Benefit-cost analysis of the policy of mandatory annual ... · Taiwan enforces rabies vaccination in both domestic dogs and 103 cats, and had been rabies-free since 1961 until an

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1 Benefit-cost analysis of the policy of mandatory annual rabies vaccination of

2 domestic dogs in rabies-free Japan

3 (Short title: Dog rabies vaccination policy in Japan)

4 Nigel C. L. Kwan1, Akio Yamada2, Katsuaki Sugiura1,*

5

6 1 Department of Global Agricultural Sciences, Graduate School of Agricultural and

7 Life Sciences, The University of Tokyo, Tokyo, Japan

8 2 Department of Veterinary Medical Sciences, Graduate School of Agricultural and

9 Life Sciences, The University of Tokyo, Tokyo, Japan

10

11

12 *Corresponding author

13 E-mail address: [email protected]

14

15

16

17

18

.CC-BY 4.0 International licenseavailable under awas not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made

The copyright holder for this preprint (whichthis version posted October 19, 2018. ; https://doi.org/10.1101/448258doi: bioRxiv preprint

https://doi.org/10.1101/448258

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19 Abstract

20 Japan is one of the few rabies-free countries/territories which implement the policy

21 of mandatory vaccination of domestic dogs. In order to assess the economic

22 efficiency of such policy in reducing the economic burden of a future canine rabies

23 outbreak in Japan, a benefit-cost analysis (BCA) was performed using probabilistic

24 decision tree modelling. Input data derived from simulation results of published

25 mathematical model, field investigation conducted by the authors at prefectural

26 governments, literature review, international or Japanese database and empirical

27 data of rabies outbreaks in other countries/territories. The current study revealed

28 that the annual costs of implementing the current vaccination policy would be

29 US$160,472,075 (90% prediction interval [PI]: $149,268,935 – 171,669,974). The

30 economic burden of a potential canine rabies outbreak in Japan were estimated to

31 be US$1,682,707 (90% PI: $1,180,289 – 2,249,283) under the current vaccination

32 policy, while it would be US$5,019,093 (90% PI: $3,986,882 – 6,133,687) under

33 hypothetical abolition of vaccination policy, which is 3-fold higher. Under a

34 damage-avoided approach, the annual benefits of implementing the current

35 vaccination policy in expected value were estimated to be US$85.75 (90% PI:

36 $55.73 – 116.89). The benefit-cost ratio (BCR) was estimated to be 5.35 X 10-7 (90%



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37 PI: 3.46 X 10-7 – 7.37 X 10-7), indicating that the implementation of the current policy

38 is very economically inefficient for the purpose of reducing the economic burden of a

39 potential canine rabies outbreak. In worse-case scenario analysis, the BCR would

40 become above 1 (indicating economic efficiency) if the risk of rabies introduction

41 increased to 0.04 corresponding to a level of risk where rabies would enter Japan in

42 26 years while the economic burden of a rabies outbreak under the abolition of

43 vaccination policy increased to $7.53 billion. Best-case analysis further revealed that

44 the economic efficiency of the current policy could be improved by decreasing the

45 vaccination price charged to dog owners, relaxing the frequency of vaccination to

46 every two to three years and implementing the policy on a smaller scale, e.g. only in

47 targeted prefectures instead of the whole Japan.

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55 1. Introduction

56 Since 1958, Japan has been free from animal rabies, i.e. classical rabies virus (RABV),

57 and is one of the few rabies-free countries or territories (under the standards of

58 World Organisation for Animal Health [OIE]) which still implement the policy of

59 mandatory vaccination of domestic dogs [1]. Under the Rabies Prevention Law

60 enacted since 1950, the policy of registration and vaccination of domestic dogs

61 against rabies is enforced by the health departments of prefectural governments

62 under the order of Ministry of Health, Labour and Welfare (MHLW) [1]. Pet owners

63 in Japan are obliged to vaccinate their dogs against rabies every year either by

64 attending private animal clinic anytime during the year or a vaccination campaign

65 organised by prefectural governments and Japan Veterinary Medical Association

66 (JVMA) during April to June. Each year the respective prefectural government would

67 assign the duty and provide a fund to the local Veterinary Medical Association to

68 organise the rabies vaccination campaign mentioned above in multiple cities within

69 the prefecture. In the decade 2007–2016, the reported national vaccination rate

70 averages 73.1%, but the actual vaccination coverage is estimated to be 43.2% when

71 adjusted for an average estimated registration rate of 59.2% during the same period

72 [2, 3].



