Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.
PLoS One. 2011;6(8):e23310. doi: 10.1371/journal.pone.0023310. Epub 2011 Aug 17.
Current human papillomavirus (HPV) vaccines that are based on virus-like particles (VLPs) of the major capsid protein L1 largely elicit HPV type-specific antibody responses. In contrast, immunization with the HPV minor capsid protein L2 elicits antibodies that are broadly cross-neutralizing, suggesting that a vaccine targeting L2 could provide more comprehensive protection against infection by diverse HPV types. However, L2-based immunogens typically elicit much lower neutralizing antibody titers than L1 VLPs. We previously showed that a conserved broadly neutralizing epitope near the N-terminus of L2 is highly immunogenic when displayed on the surface of VLPs derived from the bacteriophage PP7. Here, we report the development of a panel of PP7 VLP-based vaccines targeting L2 that protect mice from infection with carcinogenic and non-carcinogenic HPV types that infect the genital tract and skin.
METHODOLOGY/PRINCIPAL FINDINGS: L2 peptides from eight different HPV types were displayed on the surface of PP7 bacteriophage VLPs. These recombinant L2 VLPs, both individually and in combination, elicited high-titer anti-L2 IgG serum antibodies. Immunized mice were protected from high dose infection with HPV pseudovirus (PsV) encapsidating a luciferase reporter. Mice immunized with 16L2 PP7 VLPs or 18L2 PP7 VLPs were nearly completely protected from both PsV16 and PsV18 challenge. Mice immunized with the mixture of eight L2 VLPs were strongly protected from genital challenge with PsVs representing eight diverse HPV types and cutaneous challenge with HPV5 PsV.
CONCLUSION/SIGNIFICANCE: VLP-display of a cross-neutralizing HPV L2 epitope is an effective approach for inducing high-titer protective neutralizing antibodies and is capable of offering protection from a spectrum of HPVs associated with cervical cancer as well as genital and cutaneous warts.
目前基于主要衣壳蛋白 L1 的病毒样颗粒（VLPs）的人乳头瘤病毒（HPV）疫苗主要引发 HPV 型特异性抗体反应。相比之下，用 HPV 次要衣壳蛋白 L2 免疫会产生广泛交叉中和的抗体，这表明针对 L2 的疫苗可能会对感染多种 HPV 类型提供更全面的保护。然而，基于 L2 的免疫原通常会引发比 L1 VLPs 低得多的中和抗体滴度。我们之前表明，L2 近 N 端的一个保守的广泛中和表位在来自噬菌体 PP7 的 VLPs 表面展示时具有高度免疫原性。在这里，我们报告了一组针对 L2 的基于 PP7 VLP 的疫苗的开发，这些疫苗可保护小鼠免受感染生殖道和皮肤的致癌和非致癌 HPV 类型的感染。
方法/主要发现：来自八种不同 HPV 类型的 L2 肽被展示在 PP7 噬菌体 VLPs 的表面。这些重组 L2 VLPs 单独和组合使用都能引发高滴度的抗 L2 IgG 血清抗体。免疫的小鼠可免受高剂量 HPV 假病毒（PsV）感染的保护，该假病毒可包裹一个荧光素酶报告基因。用 16L2 PP7 VLPs 或 18L2 PP7 VLPs 免疫的小鼠几乎完全免受 PsV16 和 PsV18 的挑战。用八种 L2 VLPs 的混合物免疫的小鼠对代表八种不同 HPV 类型的 PsV 和 HPV5 PsV 的生殖器和皮肤挑战具有强烈的保护作用。
结论/意义：跨中和 HPV L2 表位的 VLP 展示是诱导高滴度保护性中和抗体的有效方法，并且能够提供对与宫颈癌以及生殖器和皮肤疣相关的一系列 HPV 的保护。
