Herpes zoster vaccine(EyeGene, Inc.)

PHILADELPHIA, PA, USA I September 18, 2024 I GSK plc (LSE/NYSE: GSK) today announced positive topline data from the phase 3 trial in adults 50 years and older evaluating the immunogenicity, reactogenicity and safety of AREXVY (Respiratory Syncytial Virus Vaccine, Adjuvanted) when co-administered with SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted), both AS01-adjuvanted vaccines (NCT05966090). 1,2 The data were presented as a late-breaking abstract at the European Geriatric Medicine Society (EuGMS) Congress in Valencia, Spain (September 18-20th, 2024). 2 SHINGRIX is approved for the prevention of shingles (herpes zoster) in adults aged 50 years and older. AREXVY is approved for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV) in individuals 60 years of age and older, as well as individuals 50 through 59 years of age who are at increased risk for LRTD caused by RSV. The data showed a non-inferior immune response when the vaccines were co-administered compared to when they were administered at separate visits. 2 Co-administration was also well tolerated, with acceptable reactogenicity and safety profiles. 2 In both groups, the most frequently reported adverse events were pain at the injection site, fatigue, and myalgia. 2 The duration of solicited adverse events was comparable across the two groups. 2 Len Friedland, MD, Vice President of Scientific Affairs and Public Health, GSK, said: “We are excited to share data on the co‑administration of our RSV and shingles vaccines. Adult immunization offers immense individual and societal benefits and yet, vaccination rates for adults are often inadequate. With our co-administration studies, GSK is using its science and technology to help remove barriers to adult immunization, by potentially reducing the number of visits to the healthcare offices and pharmacies and ultimately help to get ahead of RSV and shingles.” Results from this trial will be submitted for peer-reviewed scientific publication and will be used to support regulatory submissions to the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulators. Both RSV and shingles pose significant health risks to older adults, and these risks only increase with age as the immune system declines. Immunocompromised individuals and those with certain underlying medical conditions—for example, asthma and COPD—may also be at increased risk for these diseases. 3,4,5 RSV is a common, contagious respiratory virus that can lead to potentially serious respiratory illness. 3 Each year, approximately 177,000 adults 65 years and older are hospitalized in the US due to RSV and an estimated 14,000 of those cases result in death. 