Clegg Lindsay E, Stepanov Oleg, Matthews Sam, White Tom, Seegobin Seth, Thomas Steven, Tuffy Kevin M, Någård Mats, Esser Mark T, Streicher Katie, Cohen Taylor S, Aksyuk Anastasia A
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca Gaithersburg MD USA.
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca Cambridge UK.
Clin Transl Immunology. 2024 Jun 13;13(6):e1517. doi: 10.1002/cti2.1517. eCollection 2024.
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum.
SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab-cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with IC measurements.
nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC values were similar to IC values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants.
These data highlight that serum mAb concentrations and pseudovirus IC values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的不断演变，使得需要快速评估针对新出现变异株的单克隆抗体（mAb）效力的方法。真实病毒中和试验被认为是测定血清中病毒中和抗体（nAb）滴度的金标准。然而，基于真实病毒的试验在测量针对新出现的SARS-CoV-2变异株的nAb滴度时存在固有的实际挑战（例如储存传染性病毒以及在生物安全3级设施中进行检测）。在此，我们证明了假病毒中和试验数据与血清mAb浓度相结合，可有力地预测血清中的nAb滴度。
使用来自三项AZD7442（替沙格韦单抗-西加韦单抗）研究（PROVENT，NCT04625725；TACKLE，NCT04723394；以及一项1期剂量范围研究，NCT04507256）的血清学数据，通过基于真实病毒和慢病毒假病毒的中和试验来测定SARS-CoV-2的nAb滴度。使用免疫捕获法评估AZD7442的血清浓度。基于血清的半数最大抑制浓度（IC）值由假病毒nAb滴度和血清mAb浓度得出，并与IC测量值进行比较。
通过基于真实病毒和慢病毒假病毒的中和试验测得的nAb滴度，对于原始SARS-CoV-2病毒和SARS-CoV-2 Alpha变异株具有很强的相关性。对于多种SARS-CoV-2变异株，血清中AZD7442浓度与假病毒nAb滴度具有很强的相关性，所有Spearman相关系数均≥0.78。对于原始SARS-CoV-2、Alpha、Delta、奥密克戎BA.2以及奥密克戎BA.4/5变异株，基于血清的IC值与AZD7442的IC值相似。
这些数据表明，血清mAb浓度和假病毒IC值可用于快速预测血清中针对新出现和既往SARS-CoV-2变异株的nAb滴度。
