Zoster vaccine recombinant, adjuvanted(GlaxoSmithKline Plc)

你的父母是否提起过，他们曾每夜痛得睡不着觉？ 你的爷爷奶奶是否告诉过你，他们曾被“蛇缠腰”长期困扰？ “辛勤打工人”的你，会不会已经得过“带状疱疹”？  被人称为“不死的癌症”带来的“会呼吸的痛”，真的是“痛不欲生”，只有痛过的人才懂。 今天我们就来了解一下这种令不少人望而生畏的疾病！ 据报道，全球普通人群带状疱疹的发病率为（3～5）/1000人年，亚太地区为（3～10）/1000人年，并逐年递增2.5%～5.0%。 全球带状疱疹的住院率为（2～25）/10万人年，死亡率为（0.017～0.465）/10万人年，复发率1%～ 10%。 我国≥50岁人群带状疱疹发病率为（2.9～5.8）/1 000人年，女性终身患病率（3.94%～7.9%）略高于男性（2.86% ～7.6%）[1]。 一. 什么是带状疱疹？ 带状疱疹（herpes zoster）是由长期潜伏在脊髓后根神经节或颅神经节内的水痘-带状疱疹病毒（varicella-zoster virus，VZV）经再激活引起的感染性皮肤病。 带状疱疹是皮肤科常见病，除皮肤损害外，常伴有神经病理性疼痛，多见于年龄较大、免疫抑制或免疫缺陷等人群，严重影响患者生活质量。 二. 病因及发病机制 1.病原体特点及致病机制： VZV可经飞沫和（或）接触传播，原发感染主要引起水痘。当机体抵抗力降低时，潜伏的病毒被再激活引起带状疱疹。 2.带状疱疹相关性疼痛的机制： 带状疱疹后神经痛（PHN）属于典型的神经病理性疼痛。 外周机制：受损的伤害性感受器异常放电导致外周敏化。 中枢机制： ①脊髓背角神经元的敏感性增高； ②脊髓抑制性神经元的功能下降； ③脊髓背角Aβ纤维脱髓鞘，与邻近C纤维形成新的突触； ④脊髓背角伤害性神经通路代偿性形成，使中枢对疼痛的反应阈值大大降低。 三. 带状疱疹的临床表现 1.典型临床表现 ①前驱症状：可有轻度乏力、低热、食欲不振等全身症状，患处皮肤自觉灼热感或神经痛，触之有明显的痛觉敏感，也可无前驱症状。 ②皮损特点：典型皮损表现为沿皮节单侧分布的成簇性水疱伴疼痛，研究显示好发部位为肋间神经（53%）、颈神经（20%）、三叉神经（15%）及腰骶部神经（11%）相应的皮节。 皮损沿某一周围神经区域呈带状排列，多发生在身体的一侧，一般不超过正中线。病程一般2～3周，老年人为3～4周。水疱干涸、结痂脱落后留有暂时性淡红斑或色素沉着[2]。 ③自觉症状：疼痛为带状疱疹的主要症状，又称为疱疹相关性疼痛（ZAP），慢性期ZAP即PHN：出现皮疹后持续超过90 d的疼痛。 老年、体弱患者疼痛较为剧烈。除疼痛外，部分患者还会出现瘙痒。重度瘙痒会因患者不断搔抓继发皮肤苔藓样变。 2.特殊临床类型 ①眼带状疱疹：多见于老年人，表现为单侧眼睑肿胀，也可表现为双侧；结膜充血，疼痛常较为剧烈，常伴同侧头部疼痛，可累及角膜形成溃疡性角膜炎。 ②耳带状疱疹：系病毒侵犯面神经及听神经所致，表现为外耳道疱疹及外耳道疼痛。 ③顿挫型带状疱疹：仅出现红斑、丘疹而不发生水疱。 ④无疹型带状疱疹：仅有皮区疼痛而无皮疹。 ⑤复发型带状疱疹：指非首次发生的带状疱疹，其在免疫正常人群中较为罕见，在免疫受抑者中复发率更高。 ⑥中枢神经系统带状疱疹：侵犯大脑实质和脑膜时，发生病毒性脑炎和脑膜炎。 ⑦内脏带状疱疹：侵犯内脏神经纤维时，引起急性胃肠炎、膀胱炎，表现为腹部绞痛、排尿困难、尿潴留等。 ⑧泛发型带状疱疹：指同时累及2个及以上神经节，对侧或同侧多个皮节产生皮损。 ⑨播散型带状疱疹：恶性肿瘤或免疫功能极度低下者，病毒经血液播散，导致除受累皮节外全身皮肤出现广泛性水痘样疹，常伴高热等全身中毒症状。 3.并发症 PHN为带状疱疹最常见的并发症。带状疱疹患者PHN发生率为5%～30%，多见于高龄、免疫功能低下患者。其疼痛部位通常比疱疹区域有所扩大，常见于单侧肋间神经、三叉神经（主要是眼支）或颈神经。 疼痛性质多样，可为烧灼样、电击样、刀割样、针刺样或撕裂样。一种疼痛为主，或多种疼痛并存。30%～50%的患者疼痛持续超过1年，部分病程可达10年或更长。 四. 带状疱疹的治疗 带状疱疹的治疗目标包括促进皮损消退，缓解疼痛，改善患者生活质量。及时进行针对性抗病毒治疗有助于皮损及时愈合，且可能缩短ZAP持续时间。  1.系统药物治疗 ①抗病毒药物：是临床治疗带状疱疹的常用药物。目前批准使用的系统抗病毒药物包括阿昔洛韦、伐昔洛韦、泛昔洛韦、溴夫定和膦甲酸钠。这些药物的用法用量及不良反应见下表。 ②镇痛治疗：疼痛常贯穿带状疱疹疾病的全过程，建议对不同程度的疼痛选用不同的镇痛药物。 轻中度疼痛可选用对乙酰氨基酚、非甾体类抗炎药或曲马多；中重度疼痛可使用治疗神经病理性疼痛的药物，如钙离子通道调节剂加巴喷丁、普瑞巴林，三环类抗抑郁药如阿米替林。带状疱疹后神经痛一线治疗药物见下表。 ③糖皮质激素疗法：目前关于是否系统应用糖皮质激素治疗带状疱疹及PHN仍存在争议。 既往观点认为在带状疱疹急性发作3 d内系统应用糖皮质激素可以抑制炎症过程，缩短急性疼痛的持续时间和皮损愈合时间，但目前最新的欧洲及德国指南均未推荐系统应用糖皮质激素治疗。 ④特殊人群的治疗： 肾功能不全：肾功能不全或持续下降者，初始给药前应检测血肌酐水平并根据肌酐值调整剂量及给药间隔，使用溴夫定则无需检测血肌酐水平。 VZV所致的脑膜炎/脑炎：美国感染病学会指南推荐阿昔洛韦治疗本病，轻中度病例静脉滴注10mg/kg每8 h 1次，连续治疗10～14d，而严重病例应持续治疗14～21d。 免疫功能低下患者：主要包括HIV/AIDS、恶性肿瘤、器官移植、干细胞移植患者和长期接受免疫抑制剂治疗患者等，无论是局限型还是播散型带状疱疹，均推荐静脉滴注阿昔洛韦8～10 mg/kg每8 h 1次，疗程7～10 d，根据病情需要可延长至10～14 d。 儿童：带状疱疹发病率较成年人低，且病情较成人轻，可口服阿昔洛韦20mg/kg每日4次；或慎重给予泛昔洛韦口服，体重＜40kg者12.5mg/kg每8h 1次，体重≥ 40 kg者250～500 mg每8h 1次。