State Key Laboratory of Vaccines for Infectious Diseases，Xiang An Biomedicine Laboratory，School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics，National Institute of Diagnostics and Vaccine Development in Infectious Diseases，National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen 361102, China.
State Key Laboratory of Vaccines for Infectious Diseases，Xiang An Biomedicine Laboratory，School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics，National Institute of Diagnostics and Vaccine Development in Infectious Diseases，National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen 361102, China; The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China.
Vaccine. 2024 Oct 24;42(24):126245. doi: 10.1016/j.vaccine.2024.126245. Epub 2024 Aug 30.
Persistent infection with high-risk human papillomavirus (HPV) types can lead to the development of cancer in HPV-infected tissues, including the cervix, oropharynx, anus, penis, vagina, and vulva. While current HPV vaccines cover approximately 90 % of cervical cancers, nearly 10 % of cases associated with HPV types not included in the vaccines remain unaddressed, notably HPV59. This study describes the development of a chimeric virus-like particle (VLP) targeting HPV18/45/59, proposed as a vaccine candidate for high-risk HPV type (HPV59) currently lacking commercial vaccines. Given that the majority of neutralizing antibody epitopes are located on the surface loops, we engineered a strategic swap of these loops between the closely related HPV18 and HPV45. This methodology was then extended to incorporate surface loops of HPV59, resulting in the lead candidate construct of the H18-45BCEF-59HI chimeric VLP with two surface loops swapping from HPV45 to HPV18. Characterization confirmed that H18-45BCEF-59HI closely resembled the wild-type (WT) backbone types in particle size and morphology, as verified by Transmission Electron Microscopy (TEM), High-Performance Size-Exclusion Chromatography (HPSEC), and Analytical Ultracentrifugation (AUC), and demonstrated similar thermal stability as evidenced by Differential Scanning Calorimetry (DSC). Immunization studies in mice with the chimeric VLPs assessed their immunogenicity, revealing that the H18-45EF-59HI chimeric VLP exhibited optimal cross-neutralization. Additionally, when produced in a Good Manufacturing Practice (GMP)-like facility, the H18-45BCEF-59HI VLP was selected as a promising vaccine candidate for the prevention of HPV18/45/59 infection. This study not only offers a potential solution to the current vaccination gap but also provides a foundational approach for the design of vaccines targeting viruses with multiple subtypes or variants.
高危型人乳头瘤病毒（HPV）的持续感染可导致 HPV 感染组织的癌症发展，包括宫颈、口咽、肛门、阴茎、阴道和外阴。虽然目前的 HPV 疫苗涵盖了大约 90%的宫颈癌，但仍有近 10%的病例与疫苗未涵盖的 HPV 类型有关，特别是 HPV59。本研究描述了一种针对 HPV18/45/59 的嵌合病毒样颗粒（VLP）的开发，该 VLP 被提议作为目前缺乏商业疫苗的高危 HPV 类型（HPV59）的候选疫苗。鉴于大多数中和抗体表位位于表面环上，我们设计了一种策略，在密切相关的 HPV18 和 HPV45 之间交换这些环。然后，我们将这种方法扩展到包含 HPV59 的表面环，从而得到了具有两个表面环从 HPV45 交换到 HPV18 的 H18-45BCEF-59HI 嵌合 VLP 的领先候选构建体。表征证实，H18-45BCEF-59HI 在粒径和形态上与野生型（WT）骨架类型非常相似，这通过透射电子显微镜（TEM）、高效尺寸排阻色谱法（HPSEC）和分析超速离心法（AUC）得到了验证，并且在热稳定性方面表现出相似性，如差示扫描量热法（DSC）所示。在小鼠中进行的嵌合 VLPs 免疫研究评估了它们的免疫原性，结果表明，H18-45EF-59HI 嵌合 VLP 表现出最佳的交叉中和作用。此外，当在类似于良好生产规范（GMP）的设施中生产时，H18-45BCEF-59HI VLP 被选为预防 HPV18/45/59 感染的有前途的候选疫苗。本研究不仅为当前的疫苗接种空白提供了潜在的解决方案，还为设计针对具有多种亚型或变体的病毒的疫苗提供了基础方法。
