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Article(id=1217471090885054845, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1217471079325549522, articleNumber=null, orderNo=null, doi=10.13343/j.cnki.wsxb.20250558, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1753027200000, receivedDateStr=2025-07-21, revisedDate=null, revisedDateStr=null, acceptedDate=1761062400000, acceptedDateStr=2025-10-22, onlineDate=1768197327586, onlineDateStr=2026-01-12, pubDate=1767456000000, pubDateStr=2026-01-04, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768197327586, onlineIssueDateStr=2026-01-12, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768197327586, creator=13701087609, updateTime=1768197327586, updator=13701087609, issue=Issue{id=1217471079325549522, tenantId=1146029695717560320, journalId=1192105938417971205, year='2026', volume='66', issue='1', pageStart='1', pageEnd='475', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768197324830, creator=13701087609, updateTime=1768198886678, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1217477630291530315, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1217471079325549522, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1217477630291530316, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1217471079325549522, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=456, endPage=475, ext={EN=ArticleExt(id=1217471091103158671, articleId=1217471090885054845, tenantId=1146029695717560320, journalId=1192105938417971205, language=EN, title=Designing a broad-spectrum multi-epitope vaccine against human parainfluenza virus: an immunoinformatics approach, columnId=1194702985843413943, journalTitle=Acta Microbiologica Sinica, columnName=Technology and Method, runingTitle=null, highlight=null, articleAbstract=

[Objective] Human parainfluenza virus type 3 (HPIV-3) is a key factor in global acquired respiratory infections, and there is no specific therapy available. Due to the complexity and variability of the pathogen antigen, the development of vaccines against HPIV-3 is lagging behind. It is crucial to design a novel broad-spectrum vaccine for comprehensive protection against continuously mutated wild-type strains. [Methods] To overcome the antigenic variation of the virus, we downloaded different HPIV-3 antigen proteins (F, M, N, and HN proteins) from NCBI and generated consensus sequences through sequence alignment. Furthermore, a broad-spectrum T cell epitope vaccine targeting HPIV-3 was predicted and designed via methods of reverse vaccinology. [Results] The multi-epitope vaccine (MEV) incorporated 11 cytotoxic T lymphocyte (CTL) epitopes (9-mer) and 11 helper T lymphocyte (HTL) epitopes (15-mer) from the F, M, N and HN proteins, being composed of 355 amino acid residues without adjuvant. The predicted T cell epitopes had solubility, no allergenicity, high antigenicity, and immunogenicity. The designed vaccine can effectively bind to Toll-like receptors in natural immunity, with good stability, hydrophilicity, and high population coverage. [Conclusion] The designed vaccine could be a candidate vaccine against HPIV-3 infection. We provide a novel immunoinformatics approach for vaccine design and development.

, correspAuthors=Shulei JIA, authorNote=null, correspAuthorsNote=
*E-mail:
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【目的】 人副流感病毒3型(human parainfluenza virus type 3, HPIV-3)是全球获得性呼吸道感染的关键致病因素，目前尚无特异性治疗药物。鉴于该病原体抗原具有复杂性和变异性，其疫苗开发进展较为滞后。设计具有广谱特性的新型疫苗，对于为持续突变的野生型毒株提供全面防护至关重要。 【方法】 为克服病毒的抗原性变异，从NCBI下载不同的HPIV-3抗原蛋白(F、M、N和HN蛋白)序列，并通过序列比对分别生成共识序列，进一步运用反向疫苗学方法，预测并设计了一种针对HPIV-3的广谱T细胞表位疫苗。 【结果】 该多表位疫苗包含来自F、M、N和HN蛋白的11个CTL表位(9-mer)和11个HTL表位(15-mer)，由355个氨基酸组成，不含佐剂。预测的T细胞表位具备可溶性、非致敏性、高抗原性及免疫原性。设计的疫苗能有效结合天然免疫中的Toll样受体，具有较好的稳定性和亲水性，且人口覆盖度较高。 【结论】 本研究设计的HPIV-3多表位疫苗有望成为预防HPIV-3感染的候选疫苗，为疫苗的设计与开发提供了一种新颖的免疫信息学方法。

