequently in hospitalized children [4], although up to 55% of hospital diarrhea cases demonstrated human calicivirus (norovirus and/or sapovirus) infection when evaluated with both immunologic and molecular detection methods [6,7]. Following successful universal rotavirus vaccination in LMICs, norovirus is recognized as the predominant pathogen in hospitalized [8▪], outpatient [4], and community [9▪] diarrhea cases. Norovirus has also been associated with adult diarrhea in LMIC military service members [10▪▪].

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Norovirus detection in asymptomatic individuals

The detection of norovirus in stools from asymptomatic individuals complicates disease burden estimates. Globally, the pooled asymptomatic prevalence from the 20 controlled studies in Ahmed's meta-analysis was 7% [2▪]. Fifteen to 35% of norovirus infections are asymptomatic, but both symptomatically infected and asymptomatically infected individuals shed virus at similar levels for similar amounts of time, although duration may vary by genotype and variant [5▪▪]. Host genetic factors, such as the absence of the α-1,2-fucosyltransferase enzyme in ‘secretor negative’ individuals, appear to confer absolute protection to infection to specific variants [11▪]. Other host factors, such as histo-blood group antigen polymorphisms, result in heterogeneous susceptibility to norovirus infection [11▪]. Following infection, viral shedding lasts approximately 20–30 days in adults norovirus infection in an Ecuadorian birth cohort reporting all GII.4 infections occurred in secretor positive children (P < 0.001), but higher rates of non-GII.4 infections occurred in secretor-negative children.12. Levine MM, Robins-Browne RM. Factors that explain excretion of enteric pathogens by persons without diarrhea. Clin Infect Dis 2012; 55 (Suppl 4):S303–S311.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">[12]. Excretion can be prolonged in children, the elderly, and immunocompromised who serve as reservoirs for transmission [13] and may also contribute to the emergence of novel epidemic variants [1]. In Saito et al.'s [5▪▪] Peruvian birth cohort, norovirus excretion was longer for genogroup (G) II (median 34.5 days; maximum 98) than GI (median 8.5 days; maximum 49). Both symptomatic and asymptomatic infections during the first year of life were associated with lower mean length-for-age z scores (coefficient −0.33) that persisted into the second year of life [5▪▪].

In the absence of longitudinal data, distinguishing symptomatic from asymptomatic norovirus infections is difficult. Asymptomatic individuals tend to have higher real-time reverse transcriptase polymerase chain reaction cycle threshold values than individuals with acute gastroenteritis, but there is no clear viral load cutoff that corresponds with symptom resolution [14]. To illustrate the marked increase in asymptomatic norovirus prevalence resulting in small increases in basic reproduction number, Lopman et al.[15▪▪] created a dynamic norovirus transmission model of norovirus infection, immunity, and disease. In this model, the case:control prevalence ratio was high in developed settings and decreased dramatically in a high-exposure scenario with the same disease incidence [15▪▪]. This could explain why the Global Enteric Multi-Center Study (GEMS), a case−control analysis of diarrhea in the tropics, noted similar frequencies of norovirus in case and control stools, ultimately determined that norovirus contributed minimally to moderate-to-severe diarrheal disease [16]. In contrast, longitudinal studies that more clearly distinguish symptomatic and asymptomatic infections demonstrate higher burdens of norovirus-associated diarrhea in similar developing settings [5▪▪,17▪▪]. In their Peruvian birth cohort, Saito et al. [5▪▪] calculated a norovirus attributable diarrheal disease fraction of 7.8% in the first and 23.1% in the second year of life.

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Defining norovirus disease and severity

The lack of standard norovirus case definitions and clinical severity measures complicate disease burden estimation and comparative intervention evaluations in tropical settings. Historically dubbed ‘winter vomiting disease,’ norovirus often causes emesis in the absence of diarrhea. As a result, diarrhea-based gastroenteritis case definitions likely underestimate disease burden by excluding vomiting-only disease. Of the 175 studies included in Ahmed et al.'s meta-analysis of norovirus gastroenteritis, 143 (82%) either did not provide a case definition for acute gastroenteritis or excluded vomiting-only disease. Clinical severity measures are most commonly based on the 20-point Vesikari scale, which dichotomizes gastroenteritis into ‘mild’ (<11) or ‘severe’ disease [18,19]. Other measures of disease severity include the 24-point Clark scale [20], modified Vesikari scales [5▪▪], the World Health Organization scale [21], and severity scores based on signs and symptoms [22,23▪▪,24–27], reported symptoms [28–31], length of hospitalization [29,32], and impact on daily activities [33▪]. Different gastroenteritis case and severity definitions can bias results against specific pathogens. For example, defining ‘moderate-to-severe’ diarrhea as the presence of sunken eyes, loss of skin turgor, intravenous fluid prescription, dysentery, or hospital admission, GEMS reported that norovirus contributed minimally to moderate-to-severe disease [16]. In contrast, O’Ryan et al.'s [34] hospital-based study of diarrheal disease in Chile reported that norovirus was a leading cause of moderate-to-severe disease, as defined by a Vesikari score greater than 6 (of 20 possible points) [19]. Using uniform case definitions and severity measures for norovirus vaccine efficacy studies will allow direct comparison of results, avoiding the possibility that different results might be attributable to the use of different scales, as was the case when Rotateq and Rotarix were evaluated using the Clark and Vesikari scales, respectively [35].

