Qian Ciying, Chen Jie, Yang Yurou, Lu Yihan, Ren Tianyu, Jiang Yanan, Huang Yang, Chi Xin, Zhang Shuyue, Zhang Chengzong, Li Kewei, Shen Jingjia, Zhang Sibo, Wang Daning, Zhou Lizhi, Li Tingting, Zheng Qingbing, Yu Hai, Gu Ying, Xia Ningshao, Li Shaowei
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Discipline of Intelligent Instrument and Equipment, Department of Experimental Medicine, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, China.
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, China.
J Nanobiotechnology. 2025 Jan 20;23(1):28. doi: 10.1186/s12951-024-03080-5.
The numerous high-risk carcinogenic types of human papillomavirus (HR-HPV) that lack vaccine protection underscore the urgent need to develop broader-spectrum HPV vaccines. This study addresses this need by focusing on HR-HPV types 53, 56, and 66, which are not currently targeted by existing vaccines. It introduces an effective method for their soluble expression, as well as that of their mutants, within an Escherichia coli expression system. Through strategic homologous loop swapping among HPV53, HPV56, and HPV66, we designed twenty double-type chimeric molecules. Comprehensive evaluations identified unique dominant immunogenic loops for each type: the FG loop for HPV53, the HI loop for HPV56, and the DE loop for HPV66, with HPV66 emerging as the optimal chimeric backbone virus-like particle (VLP). By incorporating two identified immunodominant sites into the preferable base particle, the study constructed a triple-type chimera H66-56HI-53FG, which could efficiently self-assemble into VLPs in vitro that closely resembled the wild-type HPV66 VLP and, induced balanced triple-type neutralization titers (~ 3 log unites), as contrast to none observable HPV53 neutralization titer and lower HPV56 titer elicited by the immunization of the wild-type HPV66 alone. This research outlines an amenable way to simultaneously identify immunodominant sites and their preferable particle base context for cross-type vaccine design, thereby offering a paradigm as extending antigenic variety in single particle to broaden vaccine protection coverage.
众多缺乏疫苗保护的高危致癌型人乳头瘤病毒（HR-HPV）凸显了开发广谱HPV疫苗的迫切需求。本研究聚焦于目前现有疫苗未涵盖的HR-HPV 53型、56型和66型，以满足这一需求。该研究介绍了一种在大肠杆菌表达系统中有效表达这些病毒及其突变体的可溶性蛋白的方法。通过在HPV53、HPV56和HPV66之间进行策略性的同源环交换，我们设计了20种双型嵌合分子。综合评估确定了每种病毒的独特优势免疫原性环：HPV53的FG环、HPV56的HI环和HPV66的DE环，其中HPV66成为最佳的嵌合骨架病毒样颗粒（VLP）。通过将两个已确定的免疫显性位点整合到优选的基础颗粒中，该研究构建了三型嵌合体H66-56HI-53FG，其能够在体外有效自组装成与野生型HPV66 VLP极为相似的VLP，并诱导出平衡的三型中和效价（约3个对数单位），相比之下，单独免疫野生型HPV66未观察到HPV53中和效价，HPV56效价较低。本研究概述了一种适用于同时鉴定免疫显性位点及其优选颗粒基础背景以进行跨型疫苗设计的方法，从而提供了一种将单颗粒中的抗原多样性扩展以扩大疫苗保护覆盖范围的范例。
