新型疫苗佐剂研究进展

doi:10.16431/j.cnki.1671-7236.2023.06.030

摘要/Abstract

摘要： 佐剂是增强和调节疫苗抗原免疫反应的免疫刺激物，与抗原一起使用能产生更强的免疫反应。佐剂能激活机体的天然免疫系统，当佐剂和抗原同时或预先注射到机体内，可改变抗原的形态并延长抗原在体内的滞留时间，促进单核吞噬细胞对抗原的递呈能力及刺激淋巴细胞增殖分化，从而增强机体对抗原的免疫应答或改变免疫应答类型。佐剂的发展史长达一百多年，目前使用最广泛的疫苗佐剂是铝佐剂，传统的灭活疫苗在很大程度上依靠以铝盐为主的复合物作为主要佐剂。但近年来，随着基因工程技术和生物技术的飞速发展，重组疫苗、基因工程载体疫苗、核酸疫苗等新型疫苗逐步被开发出来，这些新型疫苗与传统疫苗相比往往存在免疫应答能力差等问题，早期的抗原不纯导致传统的铝盐佐剂已无法满足需要。为解决新型疫苗免疫原性差的问题，科研人员致力于开发广谱且高效的新型疫苗佐剂用来增强新型疫苗的作用。新型疫苗佐剂种类繁多，功能各不相同且机制较为复杂，可分为新型油乳佐剂、脂质体佐剂、CpG寡核苷酸佐剂、细胞因子佐剂、纳米佐剂、多糖佐剂及复合系统类佐剂等。笔者对疫苗佐剂的发展史、作用机制及新型疫苗佐剂的分类进行分析和评述，以期为新型疫苗佐剂的研制及开发提供参考。

关键词: 疫苗佐剂; 新型佐剂; 免疫; 纳米佐剂; 手性佐剂

Abstract: Adjuvants are immune stimulators that enhance and regulate the immune response of vaccine antigens.They can produce stronger immune response when used together with antigens.Adjuvants can activate the host's innate immune system.When adjuvants and antigens are injected into the body at the same time or in advance, they can change the shape of antigens and prolong their retention in the body, promote the presentation ability of mononuclear phagocytes to antigens and stimulate the proliferation and differentiation of lymphocytes, thereby enhancing the host's immune response to antigens or changing the type of immune response.Adjuvants have a history of more than 100 years.At present, the most widely used vaccine adjuvant is aluminum adjuvant.Traditional inactivated vaccines rely largely on aluminum salt based compounds as the main adjuvant.However, in recent years, with the rapid development of genetic engineering technology and biotechnology, recombinant vaccines, genetic engineering vector vaccines, nucleic acid vaccines and other novel vaccines have been gradually developed.Compared with traditional vaccines, these novel vaccines often have problems such as poor immune response.Due to the early antigen impurity, the traditional aluminum adjuvant can no longer meet the needs.In order to resolve the problem of poor immunogenicity of novel vaccines, researchers are committed to developing novel broad-spectrum and efficient vaccine adjuvants to enhance the efficacy of novel vaccines.Novel vaccine adjuvants have various types, different functions and complex mechanisms.They can be divided into novel oil emulsion adjuvants, liposome adjuvants, CpG oligonucleotide adjuvants, cytokine adjuvants, nano adjuvants, polysaccharide adjuvants and complex system adjuvants.Therefore, the development history, mechanism of action and classification of novel vaccine adjuvants were analyzed and summarized in this review, which would provide reference for the development of novel vaccine adjuvants.

Key words: vaccine adjuvant; novel adjuvant; immunization; nano adjuvant; chiral adjuvant

中图分类号:

S859.79⁺7

韩冰, 汤思淇, 朱大帷, 李海玲, 冯亚莉, 苏超凡, 徐艺娜, 冷昊钰, 王永涛, 张月美, 太晓春, 张莹. 新型疫苗佐剂研究进展[J]. 中国畜牧兽医, 2023, 50(6): 2460-2467.

HAN Bing, TANG Siqi, ZHU Dawei, LI Hailing, FENG Yali, SU Chaofan, XU Yina, LENG Haoyu, WANG Yongtao, ZHANG Yuemei, TAI Xiaochun, ZHANG Ying. Research Progress of Novel Vaccine Adjuvants[J]. China Animal Husbandry and Veterinary Medicine, 2023, 50(6): 2460-2467.

