Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether the antigenic distances between an individual’s first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalizations across years. Here, we develop a framework that combines detailed antigenic and genetic characterization of viruses with details on hospitalized cases from 21 years of dengue surveillance in Bangkok, Thailand, to identify the role of the antigenic profile of circulating viruses in determining disease risk. We found that the risk of hospitalization depended on both the specific order of infecting serotypes and the antigenic distance between an individual’s primary and secondary infections, with risk maximized at intermediate antigenic distances. These findings suggest that immune imprinting helps determine dengue disease risk and provide a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

中文翻译：

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原发性和继发性登革热感染之间的抗原距离与疾病风险相关

许多病原体会不断改变其蛋白质结构以响应免疫驱动的选择，从而导致即使在以前接触过的个体中的保护也减弱。此外，对于一些病原体，例如登革热病毒，针对性较差的免疫通过一种称为抗体依赖性增强的机制与严重疾病的风险增加相关。然而，目前尚不清楚个体首次感染和随后接触之间的抗原距离是否决定了疾病风险，这解释了多年来观察到的登革热住院治疗的大规模差异。在这里，我们开发了一个框架，将病毒的详细抗原和遗传特征与泰国曼谷 21 年登革热监测住院病例的详细信息结合起来，以确定循环病毒的抗原谱在确定疾病风险中的作用。我们发现，住院风险取决于感染血清型的具体顺序以及个体原发性和继发性感染之间的抗原距离，中间抗原距离时风险最大。这些发现表明，免疫印记有助于确定登革热疾病风险，并提供监测人群风险状况变化和量化候选疫苗风险状况的途径。