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分支是撒哈拉以南非洲和印度次大陆的地方病，占全球艾滋病毒感染总数的近一半，大多数大规模艾滋病毒疫苗试验针对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被定义为存在针对HIV疫苗抗原的循环抗体，这些抗体与常规HIV免疫检测中使用的同源抗原发生交叉反应，导致假阳性结果。在最近由HVTN赞助的艾滋病毒疫苗试验中，总体41.7%的艾滋病毒疫苗接受者出现了VISP。假阳性检测结果可能会造成悲惨的个人后果，从公共卫生的角度来看，预计极高的VISP率将使其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感染者。RNA检测是当前VISP测试算法的核心，它无法检测到2%-3%的已建立的艾滋病毒感染，其高昂的成本是疫苗试验预算的负担，也是资源有限的卫生服务提供者使用的障碍。第一阶段项目的目标是证明一种C级特异性HIV-1免疫分析(“HIV Selectest”)的可行性，该方法能够以高灵敏度和高特异性区分真正的HIV感染和VISP。分支特异性分析背后的基本原理是，它将通过增加分析中可用空间中的分支C HIV肽序列变体的数量来实现更高的检测灵敏度。项目目标将通过两种创新方法实现：1)针对化验抗原的特定分支，以提高检测灵敏度；2)新颖地使用数据库衍生的多肽设计工具，以实现对艾滋病毒变种的最佳覆盖。初步数据表明，通过这些方法，可以显著提高对具有挑战性的样本、早期感染和总体样本群体的检测灵敏度。将通过对个别抗原肽和多肽混合物与特征良好的血清面板进行ELISA测试来评估进展情况。通过研究和血液筛查实验室的合作者，我们将从C类地区的艾滋病毒疫苗试验以及特征良好的C类艾滋病毒阳性和阴性捐赠者那里获得血清组。在第一阶段，我们希望展示一种C级艾滋病毒选择试验的可行性，该方法能够区分真实的艾滋病毒感染和VISP，当在相同的目标血清面板上进行测试时，其灵敏度和特异性接近获得许可的艾滋病毒免疫分析方法。在第二阶段，我们将进一步优化和扩大检测范围，并进行前瞻性和前瞻性的临床研究，旨在为FDA批准使用Clade C HIV选择测试作为一种经济高效的解决方案，以解决艾滋病毒疫苗接受者因VISP导致的假阳性问题。

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.