高危型人乳头瘤病毒 (HPV) 类型的持续感染可导致 HPV 感染组织发生癌症，包括子宫颈、口咽、肛门、阴茎、阴道和外阴。虽然目前的 HPV 疫苗可覆盖大约 90% 的宫颈癌，但与疫苗中未包含的 HPV 类型相关的近 10% 的病例仍未得到解决，尤其是 HPV59。这项研究描述了针对 HPV18/45/59 的嵌合病毒样颗粒 (VLP) 的开发，该颗粒被提议作为目前缺乏商业疫苗的高危 HPV 型 (HPV59) 的候选疫苗。鉴于大多数中和抗体表位位于表面环上，我们在密切相关的 HPV18 和 HPV45 之间设计了这些环的战略交换。然后将该方法扩展到合并 HPV59 的表面环，从而产生 H18-45BCEF-59HI 嵌合 VLP 的主要候选构建体，其两个表面环从 HPV45 交换为 HPV18。表征证实，H18-45BCEF-59HI 在粒径和形态方面与野生型 (WT) 主链类型非常相似，经透射电子显微镜 (TEM)、高效尺寸排阻色谱 (HPSEC) 和分析超速离心验证。 AUC），并通过差示扫描量热法（DSC）证明了相似的热稳定性。对具有嵌合 VLP 的小鼠进行的免疫研究评估了其免疫原性，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。这项研究不仅为当前的疫苗接种缺口提供了潜在的解决方案，还为设计针对多种亚型或变体病毒的疫苗提供了基础方法。版权所有 © 2024。由 Elsevier Ltd 出版。

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.Copyright © 2024. Published by Elsevier Ltd.