6 Shingles is a painful, blistering rash that can last for weeks. Because it is caused by the reactivation of the varicella zoster virus (VZV)—the same virus that causes chickenpox—99% of US adults have the virus that causes shingles inside their body, although not everyone will develop shingles. 7 An estimated one million people develop shingles annually in the US. 8 About AREXVY (Respiratory Syncytial Virus Vaccine, Adjuvanted) AREXVY contains recombinant RSV glycoprotein F stabilized in the prefusion conformation (RSVPreF3). This antigen is combined with GSK’s proprietary AS01E adjuvant. The vaccine has been approved for the prevention of RSV-LRTD in individuals 60 years of age and older in 50 countries, including Europe, Japan and US. It is also approved in several countries for use in adults aged 50–59 at increased risk for RSV-LRTD, including European Union/European Economic Area and US. Regulatory reviews in multiple countries are ongoing. The proposed trade name remains subject to regulatory approval in other markets. The GSK proprietary AS01 adjuvant system contains QS-21 STIMULON adjuvant licensed from Antigenics Inc, a wholly owned subsidiary of Agenus Inc. Indication for AREXVY AREXVY is a vaccine indicated for active immunization for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV) in: Important Safety Information for AREXVY Please see full Prescribing Information for AREXVY. About SHINGRIX(Recombinant Zoster Vaccine or RZV) SHINGRIX is a non-live, recombinant subunit vaccine indicated for the prevention of shingles in adults 50 and over. It combines an antigen, glycoprotein E, with an adjuvant system, AS01 B , and may help overcome the natural age-related decline in responses to immunization that contributes to the challenge of protecting adults aged 50 and over from shingles. 9,10 RZV is not indicated to prevent primary varicella infection (chickenpox). In several countries, it is also approved for adults aged 18 years or over at increased risk for shingles. The use of RZV should be in accordance with official recommendations and local product label. Indication for SHINGRIX SHINGRIX is an FDA-approved vaccine for the prevention of shingles (herpes zoster) in: SHINGRIX is not used to prevent chickenpox. Important Safety Information for SHINGRIX Please see full Prescribing Information for SHINGRIX. About the NCT05966090 trial The co-administration study is a phase 3, open-label, multi-country study to assess non-inferiority of immune responses in co-administration of GSK’s RSV and Recombinant Zoster Vaccine (RZV) compared to separate administration in adults aged 50 and over. 2 530 participants were randomized 1:1 to receive either GSK’s Recombinant Zoster Virus vaccine first dose and GSK’s Respiratory Syncytial Virus, Adjuvanted at visit one (Co-ad), or GSK’s Recombinant Zoster Virus vaccine first dose alone at visit one (Control). The Control group received GSK’s RSV vaccine at day 31. 