重症患者可静脉滴注阿昔洛韦≤ 500 mg/m2或≤ 15mg/kg每8h1次。 妊娠、哺乳期：妊娠晚期患者可口服阿昔洛韦或伐昔洛韦，严重者静脉滴注阿昔洛韦，但妊娠20周前应慎用。哺乳期口服阿昔洛韦未见乳儿异常，但口服泛昔洛韦需停止哺乳。 老年人：易出现皮肤、内脏播散及其他并发症，宜采用溴夫定抗病毒药物积极治疗。 2.局部治疗 ①物理治疗：物理治疗带状疱疹目前尚缺乏高质量研究报告。国内一项小型前瞻性研究显示，局部单纯外用阿昔洛韦乳膏等联合半导体激光治疗带状疱疹的疗效明显优于单纯外用阿昔洛韦乳膏等。 ②外用治疗药物：以干燥、消炎、防止继发感染为主。 五. 带状疱疹的预防 1. 一般措施 带状疱疹患者应采取接触隔离措施，水痘和免疫功能低下的播散性带状疱疹患者还应采取呼吸道隔离措施直至皮损全部结痂。 2.接种疫苗 接种带状疱疹疫苗是预防带状疱疹的有效措施。带状疱疹疫苗接种的目标是抑制VZV再激活从而预防带状疱疹、PHN和其他并发症。 目前，全球上市的带状疱疹疫苗主要包括减毒活疫苗（ZVL）和重组亚单位疫苗（RZV）两种。2020年6月，RZV在我国正式上市，推荐用于50岁及以上免疫功能正常的人群接种以预防带状疱疹。 有关RZV接种后10年随访研究发现，体液免疫水平是接种前的6.0倍，细胞免疫水平是接种前的3.5倍。对疫苗成分过敏或以前接种同类疫苗时出现严重过敏者为疫苗接种禁忌。 对正在发热者、患急性疾病者、慢性疾病的急性发作期患者建议暂缓接种，待恢复或病情稳定后接种。RZV在我国为非免疫规划疫苗，常见不良反应为接种部位疼痛、疲劳、寒战、发热等反应，建议接种前充分告知，知情同意后自愿接种[3]。 六. 带状疱疹疫苗的种类 1.带状疱疹减毒活疫苗 接种对象：适用于40岁及以上成人。 免疫程序及剂量：于上臂外侧三角肌下缘附着处皮下注射0.5ml，共1剂。 保护效力：40～49岁人群37.41%，50～59岁人群62.72%，60～69岁人群64.43%，≥70岁人群18.63%。 注意事项： ①急性感染、慢性感染急性期应推迟接种本品。 ②育龄妇女接种后应至少6个月内避免怀孕。 ③与其它注射类减毒活疫苗如果未同时接种，应至少间隔28天。 ④接种前5个月内或接种3周内给以全血、血浆或免疫球蛋白，可能会降低效果。 2.重组带状疱疹疫苗（CHO细胞） 接种对象：适用于50岁及以上成人 免疫程序及剂量：首选接种部位为上臂三角肌，每剂0.5ml，共2剂。第2剂与第1剂间隔2个月接种，如需改变免疫程序，第2剂在第1剂后2～6个月之间接种。 保护效力：50～59岁人群96.6%，60～69岁人群97.4%，70～79岁人群91.3%，≥80岁人群91.4%。 注意事项： ①患有急性严重发热疾病的受种者应推迟接种该疫苗，若仅为感冒等轻微感染，则无需推迟接种。 ②血小板减少症患者或者任何凝血功能紊乱患者应慎重选择接种该疫苗。 ③免疫抑制人群接种后可能无法产生足够的免疫应答。 ④接种带状疱疹疫苗2-3天内，可能轻微影响驾驶和操作机器能力，接种后可能会发生疲乏与不适。 七. 得过带状疱疹还可以接种带状疱疹疫苗吗？ 可以。带状疱疹有一定的复发率，所以得了带状疱疹以后接种疫苗仍具有预防作用。如果带状疱疹正在发作，需等带状疱疹急性期结束并且症状消失后才能接种疫苗。 八. 接种完带状疱疹疫苗，还会患带状疱疹吗？ 虽然部分人在接种疫苗后仍会患上带状疱疹，但疫苗可降低严重程度和持续时间，也可以降低出现带状疱疹后神经痛的风险。 一项III期多中心临床试验评估了重组带状疱疹疫苗的疗效，该试验招募了超过3万名参与者，他们按1:1的比例随机接受疫苗或盐水安慰剂。 中位随访时间为3.2～3.7年。50～59岁的人预防带状疱疹的疗效为96.6%，60～69岁的人为97.4%。在年龄≥50岁的成年人中，预防带状疱疹后神经痛的疗效为91.2%，在年龄≥70岁的人中为88.8%。 国外一项使用减毒活疫苗针对50～59岁人群的随机临床试验发现，疗效为70%（中位随访时间为1.3年）。一项针对≥60岁人群的随机试验发现，60～69岁人群的疗效为64%，≥70岁人群为38%（中位随访时间为3.1年）。 国内减毒活疫苗的Ⅲ期试验显示，对50岁以上人群的保护效力为58.7%（平均随访396天）[4]。 九. 患有基础疾病的人群是否可以接种带状疱疹疫苗呢？ 患有基础疾病并不是接种带状疱疹疫苗的禁忌症。建议结合自身实际情况，权衡接种带状疱疹疫苗的潜在获益和风险后决定是否接种。 根据带状疱疹疫苗说明书、临床试验等资料：安全性方面，针对患有基础疾病（高血压、糖尿病、哮喘、呼吸系统疾病、各种肾脏疾病、骨关节炎和/或脊椎疾病等）的人群，带状疱疹疫苗接种与安慰剂受种者之间发生严重不良反应、潜在的免疫介导疾病和死亡的发生率是均衡的。 有效性方面，带状疱疹疫苗对患有常见疾病（冠状动脉疾病、糖尿病、哮喘、慢性阻塞性肺疾病、抑郁或慢性肾病）并确诊为带状疱疹的患者的保护效力与总体预防带状疱疹保护效力相一致。 总的来说，对于这类朋友以及正在服用相关药物者（如降压药、降血糖药、降血脂药等）是可以接种的。但对于存在基础免疫缺陷者（患有白血病、淋巴瘤、移植人群）和接受免疫抑制治疗者（使用生物制剂、中高剂量泼尼松等皮质类固醇药物及化疗药物等）是不推荐接种疫苗的[5]。 十. 马上进入流感高发季了，带状疱疹可以和流感疫苗、肺炎疫苗一起接种吗？ 根据ACIP的指南，带状疱疹疫苗和流感疫苗是可以同一天接种的，只要是不同的部位就可以了。根据CDC的推荐，带状疱疹疫苗还可以和肺炎球菌疫苗一起接种。 中国人口老龄化形势日益严峻，据测算，预计“十四五”时期，60岁及以上老年人口总量将突破2亿，占比将超过20%[6]。 随着年龄的增长，老年人的生理代谢功能和免疫机能逐渐衰老逐渐衰退，罹患带状疱疹这样的感染性疾病风险显著增加，严重影响老年人的生活质量。 带状疱疹的防治已成为中国非常重要的公共卫生问题[6]。带状疱疹的治疗，尚无特效药物，而预防接种疫苗是控制感染性疾病成为了最有效、最简单、最经济的手段。 “家有一老，如有一宝”，希望我们的父母在带状疱疹疫苗的保护下尽享天伦之乐！ 