Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway

该项目建立在已建立的PHE警报器和相关队列(Pitch和HICC)的基础上，与领先的免疫学家和科学家合作，以提高对感染和疫苗的免疫反应的理解，并详细研究那些已证明疫苗取得突破的个人。这些研究跟踪了超过45,000名医护人员，其中94%的人已经接种了两剂疫苗，并将评估他们对新冠肺炎感染和接种疫苗的免疫系统反应。了解免疫反应对于确定哪些人在接种疫苗后最容易受到感染至关重要，对于能够有效针对未来增强疫苗免疫反应的关键组成部分的疫苗开发商来说也是如此。适应性免疫系统有两个主要组成部分--B细胞和T细胞。B细胞产生抗体，在之前的感染或疫苗接种后可以检测到。我们将研究针对病毒蛋白质表达的两种蛋白质--刺突蛋白(S)和核衣壳蛋白(N)，这两种蛋白质的测量方法可以给出每种蛋白质的存在数量，还可以测量中和或“消毒”免疫--评估个人血液杀死或中和活的SARS-CoV-2病毒或实验室复制的SARS-CoV-2病毒的能力。T细胞通过释放被称为细胞因子的蛋白质直接杀死受病毒感染的细胞，这种蛋白质可以向其他细胞发出信号，并向免疫系统提供关于其强度和反应范围的指令。研究集中在关键领域：1.为什么有些人在接种疫苗后会再次感染或感染？2.在接种疫苗后感染的人中，我们能识别出他们免疫系统的哪些部分没有发挥免疫保护作用吗？3.接种疫苗的这种免疫力能持续多久，与不同的疫苗有何不同？4.免疫系统对加强剂量的疫苗接种有何反应？5.SARS-CoV-2病毒基因构成的变化如何导致免疫反应逃避？6.人类遗传密码中可以检测到的与对病毒和疫苗的不同免疫反应相关的差异有哪些？我们将使用纳入我们队列研究的关键个体群体的血液来评估免疫反应。我们将研究：a)再次感染(在之前确认感染后再次感染)和接种一剂或两剂疫苗的个人，以及b)在接种两剂疫苗后感染的个人。我们可以有效地做到这一点，因为所有参与研究的人每两周都要进行一次聚合酶链式反应检测，并定期进行血液检测，以检测储存起来的抗体，以备将来分析。此外，对于接种疫苗后出现感染的个人，我们将与他们进行更详细的讨论，以确定他们的免疫系统是否可能出现功能问题，服用可能阻止他们的免疫系统反应的特定药物，并征求他们的同意，进行额外的血液测试，以详细分析他们对CoVID的免疫反应。这将包括分析他们在感染发生之前和之后的血液测试，我们将询问他们是否愿意参与他们的DNA代码的遗传分析，以确定他们的DNA代码中是否有特定的突变可能预测对疫苗的不良反应。我们将寻求使用特定的研究设计来科学地实现这一点，该设计将比较接种疫苗后感染的个人和其他未感染的人，并与年龄、性别、种族和共病相匹配。将比较T细胞和B细胞的免疫反应，以确定这些群体之间是否存在关键的可检测到的差异。

This project builds on the established PHE SIREN and associated cohorts (PITCH and HICC) working with leading immunologists and scientists to improve understanding of the immune response to infection and vaccines and study in detail those individuals who have proven vaccine breakthrough. These studies are following more than 45,000 healthcare workers, 94% of whom have received two doses of vaccine, and will assess their immune system response to COVID-19 infections and vaccinations.Understanding the immune response is essential to determine who is most at risk of infections after vaccination, and also for vaccine developers who can target key components of the immune response effectively for future boost vaccines. The adaptive immune system has two major components - B-cells and T-cells. The B-cells produce antibodies that can be detected after previous infection or vaccination. We will be studying two that are expressed against proteins from the virus - the Spike (S) and Nucleocapsid (N) proteins that are measured using assays that can give us the quantity of each present and also a measurement of neutralising or "sterilising" immunity - assessing how well an individual's blood can kill or neutralise either a live SARS-CoV-2 virus or a lab created replica. The T-cells directly kill virus infected cells by releasing proteins known as cytokines, which can signal to other cells and provide instructions to the immune system on its strength and range of response.The research is focused on key areas:1. Why do some people get reinfections or infections after vaccination?2. In individuals who get infections after vaccination, can we identify which parts of their immune system are not working to provide immune protection?3. How long does this immunity from vaccinations last and how does it differ with different vaccines?4. How does the immune system respond to booster doses of vaccination?5. How do changes in the SARS-CoV-2 virus genetic make-up cause evasion of the immune response?6. What are the differences that can be detected in the human genetic code that are associated with different immune responses to the virus and vaccination?We will assess these questions using blood from key groups of individuals recruited into our cohort studies to assess the immune response. We will study: a) individuals who have a re-infection (a second infection after having a previous confirmed infection) and one or two doses of vaccination and b) individuals who develop an infection after two doses of vaccine. We can do this effectively because all individuals who are in the study have PCR tests every two weeks and regular blood tests for antibodies that are stored for future analysis. In addition, for individuals who develop infections after vaccination, we will discuss with them in more detail to determine whether they could have a functional problem with their immune system, take specific medications that could prevent their immune system from responding and seek their consent to take additional blood tests to perform detailed analysis of their immune response to COVID. This will involve analysis of their blood tests before and after the infection episode and we will ask if they would like to participate in genetic analysis of their DNA code to see if there are particular mutations in their DNA code that might predict a poor response to vaccination.We will seek to do this scientifically using specific study designs that will compare individuals who acquire an infection after vaccination to others who do not get infections, matched to age, sex, ethnicity, and co-morbidities. The T and B-cell immune responses will be compared to determine if there are key detectable differences between these groups.