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73

74 The current risks of rabies re-introduction into Japan have recently been assessed as

75 very low and it would take on average 49,444 years until the introduction of one

76 rabies case through the importation of dogs and cats worldwide due to a strict

77 import regime managed by the Ministry of Agriculture, Forestry and Fisheries of

78 Japan (MAFF) [4, 5]. Further, mathematical simulation model predicted a very low

79 risk of local spread, if rabies were to be introduced into Japan, as the mean outbreak

80 size was estimated to be 3.1 and 4.7 dogs in Hokkaido and Ibaraki Prefectures,

81 respectively [6]. Together with the low owner compliance mentioned above, massive

82 debate has been raised in the country over whether the current annual rabies

83 vaccination policy in domestic dogs should be maintained.

84

85 The main advantage of implementing a pre-emptive vaccination policy in a

86 rabies-free setting is that it facilitates a pre-existing herd immunity which could

87 lessen the magnitude or impact of an introduced outbreak. For canine

88 rabies-endemic countries/territories, the World Health Organization (WHO)

89 recommends a minimum 70% vaccination coverage in domestic dog population as

90 the most cost-effective control measure [7]. In contrast, there is no international



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91 standard or well-established guideline on the prevailing conditions that should

92 prompt a rabies-free country to implement a pre-emptive vaccination policy [8].

93 Indeed, major rabies-free countries including United Kingdom, France, Australia and

94 New Zealand are not relying on domestic dog vaccination as a preventive strategy

95 because it is perceived that early detection of suspected rabid animals and an

96 immediate response to contain the outbreak are most important. On the other hand,

97 Hong Kong, a rabies-free territory since 1988, implements the policy of mandatory

98 dog vaccination every three years due to substantial risk of rabies being introduced

99 from China. Malaysia also adopts a dog vaccination policy building a 50 to 80 km

100 immune belt along the border with Thailand; the country had been declared

101 rabies-free since 2012 until 2015 when the disease was introduced most probably

102 from Thailand [9]. Taiwan enforces rabies vaccination in both domestic dogs and

103 cats, and had been rabies-free since 1961 until an epizootic of Chinese ferret-badger

104 started in 2013 [10].

105

106 Benefit-cost analysis (BCA) is an important tool at both a global and national level

107 that illustrates the benefits of disease management projects per dollar spent and

108 determines the economic efficiency of alternative management actions [11]. BCA on



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109 the control interventions against various animal diseases have been conducted,

110 particularly on the oral vaccination against wildlife rabies [12, 13]. The current study

111 aimed to perform a BCA using decision tree modelling to assess the economic

112 efficiency of the current annual rabies vaccination policy in domestic dogs in Japan

113 and serve as a pilot study providing scientific insight into the rationale behind the

114 maintenance of such policy.

115

116 Materials and Methods

117 Decision tree model and cost estimation framework

118 A stochastic decision tree model was constructed comparing two strategies: 1. under

119 the current annual vaccination policy a rabid dog is introduced into Japan resulting in

120 an outbreak and 2. under hypothetical abolition of vaccination policy a rabid dog is

121 introduced into Japan resulting in an outbreak with greater impact (Fig 1). The

122 annual number of dogs and cats imported into Japan worldwide (majority through

123 airplane and a few through ship) is approximately 8,000 and 2,000 through Animal

124 Quarantine Service (AQS) managed by MAFF and United States Force Japan (USFJ),

125 respectively. Therefore, the annual probability of rabies introduction into Japan

126 through these pathways reported previously (P_annual), i.e. 2.57 X 10-5, was input



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127 into the relevant chance nodes of the decision tree, while the effect of any increase

128 in the risk of rabies introduction, e.g. illegal importation, was tested in scenario

129 analysis described below [5]. There are potentially other rabies entry pathways, e.g.

130 via fishing boat, passenger ferry and shipping containers. However, it was assumed

131 that the risk of introduction would not increase significantly even if the base model

132 took into account the risk of introduction through these pathways, which is a

133 reasonable assumption considering the very small number of dogs and cats imported

134 through these pathways and the results of a previous quantitative risk assessment

135 [4]. Finally, it should be noted that rabies introduction via the land route was not

136 considered given that Japan is geographically isolated by the sea. The time horizon of

137 the model was one year and no discount rate was applied to the calculations of

138 benefits and costs. The monetary values reported in the current study were based

139 on the exchange rate of 1 US dollar = 112.17 Japanese yen (2017 World Bank data).

