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Article(id=1190335354046611698, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1190335347767743264, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-1137, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1731686400000, receivedDateStr=2024-11-16, revisedDate=1736092800000, revisedDateStr=2025-01-06, acceptedDate=null, acceptedDateStr=null, onlineDate=1761727663766, onlineDateStr=2025-10-29, pubDate=1744387200000, pubDateStr=2025-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1761727663766, onlineIssueDateStr=2025-10-29, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1761727663766, creator=13701087609, updateTime=1761727663766, updator=13701087609, issue=Issue{id=1190335347767743264, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='4', pageStart='843', pageEnd='1182', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1761727662269, creator=13701087609, updateTime=1761729313427, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1190342273276678997, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1190335347767743264, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1190342273276678998, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1190335347767743264, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=895, endPage=902, ext={EN=ArticleExt(id=1190335354264715507, articleId=1190335354046611698, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress and new approaches in the development of human cytomegalovirus vaccines, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Human cytomegalovirus (HCMV) infection poses significant morbidity and/or mortality risks for individuals with compromised immune systems, rendering it one of the most prevalent congenital infections worldwide. The pursuit of HCMV vaccines has spanned over five decades, with clinical trials primarily focusing on various vaccine candidates, including live attenuated vaccines, viral vectored vaccines, subunit vaccines, peptide vaccines, DNA vaccines, RNA vaccines, and viral-like particle vaccines, usually accompanied by the use of adjuvants. Although the development of vaccines against HCMV is being actively promoted, there are still numerous obstacles and challenges persisting in the research process, due to unique pathogenic characteristics and infection mechanisms of HCMV. Based on the summarized research progress, this article analyzes and discusses the faced challenges and potential approaches to provide valuable insights and guidance for the exploration and development of new vaccines candidates, and ultimately achieve prevention and control of HCMV infection.

, correspAuthors=Yu-chao GU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Yuan-yuan WANG, Shi-hao CUI, Yu-chao GU), CN=ArticleExt(id=1190335459021652324, articleId=1190335354046611698, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=人类巨细胞病毒疫苗的研究进展及开发新思路, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

人类巨细胞病毒(human cytomegalovirus, HCMV) 感染可导致低免疫力人群发病和/或死亡, 是全球最常见的先天性感染之一。针对HCMV疫苗的开发工作已经持续了50年, 目前处于临床试验阶段的疫苗主要包括减毒活疫苗、病毒载体疫苗、亚单位疫苗、多肽疫苗、DNA疫苗、RNA疫苗及病毒样颗粒疫苗, 并伴随使用佐剂。尽管针对HCMV的疫苗开发正被积极推进, 但由于其所具有的独特病原学特征和感染机制, 疫苗研究过程中仍面临诸多障碍和挑战。本文在汇总HCMV疫苗研究进展的基础上, 对开发过程中的挑战和潜在思路进行了分析和讨论, 为探索和开发新型疫苗提供借鉴和参考, 以期最终实现预防和控制HCMV感染。

, correspAuthors=顾玉超, authorNote=null, correspAuthorsNote=
顾玉超, E-mail:
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Schematic structure of human cytomegalovirus (HCMV)

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Type Protein Humoral immunity Cellular immunity
Glycoprotein gB + ++
gH/gL/gO + ++
gM/gN + +
gH (PC) +++ ++
Tegument protein pp65 (UL83) ++ +++
pp150 (UL32), pp28 (UL99) + ++
pp71 (UL82) ++ ++
Regulatory protein IE1 (UL123) ++ +++
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Protein types of HCMV and their immunogenicity characteristics. +: Weak effect; ++: Moderate effect; +++: Strong effect

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Type Protein Humoral immunity Cellular immunity
Glycoprotein gB + ++
gH/gL/gO + ++
gM/gN + +
gH (PC) +++ ++
Tegument protein pp65 (UL83) ++ +++
pp150 (UL32), pp28 (UL99) + ++
pp71 (UL82) ++ ++
Regulatory protein IE1 (UL123) ++ +++
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Vaccine category Vaccine (sponsor) Antigens used Adjuvant NCT number End date
Attenuated/DISC virus vaccine V160 (Merck Sharp) PC / NCT03486834 2021(Ⅱ)
Towne-Toledo (CMV Research Foundation) / / NCT01195571 2014(Ⅰ)
