Immunogenicity of recombinant zoster vaccine in Rheumatoid arthritis patients

类风湿关节炎(RA)是最常见的炎症性关节炎，患病率约为0.6% 是退伍军人中常见的一种慢性自身免疫性疾病。类风湿关节炎患者 传染病造成的死亡率和发病率更高。这一增加的负担在一定程度上与 RA本身的免疫紊乱，其中一些可归因于免疫抑制疗法 用于治疗类风湿性关节炎。 带状疱疹(HZ)再激活是接受治疗的RA患者最常见的机会性感染， 大约是普通人口的两倍。一般来说，赫兹已经有20%-30%的终生风险 人口。在最近批准重组带状疱疹疫苗(RZV，商标名Shingrix)之前，有 只有减毒活疫苗Zostavax。它很少在RA患者的治疗中使用，因为它 免疫抑制个体的禁忌症，因为它是活病毒疫苗。RZV是一种亚单位疫苗 没有这个限制。此外，RZV在普通成年人中被发现高度流行。 有效(90%)，即使在80岁以上的人。这带来了一个重要的潜在机会 即使在接受免疫抑制治疗的情况下也能保护RA患者。 HZ的免疫保护作用与对水痘带状疱疹(VZV)感染的免疫保护有很大的不同 (水痘)，主要是由抗体介导的。来自HZ创新灵长类动物模型的研究表明 这种细胞介导的免疫(CMI)，特别是由CD4+T细胞介导的，是保护的关键。所有的疫苗 以前对类风湿关节炎患者的研究是通过抗体介导的机制获得保护的 而不是CMI。疾病修饰性抗风湿药物对疫苗免疫原性的影响 疗效，特别是RZV对CMI的激发作用尚不清楚。因此，拟议的研究是 创新之处在于，他们提出了确定RA和DMARD治疗对免疫原性的影响 RZV。本研究提出的类风湿关节炎患者对RZV的反应分析具有直接的临床相关性和 翻译潜力。它可能会影响要使用的DMARD的选择，因为有许多选项可供选择 治疗类风湿性关节炎。它可以提供支持使用药物窗口的临床试验的数据，其中治疗与 DMARD在接种疫苗后暂时停止，以改善反应。 他们假设RZV在RA患者中的免疫原性将比 非RA对照组和服用抗代谢产物合成DMARDS的RA患者将减少 免疫原性高于生物DMARD，如TNFi。 他们将对100名RA患者进行实验室盲法观察研究， 其中大多数人服用DMARDS，以及100名年龄匹配的非风湿病受试者来确定 RZV在这些人群中的免疫原性差异。 具体目标：目标1.确定合成和生物的大小和不同的影响 DMARD治疗对类风湿关节炎患者RZV免疫原性的影响 目的2确定疫苗特异性应答减弱和增强的机制途径 使用系统生物学方法获得RZV，并确定与 服用DMARDS的RA患者的这些反应。 目的3.比较类风湿关节炎患者接种RZV疫苗与年龄匹配的非类风湿性关节炎患者接种RZV疫苗的不良事件情况 风湿病患者。

Rheumatoid arthritis (RA) is the most common inflammatory arthritis with a prevalence of around 0.6% in the general population and is a common chronic autoimmune disease in the veteran population. RA patients suffer greater mortality and morbidity from infectious diseases. This increased burden is in part related to the immune derangements of RA itself, and some of it is attributable to the immunosuppressive therapies that are used to treat RA. Herpes Zoster (HZ) reactivation is the most common opportunistic infection of treated RA patients and is about double that of the general population. HZ already has a lifetime risk of 20-30% in the general population. Until the recent approval of a recombinant zoster vaccine (RZV, brand name Shingrix) there was only the live attenuated vaccine, Zostavax. It was infrequently used in RA patients on treatment due to its contraindication in immunosuppressed individuals as it is a live virus vaccine. RZV being a subunit vaccine does not have this limitation. In addition, RZV has been found in the general adult population to be highly efficacious (>90%) even in persons over age 80. This has resulted in a significant potential opportunity to protect RA patients even on immunosuppressive therapy. Immune protection from HZ is much different than immunity to primary varicella zoster (VZV) infection (chickenpox) which is primarily antibody-mediated. Work from an innovative primate model of HZ suggests that cell-mediated immunity (CMI), specifically by CD4+ T cells, is a key for protection. All of the vaccines previously studied in RA patients have been ones that elicit protection through antibody-mediated mechanisms and not CMI. The effect of disease-modifying antirheumatic drugs (DMARDs) on vaccine immunogenicity or efficacy, in particular focused on RZV elicitation of CMI is not known. The proposed study is therefore innovative, in that they propose to determine the effect of RA and DMARD treatment on the immunogenicity of RZV. Analysis of response to RZV in RA patients proposed in this study has direct clinical relevance and translational potential. It may influence the choices of DMARDs to be utilized as there are many options for treating RA. It could provide data that supports a clinical trial using drug windowing where the treatment with DMARD is withheld transiently after vaccination to improve the response. They hypothesize that RZV will have a reduced immunogenicity in RA patients compared to non-RA controls and that RA patients on anti-metabolite synthetic DMARDs will have reduced immunogenicity more than those on biologic DMARDs such as TNFi. They will perform a laboratory blinded observational study of 100 RA patients, the overwhelming majority of whom are on DMARDs, and 100 age-matched non-rheumatology subjects to determine the difference in immunogenicity of RZV between these populations. Specific Aims: Aim 1. To determine the magnitude and differential effects of synthetic and biologic DMARD therapies on the immunogenicity of RZV in RA patients. Aim 2 To determine the mechanistic pathways of both reduced and robust vaccine specific responses to RZV using systems biology approaches and to determine the signatures that is associated with these responses in RA patients on DMARDS. Aim 3. To compare adverse event profile of RZV vaccination in RA patients to age-matched non- rheumatic disease individuals.