DOES REDUCED HSV PREVALENCE RESULT IN INCREASED ZOSTER INCIDENCE IN THE US?

项目摘要 该提案汇集了三项观察结果：1）带状疱疹的发病率在欧洲不断增加 2）HSV-1和HSV-2的血清阳性率下降，以及3）发现 HSV和VZV之间广泛的T细胞交叉反应性。HSV和VZV引起非常不同的 疾病，但在免疫基础的氨基酸水平上共享低程度的序列， 交叉反应性人们普遍认为带状疱疹的风险与VZV呈负相关- 特异性T细胞免疫。我们假设带状疱疹的发病率随着时间的推移而增加 反映了HSV引起的交叉反应性免疫降低，这是由于HSV感染率降低所致。 感染我们提出了一个巢式病例对照研究来检验这一假设。我们将测试 来自安慰剂组的带状疱疹受试者和匹配对照组的基线样本 带状疱疹预防研究的一部分。这项先前完成的关于带状疱疹候选者的研究 疫苗有合适的标本库。我们将确定HSV的血清阳性率是否 低于对照组。HSV抗体状态将使用 华盛顿大学的蛋白质印迹法，目前最准确的检测方法。因为有一个 VZV与HSV-1和HSV-2之间大程度T细胞交叉反应性，Western印迹 检测将检测两种HSV类型的感染。我们的具体目标是：1）测试是否 发展带状疱疹的人比年龄，性别和健康状况更不可能有HSV感染- 匹配没有带状疱疹的人，和2）为了测试在发展带状疱疹的人中， 在先前有HSV感染的患者中，疾病的严重程度低于HSV感染者。 血清阴性。功效计算表明，我们将能够检测到HSV的比值比为1.8 使用来自200名患有带状疱疹的人的血清样品， 目标1为400个对照，目标2为92%的把握度检测带状疱疹疼痛增加1.4倍。这 该项目将揭示是否在流行病学的人群范围内的时间变化， 一种疱疹病毒对远距离序列相关病原体的发病率有影响。

PROJECT SUMMARY This proposal brings together three observations: 1) the increasing incidence of zoster in the United States, 2) the decreasing seroprevalence of HSV-1 and HSV-2, and 3) the discovery of extensive T cell cross-reactivity between HSV and VZV. HSV and VZV cause very distinct illnesses, but do share a low degree of sequence at the amino acid level that underlies immune cross-reactivity. It is widely accepted that the risk of zoster is inversely correlated with VZV- specific T cell immunity. We hypothesize that the increasing incidence of zoster over time reflects decreased cross-reactive immunity elicited by HSV, due to decreasing rates of HSV infection. We propose a nested case-control study to examine this hypothesis. We will test baseline samples of participants who developed zoster, and matched controls, from the placebo arm of the Shingles Prevention Study. This previously-completed study of a candidate zoster vaccine has a suitable Specimen Repository. We will determine if the seroprevalence of HSV is lower among cases than among controls. HSV antibody status will be measured with the University of Washington Western blot, the most accurate test available. Because there is a large degree of T cell cross-reactivity between VZV and both HSV-1 and HSV-2, Western blot assays will detect infection with both HSV types. Our Specific Aims are: 1) to test whether persons who develop zoster are less likely to have prior HSV infection than age, sex and health- matched persons without zoster, and 2) to test whether among persons who develop zoster, the disease is less severe among those that have prior HSV infection than those that are HSV seronegative. Power calculations indicate that we will be able to detect a 1.8 odds ratio of HSV infection in the control arm using serum samples from 200 persons that developed zoster and 400 controls for Aim 1, and a 92% power to detect 1.4X increase in zoster pain for Aim 2. This project will shed light on whether the population-wide temporal changes in the epidemiology of one herpesvirus have an impact on the morbidity of a distantly sequence-related pathogen.