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Trends in Pharmacological Sciences, 2017, 38(9): 771-793., articleTitle=An overview of novel adjuvants designed for improving vaccine efficacy, refAbstract=null), Reference(id=1226557154157572479, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, doi=null, pmid=null, pmcid=null, year=2022, volume=40, issue=1, pageStart=14, pageEnd=30, url=null, language=null, rfNumber=[28], rfOrder=30, authorNames=SAMAD A, AHAMMAD F, NAIN Z, ALAM R, IMON RR, HASAN M, RAHMAN MS, journalName=Journal of Biomolecular Structure & Dynamics, refType=null, unstructuredReference=SAMAD A, AHAMMAD F, NAIN Z, ALAM R, IMON RR, HASAN M, RAHMAN MS. Designing a multi-epitope vaccine against SARS-CoV-2: an immunoinformatics approach[J]. Journal of Biomolecular Structure & Dynamics, 2022, 40(1): 14-30., articleTitle=Designing a multi-epitope vaccine against SARS-CoV-2: an immunoinformatics approach, refAbstract=null), Reference(id=1226557154270818692, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, doi=null, pmid=null, pmcid=null, year=2017, volume=7, issue=null, pageStart=8285, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=31, authorNames=KHATOON N, PANDEY RK, PRAJAPATI VK, journalName=Scientific Reports, refType=null, unstructuredReference=KHATOON N, PANDEY RK, PRAJAPATI VK. Exploring Leishmania secretory proteins to design B and T cell multi-epitope subunit vaccine using immunoinformatics approach[J]. Scientific Reports, 2017, 7: 8285., articleTitle=Exploring Leishmania secretory proteins to design B and T cell multi-epitope subunit vaccine using immunoinformatics approach, refAbstract=null), Reference(id=1226557154396647815, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, doi=null, pmid=null, pmcid=null, year=2023, volume=8, issue=1, pageStart=53, pageEnd=null, url=null, language=null, rfNumber=[30], rfOrder=32, authorNames=KNISELY JM, BUYON LE, MANDT R, FARKAS R, BALASINGAM S, BOK K, BUCHHOLZ UJ, D’SOUZA MP, GORDON JL, KING DFL, LE TT, LEITNER WW, SEDER RA, TOGIAS A, TOLLEFSEN S, VAUGHN DW, WOLFE DN, TAYLOR KL, FAUCI AS, journalName=npj Vaccines, refType=null, unstructuredReference=KNISELY JM, BUYON LE, MANDT R, FARKAS R, BALASINGAM S, BOK K, BUCHHOLZ UJ, D’SOUZA MP, GORDON JL, KING DFL, LE TT, LEITNER WW, SEDER RA, TOGIAS A, TOLLEFSEN S, VAUGHN DW, WOLFE DN, TAYLOR KL, FAUCI AS. Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities-workshop report[J]. npj Vaccines, 2023, 8(1): 53., articleTitle=Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities-workshop report, refAbstract=null), Reference(id=1226557154509894027, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, doi=null, pmid=null, pmcid=null, year=2024, volume=14, issue=null, pageStart=1409111, pageEnd=null, url=null, language=null, rfNumber=[31], rfOrder=33, authorNames=CARSETTI R, QUINTI I, journalName=Frontiers in Cellular and Infection Microbiology, refType=null, unstructuredReference=CARSETTI R, QUINTI I. Editorial: IgA and mucosal immunity in vaccinology and in protection from infection[J]. Frontiers in Cellular and Infection Microbiology, 2024, 14: 1409111., articleTitle=Editorial: IgA and mucosal immunity in vaccinology and in protection from infection, refAbstract=null)], funds=[Fund(id=1226557149212487858, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, awardId=24JCQNJC00460, language=EN, fundingSource=Tianjin Natural Science Foundation Youth Project(24JCQNJC00460), fundOrder=null, country=null), Fund(id=1226557149325734075, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, awardId=24JCQNJC00460, language=CN, fundingSource=天津市自然科学基金青年基金(24JCQNJC00460), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1226557136973509358, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, xref=1., ext=[AuthorCompanyExt(id=1226557136981897965, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, companyId=1226557136973509358, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China), AuthorCompanyExt(id=1226557136990286574, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, companyId=1226557136973509358, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.天津医科大学 基础医学院，天津)]), AuthorCompany(id=1226557137090949879, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, xref=2., ext=[AuthorCompanyExt(id=1226557137099338487, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, companyId=1226557137090949879, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.National Engineering Research Center for Beijing Biochip Technology (CapitalBio), Beijing, China), AuthorCompanyExt(id=1226557137107727098, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, companyId=1226557137090949879, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.生物芯片北京国家工程研究中心，北京)])], figs=[ArticleFig(id=1226557142551933943, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 1, caption=The pipeline of the HPIV-3 vaccine construction. The candidate T cell vaccine was structurally designed by combining CTL and HTL epitopes with the C-terminus of the vaccine being added with 6×His (histidine)., figureFileSmall=pKoAvJGKgCkzluVmM0yK3w==, figureFileBig=+jD0jD3A5TGyI1K9Eu1wGQ==, tableContent=null), ArticleFig(id=1226557144087049215, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图1, caption=HPIV-3疫苗构建流程。候选T细胞疫苗通过将CTL和HTL表位组合进行结构设计，并在疫苗的C端添加了6×His (组氨酸)标签。, figureFileSmall=pKoAvJGKgCkzluVmM0yK3w==, figureFileBig=+jD0jD3A5TGyI1K9Eu1wGQ==, tableContent=null), ArticleFig(id=1226557144309346311, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 2, caption=Population coverage of the candidate vaccine. A: Global coverage of MHC class I and II epitopes; B: Global coverage of MHC class I epitopes; C: Global coverage of MHC class II epitopes; D: European population coverage of MHC class I and II epitopes; E: Northeast Asian regional population coverage of MHC class I and II epitopes; F: North American population coverage of MHC class I and II epitopes. The 90% red line represents that the cumulative population coverage reaches 90%; It is used to measure the extent of coverage of vaccine-induced immune epitopes in the target population, with the reference standard being the ability of relevant vaccine immune epitopes to elicit immune recognition and response in 90% of the target population, thereby assisting in evaluating the vaccine’s protective scope and potential for the population., figureFileSmall=zuM/dG2wl4wcWQ8hfieNOg==, figureFileBig=Q9E+GYbSyMXS0uXiLNE4Yg==, tableContent=null), ArticleFig(id=1226557144430981131, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图2, caption=候选疫苗的人群覆盖度。A：MHC I和MHC II类表位的全球人群覆盖度；B：MHC I类表位的全球人群覆盖度；C：MHC II类表位的全球人群覆盖度；D：MHC I和MHC II类表位的欧洲人群覆盖度；E：MHC I和MHC II类表位的东北亚区域人群覆盖度；F：MHC I和MHC II类表位的北美人群覆盖度。90%红线表示累积人群覆盖度达到90%，它用于衡量疫苗诱导的免疫表位覆盖目标人群的程度，有助于评估疫苗对人群的保护范围和潜力，可作为与疫苗相关的免疫表位使90%目标人群产生免疫识别和反应的参考标准。, figureFileSmall=zuM/dG2wl4wcWQ8hfieNOg==, figureFileBig=Q9E+GYbSyMXS0uXiLNE4Yg==, tableContent=null), ArticleFig(id=1226557144661667856, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 3, caption=3D refinement and validation of the HPIV-3 vaccine. A: The optimized 3D structure of the designed vaccine; B: The statistics of Ramachandran plot, indicating the most acceptable, disallowed and favorable regions; C: The ProSA-web result, with a Z-score of -2.86 for the optimized vaccine model., figureFileSmall=FQtPRSKtlzDUv984i48NDQ==, figureFileBig=fKzLncw1VaiSEFP1vW8MRw==, tableContent=null), ArticleFig(id=1226557144821051414, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图3, caption=HPIV-3疫苗的三级结构优化与评估。A：设计疫苗的3D结构优化；B：Ramachandran图统计，指示最可接受、不允许和有利的区域；C：ProSA-web结果，优化疫苗模型的Z-score值为-2.86。, figureFileSmall=FQtPRSKtlzDUv984i48NDQ==, figureFileBig=fKzLncw1VaiSEFP1vW8MRw==, tableContent=null), ArticleFig(id=1226557144963657759, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 4, caption=Disulfide bond design in the designed vaccine. The mutant variant features Gly112-Met117, Ser141-Met158, Thr201-Ile204, Val228-Gly234, Gly268-Gly274 that have been mutated into cysteine residues, which form disulfide bonds represented by yellow sticks., figureFileSmall=AIOcxHnwL9z8+shvZ3Wgvw==, figureFileBig=8mdBqvEpPfMa2Tdirohzdw==, tableContent=null), ArticleFig(id=1226557145097875490, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图4, caption=设计疫苗的二硫键设计。突变体包含Gly112-Met117、Ser141-Met158、Thr201-Ile204、Val228-Gly234、Gly268-Gly274，这些残基已被突变为半胱氨酸残基，形成由黄色棒表示的二硫键。, figureFileSmall=AIOcxHnwL9z8+shvZ3Wgvw==, figureFileBig=8mdBqvEpPfMa2Tdirohzdw==, tableContent=null), ArticleFig(id=1226557145257259046, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 5, caption=Molecular docking between HPIV-3 and the receptors. A: Molecular docking between HPIV-3 vaccine, glycoprotein and the TLR4 receptor, respectively; The model with the lowest energy was selected as the optimal binding mode; B: Molecular docking of the HPIV-3 with TLR3 receptor. The yellow dashed lines indicate hydrogen bonds, while the red dashed lines represent van der Waals forces., figureFileSmall=YiAbHN7FxI0UFd208EecPw==, figureFileBig=7wnh70Bq1S86OsQRu21T6Q==, tableContent=null), ArticleFig(id=1226557145429225516, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图5, caption=HPIV-3与受体的分子对接。A：HPIV-3疫苗、LPS糖蛋白分别与TLR4受体分子对接；选择能量最低的模型作为最佳结合模式；B：HPIV-3与TLR3受体的分子对接。黄色虚线表示氢键，红色虚线表示范德华力。, figureFileSmall=YiAbHN7FxI0UFd208EecPw==, figureFileBig=7wnh70Bq1S86OsQRu21T6Q==, tableContent=null), ArticleFig(id=1226557145567637561, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 6, caption=Molecular docking between HPIV-3 and the TLR7/8 receptors. A: Molecular docking between HPIV-3 and the TLR7 receptor, with the lowest energy of -2 485.6 kcal/mol; B: Molecular docking between HPIV-3 and the TLR8 receptor with the lowest energy of -1 310.3 kcal/mol., figureFileSmall=eZRdq5Zf7u7eNUgRrbFisw==, figureFileBig=zV6usP4CWB3bT++rFuXM6g==, tableContent=null), ArticleFig(id=1226557145693466683, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图6, caption=HPIV-3与TLR7/8受体分子对接。A：HPIV-3与TLR7受体的分子对接，最低结合能为-2 485.6 kcal/mol；B：HPIV-3与TLR8受体的分子对接，最低结合能为-1 310.3 kcal/mol。, figureFileSmall=eZRdq5Zf7u7eNUgRrbFisw==, figureFileBig=zV6usP4CWB3bT++rFuXM6g==, tableContent=null), ArticleFig(id=1226557145857044547, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 7, caption=Normal mode analysis of the vaccine-TLR4 complex. A: Affine-arrows of the vaccine-TLR4 complex; B: Covariance map of the complex [Covariance matrix indicates coupling between pairs of residues, i.e. whether they experience correlated (red), uncorrelated (white) or anti-correlated (blue) motions]; C: Deformability index; D: B-factor column; E: Eigenvalue; F: NMA variance., figureFileSmall=V8p4EEmSPwulH5LX8MR0DA==, figureFileBig=CbiEeVzwwdLe4CF9DDLLrg==, tableContent=null), ArticleFig(id=1226557145970290757, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图7, caption=疫苗-TLR4复合物的正态模式分析。A：疫苗-TLR4复合物的仿射箭头；B：复合物的协方差图[协方差矩阵表示残基对之间的耦合，即它们经历的是相关(红色)、不相关(白色)还是反相关(蓝色)运动]；C：可变形性指数；D：B因子柱状图；E：特征值；F：NMA方差。, figureFileSmall=V8p4EEmSPwulH5LX8MR0DA==, figureFileBig=CbiEeVzwwdLe4CF9DDLLrg==, tableContent=null), ArticleFig(id=1226557146091925580, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 8, caption=Normal mode analysis of the vaccine-TLR3 complex. A: Affine-arrows of the vaccine-TLR3 complex; B: Covariance map of the complex [Covariance matrix indicates coupling between pairs of residues, i.e. whether they experience correlated (red), uncorrelated (white) or anti-correlated (blue) motions]; C: Deformability index; D: B-factor column; E: Eigenvalue; F: NMA variance., figureFileSmall=/CRwkXlK0wXg15b01o8Piw==, figureFileBig=1OCq6/mAHpS9L1h/UCV7MA==, tableContent=null), ArticleFig(id=1226557146247114838, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图8, caption=疫苗-TLR3复合物的正态模式分析。A：疫苗-TLR3复合物的仿射箭头；B：复合物的协方差图[协方差矩阵表示残基对之间的耦合，即它们经历的是相关(红色)、不相关(白色)还是反相关(蓝色)运动]；C：可变形性指数；D：B因子柱状图；E：特征值；F：NMA方差。, figureFileSmall=/CRwkXlK0wXg15b01o8Piw==, figureFileBig=1OCq6/mAHpS9L1h/UCV7MA==, tableContent=null), ArticleFig(id=1226557146389721182, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 9, caption=The designed vaccine was virtually cloned into the pET-29a(+) vector. A: Virtual cloning of designed vaccine into the pET-29a(+) vector; B: Purification diagram of protein expression (The recombinate product, with the vaccine construct inserted and highlighted in green within the vector, was shown; The E. coli expression system was used to express the HPIV-3 vaccine)., figureFileSmall=cqWgMA0LC9MZtsJmBqCtQQ==, figureFileBig=Yubju9Bmt78zApPZyQ65Fg==, tableContent=null), ArticleFig(id=1226557146481995877, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图9, caption=将设计的疫苗虚拟克隆到pET-29a(+)载体。A：设计的疫苗虚拟克隆到pET-29a(+)载体；B：蛋白表达纯化图(重组载体插入了疫苗构建体，并在载体内以绿色突出显示，采用大肠杆菌表达系统表达HPIV-3疫苗)。, figureFileSmall=cqWgMA0LC9MZtsJmBqCtQQ==, figureFileBig=Yubju9Bmt78zApPZyQ65Fg==, tableContent=null), ArticleFig(id=1226557146595242092, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Figure 10, caption=Humoral immune responses induced by vaccination in mice. Mice (n=12) in each group were immunized via intranasal inoculation with the vaccine, while control mice received a placebo (PBS); Serum and bronchoalveolar lavage fluid (BALF) samples were collected at three weeks post-vaccination; The titers of binding antibodies against the HPIV-3 virus are presented as lg values, showing from left to right: total IgG in serum, total IgG in BALF, and total IgA in BALF; Each data point represents pooled samples from two mice (including BALF and serum); Statistical significance was determined by one-way ANOVA with Tukey’s correction test: *: P<0.05, **: P<0.01, ***: P<0.001., figureFileSmall=NP9it2FTH2+YGW6YffkFCw==, figureFileBig=pRY78eC0+SQV2ngVF8OOvA==, tableContent=null), ArticleFig(id=1226557146763014260, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=图10, caption=疫苗免疫小鼠诱导的体液免疫反应。每组小鼠(n=12)通过鼻内接种方式接种疫苗；对照组小鼠则接种安慰剂(PBS)；血清(serum)和支气管肺泡灌洗液(BALF)样本在疫苗接种后第3周采取；针对人副流感病毒3型的结合抗体滴度结果以lg表示，从左至右依次为血清总IgG、肺泡灌洗液总IgG和肺泡灌洗液总IgA；每个数据点代表两只小鼠的混合样本数据(包括支气管肺泡灌洗液、血清)；统计学显著性采用单因素方差分析(ANOVA)并进行Tukey校正检验，*：P<0.05，**：P<0.01，***：P<0.001。, figureFileSmall=NP9it2FTH2+YGW6YffkFCw==, figureFileBig=pRY78eC0+SQV2ngVF8OOvA==, tableContent=null), ArticleFig(id=1226557146884649076, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Table 1, caption=

