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理论上认为，治疗性疫苗可以通过增强免疫应答进而实现对乙肝病毒感染的控制。ABX203 [由古巴基因工程与生物技术中心（CIGB)研制]是一种新的由HBV表面和核心抗原组合而成的疫苗制剂，其使用方法为先滴鼻后皮下/鼻内吸入。ABX203/NASVAC 已经展现出优越的有效性在跟慢乙肝一线治疗药物 PEG-IFNα 进行比较时。德国汉诺威医学院、香港大学等研究机构的研究人员进行了一项评估在停用核苷（酸）类似物后治疗性乙肝疫苗 ABX203 能否阻止 HBeAg 阴性慢乙肝患者的病毒复发。
使用NA治疗至少2年后，HBV-DNA 阴性 ALT 水平正常的 276名HBeAg阴性无肝硬化患者被随机的分成接受24周的NA联合ABX203（首先每两周滴鼻一次，共5次，随后进行5次加强的滴鼻/皮下用药）治疗组（n = 184）和NA单药治疗组(n = 92)。在24周后，所有患者的NA均停用，包括联合治疗组。随访时间为24周或直至又必须开始使用NA治疗进行病毒控制。研究的首要目的为观察停用 NA 24周 HBV-DNA 保持在 <40 IU/ml 的比例。
基线情况为，患者平均年龄为50岁，先前使用NA治疗的平均时间为4.78 ±2.37年，94%的为亚洲人种，男性占比72%，57%患者的 HBsAg 水平 >1000 IU/ml。ABX203 疫苗的安全性和耐受性良好，两个治疗臂组中只有2.2%的不良事件发生率（跟药物治疗不相关）。达到研究首要目标的疫苗使用组患者为6.9%，NA单药治疗组为11.7%，p = 0.20。类似的，两组间 ALT 和 AST 值正常(74% vs.80%), HBV-DNA <2000 IU/ml 且 ALT <2xULN (31% vs. 41%) 和HBsAg 下降的患者百分比没有显著差异。ABX 203 没有诱导产生体液免疫反应。不过，引人注目的是，替诺福韦治疗组(>70% 在 12 周) 和恩替卡韦治疗组 (<10% 在 12周)更早发生病毒反弹(HBV-DNA >2000 IU/ml)，不管有无使用ABX 203 治疗均对结果没有影响（如图）。
研究人员在结论中写道，以上研究结果表明，这项迄今为止最大的前瞻性随机 HBV 治疗性疫苗临床研究，也是最大的 NA 停药前瞻性研究显示，ABX203 不能在停用 NA 治疗后不能阻止病毒的反弹。研究结果揭示了替诺福韦和恩替卡韦之间存在意想不到的复发时间差。未来还有必要进行更多的研究加以证实是否还有替代疫苗方案（如在停止NA治疗后注射疫苗）让停止NA治疗后可以持续对乙肝病毒进行控制。
从该项研究结果的数据来看，可以判定该研究为 ABIVAX 公司在亚太地区做的古巴治疗性乙肝疫苗ABX203（HeberNasvac）Phase II/III 期临床结果，早在去年7月下旬，公司便发出通告，表示由于研究中过多的患者出现病毒逃逸，导致该项研究的首要目标已经非常难以实现。公司也将考虑是否停止该治疗性乙肝疫苗的研发，于是在2016年11月，公司直接将该产品的信息从公司官方网站上删除，可见，公司已经彻底放弃对该疫苗的研发。
而在今年的亚太肝病年会上，一则关于该治疗性乙肝疫苗的新消息再次出现在具有影响力的国际肝病会议中，（参见：APASL2017：治疗性乙肝疫苗ABX203 (HeberNasvac)再燃希望）该研究由意大利等多个国家的研究人员共同实施，他们正在对该疫苗进行从新研究，或许，这款治疗性乙肝疫苗仍有前景。我们只能拭目以待，期待奋斗在前线的科学家们为我们带来更多的好消息。
编号：LBP-518
Therapeutic vaccination of chronic hepatitis B patients with ABX203 (NASVAC) to prevent relapse after stopping NUCs:contrasting timing rebound between tenofovir and entecavir
H. Wedemeyer1, A.J. Hui2, W. Sukeepaisarnjaroen3, P. Tangkijvanich4,W.W. Su5, G.E.G. Nieto6, P. Gineste7, J. Nitcheu7, S. Crabé7, S. Stepien8,M. Cornberg1, C. Trépo9. 1Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; 3Khon Kaen University, Khon Kaen; 4King Chulalongkorn Memorial Hospital, Bangkok,Thailand; 5Changhua Christian Hospital, Taipei, Taiwan; 6Centro de Ingeniería Genética y Biotecnología, Havana, Cuba; 7ABIVAX, Paris,France; 8Georges Institute, Sydney, Australia; 9INSERM 1052 CRCL, Lyon,France
E-mail: [email protected]
Background and Aims: Conceptually, therapeutic vaccination should boost immune responses to control HBV infection. ABX203 (developed as NASVAC by CIGB, Cuba) is a new vaccine formulation combining HBV surface and core antigens which is administered intranasally during priming followed by subcutaneous/intranasal boosting. ABX203/NASVAC has shown superior efficacy compared with PEG-IFNα in first line therapy of chronic hepatitis B. We here evaluated if ABX203 vaccination of HBeAg(-) chronic hepatitis B patients would prevent relapse after stopping antiviral therapy with nucleos(t)ides analogues (NA).
Methods: 276 HBeAg(-) non-cirrhotic patients who had been treated for at least 2 years with NA and who were HBV-DNA negative with normal ALT levelswere randomized to continue NA therapy 24weeks in combination with ABX203 [priming 5 intranasal administrations every 2nd week followed by 5 intranasal/subcutaneous booster administrations] (n = 184) vs. treatment with NA only (n = 92). After 24 weeks, NA therapy was stopped in all patients. Follow-up was 24 weeks or until NA retreatment. The primary end-point of the study was the percentage of subjects who maintained HBV-DNA levels<40 IU/ml 24 weeks after stopping NA.
Results: Patients (mean age 50 years, previous NA therapy of 4.78 ± 2.37 years) were mainly Asian (94%), male (72%) and 57% had HBsAg levels of >1000 IU/ml at baseline. ABX203 vaccination was safe and well tolerated with only 2.2% SAEs in both treatment arms (not drugrelated).The primary endpoint was reached by 6.9% of vaccinated patients and 11.7% of those receiving NA only (p = 0.20). Similarly,there were no differences between the study groups in the percentage of patients with normal ALT and AST values (74% vs.80%), HBV-DNA <2000 IU/ml with ALT <2xULN (31% vs. 41%) and HBsAg declines. Humoral immune responses were not induced by ABX203. Strikingly, however, viral rebound (HBV-DNA >2000 IU/ml) occurred much earlier in patients treated with tenofovir (>70% by week 12) vs. entecavir (<10% by week 12), irrespective of ABX203 treatment (figures) and without impacting outcomes.
Conclusions: This by far largest prospective randomized HBV therapeutic vaccine study and also the largest prospective NA-stop study showed that ABX203 did not prevent viral relapse after stopping NA. It revealed unexpected relapse timing difference between tenofovir and entecavir. Future studies need to investigate if alternative vaccine regimens (e.g. vaccination after stopping NA) may induce off-NA-therapy viral control.
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发表于 2017-4-14 15:40