Viral vectored vaccine AVX601 (AlphaVax) gB, pp65, IE1 / NCT00439803 2008(Ⅰ)
CMV-MVA Triplex (City of Hope) pp65, IE1-exon4, IE2-exon5 / NCT06059391
NCT06075745		 2028(Ⅱ)
2028(Ⅱ)
Subunit vaccine gB/MF59 (NIAID) gB MF59 NCT00133497 2013(Ⅱ)
Chimeric peptide vaccine CMVPepVax (City of Hope) HLA-A*0201-specific pp65 CD8+ T cell epitope +P2 epitope of tetanus toxin or pan-DR epitope PF03512675 NCT02396134 2024(Ⅱ)
DNA vaccine ASP0113 (Astellas) gB, pp65 CRL1005-BAK NCT01877655 2022(Ⅲ)
mRNA vaccine mRNA-1647 (Moderna) gB, PC / NCT05683457
NCT04975893
NCT05085366		 2025(Ⅱ)
2026(Ⅱ)
2026(Ⅲ)
VLP vaccine VBI-1501 (VBI Lab) gB-G eVLPs AlPO4 NCT02826798 2017(Ⅰ)
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HCMV vaccines during clinical trials. DISC: Disabled infectious single cycle; eVLP: Enveloped virus-like particle; MF59: Oil-in-water emulsion adjuvant composed of squalene droplets stabilized with small amounts of the surfactants Tween 80 and Span 85; PF03512676: Synthetic single-stranded phosphorothioate DNA containing CpG motifs, also known as CpG 7909 and CpG 2006; CRL1005: Nonionic triblock copolymer composed of blocks of polyoxypropylene (POP) and polyoxyethylene (POE); BAK: Benzalkonium chloride

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Vaccine category Vaccine (sponsor) Antigens used Adjuvant NCT number End date
Attenuated/DISC virus vaccine V160 (Merck Sharp) PC / NCT03486834 2021(Ⅱ)
Towne-Toledo (CMV Research Foundation) / / NCT01195571 2014(Ⅰ)
Viral vectored vaccine AVX601 (AlphaVax) gB, pp65, IE1 / NCT00439803 2008(Ⅰ)
CMV-MVA Triplex (City of Hope) pp65, IE1-exon4, IE2-exon5 / NCT06059391
NCT06075745		 2028(Ⅱ)
2028(Ⅱ)
Subunit vaccine gB/MF59 (NIAID) gB MF59 NCT00133497 2013(Ⅱ)
Chimeric peptide vaccine CMVPepVax (City of Hope) HLA-A*0201-specific pp65 CD8+ T cell epitope +P2 epitope of tetanus toxin or pan-DR epitope PF03512675 NCT02396134 2024(Ⅱ)
DNA vaccine ASP0113 (Astellas) gB, pp65 CRL1005-BAK NCT01877655 2022(Ⅲ)
mRNA vaccine mRNA-1647 (Moderna) gB, PC / NCT05683457
NCT04975893
NCT05085366		 2025(Ⅱ)
2026(Ⅱ)
2026(Ⅲ)
VLP vaccine VBI-1501 (VBI Lab) gB-G eVLPs AlPO4 NCT02826798 2017(Ⅰ)
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人类巨细胞病毒疫苗的研究进展及开发新思路
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王媛媛 1 , 崔世浩 2 , 顾玉超 3, *
药学学报 | 综述 2025,60(4): 895-902
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药学学报 | 综述 2025, 60(4): 895-902
人类巨细胞病毒疫苗的研究进展及开发新思路
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王媛媛1, 崔世浩2, 顾玉超3, *
作者信息
  • 1 中国海洋大学医药学院, 山东 青岛 266003
  • 2 简达生物医药 (南京) 有限公司, 江苏 南京 210031
  • 3 青岛科技大学生物工程学院, 山东 青岛 266042

通讯作者:

顾玉超, E-mail:
Research progress and new approaches in the development of human cytomegalovirus vaccines
Yuan-yuan WANG1, Shi-hao CUI2, Yu-chao GU3, *
Affiliations
  • 1School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
  • 2Jianda Biopharmaceutical (Nanjing) Co., Ltd., Nanjing 210031, China
  • 3College of Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
出版时间: 2025-04-12 doi: 10.16438/j.0513-4870.2024-1137
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人类巨细胞病毒(human cytomegalovirus, HCMV) 感染可导致低免疫力人群发病和/或死亡, 是全球最常见的先天性感染之一。针对HCMV疫苗的开发工作已经持续了50年, 目前处于临床试验阶段的疫苗主要包括减毒活疫苗、病毒载体疫苗、亚单位疫苗、多肽疫苗、DNA疫苗、RNA疫苗及病毒样颗粒疫苗, 并伴随使用佐剂。尽管针对HCMV的疫苗开发正被积极推进, 但由于其所具有的独特病原学特征和感染机制, 疫苗研究过程中仍面临诸多障碍和挑战。本文在汇总HCMV疫苗研究进展的基础上, 对开发过程中的挑战和潜在思路进行了分析和讨论, 为探索和开发新型疫苗提供借鉴和参考, 以期最终实现预防和控制HCMV感染。

人类巨细胞病毒  /  感染机制  /  抗原  /  免疫抑制  /  疫苗

Human cytomegalovirus (HCMV) infection poses significant morbidity and/or mortality risks for individuals with compromised immune systems, rendering it one of the most prevalent congenital infections worldwide. The pursuit of HCMV vaccines has spanned over five decades, with clinical trials primarily focusing on various vaccine candidates, including live attenuated vaccines, viral vectored vaccines, subunit vaccines, peptide vaccines, DNA vaccines, RNA vaccines, and viral-like particle vaccines, usually accompanied by the use of adjuvants. Although the development of vaccines against HCMV is being actively promoted, there are still numerous obstacles and challenges persisting in the research process, due to unique pathogenic characteristics and infection mechanisms of HCMV. Based on the summarized research progress, this article analyzes and discusses the faced challenges and potential approaches to provide valuable insights and guidance for the exploration and development of new vaccines candidates, and ultimately achieve prevention and control of HCMV infection.

