辐照技术在疫苗研发中的应用

doi:10.11843/j.issn.0366-6964.2024.08.012

摘要/Abstract

摘要：

病原体灭活是生产灭活疫苗最关键和最基本的技术。理想的灭活方式是彻底灭活病原体并保持抗原的免疫原性，且无化学残留。与传统灭活方式相比，辐照技术在疫苗研发中的主要优势是它能够穿透病原体，但对病原体表面抗原蛋白造成的损伤较小，且灭活后不需要去除任何化学残留物，因此更适合用于研发安全有效的灭活疫苗。本文简要回顾和总结了辐照技术应用于疫苗研发的历史和进展，讨论了辐照技术在疫苗研发中的应用的潜在策略。

关键词: 辐照技术, 电子束, γ射线, X射线, 疫苗

Abstract:

Pathogen inactivation is the most critical and basic technology for producing inactivated vaccines. The ideal inactivation method is to completely inactivate the pathogen and maintain the immunogenicity of the antigen without chemical residues. Compared with traditional inactivation methods, the main advantages of irradiation technology in vaccine development are that it can penetrate the pathogen but causes less damage to the pathogen surface antigens, and does not require the removal of any chemical residues after inactivation. Therefore, irradiation technology is more suitable for developing safe and effective vaccines. This article briefly reviews and summarizes the history and progress of using irradiation technology in vaccine development, and discusses potential strategies for developing vaccines using radiation technology.

Key words: irradiation technology, electron beam, gamma-rays, X-rays, vaccines

中图分类号:

S852.4

周婷, 孙梦坤, 余四九, 崔燕. 辐照技术在疫苗研发中的应用[J]. 畜牧兽医学报, 2024, 55(8): 3383-3394.

Ting ZHOU, Mengkun SUN, Sijiu YU, Yan CUI. Application of Irradiation Technology in Vaccine Development[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(8): 3383-3394.

图/表 6

表 1

图 1

表 2

表 3

辐照灭活细菌疫苗表"

细菌 Bacteria	灭活方式 Inactivation Method	灭活剂量 Inactivation Dose	动物模型 Model	疫苗效果 Immune effect	发表年份 Issue time
痢疾志贺菌 Shigella dysenteriae	X射线	N	兔	攻毒保护	1936^[45]
大肠杆菌 Escherichia coli	γ射线	1.2 kGy	鸡	在幼鸡显示广泛的保护作用	2023^[46]
溶血性曼氏杆菌 Mannheimia haemolytica	γ射线	20 kGy	兔	具有广泛的体液和细胞免疫功能	2022^[47]
产气荚膜梭菌 Clostridium perfringens	eBeam	10 kGy	鸡	显著降低菌株在攻毒后期的定植	2021^[16]
铜绿假单胞菌 Pseudomonas aeruginosa	X射线	7 Gy·min^-1	鼠	诱导Thl和Th2细胞应答，具有保护作用	2021^[48]
多杀性巴氏杆菌 Pasteurella multocida	γ射线	1 kGy	鸡	IgG和IgA滴度显著升高，具有保护作用	2021^[49]
布氏杆菌 Brucella abortus	γ射线	3.5 kGy	鼠	细胞毒性T细胞反应和保护	2009^[15]
布氏杆菌 Brucella abortus	γ射线	4 kGy	鼠	辐照菌株诱导的免疫反应较少	2010^[50]
布氏杆菌 Brucella abortus	γ射线	3.5 kGy	鼠	攻毒保护	2014^[51]
布氏杆菌 Brucella abortus	γ射线	3.5 kGy	鼠	攻毒保护	2011^[52]
产单核细胞李氏杆菌 Listeria monocytogenes	γ射线	6 kGy	鼠	诱导保护性T细胞反应	2006^[42]
溶血性曼氏杆菌 Mannheimia haemolytica	γ射线	2~20 kGy	兔	攻毒保护	2016^[53]
马红球菌 Rhodococcus equi	eBeam	4~5 kGy	马	产生细胞介导和上呼吸道黏膜免疫反应	2014^[54]
马红球菌 Rhodococcus equi	eBeam	5 kGy	马	对攻毒不予保护	2016^[55]
肺炎巴斯德菌 Rodentibacterc pneumotropicus	eBeam	20 kGy	鼠	攻毒保护和减少定植	2020^[56]
鼠伤寒沙门菌 Salmonella Typhimurium	γ射线	10~80 kGy	鸡	提高保护率	2011^[57]
鼠伤寒沙门菌 Salmonella Typhimurium	eBeam	2.5 kGy	鸡	异嗜粒细胞介导的先天免疫反应	2012^[58]
肠炎沙门菌 Salmonella Enteriditis	eBeam	2.5 kGy	鸡	攻毒保护和减少定植	2015^[14]
金黄色葡萄球菌 Staphylococcus aureus	γ射线	6 kGy	鼠	降低了小鼠菌血症攻击模型中的存活率	2017^[59]
肺炎链球菌 Streptococcus pneumoniae	γ射线	12 kGy	鼠	依赖于B细胞和IL-17A应答的免疫保护	2016^[60]
肺炎链球菌 Streptococcus pneumoniae	γ射线	10 kGy	鼠	有效保护小鼠免受肺炎链球菌感染	2018^[61]
肺炎链球菌 Streptococcus pneumoniae	γ射线	10 kGy	鼠	增强特异性抗体产生和辅助T细胞的激活	2021^[43]

