Namvar Ali, Bolhassani Azam, Javadi Gholamreza, Noormohammadi Zahra
Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.
Fundam Clin Pharmacol. 2021 Dec;35(6):1055-1068. doi: 10.1111/fcp.12690. Epub 2021 Jun 16.
Different types of cancer including cervical (>90%), anal (88%), vaginal (40%), and penile (~40%) cancers are associated with human papillomaviruse (HPV) infections. Three prophylactic vaccines (Cervarix, Gardasil, and Gardasil-9) were approved to provide immuno-protection against certain types of HPVs. Currently, next-generation HPV vaccines such as L1/L2-based vaccines are being developed to provide broad-type HPV protection. In this study, we introduced a comprehensive framework for design of L1/L2 polyepitope-based HPV vaccine candidate. This framework started with protein sequence retrieval and followed by conservancy analysis between high-risk HPVs, MHC-I and MHC-II epitope mapping, and B-cell and T-cell epitope mapping. Subsequently, we performed Tap transport and proteasomal cleavage, population coverage, antigenicity, allergenicity and cross-reactivity. After that, peptide-MHCI/II flexible docking and comprehensive conservancy analysis against all HPV types were carried out. The next steps were prediction of interferon-gamma and interleukin-10 inducing epitopes, epitope selection and construct design, tertiary structure prediction, refinement and validation, discontinuous B-cell epitope prediction, vaccine-TLR4 molecular docking, and codon optimization. Our data showed that two designed vaccine constructs harboring 8 L1 peptides or 7 L2 peptides, individually were highly conserved between all well-known HPV types. In addition, the combination of in silico/in vivo approaches indicated the potential ability of L1 and L2 polyepitope constructs for development of next generation prophylactic/therapeutic HPV vaccine.
不同类型的癌症，包括宫颈癌（>90%）、肛门癌（约88%）、阴道癌（约40%）和阴茎癌（约40%）都与人乳头瘤病毒（HPV）感染有关。三种预防性疫苗（希瑞适、佳达修和佳达修9）已获批准，可提供针对某些类型HPV的免疫保护。目前，正在研发下一代HPV疫苗，如基于L1/L2的疫苗，以提供广泛类型的HPV保护。在本研究中，我们引入了一个基于L1/L2多表位的HPV候选疫苗设计的综合框架。该框架始于蛋白质序列检索，随后进行高危HPV之间的保守性分析、MHC-I和MHC-II表位作图，以及B细胞和T细胞表位作图。随后，我们进行了转运相关蛋白（Tap）转运和蛋白酶体切割、人群覆盖率、抗原性、致敏性和交叉反应性分析。之后，针对所有HPV类型进行了肽-MHCI/II柔性对接和综合保守性分析。接下来的步骤是预测干扰素-γ和白细胞介素-10诱导表位、表位选择和构建体设计、三级结构预测、优化和验证、不连续B细胞表位预测、疫苗-TLR4分子对接以及密码子优化。我们的数据表明，两种分别包含8个L1肽或7个L2肽的设计疫苗构建体在所有已知HPV类型之间具有高度保守性。此外，计算机模拟/体内方法的结合表明，L1和L2多表位构建体具有开发下一代预防性/治疗性HPV疫苗的潜在能力。