参考资料 [1] 《中国带状疱疹诊疗专家共识（2022版）》 [2]中国医疗保健国际交流促进会皮肤科分会,等.带状疱疹疫苗预防接种专家共识[J].中华医学杂志,2022, 102(8):538-543. [3]Schmader KE, Levin MJ, Gnann JW Jr, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years. Clin Infect Dis 2012;54:922–8. [4]中疾控周报Meiying You, Tianqi Wang, Miaomiao Wang, Wei Jiang, Jing Jiang, Xudong Li, Yuehua Hu, Dapeng Yin. Identifying the Optimal Age for Herpes Zoster Vaccination — Yichang City, Hubei Province, China, 2017–2019[J]. China CDC Weekly, 2022, 4(29): 631-634. doi: 10.46234/ccdcw2022.137 [5]邓慧杰,刘芳勋.我国带状疱疹流行病学特征及疫苗免疫规划研究进展[J].中国继续医学教育,2021,13(19):135-138. [6]冯录召，杨涛，王晴，等.科学接种疫苗 降低感染性疾病风险护卫老年健康[J].中华医学杂志,2020,100(48):3821-3826. DOI：10.3760/cma.j.cn112137-20201020-02882 [7]疫苗说明书 识别微信二维码，可添加药时空小编 请注明：姓名+研究方向！

-- One year after the second vaccine dose, the anti-gE antibody immune response to amezosvatein continues to be non-inferior to Shingrix Jan. 12, 2025 -- Curevo Vaccine (Curevo), a privately-held clinical-stage biotechnology company dedicated to developing varicella zoster virus (VZV) vaccines with improved tolerability and accessibility, today announced positive updated immunogenicity and safety data from its 876-patient Phase 2 trial of amezosvatein (a non-mRNA, adjuvanted subunit vaccine also known as CRV-101) head-to-head versus Shingrix® in participants aged 50 years and older. At Day 421, one year after the second vaccine dose, anti-gE antibody levels for participants aged 50-69 randomized to receive the 100 μg gE antigen plus 15 μg SLA-SE adjuvant dose of amezosvatein remained non-inferior to Shingrix. Between Day 84 (one month after the second vaccine dose) and Day 421, anti-gE antibody geometric mean concentrations (GMC) declined for both amezosvatein (69.0%, n=49) and Shingrix (69.6%, n=184). In the 50-59 age group, the decline was 69.6% for both vaccines. For the 60-69 age group, the decline in anti-gE GMC antibodies was 68.4% for those receiving amezosvatein (n=25) and 69.7% for those receiving Shingrix (n=79). Declines in anti-gE antibody levels in this time frame are expected and were similar in magnitude to those seen in Shingrix’s Phase 3 trials, where Shingrix demonstrated vaccine efficacy of over 90% after three years and around 80% after 10 years. 