140

141 The present BCA adopted a societal perspective where the benefits and costs of

142 maintaining the current annual rabies vaccination policy were considered for every

143 relevant stakeholder in the community. In essence, such policy was considered to

144 benefit everyone in the community since it could reduce the impact of the outbreak



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145 (in terms of both the number of cases and the duration), hence decreasing the

146 economic burden of the outbreak in terms of lower costs in implementing rabies

147 control measures for the government and lower risk of contracting rabies for the

148 local people (which would lead to fewer people receiving medical treatment and a

149 lower probability of human death). Hence, the benefits of maintaining the current

150 rabies vaccination policy were calculated as incremental benefits using a

151 damage-avoided approach described below. On the contrary, the costs of

152 maintaining the current policy were considered to be borne by dog owners who

153 vaccinate their dogs against rabies (note that they also bear the gross profits made

154 by private animal clinic or JVMA) and the government in providing funds to JVMA to

155 organize the vaccination campaign.

156

157 The annual costs of implementing the rabies vaccination policy and the economic

158 burden of a canine rabies outbreak in Japan were estimated based on published

159 frameworks with specific modifications to accommodate the rabies-free setting of

160 Japan [14, 15]. The authors conducted three investigation trips to Ibaraki, Tokushima

161 and Miyazaki Prefectures during 20 July 2016 to 29 September 2016 and interviewed

162 the prefectural government officials to obtain necessary information regarding local



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163 rabies prevention system. Other data derived from extensive literature review,

164 international or Japanese database and empirical data of rabies outbreaks in Asian

165 countries/territories including Taiwan and Malaysia and European countries such as

166 France and the Netherlands.

167

168 Estimation of the annual costs of implementing the dog rabies

169 vaccination policy in Japan (Costsannual)

170 Direct vaccination costs

171 The key characteristics of companion dog ownership in Japan are summarized in

172 Table 2. In 2015, 4,688,240 companion dogs were vaccinated against rabies based on

173 the official figures published by MHLW [2] and the number of owners involved was

174 estimated to be 3,780,839 assuming one representative from each household with

175 dog ownership. Approximately 47.2% to 48.6% of dog owners would attend the

176 vaccination campaign based on information from the investigated prefectural

177 governments. The price of single vaccination charged in vaccination campaign in the

178 47 prefectures of Japan ranges from $20.50 to $27.64. The average single

179 vaccination price was estimated to be $24.61 based on a weighted mean of all the

180 vaccination prices accounting for the number of registered dogs vaccinated in each



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181 prefecture. In addition, owners would need to pay $4.90 for a tag certifying the dog’s

182 vaccination. Overall, the direct cost of a single dog rabies vaccination (Costvac) was

183 set as $29.52 assuming this proxy includes vaccine cost, material costs such as

184 needle, syringe and alcohol swab, overhead costs (including staff salaries and

185 administrative cost), logistic costs and gross profit. It should be noted that the value

186 of Costvac excluding gross profits would correspond to the unit value of the funds

187 provided by the government to JVMA for organization of annual vaccination

188 campaign, i.e. the total amount of funds divided by the number of dogs vaccinated in

189 campaign each year. The direct cost of single dog rabies vaccination at animal clinic

190 was also set as Costvac based on the observation that the dog rabies vaccination price

191 charged in annual campaign would be very similar to average price charged in animal

192 clinic in each respective prefecture, e.g. at Tokyo Metropolis the vaccination price

193 (excluding the price of certification tag) was $27.64 in campaign, while the median

194 price was $26.25 in animal clinics (n=1,365) based on 2015 Tokyo Veterinary

195 Medication Association survey data.

196

197 Indirect costs

198 Indirect costs included opportunity costs of time and transport costs for owners and



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199 advertisement costs for the government. The opportunity costs of time were

200 estimated using the human capital approach based on productivity or income loss.

201 Such loss was calculated by weighing the number of working days lost by the daily

202 gross domestic product (GDP) per capita. No transport cost was considered for

203 owners attending vaccination campaign assuming that the majority of them would

204 either walk or ride the bicycle based on information from the investigated

205 prefectural governments. For owners who attend an animal clinic for vaccination, it

206 was assumed half of them would drive and the other half would walk. Advertisement

207 costs were considered for the production of publicity materials such as posters and

208 leaflets by MHLW.

