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）：专家同意，针对HIV感染的有效疫苗将需要诱导有效和广泛的中和抗体反应。候选疫苗的发育和临床评估都需要敏感，可重复和高吞吐量HIV抗体中和测定法。需要敏感性和可重复性来自信地测量和评估疫苗设计和输送中适度的增量改进。在大型临床试验中，需要高通量能力来适应疫苗候选疫苗的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测定将有助于和能够选择人类试验中最有希望的候选人进行大规模评估。常规的HIV抗体中和测定（即基于手动PBMC的测定法）不能充分解决对HIV疫苗开发工作增强的当前和即将到来的需求。 为了支持这些重要目标，会标生物科学（以前是病毒学，Inc。）开发了一种敏感的中和抗体测定（势态HIV HIV抗体中和测定），该抗体中和测定法使用病毒式伪型来表达患者衍生物的包络蛋白（请参阅第一阶段的最终报告）。该测定法可以直接测量患者血浆中的自体中和滴度，它提供了筛选大型单克隆抗体面板的能力，以中和对相关的原发性菌株的活性，并可以直接比较由不同疫苗免疫原子引起的抗体反应。该测定也已适应评估猕猴模型中的SIV包膜蛋白和抗SIV抗体反应。 在该项目的第二阶段中，我们打算优化性能并完成现象识别HIV抗体中和测定的表征。该测定法的吞吐量和容量将通过自定义自动化和其他规模上的技术进行增强。测定的灵敏度，可重复性和鲁棒性将进行评估，并将其与常规的基于PBMC的方法进行比较。我们将开发有关关注包络表型和序列分析的信息数据库系统。该数据库无疑将成为疫苗设计的有用工具。 Monogram Biosciences打算将现象识别HIV抗体中和测定法和相关数据库系统商业化，以支持政府，学术和工业实验室中产生的新疫苗候选者的开发和临床评估。