Development of low cost and broadly protective human papillomavirus vaccines

描述(申请人提供)：HIV患者表现出比HIV患者更严重和更进行性的人类乳头瘤病毒(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类型感染，其中许多HPV基因型在HIV个体中很少见，因此不是当前基于L1病毒样颗粒(VLP)的HPV疫苗的靶标。这项提议的主要目标是以低成本开发一种具有广泛保护性的HPV疫苗，以满足发展中国家艾滋病毒女孩和妇女的需求，他们既负担不起目前获得许可和昂贵的HPV疫苗，也无法获得细胞学筛查。一种广泛保护性的HPV疫苗将特别有助于预防艾滋病毒人群中出现的不寻常的HPV类型和多种类型的HPV感染。鉴于HPV感染的流行和抗病毒药物的缺乏，开发HPV预防性疫苗是预防宫颈癌的一种成功策略。与宫颈癌相关的生殖器HPV有15种以上不同的“致癌”类型，预防所有类型的HPV是很重要的。重要的是，我们最近发现，HPV L2小衣壳蛋白氨基末端的序列可以诱导广泛的交叉中和抗体，并保护动物免受不同类型的乳头瘤病毒的侵袭。基于L2衣壳蛋白的疫苗的开发可以是细菌中产生的单一多肽，也可以是单一的DNA表达载体。此外，L1衣壳是VLP的五聚体亚基，可在细菌中表达，在诱导免疫方面与VLP一样有效，具有潜在的强大佐剂特性，并可与L2序列复合/连接形成杂交免疫原。因此，我们有几种很有希望的方法来研制一种“广谱”HPV疫苗，这种疫苗可以从细菌中以低成本制备。我们建议优化这类第二代预防性HPV疫苗的三种不同方法。具体目标1(R.Roden博士)：在动物挑战模型中比较候选的基于L2的HPV疫苗，以防止阴道挑战与医学上有意义的HPV基因型别。特定目的2(R.Garcea博士)：确定L1蛋白-L2多肽组合疫苗的最佳配方。特异性目的3(吴天正博士)：通过阴道激发体内电穿孔免疫小鼠，确定聚合L2表达载体或HPVL1聚合L2表达载体的免疫原性。这些方法的潜力将在阴道内HPV攻击模型中进行直接比较，以评估免疫的有效性和免疫的寿命。这些项目和PI具有高度互动性，有助于在两年内快速选择优化的候选疫苗。 公共卫生相关性：HIV患者表现出比HIV感染者更严重和更进行性的人类乳头瘤病毒(HPV)感染，因此宫颈癌被指定为HIV相关的恶性肿瘤。此外，艾滋病毒患者更容易受到多种类型的感染，其中许多HPV基因型别在艾滋病毒感染者中很少见，因此不是目前HPV疫苗的靶标。这项提议的主要目标是以低成本开发一种具有广泛保护性的HPV疫苗，以满足发展中国家艾滋病毒女孩和妇女的需求，这些女孩和妇女既负担不起目前获得许可的HPV疫苗，也无法获得细胞学筛查。

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.