进一步提高治疗性疫苗的有效性

StephenW

进一步提高治疗性疫苗的有效性
同行评审出版物

伦敦大学学院

UCL 的科学家在发现并挫败了“内部敌人”后，显着提高了旨在控制慢性乙型肝炎 (HBV) 感染的治疗性疫苗的有效性。

发表在《科学转化医学》上的研究人员表示，在小鼠身上的发现是疫苗开发领域的一项突破，因为它们揭示了如何增强治疗性疫苗旨在触发的抗病毒 T 细胞反应。对于世界各地的免疫学家来说，这一直是一个长期存在的问题和难题。

虽然有一种有效的预防性（预防性）HBV 疫苗可以预防新病例，但本研究的重点是如何在估计 2.4 亿已经慢性感染的人群中提高对治疗性疫苗（在疾病或感染已经发生后接种的疫苗）的反应已感染。

慢性 HBV 是世界上最常见的肝癌病因，每年全球约有 880,000 人死于肝硬化和肝细胞癌/肝癌 (HCC)。

在这项研究中，患有慢性 HBV 的小鼠接种了 ChAdOx1-HBV，Vaccitech，Oxford，目前正在人体 II 期试验中进行测试。

研究人员发现，去除自然杀伤 (NK) 细胞（一种通常可以抵抗感染的白细胞）可增强治疗性疫苗接种诱导的抗病毒 CD8+T 细胞的反应，并增强对 HBV 的控制。

共同主要作者 Mariana Diniz 博士（伦敦大学学院感染与免疫学部）说：“我们的研究表明，自然杀伤细胞生活在肝脏中，不是帮助 T 细胞在接种疫苗后对抗病毒，而是抑制它们并预防它们。控制感染。”

在此基础上，研究小组发现 NK 细胞使用 PD-1 抑制途径* 来抑制 T 细胞。此外，当研究人员用细胞因子（刺激免疫系统的蛋白质）激活 NK 细胞并阻断 PD-1 通路时，NK 细胞将它们从“抑制因子”转化为“辅助因子”，从而增加了疫苗诱导的 T 细胞数量来控制乙肝病毒。

使用血液和肝脏患者样本，研究小组继续表明，这些发现也适用于体外乙型肝炎患者样本，增强了将这一发现转化为新的和改进的人类疫苗的潜力。

共同主要作者 Mala Maini 教授（伦敦大学学院感染与免疫学部）说：“人们越来越认识到 NK 细胞除了具有直接的抗病毒和抗肿瘤功能外，还具有强大的正向或负向调节能力。

“我们发现在乙肝病毒感染的肝脏中发生的事情就像一个营的士兵——自然杀伤细胞——打开了一个营——T细胞——而不是共同的敌人——乙型肝炎。

“我们的研究结果描述了一种免疫治疗组合，可以克服这一限制，以提高对乙型肝炎治疗性疫苗接种的反应，这种方法可能也适用于肝癌。”

研究中使用的疫苗 ChAdOx1-HBV，Vaccitech，牛津，包含由黑猩猩腺病毒载体递送的 HBV 抗原，使用与阿斯利康 (ChAdOx1 nCoV-19) SARS-CoV-2 疫苗相同的主干平台。

对治疗性疫苗开发的重要性

Maini 教授补充说：“恢复或挽救有效的 T 细胞反应是许多针对慢性病毒感染和恶性肿瘤开发的免疫疗法的主要目标。

“迄今为止，治疗性疫苗取得的成功有限，但仍然是促进针对特定抗原的免疫反应的关键策略。

“我们的研究揭示了一种调节 T 细胞对治疗性疫苗反应的新机制以及克服这一问题的免疫治疗方法；这些见解可用于开发更有效的治疗方法。”

研究限制

这项研究是使用小鼠模型进行的 HBV 感染，该模型不能完全再现在人类中观察到的自然感染过程。然而，该模型类似于在几个人类携带者中看到的低 HBV 复制状态，并模拟了慢性 HBV 感染中免疫细胞的衰竭免疫状态，因此可用于研究治疗干预。使用患者样本再现了小鼠模型的发现。

该研究是与牛津大学的合作者进行的，并由惠康基金资助。

* PD-1 抑制途径在激活时由 T 细胞表达，并具有调节作用，将它们限制在慢性病毒感染和癌症中。
杂志

科学转化医学
DOI

10.1126/scitranslmed.3001975

StephenW

Maximizing the effectiveness of therapeutic vaccines a step closer
Peer-Reviewed Publication

University College London

Scientists at UCL have significantly boosted the effectiveness of a therapeutic vaccine designed to control chronic hepatitis B (HBV) infection, after uncovering and thwarting ‘the enemy within’.