209

210 Estimation of the economic burden of a canine rabies

211 outbreak in Japan

212 The current model predicted the economic burden of a hypothetical canine rabies

213 outbreak in Ibaraki Prefecture under the current vaccination policy with a coverage

214 of 51.8% (Burdenvac) and under the abolition of such policy, i.e. vaccination coverage

215 of 0% (Burdenabolish), respectively, according to the simulation results in Kadowaki et

216 al. [6]. Ibaraki Prefecture was selected for investigation because it is representative



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217 of the current situation of dog ownership in Japan in terms of proportion of

218 households with dog ownership, dog registration and rabies vaccination rates,

219 companion dog density and dog-to-human ratio (Table 1). The main epidemiological

220 characteristics of the simulated outbreak were considered in terms of the number of

221 rabid dogs, i.e. mean outbreak size, and the duration of the outbreak, i.e. mean

222 epidemic period – an outbreak would last for 68.2 days involving 4.7 rabid dogs

223 under the current vaccination policy, while it would last for 152.5 days involving 21.7

224 dogs under the abolition of vaccination policy. It was assumed that the introduced

225 rabies disease would not become endemic in the country and would come to an end

226 under control interventions as predicted by the simulation model and according to

227 the experiences in Western Europe [16]. Thus, the economic burden was considered

228 on the basis of incurred expenses of a single rabies outbreak.

229

230 Dog rabies control costs

231 Based on the national rabies contingency plan, it was assumed that the prefectural

232 government rabies control team would respond to the outbreak by taking actions

233 including epidemiological investigation (this involves contact tracing of all the dogs

234 and other susceptible animals in close contact with the index case and identification



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235 of potential rabid dog-bite victims), emergency vaccination of dogs and depopulation

236 (culling) of stray dogs around the outbreak area [17]. The cost of stray dog

237 depopulation was calculated as an incremental cost since the capture and

238 management of stray dogs and dogs without a registration tag and vaccination are

239 already being conducted as part of the daily rabies prevention system.

240

241 Human rabies prevention costs, i.e. post-exposure and pre-exposure

242 prophylaxis (PEP and PrEP) costs

243 PEP due to rabid dog exposure

244 The number of human victims bitten or injured by a rabid dog was based on

245 Kadowaki et al. [6]. It was assumed that all victims suffer either a Category II or III

246 exposure requiring PEP under WHO recommendations and all of them can receive

247 timely complete PEP given the fact that Japan is a developed country with a very

248 high human development index of 0.903 [15, 18, Human Development Report 2015

249 data]. Currently there are two types of human rabies vaccine available in Japan, i.e.

250 Japanese PCEC-K vaccine and imported vaccine such as Verorab and Rabipur [19]. An

251 intramuscular 5-dose Essen regimen (which is the most common method used in

252 local hospitals or clinics) with a fixed cost of $129 was considered for the direct



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253 medical cost of PEP, while the indirect costs were considered in a similar manner

254 mentioned above [20, 2018 Tokyo Metropolitan Cancer and Infectious Disease

255 Center Komagome Hospital data].

256

257 In terms of rabies immunoglobulin (RIG), it was assumed that human RIG and/or

258 equine RIG would be imported for emergency use in case of a rabies outbreak (no

259 such product is currently available in Japan) [19]. The number of patients with

260 Category III exposure requiring RIG on Day 0 was estimated based on the data of

261 outbreaks in the Netherlands and Greece: 50% (n=42) to 72% (n=96) of the patients

262 receiving PEP would have a Category III exposure when bitten by a rabid dog [21,

263 22]. The efficacy of timely complete PEP was assumed to be 100% and so no human

264 death, i.e. Years of Life Lost (YLL), was considered.

265

266 PEP due to public panic

267 In the early stage of the 2013 Taiwan epizootic, 5,335 persons injured with animal

268 bites or scratches (78% due to a dog or cat) applied for free government-funded PEP

269 during a 72-day period when 157 rabies cases were confirmed [23]. However, 35.5%

270 of these applicants came from areas where no rabies case was reported, and only



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271 seven applications were ultimately proved to be caused by a rabid animal, i.e.

272 Chinese ferret-badger. Since Japan has been rabies-free for over half a century, it can

273 be foreseen that a rabies outbreak would cause massive public panic in the country

274 leading to unnecessary use of PEP similar to the situation in the Taiwan epizootic.

275 According to the Ministry of the Environment [24], the average daily incidence of

276 dog-bite victims was reported to be 12 persons in 2016 (note that the number of

277 victims exposed to animals other than dogs was not included in the calculation due

278 to a lack of official data; for reference nine cases of fatal injury due to a cat was

279 reported in 2016). Based on this, it was assumed that on a daily basis six persons

280 (50% of the daily incidence) and ten persons (80% of the daily incidence) would

281 receive PEP due to public panic during a rabies outbreak under the current

282 vaccination policy and abolition of such policy, respectively. The direct and indirect

283 costs involved were then estimated in a similar manner as described above, while

284 the use of RIG was not considered for Category III exposure in this case.

