Clinical Development of Chimp Adenovirus Vectors

黑猩猩腺病毒载体的临床开发

• 批准号: 7681726
• 负责人: Hildegund C. J. Ertl
• 金额: $ 133.71万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681726
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adherence; African; Animal Model; Animals; Antibodies; Antigens; Asia; Biodistribution; Biological Assay; CD4 Positive T Lymphocytes; Characteristics; Clinic; Clinical; Clinical Data; Clinical Practice Guideline; Clinical Protocols; Clinical Trials; Complement; Conduct Clinical Trials; Development; Documentation; Dose; Enrollment; Ensure; Exhibits; Frequencies; Future; Gagging; Goals; Growth; Guanosine Monophosphate; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human Volunteers; Immune response; Immunity; Infection; Investigational Drugs; Lead; Macaca mulatta; Maintenance; Manufacturer Name; Modality; Pamphlets; Pan Genus; Pan troglodytes; Phase; Phase I Clinical Trials; Preparation; Production; Purpose; Quality Control; Recruitment Activity; Regulatory Affairs; Reporting; Research; Research Personnel; SIV; Safety; Scientist; Serotyping; Standards of Weights and Measures; T-Lymphocyte; Testing; Toxic effect; Toxicology; Transgenes; Translations; Treatment Protocols; United States Food and Drug Administration; United States National Institutes of Health; Vaccines; Viral Load result; Virus; base; cell mediated immune response; design; human subject; immunogenicity; neutralizing antibody; pre-clinical; research clinical testing; response; uptake; vaccine evaluation; vaccine safety; vector

This Project is designed to pursue clinical development of two replication-defective chimpanzee (chimp) adenovirus (Ad) vectors, termed AdC6 and AdC7. We developed the chimp Ad vectors to circumvent preexisting neutralizing antibodies, which are commonly found in humans to human serotypes of adenoviruses and which reduce uptake of the corresponding Ad vectors and hence their ability to induce transgene product-specific immune responses. Neutralizing antibodies to AdC6 and AdC7 are rare in humans residing in the US or Asia, and lower in Sub-Saharan Africans than antibodies against other Ad vectors currently in testing. AdC6 and AdC7 vectors expressing antigens of HIV-1 or SIV induce potent and sustained T cell mediated immune responses in experimental animals, which increase upon sequential use of the two vectors in prime boost regimens. In rhesus macaques primed with AdC7 vectors or Ad vectors of the human serotype 5 (AdHuS) and then challenged with SHIV89.6P, AdC7 primed NHPs showed better control of viral load and less loss of CD4+ T cells compared to animals primed with the AdHuS vectors. Similar to AdHuS, AdC6 and AdC7 vectors are genetically stable, exhibit suitable growth characteristics, and production and quality control of vectors have been established. We are proposing to develop AdC6 and AdC7 vectors for initial early phase human clinical trials that express gag of HIV-1 clade B (AdCGHIVgag, AdC7HIVgag). Clinical data on AdHuS based HIV-1 gag vaccines are available and this will allow for a comparison with the chimp Ad vectors. Pre-clinical development and testing of AdC6 and AdC7 vectors expressing additional sequences of HIV-1 for their potential use in future large scale clinical trials will be pursued by Project 2 of this application.In this application we plan to initiate two phase I trials which will address the safety and tolerability of the AdC6 and AdC7 vectors in separate dose escalation trials in human volunteers. In addition, since we do not expect that a single dose of a vaccine, as can be tested in the phase I trials, will result in impressive HIV-1 antigen-specific immune responses, we are proposing a phase IIA trial in which the two chimp Ad vectors are tested in a prime boost regimen, using each vector twice in a 4-dose regimen in human volunteers. We will conduct the clinical trials through HVTN, which is best poised to recruit and enroll human volunteers, conduct the trial in adherence to Good Clinical Practice (GCP) guidelines for ethical conduct of research involving human subjects and requisite standards and reporting requirements of U.S. Food and Drug Administration (FDA) and National Institutes of Health (NIH), ensure trial compliance, and assess vaccine safety and immunogenicity using sophisticated and validated assays. Studies by HVTN will be complemented by studies of Project 3, which will assess in human volunteers the quality of vaccine-induced gag-specific T cell responses in relationship to pre-existing immunity to the vaccine carrier.

该项目旨在追求两个复制缺陷的黑猩猩（Chimp）的临床开发 腺病毒（AD）向量，称为ADC6和ADC7。我们开发了黑猩猩的媒介以规避已经存在的 中和抗体，这些抗体通常在人类对腺病毒的人类血清型中发现 并减少相应的AD向量的摄取，从而诱导转基因的能力 产品特异性免疫反应。对ADC6和ADC7的中和抗体在居住的人类中很少见 在美国或亚洲，撒哈拉以南非洲人比目前针对其他AD向量的抗体低于目前 测试。表达HIV-1或SIV抗原的ADC6和ADC7载体诱导有效的T细胞 实验动物中介导的免疫反应，在顺序使用两个载体时增加 在Prime Boost方案中。在用ADC7载体或人类的AD向量启动的恒河猕猴中 血清型5（ADHUS），然后用SHIV89.6P挑战ADC7 Primed NHP显示出更好的病毒控制 与用Adhus载体引发的动物相比，CD4+ T细胞的负载和更少的损失。类似于adhus， ADC6和ADC7载体在遗传上是稳定的，具有合适的生长特征，生产以及 已经建立了对向量的质量控制。我们建议开发ADC6和ADC7向量 早期阶段的人类临床试验表达了HIV-1进化枝B（ADCGHIVGAG，ADC7HIVGAG）的GAG。 提供有关基于ADHUS的HIV-1插孔疫苗的临床数据，这将允许与 黑猩猩广告媒介。 ADC6和ADC7矢量的临床前开发和测试表达了其他 HIV-1的序列在未来的大规模临床试验中的潜在用途将由项目2的项目2进行 在本应用程序中，我们计划启动两次I期试验，以解决安全性和 在人类志愿者的单独剂量升级试验中，ADC6和ADC7载体的耐受性。此外， 由于我们不期望在I期试验中可以测试的单剂量疫苗会导致 令人印象深刻的HIV-1抗原特异性免疫反应，我们提出了一项IIA期试验，其中两者 黑猩猩AD矢量在素数方案中进行了测试，在人类的4剂量方案中使用每个矢量两次 志愿者。我们将通过HVTN进行临床试验，该试验最好准备招募和注册人类 志愿者，遵守良好临床实践（GCP）指南 涉及人类受试者以及必要标准的研究以及美国食品的报告要求 药物管理局（FDA）和国立卫生研究院（NIH），确保合规性和评估 使用复杂和经过验证的测定法，疫苗安全性和免疫原性。 HVTN的研究将是 补充项目3的研究，该研究将在人类志愿者中评估疫苗诱导的质量 与疫苗载体预先存在的免疫的关系中，GAG特异性T细胞反应。