human cytomegalovirus  /  infection mechanism  /  antigen  /  immunosuppression  /  vaccine
王媛媛, 崔世浩, 顾玉超. 人类巨细胞病毒疫苗的研究进展及开发新思路. 药学学报, 2025 , 60 (4) : 895 -902 . DOI: 10.16438/j.0513-4870.2024-1137
Yuan-yuan WANG, Shi-hao CUI, Yu-chao GU. Research progress and new approaches in the development of human cytomegalovirus vaccines[J]. Acta Pharmaceutica Sinica, 2025 , 60 (4) : 895 -902 . DOI: 10.16438/j.0513-4870.2024-1137
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人类巨细胞病毒(human cytomegalovirus, HCMV) 作为全球范围内极具影响力的公共健康威胁, 被全世界所广泛关注[1]。该病毒不仅会导致正常人群的隐性感染, 更会对接受实体器官移植以及骨髓/造血干细胞移植的患者、孕妇及胎儿构成显著风险, 导致新生儿的先天性HCMV感染及出生缺陷[2], 同时HCMV被认为是癌症进展的重要参与者, 与多种恶性肿瘤的发生密切相关[3]。对于HCMV感染通常采用抗病毒药物治疗, 首选药物治疗方式是静脉注射更昔洛韦, 但由此导致的安全性和耐药性问题成为治疗的重要障碍。疫苗是防治传染性疾病最有效的方法之一, 截至目前未有HCMV疫苗获得上市许可, 具有临床应用价值的新型疫苗仍有待开发。在此背景下, 本文提出潜在的疫苗研发策略, 以期为HCMV感染的防控提供新的思路和方法。
1 HCMV的病原学特征及感染机制
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1.1 HCMV的病原学特征
HCMV学名为人类疱疹病毒5型, 是疱疹病毒科β-疱疹病毒亚科的一员。该病毒是一种双链DNA病毒, 可感染人体内几乎所有的组织和器官, 并建立终生潜伏。HCMV能在人体多种类型细胞中复制, 包括成纤维细胞、上皮细胞、内皮细胞及巨噬细胞等。HCMV主要通过体液、血液、性接触、母婴接触及器官移植等途径传播。在免疫功能正常的人群中, HCMV感染通常不会引起严重症状, 可能出现以流感样症状为特征的非特异性腺热(单核细胞增多症) 综合征。相反, 在免疫功能低下或存在移植的患者中, HCMV原发感染或再激活将导致病毒综合征, 其特征是发热和不适, 以及白细胞、血小板减少和肝酶升高。罕见情况下, 可出现肺炎、肝炎、脑膜脑炎、胰腺炎或心肌炎。
HCMV成熟病毒粒子呈球形, 直径约为150~200 nm, 病毒颗粒由内向外依次为: 核心、衣壳、被膜和包膜[4] (图 1)。包膜是由宿主细胞膜衍生并嵌入多种病毒糖蛋白的脂质双层, 被膜内填充着多种病毒基质蛋白, 衣壳是由多种病毒蛋白构成的正二十面体结构, 核心含有线性双链DNA基因组, 长度为(235 ± 1.9) kbp, 是人类疱疹病毒中最大的基因组。HCMV基因组有超过751个开放阅读框, 其中的282个病毒转录本具有翻译活性。HCMV可表达的蛋白质包括结构蛋白和非结构蛋白, 不同的蛋白类型具有各异的免疫原性特征[5] (表 1)。结构蛋白构成了病毒颗粒的物理结构, 非结构蛋白则涉及病毒的复制、组装、宿主免疫逃逸及细胞调控等多种功能。病毒的入侵和脱离宿主细胞依赖于包膜上的糖蛋白, 如糖蛋白B (glycoprotein B, gB) 三聚体、gM/gN二聚体、gH/gL/gO三聚体和gH/gL/UL128/UL130/UL131五聚体(pentameric complex, PC)[6], 它们协同作用介导病毒与宿主细胞表面受体的结合及病毒膜与细胞膜的融合[7]。此外, HCMV还能分泌免疫调节蛋白和miRNA, 超过40种基因产物被认为在调节宿主免疫应答中发挥作用, 抑制固有免疫反应和适应性免疫反应[8], 并能对细胞周期和细胞凋亡途径产生影响, 导致癌症进展, 与乳腺癌、脑癌、结直肠癌等恶性肿瘤密切相关[3]。