285

286 Occupation PrEP

287 The original members of the prefectural government rabies control team and the

288 diagnostic laboratories were assumed to have all received PrEP. Therefore, the direct



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289 costs of PrEP, using a three-dose intramuscular WHO regimen, were considered for

290 the additional government officers who join the rabies control team in face of an

291 outbreak [18, 25]. The indirect costs were assumed to be reflected in the labour

292 costs of the officers and therefore were not considered.

293

294 Surveillance costs

295 Surveillance costs involve: 1. diagnostic testing of all rabid dogs, i.e. the positive

296 cases, and 2. ongoing testing of all suspected animals during the outbreak and after

297 the outbreak for two years to declare and verify rabies-free status according to OIE

298 standards. In terms of the testing of suspected animals, the surveillance data of

299 France was used as a proxy since the country has an intensified surveillance system

300 due to regular rabies introductions, i.e. during 2008–2017, an average of five

301 suspected animals were tested for rabies each day [16, 2017 Rabies Bulletin Europe

302 data]. It was assumed that the level of active surveillance during a rabies outbreak in

303 Japan under the abolition of vaccination policy would be the same as that in France,

304 while it would not be as intensified during an outbreak under the current vaccination

305 policy, i.e. five and three suspected animals are tested each day, respectively.

306



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307 Model implementation and outputs

308 The decision tree model (Fig 1) was developed in PrecisionTree and @Risk Version

309 7.5.1 (Palisade Corporation) within Microsoft® Excel 2016, and was run with 5,000

310 iterations using Latin Hybercube sampling for each simulation. Information on cost

311 data and input variables into the model is summarised in S1 Table.

312

313 Outputs of the model included the economic burden of a rabies outbreak in Japan

314 under mandatory vaccination policy (Burdenvac) and under abolition of vaccination

315 policy (Burdenabolish), respectively, and annual costs of implementing the current

316 vaccination policy (Costsannual) were estimated. Utilising a damage-avoided approach,

317 the annual benefits of implementing the current vaccination policy in expected value

318 (Benefitsannual) was calculated:

319 𝐵𝑒𝑛𝑒𝑓𝑖𝑡𝑠𝑎𝑛𝑛𝑢𝑎𝑙 = 𝑃_𝑎𝑛𝑛𝑢𝑎𝑙 X (𝐵𝑢𝑟𝑑𝑒𝑛𝑎𝑏𝑜𝑙𝑖𝑠ℎ ‒ 𝐵𝑢𝑟𝑑𝑒𝑛𝑣𝑎𝑐)

320

321 The benefit-cost ratio (BCR) was then given by: 𝐵𝐶𝑅 =𝐵𝑒𝑛𝑒𝑓𝑖𝑡𝑠𝑎𝑛𝑛𝑢𝑎𝑙

𝐶𝑜𝑠𝑡𝑠𝑎𝑛𝑛𝑢𝑎𝑙

322

323 If the BCR is greater than 1, the implementation of the current annual vaccination

324 policy is an economically-efficient strategy and vice versa (Shwiff et al., 2016).



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325

326 Sensitivity and scenario analyses

327 To assess the uncertainty in the current model, sensitivity analysis was conducted

328 using Spearman's correlation coefficient to rank all the input parameters according

329 to their contributions to the variance in BCR.

330

331 The following three scenario analyses were performed to assess their effects on BCR:

332 1. Reduction in the direct medical cost of single dog rabies vaccination, i.e. Costvac –

333 under the current policy, owners bear most of the costs including direct and

334 indirect costs involved in bringing their dogs to annual rabies vaccination. The

335 potential to reduce Costvac has been highlighted in certain prefectures where a

336 few veterinary clinics charge a vaccination price as low as $8.92.

337 2. Worst-case scenario – this aimed to analyse the following two possible events: 1)

338 the economic burden of a rabies outbreak under the abolition of vaccination

339 policy, i.e. Burdenabolish, was underestimated (relative to that under the current

340 vaccination policy, i.e. Burdenvac), 2) and the risk of rabies introduction into Japan

341 increases in unforeseen circumstances, e.g. smuggling of animals. The

342 parameters Burdenabolish and P_annual were increased in a stepwise fashion to



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343 model such situation. It should be noted that, by increasing the value of

344 Burdenabolish (relative to Burdenvac), this worse-case analysis would also indirectly

345 address the effect of additional economic burden due to outbreak situations not

346 considered in the current model, e.g. a rabies outbreak involving wildlife species

347 or domestic cat;

348 3. Best-case scenario – this aimed to explore under what specific circumstances the

349 economic efficiency of maintaining the current dog rabies vaccination policy

350 could be maximized. Costsannual, by considering the number of companion dogs

351 vaccinated with rabies, the frequency of vaccination and Costvac, were decreased,

352 while Burdenabolish and P_annual were increased to model the best-case situation.