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Malnutrition and norovirus infection

Undernutrition affects one in five children in the tropics and has been associated with half of deaths in children younger than 5 years worldwide [36]. Poor nutrition weakens host immune responses and alters the gut microbiota, both of which can worsen the clinical course of diarrheal disease [37▪▪]. After infecting well-nourished and protein energy deficient mice with murine norovirus, Hickman et al. [37▪▪] found that malnourished mice demonstrated more weight loss, reduced antibody responses, loss of protective immunity, and enhanced viral evolution. Although the well-nourished mice fared better in terms of disease severity, norovirus infection resulted in a gut microbial environment similar to that of malnourished mice [37▪▪]. Human studies are currently being conducted by the Interactions of Malnutrition & Enteric Infections: Consequences for Child Health and Development (MAL-ED) group, but results are pending [38▪▪,39▪–41▪,42–49]. Particularly relevant to assessing tropical norovirus infections are investigations that assess the role of the gut microbiota in nutritional status [50▪], immune markers and vaccine failure in undernourished populations [51▪,52▪], tropical enteropathy and gut function [51▪,53▪▪,54], and the long-term impact of these factors on child development [38▪▪,55].

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Norovirus coinfections

Individuals living in tropical settings often have intense exposure to enteric pathogens, and detection of more than one pathogen, particularly helminths, in stool samples is common. Helminth coinfections impair viral immunity via an innate immunomodulation pathway. In this pathway, helminth-activated TH2 cells release interleukin (IL)-4 and IL-13, which ligate IL-4 receptors on M2 macrophages [56▪▪,57▪▪]. This inhibits the production of virus-specific T-cells and greatly increases viral replication in macrophages [57▪▪]. Helminth infections are also associated with changes in the gut microbiota [58,59], although the extent to which these changes affect host responses to viruses and other enteropathogens is not clear. The type 2 immune response stimulated by helminth infection is also associated with enhanced tissue repair and reduced inflammation [60], which could mitigate the severity of disease in coinfected individuals.

The molecular and cellular interactions between enteropathogens are important to consider when evaluating norovirus disease burden and pathogen-specific interventions [61▪]. However, currently used qualitative pathogen detection [62,63▪] and regression-based coinfection adjustment [16] methods are imperfect in the setting of asymptomatic infection, postinfectious shedding [64], and varying durations of immunity [65]. Probabilistic analytical methods that give weight to first infections and account for pathogen prevalance prior to symptom onset may present a clearer picture of pathogen-specific disease burdens in tropical settings where polymicrobial infections are detected frequently [66▪▪].

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NOROVIRUS IN TRAVELERS TO THE TROPICS

Up to 100 million people from high-income countries travel to the tropics each year, and 40–60% of them develop diarrhea [67,68]. Norovirus is the second leading cause of travelersdiarrhea after enteropathogenic Escherichia coli (ETEC) [69▪]. A systematic review of 51 published studies of travelersdiarrhea reported a pooled norovirus case stool prevalence of 6.6%, with higher norovirus prevalence in stools from travelers to Latin America (16.9%) and Africa (12.8%) than travelers to Asia (3.2%) [70▪]. Norovirus has been associated with diarrhea in both children and adults returning from tropical settings [70▪], and norovirus coinfections with other pathogens, particularly ETEC, are common, [71,72]. Travelersdiarrhea is associated with alterations in the gut microbiota that appear similar, regardless of the infecting enteropathogen [69▪].

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Norovirus afloat

Norovirus has a very low infectious dose [73,74,75▪,76▪] and is extremely hard to eliminate from the environment [6], making contamination of ships common. The US Centers for Disease Control and Prevention's Vessel Sanitation Program assists to prevent outbreaks on cruise ships with foreign itineraries, where the impact of norovirus has been well documented [77]. During the 1990 s, the implementation of sanitation measures resulted in the reduction of cruise-ship norovirus outbreaks from 6.3 to 3.7 per 1,000 ship-weeks [78]. In US military populations afloat, gastroenteritis outbreaks have been reported at nearly 10 times the rate of cruise ships, with an overall incidence of 33.2 outbreaks per 1,000 ship-weeks among 44 Navy ships deployed to the Middle East during a 12-month analysis period [79]. It is assumed that norovirus contributed significantly to these outbreaks since a concurrent surveillance study identified norovirus in at least one of the 11 outbreaks included in this study, and in four of four Navy ships which submitted outbreak stool specimens for testing as part of a separate surveillance report [79]. Attack rates were similar on large and small military ships (3.3% overall), but larger ships had more frequent outbreaks than smaller ships (66 versus 26 per 1,000 ship weeks, respectively) [79]. Smaller ships had increased outbreak durations, possibly because less intense transmission resulted in slower saturation of the susceptible population relative to the more crowded big ships [79]. Unlike international cruise ships, which demonstrate a winter-spring predominance, US Navy shipboard outbreaks occurred throughout the year [79].

