Special reports from Zhen Zhao, PhD, DABCC, Associate Professor of Clinical Pathology and Laboratory Medicine, Weill Cornell Medical college, Cornell University; HE Sarina Yang, PhD, DABCC, Assistant Professor of Clinical Pathology and Laboratory Medicine, Weill Cornell Medical college, Cornell University.
During the COVID-19 pandemic, Dr. Zhen Zhao, together with Drs. Sarina Yang and Sabrina Racine-Brzostek at Weill Cornell Medicine have led a team effort to contribute to the transformation of laboratory activities in support of COVID-19-related research and patient care.
They have applied cutting-edge, versatile biosensor technologies to develop a panel of serological assays to characterize the quantity and quality of SARS-CoV-2 antibody responses in COVID-19 patients. The novel biosensor-based assays, including SARS-CoV-2 total antibodies, IgG, IgM, surrogate neutralizing antibody activity, and avidity assays, are sensitive, rapid, and fully automated. Their data contribute to the understanding of the impact of early antibody responses on the clinical outcome of hospitalized COVID-19 patients and reveal distinct antibody responses to SARS-CoV-2 in children and adults. The highly precise and versatile panel with the ability to measure SARS-CoV-2 total antibodies, surrogate neutralizing antibodies, IgG and IgM antibody levels, and avidity of individual sera on one sensor can become a valuable asset in monitoring not only SARS-CoV-2-infected patients but also the status of individual COVID-19 vaccination response.
They have published several peer-reviewed manuscripts in COVID-19 research in high profile journals, including Nature, JCI, Biosensors and Bioelectronics, Clinical Chemistry, JAMA Network Open, and JCI insight. Several works have been highlighted/interviewed by major media outlets and Journals.
Hospitalized adult COVID-19 patients: The association of mortality with the early humoral antibody response to SARS-CoV-2 infection within the first few days after onset of symptoms was thoroughly investigated in 120 SARS-CoV-2 RT-PCR positive adult hospitalized patients. Two sensitive and automated testing-on-a-probe (TOP) biosensor assays for SARS-CoV-2 viral-specific total antibody (TAb) and surrogate neutralizing antibody (SNAb) assays were validated and utilized in this study. Higher TAb and SNAb positive rates and more robust antibody responses at the initial hospital presentation were observed in inpatients who survived COVID-19 than those who died in the hospital. This work was published in Biosensors and Bioelectronics (1).
COVID-19 in Children: They showed an association of age with SARS-CoV-2 antibody response in a study (2), one of the first publications reporting SARS-CoV-2 antibody response in children. In this cross-sectional study, they asked a question, “are the quantity and quality of antibodies against SARS-CoV-2 different among children, adolescents, and young adults?” A total of 31,426 SARS-CoV-2 antibody tests performed between April 9 and August 31, 2020 were evaluated. Similar seroprevalence in the pediatric and adult patient populations, whereas IgG levels were found to vary in different age groups. SARS-CoV-2 IgG and total antibody levels, neutralizing activity, and avidity exhibited negative correlations with age in patients aged 1 to 24 years. This analysis revealed distinct antibody responses in different age groups, suggesting that age-targeted strategies for disease screening, management, and vaccine development are warranted.
SARS-CoV-2 Antibody durability: They applied the TOP-Plus platform that measured total antibody, surrogate neutralizing antibody, antibody avidity, IgM, and IgG for monitoring SARS-CoV-2 Antibody durability in Clinical Chemistry (3). They found that although total antibody and neutralization activity decreased between 1.3 and 6.2 months after infection, the antibody avidity increased significantly. Previous reports (4, 5) had shown that memory B-cell responses continue to evolve and express antibodies with increased neutralizing potency and breadth. Thus, the increased antibody avidity indicates the continued evolution of the humoral response.
COVID-19 vaccination response: With the ongoing worldwide SARS-CoV-2 vaccination programs, the TOP-plus panel can become a valuable asset in monitoring not only patients infected with SARS-CoV-2 but also the status of COVID-19 vaccination response in individuals and on a larger epidemiological scale. In a longitudinal study (6) conducted early on in the vaccination campaign, they investigated the quantity and quality of SARS-CoV-2 antibody response and demonstrated that convalescent COVID-19 individuals had more rapid, robust and sustainable antibody responses to mRNA COVID-19 vaccine.