1.2 HCMV的感染机制
HCMV可通过两种机制感染宿主细胞, 即膜融合和内吞作用, 感染过程涉及不同的包膜糖蛋白复合物, 并由此介导进入不同的细胞群[4, 7]。gM/gN二聚体在黏附过程中通过与成纤维细胞表面的硫酸乙酰肝素蛋白聚糖结合来发挥作用, gH/gL/gO三聚体则与转化生长因子β受体3和血小板衍生生长因子受体α结合, 促进病毒与宿主细胞膜融合, 而gB三聚体在膜融合过程中发挥协同作用, 能够与硫酸乙酰肝素蛋白聚糖、表皮生长因子受体和血小板衍生生长因子受体α相互作用来介导HCMV感染。PC五聚体可通过与上皮细胞和内皮细胞表面的神经纤毛蛋白2相互作用实现病毒内吞。病毒DNA进入细胞核后激活即刻早期基因, 并调控病毒基因进一步表达, 影响宿主细胞生存与增殖, 为病毒复制创造条件。早期基因参与调控DNA合成与修复, 支持病毒DNA复制。晚期基因表达后, 编码构成病毒粒子的结构蛋白, 新合成的病毒粒子在细胞质中组装并释放。
HCMV的感染特征在于其潜伏和复发性。在初次感染后, 病毒能在宿主细胞内建立潜伏感染, 并可在免疫抑制或免疫功能低下时重启复制, 引发新一轮感染。潜伏期间, 病毒表达极少量的病毒蛋白并通过多种方式干扰宿主的抗病毒免疫应答, 从而逃避宿主的免疫监视。
2 HCMV疫苗的研究现状
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疫苗接种是预防HCMV感染的唯一有效办法。HCMV疫苗的研究历史可以追溯到20世纪70年代, 当时开发了基于减毒毒株的疫苗制剂, 并在成年受试者中进行了临床试验。随后, 越来越多种类的HCMV疫苗被研究开发, 主要包括减毒活疫苗、病毒载体疫苗、亚单位疫苗、多肽疫苗、DNA疫苗、RNA疫苗及病毒样颗粒疫苗(表 2), 预设的临床应用目的包含对HCMV感染的免疫预防或免疫治疗。截至目前, 仅有一款DNA疫苗ASP0113完成III期临床研究, 该项临床研究为一项随机、双盲、安慰剂对照的III期试验, 旨在评估治疗性疫苗ASP0113在接受同种异体造血细胞移植(allogeneic hematopoietic cell transplantation, allo-HCT) 的HCMV血清阳性受试者中的保护效果和安全性。该项III期临床研究的结果表明, ASP0113在移植后的1年内并未降低总死亡率和HCMV感染终末器官疾病。在处于高度免疫抑制的allo-HCT受试者体内诱导针对HCMV的免疫反应是困难的, ASP0113在接受allo-HCT之前和之后给药, 针对HCMV诱导的T细胞或B细胞免疫反应不具有治疗效果[9]。
在一项针对CMVPepvax的随机、双盲、安慰剂对照、多中心Ⅱ期临床试验(NCT02396134) 中同样得出失败的结论, 未能证明CMVPepvax在接受allo-HCT的HCMV血清阳性受试者体内可以产生预防病毒血症/疾病方面的临床疗效[10]。另外, 分别以V160 (NCT03486834) 和gB/MF59 (NCT00133497) 为试验疫苗的两项随机、双盲、安慰剂对照Ⅱ期临床研究结果表明, 上述两款疫苗在预防血清阴性女性HCMV感染方面的表现与安慰剂相比没有显著性差异, 不能防止原发性HCMV感染[11, 12]。
针对CMV-MVA Triplex和mRNA-1647的临床试验目前仍在进行中。其中CMV-MVA Triplex是一种以安卡拉牛痘为载体的病毒载体疫苗, 可表达pp65、IE1、IE2三种抗原。早期临床研究(NCT02506933) 结果表明: CMV-MVA Triplex可安全诱导HCMV特异性T细胞的持久扩增[13]。正在开展的两项CMV-MVA Triplex临床研究分别以疫苗预防造血干细胞移植受体(NCT06059391) 和肝脏移植受体(NCT06075745) 免于HCMV感染为研究目的。研究人员还基于该种疫苗开发了新一代三重候选疫苗T10-F10, 该疫苗具有不同的序列修饰, 以增强疫苗稳定性。T10-F10在广泛的病毒传代过程中表现出可靠的遗传和表达稳定性。免疫原性研究结果表明, T10-F10具有与原始Triplex疫苗相当的免疫原性, 可在HLA转基因小鼠中引发抗原特异性T细胞反应[14]。