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Norovirus in deployed troops ashore

Norovirus outbreaks among ground troops in deployed settings are also common. Among 20,320 deployed US service members presenting with acute gastroenteritis from 2005 to 2012, 60% of cases were associated with viral pathogens, and norovirus detection increased steadily from 2006 to 2012 [80]. Still another 25,938 cases from this period were documented as ‘nonspecific diarrhea,’ although norovirus likely contributed significantly [80]. During Operations Desert Shield and Desert Storm, numerous norovirus outbreaks occurred in service members [81–83]. Norovirus outbreaks also clustered at the beginning of the conflicts in Iraq and Afghanistan [84–87]. One such outbreak resulted in the evacuation of 11 British troops from Afghanistan, including one individual with disseminated intravascular coagulation and two individuals requiring ventilator support [86]. This outbreak highlighted the potential for norovirus to cause severe disease in otherwise healthy individuals under extreme environmental stress [86]. In another norovirus outbreak in Iraq, 975 of 1,340 affected British troops were admitted to a field hospital, where significant transmission to medical staff occurred, resulting in hospital closure [85,88,89].

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NOROVIRUS VACCINES IN THE TROPICS

Recent reviews by Vesikari and Blazevic [90] and Debbink et al. [91] detail current vaccine development strategies. Briefly, LigoCyte used a baculovirus-insect cell system to develop the first virus-like particle (VLP) vaccine against norovirus GI.1 [92]. Their monophosphoryl lipid A (MPL) and chitosan-adjuvanted intranasal vaccine produced a moderate level of protection against the homologous virus in subsequent challenge studies [92,93]. This proof-of-principle vaccine was followed by an MPL-adjuvanted bivalent GI.1/GII.4 VLP vaccine candidate, delivered intramuscularly [94▪]. The corresponding challenge study was performed with a heterologous GII.4 virus, a better representation of natural infection than challenge with a virus homologous to the vaccine VLP [95▪▪]. This vaccine provided 100% protection against severe vomiting and severe diarrhea, but was not protective against infection, and only partially protective against symptoms of any severity. Using a Vesikari scale, the vaccine reduced diarrhea severity significantly, from 7.3 in the placebo group to 4.5 in the vaccine group [95▪▪]. Other candidate vaccines in development include a ‘trivalent’ vaccine containing a rotavirus VP6 protein and norovirus GI.3 and GII.4 VLPs [96,97▪▪]; an intranasal dry-powder vaccine [98]; an E. coli-produced P particle vaccine [99]; and a combined norovirus P particle–rotavirus VP8 antigen vaccine [100]. Multivalent α-virus replicon particle platforms for VLP formation [101], polyvalent norovirus P domain glutathione S-transferase complexes [102], and edible vaccine delivery mechanisms [103] are also being explored. Significant work remains to enhance the efficacy of norovirus vaccines against genetically diverse norovirus variants, lengthen the duration of vaccine-induced immunity, lower vaccination costs, determine the acceptability of an adjuvant, and optimize dosing and delivery.

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Vaccine efficacy considerations in the tropics

To date, norovirus vaccine trials have occurred in well-nourished adults from high-income countries. However, vaccine underperformance is common in developing settings [104–106], where diarrhea frequently occurs, the prevalence of undernutrition is high, and the duration of breastfeeding is suboptimal [107▪▪]. Recent mouse model studies demonstrated that malnourished mice infected with murine norovirus develop fairly normal serum antiviral immunoglobulin G responses, but have significantly reduced mucosal immunoglobulin A responses that correspond with a lack of protective immunity [37▪▪]. Parenteral vaccine administration could potentially overcome the apparent intestinal barrier to immunization in undernourished populations. Promoting exclusive breastfeeding and improving nutrition may also improve oral vaccine performance in developing settings [107▪▪]. Given that 70% of pediatric norovirus infections occur between 6 and 24 months of age worldwide, and 60% occur before 12 months of age in high-mortality developing settings, Shioda et al. estimated that a pediatric norovirus vaccine would have to be delivered before 6 months of age to prevent the majority of childhood infections [108▪].

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Vaccine cost-effectiveness in the tropics

Mirelman et al.[109▪▪] recently developed a model to evaluate norovirus vaccine cost-effectiveness in LMIC populations. When applied to a hypothetical Peruvian birth cohort, this model found that norovirus vaccination could offer economic value under the right conditions by averting poor health outcomes and substantial healthcare utilization costs [109▪▪]. Assuming a two-dose vaccination cost of $26.44 per individual vaccinated, 85% vaccine coverage, the 47% reported vaccine efficacy in Atmar et al.'s vaccine trial, and peri-urban diarrhea incidence rates reported by Saito et al., the vaccine cost-effectiveness was $19.86 per diarrhea case averted, $68.23 per outpatient visit averted, and $21,415.95 per disability adjusted life year (DALY) averted [109▪▪]. Using higher norovirus incidence rates from a less developed rural setting, vaccine cost-effectiveness improved to $9.20 per diarrhea case averted, $32.29 per outpatient visit averted, and $10,135 per DALY averted [109▪▪]. This model did not include the indirect costs of norovirus infection or the out-of-pocket direct costs for self-treatment and home care, which are expected to be significant and would further augment the economic value of norovirus vaccination [110▪]. Likewise, it did not consider the relationship between diarrhea and malnutrition, the prevention of which would result in additional health, social, and economic benefits. The impact of reduced norovirus transmission to older children and adults was not included in the model, but could also be significant, as young children play a key role in transmitting norovirus to all age groups [65].

