以多种RG-1保守表位病毒样颗粒为基础的广谱HPV预防性疫苗的研究

HPV致病型别多，且每种病变均可由多种型别感染引起（如宫颈癌相关的致癌型达20余种），现有的L1VLP疫苗主要保护疫苗构成型别，不利于广谱疫苗研发。L2 aa.17-36保守中和表位肽(RG-1)可诱发交叉中和抗体，但免疫原性弱，且单型RG-1诱发的交叉保护范围窄。为了同时发挥多型RG-1依赖抗体的交叉中和优势及多型L1VLP依赖抗体的特异性中和优势，本项目以我国5种主要高危型HPV L1VLP为载体，采用多种策略在其表面区插入不同的免疫原性强的RG-1，利用昆虫细胞表达体系，分别获得可同时发挥RG-1及L1VLP载体免疫优势的5种RG1-cVLP，混合免疫，阐明其诱发的L2依赖交叉中和抗体及L1依赖特异中和抗体的协同作用特点，获得成本低的可涵盖绝大多数致癌型（包括所有高危型）、至少包括主要低危型及主要皮肤型的广谱HPV16/-18/-58/-52/-31 cVLP混合疫苗，未见报道。

Over 200 HPVs have been identified, among them, mucosal oncogenic HPVs are considered as etiological factor in tumorigenesis of uterine cervix and other anogenital and oropharyngeal sites, mucosal low-risk HPVs induce mucosal warts, and cutaneous HPVs induce skin warts and take part in the occurrence of skin cancers. Each HPV-related lesion can be caused by infections of one or more types of HPVs, such as over 20 types of oncogenic HPVs were identified in cervical cancers. Current L1VLP-based vaccines induce protection against mainly vaccine types, thus make it infeasible to develop a broad-spectrum L1VLP-based vaccine. The immunogenicity of L2 aa.17-36 peptide (RG-1), which contains conserved neutralizing epitopes and can induce cross-neutralizing antibodies, is weak, and low titers of neutralizing antibodies induced by single type of RG-1 provide only suboptimal protection spectrum. In order to simultaneously take advantage of the cross-neutralization advantage of multiple types of RG-1 dependent antibodies and the specific neutralization advantage of multiple types of L1VLP-dependent antibodies, in this project, L1VLPs from five major high-risk HPVs (HPV16/-18/-58/-52/-31) in China will be used as carriers individually to deliver different RG-1 in their surface regions and the resultant 5 types of HPV chimeric VLPs (cVLPs) displaying different RG-1 in their surface regions will be expressed and identified individually. The neutralizing antibody responses and protection activities induced by HPV16/-18/-58/-52/-31 cVLP vaccine will be investigated to elucidate the synergistic effect of its induced multiple types of RG1-dependent cross-neutralizing antibodies and L1-dependent specific neutralizing antibodies. The protection spectrum of HPV16/-18/-58/-52/-31 cVLP vaccine will cover most oncogenic HPVs (including all high-risk HPVs), at least major low-risk HPVs and major cutaneous HPVs, and its cost is low. The HPV cVLP vaccine is innovative, no relevant reports have been found.