Division of Laboratory Medicine and Pathology, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA.
Department of Microbiology and Immunology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Microbiol Spectr. 2022 Aug 31;10(4):e0115422. doi: 10.1128/spectrum.01154-22. Epub 2022 Jul 5.
In August 2020, the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for COVID-19 convalescent plasma (CCP) specified 12 authorized serologic assays and associated assay-specific cutoff values for the selection of high-titer CCP for use in hospitalized patients. The criteria used for establishing these cutoff values remains unclear. Here, we compare the overall agreement and concordance of five serologic assays included in the August 2020 FDA EUA at both the manufacturer-recommended qualitative cutoff thresholds and at the FDA-indicated thresholds for high-titer CCP, using serum samples collected as part of the CCP Expanded Access Program (EAP). The qualitative positive percent agreement (PPA) across assays ranged from 92.3% to 98.8%. However, the high-titer categorization across assays varied significantly, with the PPA ranging from 26.5% to 82.7%. The Roche anti-NC ECLIA provided the lowest agreement compared to all other assays. Efforts to optimize high-titer cutoffs could reduce, although not eliminate, the discordance across assays. The consequences of using nonstandardized assays are apparent in our study, and the high-titer cutoffs chosen for each assay are not directly comparable to each other. The generalized findings in our study will be relevant to any future use of convalescent plasma for either COVID-19 or future pandemics of newly emerged pathogens. COVID-19 convalescent plasma (CCP) was one of the first therapeutic options available for the treatment of SARS-CoV-2 infections and continues to be used selectively for immunosuppressed patients. Given the emergence of novel SARS-CoV-2 variants which are resistant to treatment with available monoclonal antibody (MAb) therapy, CCP remains an important therapeutic consideration. The FDA has released several emergency use authorizations (EUA) that have specified which serological assays can be used for qualification of CCP, as well as assay-specific cutoffs that must be used to identify high-titer CCP. In this study, a cohort of donor CCP was assessed across multiple serological assays which received FDA EUA for qualification of CCP. This study indicates a high degree of discordance across the assays used to qualify CCP for clinical use, which may have precluded the optimal use of CCP, including during clinical trials. This study highlights the need for assay standardization early in the development of serological assays for emerging pathogens.
2020 年 8 月，食品和药物管理局（FDA）对 COVID-19 恢复期血浆（CCP）的紧急使用授权（EUA）指定了 12 种经批准的血清学检测方法和相关的检测方法特异性截止值，用于选择高滴度 CCP 用于住院患者。用于建立这些截止值的标准尚不清楚。在这里，我们使用在 COVID-19 恢复期血浆扩大获取计划（EAP）中收集的血清样本，比较了 2020 年 8 月 FDA EUA 中包含的五种血清学检测方法的总体一致性和一致性，这些检测方法包括制造商推荐的定性截止阈值和 FDA 指示的高滴度 CCP 截止阈值。五种检测方法之间的定性阳性百分比一致性（PPA）范围为 92.3%至 98.8%。然而，五种检测方法之间的高滴度分类差异很大，PPA 范围为 26.5%至 82.7%。与所有其他检测方法相比，罗氏抗 NC ECLIA 的一致性最低。优化高滴度截止值的努力可以减少，但不能消除检测方法之间的不一致性。我们的研究表明，使用非标准化检测方法的后果是明显的，并且为每个检测方法选择的高滴度截止值彼此之间不可直接比较。我们研究中的普遍发现将与未来任何 COVID-19 或新出现的病原体大流行期间使用恢复期血浆治疗相关。COVID-19 恢复期血浆（CCP）是治疗 SARS-CoV-2 感染的首批可用治疗方法之一，并且仍然被选择性地用于免疫抑制患者。鉴于新型 SARS-CoV-2 变异体的出现，这些变异体对现有的单克隆抗体（MAb）治疗具有抗药性，CCP 仍然是一个重要的治疗考虑因素。FDA 发布了几项紧急使用授权（EUA），规定了哪些血清学检测方法可用于 CCP 的资格认证，以及必须用于确定高滴度 CCP 的检测方法特异性截止值。在这项研究中，对接受 FDA EUA 用于 CCP 资格认证的多个血清学检测方法进行了评估。本研究表明，用于为临床使用鉴定 CCP 的检测方法之间存在高度不一致性，这可能会妨碍 CCP 的最佳使用，包括在临床试验期间。本研究强调了在新兴病原体的血清学检测方法开发早期进行检测标准化的必要性。