Tallant et al.'s [111▪▪] recently published a new model of diarrhea vaccine cost-effectiveness for deploying US military personnel. Using a diarrhea-based definition of norovirus disease, they calculated a norovirus vaccine cost-effectiveness of $1,344 per duty day lost averted. This model assumed a two-dose vaccination cost of $60.14 per individual vaccinated; 75% vaccine coverage; 80% vaccine effectiveness, reflecting the minimally acceptable military vaccine profile, rather than the efficacy of vaccines currently under development [112,113]; and a duration of immunity of 3.5 months, which is twice the average duration of US military deployments [111▪▪]. The estimated cost per duty day lost averted for military vaccines against Campylobacter sp., ETEC, and Shigella sp. were $800, $776, and $1,275, respectively [111▪▪]. When the norovirus disease definition was modified to include vomiting, the norovirus vaccine cost per duty day lost averted decreased to $572, making it the most cost-effective of the four hypothetical diarrhea vaccines evaluated (against Campylobacter sp., ETEC, Shigella sp., and norovirus) [111▪▪]. As a reference, deployment operational costs per troop were an estimated $935 per day, so a norovirus vaccine with the described characteristics would be considered cost-effective for deploying US military personnel (or cost-saving, if vomiting disease is considered) [111▪▪].

Apart from young children and military service members from high-income countries deployed to tropical regions, other tropical and travel-associated populations that might benefit from norovirus vaccination include the elderly [114▪], hospitalized patients [114▪], individuals with immune compromise, school-aged children, developing country military personnel [10▪▪], healthcare workers [114▪], food handlers, food processing facility workers, farm workers, and travel industry workers [1]. The key challenge of evaluating norovirus vaccine cost-effectiveness in these populations is the lack of norovirus disease burden data, in addition to uncertainty about the price, dosing, and effectiveness of candidate vaccines. To aid economic evaluations of vaccines in LMICs, norovirus-specific models should be incorporated into existing cost-effectiveness analysis tools [115▪].

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CONCLUSION

In conclusion, noroviruses are well recognized as the most common cause of acute gastroenteritis in all age groups worldwide, and they are becoming the predominant pathogen associated with pediatric diarrhea in the tropics in the wake of the global rotavirus vaccine rollout. In order to appropriately assess disease burden and plan health interventions for populations in developing settings, we will need to refine our case definitions, severity measures, and intervention assessment tools. We will also need to better elucidate the complex relationship between diarrhea, malnutrition, gut microbiota, environmental enteropathy, enteric coinfections, and the immune system. Multivalent diarrhea vaccines will likely be more cost-effective if they are effective against rotavirus, norovirus, and other enteropathogens, such as sapovirus [116], which contribute significantly to diarrheal disease. Further, as climate change increases the incidence of diarrhea disease in the tropics, we will need to develop forecasting methods in order to develop appropriate interventions and plan health services [117].

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Acknowledgements

None.

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Financial support and sponsorship

S.B.B. received support from the Fogarty International Center through the Fogarty Global Health Fellows UJMT Consortium (1R25 TW009340-01), U.S. Fulbright Program, Pat Tillman Foundation, Thrasher Research Fund Early Career Award, American Society of Tropical Medicine and Hygiene Centennial Award, Procter & Gamble Fellowship, and R. Bradley Sack Family Award. M.S. received support from the Sixth Framework Programme of the European Union, Project CONTENT INCO-CT-2006-032136, Population Health Metrics Research Consortium Project, and the Centers for Disease Control and Prevention. R.H.G. received support from National Institute of Allergy and Infectious Diseases grant number R21 AI099737.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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37▪▪. Hickman D, Jones MK, Zhu S, et al. The effect of malnutrition on norovirus infection. mBio 2014; 5:e01032-13.

Mouse model of the effect of malnutrition on norovirus infection demonstrates that malnourished mice develop more severe disease and fail to mount effective memory immunity to a secondary challenge, and both norovirus and malnutrition independently alter the gut microbiota.

38▪▪. The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments. Clin Infect Dis 2014; 59 (Suppl 4):S193–S206.

Description of the design and rationale behind the MAL-ED cohort study, which evaluates the interplay of enteric infection, undernutrition, child development, gut physiology, and the immune response to childhood vaccines.

39▪. Richard SA, Barrett LJ, Guerrant RL, et al. Disease surveillance methods used in the 8-site MAL-ED cohort study. Clin Infect Dis 2014; 59 (Suppl 4):S220–S224.

Description of the methods for collecting illness and treatment history data for the MAL-ED study. This is important for planning similar studies and comparing study results.

