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ENGLISH ABSTRACT
不同佐剂配伍的新型冠状病毒和流感病毒联合疫苗在小鼠中的免疫原性评价
杨洁
杨东升
吴杰
林凤杰
王文辉
杨安纳
庞德钦
戴旱雨
孟胜利
郭靖
王泽鋆
申硕
作者及单位信息
·
DOI： 10.3760/cma.j.cn311962-20240429-00022
Immunogenicity evaluation of SARS-CoV-2 and influenza virus combined vaccine formulated with different adjuvants in mice
Yang Jie
Yang Dongsheng
Wu Jie
Lin Fengjie
Wang Wenhui
Yang Anna
Pang Deqin
Dai Hanyu
Meng Shengli
Guo Jing
Wang Zejun
Shen Shuo
Authors Info & Affiliations
Yang Jie
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Yang Dongsheng
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Wu Jie
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Lin Fengjie
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Wang Wenhui
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Yang Anna
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Pang Deqin
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Dai Hanyu
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Meng Shengli
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Guo Jing
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Wang Zejun
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
Shen Shuo
Wuhan Institute of Biological Products Co.，Ltd.，National Engineering Technology Research Center for Combined Vaccines，National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases，Hubei Province Vaccine Technology Innovation Center，Wuhan 430207，China
·
DOI： 10.3760/cma.j.cn311962-20240429-00022
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摘要

目的评价分别用Al(OH) 3、MF59、AS03和QS21佐剂配伍的新型冠状病毒（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）和流感病毒联合疫苗在小鼠中的免疫原性。

方法分别用Al(OH) 3、MF59、AS03和QS21佐剂配制SARS-CoV-2（灭活）和四价流感病毒（裂解）联合疫苗，在第0、14天分别腹腔注射免疫BALB/c小鼠，第14、28天采血检测血清抗SARS-CoV-2抗体滴度和流感血凝抑制滴度，并在第28天分离脾脏淋巴细胞检测针对SARS-CoV-2和流感病毒的细胞免疫应答。

结果不同佐剂的SARS-CoV-2和流感病毒联合疫苗均能诱导小鼠产生抗原特异性的抗体和细胞免疫应答。初次免疫后28 d，MF59佐剂组诱导了较高的抗SARS-CoV-2结合抗体和中和抗体，几何平均滴度（geometric mean titer，GMT）分别为89 144和5 418；MF59佐剂组也诱导了较高的针对四价流感病毒（H1N1、H3N2、BV、BY）的血凝抑制抗体，GMT分别为4 457、5 120、1 470和5 881；MF59和AS03佐剂组诱导了较强的针对SARS-CoV-2的Th1型（IFN-γ、IL-2）细胞免疫应答，与正常对照组的斑点形成单位差异均有统计学意义（IFN-γ： H=16.69， P＜0.01；IL-2： H=15.21， P＜0.05）；AS03佐剂组诱导了较强的针对H1N1、H3N2、BV、BY流感病毒的Th1型（IFN-γ、IL-2）细胞免疫应答，与正常对照组的斑点形成单位差异均有统计学意义（IFN-γ： H=12.93、12.17、11.82、13.61， P＜0.05；IL-2： H=12.24、12.42、11.72、12.43， P＜0.05）。

结论不同佐剂配方的SARS-CoV-2和流感病毒联合疫苗的免疫原性及抗原特异性抗体和细胞免疫应答均不同，证明了联合疫苗配方研究中佐剂的重要性。

新型冠状病毒;流感病毒;联合疫苗;佐剂;体液免疫;细胞免疫
ABSTRACT

ObjectiveTo evaluate the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus combined vaccine formulated with 4 adjuvants Al(OH) 3, MF59, AS03 and QS21 in mice.

MethodsAdjuvants Al(OH) 3, MF59, AS03 and QS21 were used respectively to prepare SARS-CoV-2 (inactivated) and tetravalent influenza virus (split) combined vaccine. BALB/c mice were immunized by intraperitoneal injection on day 0 (D0) and D14, respectively. Blood samples were collected on D14 and D28 to detect antibody titers against SARS-CoV-2 and hemagglutination inhibition titers of influenza. Spleen lymphocytes were isolated on D28 to detect cellular immune responses to both SARS-CoV-2 and influenza virus.

