用于疫苗生产的人二倍体细胞研究进展<sup>*</sup>

doi:10.13523/j.cb.2106011

中国生物工程杂志

2021, Vol. 41

Issue (11): 74-81 DOI: 10.13523/j.cb.2106011

综述

用于疫苗生产的人二倍体细胞研究进展^*

肖云喜¹,张俊河^1,^2,^3,^**(

),杨雯雯^2,³,程洪伟¹

1 新乡医学院健康中原研究院新乡 453003
2 新乡医学院生物化学与分子生物学系新乡 453003
3 河南省重组药物蛋白表达系统国际联合实验室新乡 453003

Research Progress of Human Diploid Cells for Vaccine Production

XIAO Yun-xi¹,ZHANG Jun-he^1,^2,^3,^**(

),YANG Wen-wen^2,³,CHENG Hong-wei¹

1 Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang 453003, China
2 Department of Biochemistry and Molecular Biology, Xinxiang Medical University, Xinxiang 453003, China
3 Henan International Joint Laboratory of Recombinant Pharmaceutical Protein Expression System, Xinxiang Medical University, Xinxiang 453003, China

全文: PDF(471 KB) HTML

摘要：

人二倍体细胞(human diploid cells, HDCs)作为制备疫苗的重要培养细胞基质备受人们的关注。由于人二倍体细胞与人类基因组相同、无外源因子、对多种病毒易感性、无潜在致瘤性、所制备的人二倍体疫苗(human diploid cell vaccine, HDCV)具有良好的免疫原性和安全性,适合于疫苗的工业化生产。当前,人群中使用的灭活疫苗、减毒疫苗或亚单位疫苗等均依赖于原代细胞、传代细胞和人二倍体细胞,其中用于疫苗制备的人二倍体细胞主要有WI-38、MRC-5、2BS和KMB-17等细胞系。然而,人二倍体细胞为有限性细胞,细胞的来源和培养技术等存在某些缺陷,进而影响其应用。综述了用于疫苗生产的人二倍体细胞及其疫苗制备技术的研究进展,并分析了存在的问题及改进策略。

关键词： 人二倍体细胞; 疫苗; 细胞系; 疫苗制备技术

Abstract:

Human diploid cells (HDCs) have attracted much attention as an important culture cell matrix for vaccine preparation. Since human diploid cells are the same as the human genome without exogenous factor, susceptible to a variety of viruses, and without potential tumorigenicity, and the preparation of human diploid cell vaccine (HDCV) has good immunogenicity and safety, they are suitable for industrial production of vaccine. Currently, the inactivated, attenuated or subunit vaccines used in the population all rely on primary cells, continuous cells and human diploid cells, of which WI-38, MRC-5, 2BS and KMB-17 cell lines are the main human diploid cells used in vaccine preparation. However, human diploid cells are limited cells, and there are some defects in cell sources and culture techniques, which further affect their application. In this paper, the research progress of human diploid cells used in vaccine production and vaccine preparation technology were reviewed, and the existing problems and improvement strategies were analyzed.

Key words: Human diploid cells Vaccine Cell line Vaccine preparation technology

收稿日期: 2021-06-08 出版日期: 2021-12-01

ZTFLH:

Q819

基金资助: * 国家自然科学基金(U1604193);河南省重点研发与推广专项(科技攻关)(212102310634)

通讯作者: 张俊河 E-mail: zjh@xxmu.edu.cn

	服务
	把本文推荐给朋友
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	肖云喜
	张俊河
	杨雯雯
	程洪伟

引用本文:

肖云喜,张俊河,杨雯雯,程洪伟. 用于疫苗生产的人二倍体细胞研究进展^*[J]. 中国生物工程杂志, 2021, 41(11): 74-81.