1,2,3 In a post-hoc analysis after mean follow-up of 18.8 months in this Phase 2 trial, confirmed herpes zoster (shingles) cases were analyzed. Based on the shingles incidence rate from the placebo arm North American cohort of ZOSTER-006, a Phase 3 trial of Shingrix, 10 of the 876 participants in the Phase 2 trial should have been diagnosed with a confirmed shingles case absent effective vaccination.1 There were no confirmed shingles cases in the highest antigen dose (100 μg) arms studied for amezosvatein, including the 100/15 arm with Day 421 data reported above, and no confirmed shingles cases in the Shingrix arm. There was one confirmed case of shingles in the lowest antigen and adjuvant dose studied of amezosvatein (50 μg gE antigen plus 5 μg SLA-SE adjuvant). This 50/5 dose of amezosvatein used in Part A of the Phase 2 trial was previously determined to be immunologically inferior to Shingrix as measured by anti-gE antibody GMC and was discontinued for Part B. “The Day 421 Phase 2 data continue to support our view amezosvatein has a comparable effect on the human immune system as Shingrix,” said Dr. Guy De La Rosa, Curevo’s Chief Medical Officer. “Amezosvatein’s non-inferior immunogenicity data and comparable herpes zoster case data, combined with amezosvatein’s improved tolerability versus Shingrix in this Phase 2 trial we reported this time last year, provide us with great confidence and excitement to continue development of this vaccine.” “Shingrix is the only premium-priced, large-population vaccine without current effective competition. This is in a market expected to be worth over $5 billion in 2025,” noted George Simeon, Curevo’s Chief Executive Officer. “Past experience shows a comparable vaccine entering a market tends to split share with the incumbent vaccine. However, history also shows vaccines with better tolerability, like amezosvatein has demonstrated compared to Shingrix in our Phase 2 trial, can capture dominant market share.” The Phase 2 trial (NCT05304351) enrolled 876 participants to receive either amezosvatein or Shingrix on an identical two-dose, two months apart schedule. 876 participants were randomized to receive one of four different amezosvatein doses or Shingrix. The mean follow-up of the 619 participants receiving amezosvatein was 18.8 months. Mean follow-up of the 257 participants who received Shingrix was 21.5 months. The co-primary endpoints of the trial were anti-gE antibody humoral immune responses one month after the second vaccine dose (Day 84) and safety/reactogenicity. The randomized, observer-blind, and active-controlled trial was conducted at multiple centers in the USA. All suspected cases of shingles were confirmed by either PCR test or, if PCR testing was inconclusive or unavailable, by a blinded panel of shingles experts – a system similar to one used in multiple prior shingles vaccine pivotal studies. Day 421 measures were prospectively-defined secondary outcomes measures. Vaccines