List of the CTL and HTL epitopes selected to construct the candidate vaccine

, figureFileSmall=null, figureFileBig=null, tableContent=
类别蛋白

总平均疏水

指数(GRAVY)

蛋白肽长度位置等位基因抗原得分I类肽免疫原性IFN-γ得分

人群覆

盖度

TypesProtein

Grand

average of hydropathicity (GRAVY)

Peptide sequenceLength (mer)LocationAllelesAntigenicity scoreImmunogenicity of class I epitopeIFN-γ score

Population coverage

(%)

CTL epitopesF1.722AQITAAVAL9126-135HLA-B*15:010.6730.215N/A8.44
1.333AAVALVEAK9130-139HLA-A*11:011.3990.188N/A15.53
0.056VTSDIVPRY9368-377HLA-A*11:010.6150.158N/A15.53
2.111ITIITIAIK9509-518HLA-A*11:011.6120.451N/A15.53
M-0.911SENGHIEPL917-26HLA-B*39:011.0680.267N/A2.75
0.756GSLPIGLAK990-99HLA-A*11:010.9810.160N/A15.53
0.778VEITRVDAI9318-327HLA-B*40:011.2270.213N/A7.81
-0.789PSLPGEFRY9329-338HLA-A*01:010.9550.242N/A17.34
-0.589RYYPNIIAK9336-345HLA-A*03:010.7970.242N/A16.81
N-0.444IRYGIETRM9272-281HLA-B*27:051.0350.320N/A4.78
HN0.144PSVGPGIYY9320-329HLA-A*01:010.7670.179N/A17.34
HTL epitopesF-0.827QIYKVDSISYNIQNR15292-307HLA-DRB1*03:01, HLA-DRB1*04:010.706N/A0.20427.97
0.500SHIMTKGAFLGGADV15314-329HLA-DRB1*01:01, HLA-DRB1*09:01, HLA-DRB1*07:010.487N/A0.25634.02
0.400SVALDPIDISIELNK15448-463HLA-DRB1*03:011.366N/A0.25917.84
1.160INITIITIAIKYYRI15507-522HLA-DRB1*03:01, HLA-DRB1*07:01, HLA-DRB1*15:011.381N/A0.42049.02
M-0.493HIKTGVQTDSKGVVQ15209-224HLA-DRB1*03:010.641N/A0.13217.84
0.147MVHLGLIKRKVGRMY15236-251HLA-DRB1*03:010.592N/A0.41817.84
-0.433EFRYYPNIIAKGVGK15334-349HLA-DRB1*01:01, HLA-DRB1*04:01, HLA-DRB1*09:01, HLA-DRB1*15:01, HLA-DRB1*07:010.831N/A0.48456.72
N0.827PAIWSYAMGVAVVQN15329-344HLA-DRB1*01:01, HLA-DRB1*07:01, HLA-DRB1*09:010.592N/A0.30234.02
0.633IWSYAMGVAVVQNRA15331-346HLA-DRB1*01:01, HLA-DRB1*07:01, HLA-DRB1*09:010.646N/A0.53234.02
-1.153IIQYAWAEGNRSDDR15443-458HLA-DRB1*09:01, HLA-DRB1*04:010.440N/A0.23317.24
HN0.587GKIIFLGYGGLEHPI15330-345HLA-DRB1*15:010.673N/A0.93518.41
), ArticleFig(id=1226557147035644026, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=表1, caption=

用于构建候选疫苗的CTL和HTL表位列表

, figureFileSmall=null, figureFileBig=null, tableContent=
类别蛋白

总平均疏水

指数(GRAVY)

蛋白肽长度位置等位基因抗原得分I类肽免疫原性IFN-γ得分

人群覆

盖度

TypesProtein

Grand

average of hydropathicity (GRAVY)

Peptide sequenceLength (mer)LocationAllelesAntigenicity scoreImmunogenicity of class I epitopeIFN-γ score

Population coverage

(%)

