HBV001：评估治疗性疫苗ChAdOx1-HBV安全性和免疫原性的I期研究。
HBV001: Phase I study evaluating the safety and immunogenicity of the therapeutic vaccine ChAdOx1-HBV.
作者信息
Cargill Tamsin, Cicconi Paola, Brown Anthony, Holland Louise, Karanth Benaka, Rutkowski Kathryn, Ashwin Emily, Mehta Reena, Chinnakannan Senthil, Sebastian Sarah, Bussey Louise, Sorensen Henrik, Klenerman Paul, Evans Thomas, Barnes Eleanor
机构信息
Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
出版信息
JHEP Rep. 2023 Aug 18;5(11):100885. doi: 10.1016/j.jhepr.2023.100885. eCollection 2023 Nov.
BACKGROUND & AIMS: Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice.
METHODS
Here we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB).
RESULTS
Vaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes.
CONCLUSIONS
ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB.
IMPACT AND IMPLICATIONS
Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition.
CLINICAL TRIALS REGISTRATION
This study is registered at ClinicalTrials.gov (NCT04297917).
背景与目的
全球数百万人长期感染乙肝病毒（HBV），这导致了严重的发病率和死亡率。治疗性疫苗接种是一种旨在通过恢复针对HBV的细胞免疫来实现功能性治愈的策略。此前我们已证明候选HBV免疫治疗疫苗ChAdOx1-HBV，其编码所有主要HBV抗原和一种基因佐剂（鲨鱼恒定链），在小鼠中具有高度免疫原性。
方法
在此我们报告HBV001的结果，这是一项在健康志愿者和慢性HBV（CHB）患者中进行的ChAdOx1-HBV的首次人体、I期、非随机、剂量递增试验。
结果
在健康和CHB队列中，单剂量接种ChAdOx1-HBV均安全且耐受性良好。接种疫苗在健康志愿者中诱导了针对所有主要HBV抗原（核心、聚合酶和表面抗原）的高强度HBV特异性T细胞反应。在CHB患者中检测到了反应，但强度较低。接种疫苗产生的T细胞在HBV C和D基因型之间具有交叉反应性。
结论
ChAdOx1-HBV在健康志愿者和CHB患者中是安全且具有免疫原性的。在进一步研究中，ChAdOx1-HBV将与其他治疗策略联合使用，以克服CHB患者中减弱的免疫原性。
影响与意义
治疗性疫苗ChAdOx1-HBV是一种针对慢性乙型肝炎感染（CHB）的新型治疗方法，在临床前研究中已显示具有免疫原性。在首次人体I期研究HBV001中，我们表明接种ChAdOx1-HBV是安全的，并且在健康志愿者中产生高强度T细胞反应，在CHB患者中产生较低水平的反应。这是将ChAdOx1-HBV开发为诱导乙肝功能性治愈的更广泛治疗策略一部分的重要第一步，对CHB患者和治疗该病的临床医生具有重大意义。
临床试验注册
本研究已在ClinicalTrials.gov（NCT04297917）注册。
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