1,2 RZV second dose was administered at day 61 for both groups. 1,2 The primary endpoint was the non-inferiority of the humoral immune responses to GSK’s RSV vaccine and RZV when co-administered compared to when administered at separate visits. 1,2 Key secondary endpoints included reactogenicity and safety following co-administration versus sequential administration of GSK’s RSV vaccine and RZV. 1,2 Anti-gE antibody concentrations and RSV-A and RSV-B neutralization titers increased from pre- to post-vaccination and met the non-inferiority criteria in the primary endpoint for the humoral immune responses to GSK’s RSV and shingles vaccines. 2 In both groups, the duration of solicited adverse events was short and comparable, and the most frequently reported adverse events were pain at the injection site, fatigue, and myalgia. 2 Unsolicited adverse events reporting rates were balanced between the co-administration and control groups. 2 About RSV in Adults RSV is a common, contagious respiratory virus affecting the lungs and breathing passages. 3 Adults can be at increased risk for RSV disease due to certain underlying medical conditions, immune compromised status, or advanced age. 3 RSV can exacerbate conditions, including COPD, asthma, and chronic heart failure and can lead to severe outcomes, such as pneumonia, hospitalization, and death. 3 About Shingles Shingles is caused by the reactivation of the varicella-zoster virus (VZV), the same virus that causes chickenpox. 11 By age 50, VZV is present in most adults 12 and may reactivate with advancing age. 13 As people age, the strength of the immune system response to infection wanes, increasing the risk of developing shingles. 11 Shingles typically presents as a rash, with painful blisters across the chest, abdomen, or face. 11 The pain is often described as aching, burning, stabbing or shock-like. 14 Following the rash, a person may experience post-herpetic neuralgia (PHN), a long-lasting nerve pain that can last weeks or months and occasionally persists for several years. 14 PHN is the most common complication of shingles, occurring in 5–30% of all shingles cases from findings in various studies. 15 About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. References 1. Clinicaltrials.gov, “A Study on Safety and Immune Response of Investigational RSV OA Vaccine in Combination With Herpes Zoster Vaccine in Healthy Adults (RSV-OA=ADJ-020)”, NCT05966090 – available at: https://clinicaltrials.gov/study/NCT05966090 – Accessed in September 2024. 