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基于第二代的人乳头瘤病毒(HPV)疫苗的进展。

Developments in L2-based human papillomavirus (HPV) vaccines.

作者信息

Schellenbacher Christina, Roden Richard B S, Kirnbauer Reinhard

机构信息

Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Austria.

Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.

出版信息

Virus Res. 2017 Mar 2;231:166-175. doi: 10.1016/j.virusres.2016.11.020. Epub 2016 Nov 23.

Abstract

Infections with sexually transmitted high-risk Human Papillomavirus (hrHPV), of which there are at least 15 genotypes, are responsible for a tremendous disease burden by causing cervical, and subsets of other ano-genital and oro-pharyngeal carcinomas, together representing 5% of all cancer cases worldwide. HPV subunit vaccines consisting of virus-like particles (VLP) self-assembled from major capsid protein L1 plus adjuvant have been licensed. Prophylactic vaccinations with the 2-valent (HPV16/18), 4-valent (HPV6/11/16/18), or 9-valent (HPV6/11/16/18/31/33/45/52/58) vaccine induce high-titer neutralizing antibodies restricted to the vaccine types that cause up to 90% of cervical carcinomas, a subset of other ano-genital and oro-pharyngeal cancers and 90% of benign ano-genital warts (condylomata). The complexity of manufacturing multivalent L1-VLP vaccines limits the number of included VLP types and thus the vaccines' spectrum of protection, leaving a panel of oncogenic mucosal HPV unaddressed. In addition, current vaccines do not protect against cutaneous HPV types causing benign skin warts, or against beta-papillomavirus (betaPV) types implicated in the development of non-melanoma skin cancer (NMSC) in immunosuppressed patients. In contrast with L1-VLP, the minor capsid protein L2 contains type-common epitopes that induce low-titer yet broadly cross-neutralizing antibodies to heterologous PV types and provide cross-protection in animal challenge models. Efforts to increase the low immunogenicity of L2 (poly)-peptides and thereby to develop broader-spectrum HPV vaccines are the focus of this review.

摘要

性传播高危型人乳头瘤病毒(hrHPV)感染(至少有15种基因型)通过引发宫颈癌以及其他肛门生殖器癌和口咽癌的某些亚型,造成了巨大的疾病负担,这些癌症合计占全球所有癌症病例的5%。由主要衣壳蛋白L1自组装而成的病毒样颗粒(VLP)加佐剂组成的HPV亚单位疫苗已获许可。使用二价(HPV16/18)、四价(HPV6/11/16/18)或九价(HPV6/11/16/18/31/33/45/52/58)疫苗进行预防性接种可诱导产生高滴度中和抗体,这些抗体仅限于导致高达90%宫颈癌、部分其他肛门生殖器癌和口咽癌以及90%良性肛门生殖器疣(尖锐湿疣)的疫苗类型。生产多价L1 - VLP疫苗的复杂性限制了所包含的VLP类型数量,从而限制了疫苗的保护范围,使得一组致癌性黏膜HPV未得到解决。此外,目前的疫苗不能预防导致良性皮肤疣的皮肤HPV类型,也不能预防与免疫抑制患者非黑色素瘤皮肤癌(NMSC)发生有关的β - 乳头瘤病毒(βPV)类型。与L1 - VLP不同,次要衣壳蛋白L2含有共同型表位,可诱导产生低滴度但能广泛交叉中和异源PV类型的抗体,并在动物攻毒模型中提供交叉保护。提高L2(多)肽低免疫原性从而开发更广谱HPV疫苗的努力是本综述的重点。

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