表 3

表 4

表 5

放射性疫苗专利表"

专利号 Patent number	国家或组织 Country or organization	年份 Year	专利名称 Patent name
CN2022112307852	中国	2023	一种可辐照灭菌的病毒保存液
WO2022199317A1	中国	2022	一种金黄色葡萄球菌疫苗的工业化生产方法
CN114364787A	中国	2022	铜绿假单胞菌疫苗在呼吸系统疾病中的应用
CN113395980A	中国	2021	利用放射线制备减毒活疫苗的方法及通过其制备的减毒活疫苗组合物
US2021369829A1	美国	2021	用辐照法制备减毒活疫苗的方法及其制备的减毒活疫苗组合物
KR20210022577A	韩国	2021	用于控制肿瘤或抗肿瘤免疫力的巨噬细胞和辐照白细胞共同培养的上清液
CN112312925A	中国	2021	辐照灭活的脊髓灰质炎病毒、包含其的组合物及制备方法
CN112410240A	中国	2021	铜绿假单胞菌膜囊泡及其制备方法与应用
US2020179447A1	美国	2020	慢病毒表达CD80、IL-15和IL-15alpha受体的辐照全细胞肿瘤疫苗
WO2020069942A1	WIPO	2020	灭活液体中生物活性成分的方法
WO2019210888A2	中国	2019	抗结核病疫苗及其制备方法和用途
CN110621344A	中国	2019	利用电子射线和/或X射线辐照哺乳动物细胞群的方法
WO2019191586A2	加拿大	2019	辐射灭活的脊髓灰质炎病毒以及制备方法
CN108743931A	中国	2018	抗结核病疫苗及其制备方法和用途
WO2018167149A1	WIPO	2018	用电子束或X射线照射哺乳动物细胞的方法
KR20180036987A	韩国	2018	疫苗成分
ES2647584T3	西班牙	2017	一种辐照包含氨基酸和正磷酸锰混合物的微生物，用于生产疫苗的方法
CN105431171A	中国	2016	用于使用电子射线来病毒灭活的方法
DE102016216573A1	德国	2016	生物培养基中病原体的灭活
US20150209424A1	美国	2015	痘带状疱疹病毒灭活疫苗、生产方法及其用途
JP2014520117A	日本	2014	包含灭活基孔肯雅病毒株的疫苗组合物
CN104189898A	中国	2014	铜绿假单胞菌疫苗及其制备方法
KR20080107546A	韩国	2008	一种用于预防和治疗过敏性疾病的辐照卵清蛋白的疫苗组合物
US5637483A	美国	1997	表达GM-CSF的辐照肿瘤细胞疫苗
US5290551A	美国	1994	用一种与合酶结合的辐照黑色素瘤肿瘤细胞疫苗治疗黑色素瘤
CA2825403A1	加拿大	2012	由伽马辐照流感病毒和另一种免疫原组合而成的疫苗
CN101642566A	中国	2010	一种经紫外线和γ射线照射并经早熟选育获得的鸡球虫病疫苗的制备方法
CN101264322A	中国	2008	一种产单核细胞李氏杆菌灭活疫苗及其制备方法
WO2014165916A1	WIPO	2014	诱导免疫反应的方法和组合物
US10080795B2	美国	2013	一种用电子束灭活病毒的方法
US20130122045A1	美国	2013	流感疫苗交叉保护性
AU2012211043B2	澳大利亚	2012	混合疫苗