mRNA-1647是一种编码HCMV gB和五聚体复合物PC的mRNA疫苗, 并封装在脂质纳米颗粒中。早期临床研究(NCT03382405) 结果表明: mRNA-1647疫苗可在血清阴性和血清阳性受试者体内引发和增强具有多功能性和持久性的抗体反应。mRNA-1647引发的gB特异性抗体反应低于PC特异性抗体反应, 也低于gB/MF59引发的抗体反应。然而, mRNA-1647比gB/MF59可引起更强的中和抗体反应和ADCC反应[15]。正在开展的两项Ⅱ期临床研究分别以考察疫苗在血清阴性和阳性受试者体内引起免疫反应的持久性、安全性(NCT04975893), 以及预防造血干细胞移植受体免于HCMV感染(NCT05683457) 为研究目的。另外, 针对mRNA-1647还在进行一项Ⅲ期临床研究, 评估疫苗在16~40岁HCMV血清阴性女性受试者中的保护效力、安全性和免疫原性(NCT05085366)。
在开发HCMV疫苗的过程中, 佐剂的使用是提高疫苗免疫原性的重要手段。佐剂可以通过靶向Toll样受体和其他模式识别受体, 导致抗原提呈细胞的成熟和激活, 从而促进抗原信号和共刺激信号的产生, 激活体液免疫反应和细胞免疫反应。目前, 在HCMV疫苗制剂中添加的佐剂包括磷酸铝、MF59、PF03512675和CRL1005-BAK。
3 HCMV疫苗开发的挑战
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相比其他药物类型, 疫苗在其整个生命周期中往往会受到更多更严格的法规监管。尽管针对HCMV的疫苗开发正被积极推进, 但由于其所具有的独特病原学特征和感染机制, 疫苗研究过程中仍面临诸多障碍和挑战。
3.1 广泛的毒株抗原变异
HCMV不同毒株之间以及单个宿主内部存在着广泛抗原变异性, 特别是全基因组水平上的变异。对一种HCMV毒株的免疫力并不意味着对所有毒株的免疫力, 这为开发具有广泛保护作用的疫苗带来了复杂性。如已知HCMV的gB蛋白至少有5种主要基因型(gB-1/gB-2/gB-3/gB-4/gB-5)[16], 这将导致疫苗开发策略的调整。
3.2 无效抗原表位的干扰作用
HCMV可表达超过200种具有不同功能的蛋白质。过于丰富的抗原类型会大量消耗占用体内有限的免疫能力, 造成抗原表位竞争, 其中也可能存在诱导无效免疫反应的“诱饵”蛋白或表位, 以此来保护关键蛋白或表位免受宿主识别, 大量产生针对非中和表位的抗体。以gB/MF59疫苗为例, 研究发现它倾向于诱导对gB AD-3区域内非中和表位的免疫反应, 而非针对与降低病毒血症发生率相关的gB AD-2表位, 这种偏向性可能削弱了疫苗的保护效力[17]。并且缺少可诱导细胞免疫的抗原表位, 最终导致难以产生有效的免疫反应。
3.3 复杂的糖基化修饰
HCMV包膜蛋白的糖基化修饰程度相对复杂。糖基化修饰的确切作用尚不完全清楚, 但已知可能涉及增强病毒的免疫逃逸或促进病毒的关键生物学过程, 如细胞融合和蛋白质加工过程。特别是HCMV gB和gH/gL等聚体复合物的主要中和表位被高度糖基化, 这可能是通过屏蔽中和表位同时暴露非中和表位, 以引导免疫反应偏离对病毒的有效中和[18]。
3.4 蛋白构象的不合理性
不合理的蛋白构象会导致针对HCMV的无效免疫反应。在实验条件下, gB蛋白构象由融合前形式到融合后形式的转变, 也对疫苗设计提出了挑战。融合后形式的gB可能无法有效促进病毒与宿主细胞的融合, 这表明使用该形式的gB进行免疫可能不如使用融合前形式有效[19]。然而, 通过构象抑制剂和交联化学分子的使用, 可以稳定gB的中和表位, 为疫苗设计提供了一种潜在的解决方案。
