冷冻干燥技术在疫苗研发中的应用进展

doi:10.19586/j.2095-2341.2023.0111

生物技术进展 ›› 2024, Vol. 14 ›› Issue (1): 72-84.DOI: 10.19586/j.2095-2341.2023.0111

• 生物制品研发与技术专题 • 上一篇下一篇

冷冻干燥技术在疫苗研发中的应用进展

刘容麟¹(), 王宁², 李岩异¹(), 张卫婷¹, 罗楚¹, 牛维兵¹

^1.华北制药金坦生物技术股份有限公司，石家庄 050035
^2.石家庄市农业技术推广中心，石家庄 050000

收稿日期:2023-09-18 接受日期:2023-11-15 出版日期:2024-01-25 发布日期:2024-02-05
通讯作者: 李岩异
作者简介:刘容麟 E-mail: iuronglin6@163.com；

The Application Progress of Freeze-drying Technology in Vaccine Research and Devolopment

Ronglin LIU¹(), Ning WANG², Yanyi LI¹(), Weiting ZHANG¹, Chu LUO¹, Weibing NIU¹

^1.North China Pharmaceutical Jintan Biotechnology Co. ，Ltd. ，Shijiazhuang 050035，China
^2.Shijiazhuang Agricultural Technology Extension Center，Shijiazhuang 050000，China

Received:2023-09-18 Accepted:2023-11-15 Online:2024-01-25 Published:2024-02-05
Contact: Yanyi LI

摘要/Abstract

摘要：

随着生物技术的飞速发展，疫苗在预防和控制传染病方面的作用越发显著，广泛的疫苗接种对全球健康至关重要。然而，在中等及低收入国家，要提高疫苗接种覆盖率还存在重大挑战。由于液体疫苗存在易分解、热稳定性差、冷链配送成本高昂等不足，限制了疫苗在这些地区的分发和接种，使一些传染性疾病在偏远地区得不到有效控制。为了保证疫苗的稳定性和有效性，冷冻干燥（freeze-drying，FD）技术成为疫苗制备和保藏的关键技术之一。从冷冻干燥技术的原理、影响因素、FD技术在不同类型疫苗中的研究以及未来发展趋势等方面进行了全面、系统的综述，以期为疫苗研究和疫苗产业化的进一步发展提供有益的信息和思路。

关键词: 冷冻干燥技术, 疫苗, 喷雾干燥, 冻干

Abstract:

As the rapid development of biotechnology， the role of vaccines in the prevention and control of infectious diseases becomes increasingly significant， and widespread immunization is crucial for global health. However， there are considerable challenges in improving vaccine coverage in low- and middle-income countries. Due to the inherent instability and poor thermal stability of liquid vaccines， the high cost of cold chain distribution restricts the dissemination and administration of vaccines in these regions， leading to ineffective control of certain infectious diseases in remote areas. To ensure the stability and effectiveness of vaccines， freeze-drying （FD） technology has become one of the key technologies in vaccine preparation and preservation. This paper provided a comprehensive and systematic review of the principles of freeze-drying technology， its influencing factors， the application of FD technology in different types of vaccines， and its future development trends， which aimed to provide useful information and insights for further research and industrialization of vaccines.

Key words: freeze-drying technology, vaccine, spray drying, lyophilization

中图分类号:

刘容麟, 王宁, 李岩异, 张卫婷, 罗楚, 牛维兵. 冷冻干燥技术在疫苗研发中的应用进展[J]. 生物技术进展, 2024, 14(1): 72-84.

Ronglin LIU, Ning WANG, Yanyi LI, Weiting ZHANG, Chu LUO, Weibing NIU. The Application Progress of Freeze-drying Technology in Vaccine Research and Devolopment[J]. Current Biotechnology, 2024, 14(1): 72-84.

