柴本杰1，黄菲1，裴捷1，周明1，田大勇1,2，傅振芳1，赵凌1
1.华中农业大学农业微生物学国家重点实验室/华中农业大学动物医学院，武汉430070；2.上海青赛生物科技有限公司，上海201506
摘要狂犬病是由狂犬病病毒感染中枢神经系统引起的一种古老的人兽共患传染病，人和动物感染后一旦出现临床症状，死亡率几乎100%，至今仍无有效的治疗方法。当前，接种疫苗是预防狂犬病最为有效的途径。因此，狂犬病疫苗研发一直是狂犬病研究领域的热点之一，进而不断涌现出新型疫苗。本文对近期狂犬病新型灭活疫苗、弱毒疫苗、核酸疫苗、亚单位疫苗、病毒样颗粒疫苗、口服疫苗等基因工程疫苗研究进展进行系统梳理，以期把握狂犬病疫苗研究现状，为研发更为有效的狂犬病新型疫苗提供新思路。
关键词狂犬病；狂犬病病毒；灭活疫苗；弱毒疫苗；核酸疫苗；亚单位疫苗；病毒样颗粒疫苗；口服疫苗；基因工程
狂犬病(rabies)是由狂犬病病毒(rabiesvirus，RABV)感染引起的一种高度致死性的人兽共患传染病。RABV共编码5个结构蛋白，分别是核蛋白(nucleoprotein，N)、磷蛋白(phosphoprotein，P)、基质蛋白(matrixprotein，M)、糖蛋白(glycoprotein，G)以及RNA依赖的RNA聚合酶大蛋白(RNA-dependentRNApolymeraselargeprotein，L)，其中RABV糖蛋白(RABV-G)是病毒粒子表面唯一的蛋白，在RABV感染宿主后结合细胞表面的受体帮助入侵，同时也能够刺激机体产生保护性中和抗体(virus-inducedneutralizingantibody，VNA)。
狂犬病在全球范围内每15min发生1例，其中95%以上病例发生在亚洲、非洲的一些发展中国家和欠发达地区[1]。人通常是通过已感染RABV的动物咬伤、抓伤或舔舐等密切接触方式被感染。狂犬病一旦出现临床症状其死亡率接近100%，暴露后预防处置(包括伤口清洗、疫苗免疫和抗体注射)是预防狂犬病的唯一有效途径[2]。犬是当前狂犬病传播的主要传染源(占比95%以上)，对家养动物进行广泛免疫(达到70%以上)是消除人间狂犬病的最有效措施。
世界卫生组织(WHO)提出了2030年消灭人间狂犬病的目标[3]，而要实现这一目标就需要开发更为廉价、高效的新型狂犬病疫苗。早在1885年法国科学家路易斯·巴斯德就首次发明了狂犬病疫苗，并成功应用到人狂犬病的防控[4]。时至今日，狂犬病疫苗的发展历经组织灭活苗、禽培苗、细胞苗、基因工程苗等不同的发展阶段。得益于基因工程技术的飞速发展，近年来狂犬病新型基因工程疫苗研究获得长足进步，本文对该方面的研究进展进行系统综述。
此外，以RABV为载体来表达其他病原保护性抗原而开发的重组二联灭活疫苗也是新型灭活疫苗的发展方向之一。如基于RABV-G的蛋白三维结构，设计构建的RABV和莫科拉病毒(mokolavirus，MOKV)嵌合G蛋白重组灭活疫苗候选株免疫后能为机体提供对RABV和狂犬病病毒属的多种病毒在内的免疫保护[9]，极大地拓宽了狂犬病疫苗的应用范围。而表达犬瘟热病毒(caninedistempervirus，CDV)H(CDV-H)或F蛋白(CDV-F)的重组狂犬病灭活疫苗在提供RABV免疫保护的同时也能提供CDV免疫保护[10]；采用汽化保存的RABV-埃博拉病毒(ebolavirus，EBOV)重组灭活疫苗比冷藏保存的灭活疫苗具有更好的热稳定性，能同时保护机体免受RABV和EBOV的攻击[11]；表达SARS-CoV-2S1与RABV-G嵌合体的RABV-COVID-19重组灭活疫苗CORAVAXTM免疫小鼠56d后，仍能诱导机体同时产生针对以上2种病毒的高水平VNA[12]。
图1表达免疫增强因子的狂犬病新型弱毒疫苗示意图Fig.1Schematicdiagramofnewattenuatedrabiesvaccineexpressingimmuneenhancementfactor
通过表达细胞因子或趋化因子来提高疫苗的免疫原性可以有效提高狂犬病疫苗的免疫效力，但是在动物或人体内过表达这些细胞因子是否会存在一定的副作用或有其他安全性隐患还需进一步评估。
狂犬病RNA疫苗则是将RABV-G的编码框构建成能独立翻译RABV-G的mRNA作为免疫原而开发的新型疫苗(图2)。如编码RABV-G的非复制且耐高温狂犬病mRNA疫苗能对小鼠、新生和成年猪产生免疫保护[68-69]；人用预防性狂犬病mRNA疫苗(CV7201)是由编码RABV-G的mRNA和鱼精蛋白组合冻干的热稳定型mRNA疫苗，是第一个在健康人群中开展概念验证研究的mRNA疫苗，其临床试验也显示出较好的安全性和免疫原性[70-71]。此外，基于甲病毒(alphavirus)基因组构建并由阳离子纳米乳剂(cationicnanoemulsion，CNE)传递的狂犬病自我复制mRNA(self-amplifyingmRNA)疫苗在小鼠中具有较好的免疫效果和安全性[72]；而将编码RABV-G的cDNA进行体外转录后转染BHK-21细胞，包装成能表达RABV-G的重组SFV-RABV-G的mRNA疫苗也能在小鼠体内激发有效的免疫反应[73]。