3.5 对免疫反应的抑制作用
HCMV具备一系列免疫逃逸机制。除了具有特殊的抗原特征外, 还包括对宿主免疫反应的抑制作用。如干扰模式识别受体信号通路, 抑制I型干扰素的表达, 抑制自然杀伤细胞的活性, 下调宿主细胞MHC分子的表达, 编码IL-10和MHC I分子的同源物, 诱导TGF-β的转录和释放, 通过与IgG的Fc区结合抑制ADCC反应等方式[4, 8]。此外, HCMV血清阳性个体具有更高水平的循环调节性T细胞, 可抑制细胞介导的免疫反应, 并可能有助于HCMV感染导致的免疫抑制作用[20]。HCMV能够在宿主细胞内潜伏, 形成长期的潜伏感染, 这可能对疫苗激活有效的免疫反应造成障碍。
3.6 药效动物模型开发受限
HCMV疫苗的动物体内研究存在病毒种属特异性的限制。由于不同的进化方向, 人类与其他动物的易感CMV种属显著不同, 不存在人与动物间的自然传播。针对疫苗的攻毒研究必须选择适应动物模型的CMV抗原和攻击病毒, 无法在临床试验之前通过动物模型评估目标HCMV疫苗的有效性[21]。恒河猴及其RhCMV (Rhesus cytomegalovirus) 可被应用于发病机制、抗病毒治疗、疫苗免疫保护研究。然而即使在恒河猴模型中疫苗诱导的体液免疫和细胞免疫强于自然感染后观察到的免疫反应, 获得的临床前试验结果对临床研究仍然不具有明确的指导意义[22]。因此, 开发能够感染HCMV并具有人源化免疫系统的动物模型具有重要的现实意义。
为应对HCMV病毒株间广泛的抗原变异性和复杂的糖基化模式, 需采用创新的疫苗设计策略, 以确保其对不同病毒变体的广泛适用性。同时, 考虑到存在的免疫逃逸机制以及HCMV与其他β-疱疹病毒亚科成员之间可能存在的交叉反应性, 疫苗开发需采用先进方法, 以激发能够有效识别并中和病毒的免疫反应。此外, 疫苗在激发免疫反应时不应引发病理损伤, 特别是在孕妇、新生儿和免疫功能低下患者等特殊人群中, 必须展现出极高的安全性。这些因素共同增加了HCMV疫苗研究设计的复杂程度, 要求研究人员在确保疫苗安全、有效的前提下进行更为精细和全面的考量。
4 HCMV疫苗开发的潜在思路
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4.1 优化选择病毒蛋白作为抗原
HCMV能在人体多种细胞中复制, 并能通过多种途径传播。gB、gH/gL/gO、PC、pp65以及IE蛋白在感染宿主细胞过程中起关键作用, 是疫苗设计的重要靶点。其中, gB、gH/gL/gO、PC蛋白介导病毒与宿主细胞膜的黏附和融合, 对其引发免疫反应是阻止病毒初始感染的重要环节。pp65蛋白作为HCMV的主要结构蛋白之一, 与病毒的基因表达、免疫逃逸及细胞代谢密切相关。IE1和IE2作为即刻早期蛋白, 在病毒复制周期中扮演关键角色, 含有多个能激活宿主免疫应答的优势抗原表位。将这些蛋白纳入疫苗设计, 能够激发更有效的免疫反应, 多样的HCMV抗原类型对控制病毒复制和预防感染具有重要意义。
gB、pp65蛋白一直以来都是HCMV疫苗研究的热点, 已有大量相关候选疫苗进入临床阶段[19], 而对gH/gL/gO、PC、IE蛋白的相关研究则较少。但如果不进行任何改造修饰, 直接将这些蛋白质作为疫苗抗原可能存在风险。已知多种HCMV基因产物被认为具有调节宿主免疫反应的作用, 在免疫逃避中发挥作用。如pp65蛋白可抑制抗病毒基因的表达, IE蛋白可通过阻断细胞凋亡来调节细胞周期, 并能诱导TGF-β的转录和释放。因此, 有必要在候选疫苗开发过程中对相关蛋白的免疫调节活性进行充分评估。
4.2 基于抗原表位分析进行抗原设计
