Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles
Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles
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DOI：
10.1128/jvi.00449-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Giannini, Sandra L.
中科院分区：
文献类型：
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作者：
Boxus, Mathieu;Fochesato, Michel;Giannini, Sandra L.
至少 15 种高危人乳头瘤病毒 (HPV) 与肛门生殖器癌前病变和癌症有关。目前，有三种获得许可的预防性 HPV 疫苗基于 HPV-2、-4 或 -9 的 L1 主要衣壳蛋白的病毒样颗粒 (VLP)，其中包括 AS04 佐剂的 HPV-16/18 L1 疫苗。 L2 小衣壳蛋白含有 HPV 中和表位，这些表位在许多高危 HPV 中都非常保守。因此，我们研究的目的是评估使用基于具有一个或两个 L2 表位的 L1 VLP 嵌合体的 AS04 佐剂疫苗扩大疫苗介导的保护的能力。通过将 L2 表位插入 L1 的 DE 环和/或 C 末端构建了几种嵌合 VLP。根据形状、产量、大小和免疫原性，选择七个嵌合体之一在小鼠和兔子攻击模型中进行进一步评估。嵌合VLP由插入HPV-33 L2（氨基酸残基17至36；L1 DE环）和HPV-58 L2（氨基酸残基56至75；L1 C末端）的HPV-18 L1组成。这种嵌合 L1/L2 VLP 疫苗可诱导持续的免疫反应，并在小鼠和兔子攻击模型中针对所有评估的不同 HPV（HPV-6、-11、-16、-31、-35、-39、-45、-58 和 -59 作为假病毒粒子或准病毒粒子）提供保护。当嵌合 L1/L2 VLP 与来自 HPV-16/18 L1 疫苗的 L1 VLP 配制时，对兔子的保护程度和广度进一步增强。因此，用 AS04 配制的新型 HPV-18 L1/L2 嵌合 VLP（单独或与 HPV-16 和 HPV-18 L1 VLP 组合）有可能为人类受试者提供广泛的保护功效。
At least 15 high-risk human papillomaviruses (HPVs) are linked to anogenital preneoplastic lesions and cancer. Currently, there are three licensed prophylactic HPV vaccines based on virus-like particles (VLPs) of the L1 major capsid protein from HPV-2, -4, or -9, including the AS04-adjuvanted HPV-16/18 L1 vaccine. The L2 minor capsid protein contains HPV-neutralizing epitopes that are well conserved across numerous high-risk HPVs. Therefore, the objective of our study was to assess the capacity to broaden vaccine-mediated protection using AS04-adjuvanted vaccines based on VLP chimeras of L1 with one or two L2 epitopes. Several chimeric VLPs were constructed by inserting L2 epitopes within the DE loop and/or C terminus of L1. Based on the shape, yield, size, and immunogenicity, one of seven chimeras was selected for further evaluation in mouse and rabbit challenge models. The chimeric VLP consisted of HPV-18 L1 with insertions of HPV-33 L2 (amino acid residues 17 to 36; L1 DE loop) and HPV-58 L2 (amino acid residues 56 to 75; L1 C terminus). This chimeric L1/L2 VLP vaccine induced persistent immune responses and protected against all of the different HPVs evaluated (HPV-6, -11, -16, -31, -35, -39, -45, -58, and -59 as pseudovirions or quasivirions) in both mouse and rabbit challenge models. The degree and breadth of protection in the rabbit were further enhanced when the chimeric L1/L2 VLP was formulated with the L1 VLPs from the HPV-16/18 L1 vaccine. Therefore, the novel HPV-18 L1/L2 chimeric VLP (alone or in combination with HPV-16 and HPV-18 L1 VLPs) formulated with AS04 has the potential to provide broad protective efficacy in human subjects.