利用生物传感器技术全方面检测新冠抗体的数量与质量
从2020年3月新冠疫情在纽约爆发时起，康奈尔大学医学院的赵贞博士、杨鹤博士和Dr.Sabrina Racine-Brzostek一起合作的科研团队深入研究了一系列新冠病毒抗原抗体的实验室检查方法，并且深入分析了大量新冠病人的检测数据。他们将前沿的生物传感器技术用于全方面检测新冠抗体的数量和质量，包括SARS-CoV-2总抗体，IgM, IgG,中和抗体相对水平,和抗体抗原的免疫亲和力。他们用这些新颖的检测方法研究了早期新冠病人的血液样品，发现病人初次就诊时的抗体水平和之后的预后有显著关联。另外，他们也研究了不同年龄段的患者的抗体水平和抗体结合力。他们还着重研究了在新冠病人和疫苗接种者体内的新冠抗体水平和亲和力随时间的变化。她们的团队在一年多的时间里发表了若干篇科研文章，包括Nature, JCI, Biosensors and Bioelectronics, Clinical Chemistry, JAMA Network Open and JCI insight. 其中一些研究成果被多家国内和国际媒体报道，引起了广泛的关注。以下是一些具体的课题：
新冠住院病人在发病早期时的抗体水平和死亡率之间的联系：赵贞博士的团队研究了120名因covid-19住院的病人在初次就诊时的抗体水平和其预后的关联。她们应用了两个基于生物传感器的方法（TOP）来分别检测新冠总抗体和中和抗体水平。这两个新方法具备灵敏性高，特异性高，快捷的特点，并可以在全自动仪器上使用。她们的研究发现，相比于因COVID-19死亡的住院病人，那些战胜新冠病毒而存活的住院病人在发病早期有更高的总抗体和中和抗体。也许就是说，如果早期身体能产生更多的抗体，病人则有更大的几率能活下来。这个工作发表在Biosensors and Bioelectronics杂志上。
她们研究了不同年龄段的儿童，青少年，青年感染新冠后产生的总抗体，IgG抗体，中和抗体，和抗体亲和力。她们先分析了在2020年4月9日至8月31日期间31426名不同年龄的患者的抗体水平。研究发现在1-24岁的患者中，SARS-CoV-2总抗体，IgG, 中和抗体，和抗体亲和力都与年龄呈负相关。儿童比青少年和青年人产生的抗体水平更强。这项工作是最早研究儿童在感染新冠后产生的抗体情况的报道之一，因此被36家国内和国际媒体报道。
在TOP方法的基础上，她们又进一步推出了检测新冠总抗体，IgG, IgM, 中和抗体和抗体结合力的TOP-PLUS平台。应用这个新颖的生物传感器方法，她们研究了新冠抗体在患病1.3-6.2个月之后的抗体情况。她们发现在患病6个月的时候，尽管总抗体和中和抗体水平在下降，但是抗体亲和力在加强。之前的研究结果显示身体中的B细胞会不断进化而分泌结合力更强的抗体，体现了人体免疫系统的进化发展。这项工作发表在Clinical Chemistry杂志上，并被主编选入该杂志的播客和journal club。
TOP-PLUS方法的高灵敏性和全自动操作流程使之可以被应用于全方面评估检测COVID-19患者和疫苗接种者的抗体水平和抗体亲和力。赵贞教授的团队的研究发现，相比于没有得过新冠的人，那些新冠患者在打完疫苗后会产生更强更持久的抗体反应。这项研究发表在JCI Insight杂志上。
References:
Yang HS, Hou Y, Vasovic LV, Steel PAD, Chadburn A, Racine-Brzostek SE, Velu P, Cushing MM, Loda M, Kaushal R, Zhao Z, Wang F. Routine Laboratory Blood Tests Predict SARS-CoV-2 Infection Using Machine Learning. Clin Chem. 2020 Nov 1;66(11):1396-1404. doi: 10.1093/clinchem/hvaa200. PubMed PMID: 32821907; PubMed Central PMCID: PMC7499540.
Yang HS, Racine-Brzostek SE, Karbaschi M, Yee J, Dillard A, Steel PAD, Lee WT, McDonough KA, Qiu Y, Ketas TJ, Francomano E, Klasse PJ, Hatem L, Westblade L, Wu H, Chen H, Zuk R, Tan H, Girardin RC, Dupuis AP 2nd, Payne AF, Moore JP, Cushing MM, Chadburn A, Zhao Z. Testing-on-a-probe biosensors reveal association of early SARS-CoV-2 total antibodies and surrogate neutralizing antibodies with mortality in COVID-19 patients. Biosens Bioelectron. 2021 Apr 15;178:113008. doi: 10.1016/j.bios.2021.113008. Epub 2021 Jan 20. PubMed PMID: 33515984; PubMed Central PMCID: PMC7816890.
Yang HS, Costa V, Racine-Brzostek SE, Acker KP, Yee J, Chen Z, Karbaschi M, Zuk R, Rand S, Sukhu A, Klasse PJ, Cushing MM, Chadburn A, Zhao Z. Association of Age With SARS-CoV-2 Antibody Response. JAMA Netw Open. 2021 Mar 1;4(3):e214302. doi: 10.1001/jamanetworkopen.2021.4302. PubMed PMID: 33749770; PubMed Central PMCID: PMC7985726.
Racine-Brzostek SE, Karbaschi M, Gaebler C, Klasse PJ, Yee J, Caskey M, Yang HS, Hao Y, Sukhu A, Rand S, Chadburn A, Shi Y, Zuk R, Nussenzweig MC, Cushing MM, Zhao Z. TOP-Plus Is a Versatile Biosensor Platform for Monitoring SARS-CoV-2 Antibody Durability. Clin Chem. 2021 Sep 1;67(9):1249-1258. doi: 10.1093/clinchem/hvab069. PubMed PMID: 33914041; PubMed Central PMCID: PMC8135537.
Racine-Brzostek SE, Yee JK, Sukhu A, Qiu Y, Rand S, Barone PD, Hao Y, Yang HS, Meng QH, Apple FS, Shi Y, Chadburn A, Golden E, Formenti SC, Cushing MM, Zhao Z. More rapid, robust and sustainable antibody responses to mRNA COVID-19 vaccine in convalescent COVID-19 individuals. JCI Insight. 2021 Oct 22;6(20). doi: 10.1172/jci.insight.151477. PubMed PMID: 34499052; PubMed Central PMCID: PMC8564891.