353 In particular, it has been highlighted that the current annual vaccination policy

354 could be amended to one requiring less frequent boosters with the use of the

355 domestic RC-HL strain vaccine, i.e. a booster is required within one year after

356 primary vaccination and then every two to three years [26].

357

358 Results

359 Model outputs

360 Information on the simulated model outputs is summarised in Table 2 and Fig 2. The



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361 annual costs of implementing the current dog rabies vaccination policy were

362 estimated to be $160,472,075 (90% prediction interval [PI]: $149,268,935 –

363 171,669,974). The economic burden of a rabies outbreak in Japan was estimated to

364 be $1,682,707 (90% PI: $1,180,289 – 2,249,283) under the current vaccination policy,

365 while it would be $5,019,093 (90% PI: $3,986,882 – 6,133,687) under the abolition of

366 vaccination policy, which is 3-fold higher. The annual benefits of maintaining the

367 current vaccination policy in expected value were estimated to be $85.75 (90% PI:

368 $55.73 – 116.89). The benefit-cost ratio was estimated to be 5.35 X 10-7 (90% PI: 3.46

369 X 10-7 – 7.37 X 10-7).

370

371 Sensitivity and scenario analyses

372 Result of sensitivity analysis is illustrated in Fig 3. The top five most uncertain

373 parameters are the number of patients receiving PEP due to public panic under the

374 abolition of vaccination policy (Npanic,abolish), the daily number of suspected rabid

375 animals tested under active surveillance under the abolition of vaccination policy

376 (Nd-survey,abolish) and under the current vaccination policy (Nd-survey,vac), respectively, the

377 number of patients receiving PEP due to public panic under the current vaccination

378 policy (Npanic,vac) and the number of working days lost per owner per dog vaccination



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379 (Tlost,vac).

380

381 Results of scenario analysis are shown in Table 3 and 4 and Fig 4 and 5. The analysis

382 of reduced direct medical cost of single dog rabies vaccination revealed that the BCR

383 was 3.59 X 10-6 when Costvac was reduced to zero, highlighting that the

384 implementation of the current annual vaccination policy would still still be

385 economically inefficient if one only considered the indirect costs of vaccination for

386 the dog owners (Fig 4). The worst-case scenario analysis demonstrated that the BCR

387 (including the 90% PI) would become above 1 when the annual risk of rabies

388 introduction into Japan (P_annual) and the economic burden of a rabies outbreak

389 under the abolition of vaccination policy (Burdenabolish) simultaneously increased

390 1500-fold (Table 3). The best-case scenario analysis further revealed that under the

391 circumstance of a 100-fold increase in both P_annual and Burdenabolish, the

392 maintenance of a pre-emptive dog vaccination policy in rabies-free Japan could

393 become economically efficient, i.e. mean BCR = 2.61, if it were implemented on a

394 smaller scale, i.e. in only one of the 47 prefectures in Japan using Ibaraki Prefecture

395 as an example, with a 3-fold decrease in Costvac to $8.92 at a frequency of every two

396 to three years (Table 4).



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397

398 Discussion

399 The current study assessed the merit of implementing mandatory annual rabies

400 vaccination in domestic dogs in Japan using benefit-cost analysis. The estimated

401 values of benefit-cost ratio (BCR) were very low, i.e. well below 1, indicating that the

402 implementation of the current vaccination policy in rabies-free Japan is very

403 economically inefficient for the purpose of reducing the economic burden of a

404 potential canine rabies outbreak. The annual costs of implementing such vaccination

405 policy (Costsannual) were estimated according to the data on registered dogs reported

406 by MHLW and might have been under-estimated since the average national

407 registration rate during 2007–2016 is estimated to be only 59.2% [2, 3]. Nonetheless,

408 it is anticipated that companion dogs which are not registered by their owners are

409 less likely to be vaccinated regularly against rabies. The study by Hidano et al. [27]

410 highlighted that companion dogs taken infrequently for walks are significantly less

411 likely to be vaccinated against rabies in Japan. In addition, adverse drug reaction and

412 vaccine wastage were expected to contribute to only a minor component of

413 Costsannual and hence were not considered [28].

414



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415 The economic burden of a rabies outbreak in Japan, was estimated to be $1.69

416 million and $5.02 million, under the current vaccination policy and the abolition of

417 such policy, respectively. Such level of burdens, although not directly comparable

418 due to the differences in model framework, appear similar to the annual costs of

419 rabies control in Flores Island, Indonesia which were estimated to be $1.12 million

420 [29]. Further, the government of Taiwan have initially spent over $4.5 million for the

421 support of contingency actions and procurement of human and animal rabies

422 vaccines for the epizootic started in 2013 [10].