参考文献

[1] 曾振, 王海宁, 张志芳, 等.新型疫苗佐剂的研究进展[J].生物工程学报, 2021, 37(1):78-87. ZENG Z, WANG H N, ZHANG Z F, et al.Research progress of new vaccine adjuvants[J].Chinese Journal of Biotechnology, 2021, 37(1):78-87.(in Chinese)
[2] HASSETT K J, COUSINS M C, RABIA L, et al.Stabilization of a recombinant ricin toxin A subunit vaccine through lyophilization[J].European Journal of Pharmaceutics and Biopharmaceutics, 2013, 85(2):279-286.
[3] 夏赟, 武梦玉, 张永辉.免疫佐剂的发展现状与未来趋势[J].中国科学基金, 2020, 34(5):573-580. XIA Y, WU M Y, ZHANG Y H.Current status and future trends of immunologic adjuvants[J].Bulletin of National Natural Science Foundation of China, 2020, 34(5):573-580.(in Chinese)
[4] O'HAGAN D T, OTT G S, NEST G V, et al.The history of MF59^® adjuvant:A phoenix that arose from the ashes[J].Expert Review of Vaccines, 2013, 12(1):13-30.
[5] 于永利.AS系列佐剂[J].微生物学免疫学进展, 2017, 45(1):1-6. YU Y L.AS adjuvants[J].Progress in Microbiology and Immunology, 2017, 45(1):1-6.(in Chinese)
[6] XU L, WANG X, WANG W, et al.Enantiomer-dependent immunological response to chiral nanoparticles[J].Nature, 2022, 601(7893):366-373.
[7] BINNEWIES M, MUJAL A M, POLLACK J L, et al.Unleashing type-2 dendritic cells to drive protective antitumor CD4⁺ T cell immunity[J].Cell, 2019, 177(3):556-571.
[8] 李卓凡, 李卫东.MF59佐剂的研究进展[J].国际检验医学杂志, 2016, 37(18):2596-2598. LI Z F, LI W D.Research progress of MF59 adjuvants[J].International Journal of Laboratory Medicine, 2016, 37(18):2596-2598.(in Chinese)
[9] O'HAGAN D T, RAPPUOLI R, DE GREGORIO E, et al.MF59 adjuvant:The best insurance against influenza strain diversity[J].Expert Review of Vaccines, 2011, 10(4):447-462.
[10] 吴晓鑫, 沈吉友, 李方仲, 等.H7N9禽流感病毒裂解佐剂(MF59)疫苗的长期免疫原性研究[J].微生物学免疫学进展, 2019, 47(5):10-15. WU X X, SHEN J Y, LI F Z, et al.Long-term immunogenicity test for avian influenza A H7N9 split vaccine with MF59 adjuvant[J].Progress in Microbiology and Immunology, 2019, 47(5):10-15.(in Chinese)
[11] DOMNICH A, ARATA L, AMICIZIA D, et al.Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly:A systematic review and meta-analysis[J].Vaccine, 2017, 35(4):513-520.
[12] LANSBURY L E, SMITH S, BEYER W, et al.Effectiveness of 2009 pandemic influenza A(H1N1) vaccines:A systematic review and meta-analysis[J].Vaccine, 2017, 35(16):1996-2006.
[13] ZHANG N, JI Q, LIU Z, et al.Effect of different adjuvants on immune responses elicited by protein-based subunit vaccines against SARS-CoV-2 and its delta variant[J].Viruses, 2022, 14(3):501.
[14] OTSUKA T, NISHIDA S, SHIBAHARA T, et al.CpG ODN (K3)-toll-like receptor 9 agonist-induces Th1-type immune response and enhances cytotoxic activity in advanced lung cancer patients:A phase Ⅰstudy[J].BMC Cancer, 2022, 22(1):744.
[15] 陆晨阳, 张婷, 任超超, 等.添加CpG ODN佐剂对鸭坦布苏弱毒活疫苗免疫效果影响研究[J].中国动物传染病学报, 2022, 30(4):54-60. LU C Y, ZHANG T, REN C C, et al.Evaluation of adjuvant effect of CpG ODN on Duck Tembusu virus live attenuated vaccine[J].Chinese Journal of Animal Infectious Diseases, 2022, 30(4):54-60.(in Chinese)
[16] 王长丽, 黄祯雄, 王胜秋, 等.CpG ODN B对鸡新城疫重组杆状病毒疫苗的免疫增强效应[J].生物技术通讯, 2020, 31(4):409-415. WANG C L, HUANG Z X, WANG S Q, et al.Immune enhancement of CpG ODN B on recombinant Baculovirus vaccine against Newcastle disease in chickens[J].Letters in Biotechnology, 2020, 31(4):409-415.(in Chinese)
