A chimeric 18L1-45RG1 virus-like particle vaccine cross-protects against oncogenic alpha-7 human papillomavirus types.
A chimeric 18L1-45RG1 virus-like particle vaccine cross-protects against oncogenic alpha-7 human papillomavirus types.
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DOI：
10.1371/journal.pone.0120152
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kirnbauer R
中科院分区：
文献类型：
--
作者：
Huber B;Schellenbacher C;Jindra C;Fink D;Shafti-Keramat S;Kirnbauer R
持续感染致瘤性人乳头瘤病毒（HPV）类型可导致所有子宫颈癌和其他肛门生殖器癌和口咽癌。四种高危（hr）粘膜类型HPV16、18、45或59导致几乎所有的宫颈腺癌（AC），这是宫颈癌（CxC）的一个子集。虽然宫颈鳞状细胞癌（SCC）的发病率在引入巴氏涂片（PAP）筛查后显著下降，但AC的比例相对增加。宫颈鳞状细胞癌主要发生在宫颈外，而AC主要起源于宫颈内管，宫颈内管不易获得可行的PAP涂片。许可的（二价和四价）HPV疫苗包括最重要的hr HPV16和18的病毒样颗粒（VLP），由主要衣壳蛋白L1自组装。由于效力主要局限于类型，这两种疫苗都不针对引起30% CxC的13种额外的hr粘膜类型。乳头瘤病毒属α - 7种（α - 7）包括HPV18、45,59型在宫颈AC中比例过高的一组hr型，目前疫苗仅针对部分HPV18型。为了针对这些类型，我们生成了一种嵌合疫苗抗原，该抗原由HPV45 L2次要衣壳蛋白的交叉中和表位（HPV16 RG1的同源物）遗传地插入到HPV18 L1 VLP （18L1-45RG1）的表面环中。用18L1-45RG1 VLP加铝- mpl佐剂接种NZW家兔可诱导高滴度抗同源HPV18的中和抗体，在体外交叉中和非同源hr α7型HPV39、45、68，但不交叉中和HPV59和低风险HPV70，并诱导强效的l1特异性细胞免疫应答。被动免疫可保护小鼠免受HPV18、39、45和68假病毒粒子的阴道攻击，但对HPV59或远亲α9型HPV16无效。18L1-45RG1 VLP可能与我们先前描述的16L1-16RG1 VLP联合开发第二代具有扩展谱的抗hr HPV二价疫苗。
Persistent infection with oncogenic human papillomaviruses (HPV) types causes all cervical and a subset of other anogenital and oropharyngeal carcinomas. Four high-risk (hr) mucosal types HPV16, 18, 45, or 59 cause almost all cervical adenocarcinomas (AC), a subset of cervical cancer (CxC). Although the incidence of cervical squamous cell carcinoma (SCC) has dramatically decreased following introduction of Papanicolaou (PAP) screening, the proportion of AC has relatively increased. Cervical SCC arise mainly from the ectocervix, whereas AC originate primarily from the endocervical canal, which is less accessible to obtain viable PAP smears. Licensed (bivalent and quadrivalent) HPV vaccines comprise virus-like particles (VLP) of the most important hr HPV16 and 18, self-assembled from the major capsid protein L1. Due to mainly type-restricted efficacy, both vaccines do not target 13 additional hr mucosal types causing 30% of CxC. The papillomavirus genus alpha species 7 (α7) includes a group of hr types of which HPV18, 45, 59 are proportionally overrepresented in cervical AC and only partially (HPV18) targeted by current vaccines. To target these types, we generated a chimeric vaccine antigen that consists of a cross-neutralizing epitope (homologue of HPV16 RG1) of the L2 minor capsid protein of HPV45 genetically inserted into a surface loop of HPV18 L1 VLP (18L1-45RG1). Vaccination of NZW rabbits with 18L1-45RG1 VLP plus alum-MPL adjuvant induced high-titer neutralizing antibodies against homologous HPV18, that cross-neutralized non-cognate hr α7 types HPV39, 45, 68, but not HPV59, and low risk HPV70 in vitro, and induced a robust L1-specific cellular immune response. Passive immunization protected mice against experimental vaginal challenge with pseudovirions of HPV18, 39, 45 and 68, but not HPV59 or the distantly related α9 type HPV16. 18L1-45RG1 VLP might be combined with our previously described 16L1-16RG1 VLP to develop a second generation bivalent vaccine with extended spectrum against hr HPV.
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