Development of low cost and broadly protective human papillomavirus vaccines

开发低成本且具有广泛保护性的人乳头瘤病毒疫苗

基本信息

批准号：
7853209
负责人：
Richard Bruce Roden
金额：
$ 50万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7853209
关键词：
Adjuvant Animals Antigens Antiviral Agents Bacteria Capsid Proteins Combined Vaccines Complex DNA DNA Vaccines Data Developed Countries Developing Countries Development Drug Formulations Effectiveness Electroporation Epitopes Event Exhibits Generations Genital system Genotype Goals HIV HIV Infections Head Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Hybrids Immune response Immunity Immunization Incidence Individual Infection Injection of therapeutic agent L2 viral capsid protein Licensing Life Link Longevity Malignant Neoplasms Malignant neoplasm of cervix uteri Methodology Minor Modeling Mus Oncogenic Pan Genus Papillomavirus Patients Peptides Phase Phase I Clinical Trials Population Prevalence Property Reagent Reporter Reproduction spores Risk Screening procedure Serotyping Severities Temperature Vaccinated Vaccination Vaccines Vagina Virion Virus-like particle Woman base cervical cancer prevention comparative efficacy cost expression vector girls immunogenicity in vivo meetings neutralizing antibody peptide based vaccine polypeptide prevent programs prophylactic protective efficacy public health relevance research clinical testing vaccine candidate vaccine development

项目摘要

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.

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，因此宫颈癌已被指定为与HIV相关的恶性肿瘤。此外，HIV+患者更频繁地获得多种类型的感染，并且许多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疫苗的目标。该提案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 HIV+ 女孩和妇女的需求，这些女孩和妇女既买不起目前获得许可且昂贵的 HPV 疫苗，也无法进行细胞学筛查。具有广泛保护性的 HPV 疫苗对于预防 HIV + 人群中出现的异常 HPV 类型和多型 HPV 感染特别有帮助。由于HPV感染的流行和缺乏抗HPV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 与宫颈癌相关，因此预防所有这些类型都很重要。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引发广泛的交叉中和抗体，并保护动物免受多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细菌中产生的单一多肽或单一DNA表达载体。此外，L1壳粒是VLP的五聚体亚基，可以在细菌中表达后制备，在引发免疫方面与VLP同样有效，具有潜在的强佐剂特性，并且可以与L2序列复合/连接以形成混合免疫原。因此，我们有几种有希望的方法来生产“广谱”HPV 疫苗，可以以低成本从细菌中制备。我们建议针对第二代预防性 HPV 疫苗优化三种不同的方法。具体目标 1（R. Roden 博士）：在动物激发模型中比较候选的 L2 HPV 疫苗，以防止阴道激发与具有医学意义的 HPV 基因型。具体目标 2（R. Garcea 博士）：确定 L1 壳粒-L2 肽组合疫苗的最佳配方。具体目标 3（T.C. Wu 博士）：使用体内电穿孔疫苗接种的小鼠进行阴道激发，确定聚合 L2 表达载体或 HPV L1-聚合 L2 表达载体的免疫原性。这些方法的潜力将在阴道内 HPV 攻击模型中直接进行比较，以评估免疫效果和免疫寿命。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与HIV相关的恶性肿瘤。此外，HIV+患者更经常获得多种类型的感染，并且许多HPV基因型在HIV-个体中很少见，因此不是当前HPV疫苗的目标。该提案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 HIV+ 女孩和妇女的需求，这些女孩和妇女既买不起目前获得许可的 HPV 疫苗，也无法进行细胞学筛查。