423

424 It should also be noted that the results of the current study could be generalized to

425 other potential rabies situations in Japan, e.g. outbreaks primarily involving domestic

426 cat, particularly stray cats which are twice as common as stray dogs [24], or wildlife

427 species such as common racoon and red fox which are common in the country. If a

428 non-canine rabies outbreak occurred in Japan, dog rabies control measures

429 considered in the current model including emergency dog vaccination and stray dog

430 depopulation and epidemiological investigation would still take place as part of the

431 contingency plan, while the costs of PEP due to public panic would still be expected

432 to constitute a considerable part of the economic burden as demonstrated in the



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433 Taiwan epizootic of Chinese ferret-badger [10]. On top of these basic components of

434 the economic burden, there would be additional costs incurred in containing a

435 non-canine rabies outbreak, e.g. extra manpower would be needed to support

436 immediate stray cat depopulation in face of an outbreak involving domestic cat,

437 while oral rabies vaccination (ORV) might be implemented in the long term if a

438 wildlife rabies outbreak became endemic in the country [30]. Overall, the current

439 study provided a generic framework for future research to estimate the potential

440 economic burden of different rabies incursions in Japan.

441

442 To accommodate the unique situation in Japan, the current study did not consider

443 certain components of the economic burden of canine rabies as suggested in

444 Hampson et al. [15] and Knobel at al. [14]. Livestock losses were not included as

445 significant losses were considered unlikely due to a single dog rabies incursion as

446 indicated in historical incidence [31, 32]. In addition, the costs of potential human

447 death, i.e. Years of Life Lost (YLL), were not considered as explained above, but it is

448 possible that some patients with Category III exposure from a rabid dog could not

449 receive timely rabies immunoglobulin (RIG) since it is currently not available in

450 Japan. The reported probability of contracting rabies after Category III exposure to a



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451 rabid dog ranges between 0.03 and 0.25 when an incomplete post-exposure

452 prophylaxis (PEP) without RIG is used [33]. Zhang et al. [34] have emphasized the

453 importance of RIG in a PEP regimen and the inefficacy of receiving vaccination alone,

454 while Morimoto et al. [35] demonstrated the potential of infiltrating a Category III

455 wound site with rabies vaccine as an alternative to the administration of RIG.

456 Moreover, although a five-dose Essen regimen was considered for simplicity in the

457 calculation of the direct costs of PEP, it has been indicated that the Japanese PCEC-K

458 vaccine is less potent than those produced overseas [36]. The PEP regimen using the

459 Japanese vaccine requires five to six intramuscular doses, i.e. a potential extra dose

460 on Day 90, with clinical data suggesting that up to 85.4% of the patients (n=813)

461 acquired satisfactory antibody titres after five vaccinations [20, 37]. Finally, anxiety

462 associated with a dog bite that may develop into rabies has been suggested as an

463 additional component in Years of Life lived with Disability (YLD) contributing to the

464 economic burden of the disease, but it was not considered in the current model due

465 to a lack of scientific validation of this assumption [15].

466

467 Results of scenario analysis demonstrated that the maintenance of current annual

468 dog rabies vaccination policy could be economically efficient if several conditions



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469 were met. In worse-case analysis, the BCR would become above 1 if the risk of rabies

470 introduction increased to 0.04 corresponding to a level of risk where rabies would

471 enter Japan in 26 years while the economic burden of a rabies outbreak under the

472 abolition of vaccination policy increased to $7.53 billion, a level close to the annual

473 global burden of endemic canine rabies which was estimated to be $8.6 billion by

474 Hampson et al. [15] (Table 3). The best-case analysis further illustrated that the

475 economic efficiency of the current policy could be improved by decreasing the price

476 of single rabies vaccination, relaxing the frequency of vaccination to every two to

477 three years and implementing the policy on a smaller scale, e.g. only in targeted

478 prefectures with the highest risk of rabies incursion (similar to the concept of

479 immune belt, an example would be the one built by Malaysia along the border with

480 Thailand) (Table 4). Overall, future research is highly warranted to provide further

481 evidence-based information to determine whether the continuation of the current

482 vaccination policy, as part of national rabies prevention system, is scientifically

483 justified in the long run or not.