2. Dennis P, et al. Co-administration of the adjuvanted respiratory syncytial virus (RSV) prefusion F protein vaccine (RSVPreF3 OA) with the adjuvanted recombinant zoster vaccine (RZV) in adults ≥50 years of age. Abstract presented at European Geriatric Medicine Society (EuGMS); 18–20 September 2024, Valencia, Spain. 3. Centers for Disease Control and Prevention (CDC), RSV in Adults. Available at: https://www-cdc-gov.libproxy1.nus.edu.sg/rsv/older-adults/index.html . Last Accessed: September 2024. 4. Marra F, et al. Risk Factors for Herpes Zoster Infection: A Meta-Analysis. Open Forum Infect Dis 2020;7(1):ofaa005. 5. Chen S-Y, et al. Incidence of herpes zoster in patients with altered immune function. Infection. 2014; 42: 325–334 6. Falsey, AR et al. Respiratory syncytial virus infection in elderly and high-risk adults, in New Engl J Med 2005; 352:1749-59. 7. CDC. About Shingles (Herpes Zoster). Available at https://www-cdc-gov.libproxy1.nus.edu.sg/shingles/about/index.html 8. CDC. Shingles (Herpes Zoster): Clinical Overview. Available at: https://www-cdc-gov.libproxy1.nus.edu.sg/shingles/hcp/clinical-overview/index.html 9. Cunningham, AL, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. New England Journal of Medicine. 2016;375(11):1019–32. 10. The GSK proprietary AS01 adjuvant system contains QS-21 Stimulon® adjuvant licensed from Antigenics LLC, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes. 11. Harpaz R, et al. Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30. 12. Johnson, R.W., et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Therapeutic advances in vaccines. 2015;3(4):109–20. 13. Mueller, N.H., et al. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurologic clinics. 2008;26(3):675–97. 14. Cheng J, Rosenquist RW. Herpes zoster and postherpetic neuralgia. Fundamentals of Pain Medicine . 2018:221-5. 15. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open. 2014;4:e004833. doi: 10.1136/bmjopen-2014-004833. SOURCE: GlaxoSmithKline

感染性疾病是风湿免疫性疾病患者面临的重大挑战，极大影响了疾病进程和患者预后。疫苗接种是风湿免疫性疾病患者感染防治中的重要一环，近年来在国际上获得了越来越多的重视，已被纳入风湿免疫人群的医疗决策。然而，中国风湿免疫性疾病患者尚缺乏疫苗接种的临床指南和共识。因此，本共识编写组组织疾病预防控制中心和风湿免疫科专家共同撰写了《中国成人风湿免疫性疾病患者疫苗接种专家共识》。本共识基于现有的临床证据，参考美国风湿病学会（American College of Rheumatology，ACR）和欧洲风湿病联盟（European Alliance of Associations for Rheumatology，EULAR）的推荐建议［1,2］，结合了国内疫苗接种的实践经验，以期为广大预防接种人员和风湿免疫科医师提供科学、简明、操作性强的技术指南。风湿免疫性疾病概述风湿免疫性疾病是由多种致病因素参与的系统性疾病，可累及全身多个脏器，异质性强，病种复杂，包括系统性红斑狼疮、炎症性肌病、系统性血管炎、系统性硬化症、干燥综合征、类风湿关节炎、强直性脊柱炎、骨关节炎、痛风性关节炎、成人斯蒂尔病、抗磷脂综合征、免疫球蛋白G（immunoglobulin G，IgG）4相关疾病、复发性多软骨炎和自身炎症性疾病等。风湿免疫性疾病极大地影响了人民群众的生活质量和预期寿命。免疫系统紊乱是风湿免疫性疾病发生和进展的核心环节，针对异常自身炎症和自身免疫的调节也成为治疗的基础。