表位结构指导免疫优势转移的HPV交叉疫苗的理性设计  

Rational design of a cross-type HPV vaccine through immunodominance shift guided by a cross-neutralizing antibody

作　　者：王致萍 王大宁 陈洁 高飞 江雅楠 杨澄宇 钱兹英 池鑫 张姝玥 许钰洁 卢一涵 沈璟佳 张承宗 李瑾瑾 周立志 李婷婷 郑清炳 俞海 李少伟 夏宁邵 顾颖 Zhiping Wang;Daning Wang;Jie Chen;Fei Gao;Yanan Jiang;Chengyu Yang;Ciying Qian;Xin Chi;Shuyue Zhang;Yujie Xu;Yihan Lu;Jingjia Shen;Chengzong Zhang;Jinjin Li;Lizhi Zhou;Tingting Li;Qingbing Zheng;Hai Yu;Shaowei Li;Ningshao Xia;Ying Gu(State Key Laboratory of Vaccines for Infectious Diseases,Xiang An Biomedicine Laboratory,School of Life Sciences,School of Public Health,Xiamen University,Xiamen 361102,China;National Institute of Diagnostics and Vaccine Development in Infectious Diseases,State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,Collaborative Innovation Center of Biologic Products,National Innovation Platform for Industry-Education Integration in Vaccine Research,Xiamen University,Xiamen 361102,China;Research Unit of Frontier Technology of Structural Vaccinology,Chinese Academy of Medical Sciences,Xiamen 361102,China;Xiamen Innovax Biotech Co.,Ltd.,Xiamen 361022,China)

机构地区：[1]State Key Laboratory of Vaccines for Infectious Diseases,Xiang An Biomedicine Laboratory,School of Life Sciences,School of Public Health,Xiamen University,Xiamen 361102,China [2]National Institute of Diagnostics and Vaccine Development in Infectious Diseases,State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,Collaborative Innovation Center of Biologic Products,National Innovation Platform for Industry-Education Integration in Vaccine Research,Xiamen University,Xiamen 361102,China [3]Research Unit of Frontier Technology of Structural Vaccinology,Chinese Academy of Medical Sciences,Xiamen 361102,China [4]Xiamen Innovax Biotech Co.,Ltd.,Xiamen 361022,China

出　　处：《Science Bulletin》2024年第4期512-525,共14页科学通报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2021YFC2301404);the National Natural Science Foundation of China(82271873);the CAMS Innovation Fund for Medical Sciences(2019RU022);the Xiamen Industry-University-Research Project(2022CXY0107);the Natural Science Foundation of Xiamen City(3502Z20227165);the Fundamental Research Funds for the Central Universities(20720220006 and 20720220004).

摘　　要：In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance protection.Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies.However,the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated.In this study,we discovered a cross-type neutralizing monoclonal antibody,13H5,against human papillomavirus 6(HPV6)and HPV11.This nAb exhibited a marked preference for HPV6,demonstrating superior binding activity to virus-like particles(VLPs)and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum(90%vs.31%).Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex,we delineated the epitope as spanning four segments of amino acids(Phe42-Ala47,Gly172-Asp173,Glu255-Val275,and Val337-Tyr351)on the L1 surface loops.Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1.Substituting Ser341 with alanine,which is the residue type present in HPV11 L1,almost completely abolished binding activity to 13H5.By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1(Ser341,Thr338,and Thr339),we engineered chimeric HPV11-6HI VLPs.Remarkably,the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates.This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

关 键 词：Human papillomavirus Cross-neutralization antibody Immunodominance shift Vaccine design 

分 类 号：R392-33[医药卫生—免疫学]