XIAO Yun-xi,ZHANG Jun-he,YANG Wen-wen,CHENG Hong-wei. Research Progress of Human Diploid Cells for Vaccine Production. China Biotechnology, 2021, 41(11): 74-81.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2106011 或 https://manu60.magtech.com.cn/biotech/CN/Y2021/V41/I11/74

表1 主要人二倍体细胞在疫苗研发中的应用

表2 在细胞基因工程中不同细胞途径改变对病毒生长特性的影响

表3 疫苗开发中病毒载体的优缺点

[1]	Delany I, Rappuoli R, de Gregorio E. Vaccines for the 21st century. EMBO Molecular Medicine, 2014, 6(6):708-720. doi: 10.1002/emmm.v6.6
[2]	Hayflick L, Plotkin S A, Norton T W, et al. Preparation of poliovirus vaccines in a human fetal diploid cell strain. American Journal of Hygiene, 1962, 75:240-258.
[3]	Zhou X Y, Wu X H, Cai Y, et al. Pre-marketing immunogenicity and safety of a lyophilized purified human diploid cell rabies vaccine produced from microcarrier cultures: a randomized clinical trial. Human Vaccines & Immunotherapeutics, 2019, 15(4):828-833.
[4]	Olshansky S J, Hayflick L,. The role of the WI-38 cell strain in saving lives and reducing morbidity. AIMS Public Health, 2017, 4(2):127-138. doi: 10.3934/publichealth.2017.2.127 pmid: 29546209
[5]	Jacobs J P. The status of human diploid cell strain MRC-5 as an approved substrate for the production of viral vaccines. Journal of Biological Standardization, 1976, 4(2):97-99. pmid: 932048
[6]	王传林. 狂犬病疫苗研究进展. 中华实验和临床病毒学杂志, 2018, 32(3):323-327.
	Wang C L. Research progress in rabies vaccine. Chinese Journal of Experimental and Clinical Virology, 2018, 32(3):323-327.
[7]	胡昭烈. 人二倍体细胞2BS株小儿麻痹活疫苗Ⅰ型安全性和免疫原性观察. 医学研究通讯, 1978, 7(11):26-30.
	Hu Z L. Observation on the safety and immunogenicity of human diploid cell 2BS strain polio vaccine type I. Journal of Medical Research, 1978, 7(11):26-30.
[8]	杜桂枝, 闻仲权, 郝荣宽, 等. 人二倍体细胞2BS株制备三价脊髓灰质炎活疫苗免疫原性研究. 中国公共卫生学报, 1989, 8(2):83-85.
	Du G Z, Wen Z Q, Hao R K, et al. Immunologic effect of trivalent oral poliovaccine (TOPV) prcduced in human diploid cell 2BS strain. Chinese Journal of Public Health, 1989, 8(2):83-85.
[9]	黄小琴, 杨净思, 周德久, 等. H2株甲肝病毒经KMB17细胞培养的毒力及核苷酸序列. 中国生物制品学杂志, 2000, 13(3):133-135.
	Huang X Q, Yang J S, Zhou D J, et al. Virulence and nucleotide sequences of HAV (H2 strain) cultured in KMB17 cell. Chinese Journal of Biologicals, 2000, 13(3):133-135.
[10]	马应霞, 易山, 张光明, 等. 轮状病毒P[8]G1株在KMB17细胞上的适应性及其免疫原性. 中国生物制品学杂志, 2010, 23(9):942-945.
	Ma Y X, Yi S, Zhang G M, et al. Adaptability of Rotavirus P[8]G1 strain in KMB17 cells and immunogenicity of adapted strain. Chinese Journal of Biologicals, 2010, 23(9):942-945.
[11]	Ma B, He L F, Zhang Y L, et al. Characteristics and viral propagation properties of a new human diploid cell line, walvax-2, and its suitability as a candidate cell substrate for vaccine production. Human Vaccines & Immunotherapeutics, 2015, 11(4):998-1009.
[12]	Wibawa T. COVID-19 vaccine research and development: ethical issues. Tropical Medicine & International Health, 2021, 26(1):14-19.
[13]	柯尊阳, 王宇, 李忠明, 等. mRNA技术及其在传染病疫苗研发中的应用. 中华微生物学和免疫学杂志, 2020, 40(9):661-667.
	Ke Z Y, Wang Y, Li Z M, et al. mRNA technology for the development of vaccines against infectious diseases. Chinese Journal of Microbiology and Immunology, 2020, 40(9):661-667.
[14]	Rodrigues A F, Soares H R, Guerreiro M R, et al. Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology. Biotechnology Journal, 2015, 10(9):1329-1344. doi: 10.1002/biot.201400387 pmid: 26212697
[15]	张燕, 石金辉, 朱梦然, 等. 新建人二倍体细胞株国内外研究概况. 国际生物制品学杂志, 2018, 41(4):179-184.
	Zhang Y, Shi J H, Zhu M R, et al. Overview in research of newly established human diploid cell lines at home and abroad. International Journal of Biologicals, 2018, 41(4):179-184.