近几十年来，风湿免疫性疾病的治疗有了长足发展，已经极大改善了患者预后。风湿免疫性疾病的常用药物包括非甾体抗炎药、糖皮质激素、抗疟药、改善病情的抗风湿药物等。非甾体抗炎药：如双氯芬酸、塞来昔布、尼美舒利、依托考昔等；糖皮质激素：包括泼尼松，泼尼松龙，甲基泼尼松龙，地塞米松、倍他米松等；传统的改善病情抗风湿药物：包括甲氨蝶呤、来氟米特、环磷酰胺、硫唑嘌呤、环孢素、吗替麦考酚酯、他克莫司、柳氮磺吡啶等；常用的靶向治疗药物：包括细胞因子抑制剂、T细胞抑制剂、B细胞抑制剂、补体抑制剂，以及靶向信号通路的小分子抑制剂等。风湿免疫性疾病患者接种疫苗的必要性由于免疫机制的紊乱，风湿免疫性疾病患者免疫防御功能降低，罹患感染的风险远高于健康人群。同时，免疫抑制药物（如糖皮质激素和免疫抑制剂治疗）使患者发生感染的概率进一步增加［3,4］。近年来，新的生物制剂和小分子化合物被越来越广泛地应用于风湿免疫性疾病患者的达标治疗［5］，控制疾病活动性的同时也造成了某些病原体易感性增加［6,7］。中国台湾一项纳入76966例患者的研究显示，风湿免疫性疾病患者机会性感染的累积发病率逐年增高［8］，严重感染造成的不良预后成为影响患者生存和生活质量的重大挑战。在临床实践中，由于疾病模式、个体差异、合并症、治疗用药、环境等因素的不同，风湿免疫性疾病患者可发生细菌、病毒、真菌和寄生虫感染。由于病原体毒力、数量和侵入方式不同，自身免疫性疾病患者感染类型、部位和严重程度上存在极大差别。免疫抑制的患者对病毒和细菌感染均易感。革兰阴性菌是肺部感染最常见的病原体；结核分枝杆菌和非结核分枝杆菌感染好发于全身类固醇激素使用和接受肿瘤坏死因子拮抗剂治疗的患者；耶氏肺孢子菌、曲霉菌和隐球菌是造成患者严重感染的常见致病真菌［5］。疫苗接种是预防病毒和细菌感染的重要手段，已成为国际共识［1,2,9,10］。与健康人群相比，风湿免疫性疾病患者接种疫苗的免疫原性和安全性有所不同，因此对患者疫苗接种进行管理十分重要［1］。本共识对中国成人风湿免疫性疾病患者常用的8种疫苗接种提出建议，包括流感疫苗、肺炎球菌疫苗、新型冠状病毒（简称“新冠病毒”）疫苗、带状疱疹疫苗［2］、人乳头瘤病毒疫苗（human papillomavirus，HPV）、甲型肝炎疫苗、乙型肝炎疫苗、狂犬病毒疫苗。疫苗应答的可能影响因素有效的疫苗应答取决于受种者的先天性和适应性免疫应答，适应性免疫包括特异的体液免疫和细胞免疫，即B细胞和T细胞参与的免疫。疫苗种类、佐剂类型和机体免疫状态等都与疫苗应答有关。疫苗可以刺激机体产生记忆性T辅助细胞和B细胞，诱发细胞毒性T细胞的产生；另一方面，减毒活疫苗存在突变和造成感染的风险。针对不同病原体的疫苗产生保护性免疫的持续时间和强度各有差异，这也是确定疫苗接种程序的免疫学基础。对多种疫苗的研究发现，增加疫苗接种剂次可以促进有效应答的产生［11］。佐剂是疫苗制备过程中的重要成分，用以增强免疫反应的程度、广度和持久性。佐剂的免疫学机制包括延长免疫原效应时间，刺激趋化因子和炎症因子分泌，活化淋巴细胞，增强生发中心和抗体反应等［12］。机体免疫状态是影响疫苗应答的重要因素。在风湿免疫人群中，由于疾病本身造成的免疫紊乱和免疫抑制剂的使用，疫苗免疫应答的过程更为复杂。患者往往存在细胞免疫和体液免疫低下，影响疫苗的免疫原性；同时，外来刺激也可能诱发患者异常免疫应答和疫苗的部分不良反应有关［9］。风湿免疫性疾病患者治疗药物和疫苗免疫原性密切相关。患者通常使用的免疫抑制药物包括糖皮质激素、传统合成的改变病情抗风湿药（conventional synthetic disease-modifying antirheumatic drug，csDMARD）、生物类改变病情的抗风湿药（biologic disease-modifying antirheumatic drug，bDMARD）以及靶向合成改变病情的抗风湿药（targeted synthetic disease-modifying antirheumatic drug，tsDMARD）。接种时服用小于10 mg/d泼尼松或等效剂量的其他糖皮质激素不影响疫苗的免疫原性，20 mg/d以上泼尼松或等效剂量的其他糖皮质激素与疫苗较低的保护效能相关。csDMARD、bDMARD和tsDMARD对不同疫苗免疫原性的影响不尽相同。甲氨蝶呤已经被证实可以造成疫苗接种的低反应性［1］，B细胞靶向药物比如利妥昔单抗、T细胞靶向药物如阿巴西普等对多种疫苗应答有显著影响。肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素17抑制剂、白细胞介素12/23抑制剂对疫苗的免疫应答相对影响较小［13］。在新冠病毒mRNA疫苗的研究中发现，接种前较低的免疫球蛋白IgG水平与mRNA疫苗的低免疫原性相关，因此在接种前评估患者免疫球蛋白水平和淋巴细胞亚群可能有助于预测mRNA疫苗诱导的保护性应答［14］。因此，对风湿免疫人群进行免疫规划，适当调整疫苗接种的时间或者药物使用，有助于提高疫苗接种的保护效能，并减少不良反应的发生。·风湿免疫性疾病疫苗接种指导建议总则 ·1.建议在风湿免疫性疾病患者中积极开展预防接种。2.通常情况下，建议在疾病稳定期进行预防接种。如有可能，在免疫抑制治疗开始2~4周前接种。3.建议首选接种灭活疫苗和重组蛋白疫苗，可选择mRNA疫苗，不建议接种病毒载体疫苗。在其他工艺疫苗可获得的情况下，不建议接种减毒活疫苗。4.建议在疫苗接种前接受专科医生评估。对既往疫苗针对疾病的感染史、疫苗接种史、患者疾病状态和免疫调节药物的使用进行评估。5.患者接种后可能出现异常的免疫应答和不良反应，推荐在专科医生指导下诊治。6.根据中国接种要求进行新冠病毒疫苗接种。中国成人风湿免疫性疾病患者较接种疫苗一、流感疫苗1.概述季节性流感每年在全球可导致29万~65万呼吸道疾病相关死亡，风湿免疫性疾病患者是流感感染的高危人群［15］。流感疫苗接种显著减少了风湿免疫性疾病患者流感和相关并发症发生的风险，降低了患者住院率和死亡率［2,16,17］。同时，没有明确证据显示流感疫苗接种会造成自身免疫病恶化［18,19］。风湿免疫人群接种流感疫苗的不良反应和健康人群类似［2］。不同流感疫苗株在不同风湿免疫性疾病患者中的免疫原性存在差异［20］。小剂量糖皮质激素（<10 mg/d的泼尼松及等效剂量的其他糖皮质激素）不影响流感疫苗的免疫应答。