The Durability of immune Responses to vaccination against SARS-CoV-2 and its Variants.

SARS-CoV-2 及其变种疫苗接种后免疫反应的持久性。

• 批准号: MR/W020610/1
• 负责人: Rosemary Boyton
• 金额: $ 100.36万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW020610%2F1
• 关键词: Durability; immune; Responses; vaccination; against

This proposal has been developed by a team who have worked at the forefront of studies to understand immunity to the SARS-COV-2 virus throughout the pandemic. With time, the focus of these questions has changed. As more people receive COVID-19 vaccination, a key concern becomes the need to understand the details of protective immunity and how long it is typically likely to remain protective in the 'real-life settings' of the many different vaccines available globally. Furthermore, compared to the reductionist conditions under which initial clinical trials were conducted, we now face a situation whereby many people receiving vaccines having been previously infected by SARS-CoV-2 or its alpha to delta variants. We showed that prior infection substantially boosts the response to vaccination. These points in mind, our aim is to generate the detailed immunological datasets enabling us to understand how long protective immunity lasts and thus, when boosts are likely to be needed. To do this, we bring together our work on diverse, longitudinal, COVID-19 cohorts, already developed and characterised with our collaborators over the past year. Our cohorts encompass 12097 individuals, with different exposures to SARS-CoV-2 and its variants, in the UK, South Africa and Brazil. We will be able to study people receiving different vaccines, with or without infection by SARS-CoV-2 and the alpha, beta, gamma and delta variants of concern. Our work aims to understand the durability and nature of immune protection, including susceptibility to reinfection and breakthrough infections. To track longitudinal immunity we will use existing protocols to measure diverse aspects of immunity in sequential blood samples. Tests will consider virus neutralisation by antibody, as well as assessing 'immune memory' (-ability of a primed immune response to 'remember' the virus and so protect) in B cells (which make antibody) and T cells (which orchestrate the antiviral response). Put simply, our question can be framed as: some studies indicate that protective antibodies in serum wane rapidly, so that relatively frequent boosters may be needed, while others show that immunity progressively improves after vaccination, termed 'affinity maturation', and that B and T cell memory are long-lived, implying the possibility of longer delays to boosting. By building a detailed, longitudinal dataset of many measures of immunity, we will model the timecourse from vaccination to the predicted loss of protective immunity. This will enable us to offer precise input to policy-making about immune-monitoring and boosting strategy, as well as informing the realities of applying 'immune certification' measures in everyday life - assessing how long certification is likely to be meaningful. Analysis needs to be mindful of the point that people are diverse. We know that vaccination responses encompass a spectrum, with high-responders and poor-responders at each end. We will analyse data from our large sample in the context of factors such as gender, ethnicity, age and obesity. From past studies, some will make a sub-optimal immune response because of the medicines they are taking. We here include two such cohorts. In one, we consider the impact of one of the most common drugs given to people with autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis (anti-TNF biologics). In another, we consider the impact of drug treatment in people with chronic myelogenous leukaemia. In summary, the knowledge-gap we aim to fill is the definition of protective immunity and its stability in longitudinal analysis during the year following vaccination. This will supply the dataset and predictive models to inform decision-making on timing of boosters, variant breakthrough, diversity of protective responses within the population and optimisation of protocols for the immunosuppressed.

该提案是由一个致力于了解整个大流行期间对 SARS-COV-2 病毒的免疫力的研究前沿的团队提出的。随着时间的推移，这些问题的焦点已经发生了变化。随着越来越多的人接种 COVID-19 疫苗，一个关键问题是需要了解保护性免疫的细节，以及在全球可用的许多不同疫苗的“现实环境”中，这种免疫通常可以保持多长时间的保护性。此外，与进行初始临床试验时的简化条件相比，我们现在面临的情况是，许多接受疫苗的人之前曾感染过 SARS-CoV-2 或其 α 至 δ 变体。我们发现，先前的感染大大增强了对疫苗接种的反应。考虑到这些要点，我们的目标是生成详细的免疫学数据集，使我们能够了解保护性免疫的持续时间，从而了解何时可能需要加强免疫。为此，我们汇集了我们在过去一年中与我们的合作者一起开发和表征的多样化、纵向的 COVID-19 队列的工作。我们的队列包括来自英国、南非和巴西的 12097 名个体，他们对 SARS-CoV-2 及其变种的接触情况不同。我们将能够研究接受不同疫苗的人，无论是否感染 SARS-CoV-2 以及相关的 α、β、γ 和 δ 变体。我们的工作旨在了解免疫保护的持久性和性质，包括对再感染和突破性感染的易感性。为了追踪纵向免疫力，我们将使用现有方案来测量连续血液样本中免疫力的各个方面。测试将考虑抗体对病毒的中和作用，以及评估 B 细胞（产生抗体）和 T 细胞（协调抗病毒反应）的“免疫记忆”（启动免疫反应“记住”病毒并提供保护的能力）。简而言之，我们的问题可以概括为：一些研究表明，血清中的保护性抗体迅速减弱，因此可能需要相对频繁的加强免疫，而另一些研究则表明，接种疫苗后免疫力逐渐改善，称为“亲和力成熟”，而且 B 细胞和 T 细胞记忆是长期存在的，这意味着加强免疫可能会延迟更长的时间。通过建立许多免疫指标的详细纵向数据集，我们将对从疫苗接种到预测的保护性免疫力丧失的时间过程进行建模。这将使我们能够为有关免疫监测和增强策略的政策制定提供精确的投入，并告知在日常生活中应用“免疫认证”措施的现实情况——评估认证的持续时间可能有意义。分析需要注意人们是多样化的这一点。我们知道，疫苗接种反应涵盖一个范围，每一端都有高反应者和低反应者。我们将根据性别、种族、年龄和肥胖等因素分析来自大样本的数据。根据过去的研究，有些人会因为服用的药物而产生次优的免疫反应。我们这里包括两个这样的群体。在其中一项研究中，我们考虑了对炎症性肠病和类风湿性关节炎等自身免疫性疾病患者使用的最常见药物之一（抗 TNF 生物制剂）的影响。在另一项研究中，我们考虑了药物治疗对慢性粒细胞白血病患者的影响。总之，我们旨在填补的知识空白是保护性免疫的定义及其在疫苗接种后一年内纵向分析的稳定性。这将提供数据集和预测模型，为加强免疫时机、变异突破、人群内保护反应的多样性以及免疫抑制方案的优化等决策提供信息。