40▪. Houpt E, Gratz J, Kosek M, et al. Microbiologic methods utilized in the MAL-ED cohort study. Clin Infect Dis 2014; 59 (Suppl 4):S225–S232.

Article aimed at harmonizing micribiological protocols for testing for a range of pathogens, providing quality assurance between multiple study sites, and identifying cost-effective assays for the MAL-ED cohort.

41▪. Platts-Mills JA, McCormick BJ, Kosek M, et al. Methods of analysis of enteropathogen infection in the MAL-ED Cohort Study. Clin Infect Dis 2014; 59 (Suppl 4):S233–S238.

Provides the rationale and approach to evaluating diarrhea cause using a prospective cohort design and accounting for coinfections during data analysis.

42. Ahmed T, Mahfuz M, Islam MM, et al. The MAL-ED cohort study in Mirpur, Bangladesh. Clin Infect Dis 2014; 59 (Suppl 4):S280–S286.
43. Lima AA, Oria RB, Soares AM, et al. Geography, population, demography, socioeconomic, anthropometry, and environmental status in the MAL-ED cohort and case-control study Sites in Fortaleza, Ceara, Brazil. Clin Infect Dis 2014; 59 (Suppl 4):S287–S294.
44. John SM, Thomas RJ, Kaki S, et al. Establishment of the MAL-ED birth cohort study site in Vellore, Southern India. Clin Infect Dis 2014; 59 (Suppl 4):S295–S299.
45. Shrestha PS, Shrestha SK, Bodhidatta L, et al. Bhaktapur, Nepal: the MAL-ED birth cohort study in Nepal. Clin Infect Dis 2014; 59 (Suppl 4):S300–S303.
46. Turab A, Soofi SB, Ahmed I, et al. Demographic, socioeconomic, and health characteristics of the MAL-ED network study site in rural Pakistan. Clin Infect Dis 2014; 59 (Suppl 4):S304–S309.
47. Yori PP, Lee G, Olortegui MP, et al. Santa Clara de Nanay: the MAL-ED cohort in Peru. Clin Infect Dis 2014; 59 (Suppl 4):S310–S316.
48. Bessong PO, Nyathi E, Mahopo TC, Netshandama V. Development of the Dzimauli community in Vhembe District, Limpopo province of South Africa, for the MAL-ED cohort study. Clin Infect Dis 2014; 59 (Suppl 4):S317–S324.
49. Mduma ER, Gratz J, Patil C, et al. The etiology, risk factors, and interactions of enteric infections and malnutrition and the consequences for child health and development study (MAL-ED): description of the Tanzanian site. Clin Infect Dis 2014; 59 (Suppl 4):S325–S330.
50▪. Lang D. Opportunities to assess factors contributing to the development of the intestinal microbiota in infants living in developing countries. Microb Ecol Health Dis 2015; 26:28316.

Discusses factors that should be considered when evaluating interventions designed to improve child health and development in resource-poor settings, including breastfeeding, prelacteal feeding, poor water quality and sanitation, enteric coinfections, and antibiotic use.

51▪. Hoest C, Seidman JC, Pan W, et al. Evaluating associations between vaccine response and malnutrition, gut function, and enteric infections in the MAL-ED cohort study: methods and challenges. Clin Infect Dis 2014; 59 (Suppl 4):S273–S279.

Outlines the challenges of measuring the immune response to oral and parenteral vaccines in the MAL-ED cohort, including the evaluation of illness, growth, intestinal physiology, pathogen infection, diet, and micronutrient status.

52▪. Keusch GT, Denno DM, Black RE, et al. Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences. Clin Infect Dis 2014; 59 (Suppl 4):S207–S212.

Review of the challenges of assessing intestinal function and diagnosing enteropathy in young children in developing settings.

53▪▪. Kosek M, Guerrant RL, Kang G, et al. Assessment of environmental enteropathy in the MAL-ED cohort study: theoretical and analytic framework. Clin Infect Dis 2014; 59 (Suppl 4):S239–S247.

Presents a framework for understanding the relationship between infection, nutrition, and gut function, in addition to providing the rationale for selecting certain tests to evaluate gut function in the MAL-ED study.

54. Denno DM, VanBuskirk K, Nelson ZC, et al. Use of the lactulose to mannitol ratio to evaluate childhood environmental enteric dysfunction: a systematic review. Clin Infect Dis 2014; 59 (Suppl 4):S213–S219.
55. Murray-Kolb LE, Rasmussen ZA, Scharf RJ, et al. The MAL-ED cohort study: methods and lessons learned when assessing early child development and caregiving mediators in infants and young children in 8 low- and middle-income countries. Clin Infect Dis 2014; 59 (Suppl 4):S261–S272.
56▪▪. Osborne LC, Monticelli LA, Nice TJ, et al. Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation. Science (New York, NY) 2014; 345:578–582.

Describes how helminth coinfection impairs immunity to enteric viral infection via a pathway of innate immunomodulation independent of changes in the gut microbiota.

57▪▪. Maizels RM, Gause WC. Immunology. How helminths go viral. Science (New York, NY) 2014; 345:517–518.

