Metabolomics Core Resource Laboratory, NYU Langone Health, New York, NY 10016, USA.
Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA.
Viruses. 2023 Jan 14;15(1):242. doi: 10.3390/v15010242.
Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as “High”, “Low”, or “None” based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p < 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus.
流感是一个重大且持续存在的公共卫生危害。目前的合作努力旨在开发一种通用流感疫苗，目标是提高疫苗接种反应，增加单一疫苗对多种菌株和谱系的保护范围。作为实现这些目标的中间步骤，目前的工作集中在评估正常和高风险人群（如肥胖和老年人群）对疫苗接种的全身宿主反应，这些人群与疫苗接种反应不佳有关。因此，我们采用代谢组学方法，对流感疫苗接种前后的时间过程（n = 5 个时间点）进行了研究，时间范围从接种前（pre）到接种后 90 天。我们分析了一组 179 名受试者的尿液谱，这些受试者的年龄、性别、BMI 和其他人口统计学因素均匀分布，根据接种后 28 天血浆样本中的血凝抑制试验（HAI）测量的血清转化率，将他们的反应分为“高”、“低”或“无”。总体而言，我们在分析的 895 个样本中推测出 15903 种不同的、命名的小分子结构（在 FDR 为 10%时为 4473 种），目的是确定疫苗反应的代谢物相关性，以及接种前后的预后和诊断标志物。值得注意的是，我们发现，在接种后 3 天内，代谢谱可以无偏地将高危高反应者与高危无反应者（肥胖/老年）区分开来。嘌呤代谢物鸟嘌呤和次黄嘌呤与高血清转化率呈负相关（p = 0.0032，p < 0.0001），而乙酰亮氨酸和 5-氨基戊酸呈正相关。胱氨酸、谷氨酸、犬尿氨酸和其他代谢物的进一步变化表明，接种后 3 天（早期）氧化应激是高反应者的特征。目前正在努力使用流感感染的雪貂模型以及独立的季节性人类疫苗接种和人类活体病毒挑战研究队列来验证这些假定的标志物。
