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) 感染都是短暂的，但有一部分会变成慢性感染，并可能发展为恶性肿瘤，在 HIV 感染者中发生率更高。只有十几种“高风险”HPV 类型会导致癌症，但仅 HPV16 就导致了 >90% 的肛门癌、头颈癌和 50% 的宫颈癌。此外，“低风险”HPV 类型会给 HIV+ 患者带来相当大的发病率。不幸的是，这两种获得许可的 HPV 疫苗都不能有效治疗现有感染，并且持续性 HPV 感染和疾病仍然非常普遍且存在问题。尽管进行了 HAART，HIV+ 患者仍比健康个体表现出更多的慢性和进行性 HPV 感染，并且患 HPV 相关癌症的风险显着升高。 HPV 感染的不良后果与 HIV + 患者的 CD4 T 细胞免疫力下降有关。目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，以治疗 HIV 背景下的慢性 HPV 感染，尽管 CD4 T 细胞的帮助有所减少。最近发现了一种实验室小鼠乳头瘤病毒（MusPV）并进行了测序。已发表的研究表明，MusPV 感染在免疫缺陷小鼠中持续存在，但在免疫能力强的小鼠中 8 周后被清除，这种情况与 CD4 T 细胞免疫受损患者与健康个体中的 HPV 疾病非常相似。因此，我们假设小鼠 CD4 T 细胞免疫受损将导致慢性 MusPV 感染，并且我们建议确定 MusPV 感染持续性与 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。多项研究表明，通过体内电穿孔进行免疫将改善 DNA 疫苗的递送和功效。此外，E6和E7病毒癌蛋白与热休克蛋白钙网蛋白（CRT）的融合极大地增强了抗原特异性CD8 T细胞依赖性细胞免疫的诱导，甚至在CD4 T细胞耗尽的动物中也是如此。用表达与 HPV16 E6、E7 和衣壳蛋白 L2 融合的 CRT 的 DNA（pNGVL4a-CRTE6E7L2，（PVX01））对小鼠进行疫苗接种，可诱导抗肿瘤免疫和 L2 特异性中和抗体。我们假设通过体内电穿孔用 MusPV 版本的 PVX01 DNA 接种 CD4 T 细胞耗尽的小鼠将消除慢性乳头瘤病毒病并引发保护性免疫。因此，在这里，我们建议表征 MusPV 版本的 PVX01 DNA 疫苗体内电穿孔产生的免疫反应，包括对病毒攻击的保护，及其对 CD4 T 细胞耗尽的小鼠中慢性 MusPV 感染的治疗作用。对 HIV+ 患者的 HPV 疾病进行有效治疗，并保护他们免受多种 HPV 感染的能力，仍然是一个重要的未满足的医疗需求。当前提案的成功实施将为未来通过电穿孔提供的PVX01 DNA疫苗过渡到HPV16+肿瘤和HIV合并感染患者的临床试验奠定重要基础。