Explains the helminth-induced pathways of enhanced viral infection proposed by Osborne and Reese et al.

58. Walk ST, Blum AM, Ewing SA, et al. Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflam Bowel Dis 2010; 16:1841–1849.
59. Rausch S, Held J, Fischer A, et al. Small intestinal nematode infection of mice is associated with increased enterobacterial loads alongside the intestinal tract. PloS One 2013; 8:e74026.
60. Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 2013; 13:607–614.
61▪. Kjetland EF, Hegertun IE, Baay MF, et al. Genital schistosomiasis and its unacknowledged role on HIV transmission in the STD intervention studies. Intern J STD AIDS 2014; 25:705–715.

Study that illustrates how unacknowleged infections can bias study results and obscure the findings of clinical trials. This is relevant to norovirus in developing settings where coinfections frequently occur.

62. Liu J, Gratz J, Amour C, et al. A laboratory-developed TaqMan Array Card for simultaneous detection of 19 enteropathogens. J Clin Microbiol 2013; 51:472–480.
63▪. Platts-Mills JA, Gratz J, Mduma E, et al. Association between stool enteropathogen quantity and disease in Tanzanian children using TaqMan array cards: a nested case-control study. Am J Trop Med Hyg 2014; 90:133–138.

Describes a method to quantitatively measure norovirus infection in order to refine the assessment of the association between pathogen detection and disease in endemic settings.

64. Rao MR, Naficy AB, Savarino SJ, et al. Pathogenicity and convalescent excretion of Campylobacter in rural Egyptian children. Am J Epidemiol 2001; 154:166–173.
65. Simmons K, Gambhir M, Leon J, Lopman B. Duration of immunity to norovirus gastroenteritis. Emerg Infect Dis 2013; 19:1260–1267.
66▪▪. Taniuchi M, Sobuz SU, Begum S, et al. Etiology of diarrhea in Bangladeshi infants in the first year of life analyzed using molecular methods. J Infect Dis 2013; 208:1794–1802.

Describes a probabilistic method of anlyzing longitudinally collected quantitative enteropathogen data. This offers an alternative to attributable fraction methods used by other cohort studies.

67. Harvey K, Esposito DH, Han P, et al. Surveillance for travel-related disease: GeoSentinel Surveillance System, United States, 1997–2011. Morbid Mortal Wkly Rep. Surveillance Summaries 2002; 62:1–23.
68. de la Cabada Bauche J, Dupont HL. New developments in traveler's diarrhea. Gastroenterol Hepatol 2011; 7:88–95.
69▪. Youmans BP, Ajami NJ, Jiang ZD, et al. Characterization of the human gut microbiome during travelersdiarrhea. Gut Microbes 2015; 6:110–119.

Analysis of gut microbiota in healthy individuals, asymptomatic travelers and travelers with diarrhea associated with ETEC, norovirus, and mixed infections.

70▪. Beckmann C, Heininger U, Marti H, Hirsch HH. Gastrointestinal pathogens detected by multiplex nucleic acid amplification testing in stools of pediatric patients and patients returning from the tropics. Infection 2014; 42:961–970.

Analysis of multiplex nuceic amplification testing that provides stool prevalences of 15 diarrhea-associated pathogens in children and adults returning from the tropics with gastroenteritis.

71. Gonzaga VE, Ramos M, Maves RC, et al. Concurrent outbreak of norovirus genotype I and enterotoxigenic Escherichia coli on a U.S. Navy ship following a visit to Lima, Peru. PloS One 2011; 6:e20822.
72. Paschke C, Apelt N, Fleischmann E, et al. Controlled study on enteropathogens in travellers returning from the tropics with and without diarrhoea. Clin Microbiol Infect 2011; 17:1194–1200.
73. Teunis PF, Moe CL, Liu P, et al. Norwalk virus: how infectious is it? J Med Virol 2008; 80:1468–1476.
74. Thebault A, Teunis PF, Le Pendu J, et al. Infectivity of GI and GII noroviruses established from oyster related outbreaks. Epidemics 2013; 5:98–110.
75▪. Kirby AE, Teunis PF, Moe CL. Two human challenge studies confirm high infectivity of Norwalk virus. J Infect Dis 2015; 211:166–167.

Analysis of methods used to evaluate norovirus infectivity in two separate challenge studies. They conclude that the apparent difference in results are due to different statistical approaches and the results of the two studies are consistent.

76▪. Atmar RL, Opekun AR, Gilger MA, et al. Determination of the 50% human infectious dose for Norwalk virus. J Infect Dis 2014; 209:1016–1022.

Estimates a norovirus human infectious dose 50% of 18.2 genomic equivalents (95% confidence interval 1.03−4350) using dose-response data from a norovirus challenge study.

