Clade C-specific HIV assay to distinguish true infection from vaccine-induced ser

描述（由申请人提供）：艾滋病毒C分支，在撒哈拉以南非洲和印度次大陆流行，是负责近一半的全球艾滋病毒感染，大多数大规模的艾滋病毒疫苗试验是针对C分支地区。不幸的是，候选HIV疫苗的开发和试验带来了疫苗诱导的HIV血清阳性（VISP）的重大风险。VISP定义为存在HIV疫苗抗原的循环抗体，其与常规HIV免疫测定中使用的同源抗原交叉反应，导致假阳性结果。在最近HVTN赞助的HIV疫苗试验中，总共有41.7%的HIV疫苗接种者表现出VISP。假阳性检测结果可能会对个人造成悲惨的后果，从公共卫生的角度来看，预期的高VISP率将使人们无法监测艾滋病毒疫苗试验或疫苗接种活动的有效性，也无法正确诊断和治疗受感染者。RNA检测是目前VISP检测算法的核心，无法检测到2-3%的已确定的HIV感染，其高昂的成本对疫苗试验预算构成负担，并阻碍了资源有限的卫生服务提供者的使用。I期项目的目标是证明能够以高灵敏度和特异性区分真正的HIV感染与VISP的进化枝C特异性HIV-1免疫测定（“HIV Selectest”）的可行性。进化枝特异性测定的基本原理是，通过增加测定孔中可用空间中进化枝C HIV肽序列变体的数量，能够实现更高的检测灵敏度。该项目的目标将通过两种创新方法实现：1）检测抗原的分支特异性靶向，以提高检测灵敏度; 2）数据库衍生肽设计工具的新用途，以实现HIV变体的最佳覆盖率。初步数据表明，通过这些方法，有可能显著提高挑战性样本、早期感染和总体样本群体的检测灵敏度。将通过ELISA检测单个抗原肽和肽混合物与充分表征的血清组来评估进展。通过研究和血液筛查实验室的合作者，我们将从C进化枝地区的艾滋病毒疫苗试验以及特征明确的C进化枝艾滋病毒阳性和阴性供体中获得血清组。在I期研究中，我们希望证明能够区分真正HIV感染与VISP的进化枝C HIV Selectest检测试剂盒的可行性，当对相同的靶血清样本组进行检测时，其灵敏度和特异性接近已获得许可的HIV免疫检测试剂盒。在第二阶段，我们将进一步优化和扩大检测规模，并进行前瞻性和回顾性临床研究，旨在获得FDA批准，使用Clade C HIV Selectest检测试剂盒作为一种具有成本效益的解决方案，以解决HIV疫苗接种者中VISP引起的假阳性。

DESCRIPTION (provided by applicant): HIV clade C, endemic in sub-Saharan Africa and the Indian subcontinent, is responsible for nearly half of all global HIV infections, and most large-scale HIV vaccine trials are targeted to clade C regions. Unfortunately, the development and trialing of candidate HIV vaccines brings with it the significant risk of vaccine-induced HIV seropositivity (VISP). VISP is defined as the presence of circulating antibodies to HIV vaccine antigens which cross-react with homologous antigens used in conventional HIV immunoassays, leading to a false positive result. In recent HVTN-sponsored HIV vaccine trials, an overall 41.7% of HIV vaccine recipients exhibited VISP. False positive test results can have tragic personal consequences and, from a public health perspective, the anticipated high rate of VISP would make it impossible to monitor effectiveness of an HIV vaccine trial or vaccination campaign, or to correctly diagnose and treat infected individuals. RNA testing, central to current VISP testing algorithms, fails to detect 2-3% of established HIV infections, and its high cost is a burden to vaccine trial budgets and a barrier to use by resource-limited health providers. The goal of the Phase I project is to demonstrate feasibility of a clade C-specific HIV-1 immunoassay ("HIV Selectest") capable of distinguishing true HIV infection from VISP with high sensitivity and specificity. The rationale behind a clade-specific assay is that it will enable greater detection sensitivity by increasing the number of clade C HIV peptide sequence variants in the space available in the assay well. The project objectives will be achieved through two innovative approaches: 1) clade-specific targeting of assay antigens to improve detection sensitivity and 2) the novel use of database-derived peptide design tools to achieve optimal coverage of HIV variants. Preliminary data have demonstrated that significant gains in detection sensitivity for challenging samples, early infections and overall sample populations are possible through these approaches. Progress will be assessed by ELISA testing of individual antigenic peptides and peptide mixes vs well-characterized serum panels. Through collaborators in research and blood screening laboratories we will acquire panels of sera from HIV vaccine trials in clade C regions as well as from well-characterized clade C HIV-positive and negative donors. In Phase I we expect to demonstrate feasibility of a clade C HIV Selectest assay capable of distinguishing true HIV infection from VISP, with sensitivity and specificity approaching those of licensed HIV immunoassays when tested on the same target serum panels. In Phase II we will further optimize and scale up the assay and perform prospective and retrospective clinical studies aimed at FDA clearance for use of the Clade C HIV Selectest assay as a cost effective solution to resolve false positives due to VISP in HIV vaccine recipients.