Immunogenicity of recombinant zoster vaccine in Rheumatoid arthritis patients

重组带状疱疹疫苗对类风湿关节炎患者的免疫原性

• 批准号: 10426040
• 负责人: DAVID H CANADAY
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426040
• 关键词: Acute; Adjuvant; Adult; Adverse event; Age; Aged, 80 and over; Antibodies; Antimetabolites; Attenuated Vaccines; Autoimmune; Biological; Blinded; CD4 Positive T Lymphocytes; Cellular Immunity; Chickenpox; Clinical; Clinical Trials; Communicable Diseases; Complication; Data; Dermatologic; Disease-Modifying Second-Line Drugs; Drug usage; Event; FDA approved; Flare; Future; General Population; Herpes zoster disease; Humoral Immunities; Immune; Immunity; Immunologics; Immunosuppression; Individual; Infection; Inflammatory Arthritis; Influenza vaccination; Laboratories; Measures; Mediating; Methotrexate; Modeling; Morbidity - disease rate; Myocardial Infarction; Names; Observational Study; Opportunistic Infections; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Population; Postherpetic neuralgia; Prevalence; Primates; Recombinants; Regimen; Rheumatoid Arthritis; Rheumatology; Risk; Stroke; Subunit Vaccines; Syndrome; Systems Biology; Therapeutic immunosuppression; Vaccination; Vaccines; Virus; Work; Zoster Vaccine; adverse event monitoring; anti-influenza; chronic autoimmune disease; chronic pain; clinical efficacy; clinically relevant; effective therapy; gastrointestinal; immunogenicity; immunosuppressed; improved; innovation; lifetime risk; military veteran; mortality; novel therapeutics; responders and non-responders; response; thrombotic; translational potential; tumor necrosis factor-alpha inhibitor; vaccine efficacy; vaccine immunogenicity; varicella-zoster virus glycoprotein gp1

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.

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％ 在普通人群中，是退伍军人人口中常见的慢性自身免疫性疾病。 RA患者 感染疾病的死亡率和发病率更高。这种增加的负担部分与 RA本身的免疫危险，其中一些归因于免疫抑制疗法 用于治疗RA。 疱疹带状疱疹（Hz）重新激活是治疗的RA患者和 大约是普通人群的两倍。 HZ的一般风险已经为20-30％ 人口。直到最近批准重组带轮蛋白疫苗（RZV，品牌shingrix） 只有活疫苗Zostavax。它由于其治疗而很少在RA患者中使用 免疫抑制个体的禁忌症是一种活病毒疫苗。 RZV是亚基疫苗 没有这种限制。此外，在一般成年人口中发现RZV高度高 即使在80岁以上的人中，有效的（> 90％）也带来了巨大的潜在机会 即使在免疫抑制治疗中保护RA患者。 HZ免疫保护与对原发性水痘带状疱疹（VZV）感染的免疫力大不相同 （水痘），主要是抗体介导的。来自HZ创新的灵长类动物模型的工作表明 该细胞介导的免疫（CMI），特别是通过CD4+ T细胞，是保护的关键。所有疫苗 先前在RA患者中研究的是通过抗体介导的机制引起保护的患者 而不是CMI。调整疾病抗疾病药物（DMARD）对疫苗免疫原性或 功效，特别是集中于RZV启发CMI的功效尚不清楚。因此，拟议的研究是 创新的，因为他们建议确定RA和DMARD处理对免疫原性的影响 RZV。分析本研究中提出的RA患者对RZV的反应具有直接的临床相关性，并且 翻译潜力。由于有很多选择 治疗RA。它可以提供支持使用药物窗口的临床试验的数据 疫苗接种后暂时固定DMARD，以改善反应。 他们假设RZV与RA患者的免疫原性降低了 非RA对照和抗代谢物合成DMARD的RA患者将减少 免疫原性比生物dmard（例如TNFI）的免疫原性更重要。 他们将对100名RA患者进行实验室盲目的观察性研究，这是压倒性的 大多数人都在DMARDS上，100个年龄匹配的非rheumatogy受试者确定 这些人群之间RZV免疫原性的差异。 具体目的：目标1。确定合成和生物学的大小和差异效应 RA患者RZV的免疫原性的DMARD疗法。 目标2以确定降低和鲁棒疫苗特异性反应的机械途径 使用系统生物学方法进行RZV，并确定与 RA患者在DMARDS上的这些反应。 目标3。要比较RA患者RZV疫苗接种的不良事件特征与年龄匹配的非 - 风湿病个体。