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

Zhiping Wang ¹Daning Wang ²Jie Chen ¹Fei Gao ¹Yanan Jiang ¹Chengyu Yang ¹Ciying Qian ¹Xin Chi ¹Shuyue Zhang ¹Yujie Xu ¹Yihan Lu ¹Jingjia Shen ¹Chengzong Zhang ¹Jinjin Li ¹Lizhi Zhou ¹Tingting Li ¹Qingbing Zheng ¹Hai Yu ¹Shaowei Li ¹Ningshao Xia ³Ying Gu¹

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作者信息

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;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
2. 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;Xiamen Innovax Biotech Co.,Ltd.,Xiamen 361022,China
3. 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
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Abstract

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 crit-ical 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.

Key words

Human papillomavirus/Cross-neutralization antibody/Immunodominance shift/Vaccine design

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基金项目

National Key Research and Development Program of China(2021YFC2301404)

National Natural Science Foundation of China(82271873)

CAMS Innovation Fund for Medical Sciences(2019RU022)

Xiamen Industry-University-Research Project(2022CXY0107)

Natural Science Foundation of Xiamen City(3502Z20227165)

Fundamental Research Funds for the Central Universities(20720220006)

Fundamental Research Funds for the Central Universities(20720220004)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

参考文献量54

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