图/表 2

参考文献 55

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疫苗	疫苗类型	冻干方式	稳定性	使用配方	参考文献
重组牛痘疫苗（rTTV-OVA）	病毒载体疫苗	冷冻干燥	在4 ℃和25 ℃均能提高热稳定性，保持了良好的免疫反应性和免疫原性	聚乙二醇∶右旋糖酐∶牛血清白蛋白= 50∶5∶4	[1]
人5型腺病毒疫苗（Ad5-ENV）	病毒载体疫苗	冷冻干燥	在4 ℃和25 ℃均能提高热稳定性，保持了良好的感染性和免疫原性	聚乙二醇∶L-谷氨酰胺=50∶9	[1]
口服轮状疫苗-默克公司RotaTeq^®	减毒活疫苗	冷冻干燥	5 ℃下稳定超过36个月，在37 ℃下稳定20个月，在45 ℃下稳定7个月仍然保持良好疫苗效力	HSRV04D5配方	[17]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	冻干后脂质体封装完整，在4、22和37 ℃条件至少可以保持12周且转染性无明显变化	脂质体∶mRNA=20∶1；12.5%蔗糖、Tris或磷酸盐	[14]
四价流感疫苗Fluad^®	基因重组疫苗	薄膜冷冻干燥	重组血凝素（rHA）抗原的完整性和血凝活性，冻干制剂对重复冻融不敏感，具有良好的稳定性	蔗糖	[33]
牛合并病毒灭活疫苗（pneumo-5）	灭活疫苗	冷冻干燥	5种病毒：牛病毒性腹泻病毒（BVDV）1和2型、牛单纯疱疹病毒1.1型（BoHV-1.1）、牛流感病毒3型（BPSV）和牛呼吸道合胞病毒（BRSV）均能够保护小牛，并且具有安全性和有效性	—	[37]
炭疽疫苗（anthrax vaccine）	减毒活疫苗	冷冻干燥	20 ℃储存条件下可以在180 d内保持高效力	—	[40]
风疹疫苗（rubella vaccine）	减毒活疫苗	冷冻干燥	与商用的明胶稳定剂配方对比，表现出充分的稳定性	海藻糖	[41]
腮腺炎活疫苗（mumps vaccine RS-12 株）	减毒活疫苗	冷冻干燥	在37 ℃条件下存储1周，CCID50下降幅度不到10倍	海藻糖二水合物	[42]
带状疱疹病毒疫苗	减毒活疫苗	冷冻干燥	临床接种无论年龄、性别或合并症，都能有效降低被接种者患上带状疱疹的风险	—	[43]
黄热病毒（vYF）	减毒活疫苗	喷雾干燥	具有良好的断裂力和高抗溃散性；2~8 ℃下冷藏3年，这种干燥微粒的vYF感染滴度与冷冻干燥产品相似，都具有良好的稳定性；在25 ℃和37 ℃的加速稳定性研究中，微粒中vYF的降解动力学与常规冻干产品无显著差异	糖/聚合物	[44]
结核分枝杆菌疫苗	亚单位疫苗	冷冻干燥	45 ℃条件下加热1周后进行免疫，舌下抗体反应并未减弱	糖类和佐剂	[45]
水痘带状疱疹病毒疫苗（VZV）	亚单位疫苗	冷冻干燥	体液免疫和细胞免疫反应方面均表现出极高的效果，稳定性良好	CIA09A的新型脂质体佐剂	[46]
埃博拉病毒疫苗（EBOV）	重组病毒载体疫苗	冷冻干燥	40 ℃下稳定12周，且仍保持免疫原性	9.5%海藻糖为稳定剂，乙酸铵调节冻干过程中的离子强度	[48]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	疫苗在25 ℃条件下保持6个月的物理化学性质和生物活性稳定，可以产生强大的免疫效应，且没有严重不良事件	脂质、mRNA	[50]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	-20 ℃储存条件下至少能保持12个月，无转染效果损失	乳酸-共-缩-乙二醇、mRNA	[51]
人乳头瘤病毒（HPV MS2-L2）	病毒样颗粒疫苗	喷雾干燥	37 ℃条件下可以存放2个月仍保持良好的免疫效果，所产生的抗体持久性也很好，在10个月期间没有明显的衰减	-	[53]
二价诺如病毒疫苗（norovirus）	病毒样颗粒疫苗	薄膜冷冻干燥	冻干粉在40 ℃、相对湿度为75%条件下储存8周后，抗原的效力仍保持在指定的可接受范围内	4.55%或5.55%蔗糖，或3%~4%海藻糖加上0.55%蔗糖	[54]
肺炎球菌疫苗(pneumococcal vaccine)	结合类疫苗	冷冻干燥	冻干过程中疫苗的凝聚和效力无降低，热稳定性良好	0.5%丙二醇和6%甘露醇、0.5%羧甲基纤维素钠和4%蔗糖	[55]