[16]	Zhang K H, Na T, Wang L, et al. Human diploid MRC-5 cells exhibit several critical properties of human umbilical cord-derived mesenchymal stem cells. Vaccine, 2014, 32(50):6820-6827. doi: 10.1016/j.vaccine.2014.07.071
[17]	Chen P, Zhang K H, Na T, et al. The hUC-MSCs cell line CCRC-1 represents a novel, safe and high-yielding HDCs for the production of human viral vaccines. Scientific Reports, 2017, 7:12484. doi: 10.1038/s41598-017-11997-1
[18]	ACOG Committee Opinion No. 648: umbilical cord blood banking. Obstetrics and Gynecology, 2015, 126(6):e127-e129. doi: 10.1097/AOG.0000000000001212
[19]	Armson B A, Society of Obstetricians and Gynaecologists of Canada M M C. Umbilical cord blood banking: implications for perinatal care providers. Journal of Obstetrics and Gynaecology Canada, 2005, 27(3):263-290. doi: 10.1016/S1701-2163(16)30520-5
[20]	Grieco D, Lacetera N, Macis M, et al. Motivating cord blood donation with information and behavioral nudges. Scientific Reports, 2018, 8:252. doi: 10.1038/s41598-017-18679-y
[21]	Wang T, Zhang J, Liao J Q, et al. Donor genetic backgrounds contribute to the functional heterogeneity of stem cells and clinical outcomes. Stem Cells Translational Medicine, 2020, 9(12):1495-1499. doi: 10.1002/sct3.v9.12
[22]	Costa L A, Eiro N, Fraile M, et al. Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses. Cellular and Molecular Life Sciences, 2021, 78(2):447-467. doi: 10.1007/s00018-020-03600-0
[23]	Yeo J H M, Ho S C L, Mariati M, et al. Optimized selection marker and CHO host cell combinations for generating high monoclonal antibody producing cell lines. Biotechnology Journal, 2017, 12(12):1700175. doi: 10.1002/biot.v12.12
[24]	Fan L C, Kadura I, Krebs L E, et al. Improving the efficiency of CHO cell line generation using glutamine synthetase gene knockout cells. Biotechnology and Bioengineering, 2012, 109(4):1007-1015. doi: 10.1002/bit.24365
[25]	Mensah E O, Guo X Y, Gao X D, et al. Establishment of DHFR-deficient HEK293 cells for high yield of therapeutic glycoproteins. Journal of Bioscience and Bioengineering, 2019, 128(4):487-494. doi: 10.1016/j.jbiosc.2019.04.005
[26]	Moulia-Pelat J P, Spiegel A, Martin P M V, et al. A 5-year immunization field trial against hepatitis B using a Chinese hamster ovary cell recombinant vaccine in French Polynesian newborns: results at 3 years. Vaccine, 1994, 12(6):499-502. pmid: 8036822
[27]	Zhang W, Han L L, Lin C Y, et al. Surface antibody and cytokine response to recombinant Chinese hamster ovary cell (CHO) hepatitis B vaccine. Vaccine, 2011, 29(37):6276-6282. doi: 10.1016/j.vaccine.2011.06.045 pmid: 21722684
[28]	Rodrigues A F, Carrondo M J T, Alves P M, et al. Cellular targets for improved manufacturing of virus-based biopharmaceuticals in animal cells. Trends in Biotechnology, 2014, 32(12):602-607. doi: 10.1016/j.tibtech.2014.09.010 pmid: 25450042
[29]	鲁国涛, 王辉, 曾为俊, 等. 利用CRISPR/Cpf1技术构建HEK293细胞DDX21基因稳定敲除株及功能鉴定. 中国兽医学报, 2020, 40(2):257-263.
	Lu G T, Wang H, Zeng W J, et al. Construction of DDX21 knockout gene stable strain using CRISPR/Cpf1 gene editing technology and identification of functions. Chinese Journal of Veterinary Science, 2020, 40(2):257-263.
[30]	Zhang W F, Xiao D, Shan L L, et al. Generation of apoptosis-resistant HEK293 cells with CRISPR/Cas mediated quadruple gene knockout for improved protein and virus production. Biotechnology and Bioengineering, 2017, 114(11):2539-2549. doi: 10.1002/bit.v114.11
[31]	Gallo-Ramírez L E, Nikolay A, Genzel Y, et al. Bioreactor concepts for cell culture-based viral vaccine production. Expert Review of Vaccines, 2015, 14(9):1181-1195. doi: 10.1586/14760584.2015.1067144 pmid: 26178380