77. Beaumier L. The Vessel Sanitation Program: government partnering with the cruise ship industry to improve public health. J Environ Health 2007; 70:53–55.
78. Cramer EH, Gu DX, Durbin RE. Vessel Sanitation Program Environmental Health Inspection T. Diarrheal disease on cruise ships, 1990–2000: the impact of environmental health programs. Am J Prev Med 2003; 24:227–233.
79. Riddle MS, Smoak BL, Thornton SA, et al. Epidemic infectious gastrointestinal illness aboard U.S. Navy ships deployed to the Middle East during peacetime operations: 2000–2001. BMC Gastroenterol 2006; 6:9.
80. Gastrointestinal infections, active component, U.S. Armed Forces, 2002–2012. MSMR 2013; 20:7–11.
81. Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during Operation Desert Shield. N Engl J Med 1991; 325:1423–1428.
82. McCarthy M, Estes MK, Hyams KC. Norwalk-like virus infection in military forces: epidemic potential, sporadic disease, and the future direction of prevention and control efforts. J Infect Dis 2000; 181 (Suppl 2):S387–S391.
83. DeMaio J, Bailey L, Hall K, Boyd R. A major outbreak of foodborne gastroenteritis among Air Force personnel during Operation Desert Storm. Military Medicine 1993; 158:161–164.
84. Ahmad K. Norwalk-like virus attacks troops in Afghanistan. Lancet Infect Dis 2002; 2:391.
85. Bailey MS, Gallimore CI, Lines LD, et al. Viral gastroenteritis outbreaks in deployed British troops during 2002-7. J Royal Army Medical Corps 2008; 154:156–159.
86. Outbreak of acute gastroenteritis associated with Norwalk-like viruses among British military personnel: Afghanistan, May 2002. MMWR Morbid Mortal Wkly Rep 2002; 51:477–479.
87. Matson DO. Norovirus gastroenteritis in US Marines in Iraq. Clin Infect Dis 2005; 40:526–527.
88. Delacour H, Dubrous P, Koeck JL. Noroviruses: a challenge for military forces. J Royal Army Medical Corps 2010; 156:251–254.
89. Bailey MS, Boos CJ, Vautier G, et al. Gastroenteritis outbreak in British troops. Iraq Emerg Infect Dis 2005; 11:1625–1628.
90. Vesikari T, Blazevic V. Norovirus vaccine: one step closer. J Infect Dis 2015; 211:853–855.
91. Debbink K, Lindesmith LC, Baric RS. The state of norovirus vaccines. Clin Infect Dis 2014; 58:1746–1752.
92. El-Kamary SS, Pasetti MF, Mendelman PM, et al. Adjuvanted intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that express homing receptors for mucosal and peripheral lymphoid tissues. J Infect Dis 2010; 202:1649–1658.
93. Atmar RL, Bernstein DI, Harro CD, et al. Norovirus vaccine against experimental human Norwalk Virus illness. N Engl J Med 2011; 365:2178–2187.
94▪. Treanor JJ, Atmar RL, Frey SE, et al. A novel intramuscular bivalent norovirus virus-like particle vaccine candidate: reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults. J Infect Dis 2014; 210:1763–1771.

Phase I trial of this two-dose intramuscular bivalent vaccine containing a GI.1 and a GII.4 consensus VLP demonstrates vaccine was well tolerated and immunogenic with a rapid immune response to the first dose, indicating a single dose may be effective for military personnel, travelers, and outbreak control.

95▪▪. Bernstein DI, Atmar RL, Lyon GM, et al. Norovirus vaccine against experimental human GII.4 virus illness: a challenge study in healthy adults. J Infect Dis 2015; 211:870–878.

Heterologous GII.4 virus challenge study of individuals vaccinated with the intramuscular bivalent GI.1/GII.4 consensus VLP vaccine provides 100% protection against severe gastroenteritis symptoms, but was not protective against infection.

96. Blazevic V, Lappalainen S, Nurminen K, et al. Norovirus VLPs and rotavirus VP6 protein as combined vaccine for childhood gastroenteritis. Vaccine 2011; 29:8126–8133.
97▪▪. Tamminen K, Lappalainen S, Huhti L, et al. Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice. PloS One 2013; 8:e70409.

Trivalent mouse diarrhea vaccine consisting of GI.3 and GII.4 VLPs and tubular rotavirus recombinant VP6 demonstrates broader norovirus cross-reactivity than either norovirus VLP alone. This article introduces the concept of a combined diarrhea vaccine against rotavirus and norovirus.

98. Velasquez LS, Shira S, Berta AN, et al. Intranasal delivery of Norwalk virus-like particles formulated in an in situ gelling, dry powder vaccine. Vaccine 2011; 29:5221–5231.
99. Fang H, Tan M, Xia M, et al. Norovirus P particle efficiently elicits innate, humoral and cellular immunity. PloS One 2013; 8:e63269.
100. Tan M, Huang P, Xia M, et al. Norovirus P particle, a novel platform for vaccine development and antibody production. J Virol 2011; 85:753–764.
101. LoBue AD, Lindesmith L, Yount B, et al. Multivalent norovirus vaccines induce strong mucosal and systemic blocking antibodies against multiple strains. Vaccine 2006; 24:5220–5234.
102. Wang L, Huang P, Fang H, et al. Polyvalent complexes for vaccine development. Biomaterials 2013; 34:4480–4492.
103. Tacket CO, Sztein MB, Losonsky GA, et al. Humoral, mucosal, and cellular immune responses to oral Norwalk virus-like particles in volunteers. Clin Immunol (Orlando, Fla) 2003; 108:241–247.
104. von Bubnoff A. A gut response to vaccines. IAVI Rep: newsletter on international AIDS vaccine research 2011; 15:12–14.
105. Qadri F, Bhuiyan TR, Sack DA, Svennerholm AM. Immune responses and protection in children in developing countries induced by oral vaccines. Vaccine 2013; 31:452–460.
106. Lopman BA, Pitzer VE, Sarkar R, et al. Understanding reduced rotavirus vaccine efficacy in low socio-economic settings. PloS One 2012; 7:e41720.
107▪▪. Haque R, Snider C, Liu Y, et al. Oral polio vaccine response in breast fed infants with malnutrition and diarrhea. Vaccine 2014; 32:478–482.

