2025 01 v.41 23-32
BCR免疫组库分析SARS-CoV-2疫苗同源及异源免疫B细胞应答差异
基金项目(Foundation):
邮箱(Email):
changguili@aliyun.com;
DOI:
10.13242/j.cnki.bingduxuebao.004633
中文作者单位:
武汉生物制品研究所有限责任公司病毒性疫苗研究二室;中国食品药品检定研究院呼吸道病毒疫苗室;
摘要(Abstract):
比较新型冠状病毒（Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）灭活疫苗（Inactivated vaccine, In）和腺病毒载体疫苗（Adenoviral vector vaccine, Ad）同源和异源免疫引起的B细胞抗原受体（B-cell receptor, BCR）差异，探究SARS-CoV-2疫苗异源加强引起的抗体应答增强的原因。分别给小鼠同源免疫灭活疫苗In～4In、异源免疫3InAd，并于每次免疫10 d后采外周血检测各组血清针对SARS-CoV-2原型株和XBB.1.16变异株的中和抗体水平；提取同源和异源免疫后小鼠脾脏RNA，逆转录为cDNA后，对BCR重链的CDR3区序列进行BCR免疫组库测序，分析同源和异源免疫策略中CDR3的氨基酸长度多样性、V基因使用频率、V-J基因配对频率、BCR克隆多样性和克隆扩增水平。结果显示，异源3InAd组引起的针对原型株和XBB.1.16毒株的中和抗体水平显著高于同源免疫组；3InAd组CDR3氨基酸长度分布与同源免疫In～4In组不同；3InAd组V基因IGHV11-1、IGHV4-2使用频率显著高于同源4In组，IGHV5-6基因的使用频率低于4In组，IGHV9-3基因的使用频率在同源和异源免疫组无差异；同源免疫In～4In后，BCR克隆种类逐渐丰富，但BCR top 50的频率逐渐降低；3InAd组BCR种类丰富性与4In组相比没有明显增加，BCR top 50的频率逐渐增加，表明异源免疫增加了主要BCR克隆的扩增。本研究发现SARS-CoV-2异源免疫改变了B细胞CDR3长度、V基因频率、V-J基因配对频率、BCR种类多样性和BCR克隆扩增水平。
关键词(KeyWords):
BCR免疫组库;同源免疫;异源免疫;SARS-CoV-2;灭活疫苗;腺病毒载体疫苗
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[2] Wu S, Huang J, Zhang Z, et al. Safety, tolerability,and immunogenicity of an aerosolised adenovirus type-5vector-based COVID-19 vaccine(Ad5-nCoV)in adults∶preliminary report of an open-label and randomised phase 1 clinical trial[J]. Lancet Infect Dis, 2021, 21(12)∶1654-1664. DOI∶10. 1016/S1473-3099(21)00396-0.
[3] Kurahashi Y, Sutandhio S, Furukawa K, et al. Crossneutralizing breadth and longevity against SARS-CoV-2variants after infections[J]. Front Immunol, 2022, 13∶773652. DOI∶10. 3389/fimmu. 2022. 773652.
[4] Luan N, Wang Y, Cao H, et al. Comparison of immune responses induced by two or three doses of an alum-adjuvanted inactivated SARS-CoV-2 vaccine in mice[J]. J Med Virol, 2022, 94(5)∶2250-2258. DOI∶10. 1002/jmv. 27637.
[5] He Q, Mao Q, An C, et al. Heterologous prime-boost∶breaking the protective immune response bottleneck of COVID-19 vaccine candidates[J]. Emerg Microbes Infect, 2021, 10(1)∶629-637. DOI∶10. 1080/22221751. 2021. 1902245.
[6] Rice A, Verma M, Voigt E, et al. Heterologous saRNA prime, DNA dual-antigen boost SARS-CoV-2vaccination elicits robust cellular immunogenicity and cross-variant neutralizing antibodies[J]. Front Immunol, 2022, 13∶910136. DOI∶10. 3389/fimmu. 2022. 910136.
[7] Ai J, Guo J, Zhang H, et al. Cellular basis of enhanced humoral immunity to SARS-CoV-2 upon homologous or heterologous booster vaccination analyzed by single-cell immune profiling[J]. Cell Discov, 2022, 8∶114. DOI∶10. 1038/s41421-022-00480-5.
[8] Li X, Zeng F, Yue R, et al. Heterologous booster immunization based on inactivated SARS-CoV-2 vaccine enhances humoral immunity and promotes BCR repertoire development[J]. Vaccines(Basel), 2024, 12(2)∶120. DOI∶10. 3390/vaccines12020120.
