Vaccine Induced Immune-Inflammatory Response and Cardiovascular Risk

项目摘要 在来自散发性病毒实体的新兴威胁中，常年性流感病毒株继续在 造成发病率和死亡率的巨大负担，使人口每年面临的总风险增加， 大.上个季节（2018-19），流感影响了3550万人，导致490，600人住院，34，200人死亡。 这些重要的统计数据每年都在稳步上升。心血管疾病患者 疾病特别容易受到与社区获得性病毒相关的发病率和死亡率的影响， 感染，如流感。接种疫苗可显著降低心血管事件的发生率， 人群水平;然而，个体水平的流感疫苗接种存在极大差异 关于（i）达到的体液抗体应答的程度，和（ii）心脏保护的程度 授予。有趣的是，所赋予的心脏保护程度并不完全取决于 体液免疫的实现，突出了进一步的机会，发现和获得临床效益， 预防性治疗具有复杂和不均匀的效果。越来越多的证据表明， 内源性免疫炎症通路的上游介质可能是免疫炎症的关键决定因素。 个体水平的反应和受益于所施用的疫苗接种。这些分子介体 称为类二十烷酸系统性免疫-炎症活性包括小生物活性脂质的不同家族 其酶促衍生自多不饱和脂肪酸。根据初步研究结果，我们 假设特异性类二十烷酸不仅预测对流感疫苗接种免疫应答， 还预测其对不良心血管事件的保护作用，无论感染状况如何。 因此，我们建议对NHLBI资助的流感疫苗进行一项辅助研究， 心胸事件和失代偿性心力衰竭（INVESTED）试验，旨在：（1）确定 类花生酸可预测流感患者对流感疫苗接种的经典体液抗体应答 慢性心血管疾病，代表不良事件风险最高的人群亚组;以及， (2)鉴定响应于疫苗接种产生的类二十烷酸，其对应于降低的 心血管事件，与体液免疫和感染状态无关。的现有基础设施 INVESTED试验提供了一种具有成本效益的方法，可以接触到流感风险最高的个人- 相关事件，并能够进行严格的研究设计，以调查对 从疫苗接种中受益。

Project Summary In the midst of emerging threats from sporadic viral entities, the perennial influenza viral strains continue to impose a substantial burden of morbidity and mortality that compounds total annual risks to the population at large. Last season (2018-19), influenza affected 35.5 million and led to 490,600 hospitalizations and 34,200 deaths in the U.S. These vital statistics have been steadily rising each year. Individuals with cardiovascular disease are especially susceptible to the morbidity and mortality associated community-acquired viral infections such as influenza. Vaccination significantly reduces the incidence of cardiovascular events at the population level; However, administration of influenza vaccination at the individual level is extremely variable with respect to (i) the extent of humoral antibody response achieved, and (ii) the degree of cardioprotection conferred. Intriguingly, the degree of cardioprotection conferred does not depend entirely on the level of humoral immunity achieved, highlighting further opportunities to discover and derive clinical benefit from a preventive therapy with both complex and non- uniform effects. Accumulating evidence now indicates that upstream mediators of endogenous immune- inflammatory pathways are likely key determinants of the individual-level response to and benefit from an administered vaccination. These molecular mediators of systemic immune-inflammatory activity, termed eicosanoids, include a diverse family of small bioactive lipids that are enzymatically derived from polyunsaturated fatty acids. Based on results from preliminary studies, we hypothesize that specific eicosanoids not only predict the immunologic response to influenza vaccination but also predict its conferred protection from adverse cardiovascular events, irrespective of infection status. Therefore, we propose an ancillary study for the NHLBI-funded INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure (INVESTED) trial, that aims to: (1) identify eicosanoids that predict the classic humoral antibody response to influenza vaccination in patients with chronic cardiovascular disease, who represent the population subset most at-risk for adverse events; and, (2) identify eicosanoids generated in response to vaccination that correspond with reduced risk for cardiovascular events, irrespective of humoral immunity and infection status. The existing infrastructure of the INVESTED trial offers a cost-effective way to reach individuals who are at the highest risk for influenza- associated events and enable a rigorous study design for investigating heterogeneity in the response to and benefit from vaccination.