甲氨蝶呤影响流感抗体生成，阿巴西普、肿瘤坏死因子抑制剂、Janus激酶（Janus kinase，JAK）抑制剂可能影响抗体滴度。白细胞介素6、白细胞介素12/23和白细胞介素17的抑制剂对疫苗的免疫原性无明显影响［13］。2.中国应用的疫苗类型成人使用的三价灭活疫苗（trivalent inactivated influenza vaccine，IIV3）；四价灭活疫苗（quadrivalent inactivated influenza vaccine，IIV4）。3.接种建议（1）建议接种：建议所有风湿免疫病患者每年接种流感病毒灭活疫苗，免疫程序按照疫苗说明书执行，全程接种。推荐在使用小剂量糖皮质激素即≤10 mg/d的泼尼松及等效剂量的其他糖皮质激素时完成接种；使用10~20 mg/d泼尼松等效剂量或更高剂量糖皮质激素的患者仍可接种流感疫苗。（2）建议调整接种或用药时机：①如未使用抗CD20单抗治疗，建议使用前至少2周接种流感疫苗。如已经使用，则可按照免疫计划接种流感疫苗和药物使用时间的更长间隔有利于增强疫苗应答。②使用甲氨蝶呤治疗的患者建议在接种后停用2周。③接受生物制剂如肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素12/23抑制剂和白细胞介素17抑制剂治疗的患者，无须停止药物。二、肺炎球菌疫苗1.概述呼吸道感染是风湿免疫性疾病患者最常见的感染，肺炎球菌是呼吸道感染常见的病原体。风湿免疫性疾病患者肺部感染风险显著高于一般人群。荷兰一项研究显示，系统性红斑狼疮患者侵袭性肺炎球菌感染的发生率是荷兰普通人群的13倍［21］。在患有类风湿关节炎的美国退伍军人中，使用生物制剂治疗的患者因肺部感染住院的比例高达37%［22］。因此，在免疫低下宿主中，接种肺炎球菌疫苗有助于预防肺部感染［2］。利妥昔单抗、甲氨蝶呤、环磷酰胺、硫唑嘌呤、阿巴西普和JAK抑制剂可影响疫苗免疫原性。肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素12/23抑制剂和白细胞介素17抑制剂对疫苗应答无明显影响［13］。2.中国应用的疫苗类型23价肺炎球菌多糖疫苗（23-valent pneumococcal polysaccharide vaccine，PPV23）13价肺炎球菌多糖结合疫苗（13-valent pneumococcal polysaccharide conjugate vaccine，PCV13，用于6 周龄至 5 岁婴幼儿和儿童，暂未获批成人适应证）。3.接种建议（1）建议接种：65岁以上风湿免疫病患者和18岁以上接受免疫抑制治疗的风湿免疫病患者均建议接种肺炎球菌疫苗，免疫程序按照疫苗说明书执行。免疫抑制患者建议在免疫抑制治疗开始前2~4周接种，并在5年后加强接种1剂PPV23。（2）建议调整接种或用药时机：① 使用抗CD20单抗治疗的患者，建议在下一剂抗CD20单抗使用前至少2周接种疫苗。②接种时糖皮质激素建议小于20 mg/d泼尼松等效剂量，低于10 mg/d更优。③接受生物制剂如肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素12/23抑制剂和白细胞介素17抑制剂治疗的患者，无须停止药物。④鉴于不良事件的潜在风险，肺炎球菌疫苗在隐热蛋白相关周期性综合征（cryopyrin-associated periodic syndromes，CAPS）患者中的接种应谨慎考虑。三、新冠病毒疫苗1.概述新冠病毒感染导致的新冠病毒病造成了全球大流行，病毒变异也对现有的预防接种策略提出了新的挑战。风湿免疫性疾病患者感染新冠病毒的风险和感染后呼吸衰竭的风险高于健康人群［23］，新冠病毒和其他常见病毒如流感病毒相互叠加可增加患者重症和死亡的风险［24］，部分抗风湿药物的使用可能和患者感染新冠病毒后的疾病严重程度相关［25］。因此，患者接种新冠病毒疫苗十分必要，尤其在新冠病毒感染的高危地区。建议病情稳定的风湿免疫性疾病患者在专科医生指导和监测下接种新冠病毒疫苗［26,27］。糖皮质激素和免疫抑制剂会影响疫苗的免疫原性和免疫应答，因此调整接种时机，可以达到更好的保护效力。对接种两剂 mRNA 疫苗后血清转化率的研究显示，在使用羟氯喹、肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素12/23抑制剂和白细胞介素17抑制剂的患者中，mRNA疫苗的应答良好；抗CD20单抗和阿巴西普治疗显著影响疫苗血清转化率；糖皮质激素、羟氯喹、来氟米特、JAK抑制剂、吗替麦考酚酯则轻度影响血清转化率［28］。中国的一项研究也显示，风湿免疫性疾病患者接受灭活疫苗接种后，其中和抗体滴度低于健康人群，这一结果与患者滤泡状T辅助细胞减少有关，加强接种可以提高患者中和抗体滴度［29］。泰国一项对于系统性红斑狼疮人群的研究显示，接种两剂灭活疫苗后，采用mRNA疫苗或者腺病毒载体疫苗加强接种，具有良好的安全性，并可以提高疫苗诱导的保护性应答［30］。中国新冠病毒疫苗的临床研究和使用经验在不断积累，临床证据逐渐增多，对疫苗有效性和安全性的认识也将进一步增加。对患者基础免疫状态的评估和接种时机选择有助于改善疫苗接种后的免疫应答水平。2.中国目前应用的疫苗类型灭活疫苗、重组蛋白疫苗、腺病毒载体疫苗、mRNA疫苗。3.接种建议（1）建议接种：所有患者可接种病毒灭活疫苗、重组蛋白疫苗和mRNA疫苗，免疫程序按照疫苗说明书执行，全程接种。完成常规基础免疫系列接种后，根据中国疾控中心推荐进行加强接种。（2）建议调整接种或用药时机：①使用抗CD20单抗治疗的患者，建议在下一个疗程抗CD20单抗治疗使用前至少2周接种疫苗。②接种时糖皮质激素建议小于20 mg/d泼尼松等效剂量，低于10 mg/d更优。③使用环磷酰胺治疗的患者，建议在注射前1~2周接种疫苗。④使用非甾体抗炎药的患者，建议接种前停药24 h。⑤使用其他免疫抑制剂的患者，如病情许可，建议接种前后停药1~2周。如不能实现，建议在给药间隔接种。⑥使用羟氯喹和静脉用免疫球蛋白的患者，无须调整接种时机。⑦新冠病毒感染史的患者建议相隔3~6个月后接种疫苗。（3）有以下情况谨慎接种：①快速进展性肺部病变病史的炎症性肌病患者；②抗磷脂综合征患者；③既往出现动静脉血栓、血栓性微血管病、毛细血管渗漏综合征、脑脊髓炎、噬血细胞综合征、多系统炎症综合征的患者，建议在医生指导下谨慎接种。