Published in Science Translational Medicine, researchers say the findings in mice are a breakthrough in the field of vaccine development, as they reveal how to enhance the antiviral T cell response that therapeutic vaccines are intended to trigger. This has been a long-time problem and puzzle for immunologists around the world.

While there is an effective prophylactic (preventative) HBV vaccine to prevent new cases, this study focused on how to enhance the response to therapeutic vaccines (those administered after a disease or infection has already occurred) among the estimated 240 million people who are already chronically infected.

Chronic HBV is the most common cause of liver cancer in the world, and each year globally, the infection causes an estimated 880,000 deaths from liver cirrhosis and hepatocellular carcinoma/liver cancer (HCC).

For the study, mice with chronic HBV were vaccinated with ChAdOx1-HBV, Vaccitech, Oxford, which is currently being tested in Phase II trials in humans.

Researchers found that removing natural killer (NK) cells, a white blood cell that normally fights infection, boosted the response of the antiviral CD8+T cells induced by the therapeutic vaccination and enhanced the control of HBV.

Co-lead author, Dr Mariana Diniz (UCL Division of Infection & Immunity), said: “Our study shows that natural killer cells living in the liver, rather than helping T cells to fight the virus after vaccination, instead suppress them and prevent them from controlling the infection.”

Building on this, the team discovered that NK cells use the PD-1 inhibitory pathway* to suppress T cells. Further, when researchers activated the NK cells with cytokines (proteins that stimulate the immune system) and blocked the PD-1 pathway, NK cells were converted them from ‘suppressors’ into ‘helpers’, boosting the number of vaccine-induced T cells able to control HBV.

Using blood and liver patient samples, the research team went on to show that the findings also applied to hepatitis B patient samples in vitro, reinforcing the potential to translate this discovery into new and improved human vaccines.

Co-lead author, Professor Mala Maini (UCL Division of Infection & Immunity), said: “NK cells are increasingly recognised to have potent positive or negative regulatory capacities in addition to their direct antiviral and anti-tumour functions.

“What we found happening in the HBV-infected liver is like one battalion of soldiers – the natural killer cells – turning on a fellow battalion – the T cells – rather than the common enemy, hepatitis B.

“Our findings describe an immunotherapeutic combination that can overcome this constraint to boost the response to therapeutic vaccination in hepatitis B, an approach that is potentially also applicable to liver cancer.”

The vaccine used in the study, ChAdOx1-HBV, Vaccitech, Oxford, contains HBV antigens delivered by a chimpanzee adenoviral vector, using the same backbone platform as the AstraZeneca (ChAdOx1 nCoV-19) SARS-CoV-2 vaccine.

Importance to therapeutic vaccine development

Professor Maini added: “Restoring or rescuing an effective T cell response is the primary goal of many immunotherapies being developed for chronic viral infections and malignancies.

“To date, therapeutic vaccines have shown limited success but remain a key strategy to promote immune responses targeting specific antigens.

“Our study uncovers a new mechanism that regulates T cell responses to therapeutic vaccines and an immunotherapeutic approach to overcome this; insights which could be applied to develop more effective treatments.”

Study limitations

This study was performed using a mouse model for HBV infection that does not fully reproduce the natural infection process observed in humans. However, the model resembles the state of low HBV replication seen in several human carriers and mimics the exhausted immunological state of immune cells in chronic HBV infection and is, therefore, useful to study therapeutic interventions. Findings from the mouse model were reproduced using patient samples.

The research was conducted with collaborators at the University of Oxford and funded by a Wellcome grant.

* The PD-1 inhibitory pathway is expressed by T cells when activated and has a regulatory role, constraining them in chronic viral infection and cancer.
Journal

Science Translational Medicine
DOI

10.1126/scitranslmed.3001975