Therapeutic/preventive vaccination against MusPV

针对 MusPV 的治疗性/预防性疫苗接种

基本信息

批准号：
8731738
负责人：
Yung-Nien Chang
金额：
$ 29.98万
依托单位：
PAPIVAX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731738
关键词：
AIDS/HIV problem Ablation Animals Anogenital cancer Anogenital venereal warts Antibodies Antigens Attention Benign Biology CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cauterization - action Cellular Immunity Cervical Chronic Clinical Trials Cold Therapy Cutaneous Cytotoxic T-Lymphocytes DNA DNA Tumor Viruses DNA Vaccines Development Disease Electroporation Exhibits Foundations Frequencies Future Gardasil Genetic Genotype HIV HPV-High Risk Head and Neck Cancer Heat shock proteins Highly Active Antiretroviral Therapy Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 11 Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Imiquimod Immune Immune response Immunity Immunization Immunocompromised Host Immunodeficient Mouse Individual Infection Infection prevention Injection of therapeutic agent Intramuscular Injections Knock-out L2 viral capsid protein Laboratory mice Licensing Life Low risk HPV Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Medical Modeling Morbidity - disease rate Mouse Strains Mouth Diseases Mus Neoplasms Oncogene Proteins Operative Surgical Procedures Outcome Papilloma Papillomavirus Papillomavirus Infections Patients Preventive Publishing Reagent Recurrence Risk Site Skin Squamous Papilloma of the Larynx System T cell response T-Cell Depletion T-Lymphocyte Therapeutic Therapeutic Effect Universities Vaccinated Vaccination Vaccine Therapy Viral calreticulin cell mediated immune response effective therapy high risk immunogenicity improved in vivo mortality mouse model neutralizing antibody public health relevance therapeutic vaccine tumor vaccine delivery vaccine development vaccine efficacy vector

项目摘要

DESCRIPTION (provided by applicant): While most human papillomavirus (HPV) infections are short-lived, a subset become chronic and can progress to malignancy, with much greater frequency in HIV infected individuals. Only a dozen 'high risk' HPV types cause cancer but HPV16 alone is responsible for >90% of anal cancer, head and neck cancer and 50% of cervical cancer. Further, 'low risk' HPV types produce considerable morbidity for HIV+ patients. Unfortunately, neither licensed HPV vaccine is effective for treatment of existing infections, and persistent HPV infection and disease remain very prevalent and problematic. HIV+ patients exhibit more chronic and progressive HPV infections than healthy individuals despite HAART, and are at significantly elevated risk for HPV-associated cancers. Poor outcomes of HPV infection are associated with declining CD4 T cell immunity in HIV+ patients. Current non-specific wart treatments frequently fail. Therefore our objective is to develop a therapeutic vaccine to treat chronic HPV infections in the context of HIV despite reduced CD4 T cell help. Recently a laboratory mouse papillomavirus (MusPV) was discovered and sequenced. Published studies suggest that MusPV infection persists in immunodeficient mice but is cleared by 8 weeks in immune competent mice, a situation that closely parallels HPV disease in patients with compromised CD4 T cell immunity versus healthy individuals. We therefore hypothesize that compromised CD4 T cell immunity in mice will permit chronic MusPV infection, and we propose to determine the relationship between persistence of MusPV infection and CD4 T cell immunity. We will explore the impact of CD4 T cell depletion on the development of chronic MusPV infection and papillomas. Several studies indicate that immunization via in vivo electroporation will improve DNA vaccine delivery and efficacy. Furthermore, fusion of the E6 and E7 viral oncoproteins to a heat shock protein, calreticulin (CRT), profoundly enhances the induction of antigen-specific CD8 T cell dependent cellular immunity, even in CD4 T cell-depleted animals. Vaccination of mice with a DNA expressing CRT fused to HPV16 E6, E7 and capsid protein L2 (pNGVL4a-CRTE6E7L2, (PVX01)) induces both antitumor immunity and L2-specific neutralizing antibodies. We hypothesize that vaccination of CD4 T cell-depleted mice with a MusPV version of PVX01 DNA via in vivo electroporation will eliminate chronic papillomavirus disease and elicit protective immunity. Thus, here we propose to characterize the immune response generated by in vivo electroporation of the MusPV version of PVX01 DNA vaccine, including protection from viral challenge, and its therapeutic effect against chronic MusPV infection in CD4 T cell-depleted mice. An effective treatment for HPV disease in HIV+ patients, and the ability to protect them from diverse HPV infections, remains an important unmet medical need. Successful implementation of the current proposal will serve as an important foundation for future transition of the PVX01 DNA vaccine delivered by electroporation to clinical trials in patients with HPV16+ neoplasia and HIV co-infection.

描述（由申请人提供）：虽然大多数人乳头瘤病毒（HPV）感染是短暂的，但子集变为慢性并可以发展为恶性肿瘤，而在HIV感染的个体中频率更高。只有十二种“高风险” HPV类型会导致癌症，但仅HPV16就造成了90％的肛门癌，头颈癌和50％的宫颈癌。此外，“低风险” HPV类型为HIV+患者产生了相当大的发病率。不幸的是，没有许可的HPV疫苗可有效治疗现有感染，并且持续的HPV感染和疾病仍然非常普遍和有问题。尽管HAART，HIV+患者表现出比健康个体更慢性和进行性HPV感染，并且与HPV相关癌症的风险显着升高。 HPV感染的不良预后与HIV+患者的CD4 T细胞免疫降低有关。当前的非特异性疣治疗经常失败。因此，我们的目标是开发一种治疗性疫苗，尽管CD4 T细胞帮助降低，但在HIV的情况下，在HIV中治疗慢性HPV感染。最近发现并测序了一个实验室小鼠乳头瘤病毒（MUSPV）。发表的研究表明，MUSPV感染持续存在于免疫缺陷的小鼠中，但在免疫胜任的小鼠中被清除了8周，这种情况与受损的CD4 T细胞免疫力与健康个体的患者紧密相似。因此，我们假设小鼠中CD4 T细胞免疫受损将允许慢性MUSPV感染，我们建议确定MUSPV感染的持续性与CD4 T细胞免疫之间的关系。我们将探讨CD4 T细胞耗竭对慢性MUSPV感染和乳头状瘤发展的影响。几项研究表明，通过体内电穿孔免疫将改善DNA疫苗的递送和功效。此外，E6和E7病毒果蛋白与热休克蛋白（CRT）的融合会深刻地增强了抗原特异性CD8 T细胞依赖性细胞免疫的诱导，即使在CD4 T细胞耗尽的动物中，也会增强。用融合HPV16 E6，E7和衣壳蛋白L2（PNGVL4A-CRTE6E7L2，（PVX01））的DNA疫苗接种的小鼠诱导抗肿瘤免疫和L2特异性中和中和抗体。我们假设通过体内电穿孔的MUSPV版本的PVX01 DNA接种CD4 T细胞耗电小鼠将消除慢性乳头瘤病毒疾病并引起保护性免疫。因此，在这里，我们建议表征通过MUSPV版本的PVX01 DNA疫苗在体内电穿孔产生的免疫反应，包括保护病毒攻击的保护及其对CD4 T细胞耗尽小鼠中慢性MUSPV感染的治疗作用。 HIV+患者的HPV疾病的有效治疗方法，以及保护其免受不同HPV感染的能力，仍然是重要的未满足医疗需求。当前建议的成功实施将是通过电穿孔到HPV16+肿瘤和HIV共感染患者的临床试验中的PVX01 DNA疫苗将来过渡的重要基础。