CTL epitopesF1.722AQITAAVAL9126-135HLA-B*15:010.6730.215N/A8.44
1.333AAVALVEAK9130-139HLA-A*11:011.3990.188N/A15.53
0.056VTSDIVPRY9368-377HLA-A*11:010.6150.158N/A15.53
2.111ITIITIAIK9509-518HLA-A*11:011.6120.451N/A15.53
M-0.911SENGHIEPL917-26HLA-B*39:011.0680.267N/A2.75
0.756GSLPIGLAK990-99HLA-A*11:010.9810.160N/A15.53
0.778VEITRVDAI9318-327HLA-B*40:011.2270.213N/A7.81
-0.789PSLPGEFRY9329-338HLA-A*01:010.9550.242N/A17.34
-0.589RYYPNIIAK9336-345HLA-A*03:010.7970.242N/A16.81
N-0.444IRYGIETRM9272-281HLA-B*27:051.0350.320N/A4.78
HN0.144PSVGPGIYY9320-329HLA-A*01:010.7670.179N/A17.34
HTL epitopesF-0.827QIYKVDSISYNIQNR15292-307HLA-DRB1*03:01, HLA-DRB1*04:010.706N/A0.20427.97
0.500SHIMTKGAFLGGADV15314-329HLA-DRB1*01:01, HLA-DRB1*09:01, HLA-DRB1*07:010.487N/A0.25634.02
0.400SVALDPIDISIELNK15448-463HLA-DRB1*03:011.366N/A0.25917.84
1.160INITIITIAIKYYRI15507-522HLA-DRB1*03:01, HLA-DRB1*07:01, HLA-DRB1*15:011.381N/A0.42049.02
M-0.493HIKTGVQTDSKGVVQ15209-224HLA-DRB1*03:010.641N/A0.13217.84
0.147MVHLGLIKRKVGRMY15236-251HLA-DRB1*03:010.592N/A0.41817.84
-0.433EFRYYPNIIAKGVGK15334-349HLA-DRB1*01:01, HLA-DRB1*04:01, HLA-DRB1*09:01, HLA-DRB1*15:01, HLA-DRB1*07:010.831N/A0.48456.72
N0.827PAIWSYAMGVAVVQN15329-344HLA-DRB1*01:01, HLA-DRB1*07:01, HLA-DRB1*09:010.592N/A0.30234.02
0.633IWSYAMGVAVVQNRA15331-346HLA-DRB1*01:01, HLA-DRB1*07:01, HLA-DRB1*09:010.646N/A0.53234.02
-1.153IIQYAWAEGNRSDDR15443-458HLA-DRB1*09:01, HLA-DRB1*04:010.440N/A0.23317.24
HN0.587GKIIFLGYGGLEHPI15330-345HLA-DRB1*15:010.673N/A0.93518.41
), ArticleFig(id=1226557148390404226, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Table 2, caption=

Physicochemical properties, immuno-reactivity and secondary structure of the multi-epitope vaccine

, figureFileSmall=null, figureFileBig=null, tableContent=
ItemResults

理化性质

Physical and chemical properties

Number of amino acids335
Molecular weight37 049.6 Da
Predicted scaled solubility0.43

总平均疏水指数

Grand average of hydropathicity (GRAVY)

0.037

不稳定性和理论等电点

Instability and theoretical pI

Instability index (II)25.67
Aliphatic index90.79
Theoretical pI9.42

免疫反应性

Immuno-reactivity

Non-allergen
Immunogenicity5.48
Antigen0.67

二级结构

Secondary structure

α-helix21% (73/349)
β-strand25% (86/349)
Random coils54% (190/349)
), ArticleFig(id=1226557148457513096, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=表2, caption=

多表位疫苗的理化特性、免疫反应性和二级结构

, figureFileSmall=null, figureFileBig=null, tableContent=
ItemResults

理化性质

Physical and chemical properties

Number of amino acids335
Molecular weight37 049.6 Da
Predicted scaled solubility0.43

总平均疏水指数

Grand average of hydropathicity (GRAVY)

0.037

不稳定性和理论等电点

Instability and theoretical pI

Instability index (II)25.67
Aliphatic index90.79
Theoretical pI9.42

免疫反应性

Immuno-reactivity

Non-allergen
Immunogenicity5.48
Antigen0.67

二级结构

Secondary structure

α-helix21% (73/349)
β-strand25% (86/349)
Random coils54% (190/349)
), ArticleFig(id=1226557148587536525, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Table 3, caption=

List of potential disulfide bond residues in the designed vaccine

, figureFileSmall=null, figureFileBig=null, tableContent=

氨基酸残基1

Residues 1 (AA)

氨基酸残基2

Residues 2 (AA)

第三侧链二面角

Chi3 (°)

能量

Energy (kcal/mol)

Leu57Ala8377.892.82
Gly61Pro85111.133.20
Ala83Ala107119.495.04
Gly112Thr115117.513.27
Gly112Met117-76.380.46
Ser122Ser143115.825.07
Gly126Ile146117.226.44
Tyr128Gly134-111.987.39
Tyr129Arg149117.186.33
Ser141Met158-82.661.63
Asn148Gly15473.852.51
Thr159Asp179-104.546.01
Asp168Gly174-79.292.56
Pro180Ser184-116.273.30
Thr198Thr218-90.144.78
Thr201Ile204122.442.19
Ile209Gln229126.766.77
Ser224Lys24492.615.47
Val228Gly234-92.281.46
His237Arg257125.126.92
Leu240Pro260-114.542.52
Glu255Pro275-96.095.96
Tyr259Ser279109.266.19
Asn261Ala26491.884.16
Ala264Val284-95.055.17
Gly268Gly274-105.301.16
Ala276Trp29691.263.62
Gly283Ala30387.113.94
Tyr298Gly301-116.055.15
Val305Arg325125.546.80
Asn307Asp327124.326.41
Tyr318Ala321-74.974.97
), ArticleFig(id=1226557148725948560, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=表3, caption=

设计疫苗中的潜在二硫键残基对列表

, figureFileSmall=null, figureFileBig=null, tableContent=

氨基酸残基1

Residues 1 (AA)

氨基酸残基2

Residues 2 (AA)

第三侧链二面角

Chi3 (°)

能量

Energy (kcal/mol)

Leu57Ala8377.892.82
Gly61Pro85111.133.20
Ala83Ala107119.495.04
Gly112Thr115117.513.27
Gly112Met117-76.380.46
Ser122Ser143115.825.07
Gly126Ile146117.226.44
Tyr128Gly134-111.987.39
Tyr129Arg149117.186.33
Ser141Met158-82.661.63
Asn148Gly15473.852.51
Thr159Asp179-104.546.01
Asp168Gly174-79.292.56
Pro180Ser184-116.273.30
Thr198Thr218-90.144.78
Thr201Ile204122.442.19
Ile209Gln229126.766.77
Ser224Lys24492.615.47
Val228Gly234-92.281.46
His237Arg257125.126.92
Leu240Pro260-114.542.52
Glu255Pro275-96.095.96
Tyr259Ser279109.266.19
Asn261Ala26491.884.16
Ala264Val284-95.055.17
Gly268Gly274-105.301.16
Ala276Trp29691.263.62
Gly283Ala30387.113.94
Tyr298Gly301-116.055.15
Val305Arg325125.546.80
Asn307Asp327124.326.41
Tyr318Ala321-74.974.97
), ArticleFig(id=1226557148847583385, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=EN, label=Table 4, caption=

The binding energy between the vaccine and TLR4 receptor

, figureFileSmall=null, figureFileBig=null, tableContent=
ClusterMembersRepresentativeWeighted score
0136Lowest energy-1 287.6
1118Lowest energy-1 287.0
251Lowest energy-1 220.5
349Lowest energy-1 247.5
446Lowest energy-1 255.8
532Lowest energy-1 187.4
626Lowest energy-1 289.0
726Lowest energy-1 299.7
824Lowest energy-1 202.6
922Lowest energy-1 143.1
1021Lowest energy-1 274.7
1121Lowest energy-1 112.7
1220Lowest energy-1 210.2
1319Lowest energy-1 191.4
1416Lowest energy-1 194.7
1515Lowest energy-1 097.2
1615Lowest energy-1 138.9
1714Lowest energy-1 291.1
1814Lowest energy-1 057.1
1914Lowest energy-1 183.7
2014Lowest energy-1 116.5
2113Lowest energy-1 151.3
2213Lowest energy-1 059.1
2312Lowest energy-1 040.9
2412Lowest energy-1 092.6
2512Lowest energy-1 070.2
2611Lowest energy-1 115.4
2711Lowest energy-1 068.6
2811Lowest energy-1 065.8
2910Lowest energy-1 063.3
), ArticleFig(id=1226557148977606816, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1217471090885054845, language=CN, label=表4, caption=