疫苗	疫苗类型	冻干方式	稳定性	使用配方	参考文献
重组牛痘疫苗（rTTV-OVA）	病毒载体疫苗	冷冻干燥	在4 ℃和25 ℃均能提高热稳定性，保持了良好的免疫反应性和免疫原性	聚乙二醇∶右旋糖酐∶牛血清白蛋白= 50∶5∶4	[1]
人5型腺病毒疫苗（Ad5-ENV）	病毒载体疫苗	冷冻干燥	在4 ℃和25 ℃均能提高热稳定性，保持了良好的感染性和免疫原性	聚乙二醇∶L-谷氨酰胺=50∶9	[1]
口服轮状疫苗-默克公司RotaTeq^®	减毒活疫苗	冷冻干燥	5 ℃下稳定超过36个月，在37 ℃下稳定20个月，在45 ℃下稳定7个月仍然保持良好疫苗效力	HSRV04D5配方	[17]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	冻干后脂质体封装完整，在4、22和37 ℃条件至少可以保持12周且转染性无明显变化	脂质体∶mRNA=20∶1；12.5%蔗糖、Tris或磷酸盐	[14]
四价流感疫苗Fluad^®	基因重组疫苗	薄膜冷冻干燥	重组血凝素（rHA）抗原的完整性和血凝活性，冻干制剂对重复冻融不敏感，具有良好的稳定性	蔗糖	[33]
牛合并病毒灭活疫苗（pneumo-5）	灭活疫苗	冷冻干燥	5种病毒：牛病毒性腹泻病毒（BVDV）1和2型、牛单纯疱疹病毒1.1型（BoHV-1.1）、牛流感病毒3型（BPSV）和牛呼吸道合胞病毒（BRSV）均能够保护小牛，并且具有安全性和有效性	—	[37]
炭疽疫苗（anthrax vaccine）	减毒活疫苗	冷冻干燥	20 ℃储存条件下可以在180 d内保持高效力	—	[40]
风疹疫苗（rubella vaccine）	减毒活疫苗	冷冻干燥	与商用的明胶稳定剂配方对比，表现出充分的稳定性	海藻糖	[41]
腮腺炎活疫苗（mumps vaccine RS-12 株）	减毒活疫苗	冷冻干燥	在37 ℃条件下存储1周，CCID50下降幅度不到10倍	海藻糖二水合物	[42]
带状疱疹病毒疫苗	减毒活疫苗	冷冻干燥	临床接种无论年龄、性别或合并症，都能有效降低被接种者患上带状疱疹的风险	—	[43]
黄热病毒（vYF）	减毒活疫苗	喷雾干燥	具有良好的断裂力和高抗溃散性；2~8 ℃下冷藏3年，这种干燥微粒的vYF感染滴度与冷冻干燥产品相似，都具有良好的稳定性；在25 ℃和37 ℃的加速稳定性研究中，微粒中vYF的降解动力学与常规冻干产品无显著差异	糖/聚合物	[44]
结核分枝杆菌疫苗	亚单位疫苗	冷冻干燥	45 ℃条件下加热1周后进行免疫，舌下抗体反应并未减弱	糖类和佐剂	[45]
水痘带状疱疹病毒疫苗（VZV）	亚单位疫苗	冷冻干燥	体液免疫和细胞免疫反应方面均表现出极高的效果，稳定性良好	CIA09A的新型脂质体佐剂	[46]
埃博拉病毒疫苗（EBOV）	重组病毒载体疫苗	冷冻干燥	40 ℃下稳定12周，且仍保持免疫原性	9.5%海藻糖为稳定剂，乙酸铵调节冻干过程中的离子强度	[48]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	疫苗在25 ℃条件下保持6个月的物理化学性质和生物活性稳定，可以产生强大的免疫效应，且没有严重不良事件	脂质、mRNA	[50]
新型冠状病毒疫苗	核酸疫苗	冷冻干燥	-20 ℃储存条件下至少能保持12个月，无转染效果损失	乳酸-共-缩-乙二醇、mRNA	[51]
人乳头瘤病毒（HPV MS2-L2）	病毒样颗粒疫苗	喷雾干燥	37 ℃条件下可以存放2个月仍保持良好的免疫效果，所产生的抗体持久性也很好，在10个月期间没有明显的衰减	-	[53]
二价诺如病毒疫苗（norovirus）	病毒样颗粒疫苗	薄膜冷冻干燥	冻干粉在40 ℃、相对湿度为75%条件下储存8周后，抗原的效力仍保持在指定的可接受范围内	4.55%或5.55%蔗糖，或3%~4%海藻糖加上0.55%蔗糖	[54]
肺炎球菌疫苗(pneumococcal vaccine)	结合类疫苗	冷冻干燥	冻干过程中疫苗的凝聚和效力无降低，热稳定性良好	0.5%丙二醇和6%甘露醇、0.5%羧甲基纤维素钠和4%蔗糖	[55]

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冷冻干燥技术在疫苗研发中的应用进展

The Application Progress of Freeze-drying Technology in Vaccine Research and Devolopment

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