[32]	唐取来, 顾力行, 周勇, 等. 机械搅拌式生物反应器悬浮培养293T细胞生产慢病毒的工艺. 河南农业大学学报, 2021, 55(2):314-320.
	Tang Q L, Gu L X, Zhou Y, et al. Producing Lentivirus by suspension culture of 293T cells in a stirred bioreactor. Journal of Henan Agricultural University, 2021, 55(2):314-320.
[33]	Venereo-Sanchez A, Gilbert R, Simoneau M, et al. Hemagglutinin and neuraminidase containing virus-like particles produced in HEK-293 suspension culture: an effective influenza vaccine candidate. Vaccine, 2016, 34(29):3371-3380. doi: 10.1016/j.vaccine.2016.04.089 pmid: 27155499
[34]	Rourou S, Ben Zakkour M, Kallel H. Adaptation of Vero cells to suspension growth for rabies virus production in different serum free media. Vaccine, 2019, 37(47):6987-6995. doi: S0264-410X(19)30749-2 pmid: 31201054
[35]	Petiot E, Cuperlovic-Culf M, Shen C F, et al. Influence of HEK293 metabolism on the production of viral vectors and vaccine. Vaccine, 2015, 33(44):5974-5981. doi: 10.1016/j.vaccine.2015.05.097 pmid: 26073013
[36]	Shirvani E, Samal S K. Newcastle disease virus as a vaccine vector for SARS-CoV-2. Pathogens, 2020, 9(8):619. doi: 10.3390/pathogens9080619
[37]	Zaiss A K, Machado H B, Herschman H R. The influence of innate and pre-existing immunity on adenovirus therapy. Journal of Cellular Biochemistry, 2009, 108(4):778-790. doi: 10.1002/jcb.22328 pmid: 19711370
[38]	王传林, 李明, 吕新军. 人用疫苗的分类及生产工艺. 中华预防医学杂志, 2020, 54(9):1017-1025. doi: 10.3760/cma.j.cn112150-20200520-00756 pmid: 32907295
	Wang C L, Li M, Lu X J. Classification and production process of human vaccine. Chinese Journal of Preventive Medicine, 2020, 54(9):1017-1025. doi: 10.3760/cma.j.cn112150-20200520-00756 pmid: 32907295
[39]	李莉莉, 周玉柏, 曾毅. 改良型痘苗病毒安卡拉株(MVA)作为递送载体在抗感染治疗中的应用. 中华微生物学和免疫学杂志, 2015, 35(7):550-555.
	Li L L, Zhou Y B, Zeng Y. Modified vaccinia virus Ankara (MVA) is used as a delivery vector in anti-infective treatment. Chinese Journal of Microbiology and Immunology, 2015, 35(7):550-555.
[40]	Meyer H, Sutter G, Mayr A. Mapping of deletions in the genome of the highly attenuated vaccinia virus MVA and their influence on virulence. The Journal of General Virology, 1991, 72(Pt 5):1031-1038. doi: 10.1099/0022-1317-72-5-1031
[41]	Garber D A, O’Mara L A, Zhao J, et al. Expanding the repertoire of Modified Vaccinia Ankara-based vaccine vectors via genetic complementation strategies. PLoS One, 2009, 4(5):e5445. doi: 10.1371/journal.pone.0005445
[42]	Alharbi N K. Poxviral promoters for improving the immunogenicity of MVA delivered vaccines. Human Vaccines & Immunotherapeutics, 2019, 15(1):203-209.
[43]	Sutter G. A vital gene for modified vaccinia virus Ankara replication in human cells. PNAS, 2020, 117(12):6289-6291. doi: 10.1073/pnas.2001335117 pmid: 32179684
[44]	Liu R K, Mendez-Rios J D, Peng C, et al. SPI-1 is a missing host-range factor required for replication of the attenuated modified vaccinia Ankara (MVA) vaccine vector in human cells. PLoS Pathogens, 2019, 15(5):e1007710. doi: 10.1371/journal.ppat.1007710
[45]	Cho S H, Kwon H J, Kim T E, et al. Characterization of a recombinant Newcastle disease virus vaccine strain. Clinical and Vaccine Immunology, 2008, 15(10):1572-1579. doi: 10.1128/CVI.00156-08
[46]	Sun W N, Leist S R, S, et al. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate. EBioMedicine, 2020, 62:103132. doi: 10.1016/j.ebiom.2020.103132
[47]	Silveira M M, Moreira G M S G, Mendonça M. DNA vaccines against COVID-19: Perspectives and challenges. Life Sciences, 2021, 267:118919. doi: 10.1016/j.lfs.2020.118919

