新冠病毒变异株RBD二聚体mRNA疫苗广谱免疫原性研究  

Evaluation of the broad-spectrum immunogenicity of RBD dimer mRNA vaccines against SARS-CoV-2 variants

作　　者：赵旭[1] 吴鑫凯 杜沛 陈茜 马雪慧 胡世雄 吴春丽 杨惠婷 马任义 李爽[1] 孔天翔 李睿琦 冯英浩 王晓云[1] 荣笑雨 郑安琪 陆剑[2] 高福[1,6,7] 王奇慧 Xu Zhao;Xinkai Wu;Pei Du;Qian Chen;Xuehui Ma;Shixiong Hu;Chunli Wu;Huiting Yang;Renyi Ma;Shuang Li;Tianxiang Kong;Ruiqi Li;Yinghao Feng;Xiaoyun Wang;Xiaoyu Rong;Anqi Zheng;Jian Lu;George Fu Gao;Qihui Wang(CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China;School of Life Sciences,Peking University,Beijing 100871,China;Faculty of Health Sciences,University of Macao,Macao 999078,China;College of Veterinary Medicine,Shanxi Agricultural University,Jinzhong 030801,China;School of Life Sciences,Yunnan University,Kunming 650091,China;School of Medicine,Tsinghua University,Beijing 100084,China;Savaid Medical School,University of Chinese Academy of Sciences,Beijing 100049,China;School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou 325035,China)

机构地区：[1]中国科学院病原微生物与免疫学重点实验室,北京100101 [2]北京大学生命科学学院,北京100871 [3]澳门大学健康科学学院,中国澳门999078 [4]山西农业大学动物医学学院,晋中030801 [5]云南大学生命科学学院,昆明650091 [6]清华大学医学院,北京100084 [7]中国科学院大学存济医学院,北京100049 [8]温州医科大学检验医学与生命科学学院,温州325035

出　　处：《科学通报》2024年第33期4905-4916,共12页Chinese Science Bulletin

基　　金：国家重点研发计划(2022YFC2303403);国家自然科学基金杰出青年科学基金(82225021);中国科学院稳定支持基础研究领域青年团队项目(YSBR-010)资助。

摘　　要：严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)是导致新冠病毒病(coronavirus disease 2019,COVID-19)的病原体.2019年末至今,SARS-CoV-2在全球范围流行,氨基酸突变累积产生多种具有较高传播力或较强免疫逃逸能力的变异株.目前广泛使用的COVID-19疫苗大多基于SARS-CoV-2原型株(prototype,PT)进行免疫原设计.这些疫苗针对早期变异株具有较好的保护效果,然而面对后续出现的Omicron系列变异株,以原型株为免疫原的疫苗保护效力显著下降,特别是在面对免疫逃逸极强的BF.7、BQ.1.1、CH.1.1、XBB及XBB.1.5等变异株时,难以激发较高水平特异性中和抗体.因此,亟须研发针对多种SARS-CoV-2变异株产生高效中和抗体的新一代广谱疫苗.本研究基于SARS-CoV-2受体结合域(receptor-binding domain,RBD)重复串联二聚体的构型,设计了6种包含Delta RBD以及BA.1、BA.2和BA.5等Omicron亚型RBD的串联二聚体mRNA疫苗,并对其表达情况及免疫原性进行了系统性评价.同时,还验证了在两针灭活疫苗基础上以mRNA疫苗作为加强针的序贯免疫效果.假病毒中和数据显示,Delta-BA.2(DO2)与Delta-BA.5(DO5)RBD二聚体疫苗表现出较优的免疫原性,且两者诱导的中和抗体分别针对BA.2之前和BA.5之后出现的变异株有较好的中和活性,表现出一定的互补趋势.因此,我们设计了DO2和DO5混合免疫的策略,实现了对二者优势的互补,进一步扩宽了疫苗中和抗体谱.在三剂免疫的结果中,DO5及DO2+DO5免疫可产生针对CH.1.1、XBB及XBB.1.5的高水平中和抗体.这些结果有助于我们理解不同分支变异株中和抗体谱的变化规律,并为广谱COVID-19疫苗设计提供了参考.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has been spreading globally since the end of 2019.During this period,the virus has undergone mutations that led to the emergence of multiple variants with high transmissibility or capability of immune evasion.To prevent the spread of the virus,large-scale vaccination campaigns were conducted in many countries.However,as SARS-CoV-2 continues to mutate,the prevalent COVID-19 vaccines,which were primarily designed using the SARS-CoV-2 prototype(PT)and effectively safeguarded against early SARS-CoV-2 variants,have displayed considerably diminished efficacy against subsequent Omicron sub-variants,especially against the more recent BF.7,BQ.1.1,CH.1.1,XBB,and XBB.1.5 that has higher capability immune escape.Therefore,there is an urgent need to develop a new generation of broad-spectrum vaccines that can generate high levels of neutralizing antibodies against multiple SARS-CoV-2 variants.Previously,our group developed the ZF2001 vaccine with a tandem repeat homodimer of the SARS-CoV-2 receptor-binding domain(RBD),which has been approved in 4 countries and vaccinated over 300 million doses worldwide.To tackle the Omicron variant,we also upgraded the RBD homodimer of ZF2001 vaccine to a Delta-BA.1 chimeric heterodimer and developed protein subunit and mRNA vaccine that both demonstrated potent broad-spectrum immunogenicity against pre-Omicron variants as well as some Omicron sub-variants such as BA.1 and BA.2.With further evolution of Omicron,the prevalent XBB derivatives have displayed severe immune escape to the BA.1 immunogen.Therefore,we aim to further broaden the immunogenicity of RBD dimer vaccines by upgrading the Delta-BA.1 RBD dimer immunogen using the RBDs of more recent Omicron sub-variants.In this study,we developed six novel RBD dimer mRNA vaccines,each incorporating an RBD dimer consisting of Delta RBD or the RBD from specific Omicron sub-variants such as BA.1,BA.2,or BA.5.By systematically ev

关 键 词：SARS-CoV-2 Omicron变异株 mRNA疫苗 广谱疫苗 

分 类 号：R392[医药卫生—免疫学]