Longitudinal birth cohort study demonstrates diminished serum neutralizing response to oral poliovirus vaccine, but not to intramuscularly administered vaccines, was associated with malnutrition, diarrhea, and shorter breastfeeding duration.

108▪. Shioda K, Kambhampati A, Hall AJ, Lopman BA. Global age distribution of pediatric norovirus cases. Vaccine 2015; [Epub ahead of print].

Systematic review finding that the majority of pediatric norovirus cases occurred between 6 and 24 months of age with a younger age distribution in lower income countries and inpatient settings. This suggests that norovirus vaccines would need to be delivered by 6 months of age in order to prevent most childhood norovirus cases.

109▪▪. Mirelman AJ, Ballard SB, Saito M, et al. Cost-effectiveness of norovirus vaccination in children in Peru. Vaccine 2015; 33:3084–3091.

Markov decision model evaluating the cost-effectiveness of a potential pediatric norovirus vaccine in Peru finding that a norovirus vaccine would prevent many poor health outcomes and healthcare utilization costs, which could make it cost-effective under certain conditions. This model could be applied to other populations in LMIC settings.

110▪. Rapoport LB, Colquechagua Aliaga FD, Mirelman AJ, et al. Food insecurity and indirect costs of medically attended gastroenteritis in children younger than five years of age in a ‘postrotavirus’ setting. 63rd Annual Meeting of the American Society of Tropical Medicine and Hygiene 2014; p. 636.

Pilot study evaluating out-of-pocket costs and food insecurity in households of children presenting to the National Children's Hospital in Peru with diarrhea found that the median estimated total indirect costs of a diarrheal episode was $75 (median household income $306). As a result of time and money lost due to the diarrheal episode, 70% of caregivers reported being worried about not having enough money for food, and 17% reported not having enough money to buy food. Significant indirect costs are incurred from a single diarrhea episode and contributed to food insecurity in a segment of this population.

111▪▪. Tallant A, Porter CK, Putnam SD, et al. Relative cost-effectiveness of a norovirus vaccine in the deployed military setting compared to a vaccine against Campylobacter sp., ETEC, and Shigella sp. Vaccine 2014; 32:5156–5162.

Cost-effectiveness analysis in a military population estimates a potential vaccine cost-effectiveness ratio per duty day lost to illness of $776, $800, $1,275, and $1,344 for ETEC, Campylobacter, Shigella, and norovirus using a diarrhea-based case definition, and $572 for norovirus using a gastroenteritis-based case definition. Norovirus vaccines could be cost saving or cost-effective in military populations.

112. Riddle MS, Tribble DR. Reaching a consensus on management practices and vaccine development targets for mitigation of infectious diarrhoea among deployed US military forces. J Eval Clin Pract 2008; 14:266–274.
113. Riddle MS, Tribble DR, Cachafiero SP, et al. Development of a travelersdiarrhea vaccine for the military: how much is an ounce of prevention really worth? Vaccine 2008; 26:2490–2502.
114▪. Kambhampati A, Koopmans M, Lopman BA. Burden of norovirus in healthcare facilities and strategies for outbreak control. J Hosp Infect 2015; 89:296–301.

Review reports that excess mortality occurs during norovirus outbreak periods in healthcare facilities.

115▪. Jauregui B, Garcia AG, Bess Janusz C, et al. Evidence-based decision-making for vaccine introductions: overview of the ProVac International Working Group's experience. Vaccine 2015; 33 (Suppl 1):A28–A33.

Overview of the Pan American Health Organization's ProVac Initiative, which aims to strengthen LMIC's technical capacity to make evidence-based immunization policy by providing cost-effectiveness analysis tools. A tool specific to norovirus vaccine cost-effectiveness would be useful for LMIC decision makers interested in evaluating future norovirus vaccine implementation strategies.

116. Oka T, Wang Q, Katayama K, Saif LJ. Comprehensive review of human sapoviruses. Clin Microbiol Rev 2015; 28:32–53.
117. Checkley W, Epstein LD, Gilman RH, et al. Effect of El Nino and ambient temperature on hospital admissions for diarrhoeal diseases in Peruvian children. Lancet 2000; 355:442–450.
Keywords:

calicivirus; diarrhea; gastroenteritis; low-income and middle-income country; norovirus; travelers; vaccine

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