Table 7.

Overview of studies that address the potential value of a norovirus vaccine on health, social and economic impacts on disease burden and transmission.

Policy question	Assessment method/measure	Additional information specific to models	Assumptions	Outcomes/interpretation
Understand the transmission dynamics of norovirus and to predict the likely impact of vaccination.	Dynamic age-specific mathematical model of norovirus transmission and vaccination.	Model fitted to age-stratified time series case notification data available from Germany. Includes the use of a self-reporting Markov model to account for variation by age and over time in the statutory reporting of norovirus in Germany. The model uses a sequential Monte Carlo particle filter. The estimated model was then extended and applied to investigate the potential impact of a range of immunization strategies. Sensitivity analyses were performed on the mode of vaccine action and other vaccine-related parameters.	SEIR-type model with maternal immunity and vaccinated classes Asymptomatic contribute to transmission greater than 90 % coverage for children; 50 % for elderly 50 % VE for kids; 70 % for elderly Duration of protection 5 years	Routine immunization could reduce the incidence of norovirus by up to 70.5 % even when those vaccines do not provide complete protection from disease. Relative efficiency of alternative strategies targeting different age groups are dependent on the outcome. Results sensitive to assumptions on the mode of vaccine action [75].
Which age groups should be vaccinated to maximize population impact?	Deterministic, age-structured compartmental model of norovirus transmission and immunity in the U.S. population.	Model was fit to age-specific monthly norovirus-associated U.S. hospitalizations between 1996 and 2007 Simulated mass immunization ofbothpediatric and elderly populations	Assumed coverages of 90 % and 65 %, for pediatric and elderly populations respectively. Considered two mechanisms of vaccine action, resulting in lower vaccine efficacy (lVE) between 22 % and 43 % and higher VE (hVE) of 50 % Maternal immunity is short-lived and negligible Vaccine response was “take-type:”	Pediatric vaccination was predicted to avert 33 % (95 % CI: 27 %, 40 %) and 60 % (95 % CI: 49 %, 71 %) of norovirus episodes among children under five years for lVE and hVE, respectively. Vaccinating the elderly averted 17 % (95 % CI: 12 %, 20%) and 38 % (95 % CI: 34 %, 42 %) of cases in 65 + year old individuals for lVE and hVE, respectively. At a population level, pediatric vaccination was predicted to avert 18–21 times more cases and twice as many deaths per vaccine compared to vaccination of the elderly. Potential benefits are likely greater for a pediatric program, both via direct protection of vaccinated children and indirect protection of unvaccinated individuals, including adults and the elderly [76].
Is pediatric norovirus vaccination cost- effective in daycare settings?	Transmission-model-based cost-effectiveness analysis	A dynamic SEIR-like transmission model of norovirus outbreaks in daycare settings was calibrated to NORS outbreak data and adapted to include vaccination. The model incorporated detailed dynamics of pediatric transmission within daycare settings (including infection via human-to-human and fomite-to-human contacts). The economic analysis utilized an incremental cost-effectiveness ratio to compare costs and QALYS of vaccination and no vaccination (observed standard of care only, in which symptomatic children are excluded from daycare). The model did not include secondary transmission outside of daycare centers.	