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. 2016 Mar 15;13(3):e1001975.
doi: 10.1371/journal.pmed.1001975. eCollection 2016 Mar.

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

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

Joseph T Wu et al. PLoS Med. .
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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.

Conflict of interest statement

BJC has received research funding from MedImmune Inc. and Sanofi Pasteur for studies of influenza vaccine effectiveness, and BJC has consulted for Crucell NV on influenza prevention. None of these companies manufacture EV71 vaccines. All other authors have declared that no competing interests exist.


Fig 1
Fig 1. Model structure and parameterization.
(A) The static model used in the CEA with vaccine coverage θ and vaccine efficacy ε. (B) A schematic that describes how the data sources were used to parameterize the model. See S1 Text for more details. QALY, quality-adjusted life year.
Fig 2
Fig 2. Estimating the percentage of mild and severe HFMD cases attributed to EV71 in China.
(A) The number of specimens tested and the distribution of test results in each of the 31 provinces during 2010–2013. (B) Twenty-one scenarios were generated by making assumptions regarding the percentage of test-negative cases that were mild during 2010–2012 (the first branching point; annotated in red text) and the percentage of test-negative mild and severe/fatal cases that were EV71 during 2010–2013 (the second branching point; annotated in yellow and blue shades), respectively. The outcomes in the three scenarios colored in cyan were identical; hence, there were only 19 unique scenarios (labeled A–S). The base case (scenario A) is colored in pink. The sizes of the wedges illustrate the underlying assumptions and are not proportional to the actual percentages (the differences in serotype and severity distribution for severe/fatal cases between scenarios would not be apparent otherwise because the number of mild cases was much larger than that of severe/fatal cases).
Fig 3
Fig 3. The risk, expected costs, and health utility loss of EV71-HFMD per birth in the base case.
Error bars indicate 95% CIs. (A) Risk of mild, severe, and fatal EV71-HFMD. The 95% CIs are annotated because they are not graphically apparent. (B) Expected costs and health utility loss attributable to EV71-HFMD stratified by severity. To indicate the relative contribution of cost and health utility loss in EVCmax, health utility loss was expressed in monetary terms as the product of QALY loss and willingness-to-pay threshold, which is set at one times GDPpc (US$6,700). (C) Percentage breakdown of EVCmax.
Fig 4
Fig 4. Cost-effectiveness of routine pediatric EV71 vaccination in China with a willingness-to-pay threshold of one times GDPpc.
The 21 scenarios from Fig 2 are listed along the x-axis in ascending order of EVCmax. The base case was scenario A, which had the lowest EVCmax. The color shades at the bottom indicate the assumptions regarding the percentage of test-negative cases that were mild during 2010–2012 (bottom row), the percentage of test-negative severe/fatal cases that were EV71-HFMD (middle row), and the percentage of test-negative mild cases that were EV71-HFMD (top row) in each scenario, where darker shades correspond to higher percentages. As described in Fig 2B, three combinations of these percentages resulted in the same scenario, namely scenario E. The size of the 95% prediction intervals was driven by the parametric uncertainty associated with our estimates of the risk of EV71-HFMD and the mean cost and QALY loss attributed to EV71-HFMD in our probability sensitivity analysis (as in Fig 2B). (A) Pediatric EV71 vaccination would be cost-saving and cost-effective if EVC was below the cost of EV71-HFMD (blue bars) and EVCmax (blue plus green bars), respectively. (B–D) The risk of mild, severe, and fatal EV71-HFMD in each scenario. The error bars show the 95% CIs, but in some cases they are not apparent for the risk of mild and severe EV71-HFMD.
Fig 5
Fig 5. Comparative cost-effectiveness analysis of the three vaccine candidates based on the base-case EVCmax.
The color coding indicates the optimal vaccine given the costs of the three vaccines (V Vigoo, V Sinovac, V CAMS).

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