ResultsSARS-CoV-2 and influenza virus combined vaccine with different adjuvants induced both antigen-specific antibody responses and cellular immune responses in mice. At D28 post-initial immunization, MF59 adjuvant group induced high levels of SARS-CoV-2 binding antibodies and neutralizing antibodies, with geometric mean titers (GMTs) of 89 144 and 5 418, respectively, and MF59 group also induced high levels of hemagglutination-inhibiting antibodies against the quadrivalent influenza virus strains (H1N1, H3N2, BV, BY), with GMTs of 4 457, 5 120, 1 470 and 5 881, respectively. Both the MF59 and AS03 groups induced robust Th1-type (IFN-γ, IL-2) cellular immune responses against SARS-CoV-2, with spot forming units (SFUs) statistically significantly higher than those of Mock group（IFN-γ： H=16.69， P＜0.01；IL-2： H=15.21， P＜0.05）. The AS03 group induced a strong Th1-type (IFN-γ, IL-2) cellular immune response against the quadrivalent influenza virus strains (H1N1, H3N2, BV, BY), with SFUs statistically significantly higher than those of Mock group（IFN-γ： H=12.93, 12.17, 11.82, 13.61, P＜0.05；IL-2： H=12.24, 12.42, 11.72, 12.43， P＜0.05）.

ConclusionThe immunogenicity as well as specific antibody and cellular immune responses of SARS-CoV-2 and influenza virus combined vaccine with different adjuvant formulations are different, indicating the importance of adjuvants in the development of combined vaccine formulations.

Sever acute respiratory syndrome coronavirus 2;Influenza virus;Vaccines，combined;Adjuvant;Humoral immunity;Cellar immunity
Shen Shuo, Email: mocdef.qabq7220ouhsnehs
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引用本文

杨洁,杨东升,吴杰,等. 不同佐剂配伍的新型冠状病毒和流感病毒联合疫苗在小鼠中的免疫原性评价[J]. 国际生物制品学杂志,2025,48(01)：1-9.

DOI:10.3760/cma.j.cn311962-20240429-00022

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2019年底，新型冠状病毒（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）出现并引发了COVID-19 ［ 1 ］ 。WHO已记录超7.6亿COVID-19发病病例和690万死亡病例 ［ 2 ］ ，该疫情持续暴发严重扰乱了全球社会、经济、公共卫生秩序 ［ 3 ］ 。研究表明COVID-19与其他呼吸道疾病有同时流行的可能，存在多种呼吸道病原体共同感染的潜在风险 ［ 4 , 5 ］ 。流感临床表现主要为急性呼吸系统疾病，是世界范围内的季节性传染病 ［ 6 ］ 。SARS-CoV-2和流感病毒除同为RNA病毒外，还在传播途径、疾病机制、呼吸综合征的临床表现及流行季节等方面有许多相似之处 ［ 7 , 8 ］ 。不同国家和地区的研究均表明，SARS-CoV-2和流感病毒会发生共同感染 ［ 9 , 10 , 11 , 12 ］ 。
接种疫苗是预防疾病最经济且有效的方式之一，COVID-19疫苗和流感疫苗的联合用药可能会产生一些潜在的好处，包括减轻医疗负担、降低成本以及可能增加2种疫苗的接种率 ［ 13 , 14 , 15 ］ 。佐剂又称免疫调节剂或免疫增强剂，能够增强机体对抗原的免疫应答或者改变免疫应答的类型 ［ 16 ］ 。佐剂的成分经历了从天然成分到人工合成化合物的转变过程 ［ 17 ］ ，1926年铝盐佐剂被发现 ［ 18 ］ ，1997年MF59继铝佐剂后被列入人用新型疫苗佐剂 ［ 19 ］ ，接下来的20年里AS04、AS03、AS01和CpG ODN 1018佐剂先后获得了用于人用疫苗的许可 ［ 20 ］ 。
目前尚无有效的可同时用于预防SARS-CoV-2和流感病毒的疫苗上市，突出了开发COVID-19/流感联合疫苗的迫切需要。本研究拟在BALB/c小鼠体内探究不同佐剂〔Al（OH） 3、MF59、AS03、QS21〕配伍的SARS-CoV-2灭活疫苗和四价流感病毒裂解疫苗联合疫苗（以下简称“联合疫苗”）诱导的体液和细胞免疫应答，为相关产品研发奠定基础。
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备注信息
A
申硕，Email： mocdef.qabq7220ouhsnehs
B

杨洁：实验设计、数据采集、数据分析、论文撰写；杨东升、吴杰：研究实施；林凤杰：数据采集、数据分析；王文辉、杨安纳：技术支持；庞德钦、戴旱雨：数据采集；孟胜利：论文修改；郭靖、王泽鋆：研究指导；申硕：论文修改、经费获取、研究指导

C
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国家重点研发计划 (2020YFC0842100)
湖北省科技重大专项 (2021ACB005)
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