[17] 闫江泓, 于鹏程, 陶晓燕, 等.CpG寡聚脱氧核苷酸佐剂对狂犬病疫苗免疫效果的影响[J].中国生物制品学杂志, 2017, 30(6):566-570. YAN J H, YU P C, TAO X Y, et al.Influence of CpG oligodeoxynucleotide adjuvant on immune effect of rabies vaccine[J].Chinese Journal of Biologicals, 2017, 30(6):566-570.(in Chinese)
[18] OUYANG K, HIREMATH J, BINJAWADAGI B, et al.Comparative analysis of routes of immunization of a live Porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in a heterologous virus challenge study[J].Veterinary Research, 2016, 47(1):45.
[19] LU W, CUI C, WANG Y, et al.CpG ODN as an adjuvant arouses the vigor of B cells by relieving the negative regulation of surface TLR9 to enhance the antibody response to vaccine[J].Applied Microbiology and Biotechnology, 2021, 105(10):4213-4224.
[20] COOPER C, MACKIE D.Hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine:A review of HEPLISAV^TM safety and efficacy[J].Expert Review of Vaccines, 2011, 10(4):417-427.
[21] HALPERIN S A, MCNEIL S, LANGLEY J M, et al.Safety and immunogenicity of different two-dose regimens of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in healthy young adults[J].Vaccine, 2012, 30(36):5445-5448.
[22] LIN S Y, YAO B Y, HU C J, et al.Induction of robust immune responses by CpG-ODN-loaded hollow polymeric nanoparticles for antiviral and vaccine applications in chickens[J].International Journal of Nanomedicine, 2020, 11(15):3303-3318.
[23] 徐莉, 李敏.CpG ODN佐剂的研究进展及其药学研究的思考[J].中国生物制品学杂志, 2021, 34(12):1524-1528. XU L, LI M.Research progress of CpG ODN adjuvants and thoughts on pharmaceutical research[J].Chinese Journal of Biologicals, 2021, 34(12):1524-1528.(in Chinese)
[24] KHAYYATI K M, DELIREZH N, AGHEBATI M L.CpG-Containing oligodeoxynucleotides and Freund adjuvant in combination with alum augment the production of monoclonal antibodies against recombinant HBsAg[J].Avicenna Journal of Medical Biotechnology, 2022, 14(2):125-131.
[25] JARCZAK D, NIERHAUS A.Cytokine storm-definition, causes, and implications[J].International Journal of Molecular Sciences, 2022, 23(19):11740.
[26] 吴正锋, 彭钰君, 柏银兰.疫苗佐剂的研究进展[J].微生物学免疫学进展, 2022, 50(5):72-77. WU Z F, PENG Y J, BAI Y L.Advances of adjuvants for vaccines[J].Progress in Microbiology and Immunology, 2022, 50(5):72-77.(in Chinese)
[27] DECKER W K, SAFDAR A.Cytokine adjuvants for vaccine therapy of neoplastic and infectious disease[J].Cytokine and Growth Factor Reviews, 2011, 22(4):177-187.
[28] 那君, 胡婧雯, 杨小茜, 等.细胞因子作为人类疫苗佐剂的研究进展[J].现代免疫学, 2016, 36(4):337-340. NA J, HU J W, YANG X Q, et al.Research progress of cytokines as adjuvants of human vaccines[J].Current Immunology, 2016, 36(4):337-340.(in Chinese)
[29] 匡露寒, 季国荣, 杨灿灿, 等. 基于抗原蛋白Fiber-2及细胞因子佐剂的Ⅰ群4型禽腺病毒亚单位疫苗的开发[J]. 中国兽医科学, 2020, 50(4):452-458. KUANG L H, JI G R, YANG C C, et al. Development of group Ⅰ serotype 4 Fowl adenovirus subunit vaccine based on antigen protein Fiber-2 and cytokine adjuvants[J]. Chinese Veterinary Science, 2020, 50(4):452-458. (in Chinese)
[30] MOHAN T, ZHU W, WANG Y, et al.Applications of chemokines as adjuvants for vaccine immunotherapy[J].Immunobiology, 2018, 223(6-7):477-485.