疫苗与TLR4受体对接结合能

, figureFileSmall=null, figureFileBig=null, tableContent=
ClusterMembersRepresentativeWeighted score
0136Lowest energy-1 287.6
1118Lowest energy-1 287.0
251Lowest energy-1 220.5
349Lowest energy-1 247.5
446Lowest energy-1 255.8
532Lowest energy-1 187.4
626Lowest energy-1 289.0
726Lowest energy-1 299.7
824Lowest energy-1 202.6
922Lowest energy-1 143.1
1021Lowest energy-1 274.7
1121Lowest energy-1 112.7
1220Lowest energy-1 210.2
1319Lowest energy-1 191.4
1416Lowest energy-1 194.7
1515Lowest energy-1 097.2
1615Lowest energy-1 138.9
1714Lowest energy-1 291.1
1814Lowest energy-1 057.1
1914Lowest energy-1 183.7
2014Lowest energy-1 116.5
2113Lowest energy-1 151.3
2213Lowest energy-1 059.1
2312Lowest energy-1 040.9
2412Lowest energy-1 092.6
2512Lowest energy-1 070.2
2611Lowest energy-1 115.4
2711Lowest energy-1 068.6
2811Lowest energy-1 065.8
2910Lowest energy-1 063.3
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人副流感病毒广谱T细胞表位疫苗设计：一种免疫信息学方法
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陈苓苓 1 , 李旸 2 , 曹赫男 1 , 江晓 1 , 聂嘉琪 1 , 贾书磊 1, *
微生物学报 | 技术与方法 2026,66(1): 456-475
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微生物学报 | 技术与方法 2026, 66(1): 456-475
人副流感病毒广谱T细胞表位疫苗设计：一种免疫信息学方法
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陈苓苓1, 李旸2, 曹赫男1, 江晓1, 聂嘉琪1, 贾书磊1, *
作者信息
  • 1.天津医科大学 基础医学院，天津
  • 2.生物芯片北京国家工程研究中心，北京
Designing a broad-spectrum multi-epitope vaccine against human parainfluenza virus: an immunoinformatics approach
Lingling CHEN1, Yang LI2, Henan CAO1, Xiao JIANG1, Jiaqi NIE1, Shulei JIA1, *
Affiliations
  • 1.School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
  • 2.National Engineering Research Center for Beijing Biochip Technology (CapitalBio), Beijing, China
出版时间: 2026-01-04 doi: 10.13343/j.cnki.wsxb.20250558
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【目的】 人副流感病毒3型(human parainfluenza virus type 3, HPIV-3)是全球获得性呼吸道感染的关键致病因素，目前尚无特异性治疗药物。鉴于该病原体抗原具有复杂性和变异性，其疫苗开发进展较为滞后。设计具有广谱特性的新型疫苗，对于为持续突变的野生型毒株提供全面防护至关重要。 【方法】 为克服病毒的抗原性变异，从NCBI下载不同的HPIV-3抗原蛋白(F、M、N和HN蛋白)序列，并通过序列比对分别生成共识序列，进一步运用反向疫苗学方法，预测并设计了一种针对HPIV-3的广谱T细胞表位疫苗。 【结果】 该多表位疫苗包含来自F、M、N和HN蛋白的11个CTL表位(9-mer)和11个HTL表位(15-mer)，由355个氨基酸组成，不含佐剂。预测的T细胞表位具备可溶性、非致敏性、高抗原性及免疫原性。设计的疫苗能有效结合天然免疫中的Toll样受体，具有较好的稳定性和亲水性，且人口覆盖度较高。 【结论】 本研究设计的HPIV-3多表位疫苗有望成为预防HPIV-3感染的候选疫苗，为疫苗的设计与开发提供了一种新颖的免疫信息学方法。

人副流感病毒3型  /  免疫信息学  /  多表位疫苗  /  反向疫苗学

[Objective] Human parainfluenza virus type 3 (HPIV-3) is a key factor in global acquired respiratory infections, and there is no specific therapy available. Due to the complexity and variability of the pathogen antigen, the development of vaccines against HPIV-3 is lagging behind. It is crucial to design a novel broad-spectrum vaccine for comprehensive protection against continuously mutated wild-type strains. [Methods] To overcome the antigenic variation of the virus, we downloaded different HPIV-3 antigen proteins (F, M, N, and HN proteins) from NCBI and generated consensus sequences through sequence alignment. Furthermore, a broad-spectrum T cell epitope vaccine targeting HPIV-3 was predicted and designed via methods of reverse vaccinology. [Results] The multi-epitope vaccine (MEV) incorporated 11 cytotoxic T lymphocyte (CTL) epitopes (9-mer) and 11 helper T lymphocyte (HTL) epitopes (15-mer) from the F, M, N and HN proteins, being composed of 355 amino acid residues without adjuvant. The predicted T cell epitopes had solubility, no allergenicity, high antigenicity, and immunogenicity. The designed vaccine can effectively bind to Toll-like receptors in natural immunity, with good stability, hydrophilicity, and high population coverage. [Conclusion] The designed vaccine could be a candidate vaccine against HPIV-3 infection. We provide a novel immunoinformatics approach for vaccine design and development.

