Huber Bettina, Schellenbacher Christina, Jindra Christoph, Fink Dieter, Shafti-Keramat Saeed, Kirnbauer Reinhard
Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases (DIAID), Laboratory of Viral Oncology (LVO), Medical University Vienna (MUW), Vienna, Austria.
Institute of Laboratory Animal Science, Department of Biomedical Science, Veterinary University Vienna, Vienna, Austria.
PLoS One. 2015 Mar 19;10(3):e0120152. doi: 10.1371/journal.pone.0120152. eCollection 2015.
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.
致癌性人乳头瘤病毒（HPV）的持续感染会引发所有宫颈癌以及其他一部分肛门生殖器癌和口咽癌。四种高危（hr）黏膜型HPV16、18、45或59几乎导致了所有宫颈腺癌（AC），这是宫颈癌（CxC）的一个子集。尽管在引入巴氏（PAP）筛查后宫颈鳞状细胞癌（SCC）的发病率大幅下降，但AC的比例相对有所增加。宫颈SCC主要起源于宫颈外口，而AC主要起源于宫颈管，获取可行的PAP涂片较难。已获许可的（二价和四价）HPV疫苗包含由主要衣壳蛋白L1自组装而成的最重要的hr HPV16和18的病毒样颗粒（VLP）。由于主要是类型限制的效力，这两种疫苗并未针对导致30%的CxC的另外13种hr黏膜型。乳头瘤病毒属α7种包括一组hr型，其中HPV18、45、59在宫颈AC中所占比例过高，且目前的疫苗仅部分（HPV18）针对它们。为了针对这些类型，我们构建了一种嵌合疫苗抗原，其由HPV45次要衣壳蛋白L2的交叉中和表位（HPV16 RG1的同源物）组成，该表位经基因插入HPV18 L1 VLP（18L1 - 45RG1）的一个表面环中。用18L1 - 45RG1 VLP加明矾 - MPL佐剂对新西兰白兔进行免疫接种可诱导出针对同源HPV18的高滴度中和抗体，该抗体在体外可交叉中和非同源hr α7型HPV39、45、68，但不能中和HPV59以及低风险HPV70，并诱导出强烈的L1特异性细胞免疫反应。被动免疫可保护小鼠免受HPV18、39、45和68假病毒的实验性阴道攻击，但不能保护其免受HPV59或远亲α9型HPV16的攻击。18L1 - 45RG1 VLP可与我们之前描述的16L1 - 16RG1 VLP联合，以开发一种针对hr HPV的具有更广泛谱的第二代二价疫苗。