图2狂犬病新型mRNA疫苗示意图Fig.2SchematicdiagramofnewmRNAvaccineforrabies
直接将人工表达的RABV-G作为免疫原而开发的疫苗称为狂犬病亚单位疫苗。传统RABV-G表达采用原核表达系统或昆虫细胞表达系统[74]，而采用黑腹果蝇S2(schneider2)细胞表达的RABV-G也具有较好的免疫效果[73,75]。而采用哺乳动物细胞HEK-293T表达的嵌合有GCN4-pⅡ三聚化功能域的RABV-G胞外域嵌合体蛋白可以三聚体形式存在，因而更接近天然的RABV-G从而具有更好的免疫原性，能为小鼠提供更好的免疫保护[76]。此外，添加犬热休克蛋白Gp96佐剂的狂犬病多肽疫苗免疫试验和攻毒保护试验结果显示能为小鼠和比格犬提供免疫保护[77]，表明合成肽也具有发展狂犬病疫苗的应用前景。
图3新型狂犬病病毒样颗粒疫苗VEEV-RABV-G示意图Fig.3Schematicdiagramofthenewrabiesvirus-likeparticlevaccineVEEV-RABV-G
除了病毒载体，利用可食用转基因植物表达保护性抗原从而免疫人群和动物也是提高群体免疫的有效途径[96]。而据此开发的表达RABV-G的转基因玉米口服绵羊后能诱导机体产生针对RABV的保护性免疫应答[97]。此外，在番茄毛状根中表达RABV-G也可被开发为动物用口服疫苗[98]。
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CHAIBenjie1，HUANGFei1，PEIJie1，ZHOUMing1，TIANDayong1,2，FUZhenfang1，ZHAOLing1
1.StateKeyLaboratoryofAgriculturalMicrobiology/CollegeofVeterinaryMedicine，HuazhongAgriculturalUniversity,Wuhan430070,China；2.ShanghaiKing-CellBiotechnologyCo.，Ltd.，Shanghai201506,China
AbstractRabiesisanancientzoonosiscausedbyrabiesvirus,whichinfectsthecentralnervoussystem,causingalmost100%mortalityoncetheclinicalsymptomsappear.Thereisnoeffectivetreatmentavailablesofar.Currently,vaccinationisstillthemosteffectivewaytopreventrabies,sodevelopingrabiesvaccinesisoneofthehotspotsinthefieldofrabiesresearch.Withtherapiddevelopmentofbiotechnology,novelrabiesvaccinesfordifferentuseshavebeencontinuouslyemerged.Inthisreport,theresearchprogressoflatestgeneticengineeringrabiesvaccinesincludinginactivatedvaccine,attenuatedvaccine,nucleicacidvaccine,subunitvaccine,virus-likeparticlevaccine,oralvaccineetc.isreviewedtograspthecurrenttrendofrabiesvaccineandlaythefoundationfordevelopingnextgenerationofrabiesvaccines.
Keywordsrabies；rabiesvirus；inactivatedvaccine；attenuatedvaccine；nucleicacidvaccine；subunitvaccine；virus-likeparticlevaccine；oralvaccine；geneticengineering
柴本杰，黄菲，裴捷，等.狂犬病新型基因工程疫苗研究进展[J].华中农业大学学报，2021,40(3)：75-84.
DOI:10.13300/j.cnki.hnlkxb.2021.03.009
收稿日期：2020-10-27
基金项目：国家自然科学基金青年科学家基金项目(31702248)