Vaccination Assumptions 90% vaccination coverage Compared 50% and 80% all-or-nothing vaccination efficacy Vaccination in addition to standard of care (exclusion of symptomatic children from childcare) Two-year modelling period Cost Analysis Assumptions From a societal perspective (including child medical costs and loss of productivity to parents). Two-year time horizon	Primary Outcomes: Due to large burden of disease, vaccinating children in daycares would likely be cost-effective. Norovirus vaccination is more costly than the standard of care but leads to more QALYs than the standard of care. Vaccination leads to modest reduction in costs to manage norovirus infections, but primarily gains QALYS (gains 253 QALYS per 10,000 children). Similar cost-effectiveness ratio to other recommender childhood vaccines. Health Outcomes: 50% efficacious vaccine averts 571.83 norovirus cases per 10,000 children and 0.003 norovirus-related deaths. Costs, incremental cost-effectiveness ratio (ICER): 50% efficacious vaccine at $200/vaccination series results in net cost increase of $178.10 per child, with an ICER of $7028/QALY Based on probabilistic sensitivity analysis, Willingness-to-pay $100,000/QALY: 94.0% likely to be cost effective Even with cost of $500 per child vaccinated and modest efficacy of 50%, vaccination is likely to be cost-effective (86.7%) at threshold of $100,000 per additional QALY ICERs most sensitive to probability of norovirus introduction within the vaccination efficacy period, days in supportive care, and quality-of-life being in supportive care [77]
Clinical impact and cost effectiveness thresholds for vaccinating children or older adults in community settings	Age-structured compartmental transmission model and cost effectiveness analysis.	Norovirus Model: Compartmental SEIR- like transmission model with 4 age groups: preschool-aged children (0–4 years), school-aged children (5–17 years), adults (18 – 64 years) and older adults (> 65 years) applied to the US Cost estimates: Compared third payer perspective, including all direct medical costs, to societal perspective included direct and indirect (productivity losses) costs. Calculated ICER use of QALYs and DALYs. Sensitivity analysis: Monte Carlo simulations of 2000 trials, sensitivity in terms of population size, vaccine cost, vaccine efficacy, and vaccine coverage (population of 2500 to 7500 people). Model Calibration: Calibrated model to US population incidence and age-specific incidence trends.	Vaccine and natural infection assumed to provide protection from symptomatic illness for one year. Assumed productivity losses for all symptomatic norovirus infections and modelled annual norovirus vaccination. ICER based on willingness-to-pay threshold of $50,000/QALY	Vaccination coverage as low as 10% can provide clinical and economic benefits Health outcomes with varying vaccine efficacy (25%—75%) and vaccination coverage (10%—80%): Vaccinating preschool-aged children averted 8–72% of symptomatic cases in community Vaccinating older adults averted 2% — 29% of symptomatic cases Vaccine is cost effective at higher cost thresholds for vaccinating preschool-aged children compared to vaccinating older adults alone (cost thresholds below using societal perspective): Vaccinating children: Low efficacy (25%) vaccine was cost effective at ≤ $445, cost saving at ≤ $370; higher efficacy (75%) vaccine was cost effective at ≤ $1600, cost saving at ≤ $1300 per vaccinated person (including vaccine, administration and associated costs) Vaccinating older adults: Low efficacy (25%) vaccine was cost effective at <$42 and cost saving at < $30, higher efficacy (75%) vaccine was cost effective at < $165 and cost saving at < $100 per vaccinated person (including vaccine, administration and associated costs) Thresholds were substantially lower from the third-party payer perspective, given that the majority of savings from averted cases are a result of reduced productivity losses [78].
