Xu Shilian, Yang Jiaru
Department of Environment and Genetics, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, 3086, Australia.
Department of Mathematical and Physical Sciences, La Trobe University, Bundoora, VIC, 3086, Australia.
Infect Dis Model. 2024 Jul 18;9(4):1265-1275. doi: 10.1016/j.idm.2024.07.003. eCollection 2024 Dec.
Antibody dependant enhancement refers that viral infectivity was unexpectedly enhanced at low antibody concentration compared to when antibodies were absent, such as Dengue, Zika and influenza virus. To mathematically describe switch from enhancement to neutralisation with increase of antibody concentration, one hyperbolic tangent variant is used as switching function in existed models. However, switching function with hyperbolic tangent contains four parameters, and does not always increase with antibody concentration. To address this problem, we proposed a monotonically increasing Logistical function variant as switching function, which only contains position parameter and magnitude parameter. Analysing influenza viral titre estimated from 21 focus reduction assay (FRA) datasets from neutralisation group (viral titre lower than negative control on all serial dilutions) and 20 FRA dataset from enhancement group (viral titre higher than negative control on high serial dilution), switching function with Logistic function performs better than existed model independent of both groups and exhibited different behaviour/character; specifically, magnitude parameter estimated from enhancement group is lower, but position parameter estimated from enhancement group is higher. A lower magnitude parameter refers that enhancement group more rapidly switches from enhancement to neutralisation with increase of antibody concentration, and a higher position parameter indicates that enhancement group provides a larger antibody concentration interval corresponding to enhancement. Integrating estimated neutralisation kinetics with viral replication, we demonstrated that antibody-induced bistable influenza kinetics exist independent of both groups. However, comparing with neutralisation group, enhancement group provides higher threshold value of antibody concentration corresponding to influenza infectivity. This explains the observed phenomenon that antibody dependent enhancement enhances susceptibility, severity, and mortality to influenza infection. On population level, antibody dependant enhancement can promote H1N1 and H3N2 influenza virus cooperate to sustain long-term circulation on human populations according to antigenic seniority theory.
抗体依赖增强作用是指在低抗体浓度下，与无抗体时相比，病毒感染性意外增强，如登革热病毒、寨卡病毒和流感病毒。为了从数学上描述随着抗体浓度增加从增强到中和的转变，现有模型使用一种双曲正切变体作为切换函数。然而，双曲正切切换函数包含四个参数，且并不总是随抗体浓度增加。为解决此问题，我们提出一种单调递增的逻辑函数变体作为切换函数，它仅包含位置参数和幅度参数。分析来自中和组的21个蚀斑减少试验（FRA）数据集（所有系列稀释中病毒滴度均低于阴性对照）和增强组的20个FRA数据集（高系列稀释时病毒滴度高于阴性对照）估算的流感病毒滴度，逻辑函数切换函数在两组中均比现有模型表现更好，且呈现出不同的行为/特征；具体而言，增强组估算的幅度参数较低，但位置参数较高。较低的幅度参数表明增强组随着抗体浓度增加更快地从增强转变为中和，而较高的位置参数表明增强组对应于增强的抗体浓度区间更大。将估算的中和动力学与病毒复制相结合，我们证明抗体诱导的双稳态流感动力学在两组中均存在。然而，与中和组相比，增强组对应流感感染性的抗体浓度阈值更高。这解释了所观察到的抗体依赖增强作用会增加对流感感染的易感性、严重程度和死亡率这一现象。在群体水平上，根据抗原优势理论，抗体依赖增强作用可促进H1N1和H3N2流感病毒协同作用以在人群中长期循环传播。