将多种HCMV抗原全部混合纳入疫苗制剂似乎并不是一个容易实现的开发方向, 首先抗原种类过多会造成生产困难, 增加疫苗生产成本, 其次表达出的蛋白构象与HCMV天然的病毒蛋白构象可能并不完全相同, 尤其是当仅对抗原中部分蛋白结构进行表达的时候, 过多的非中和表位导致不能产生有效的体液免疫反应。除了优化选择病毒蛋白作为抗原, 还需要对不同蛋白的抗原表位进行更深入的研究和确认, 从中寻找对预防病毒感染最有价值的中和表位。应用先进的计算机算法通过实现最大程度的氨基酸序列保守性(以减轻潜在的遗传漂移或免疫逃逸)、MHC-肽结合亲和力(用于有效的MHC呈递)、HLA等位基因群体覆盖率(用于多种族的覆盖) 和最小的人类蛋白质交叉反应性(以避免自身免疫) 来过滤表位, 从而获得最具有临床应用价值的多肽序列。将获得的多肽序列连接在一起, 由此构建出新的多表位抗原。同样也可基于抗原表位分析实现对原有蛋白结构的改造, 如对于gB蛋白, 可将AD-3、AD-1编码区从多肽序列中去除, 减少非中和免疫反应的发生。而对于AD-2位点1 (AD2S1)、AD-4和AD-5, 由于可诱导有效和广泛的中和免疫反应, 应增加其在疫苗中的添加量。另外, 还可通过引入某些保守的抗原表位, 如gB AD-2、UL128, 产生特异性的抗体, 实现靶向遗传多样性的HCMV。
有研究通过应用组合筛选算法, 开发了一种创新的亚单位疫苗。该疫苗组合了多种抗原表位: B细胞表位、CD4+和CD8+ T细胞表位, 选择特定的连接子将各部分连接。并巧妙地融合了具有TLR-4激动活性的多肽作为佐剂, 赋予了疫苗激活IFN-γ细胞因子释放的能力, 从而增强免疫应答。研究还发现, 所选择的抗原表位在不同的毒株间具有保守性, 意味着该疫苗可能具有广泛的适用性。这种精心设计的亚单位疫苗为预防HCMV感染提供了新的思路[23]。
4.3 以激发细胞免疫反应为先导
原发性HCMV感染可诱导针对多种HCMV抗原的强烈体液反应, 这些抗体可以阻止病毒进入成纤维细胞、上皮细胞和内皮细胞, 以及在抑制病毒复制中发挥重要作用。过往的HCMV疫苗研究通常以获得有效的体液免疫(中和抗体) 为主要目标, 而对获得有效的细胞免疫并不重视。
HCMV感染后同样可引起由T淋巴细胞介导的细胞反应(包括CD4+和CD8+ T细胞介导的抗病毒功能), 有效抑制病毒复制并预防严重疾病。原发性HCMV感染期间产生的T细胞免疫反应主要靶向保守的病毒功能抗原, 如IE1和pp65。通过抗原表位分析, HCMV有40%的T细胞表位和15%的B细胞表位是保守的。这表明高序列变异性可促使HCMV逃避免疫反应, 特别是抗体反应。由此强调了T细胞反应在控制感染个体HCMV中的关键作用。与体液免疫相比, 人体似乎更容易获得有效的细胞免疫反应, 能够在大于90%的人群中发挥免疫保护作用[24]。
特异性CD4+和CD8+ T细胞对健康和免疫功能低下患者(如实体器官移植受者和AIDS患者) 在HCMV感染时可发挥特异性抗病毒作用[25-28], 另外也有研究表明特异性CD8+ T细胞有助于预防先天性HCMV感染[29]。通过人体研究还证明了对pp65特异性的CD4+ T细胞的特殊免疫作用, 该类特异性的CD4+ T细胞可防止发生HCMV垂直传播[30], 产生的保护作用可能与CD4+ T细胞介导的抗体成熟有关。RhCMV感染的非人灵长类动物模型也表明了母体CD4+ T细胞在预防先天性HCMV传播和疾病方面的重要性[31]。
4.4 选择新型佐剂引发更大免疫效果
除了精选蛋白抗原外, 佐剂的选用同样对提升疫苗效果至关重要。为了克服传统铝佐剂在增强细胞免疫应答方面的局限性, AS01、AS02、CpG OND以及IL-12等新型佐剂或佐剂系统正在被研究开发。将这些新型佐剂应用到HCMV疫苗制剂中有望实现更为有效的细胞免疫应答, 同时纠正HCMV对宿主免疫反应的抑制作用, 特别是能够上调病毒感染细胞中MHC I分子表达的佐剂, 对清除细胞内病毒至关重要。同时, 纳米技术和脂质体等新型递送系统的应用, 为疫苗开发开辟了新的可能性, 它们通过提高抗原递送效率和控制佐剂释放, 优化了免疫反应的强度和持久性, 模拟病毒颗粒特征的脂质体还能增强抗原提呈细胞的活性, 进一步提升了疫苗的免疫效果。不同创新策略的融合, 为预防和控制HCMV引起的疾病提供了更为全面和有效的新思路。
4.5 不同疫苗联合使用实现序贯免疫
