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

• 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
• 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

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，因此宫颈癌被指定为HIV相关恶性肿瘤。此外，HIV+患者获得更频繁的多类型感染，并且这些HPV基因型中的许多在HIV-个体中不常见，因此不被当前基于L1病毒样颗粒（VLP）的HPV疫苗靶向。该提案的主要目标是开发一种低成本的广泛保护性HPV疫苗，以满足发展中国家艾滋病毒阳性女孩和妇女的需求，这些女孩和妇女既负担不起目前获得许可的昂贵HPV疫苗，也无法获得细胞学筛查。广泛保护的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与宫颈癌相关，重要的是要防止所有这些。重要的是，我们最近发现，在HPV L2次要衣壳蛋白的氨基末端的序列引发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。基于L2衣壳蛋白的疫苗的开发可以是在细菌中产生的单一多肽或单一DNA表达载体。此外，可以在细菌中表达后制备的VLP的五聚体亚基L1壳粒在引发免疫方面与VLP同样有效，具有潜在的强佐剂性质，并且可以与L2序列复合/连接以形成杂合免疫原。因此，我们有几种很有前途的方法可以用细菌以低成本制备"广谱" HPV疫苗。我们建议优化三种不同的方法，这样的第二代预防性HPV疫苗。具体目标1（R.罗登）：在动物攻毒模型中比较候选的L2型HPV疫苗对具有医学意义的HPV基因型阴道攻毒的保护作用。具体目标2（R. Garcea）：确定L1壳粒-L2肽组合疫苗的最佳制剂。具体目标3（T.C.博士吴）：在通过体内电穿孔接种的小鼠中使用阴道攻击来确定聚合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，以评估免疫的有效性和免疫的持久性。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。 公共卫生关系：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，并且这些HPV基因型中的许多在HIV-个体中不常见，因此不是当前HPV疫苗的靶向。该提案的主要目标是开发一种低成本的广泛保护性HPV疫苗，以满足发展中国家既负担不起目前许可的HPV疫苗，也无法获得细胞学筛查的HIV阳性女孩和妇女的需求。