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標題: 台灣豬場第一基因型日本腦炎病毒之分子流行病學監測及種母豬施打第三基因型日本腦炎活性減毒疫苗對第一基因型日本腦炎病毒之保護效用分析
Molecular Surveillance of Genotype I Japanese Encephalitis Virus in Pig Farms and Vaccine Effectiveness of Live-attenuated Genotype III Japanese Encephalitis Virus Vaccine Against Genotype I Virus in Sows
作者: 陳怡瑩
Yi-Ying Chen
關鍵字: 第一基因型日本腦炎病毒;分子流行病學監測;養豬場;日本腦炎疫苗效用;Genotype I Japanese Encephalitis Virus;Molecular Surveillance;Pig farms;Vaccine Effectiveness
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首先,本研究於2009~2018年的田間研究中,共在養豬場收集的三斑家蚊上檢測出80池日本腦炎病毒陽性,均為第一基因型日本腦炎病毒。進一步經由E蛋白基因進行親緣演化分析台灣分離之第一基因型日本腦炎病毒依其演化分支分屬於Subcluster I 及Subcluster II病毒,且所有病毒均源自於2009年台灣所分離之第一基因型日本腦炎病毒,推論第一基因型病毒在台灣已形成地方性流行。經由分離率之相對百分比分析發現第一基因型日本腦炎病毒Subcluster I於2015~2018年較Subcluster II具優勢,推論在台灣第一基因型日本腦炎病毒不同Subcluster型別可能產生病毒競爭的現象。因於同一養豬場同時分離到第一基因型日本腦炎病毒Subcluster I及Subcluster II有可能造成病毒重組機會,因此選擇代表性第一基因型日本腦炎病毒分離株進行全長序列定序分析,結果發現原屬於Subcluster I的TC2015-5、YL1206a病毒株在部分核苷酸特異位與Subcluster II病毒之核苷酸相同,以生物分析軟體RDP Beta 4.0版本分析後發現,TC2015-5主要與同為Subcluster I 型別之TC2015-4相似,但其結構蛋白核苷酸位置443~1004區間則與Subcluster II 型別之TC2012-4相似;而YL1206a主要與同為Subcluster I 型別之TC2009-1相似,但其結構蛋白核苷酸位置1~1387則與Subcluster II 型別之YL2009-4相似;此結果表示在同一地區共同流行的日本腦炎病毒可能產生病毒重組的現象。最後為了探討基因型轉變後豬隻用第三基因型日本腦炎活性減毒疫苗是否對於第一基因型病毒感染仍具保護效用,調查發現種母豬有施打日本腦炎疫苗時於第一基因型日本腦炎病毒流行期間造成的流產率為11.2%,未施打日本腦炎疫苗的種母豬流產率為36%,以此推算疫苗保護效用為68.8% (95%信賴區間為50.2%~80.5%);於流行期間施打疫苗種母豬流產胎兒檢出日本腦炎病毒的陽性率為2.2%,未施打疫苗種母豬流產胎兒日本腦炎病毒陽性率為8.8%,以此推算疫苗效用為74.8%(95%信賴區間為0~95.6%);本研究觀察之日本腦炎疫苗對於第一基因型日本腦炎病毒保護效力明顯低於Hsu等人於1972年發表日本腦炎活性減毒疫苗對於第三基因型病毒之疫苗保護效用95.6%。

The dominant genotype III (GIII) Japanese encephalitis virus (JEV) has been replaced by genotype I (GI) virus in East and Southeast Asian regions. In Taiwan, the GI JEVs were first isolated in mosquitoes captured from the wetlands of Taipei City and Yilan county in 2008. While GI JEVs have gradually became the dominant genotype in Taiwan, GIII JEV was still detected in two of the most recent isolates in 2012. However, the epidemiology of GI and GIII JEVs in Taiwan remains unknown, hence the aims of this study were (i) to understand the epidemiology and evolution of the emerging GI JEVs in Taiwan after genotype replacement, and (ii) to estimate vaccine effectiveness of live-attenuated GIII JEV vaccine against GI virus in sows.
Initially, we conducted JEV surveillance among mosquitoes collected from pig farms in Taiwan from 2009 until 2018. A total of 80 Culex tritaeniorhynchu mosquito pools were positive for GI JEV. These GI viruses were further classified into two subclusters namely, subclusters I and II in the phylogenetic tree analysis using nucleotide sequences of the viral envelope (E) proteins. Either GI subcluster I or II isolates showed an evolutionary association with 2009 isolates, suggesting the endemicity of GI JEV in Taiwan. Results also showed that GI subcluster I isolates were more dominant than subcluster II between 2015 and 2018, while co-circulation of the two subclusters was observed in one pig farm. This inferred the possibility of competition and genetic recombination between the two GI subclusters thus, we analysed and compared the complete genome of selected Taiwan JEV GI subclusters I and II. Interestingly, partial sequences of GI subcluster I TC2015-4 and YL1206a strains were found to be homologous to subclubster II. The possible recombination of TC2015-4 and YL1206a strains was supported by the analysis from Recombination Detection Program (RDP ver 4.0 Beta). Nucleotide positions 443-1004 of TC2015-5 were similar to subcluster II TC2012-4 strain, while the remaining nucleotides were similar to subcluster I TC2015-4 strain. The 5' terminus-1387 nucleotide sequences of the YL1206a strain were similar to YL2009-4 strain, while the remaining nucleotides were similar to GI subcluster I TC2009-1 strain. Results showed that JEV recombination was observed among isolates in co-circulation. Lastly, we investigated the vaccine effectiveness of live-attenuated GIII JEV vaccine in sows after genotype shift. The estimated abortion rates during GI-virus epidemic season was shown to be 11.2% and 36% among vaccinated and non-vaccinated sows, respectively, with vaccine effectiveness presented as 68.8% (50.2~80.5%, 95% confidence interval). JEV was detected in stillborn/aborted fetus samples among vaccinated (2.2%) and non-vaccinated (8.8%) sows. The vaccine effectiveness was 74.8% (0~95.6%, 95% confidence interval). In this study, live-attenuated GIII JEV vaccine exhibited significantly lower vaccine effectiveness against GI virus than GIII virus in sows. This is in contrast to the results of Hsu and colleagues (1972) whose vaccine effectiveness was 95.6% against GIII virus.
Taken all data together, these results showed the endemicity of GI JEV in Taiwan, which could have evolved from genetic recombination of JEVs. Further, the current live-attenuated GIII JEV vaccine provided partial protection against GI virus in sows. Finally, research on the epidemiology of JE viruses in Taiwan is crucial to evaluate and establish possible GI-virus derived JEV vaccines in the future.
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