human parainfluenza virus type 3  /  immunoinformatics  /  multi-epitope vaccine  /  reverse vaccinology
陈苓苓, 李旸, 曹赫男, 江晓, 聂嘉琪, 贾书磊. 人副流感病毒广谱T细胞表位疫苗设计：一种免疫信息学方法. 微生物学报, 2026 , 66 (1) : 456 -475 . DOI: 10.13343/j.cnki.wsxb.20250558
Lingling CHEN, Yang LI, Henan CAO, Xiao JIANG, Jiaqi NIE, Shulei JIA. Designing a broad-spectrum multi-epitope vaccine against human parainfluenza virus: an immunoinformatics approach[J]. Acta Microbiologica Sinica, 2026 , 66 (1) : 456 -475 . DOI: 10.13343/j.cnki.wsxb.20250558
正文
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人副流感病毒(human parainfluenza virus, HPIV)是有包膜的负链单链RNA病毒，属于副黏病毒科，这些病毒是所有年龄段人群，尤其是婴儿、幼儿和免疫系统受损个体发生急性呼吸道感染(acute respiratory infections, ARIs)的主要且常见病因[1-2]。HPIV基因组包含6个转录基因单元，其翻译的蛋白质包括核衣壳蛋白(N)、磷蛋白(P)、基质蛋白(M)、融合蛋白(F)、血凝素-神经氨酸酶蛋白(HN)和大蛋白(L)[2]。F和HN蛋白是HPIV的表面蛋白，前者负责将病毒结合到细胞膜表面的唾液酸，后者介导病毒与宿主细胞膜的融合，二者的结合是呼吸道上皮细胞感染的第一步，这2种蛋白是该病毒的主要保护性抗原[2-3]。M蛋白对病毒粒子的组装和释放至关重要，它覆盖在包膜的内表面；N蛋白包裹病毒RNA，形成稳定的核衣壳；P和L蛋白则与N蛋白结合并相互作用形成病毒RNA聚合酶[2-4]。HPIV有4种主要类型(HPIV 1-4)，其中HPIV-1和HPIV-2是已知引起哮吼(croup)的最主要原因，而HPIV-3则通过引发细支气管炎和肺炎成为下呼吸道感染的常见病因[5]。在不同类型的HPIV中HPIV-3是导致住院的主要原因，也是免疫功能低下个体发病和死亡的主要原因之一[2,5-6]。在罕见情况下，也有报道称与HPIV-3感染相关的急性脑脊髓炎和脑膜炎[7-8]。因此，控制该病毒感染对婴幼儿、成人及免疫功能低下者均至关重要。目前尚无特定的抗HPIV药物或获批疫苗用于预防和控制该病毒[9]。多项人体和动物研究表明，针对HPIV抗原的体液免疫和细胞免疫对于提供针对该病毒的保护性免疫和控制感染是有效且必要的[5,10-11]。
靶向F和HN表面糖蛋白的中和抗体在长期防护HPIV中起着重要作用[10]。值得注意的是，只有在CD4+辅助性T淋巴细胞存在时才会发生有效且持久的体液免疫及CD8+ T细胞反应[10,12]。因此，在设计有效疫苗时纳入CD4+ T细胞反应似乎对于诱导针对这种病毒感染的细胞和体液免疫反应是必要的。对于存在免疫缺陷的人群，目前白血病患者以及遗传性免疫缺陷个体的一种候选治疗方法是造血干细胞移植(hematopoietic stem cell transplantation, HSCT)，在此治疗中受者患者的血细胞被完全清除，然后将造血干细胞(hematopoietic stem cells, HSCs)注入患者体内[13-15]。然而，该治疗存在一个问题，即具有抗感染能力的免疫细胞再生缓慢且薄弱，在HSC注射后到免疫细胞分化与重建的期间，潜伏病毒感染的再激活或机会性感染威胁着患者的生命[13-15]。这个问题在接受实体器官移植的患者中也同样存在，这是由于他们需要接受免疫抑制剂以防止移植排斥[13-15]。对抗移植患者中常见病毒感染(如HPIV-3)的一种新治疗策略是过继转移病毒特异性T细胞，以在移植时间与免疫系统重建之间的间隔期建立抗病毒免疫力[14-15]。在此方法中，供体白细胞在体外暴露于病毒抗原，待病毒抗原特异性T细胞被刺激和增殖后将病毒特异性T细胞注射到移植受者体内[14-15]。因此，设计一种抗HPIV-3的预防性疫苗是针对免疫系统健全人群的有效策略，而转移用HPIV-3病毒抗原刺激的特异性T细胞是针对存在免疫缺陷人群的有效策略。目前，利用表位设计疫苗已成为传染病防治的一个重点领域[16]。表位疫苗能够同时激发免疫系统的体液免疫和细胞免疫分支，其由高免疫原性的T细胞表位构成，可特异性激活细胞毒性T淋巴细胞(cytotoxic T lymphocyte, CTL)及辅助T淋巴细胞(helper T lymphocyte, HTL)，从而诱导针对特定表位的免疫应答[17]。在许多细菌感染中HTL会显著刺激保护性免疫反应，识别负责T细胞反应的肽对于创建强大的基于表位的肽疫苗至关重要[17]。利用表位的肽疫苗可以提供诸如可负担的生产、选择免疫类型的能力和更好的安全性等好处。免疫信息学或计算生物学的方法在基于表位设计肽疫苗方面至关重要[10,17]。由于病原体的不断突变，传统疫苗无法为人体提供有效的疗效保护，有必要设计广谱疫苗来预防大量野生型病原。基于抗原保守区的疫苗设计可以有效避免因病原体突变导致的失败。因此，本研究的目标是通过HPIV-3抗原蛋白的保守区域设计共识序列，以广泛覆盖不同来源的HPIV-3菌株。这里提出的疫苗免疫信息学方法可以作为治疗病毒相关感染的病原体特异性疫苗的有前景的候选方案得到广泛应用。
1 材料与方法
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1.1 蛋白质组数据与共识序列
选择HPIV-3的完整生物结构蛋白，包括F、M、N和HN，用于预测有效的CTL和HTL表位。使用CD-HIT以100%一致性对这些蛋白进行去冗余处理。采用MAFFT v7.487对这些蛋白进行多序列比对。在进一步验证这些比对序列后使用Python脚本识别它们的共有区域，保留出现频次最高的氨基酸，从而形成共识序列。比对不同物种或个体的基因组序列，可以识别出共同的保守区域，这些区域通常与基因功能密切相关。
1.2 MHC I和II表位的预测与评估
分别使用NetMHCIIpan-3.2和NetMHCpan-4.1评估结合主要组织相容性复合体I类(MHC I, 9-mer)和II类(MHC II, 15-mer)的位点。根据Guan等[18]的研究选择了相应的人类白细胞抗原(human leukocyte antigen, HLA)等位基因。对于MHC I，选择对HLA具有最高亲和力的表位(<0.5%)；而对于MHC II，选择亲和力相对较低的表位(<10%)。分别使用VaxiJen v2.0、IEDB-tools和ToxinPred等工具进行抗原性预测、表位保守性分析和毒性肽预测[18]。
1.3 MHC I类肽的免疫原性
使用IEDB免疫表位数据库(https://www.immuneepitope.org/)中的Class I Immunogenicity在线工具(http://tools.iedb.org/immunogenicity/)预测MHC I类肽的免疫原性。该工具通过分析氨基酸的理化特性及其序列特异性定位来评估免疫原性表位。预测为阳性的肽可能具有免疫原性，保留得分超过0.12的表位。
1.4 抗原性和致敏性分析
对肽进行进一步研究以验证其诱导过敏和免疫原性的潜力。对于抗原性预测，使用VaxiJen v2.0 (阈值≥0.4)确定多表位引发免疫反应的能力，并使用AllerTOP v2.0 (https://www.ddg-pharmfac.net/AllerTOP/)评估其致敏性。
1.5 MHC II类肽的细胞因子诱导
通过评估MHC II类表位诱导细胞因子IFN-γ产生的能力及致敏性，对MHC II类表位进行评估。在此情况下，使用IFNepitope服务器以默认参数预测这些表位的特性[18]。
1.6 人群覆盖率预测
使用T细胞表位及其相应的HLA结合等位基因计算人群覆盖率。使用Population Coverage工具(http://tools.immuneepitope.org/population)预测每个表位的人群覆盖率。
1.7 多表位疫苗构建
使用在先前的预测和序列筛选中显示出最佳抗原性和免疫原性的表位构建多表位疫苗(multi-epitope vaccine, MEV)。具体而言，HTL表位通过柔性连接子“GPGPG”连接，线性CTL表位则通过柔性AAY连接子连接[18]。有效的连接子可以防止蛋白质错误折叠和功能区域重叠。
1.8 理化特性和溶解性
理化特性是蛋白质的重要特征，使用Expasy ProtParam (https://web.expasy.org/protparam/)分析预测表位的理化特性，以深入了解疫苗的基本性质。此外，通过Protein-Sol网站(http://protein-sol.manchester.ac.uk)分析疫苗的溶解性。
1.9 二级结构、三维结构优化与验证
在PSIPRED服务器(http://bioinf.cs.ucl.ac.uk/psipred/)上预测疫苗的二级结构，该服务器提供了一系列蛋白质结构预测方法。使用AlphaFold 3.0网站(https://alphafoldserver.com/)预测所开发疫苗的三维(3D)结构。随后，通过GalaxyRefine服务器(http://galaxy.seoklab.org/refine)对已识别的3D结构进行优化。根据最低能量得分和最高RMSD值确定所选结构，优化和识别后使用PyMOL v2.5.7对结构进行可视化。
3D模型评估通过PROCHECK (https://saves.mbi.ucla.edu/)和ProSA在线网站(https://prosa.services.came.sbg.ac.at/prosa.php)，分析其与平均值间的偏差[18]。