are studied for both safety and reactogenicity/tolerability. Data on the reactogenicity/tolerability of amezosvatein and Shingrix were collected via a participant diary filled out for the seven days after each injection. Participants were asked to grade the tolerability of each vaccine on a scale of Grade 1 to Grade 3. Grade 1 represents what are considered normal reactions to an active vaccine that do not interfere or prevent daily activity. Grade 2 represents reactogenicity events interfering with daily activities. Grade 3 represents reactogenicity events preventing daily activities. As previously reported, the 100/15 dose of amezosvatein demonstrated a clinically-meaningful and statistically-significant improvement for Grade 2 and Grade 3 reactogenicity versus Shingrix. Just 7.3% of participants in the trial receiving the highest dose of amezosvatein (n=55) reported a Grade 2 (interferes with daily activity) or Grade 3 (prevents daily activity) reactogenicity event compared to 33.3% of participants receiving Shingrix (n=225). Amezosvatein’s advantage over Shingrix was statistically significant (ppost hoc analysis unadjusted for multiple comparisons) and consistent with both local and systemic reactions. Serious adverse events (SAEs), potentially immune-mediated adverse events (PIMMCs), and medically-attended adverse events (MAAEs) were comparable at Day 421 between amezosvatein (n=166 across all doses studied) and Shingrix (n=225). All amezosvatein SAEs were "not related"; All Shingrix SAEs were “not related” or “unlikely related”. Amezosvatein had no PIMMCs reported. Shingrix had one PIMMC reported (polymyalgia rheumatica). All amezosvatein MAAEs were considered “not related” or “unlikely related”, except one event of non-shingles bilateral rash. One Shingrix participant reported four MAAEs as part of a constellation of symptoms considered “possibly related” (fatigue, myalgia, headache, migraine), and one additional Shingrix participant had presyncope (near fainting) considered “definitely related” with the investigator noting it was related to study procedure of blood collection. No deaths were reported in the amezosvatein arms. One unrelated death was reported in Shingrix arm (metastatic sarcoma & venous thrombosis). ‘Amezosvatein’ is the assigned non-proprietary name for CRV-101, a non-mRNA adjuvanted subunit vaccine under investigation by Curevo. Like Shingrix, amezosvatein uses a subunit protein antigen called glycoprotein ‘E’ (gE). Targeting the gE antigen is proven to elicit a long-term, protective immune response to prevent