Front Immunol:隐匿性乙型肝炎病毒感染者乙肝疫苗免疫应答的调查

2022-06-27 从医路漫漫 MedSci原创

OBI被定义为血清HBsAg阴性,乙型肝炎核心抗体(抗-HBc)阳性,ALT值正常,通常但不总是检测不到血清HBV DNA,但在肝脏中可检测到HBV共价闭合环状DNA(cccDNA)。

背景:全世界约有2.96亿乙型肝炎表面抗原(HBsAg)阳性的慢性乙型肝炎病毒感染(CHB)患者,每年约有820,000人死于HBV相关的肝硬化或/和HBV相关的肝细胞癌(HCC) 。根据欧洲肝脏研究协会(EASL)的最新指南,OBI被定义为血清HBsAg阴性,乙型肝炎核心抗体(抗-HBc)阳性,ALT值正常,通常但不总是检测不到血清HBV DNA,但在肝脏中可检测到HBV共价闭合环状DNA(cccDNA)。HBV前基因组RNA (pgRNA)和乙肝核心相关抗原(HBcrAg)是cccDNA的可靠替代品。HBsAg阴性的OBI患者的患病率并不显著,并且因地区和疾病而异。苏丹OBI的总患病率为15.51%,具有高度异质性。一项荟萃分析显示,在西欧和北美,OBI的总体患病率为34%,在329名无慢性肝病的受试者中为28%,在2400名慢性肝病患者中为35%。不同疾病的患者对B I的认识有很大差异。也就是说,在隐源性肝硬化或晚期肝纤维化患者中,OBI的患病率范围为4%至38%,在非肠道血液暴露的情况下,约为45%,在慢性丙型肝炎患者中,估计为52%,在HIV感染患者中,为0%至45%,在献血者中为0%至22.7%,在血液透析患者中,为0%至54%。在中国局部地区,未接种乙肝疫苗的年轻人OBI患病率为19.48% (640/3100例),接种乙肝疫苗的年轻人OBI患病率为4.70% (170/ 3615例)。我们的研究团队估计中国至少有2000万OBI患者。

目前,主要的国际指南认为,一旦CHB达到“功能性治愈”(即HBsAg阴性OBI状态),就没有必要进行治疗。然而,即使当HBsAg阴性转化时,cccDNA仍留在肝脏中,HBV以低水平复制并整合到宿主中,导致“无症状”的慢性炎症。奥比是目前正在传播的一种独特类型的HBV感染。我们的研究团队和其他人发现,奥比可以导致HBV再激活,肝硬化和HCC。

慢性暴露于高水平的HBsAg导致免疫细胞耗竭和慢性乙型肝炎反应不足。OBI的免疫反应明显好于CHB,但仍低于健康人。恢复HBV感染患者的免疫功能可能会根除病毒。已知抗-HBs是保护性抗体,能够防止再感染并维持宿主对HBV的免疫抑制,我们的研究小组发现抗-HBs也可能防止HCC进展。

目的:OBI患者尚无有效的治疗方法,免疫治疗可能是最有希望的选择之一。我们的目的是研究乙肝疫苗免疫治疗OBI患者的潜在机制和治疗潜力。

方法:筛选门诊OBI患者,随机分为治疗组(A组)和对照组(B组)。在第0周、第4周和第24周,A组患者根据标准疫苗接种方案接受了乙型肝炎疫苗(Engerix-B,20 mg/次)的皮下/肌肉注射;B组为空白对照组。对患者随访36周,分别在第0、12、24和36周收集和分析临床、生化、病毒学、免疫学和影像学数据,并分析病毒学和免疫学结果之间的关系。

结果:在228例OBI患者中,28例被排除,200例被纳入观察。最终排除失访病例后,A组44例,B组39例。在第0周(基线),两组中的一些患者出现肝病症状、HBV相关的肝功能损害和肝纤维化。A组和B组分别有86.36% (38/44)和82.05% (32/39)的患者血清乙肝表面抗体(抗-HBs)阳性,中位数(四分位数)分别为42.47 (16.85,109.1)和39.27 (16.06,117.4) mIU/ml。两组中部分患者外周血CD4+T、CD8+T和B淋巴细胞减少。这些结果在A组和B组之间没有统计学差异(P>0.05)。第36周,A组所有患者血清抗-HBs (+)中位数(四分位数)为1000 (483.9,1000) mIU/ml,显著高于第0周(P<0.05)和B组(P<0.05)。与第0周相比,CD8+ T和B淋巴细胞数量显著增加,且在相同时间点显著高于B组。B组中有2例患者在第12周到第36周发现乙肝病毒再激活。

相关性分析:在第12、24和36周,A组患者的抗-HBs与B淋巴细胞呈正相关(r分别为0.3431、0.3087和0.3041),与CD8+ T淋巴细胞呈正相关(r分别为0.4954、0.3054和0.3455)。

表1 第0周OBI患者的生化和影像检查结果。

表2 OBI患者的乙肝病毒血清标志物结果。

表3 OBI患者血清乙型肝炎病毒表面抗体检测结果。

图1 | A组在第12周(A-D)、第24周(E-G)、第36周(H-J)的丹蒂-HBs和Dimmune细胞的相关性分析。

图2|B组12周(A-C)、24周(D,E)、36周(F,G)Danti-HBs与免疫细胞的相关性分析。

结论:病毒再激活对OBI患者是一种风险。乙肝疫苗治疗后血清乙肝表面抗体明显升高,外周血B和CD8+ T淋巴细胞数量也明显升高;乙肝表面抗体水平的变化与外周血B和CD8+ T淋巴细胞的变化呈正相关。

原文出处:Peng J,  Yao X,  Yuan C, et al.The Investigation of Hepatitis B Vaccine Immune Responses in Occult Hepatitis B Virus-Infected Patients.Front Immunol 2022;13

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