目前针对HCMV的疫苗研究涵盖了多种开发策略, 主要包括减毒活疫苗、病毒载体疫苗、亚单位疫苗、多肽疫苗、DNA疫苗、RNA疫苗及病毒样颗粒疫苗。这些疫苗选择了不同的抗原类型组合, 具有不同的毒株覆盖性, 在临床试验中表现出不同的安全性和免疫原性特征。理想的HCMV疫苗可能需要多类型抗原, 具有不同的抗原表位, 最佳地实现体液和细胞免疫, 从而最大限度地拓展所引发的免疫保护。在未来的研究中, 可以通过初免-加强和/或联合给药的方式组合不同类型的疫苗实现序贯免疫, 如优先激发细胞免疫反应, 后续再激发体液免疫反应, 通过最先激发的细胞免疫为后续激发的体液免疫构建针对特定抗原表位免疫反应的方向性引导, 以此来最大限度地提高细胞反应和体液反应的有效性。
4.6 临床试验策略的改进
HCMV主要通过体液、血液、性接触、母婴接触及器官移植等途径传播。原则上, HCMV疫苗接种的目标人群包括4类: 血清阴性的育龄妇女、血清阳性的育龄妇女、实体器官移植和造血干细胞移植受体、造血干细胞移植供体。通过对移植供体和/或受体接种HCMV疫苗, 并采用与抢先抗病毒治疗(pre-emptive antiviral therapy, PET) 相互联合的治疗策略, 可以更有效地实现预防病毒感染或降低并发症发生率、死亡率。虽然目前的临床研究结果表明, HCMV疫苗在预防女性病毒感染方面的表现并不理想, 不能防止HCMV感染或病毒再激活, 但一种替代建议是将降低胎儿感染发生率作为临床终点, 在原有胎盘屏障隔离作用的基础上, 通过接种HCMV疫苗似乎更容易实现对先天性感染的预防。一项针对3 461名产妇的大型队列研究表明, 血清阴性产妇所生婴儿的先天性HCMV感染率为3%, 而血清阳性产妇所生婴儿的先天性HCMV感染率为1%, 预先存在的自然母体免疫力与降低垂直传播的风险有关[32]。即使在早期妊娠阶段被诊断为存在母体HCMV感染, 给予产妇高亲和力免疫球蛋白也可降低胎儿先天性感染风险[33]。
上述研究结果同样在动物模型中得到验证, 被动输注多克隆RhCMV中和抗体并不能阻止母体感染, 但能够预防胎儿先天性感染, 即使在母体CD4+ T细胞耗竭的情况下, 也能降低母体病毒血症水平, 这种病毒血症已被证明通常会导致先天性感染[34]。因此, 与预防或治疗成人病毒感染相比, 预防HCMV垂直传播可能是展现疫苗临床保护效力的更理想开发方向。
5 总结与展望
收起
HCMV疫苗的开发工作已经持续了50年, 尽管至今仍没有HCMV疫苗获得上市许可, 但在临床前和临床试验中都取得了令人鼓舞和有希望的结果。HCMV感染可诱导广泛的体液和T细胞介导的免疫反应, 并且这两种免疫反应都与保护相关。通过深入理解HCMV的感染机制, 识别病毒感染过程中的关键蛋白和构象, 合理设计多抗原/表位制剂组合, 由此开发HCMV候选疫苗可以引发最佳的免疫反应, 并通过序贯免疫的方式实现不同类型疫苗的强强联合, 可最大限度地提高对HCMV感染的保护力。基于免疫信息学和相关人工智能的快速发展, 并与传统实验验证相结合, 新疫苗的开发过程必将被极大地促进, 最终成功开发HCMV疫苗。
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doi: 10.16438/j.0513-4870.2024-1137
  • 接收时间：2024-11-16
  • 首发时间：2025-10-29
  • 出版时间：2025-04-12
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  • 收稿日期：2024-11-16
  • 修回日期：2025-01-06
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    1 中国海洋大学医药学院, 山东 青岛 266003
    2 简达生物医药 (南京) 有限公司, 江苏 南京 210031
    3 青岛科技大学生物工程学院, 山东 青岛 266042

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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