Broadly neutralising antibodies after vaccination

该奖学金研究人类对疫苗接种的反应。SARS-CoV-2大流行再次强调了开发针对现有和新传染病的有效疫苗的重要性。现有的SARS-CoV-2疫苗通过几种方式提供疾病保护。最重要的方法是通过训练免疫系统来产生中和抗体，这些抗体结合病毒并阻止其进入细胞。这就是用于治疗COVID-19的单克隆抗体的工作原理--通过包裹病毒并防止其感染附近的细胞--这些治疗方法可以清除缺乏免疫系统的患者体内的SARS-CoV-2。一些人对SARS-CoV-2疫苗的反应是产生仅结合病毒的抗体，而不是中和病毒。这些人可能仍然容易受到感染，即使他们的疫苗训练的免疫系统的其他部分可以预防严重的疾病。接种疫苗的最终目标是预防任何感染，即使是轻微的感染，也有助于控制传播。为了实现这一点，疫苗需要诱导中和抗体。SARS-CoV-2的变异体（VOC）使这一点更具挑战性。我们发现，在接种两次疫苗后，一些人产生的抗体只能中和一些VOC。例如，几乎每个人都需要三剂疫苗才能中和Omicron，而许多健康的人可以在两剂疫苗后中和Delta。只有少数人可以在两次剂量后中和Omicron。为什么会这样呢？是什么控制了VOC中和抗体的广度？是否有方法可以影响中和的广度，以便我们可以使疫苗接种更加有效，或者简化对新VOC重复剂量的需求？本研究金旨在解决这些问题。我将研究几组健康个体中不同VOC的中和宽度，以及它们随时间的变化模式。这些队列是对英国14万多名医疗工作者的SIREN研究，详细的子队列研究PITCH和VIBRANT，以及对伦敦西北部500多名医疗和实验室工作者的Legacy研究。我们还将研究英国血液透析患者中中和抗体的广度和轨迹，我已经表明，这一患者群体对SARS-CoV-2疫苗的反应较差，并且存在因COVID-19住院或死亡的过度风险。这项工作将在弗朗西斯克里克研究所和伦敦大学学院进行。我们将使用克里克的高通量活病毒微量中和试验来确定这些抗体模式。在确定了具有不同中和宽度的个体后，我将研究他们血液中与病毒刺突蛋白结合的B细胞，刺突蛋白是当前疫苗的靶点。通过观察这些B细胞产生的抗体，我可以研究这些抗体是如何被免疫系统精心挑选出来的。不同的人的免疫系统对抗体做出选择决定吗？我们能通过观察这个过程中选择的B细胞来解开这些决定吗？前两种疫苗的种类重要吗？接下来，我将寻找控制这一过程的机制，因为我们可能想在接种疫苗时或抗体介导的自身免疫性疾病期间尝试抑制或增强它们。遗传和环境因素会干扰这些机制。在这项研究中，我将研究潜在的遗传因素（遗传结果告知哪些环境因素优先进行研究）。这些机制可能反映了人类免疫系统中抗体生成决策过程的重要部分，因此可以支持疫苗接种和抗体介导的疾病治疗的新方法。

This fellowship studies the response to vaccination in humans. The SARS-CoV-2 pandemic has re-emphasised the importance of developing efficient vaccines against existing, and new, infectious diseases. Existing SARS-CoV-2 vaccines offer protection from disease in several ways. The most important way is through training the immune system to make neutralising antibodies, which bind the virus and prevent it from entering cells. This is how the monoclonal antibodies used to treat COVID-19 work - by coating the virus and preventing it from infecting nearby cells - and these treatments can clear SARS-CoV-2 in patients who otherwise lack an immune system.Some individuals respond to the SARS-CoV-2 vaccines by producing antibodies that only bind the virus, and do not neutralise it. These individuals are probably still vulnerable to infection, even if the other parts of their vaccine-trained immune system can prevent severe disease. The ultimate goal for vaccination is to prevent any infection, even if mild, so as to also help control transmission. To achieve this, vaccines need to induce neutralising antibody.Variants of concern (VOC) of SARS-CoV-2, make this more challenging. We find that after two vaccinations some individuals make antibodies that only neutralise some of the VOCs. For example, nearly everyone needs three doses of vaccine to neutralise Omicron, whereas many healthy individuals could neutralise Delta after two doses. A small number of individuals could neutralise Omicron after two doses only. Why might this be? What is it that controls the breadth of VOC-neutralising antibodies? Are there ways to influence to breadth of neutralisation, so we can make vaccination even more effective, or streamline the need to repeat doses for new VOCs?This fellowship seeks to address these questions. I will study the breadth of neutralisation of different VOCs in several cohorts of healthy individuals, and their patterns over time. These cohorts are the SIREN study of over 140,000 healthcare workers around the UK, it's detailed sub-cohort studies PITCH and VIBRANT, and the Legacy study of over 500 healthcare and laboratory workers in northwest London. We will also study the breadth and trajectories of neutralising antibody in UK haemodialysis patients, and I have shown this patient group are poor responders to SARS-CoV-2 vaccines and are at an excess risk of hospitalisation or death from COVID-19. This work will take place in the Francis Crick Institute and UCL. We will use the Crick's high throughput live virus microneutralisation assay to define these antibody patterns.Having defined individuals with different breadths of neutralisation, I will study the B cells in their blood that bind to the virus' spike protein, the target of current vaccines. Looking at the antibody these B cells makes allows me to study how carefully these antibodies have been selected by the immune system. Do different people's immune systems make selection decisions about antibody? Can we unpick those decisions, by looking at the B cells that have been selected by that process? Does the type of the first two vaccines matter?Next I will look for mechanisms that control this process, as we may want to try to dampen or enhance them at the time of vaccination, or during antibody mediated autoimmune diseases. Genetic and environmental factors will perturb these mechanisms. In this fellowship, I will examine underlying genetic factors (as the genetic results inform which environmental factors to prioritise for study). The mechanisms are likely to reflect important parts of the decision making process for antibody generation in the human immune system, so could underpin new approaches to vaccination, and antibody-mediated disease treatments.