Vaccine immunity in patients with chronic lymphocytic leukaemia; mechanisms of response and optimisation strategies for patients on targeted therapies

慢性淋巴细胞白血病患者的疫苗免疫力；

• 批准号: MR/X006891/1
• 负责人: Helen Parry
• 金额: $ 159.52万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX006891%2F1
• 关键词: Vaccine; immunity; patients; chronic; lymphocytic

Chronic lymphocytic leukaemia ('CLL') is a blood cancer that affects the white blood cells called lymphocytes. It is the most common adult leukaemia and is more common in people aged over 60. In the UK around 31,900 people have CLL. CLL develops slowly and there is no cure. People with CLL have a weakened immune system and suffer from infections. COVID-19 has been particularly problematic for patients with CLL and high mortality rates are associated. Another virus that often reactivates in patients is Varicella Zoster Virus (VZV), which is also known as Shingles. Shingles is associated with considerable pain and this is often long-lasting for patients. People with CLL are known to have very poor responses to vaccines in comparison to the general population. New drugs called Bruton Tyrosine Kinase inhibitors (BTKi) and BCL2 inhibitors (BCL2i) are used to treat CLL. They are very effective but they can prevent the immune system from making antibodies to vaccination. Both drugs need to be taken daily. BTKi treatment is taken continuously, whilst BCL2i therapy is taken for 1-2 years before stopping. In the UK, both drugs are used at all stages of treatment for CLL. Their use is being expanded to other diseases such as different types of blood cancer and autoimmune diseases. It is really important that we understand how they alter immunity and if we can improve it. CLL-VR is a study which is already running in the UK, with 500 patients recruited. For my fellowship, local participants within CLL-VR will be asked on an annual basis if they can donate a blood sample. With this sample, I aim to: - Firstly study antibody and cellular immunity in patients with CLL at different stages of their disease for COVID-19 and VZV, including patients who are on a BTKi or BCL2i treatment. The findings will be compared with control donors. -I will also look at immune responses to 2 different vaccines that are recommended for patients with CLL. These are the COVID-19 vaccination and the Shingrix vaccination for preventing Shingles. Blood sampling will be taken shortly after vaccination.-In addition, the IMPROVE study is a clinical trial that is opening in the Autumn of 2022. It will look at whether pausing BTKi therapy before being vaccinated improves antibody responses. Using samples from IMPROVE study participants, this work will investigate why immune responses occur in certain donors and not others and whether pausing therapy improves responses. -Similarly, patients who take BCL2i therapy for CLL, complete therapy after 1 or 2 years. This work will compare immune responses to vaccination before and after completing therapy in order to understand if immune responses are reversible or long lasting. -Cellular immune responses may be particularly important for patients who produce poor antibody responses, so I will assess cellular responses in each of the scenarios above. I will also test if a home testing finger prick kit can provide comparable cellular information for patients to the usual tests that we routinely use in the laboratory. Improving vaccination responses has been a hot topic between clinicians and the CLL community for many years. People with CLL have co-created the study plan and will be partners throughout the fellowship. I will publish results in academic journals, and share them with clinicians, policy makers, and people with CLL and their families by email or post, social media and webinars.

慢性淋巴细胞白血病（“CLL”）是一种影响称为淋巴细胞的白细胞的血癌。它是最常见的成人白血病，在 60 岁以上的人群中更为常见。在英国，大约 31,900 人患有 CLL。 CLL 发展缓慢且无法治愈。慢性淋巴细胞白血病患者的免疫系统较弱，容易受到感染。 COVID-19 对 CLL 患者来说尤其成问题，并且死亡率很高。另一种经常在患者体内重新激活的病毒是水痘带状疱疹病毒 (VZV)，也称为带状疱疹。带状疱疹会带来相当大的疼痛，而且这种疼痛对于患者来说通常会持续很长时间。众所周知，与普通人群相比，慢性淋巴细胞白血病患者对疫苗的反应非常差。称为布鲁顿酪氨酸激酶抑制剂 (BTKi) 和 BCL2 抑制剂 (BCL2i) 的新药用于治疗 CLL。它们非常有效，但会阻止免疫系统产生疫苗接种抗体。这两种药物都需要每天服用。 BTKi 治疗需要持续进行，而 BCL2i 治疗需要持续 1-2 年才停止。在英国，这两种药物均用于 CLL 治疗的各个阶段。它们的用途正在扩展到其他疾病，例如不同类型的血癌和自身免疫性疾病。了解它们如何改变免疫力以及我们是否可以提高免疫力非常重要。 CLL-VR 是一项已在英国开展的研究，招募了 500 名患者。对于我的奖学金，CLL-VR 的当地参与者每年都会被询问是否可以捐献血液样本。通过这个样本，我的目标是： - 首先研究处于不同疾病阶段的 CLL 患者的 COVID-19 和 VZV 抗体和细胞免疫，包括接受 BTKi 或 BCL2i 治疗的患者。研究结果将与对照捐赠者进行比较。 -我还将研究对 CLL 患者推荐的两种不同疫苗的免疫反应。这些是用于预防带状疱疹的 COVID-19 疫苗接种和 Shingrix 疫苗接种。疫苗接种后不久将进行血液采样。-此外，IMPROVE 研究是一项将于 2022 年秋季启动的临床试验。它将研究在接种疫苗之前暂停 BTKi 治疗是否可以改善抗体反应。这项工作将使用 IMPROVE 研究参与者的样本来调查为什么某些捐赠者会出现免疫反应，而其他捐赠者则不会，以及暂停治疗是否会改善反应。 -同样，接受 BCL2i 治疗 CLL 的患者在 1 或 2 年后完成治疗。这项工作将比较完成治疗之前和之后对疫苗接种的免疫反应，以便了解免疫反应是否可逆或持久。 -细胞免疫反应对于产生不良抗体反应的患者可能特别重要，因此我将评估上述每种情况下的细胞反应。我还将测试家庭测试指尖刺破套件是否可以为患者提供与我们在实验室常规使用的常规测试相当的细胞信息。多年来，改善疫苗接种反应一直是临床医生和 CLL 社区的热门话题。 CLL 患者共同制定了研究计划，并将在整个研究期间成为合作伙伴。我将在学术期刊上发表研究结果，并通过电子邮件或帖子、社交媒体和网络研讨会与临床医生、政策制定者以及 CLL 患者及其家人分享。

项目成果

Robust generation of neutralising antibodies against Omicron variants following bivalent mRNA booster vaccine in elderly people aged >80 years

80 岁以上老年人接种二价 mRNA 加强疫苗后，可产生针对 Omicron 变体的中和抗体

• DOI: 10.1016/j.jinf.2023.08.014
• 发表时间: 2024
• 期刊: Journal of Infection
• 影响因子: 28.2
• 作者: Parry H