[9]姜琼，郑文红，王晨辉，等. BCR组库分析乙肝疫苗接种反应及初步机理分析[J].免疫学杂志，2017, 33(9)∶743-748. DOI∶10. 13431/j. cnki. immunol.j. 20170131.
[10]侯显良，汤冬娥，蔡晚霞，等.系统性红斑狼疮的TCR免疫组库研究进展[J].临床医学工程，2021, 28(1)∶63–65.
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[12]Xu JL, Davis MM. Diversity in the CDR3 region of VH is sufficient for most antibody specificities[J].Immunity, 2000, 13(1)∶37-45. DOI∶10. 1016/S1074-7613(00)00006-6.
[13]Rock EP, Sibbald PR, Davis MM, et al. CDR3 length in antigen-specific immune receptors[J]. J Exp Med,1994, 179(1)∶323-328. DOI∶10. 1084/jem. 179. 1. 323.
[14]Barbas CF, Bain JD, Hoekstra DM, et al.Semisynthetic combinatorial antibody libraries∶a chemical solution to the diversity problem[J]. Proc Natl Acad Sci USA, 1992, 89(10)∶4457-4461. DOI∶10. 1073/pnas. 89. 10. 4457.
[15]Luo S, Jing C, Ye AY, et al. Humanized V(D)Jrearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors[J]. Proc Natl Acad Sci USA, 2023, 120(1)∶e2217883120. DOI∶10. 1073/pnas. 2217883120.
[16]Cao Y, Wang J, Jian F, et al. Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies[J]. Nature, 2022, 602∶657-663. DOI∶10. 1038/s41586-021-04385-3.
[17]Skinner NE, Ogega CO, Frumento N, et al.Convergent antibody responses are associated with broad neutralization of hepatitis C virus[J]. Front Immunol,2023, 14∶1135841.DOI∶10. 3389/fimmu. 2023. 1135841.
[18]Yang X, Chi H, Wu M, et al. Discovery and characterization of SARS-CoV-2 reactive and neutralizing antibodies from humanized CAMouseHG mice through rapid hybridoma screening and highthroughput single-cell V(D)J sequencing[J]. Front Immunol, 2022, 13∶992787. DOI∶10. 3389/fimmu. 2022. 992787.
[19]Ju B, Zhang Q, Ge J, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection[J].Nature, 2020, 584∶115-119. DOI∶10. 1038/s41586-020-2380-z.
[20]Funakoshi Y, Ohji G, Yakushijin K, et al. Massive surge of mRNA expression of clonal B-cell receptor in patients with COVID-19[J]. Heliyon, 2021, 7(8)∶e07748. DOI∶10. 1016/j. heliyon. 2021. e07748.
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[23]Teijaro JR, Farber DL. COVID-19 vaccines∶modes of immune activation and future challenges[J]. Nat Rev Immunol, 2021, 21∶195-197. DOI∶10. 1038/s41577-021-00526-x.
[24]Sprent J, King C. COVID-19 vaccine side effects∶The positives about feeling bad[J]. Sci Immunol, 2021, 6(60)∶eabj9256. DOI∶10. 1126/sciimmunol. abj9256.
[25]Mettelman RC, Allen EK, Thomas PG. Mucosal immune responses to infection and vaccination in the respiratory tract[J]. Immunity, 2022, 55(5)∶749-780.DOI∶10. 1016/j. immuni. 2022. 04. 013.
[26]He R, Zheng X, Zhang J, et al. SARS-CoV-2 spikespecific TFH cells exhibit unique responses in infected and vaccinated individuals[J]. Signal Transduct Target Ther, 2023, 8∶393. DOI∶10. 1038/s41392-023-01650-x.
[27]Zou P, Zhang P, Deng Q, et al. Two novel adenovirus vectors mediated differential antibody responses via interferon-α and natural killer cells[J]. Microbiol Spectr, 2023, 11(4)∶e0088023. DOI∶10. 1128/spectrum. 00880-23.
基本信息:
DOI：10.13242/j.cnki.bingduxuebao.004633
中图分类号:R392
引用信息:
[1]宋彦丽,孙誉芳,鲍春婷等.BCR免疫组库分析SARS-CoV-2疫苗同源及异源免疫B细胞应答差异[J].病毒学报,2025,41(01):23-32.DOI:10.13242/j.cnki.bingduxuebao.004633.
基金信息:
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