项目成果

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

• DOI: 10.1016/s2468-1253(22)00274-6
• 发表时间: 2022-11
• 期刊: LANCET GASTROENTEROLOGY & HEPATOLOGY
• 影响因子: 35.7
• 作者: Alexander, James L.;Liu, Zhigang;Sandoval, Diana Munoz;Reynolds, Catherine;Ibraheim, Hajir;Anandabaskaran, Sulak;Saifuddin, Aamir;Seoane, Rocio Castro;Anand, Nikhil;Nice, Rachel;Bewshea, Claire;D'Mello, Andrea;Constable, Laura;Jones, Gareth R.;Balarajah, Sharmili;Fiorentino, Francesca;Sebastian, Shaji;Irving, Peter M.;Hicks, Lucy C.;Williams, Horace R. T.;Kent, Alexandra J.;Linger, Rachel;Parkes, Miles;Kok, Klaartje;Patel, Kamal V.;Teare, Julian P.;Altmann, Daniel M.;Goodhand, James R.;Hart, Ailsa L.;Lees, Charlie W.;Boyton, Rosemary J.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick

Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study).

• DOI: 10.1136/bmjopen-2022-062599
• 发表时间: 2022-05-03
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Abhishek, Abhishek;Boyton, R. J.;McKnight, Aine;Coates, Laura;Bluett, James;Barber, Vicki S.;Cureton, Lucy;Francis, Anne;Appelbe, Duncan;Eldridge, Lucy;Julier, Patrick;Peckham, Nicholas;Valdes, Ana M.;Rombach, Ines;Altmann, Daniel M.;Nguyen-Van-Tam, Jonathan;Williams, Hywel C.;Cook, Jonathan Alistair
• 通讯作者: Cook, Jonathan Alistair

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

• DOI: 10.1016/s2468-1253(22)00005-x
• 发表时间: 2022-04
• 期刊: The lancet. Gastroenterology & hepatology
• 作者: Alexander JL;Kennedy NA;Ibraheim H;Anandabaskaran S;Saifuddin A;Castro Seoane R;Liu Z;Nice R;Bewshea C;D'Mello A;Constable L;Jones GR;Balarajah S;Fiorentino F;Sebastian S;Irving PM;Hicks LC;Williams HRT;Kent AJ;Linger R;Parkes M;Kok K;Patel KV;Teare JP;Altmann DM;Boyton RJ;Goodhand JR;Hart AL;Lees CW;Ahmad T;Powell N;VIP study investigators
• 通讯作者: VIP study investigators

The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients.

• DOI: 10.1016/j.ebiom.2022.104430
• 发表时间: 2023-02
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Alexander, James L.;Mullish, Benjamin H.;Danckert, Nathan P.;Liu, Zhigang;Olbei, Marton L.;Saifuddin, Aamir;Torkizadeh, Melissa;Ibraheim, Hajir;Blanco, Jesus Miguens;Roberts, Lauren A.;Bewshea, Claire M.;Nice, Rachel;Lin, Simeng;Prabhudev, Hemanth;Sands, Caroline;Horneffer-van der Sluis, Verena;Lewis, Matthew;Sebastian, Shaji;Lees, Charlie W.;Teare, Julian P.;Hart, Ailsa;Goodhand, James R.;Kennedy, Nicholas A.;Korcsmaros, Tamas;Marchesi, Julian R.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick

Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers.

• DOI: 10.1016/j.jinf.2021.01.020
• 发表时间: 2021-03
• 期刊: The Journal of infection
• 作者: Adrielle Dos Santos L;Filho PGG;Silva AMF;Santos JVG;Santos DS;Aquino MM;de Jesus RM;Almeida MLD;da Silva JS;Altmann DM;Boyton RJ;Alves Dos Santos C;Santos CNO;Alves JC;Santos IL;Magalhães LS;Belitardo EMMA;Rocha DJPG;Almeida JPP;Pacheco LGC;Aguiar ERGR;Campos GS;Sardi SI;Carvalho RH;de Jesus AR;Rezende KF;de Almeida RP
• 通讯作者: de Almeida RP