HIV-1/SIV Antibody Neutralization Assay Improvements and Database Development

HIV-1/SIV 抗体中和测定的改进和数据库开发

• 批准号: 7451048
• 负责人: CHRISTOS J PETROPOULOS
• 金额: $ 100万
• 依托单位: MONOGRAM BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7451048
• 关键词: Address; Antibodies; Antibody Formation; Antigens; Applications Grants; Autologous; Automation; Biological Assay; Cataloging; Catalogs; Clinical Trials; Custom; Data; Databases; Development; Evaluation; Genes; Government; HIV; HIV Antibodies; HIV Infections; HIV vaccine; Human; Immunity; Information Systems; Laboratories; Link; Macaca; Manuals; Measurement; Measures; Methods; Modeling; Patients; Performance; Peripheral Blood Mononuclear Cell; Phase; Phase II Clinical Trials; Phenotype; Plasma; Relative (related person); Reporting; Reproducibility; SIV; Sampling; Sequence Analysis; Site; System; Techniques; Vaccine Design; Vaccines; Viral; base; cost effective; design; env Gene Products; improved; neutralizing antibody; neutralizing monoclonal antibodies; novel vaccines; research clinical testing; scale up; tool; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Experts agree that an effective vaccine against HIV infection will require the induction of potent and broad neutralizing antibody responses. Both the development and clinical evaluation of vaccine candidates requires a sensitive, reproducible and high throughput HIV antibody neutralization assay. Sensitivity and reproducibility are required to confidently measure and assess modest incremental improvements in vaccine design and delivery. High throughput capability is required to accommodate the cost effective and timely evaluation of vaccine candidates in large clinical trials. In addition, a neutralization assay that can be used to evaluate protective immunity in the SIV/macaque model will aid and enable the selection of the most promising candidates for large scale evaluations in human trials. Conventional HIV Antibody Neutralization Assays (i.e. manual PBMC based assays) do not adequately address the current and upcoming demands of heightened HIV vaccine development efforts. In support of these important objectives, Monogram Biosciences (formerly ViroLogic, Inc.) has developed a sensitive neutralizing antibody assay (PhenoSense HIV Antibody Neutralization Assay) that uses viral pseudotypes that express the envelope proteins of patient-derived isolates (see Phase I final report). This assay allows for the direct measurement of autologous neutralizing titers in patient plasma, provides the ability to screen large panels of monoclonal antibodies for neutralizing activity to relevant primary strains, and allows for the direct comparison of antibody responses elicited by different vaccine immunogens. The assay has also been adapted to evaluate SIV envelope proteins and anti-SIV antibody responses in the macaque model. In phase II of this project, we intend to optimize the performance and complete the characterization of the Phenosense HIV Antibody Neutralization Assay. The throughput and capacity of this assay will be augmented using custom automation and other scale-up techniques. The sensitivity, reproducibility and robustness of the assay will be evaluated and compared to the conventional PBMC-based method. We will develop informational database systems focused on linking envelope phenotype and sequence analysis. This database will undoubtedly become a useful tool for vaccine design. Monogram Biosciences intends to commercialize the PhenoSense HIV Antibody Neutralization Assay and associated database systems to support the development and clinical evaluation of new vaccine candidates generated in government, academic, and industrial laboratories.

描述(由申请人提供)：专家们一致认为，有效的艾滋病毒感染疫苗需要诱导有效和广泛的中和抗体反应。候选疫苗的开发和临床评估都需要一种灵敏、可重复性和高通量的HIV抗体中和试验。要自信地衡量和评估疫苗设计和交付方面的适度增量改进，就需要敏感度和重复性。需要高通量能力，以适应在大型临床试验中对候选疫苗进行成本效益和及时评估。此外，可用于评估SIV/猕猴模型中的保护性免疫的中和试验将有助于并使其能够在人体试验中选择最有希望进行大规模评估的候选者。传统的艾滋病毒抗体中和分析(即基于人工PBMC的分析)不能充分满足当前和即将到来的加强艾滋病毒疫苗开发工作的需求。 为了支持这些重要目标，Mongraph Biosciences(前身为病毒学公司)已经开发出一种敏感的中和抗体分析(PhenoSense HIV抗体中和分析)，它使用表达患者来源分离株包膜蛋白的病毒假型(见第一阶段最终报告)。这种检测方法可以直接测量患者血浆中的自体中和效价，能够筛选大量的单抗对相关主要毒株的中和活性，并允许直接比较不同疫苗免疫原引起的抗体反应。该方法还可用于在猕猴模型中评估SIV包膜蛋白和抗SIV抗体反应。 在这个项目的第二阶段，我们打算对Phenosense HIV抗体中和试验的性能进行优化并完成鉴定。该分析的吞吐量和容量将使用定制的自动化和其他放大技术来扩大。将对该方法的灵敏度、重复性和稳定性进行评估，并与传统的基于PBMC的方法进行比较。我们将开发信息数据库系统，重点是将包膜表型和序列分析联系起来。这个数据库无疑将成为疫苗设计的有用工具。Mongraph生物科学公司打算将PhenoSense HIV抗体中和分析和相关数据库系统商业化，以支持政府、学术和工业实验室产生的新候选疫苗的开发和临床评估。