1.10 潜在二硫键预测
二硫键通常通过减少结构无序性和增强能量稳定性在稳定蛋白质折叠状态中起关键作用。为增强疫苗的稳定性，使用Disulfide by Design 2.0网站(http://cptweb.cpt.wayne.edu/DbD2/)来预测构建疫苗的二硫键。利用该结构来仔细检查潜在的半胱氨酸突变，这导致在疫苗内形成二硫键。选择残基对能量≤2.2 kcal/mol作为阈值[18-19]。
1.11 疫苗-受体分子对接
分子对接用于解释疫苗蛋白与受体分子的结合情况。由于病毒糖蛋白和dsRNA总能识别Toll样受体TLR4 (PDB编号为2Z63)和TLR3 (PDB编号为1ZIW)，因此选择这2种受体作为免疫受体。在此情况下，将优化后的3D模型作为配体提交至ClusPro v2.0 (https://cluspro.bu.edu/)进行分子对接。对接前，用PyMOL v2.5.7去除配体和受体中的水分子，同时添加氢离子。
1.12 疫苗的稳定性评估
在内(二面角)坐标系中，正态模式分析(normal mode analysis, NMA)能自然地再现生物大分子的集体功能运动。使用iMODS工具(http://imods.chaconlab.org/)探索疫苗-受体对接复合物的稳定性和物理运动。该工具可使用内部坐标中的NMA来预测蛋白质的集体运动。iMODS工具能计算疫苗-受体复合物的可变形性、特征值、方差、协方差图、B因子和弹性网络。
1.13 In silico 疫苗克隆
利用优化的密码子可最大限度地提高宿主中疫苗抗原的产量。由此，使用EMBOSS backtranseq (https://www.ebi.ac.uk/jdispatcher/st/emboss_backtranseq)反向翻译疫苗蛋白。使用JCat网站(http://www.jcat.de/)获取蛋白质表达水平。本研究选择大肠杆菌(Escherichia coli) K12作为宿主表达生物。通过密码子适应指数(codon adaptation index, CAI)和G+C含量推断蛋白质表达水平。据报道，CAI≥0.8通常处于合理范围，而30%-70%的G+C含量意味着较高的基因翻译和转录效率[20]。
1.14 实验动物与细胞系
6-8周龄的雌性C57BL/6J小鼠购自北京维通利华实验动物技术有限公司。所有不涉及致病性病原体的动物研究均在SPF级设施中开展。HEK-293细胞在生长培养基(杜尔贝科改良伊格尔培养基，含10%胎牛血清及抗生素)中培养，并于37 °C、5% CO2条件下孵育。本研究所有动物实验均通过深圳灵赋拓普生物科技有限公司实验动物管理和使用委员会(IACUC)审批，编号为TOP-2PZ-GM250808。
1.15 小鼠免疫接种及特异性抗体水平检测
基于设计的序列构建并合成重组质粒pET-29a(+)HPIV-3。将重组质粒转化至大肠杆菌BL21(DE3)感受态细胞，构建重组菌pET-29a(+)HPIV-3。pET-29a(+)HPIV-3和弗式佐剂混合比为1:1，充分涡旋乳化，制备pET-29a(+)HPIV-3亚单位疫苗。将小鼠分为2组并标记，小鼠经腹腔注射三溴乙醇麻醉后，通过滴鼻方式给予20 μg疫苗，对照组给予安慰剂(PBS)。在实验终点，通过颈椎脱位法处死小鼠收集支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)或肺组织。
通过ELISA检测小鼠血清和支气管肺泡灌洗液中的IgG和IgA抗体水平。对于IgG检测，血清样品以1:400为起始稀释度进行3倍系列稀释，肺泡灌洗液样品以1:5为起始稀释度进行 2倍系列稀释。对于IgA检测，肺泡灌洗液样品使用未稀释的原液作为起始稀释度进行2倍系列稀释。在37 °C孵育2 h后，加入二抗：HRP标记的抗小鼠IgG抗体(1:100 000稀释)；HRP标记的抗小鼠IgA抗体(1:5 000稀释)。再次在37 °C孵育1 h，随后加入TMB底液(苏州新赛美生物科技有限公司)。结合抗体的终点滴度定义为产生的吸光度值高于免疫前样品吸光度值至少0.1 OD单位的最高血清稀释度的倒数。
2 结果与分析
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2.1 疫苗设计流程
抗原肽疫苗由T细胞表位组成。从美国国家生物技术信息中心(NCBI)选择并下载了结构蛋白，包括F蛋白(n=143)、M蛋白(n=102)、N蛋白(n=118)和HN蛋白(n=533) (图1)。生成的共识序列与参考序列[如F (NP_067151.1)、M (NP_067150.1)、N (NP_067148.1)和HN (NP_067152.1)]分别显示出96.47%、98.30%、98.25%和94.25%的氨基酸序列相似性。然后选择共识序列来预测用于疫苗设计的假定T细胞表位。疫苗设计逻辑是先连接CTL表位，再连接HTL表位。佐剂应连接在N端，使用AAY连接子连接CTL表位，使用GPGPG连接子连接HTL表位，然后用于进一步的疫苗评估。
利用IEDB数据库工具(http://tools.iedb.org/)从HPIV-3的结构蛋白中识别潜在的CTL和HTL表位。在选定的F、M、N和HN蛋白中共识别出335个CTL表位(9-mer)。进一步筛选后，确定了11个最佳的CTL表位，这11个CTL表位表现出高抗原性、高免疫原性、无毒性和非致敏性，被选用于最终的疫苗开发(表1)。类似地，使用IEDB数据库工具共识别出1 144个HTL表位(15-mer)，其中只有11个最佳HTL表位能触发产生特异性细胞因子IFN-γ (表1)，被选用于疫苗设计。最终，构建的疫苗由355个氨基酸组成，基于22个表位设计，包括11个CTL表位和11个HTL表位(表1)。
2.2 全球人群覆盖度
如表1所示，评估了所选CTL和HTL表位的人群覆盖度。在全球范围内，CTL和HTL表位的人群覆盖度为86.52%。其中，CTL表位的全球平均人群覆盖度为57.65%，HTL表位为68.16% (图2A)。所选表位能与多个地理区域[包括东北亚(79.27%)、欧洲(91.68%)和北美(88.17%)]的多种HLA等位基因结合(图2B)。全球人群覆盖度表明，用这些表位设计的疫苗可能对全球大多数人群有效。
2.3 理化特性和免疫学评估
本研究评估了未连接任何佐剂的疫苗的物理和化学特性。结果显示，疫苗的分子量为37 049.6 Da，抗原性评分为0.67 (参考值：0.40)，免疫原性评分为5.48，表明其具有显著的抗原性和较强的免疫原性(表2)。此外，还评估了其他特性，如理论等电点pI (9.42)、不稳定指数(25.67)、脂肪族指数(90.79)、亲水性总平均值GRAVY (0.037)和标准化溶解度(0.43)，显示出高溶解度和亲水性(表2)。在PSIPRED网站上对疫苗的二级结构(如β-折叠、α-螺旋和无规卷曲)进行分析。结果显示，其二级结构包含21% (73/349) α-螺旋，25% (86/349) β-折叠和54% (190/349)无规卷曲(表2)。通过IEDB数据库(http://tools.iedb.org/)进一步分析表明，串联后的疫苗未产生新的抗原表位。
2.4 多表位疫苗的3D结构、验证与优化
对疫苗的3D结构进行结构优化以进行评估和验证(图3A)。优化后疫苗模型的Ramachandran图显示，88.2%的残基位于有利区域，11.8%位于允许区域，无残基位于不允许区域(图3B)。类似地，ProSA服务器生成的Z-score值表明了模型的整体质量，该Z-score与核磁共振(NMR)光谱和X射线区域相似，表明结构质量优异。结果显示，优化后的模型Z-score值为-2.86 (图3C)，更接近于NMR和X射线产生的区域。
2.5 二硫键工程
二硫键通过减少构象熵、增加变性状态下的自由能来增强许多胞外和分泌蛋白的稳定性，从而稳定其折叠形式[19]。本研究依靠残基间建立的二硫键来维持疫苗结构的稳定性。使用Disulfide by Design 2.0网站(http://cptweb.cpt.wayne.edu/DbD2/)进行研究后，结果表明在疫苗构建体中包含32个潜在的残基对，它们具有形成二硫键的潜力(表3)。总共有5对残基可以突变为半胱氨酸，包括Gly112-Met117、Ser141-Met158、Thr201-Ile204、Val228-Gly234、Gly268-Gly274，这些残基对具有较低的结合能(<2.20 kcal/mol) (图4，表3)。
2.6 疫苗分子对接
将疫苗作为配体与TLR4/3受体进行分子对接，以预测它们的相互作用和结合亲和力。在此场景中，ClusPro v2.0服务器生成了30个具有不同构象的对接复合物。本研究进行了疫苗及TLR4激动剂与TLR4的对接，从生成的30个聚类结果中选择了具有优异综合评估(氢键、范德华力)的cluster 7。Benchmarking基准测试表明，在cluster 7中疫苗与TLR4对接的最低结合能为-1 299.7 kcal/mol (表4)。相比之下，糖蛋白LPS与TLR4对接的最低结合能为-1 027.0 kcal/mol，两者非常接近(图5A)，表明疫苗-TLR4复合物具有相对紧凑的构象和稳定的结合相互作用。对所选复合物的结合相互作用进行了分析，并探索了其参与活性位点残基的情况。在相互作用平面上，疫苗-TLR3复合物显示出1个范德华力和6个氢键的相互作用。疫苗的Ile65、Val7、Asn196、Ser155、Thr159、Ile181残基分别能与TLR3的Tyr436、His513、Lys174、Glu101、Asn226、Tyr276残基形成氢键。类似地，在范德华力方面，疫苗的Arg92残基可以与TLR3受体的Glu434残基发生强相互作用(图5B)。
HPIV-3作为单链RNA病毒，TLR7/8 (识别ssRNA)也可能是天然免疫受体。因此，进一步将疫苗分别与TLR7 (编号为Q9NYK1)、TLR8 (编号为3W3J)受体进行分子对接，结果显示疫苗与TLR7/8受体分子对接具有较低的结合能，表明对接效果良好(图6A、6B)。
2.7 正态模式分析
