Development of low cost and broadly protective human papillomavirus vaccines

描述（由申请人提供）：HIV+患者比HIV-个体表现出更严重和进行性的人乳头瘤病毒（HPV）感染，因此宫颈癌被指定为HIV相关的恶性肿瘤。此外，HIV+患者获得更频繁的多型感染，并且许多这些HPV基因型在HIV-个体中很少见到，因此目前基于L1病毒样颗粒（VLPs）的HPV疫苗无法靶向。这项建议的主要目标是开发一种低成本、具有广泛保护作用的人乳头瘤病毒疫苗，以满足发展中国家艾滋病毒阳性女孩和妇女的需求，她们既负担不起目前获得许可的昂贵的人乳头瘤病毒疫苗，也无法获得细胞学筛查。一种具有广泛保护作用的HPV疫苗将特别有助于预防HIV+人群中出现的不寻常的HPV类型和多类型HPV感染。由于HPV感染的普遍性和缺乏抗病毒药物，开发针对HPV的预防性疫苗是预防宫颈癌的成功策略。有超过15种不同的“致癌”类型的生殖器HPV与子宫颈癌有关，重要的是要预防所有这些类型。重要的是，我们最近发现，在HPV L2次要衣壳蛋白的氨基端序列引发广泛的交叉中和抗体，并保护动物免受各种乳头瘤病毒类型的侵害。基于L2衣壳蛋白的疫苗的开发可以是在细菌中产生的单个多肽或单个DNA表达载体。此外，在细菌中表达后可以制备的VLPs的五聚体亚基L1 capsomeres与VLPs一样有效地诱导免疫，具有潜在的强佐剂特性，并且可以与L2序列络合/连接形成杂交免疫原。因此，我们有几种很有前途的方法，可以用低成本的细菌制备“广谱”HPV疫苗。我们建议优化三种不同的方法为这种第二代预防性HPV疫苗。特定目的1 (Dr. R. Roden)：在动物攻击模型中比较基于l2的候选HPV疫苗对阴道攻击的保护与医学上重要的HPV基因型。特定目标2 (Dr. R. Garcea)：确定L1衣体- L2肽联合疫苗的最佳配方。特异性目的3 (Dr. T.C. Wu)：在小鼠体内电穿孔疫苗中，使用阴道攻击确定聚合L2表达载体或HPV l1 -聚合L2表达载体的免疫原性。这些方法的潜力将直接在阴道内HPV攻击模型中进行比较，以评估免疫的功效和免疫的寿命。这些项目和项目规划是高度互动的，以促进在两年内快速选择优化的候选疫苗。

DESCRIPTION (provided by applicant): HIV+ patients exhibit more severe and progressive human papillomavirus (HPV) infections than HIV- individuals, and consequently cervical cancer has been designated an HIV-associated malignancy. In addition, HIV+ patients acquire more frequent multi-type infections, and many of these HPV genotypes are infrequently seen in HIV- individuals, and consequently are not targeted by the current HPV vaccines based upon L1 virus-like particles (VLPs). The principal goal of this proposal is to develop a broadly protective HPV vaccine, at low cost, to meet the needs of HIV+ girls and women in the developing world who can neither afford the currently licensed and costly HPV vaccines, nor have access to cytologic screening. A broadly protective HPV vaccine would be particularly helpful in preventing the unusual HPV types and multi-type HPV infections seen in the HIV+ population. Due to the prevalence of infection and the lack of antiviral agents for HPV, development of prophylactic vaccines against HPV is a successful strategy in the prevention of the cervical cancer. There are more than 15 different "oncogenic" types of genital HPV associated with cervical cancer and it is important to protect against all of them. Importantly, we recently discovered that sequences at the amino-terminus of the HPV L2 minor capsid protein elicit broadly cross-neutralizing antibodies and protect animals from diverse papillomavirus types. The development of a vaccine based on the L2 capsid protein could be a single polypeptide produced in bacteria or a single DNA expression vector. Furthermore, L1 capsomeres, the pentameric subunits of VLPs that can be prepared after expression in bacteria, are equally efficacious in eliciting immunity as VLPs, have potentially strong adjuvant properties, and can be complexed/linked with L2 sequences to form a hybrid immunogen. Thus we have several promising approaches for a "broad spectrum" HPV vaccine that can be prepared from bacteria at low cost. We propose to optimize three different approaches for such second generation prophylactic HPV vaccines. SPECIFIC AIM 1 (Dr. R. Roden): Compare candidate L2-based HPV vaccines in an animal challenge model for protection against vaginal challenge with medically significant HPV genotypes. SPECIFIC AIM 2 (Dr. R. Garcea): Determine the optimal formulation of an L1 capsomere- L2 peptide combination vaccine. SPECIFIC AIM 3 (Dr. T.C. Wu): Determine the immunogenicity of polymeric L2 expression vectors or HPV L1-polymeric L2 expression vectors using vaginal challenge in mice vaccinated by in vivo electroporation. The potential of these approaches will be directly compared in an intravaginal HPV challenge model to assess the efficacy of immunization and the longevity of immunity. These projects and PIs are highly interactive to facilitate rapid selection of the optimized vaccine candidates within two years. PUBLIC HEALTH RELEVANCE: HIV+ patients exhibit more severe and progressive human papillomavirus (HPV) infections than HIV- individuals, and consequently cervical cancer has been designated an HIV-associated malignancy. In addition, HIV+ patients more often acquire multi-type infections and many of these HPV genotypes are infrequently seen in HIV- individuals, and consequently are not targeted by the current HPV vaccines. The principal goal of this proposal is to develop a broadly protective HPV vaccine, at low cost, to meet the needs of HIV+ girls and women in the developing world who can neither afford the currently licensed HPV vaccines, nor have access to cytologic screening.