④抗凝治疗不是新冠疫苗接种的禁忌证。（4）接种后监测：风湿免疫性疾病患者接种前后建议检查自身抗体等血清学相关指标，如存在无法缓解的不适，立即至专科医生处诊治。四、带状疱疹疫苗1.概述带状疱疹（herpes zoster，HZ）是常见的病毒感染性疾病，50岁以上人群及免疫低下人群相对易感。几乎所有成人均感染过水痘-带状疱疹病毒［31］，约9%~34%带状疱疹患者会发生带状疱疹后神经痛（postherpetic neuralgia，PHN）［32］。风湿免疫性疾病患者带状疱疹的发病风险明显高于正常人群，T细胞介导的应答与未来带状疱疹的发生风险更为相关［33］。PHN是最重要的并发症，严重影响患者的生活质量。同时，带状疱疹再激活可能诱导风湿免疫性疾病活动或者复发［34］。ACR推荐风湿免疫性疾病患者中的高危人群如接受免疫抑制治疗的患者或者50岁以上患者接种带状疱疹疫苗［2］。2022年美国对于50岁以上炎症性关节病、系统性红斑狼疮和炎症性肠病患者的研究显示，接种重组带状疱疹疫苗与疾病复发无关［35］。糖皮质激素和免疫抑制剂会影响疫苗的免疫原性和免疫应答，可以通过调整接种时机，达到更好的保护效力。2.中国应用的疫苗类型重组蛋白疫苗（50周岁及以上人群，扩大年龄范围和特殊人群接种的研究正在进行中）；减毒活疫苗（40周岁及以上人群）。3.接种建议（1）建议接种：①50岁以上患者（可以在应用糖皮质激素和免疫抑制剂的情况下）全程接种重组蛋白疫苗。免疫程序按照疫苗说明书执行；②带状疱疹再激活的患者急性期发作3个月后可以接种，有助于预防PHN；③小分子靶向药JAK抑制剂使用前建议接种带状疱疹疫苗；④如疫苗适应人群扩龄，建议接受免疫抑制治疗的18岁以上患者接种重组蛋白疫苗。（2）建议调整接种或用药时机：①带状疱疹急性发作期暂缓接种。②使用抗CD20单抗治疗的患者，建议在下一剂抗CD20单抗使用前至少2周接种疫苗。③如在小分子靶向药JAK抑制剂使用前接种带状疱疹疫苗，建议2剂接种后至少间隔2周再给予JAK抑制剂治疗；如在JAK抑制剂使用中，建议每剂接种前后停用JAK抑制剂1~2周。④使用大多数免疫抑制剂的患者，如病情许可，建议接种前后停药1~2周。⑤接种时糖皮质激素建议小于20 mg/d泼尼松等效剂量，低于10 mg/d更优。五、人乳头瘤病毒疫苗1.概述风湿免疫性疾病患者是HPV感染和宫颈癌的高危人群［36］。HPV主要通过性生活或密切接触传播，90%以上HPV感染在2年内自然清除。高危型HPV持续性感染是子宫颈癌发生的必要条件。WHO将HPV 16/18/31/33/35/39/45/51/52/56/58/59/68定义为高危型，HPV 26/53/66/73/82为中危型，其中HPV 16/18诱发癌变的风险最高［37］。中国流行的前10位HPV为 16/58/52/18/33/31/55/68/53/45，感染高峰在20~24岁和45~55岁［38］。HPV疫苗接种是预防HPV感染和相关肿瘤等疾病的有效途径。无论是否存在HPV感染或细胞学异常，对适龄女性均推荐接种HPV疫苗，且接种之前无须常规进行细胞学及HPV检测［39］。由于男性患者也普遍存在HPV感染，ACR指南也推荐男性患者参照一般人群的建议接种。2015年的一项系统综述表明，在绝大多数风湿免疫性疾病患者中，HPV疫苗接种安全有效［40］。4价HPV疫苗在疾病稳定期的系统性红斑狼疮患者中显示出良好的安全性和有效性。在9~20岁的系统性红斑狼疮患者中，接受3剂次免疫的患者，其 HPV16和HPV18的血清学阳性率更高［41,42］。研究也表明，幼年特发性关节炎女性患者接种2价HPV疫苗安全性和耐受性良好，但抗体应答有所减弱［43］。2.中国应用的疫苗类型重组蛋白疫苗。3.接种建议（1）建议接种：年龄18~45岁患者尤其是系统性红斑狼疮患者，均建议接种HPV疫苗。可选择2价、4价和9价HPV重组蛋白疫苗，接种年龄和程序按照疫苗说明书执行，全程接种。（2）建议调整接种或用药时机：使用抗CD20单抗治疗的患者，建议在下一剂抗CD20单抗使用前至少2周接种首剂疫苗。（3）免疫抑制剂的影响：由于疫苗接种周期较长，可以在使用糖皮质激素和免疫抑制药物的情况下接种。①甲氨蝶呤和肿瘤坏死因子抑制剂不影响免疫后的血清转换率（抗体滴度增加超过4倍）；②吗替麦考酚酯和小剂量糖皮质激素对HPV16和HPV18的血清转换率有轻度影响。（4）有以下情况慎重接种：既往表现为吉兰-巴雷综合征和脑脊髓炎的患者。六、乙型肝炎疫苗1.概述免疫抑制剂可能造成风湿免疫性疾病患者乙型肝炎病毒（hepatitis B virus，HBV）易感或再激活［44,45,46］，诱发肝脏损伤甚至爆发性肝衰竭［47］，尤其是在应用肿瘤坏死因子单抗或B细胞靶向治疗的患者中［48,49］，白细胞介素12/23的抑制剂也存在潜伏HBV再激活的风险 ［50］。此外，HBV感染会增加患者罹患肝脏恶性肿瘤的风险［51］。因此，在接受免疫抑制剂治疗的患者中，建议筛查HBV，必要时进行预防性抗病毒治疗［46,52］。荟萃分析显示，乙型肝炎疫苗接种与自身免疫性疾病的发病没有相关性[53]，风湿免疫性疾病患者接种的安全性良好[44,47,54,55,56]。接种后血清乙型肝炎表面抗体（简称“抗HBsAb”）达到10 IU/L时，可以预防HBV感染［2,44］。免疫抑制剂可能影响部分人群疫苗应答的效果［44］。肿瘤坏死因子抑制剂和白介素12/23抑制剂减弱HBV疫苗的应答。与肿瘤坏死因子受体可溶性蛋白相比，肿瘤坏死因子单克隆抗体对抗HBsAb保护性抗体水平的影响更大［13］。2.中国应用的疫苗类型重组蛋白疫苗。3.接种建议（1）建议接种：建议未感染乙肝病毒并且未检测到血清保护性抗HBsAb的所有患者接种：①免疫程序按照疫苗说明书执行，全程接种。②如果接种益处高于风险，活动期患者在风湿免疫专科医生评估和监测下可以接种。③存在免疫性疾病神经系统累及、结节性多动脉炎病史的患者，在权衡利弊和充分告知后可以接种。（2）建议调整接种或用药时机：①使用抗CD20单抗治疗的患者，建议在下一剂抗CD20单抗使用前至少2周接种疫苗。②接种时糖皮质激素建议小于20 mg/d泼尼松等效剂量，低于10 mg/d更优。③建议使用肿瘤坏死因子抑制剂之前2~4周接种乙型肝炎疫苗。