使用iMODS工具进一步探索疫苗-TLR4/TLR3对接复合物的稳定性和运动。采用正态模式分析(NMA)对接复合物的慢动力学及其表现出的大幅度构象变化进行研究。结果显示，受体和配体倾向于聚集在一起(图7A、图8A)，协方差图显示结合区域覆盖了许多红色，表明疫苗蛋白的关键区域具有协调的氨基酸运动和稳定的配体结合(图7B、图8B)。可变形性通过链铰链方法描绘了每个残基的独立扭曲(图7C、图8C)。疫苗-TLR4/TLR3复合物的整体结合峰适中，表明具有一定的灵活性，但不会过度扭曲，这是对接结果的良好体现。对接后，B因子在合理范围内波动，不影响蛋白质的自然运动模式(图7D、8D)。特征值(eigenvalue)是稳定结构的关键参数，必须较高才能拥有稳定的复合物。研究发现该复合物的特征值分别为2.56×10-5 (疫苗- TLR4)和1.22×10-5 (疫苗-TLR3)，且每个典型模式的方差逐渐减小(图7E、7F；图8E、8F)，这些速率对于结构稳定性显著较高。适中的特征值表明疫苗蛋白在结合后保持了其生物活性并适应了配体结合。
2.8 密码子优化与疫苗克隆
为确保疫苗实现高水平表达且易于生产，通过JCat网站对疫苗进行密码子优化。设计的疫苗cDNA长度为1 065 bp，在cDNA末端添加了终止密码子。该疫苗的CAI值(score：1)和G+C含量(50.73%)均较为理想，这表明其在模式菌株E. coli K12中具有较高的基因表达潜力和优异的表达能力。使用SnapGene v5.2.3软件将疫苗的cDNA序列克隆到pET29a(+)载体中(图9)。在pET-29a(+)载体中T7启动子和T7终止子分别如同“开关”和“刹车”。插入它们之间的基因即为想要表达的疫苗相关序列(图中标记为HPIV-3)。该序列将在T7启动子的驱动下进行转录，并最终用于后续的疫苗合成。
2.9 初次免疫诱导的体液免疫反应
本研究评估了HPIV-3疫苗作为鼻内疫苗的体液免疫原性，采用ELISA法检测了小鼠血清和支气管肺泡灌洗液中的IgG与IgA抗体水平。如图10所示，通过中和抗体(neutralizing antibodies, NAbs)和结合抗体(binding antibodies, BAbs)来评估疫苗接种后的体液免疫反应。接种后3周，初次免疫后的小鼠在血清和支气管肺泡灌洗液中均能诱导产生HPIV-3特异性的免疫球蛋白(Ig) G抗体(图10)。对于支气管肺泡灌洗液中的黏膜IgA，免疫后的小鼠也能够激发产生一定量的抗HPIV-3的IgA抗体，这表明疫苗的免疫效果良好，疫苗总体设计合理。
3 讨论
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人类副流感病毒3型(HPIV-3)是引发儿童下呼吸道感染的一种病毒，其致病性仅次于呼吸道合胞病毒(RSV)，目前尚无可用的疫苗或抗病毒药物[18]。当代免疫信息学工具为传统疫苗开发提供了一种实用且高效的替代方案，其劳动强度较低，是一种有效的筛选方法，疫苗在预防传染病方面始终展现出高安全性和有效性，能够提供针对疾病的获得性免疫力[21-22]。理想的靶标应高度保守，能够诱导产生中和性细胞免疫，并生成针对HPIV-3的抗体，这对于开发有效疫苗尤为重要。
HPIV-3的膜相关蛋白和细胞黏附蛋白在疾病进展过程中广泛存在，且表现出高度的保守性和免疫原性，使其成为触发体液和细胞介导免疫反应的最佳免疫原。由于野生型病毒持续发生突变，本研究通过开发一种基于T细胞表位的疫苗，以提供针对各种野生型的交叉保护。尽管疫苗有潜力成为未来流行病发生的预防工具，但在当前情况下开发有效的广谱疫苗仍是一项具有挑战性的任务，需要新的疫苗开发方法来应对紧迫的公共卫生威胁。鉴于F、M、N和HN作为免疫逃避和人际传播关键决定因素的确立作用，本研究优先设计了多表位疫苗构建体[23-24]。这涉及通过严格的多序列比对生成目标结构蛋白的共识序列，以最大限度地覆盖流行临床分离株中进化保守的残基，从而靶向具有高人群覆盖频率的免疫优势表位。此外，本研究通过识别抗原上便于体液免疫和细胞免疫系统识别的表面抗原区域，采用免疫信息学驱动的方法筛选针对HPIV-3的重要优势免疫原，结果表明所有膜结合蛋白和细胞黏附蛋白均具有良好的抗原性，抗原评分较高。前瞻性筛选和鉴定有效的HTL及CTL表位是疫苗理性设计的关键基础。尽管CD8⁺ T细胞(CTL)介导的免疫反应是清除病毒的核心机制，但有关HPIV-3感染在人与小鼠体内诱导CTL应答的研究报道仍显不足[25-26]。在此背景下，深入发掘能够驱动强效CTL应答的特异性表位，对于开发新一代抗HPIV-3疫苗具有重要的科学价值与应用前景。本研究在最终疫苗中采用综合排序过程，对包括表位(HTL和CTL)和所需连接子在内的各项内容进行了评估。疫苗开发过程对于增强表达谱、疫苗折叠特性和稳定性至关重要。通过EAAAK连接子连接佐剂和CTL表位可增加疫苗的稳定性和持久性，这有助于引发针对特定抗原的强细胞和体液免疫[27-28]。然而，在本研究中未评估连接佐剂后的疫苗效力，这是因为不同佐剂可能对疫苗效力产生不同影响。疫苗蛋白本身的特性似乎更受关注，这有助于对设计的疫苗进行合理调整。此外，溶解性是任何潜在疫苗的基本理化特性，是重组疫苗的重要特征[29]。溶解性评估工具可用于预测疫苗的溶解质量，本研究通过该方法证实设计的多表位疫苗具有良好的溶解性。同时，根据理论pI值发现疫苗特性呈碱性。分析表明，该蛋白质在合成后将保持其稳定性。相反，疫苗能够耐受高温且具有亲水性，这得到了GRAVY值和脂质指数的数据支持。综上所述，设计疫苗预测的有利理化特性和相关参数评分表明其可能成为抗感染的有效候选疫苗。通过本研究的方法，最佳人群的全球覆盖率已达到较高比例，因此所设计的疫苗将成为极具潜力的竞争者。Ramachandran图用于评估蛋白质构象的合理性，它不考虑能量问题，仅评估构象是否合理。同源建模后模型质量的评估显示，落在允许区域和最大允许区域的氨基酸残基比例接近90%，进一步表明模型的构象合理。此外，分子对接后肽疫苗显示出通过与有利受体TLR3/TLR4相互作用来抑制感染的潜力。疫苗模型可能作为配体，通过TLR3/TLR4受体表面发生的重要相互作用发挥作用。此外，还对疫苗-TLR3/TLR4对接复合物进行了正态模式分析以确定其稳定性，结果显示疫苗能够适应配体而不会发生剧烈波动，显示出稳定的结合力。CAI值和G+C含量用于评估疫苗开发过程的有效性。预测设计的疫苗在E. coli K12系统中表达良好。为控制呼吸道病毒感染，感染部位的黏膜免疫应答(包括中和抗体、免疫球蛋白A、免疫球蛋白G)至关重要[30]。免疫球蛋白A是黏膜免疫的标志性抗体，它通过中和黏膜表面的病毒来阻止病毒进入宿主细胞，从而建立第一道防御屏障[31]。在本研究中，经HPIV-3疫苗免疫后除了能够诱导产生中和抗体IgG外，黏膜免疫IgA也能够被激活，由此弥补了现有疫苗在诱导黏膜免疫方面的不足。
本研究在疫苗设计方法上体现了多项技术创新。与传统依赖单一毒株序列的疫苗设计策略不同，本研究采用共识序列法，通过对大量临床分离株进行多序列比对，获得代表多个HPIV-3流行株共同特征的保守序列，从而在源头上增强疫苗的广谱性与交叉保护潜力。在表位筛选阶段，本研究整合了多重免疫信息学工具，系统评估表位的抗原性、免疫原性、毒性、致敏性及人群覆盖度，实现了从海量候选表位中高效、精准地筛选最优组合，显著提升了疫苗设计的理性化与可控性。此外，本研究在疫苗结构优化中引入了二硫键工程与正态模式分析，从构象稳定性角度进一步优化疫苗蛋白，其效果显著优于现有的免疫信息学研究。尽管免疫信息学方法在表位疫苗设计中已广泛应用，但本研究在表位组合策略、连接子选择、受体对接广度(TLR3/4/7/8)以及动态稳定性评估等方面均有所突破，体现了多维度、多层次的设计理念，为复杂病原体的疫苗开发提供了更为系统的技术框架。
4 结论
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本研究利用共识序列预测了结构蛋白中的潜在T细胞表位，确保了抗原的广谱性和保守性。这种设计的广谱保护性疫苗具备显著的免疫原性优势、广泛的人群覆盖率，以及能够有效激活TLR3/4和TLR7/8受体的能力，从而诱导机体产生特异性的免疫保护。将这款候选疫苗与已上市的流感疫苗组成异源接种方案有望提升基础免疫所诱导的适应性免疫应答，从而产生全面的免疫保护效果。
基金
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  • 天津市自然科学基金青年基金(24JCQNJC00460)
文献
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参考文献 引证文献
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doi: 10.13343/j.cnki.wsxb.20250558
  • 接收时间：2025-07-21
  • 首发时间：2026-01-12
  • 出版时间：2026-01-04
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  • 收稿日期：2025-07-21
  • 录用日期：2025-10-22
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Tianjin Natural Science Foundation Youth Project(24JCQNJC00460)
天津市自然科学基金青年基金(24JCQNJC00460)
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    1.天津医科大学 基础医学院，天津
    2.生物芯片北京国家工程研究中心，北京

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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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