484

485 If the current policy were to be abolished, resources, specifically the recurrent funds

486 provided by the government to JVMA for organization of annual vaccination



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487 campaign in all the 47 prefectures of Japan, could be allocated to more efficient uses

488 to strengthen the national rabies prevention system. Based on the information from

489 the investigated prefectural governments, a vaccination campaign in a particular

490 prefecture with a capacity to vaccinate 12,000 to 14,000 dogs would receive financial

491 support of about $173,665 and this suggests that with the abolition of the current

492 policy a fund of around $12 to $14 could potentially be saved from each dog that

493 would otherwise be vaccinated in the campaign. It should be noted that dog owners

494 would still have the option to voluntarily vaccinate their dogs against rabies in

495 private clinic even when vaccination campaign became unavailable under the

496 abolition of the current policy. In terms of recommended reinforcement of the

497 current rabies prevention system, simulation exercises of the contingency plan

498 should be conducted regularly and continuous training of private veterinary

499 clinicians and government officers in the rabies control team are very important [38].

500 Moreover, the current PEP delivery system must be strengthened in terms of the

501 stockpile of human rabies vaccine and the emergency supply of RIG. Currently, there

502 are approximately 114 local hospitals or clinics which offer rabies PrEP or PEP and

503 about 40,000 to 50,000 Japanese human rabies vaccines are produced locally with a

504 similar amount being imported each year [19, 2018 MHLW data]. Nevertheless, the



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505 local stockpile of human rabies vaccines appeared temporarily exhausted when

506 there were two reports of introduced human rabies cases from the Philippines in

507 November 2006 and the number of tourists seeking PEP after returning from

508 overseas increased three-fold [19, 20]. Training of doctors and medical professionals

509 is also essential to facilitate correct and efficient delivery of PEP to patients with real

510 need. The potential use of PEP due to public panic would incur a substantial and

511 unnecessary economic burden, emphasising that the importance of continuous

512 public education to raise awareness and knowledge of rabies (Fig 2). Furthermore,

513 the cost-effectiveness of PEP has been an international research topic and regimens

514 consisting of fewer doses to reduce costs and fewer consultations to promote

515 patient’s compliance have been examined [39, 40]. The use of Japanese PCEC-K

516 vaccine in a three-dose intradermal PrEP regimen has been proved safe and

517 efficacious [41, 42] (Shiota et al., 2008; Yanagisawa et al., 2012). Thus, further

518 research on the suitability of the Japanese vaccine to time-and dose-sparing PEP

519 regimens such as 4-dose Essen regimen, Zagreb regimen and one-week, 2-site ID

520 regimen is highly warranted [39]. Lastly, it is expected that the active surveillance

521 system on wild animals and the diagnostic capacity of reference laboratories in Japan

522 will continue to be reinforced given the national guidelines of animal rabies survey



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523 was released in 2015.

524

525 Conclusions

526 The implementation of the policy of mandatory annual vaccination of domestic dogs

527 in rabies-free Japan is very economically inefficient for the purpose of reducing the

528 economic burden of a potential canine rabies outbreak. Scenario analysis revealed

529 that the economic efficiency of the current policy could be improved by decreasing

530 the vaccination price charged to dog owners, relaxing the frequency of vaccination

531 to every two to three years and implementing the policy on a smaller scale such as

532 targeted prefectures instead of the whole Japan.

533

534 Acknowledgements

535 We would like to thank Dr. Shoji Miyagawa from the Ministry of Health, Labour and

536 Welfare, the prefectural government officials from Ibaraki, Tokushima and Miyazaki

537 Prefectures and Dr. Satoshi Inoue from the National Institute of Infectious Disease

538 for providing valuable information and comments to this study.

539

540 Author Contributions



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541 Conceptualization: Akio Yamada, Katsuagi Sugiura

542 Investigation and Methodology: Nigel C.L. Kwan, Katsuagi Sugiura

543 Data Curation, Formal Analysis, Software and Visualization: Nigel C.L. Kwan

544 Resources and Supervision: Katsuagi Sugiura

545 Validation: Akio Yamada, Katsuagi Sugiura

546 Writing – Original Draft Preparation: Nigel C.L. Kwan

547 Writing – Review & Editing: Nigel C.L. Kwan, Akio Yamada, Katsuagi Sugiura

548

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