④使用大多数免疫抑制剂的患者，如病情许可，建议接种前后停药1~2周或者在用药间隔接种。（3）接种后监测：抗HBsAb与HBV的血清学保护密切相关。建议患者在全程接种疫苗后4~6周检测血清抗HBsAb浓度（达到10 IU/L以上）。如果疫苗接种后抗HBsAb阴性或未达到有效浓度的患者在疾病稳定期（可以在应用糖皮质激素和免疫抑制剂的情况下），推荐重复全程接种乙型肝炎疫苗或加强免疫。七、甲型肝炎疫苗1.概述风湿免疫性疾病患者可存在免疫机制导致的肝脏功能异常或者自身免疫性肝病，比如原发性胆汁性胆管炎和自身免疫性肝炎。甲型肝炎病毒（hepatitis A virus，HAV）感染可能是引起自身免疫性肝炎的诱因之一［57,58］，可加重免疫性肝病患者的肝功能恶化［57］；HAV感染可以引起自身免疫性溶血性贫血［57］，甚至有诱发风湿免疫性疾病患者噬血细胞综合征的风险［60］。HAV灭活疫苗在风湿免疫性疾病患者中的免疫原性与健康对照人群类似[47,60,61,62]，疫苗耐受性和安全性良好［47,60,61,62,63］。接种后，有报道少数病例发生异常免疫应答造成疾病状态，糖皮质激素单药或者联合免疫抑制剂治疗有效［62］。2.中国应用的疫苗类型灭活疫苗、减毒活疫苗。3.接种建议（1）建议接种：建议所有未曾感染甲肝病毒的患者接种灭活疫苗，可以在应用糖皮质激素和免疫抑制剂情况下接种。免疫程序按照疫苗说明书执行，全程接种。（2）建议调整接种或用药时机：① 使用抗CD20单抗治疗的患者，建议在下一剂抗CD20单抗使用前至少2周接种疫苗。② 接种时糖皮质激素建议小于20 mg/d泼尼松等效剂量，低于10 mg/d更优。③ 使用其他免疫抑制剂的患者，如病情许可，建议接种前后停药1~2周或者在用药间隔接种。八、人用狂犬病疫苗1.概述狂犬病是狂犬病毒所致的动物源性人畜共患急性传染病，病死率极高。狂犬病疫苗可用于可能接触病毒的高危人群暴露前预防或狂犬病毒暴露后处置。2.中国应用的疫苗类型灭活疫苗。3.接种建议（1）免疫程序按照疫苗说明书执行，全程免疫。（2）接种策略：①暴露后接种无绝对禁忌证：被狂犬或其他动物咬伤、抓伤，立即用一定压力的流动清水和肥皂水（或其他弱碱性清洗剂）交替清洗并使用稀碘伏、苯扎氯铵或其他具有病毒灭活效力的皮肤黏膜消毒剂消毒伤口，按照暴露后免疫程序接种本疫苗。使用免疫抑制剂的患者建议尽早使用狂犬病被动免疫制剂。②暴露前接种：有接触狂犬病毒风险的人员，如长期旅行、预期会大量接触动物的个人，按照暴露前免疫程序接种本疫苗。风湿免疫性疾病活动期，存在未控制的癫痫、神经精神疾患、严重慢性疾病、感染、使用免疫抑制剂等患者暂缓接种。4.接种后监测（1）建议末次接种疫苗后7~14 d检测中和抗体滴度。（2）曾有接种后出现反应性关节炎、过敏性紫癜、大疱性类天疱疮、多发性一过性白点综合征、吉兰-巴雷综合征、急性横贯性脊髓炎等的报道，如有不适症状，建议及时专科就诊。结语由于风湿免疫病患者免疫状态的个体性、抗风湿药物治疗方案的复杂性和疫苗免疫原性评估研究的多样性，疫苗接种高质量的循证医学证据有限。本共识结合现有临床证据、国际同类指南和共识以及国内真实世界疫苗接种的实践经验，针对8种疫苗给出了推荐意见，见表1。表1风湿免疫性疾病患者常用疫苗接种建议要点a注：a.推荐疾病稳定期接种；使用小剂量糖皮质激素（相当于泼尼松剂量≤10 mg/d），无须调整药物；如无说明，使用生物制剂如肿瘤坏死因子抑制剂、白细胞介素6抑制剂、白细胞介素12/23和白细胞介素17抑制剂的患者无须调整药物；羟氯喹、柳氮磺吡啶、秋水仙碱、阿普斯特、地舒单抗、静脉用人免疫球蛋白不属于免疫抑制剂；b糖皮质激素建议日剂量小于20 mg/d泼尼松等效剂量，低于10 mg/d更优本共识力求推动中国成人风湿免疫性疾病患者规范化的疫苗接种和感染防治，今后将依据国际国内临床研究和临床实践进行及时更新。参考文献[1]Bass AR , Chakravarty E , Akl EA ,et al. 2022 American college of rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases[J]. Arthritis Care Res (Hoboken), 2023,75(3):449-464. DOI: 10.1002/acr.25045.[2]Furer V , Rondaan C , Heijstek MW ,et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases[J]. Ann Rheum Dis, 2020,79(1):39-52. DOI: 10.1136/annrheumdis-2019-215882[3]Danza A , Ruiz-Irastorza G . Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies[J]. Lupus, 2013,22(12):1286-1294. DOI: 10.1177/0961203313493032.[4]Weaver A , Troum O , Hooper M ,et al. Rheumatoid arthritis disease activity and disability affect the risk of serious infection events in RADIUS 1[J]. J Rheumatol, 2013,40(8):1275-1281. DOI: 10.3899/jrheum.121288.[5]李佳,吕良敬. 靶向治疗时代议自身免疫病的感染挑战[J]. 诊[6]Md Yusof MY , Vital EM , McElvenny DM ,et al. Predicting severe infection and effects of hypogammaglobulinemia during therapy with rituximab in rheumatic and musculoskeletal diseases[J]. Arthritis Rheumatol, 2019,71(11):1812-1823. 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