[1]	朱潇静,王芮,张欣欣,靳家鑫,路闻龙,丁大顺,霍翠梅,李青梅,孙爱军,庄国庆. 利用细菌人工染色体技术构建整合F基因的重组MDV疫苗株^*[J]. 中国生物工程杂志, 2021, 41(10): 33-41.
[2]	程旭,杨雨睛,吴赛男,侯勤龙,李咏梅,韩慧明. 金黄色葡萄球菌SarA、IcaA及其融合基因的DNA疫苗构建及在小鼠免疫应答中的初步研究 ^*[J]. 中国生物工程杂志, 2020, 40(7): 41-50.
[3]	刘珍珍,田大勇. 狂犬病疫苗蔗糖密度梯度离心纯化工艺开发 ^*[J]. 中国生物工程杂志, 2020, 40(4): 25-33.
[4]	钱颖,钱晨,白晓庆,王晶晶. 免疫佐剂在肿瘤免疫疗法中的应用进展 ^*[J]. 中国生物工程杂志, 2020, 40(3): 96-103.
[5]	谢华玲,吕璐成,杨艳萍. 全球冠状病毒疫苗专利分析[J]. 中国生物工程杂志, 2020, 40(1-2): 57-64.
[6]	井汇源,段二珍,董望. 体外转录的自我复制型mRNA疫苗研究进展^*[J]. 中国生物工程杂志, 2020, 40(12): 25-30.
[7]	廖小艳,陈丽丽. COVID-19疫苗研究现状^*[J]. 中国生物工程杂志, 2020, 40(12): 8-17.
[8]	冯雪娇,侯海龙,喻琼,王俊姝. 我国宫颈癌疫苗市场分析及对策研究^*[J]. 中国生物工程杂志, 2020, 40(11): 96-101.
[9]	高彦,杜晶晶,王斌,刘琦,申志强. 气相色谱法对狂犬病疫苗灭活工艺中β-丙内酯研究[J]. 中国生物工程杂志, 2019, 39(6): 25-31.
[10]	杨琳,傅哲彦,吕正兵,舒建洪. 免疫佐剂分类及作用机制[J]. 中国生物工程杂志, 2019, 39(5): 114-119.
[11]	许嘉越,李紫倩,张革. 登革病毒3'UTRΔ30系列疫苗的研究进展[J]. 中国生物工程杂志, 2019, 39(3): 97-104.
[12]	蒋析文,董子维,刘悦,朱小亚. 生物标记物与精准医疗研究进展[J]. 中国生物工程杂志, 2019, 39(2): 74-81.
[13]	孙思,邱喻兰,颜菊荣,杨静,吴光英,王玲,胥文春. 重组质粒pcDNA3-dnaJ/蛋白DnaJ异源免疫诱导Th1和Th17细胞免疫应答抵抗肺炎链球菌感染 ^*[J]. 中国生物工程杂志, 2019, 39(12): 9-17.
[14]	郭乐,王淑娥,何萌,张帆,刘宏鹏,刘昆梅. 幽门螺杆菌多价表位疫苗CWAE的表达及其免疫学性质的研究 ^*[J]. 中国生物工程杂志, 2019, 39(12): 1-8.
[15]	胡瞬,易有金,胡涛,李福胜. mRNA疫苗的开发及临床研究进展[J]. 中国生物工程杂志, 2019, 39(11): 105-112.

Viewed

Full text

Abstract

Cited

Shared

Discussed