Janssen Research and Development, Beerse, Belgium (A.D., R.M.W.H., J.-J.P.-R., M.B.); and Janssen Vaccines and Prevention B.V., Leiden, The Netherlands (L.S., R.R.)
Janssen Research and Development, Beerse, Belgium (A.D., R.M.W.H., J.-J.P.-R., M.B.); and Janssen Vaccines and Prevention B.V., Leiden, The Netherlands (L.S., R.R.).
J Pharmacol Exp Ther. 2023 Oct;387(1):121-130. doi: 10.1124/jpet.123.001591. Epub 2023 Aug 3.
Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biologic drivers in antibody production. We used a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.S according to either a single-dose regimen (1 × 10 or 5 × 10 viral particles [vp]) or a two-dose homologous regimen (5 × 10 vp) given in an interval of 4 or 8 weeks. Humoral immune responses were quantified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific binding antibody concentrations as determined by spike protein-enzyme-linked immunosorbent assay. The mechanistic model adequately described the central tendency and variability of binding antibody concentrations through 20 weeks in all vaccination arms. The estimation of mechanistic modeling parameters revealed greater contribution of the antibody production mediated by short-lived cells as compared with long-lived cells in driving the peak response, especially post second dose when a more rapid peak response was observed. The antibody production mediated by long-lived cells was identified as relevant for generating the first peak and for contributing to the long-term time course of sustained antibody concentrations in all vaccination arms. The findings contribute evidence on the key biologic components responsible for the observed time course of vaccine-induced humoral immunity in NHPs and constitute a step toward defining immune biomarkers of protection against SARS-CoV-2 that might translate across species. SIGNIFICANCE STATEMENT: We demonstrate the adequacy of a mechanistic modeling approach describing the time course of binding antibody concentrations in non-human primates (NHPs) elicited by different dose levels and regimens of Ad26.COV2.S. The findings are relevant for informing the mechanism-based accounts of vaccine-induced humoral immunity in NHPs and translational research efforts aimed at identifying immune biomarkers of protection against SARS-CoV-2 infection.
机制模型可用于描述疫苗诱导的体液免疫的时间过程，并确定抗体产生中的关键生物学驱动因素。我们使用一个六室机制模型来描述 56 只非人类灵长类动物（NHP）在接种 Ad26.COV2.S 后 20 周内的体液免疫反应时间过程，这些 NHP 接种的方案是单剂量方案（1×10 或 5×10 病毒颗粒[vp]）或两剂量同源方案（5×10 vp，间隔 4 或 8 周接种）。体液免疫反应通过严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）刺突特异性结合抗体浓度来定量，这是通过刺突蛋白酶联免疫吸附试验确定的。在所有接种方案中，机制模型都充分描述了 20 周内结合抗体浓度的中心趋势和变异性。机制模型参数的估计结果显示，与长寿命细胞相比，短暂寿命细胞介导的抗体产生对峰值反应的驱动作用更大，特别是在第二次接种后观察到更快的峰值反应时。长寿命细胞介导的抗体产生被确定为在所有接种方案中产生第一个峰值和对维持抗体浓度的长期时间过程做出贡献的相关因素。这些发现为 NHP 中观察到的疫苗诱导的体液免疫时间过程中负责的关键生物学成分提供了证据，并为确定针对 SARS-CoV-2 的保护性免疫生物标志物迈出了一步，这些标志物可能在物种间转化。 意义声明：我们证明了一种机制建模方法在描述不同剂量水平和 Ad26.COV2.S 接种方案在非人类灵长类动物（NHP）中引起的结合抗体浓度时间过程中的充分性。这些发现对于为 NHP 中疫苗诱导的体液免疫的基于机制的解释以及旨在确定针对 SARS-CoV-2 感染的保护性免疫生物标志物的转化研究工作提供了信息。