shingles. Also like Shingrix, amezosvatein uses an adjuvant targeting the TLR4 pathway to boost the immune response to the gE antigen. Amezosvatein was engineered to have a best-in-class safety profile in addition to manufacturing advantages to improve vaccine accessibility. The SLA-SE adjuvant formulation was developed at Seattle-based Access to Advanced Health Institute (AAHI) and amezosvatein was licensed from the Mogam Institute for Biomedical Research, a research institute funded by South Korea’s GC Biopharma. Also called ‘herpes zoster’, shingles occurs when the varicella zoster virus causing childhood chickenpox re-emerges from sensory ganglion nervous system cells where the virus lies dormant after initial exposure. Virtually all adults have been exposed to the varicella zoster virus and around 30% will develop shingles at least once in their lifetime. The blistering skin rash accompanying shingles also causes severe pain, with both pain and rash lasting up to four weeks. Between 10-18% of those who get shingles develop post-herpetic neuralgia (PHN), a condition marked by debilitating nerve pain lasting over six months and often beyond one year. There is no approved treatment for PHN. Shingles may also affect the eyes, potentially causing loss of vision. Contracting shingles has also been linked with increased risk of heart attack, stroke, and dementia/Alzheimer’s disease. Curevo is a privately held, clinical-stage biotechnology company based near Seattle dedicated to reducing the burden of infectious disease by developing vaccines with improved tolerability and accessibility. Curevo’s lead product is amezosvatein, a non-mRNA adjuvanted sub-unit vaccine to prevent shingles, a serious medical condition involving a painful, blistering skin rash where 10-18% of people also develop serious, long-lasting nerve pain. The current $5+ billion shingles vaccine market is characterized by accessibility issues and vaccine hesitancy/dose avoidance related to vaccine tolerability. Curevo is also developing a non-live, non-mRNA adjuvanted subunit chickenpox vaccine intended to reduce or eliminate barriers to immunizing immunocompromised children. For more information visit https://curevovaccine.com/. 1. Lal, et al. New England Journal of Medicine, May 2015. 2. Boutry, et al. Clinical Infectious Disease, April 2022 3. Diez-Domingo J, et al. Abstract presented at European Society of Clinical Microbiology and Infectious Diseases (ESCMID); 27–30 April 2024, Barcelona, Spain. The content above comes from the network. if any infringement, please contact us to modify.