Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis

Background: China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010–2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6–71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China. Methods and Findings: We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7–US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9–US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%–14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%–84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%–19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%–50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010–2013. Conclusions: Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0–US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192–US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known. Using surveillance and survey data, Joseph T. Wu and colleagues assess the cost-effectiveness of routine pediatric EV71 vaccination in China.Background: Since 2007, outbreaks of hand, foot, and mouth disease (HFMD)—a contagious infection that mainly affects young children—have been occurring annually in China. Between 2010 and 2014, China accounted for 9.8 million of the 11.3 million cases of HFMD reported to the World Health Organization (WHO); in 2012, HFMD was the leading notifiable disease in China among children under five years old. HFMD is caused by a group of viruses called enteroviruses that are transmitted through contact with the mucus produced when an infected individual coughs or sneezes, through contact with the feces of an infected person, and through contact with contaminated surfaces. Good hygiene and frequent handwashing can reduce the spread of HFMD. The characteristic symptoms of HFMD are a non-itchy red rash with blisters on the hands and feet and painful mouth ulcers. There is no cure for HFMD, and most infected children get better within 7–10 days. However, some individuals develop potentially fatal complications such as encephalitis (infection and inflammation of the brain). Why Was This Study Done?: In China, enterovirus 71 (EV71) causes most laboratory-confirmed fatal cases of HFMD. Routine vaccination against EV71 during the first few months of life might therefore be one way to reduce China’s HFMD burden. In clinical trials, three inactivated monovalent EV71 vaccines made in China were shown to be safe and highly efficacious against EV71-associated HFMD (inactivated monovalent vaccines contain a single virus strain that cannot replicate; exposure to the vaccine “primes” the immune system to respond quickly when challenged with live virus, thereby preventing infection with that virus). However, before implementing routine EV71 vaccination, it is important to know whether this intervention is a good value for the money it would cost. For example, how much money needs to be spent on vaccination to save one life? In this cost-effectiveness analysis (a study that estimates the costs and health effects of a medical intervention), the researchers assess the value for money of routine vaccination of young children against EV71 in China. What Did the Researchers Do and Find?: The researchers characterized the health and economic burden of EV71-associated HFMD in China using the national surveillance database, HFMD laboratory test results, and information on household costs and health utility loss associated with HFMD cases (health utility is a number that is assigned to a state of health; perfect health and death have utility values of 1 and 0, respectively) collected in a caregiver survey. They then used a mathematical model to estimate the effective vaccine cost (EVC; vaccine cost divided by efficacy) below which routine pediatric vaccination would be cost-effective; WHO defines a cost-effective intervention as one in which the incremental cost-effectiveness ratio (the incremental costs of introducing an intervention divided by the incremental benefits accrued by that introduction) is between one and three times the country’s gross domestic product (GDP) per capita. Routine pediatric vaccination was cost-effective in the researchers’ base-case analysis—which assumed a willingness-to-pay threshold of one times GDP per capita—if the EVC was below US$17.9. Increasing the willingness-to-pay threshold to three times GDP per capita increased the EVC below which routine vaccination would be cost-effective by 58%–84%, whereas excluding consideration of the productivity loss of parents/caregivers while caring for a child with HFMD reduced the EVC below which routine vaccination would be cost-effective by 10%–14%. What Do These Findings Mean?: The validity of these findings depends on the assumptions included in the mathematical model and on the accuracy of the data fed into the model. However, routine pediatric EV71 vaccination remained cost-effective at broadly similar EVCs in sensitivity analyses in which the assumptions built into the model were altered. Overall, these findings suggest that routine pediatric EV71 vaccination would be very cost-effective in China provided the cost of immunization (including the cost of the vaccine and all the logistical and administration costs of vaccination) is below between US$12.0 and US$18.3 per vaccination; because the different vaccines have different efficacies, the exact value depends on which vaccine is used for vaccination. Thus, with 16 million births each year, the annual costs for routine pediatric EV71 vaccination in China should not exceed US$192–US$293 million. Importantly, when combined with the findings of a previous study in which the same researchers showed large geographical variations in the risk of EV71-associated HFMD across China, these findings can help policymakers identify those regions in China where EV71 vaccination is likely to be most cost-effective. 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