Cost effectiveness of norovirus vaccine compared to other enteric vaccines for military use	Modified version of an economic model developed to evaluate the cost-effectiveness of a vaccine acquisition strategy within the Department of Defense adapted to norovirus.	Cost-effectiveness analysis for use of nor- ovirus vaccine in the military using a previously developed model that evaluated vaccines for ETEC, Campylobacter, and Shigella for the prevention of non-outbreak associated travelers’ diarrhea. One-way sensitivity analysis performed using high and low values for each input variable.	Duty days lost to acute gastroenteritis chosen as an outcome measure Incidence of norovirus-attributable illness based on systematic review of incidence of sporadic travelers’ diarrhea cases in a deployed military setting Troops vaccinated prior to every deployment based on current predeployment vaccine coverage rates Vaccine coverage: 75% Vaccine efficacy: 80% Did not consider potential for herd immunity or value of preventing domestically-acquired infection Considered purchase price of vaccine ($28.59/dose), administrative costs ($2.96/dose), and costs oftreating a vaccine-associated adverse event. One-year time horizon chosen for this model and 2013 USD costs.	Absolute cost-effectiveness of a norovirus vaccine appears to be favorable: Norovirus cost effectiveness equivalent to Shigella but not as favorable as an ETEC of Campylobacter vaccine. When adjusting case definition to account for vomiting predominant illness, the cost-effectiveness ratio per duty day lost to illness (CERDDL) for norovirus vaccine is $572, which makes it the most cost effective. The CERDDL of $1,344 compared to $776 for ETEC, $800 for Campylobacter, and $1,275 for Shigella. Norovirus vaccine adoption by the DoD could prevent 12,490 cases of gastroenteritis annually during deployment. After norovirus vaccine introduction, the number of duty days lost due to gastroenteritis predicted to drop from 4,930 to 986 per year. Annual total cost of care after norovirus vaccine introduction predicted to drop from $1,952,500 to $292,875. Total annual cost of vaccination of $6,956,775 at $60.14/vaccine administered. Sensitivity analysis: 48% of variation in the economic model accounted for by inverse relationship between duration of deployment and cost-effectiveness. Increasing duration of deployment to a year leads to norovirus vaccine cost-effectiveness approaches a cost-neutral threshold when medical treatment costs alone are considered Other most influential parameters include pathogen prevalence, incidence, coverage, probability of seeking medical treatment [52].
Cost effectiveness of norovirus vaccination in LMIC military population	Adapted economic model developed by the United States Department of Defense to evaluate cost-effectiveness of vaccine acquisition strategies utilizing a static decision tree model to compare cost-effectiveness of vaccine implementation.	Evaluated the cost-effectiveness of vaccine acquisition and implementation for norovirus, Campylobacter, ETEC, and Shigella compared with current medical management. The cost effectiveness ratio was calculated based on (1) the pathogen-specific gastroenteritis prevalence, management approaches, and treatment costs; (2) the cost of administering the vaccine in the Peruvian military population, and (3) the duty days lost to gastroenteritis averted by vaccination. Performed a one-way sensitivity analysis using high and low values for each parameter.	Cost effectiveness analysis performed in the context of the Peruvian armed forces (population of LMIC adults with high incidence of infectious gastroenteritis) for a one-year time horizon in 2019 costs. Vaccine Assumptions: Imperfect vaccine efficacy could protect from gastroenteritis or susceptibility to the pathogens Assumed vaccine administration before each deployment to account for waning immunity Vaccine Efficacy: 80% (minimal military parameter requirements) Vaccine associated costs: purchase price of two dose vaccine, program administration costs, adverse event treatments Vaccine cost: $13 per vaccine series (estimated vaccine costs for Peruvian military based on prices of Rotarix)	After Shigella vaccination, norovirus vaccination was most-cost-effective in preventing gastroenteritis-associated DDL (then ETEC and Campylobacter), suggesting that norovirus military vaccination should be prioritized. Norovirus cost effectiveness estimates compare favorably to US estimates of nor- ovirus vaccine cost effectiveness in the military, suggesting that norovirus vaccine may be cost effective in the Peruvian military. Norovirus vaccination for the Peruvian military could prevent 3870 cases of gastroenteritis and decrease norovirus- associated duty days lost from 940 to 368 days. Reduction in total annual cost of gastroenteritis care from $25.942 to $17,013 annually. Cost per duty day lost averted: $803; cost per diarrheal day averted: $199 Model outcomes were most sensitive to length and frequency of individual deployments, with longer, more frequent deployments resulting in more exposure and improving cost-effectiveness [79].