[31] REZAEI F, KESHVARI H, SHOKRGOZAR M A, et al.Nano-adjuvant based on silk fibroin for the delivery of recombinant hepatitis B surface antigen[J].Biomaterials Science, 2021, 9(7):2679-2695.
[32] XU Y, TANG H, LIU J H, et al.Evaluation of the adjuvant effect of silver nanoparticles both in vitro and in vivo[J].Toxicology Letters, 2013, 219(1):42-48.
[33] ASGARY V, SHOARI A, BAGHBANI-ARANI F, et al.Green synthesis and evaluation of silver nanoparticles as adjuvant in rabies veterinary vaccine[J].International Journal of Nanomedicine, 2016, 11:3597-3605.
[34] RAO K, AZIZ S, ROOME T, et al.Gum acacia stabilized silver nanoparticles based nano-cargo for enhanced anti-arthritic potentials of hesperidin in adjuvant induced arthritic rats[J].Artificial Cells, Nanomedicine, and Biotechnology, 2018, 46(sup1):597-607.
[35] LIU H, XIE Z, ZHENG M.Unprecedented chiral nanovaccines for significantly enhanced cancer immunotherapy[J].ACS Applied Materials & Interfaces, 2022, 14(35):39858-39865.
[36] 曲广波, 江桂斌.手性纳米材料的免疫佐剂效应[J].化学进展, 2022, 34(2):239-240. QU G B, JIANG G B.Immune adjuvant effect of chiral nanomaterials[J].Progress in Chemistry, 2022, 34(2):239-240.(in Chinese)
[37] SUN B, YU S, ZHAO D, et al.Polysaccharides as vaccine adjuvants[J].Vaccine, 2018, 36(35):5226-5234.
[38] DMOUR I, ISLAM N.Recent advances on chitosan as an adjuvant for vaccine delivery[J].International Journal of Biological Macromolecules, 2022, 200:498-519.
[39] ACEVEDO K Y, RENU S, SHANMUGASUNDARAM R, et al.Salmonella chitosan nanoparticle vaccine administration is protective against Salmonella Enteritidis in broiler birds[J].PLoS One, 2021, 16(11):e0259334.
[40] 鲁振国.中药多糖提取方法及其免疫增强效果的初步研究[D].广州:华南农业大学, 2019. LU Z G.Extraction method of Chinese traditional medicine polysaccharide and initial study on its immune enhancement effect[D].Guangzhou:South China Agricultural University, 2019.(in Chinese)
[41] 李慧, 宋杰, 董少忠.复合免疫佐剂在疫苗开发中的应用研究进展[J].国际免疫学杂志, 2020, 2:201-208. LI H, SONG J, DONG S Z.Research progress in the application of compound immune adjuvants in vaccine development[J].International Journal of Immunology, 2020, 2:201-208.(in Chinese)
[42] DIDIERLAURENT A M, LAUPEZE B, DI PASQUALE A, et al.Adjuvant system AS01:Helping to overcome the challenges of modern vaccines[J].Expert Review of Vaccines, 2017, 16(1):55-63.
[43] TAKASHIMA E, TACHIBANNA M, MORITA M, et al.Identification of novel malaria transmission-blocking vaccine candidates[J]. Frontiers in Cellular and Infection Microbiology, 2021, 30(11):805-482.
[44] SCARIA P V, ROWE C G, CHEN B B, et al.Protein-protein conjugation enhances the immunogenicity of SARS-CoV-2 receptor-binding domain (RBD) vaccines[J].iScience, 2022, 25(8):104739.
[45] 林海祥, 俞永新.皮卡佐剂和皮卡狂犬病疫苗的安全性[J].中国生物制品学杂志, 2010, 23(1):98-100. LIN H X, YU Y X.Safeties of PICKCa as an adjuvant and rabies vaccine using the adjuvant[J].Chinese Journal of Biologicals, 2010, 23(1):98-100.(in Chinese)
[46] 王树声.一种新型的皮卡(PIKA)佐剂狂犬病疫苗-抢救生命的治疗性疫苗[J].应用预防医学, 2010, 16(1):1-4. WANG S S.A new rabies vaccine with PIKA adjuvant-A life saving therapeutic vaccine[J].Applied Preventive Medicine, 2010, 16(1):1-4.(in Chinese)