表 5

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项目类别 Items	γ射线 Gamma-ray	X射线 X-ray	电子束 Electron beam radiation
辐射源 Radiant source	放射性同位素	电子加速器	电子加速器
高能粒子 High energy particles	光子	光子	电子
穿透能力 Penetration	穿透力强	穿透力强	穿透力较弱
生产效率 Production efficiency	生产效率低	生产效率高	生产效率高
控制情况 Switch	不能关闭	可控开关	可控开关
成本费用 Costs	相对较高	相对较高	相对较低
安全情况 Security	存在安全问题	相对安全	相对安全

病毒 Virus	灭活方式 Inactivation Method	灭活剂量/kGy Inactivation Dose	动物模型 Model	免疫效果 Immune effect	发表年份 Issue time
SARS-CoV-2	γ射线	50	鼠	佐剂疫苗诱导T细胞和B细胞反应	2021^[22]
SARS-CoV-2	γ射线	25	鼠	体液和细胞免疫反应、诱导中和抗体	2021^[24]
禽流感病毒 AIV	γ射线	30	鸡	抗体效价显著增加	2022^[25]
流感病毒 IV	γ射线	50	鼠	鼻腔内接种疫苗可提供完全保护	2017^[26]
流感病毒 IV	eBeam	30	鼠	激发保护性免疫反应	2016^[27]
流感病毒 IV	eBeam	25~40	灵长类动物	诱导血清转化	2014^[28]
流感病毒 IV	γ射线	10~40	鼠	诱导交叉反应和细胞毒性T细胞反应	2011^[29]
流感病毒 IV	γ射线	10	鼠	攻毒保护	2010^[30]
流感病毒 IV	γ射线	10	鼠	攻毒保护	2009^[31]
脊髓灰质炎病毒 PV	γ射线	45	鼠	攻毒保护	2020^[32]
蜱传脑炎病毒 TBEV	eBeam	25	鼠	攻毒保护	2022^[33]
白斑综合征病毒 WSSV	eBeam	0~15	虾	攻毒保护	2017^[34]
中东呼吸综合征病毒 MERS	γ射线	50	鼠	接种疫苗的小鼠在攻毒后肺部病毒减少	2016^[35]
呼吸道合胞病毒 RSV	eBeam	20	鼠	降低攻毒后病毒载量	2018^[23]
轮状病毒 Rotavirus	γ射线	50	鼠	诱导特异性中和抗体反应	2018^[36]
埃博拉病毒 EBOV	γ射线	100	灵长类动物	攻毒后不能免疫保护	2015^[37]
委内瑞拉马脑炎病毒 VEE	γ射线	0~15	豚鼠	攻毒保护	2010^[38]
牛痘病毒 VACV	γ射线	0~15	兔	灭活病毒具有免疫原性	1960^[39]

寄生虫 Protozoa	灭活方式 Inactivation Method	灭活剂量/kGy Inactivation Dose	动物模型 Model	疫苗效果 Immune effect	发表年份 Issue time
弓形虫Toxoplasma	eBeam	0.01~0.5	鼠	产生高水平抗体	2023^[65]
柔嫩艾美耳球虫Eimeria tenella	eBeam	0.1~0.5	鸡	对攻毒具有部分保护作用	2019^[44]
恶性疟原虫Plasmodium falciparum	γ射线	0.12~0.15	人	持久的保护性免疫	2002^[66]
恶性疟原虫Plasmodium falciparum	γ射线	未提供	人	预防恶性疟原虫感染的保护	2021^[67]
弓形虫Toxoplasma	γ射线	0.225	鼠	诱导与自然感染相同的免疫力	2011^[68]
弓形虫Toxoplasma	γ射线	0.2	鼠	攻毒保护	2002^[69]
柔嫩艾美耳球虫Eimeria tenella	X射线	0.2	鸡	攻毒保护	1991^[70]

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