Cost-effectiveness of norovirus vaccination in children in LMICs (Peru)	Markov decision model to evaluate cost- effectiveness of a two-dose norovirus vaccine in Peru’s routine childhood immunization schedule based on two recent estimates of NV incidence (one for peri-urban region, one for jungle region).	Evaluated cost-effectiveness of a two- dose norovirus vaccine added to Peru’s routine childhood immunization schedule using a probabilistic three-box Markov model for a Peruvian birth cohort. Conducted a probabilistic sensitivity analysis using Monte Carlo simulation with 20,000 draws. Model does not include the indirect costs of norovirus vaccination nor any additional direct costs of self-treatment or home care (which may be significant), also model does not account for indirect benefits attributable to reduced shedding in the community, reduced disease transmission	Based health effects on norovirus diarrhea incidence data from community-level study in peri-urban area of Lima and rural jungle diarrheal surveillance site in the Amazon Basin. Assumed diarrheal incidence at 5 years old was half that at 12 – 24 months and declined linearly with time. For healthcare costs associated with norovirus, used weighted averages of urban and rural treatment costs. Assumed 85% norovirus vaccination coverage with a two-dose vaccine with 47% efficacy against diarrhea within Peru’s routine childhood immunization schedule (similar to the rotavirus vaccine). Estimated cost of $13.19 per dose (based on cost estimates for another VLP-based vaccination (HPV)) with no additional vaccination administration costs. Ran model for 60 months, cost effectiveness calculated for children < 5 years old only Costs reported in 2012 USD	Vaccinating young children against nor- ovirus could offer economic value under the right conditions in Peru: Potentially cost effective in scenarios with high norovirus incidence In scenarios with higher norovirus incidence (jungle setting), more favorable cost-effectiveness estimates Strongly dependent on vaccine price and efficacy based on sensitivity analysis With varied incidence rates, cost per DALY averted ranged from $15,616 to $41,512 in peri-urban area and from $4,483 to $14,700 in rural jungle setting. Using a willingness-to-pay threshold of the GDP per capita of Peru ($6242 in 2012), the vaccine would have to be at least 70% effective at the lowest cost of $8.50 per dose to be cost effective. If the vaccine cost $11.20 per dose, vaccine effectiveness would have to be 91% to be cost effective. The annual cost of vaccination would be 13.0 million, with $2.6 million in treatment savings, resulting in the following outcomes: Vaccination could avert 473 DALYS, over 526,000 diarrheal cases, 153,735 outpatient visits, and 414 hospitalizations between birth and the fifth year of life. The ICER for norovirus vaccination would be $21,415 per DALY averted, $19.86 per diarrhea case averted, $68.23 per outpatient visit averted, $26,298 per hospitalization averted [39]
Potential economic value of human norovirus vaccine for the United States	Markov simulation model of vaccine cost- effectiveness from societal perspective (including direct medical costs and indirect costs)	Markov model selected to determine potential impact of vaccine over time (compared to traditional decision tree model) Probabilistic sensitivity analysis (i.e., Monte Carlo simulation) for all parameters One-way sensitivity analysis for vaccine efficacy (25%, 50%, 75%), protection duration (12, 24, 48 months) and vaccine cost ($25, $50, $75)	Norovirus incidence based on community-based study of AGE from England and Wales to estimate age-specific nor- ovirus incidence. Healthcare utilization based on selfreported healthcare utilization for persons with acute diarrheal disease from the US Foodborne Diseases Active Surveillance Network. Model simulations based on 1000 individuals ages 0 to 85. Assumed 43% versus 95% vaccination coverage across every age group.	Norovirus vaccination could be cost effective, depending on price, efficacy, and duration of protection: Vaccine cost-saving for young children with minimal vaccine cost (<$25) Cost of < $1,500/case averted with highest cost ($75) vaccine with efficacy of >50% and protection of 24 months For vaccine providing 48 months protection, costs per case averted was < $700 Clinical outcomes and costs: Vaccination could avert 1.0–2.2 million cases (efficacy 50%, 12-month duration) Vaccine cost $400 million - $1.0 billion Vaccine savings <2.1 billion (48-month duration) Protection duration is an important driver of cost-effectiveness. Children under five are suggested as the most attractive target vaccination population, in terms of cases averted and costs, followed by older adults (>65 years) [48]