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 SIREN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，提高对感染和疫苗免疫反应的理解，并详细研究那些已经证明疫苗取得突破的个体。这些研究追踪了4.5万多名卫生保健工作者，其中94%接种了两剂疫苗，并将评估他们的免疫系统对COVID-19感染和疫苗接种的反应。了解免疫反应对于确定接种疫苗后感染风险最高的人群至关重要，对于疫苗开发人员也至关重要，他们可以针对免疫反应的关键成分有效地开发未来的增强疫苗。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，可以在以前感染或接种疫苗后检测到。我们将研究两种针对病毒蛋白质表达的蛋白——Spike (S)和Nucleocapsid (N)蛋白，这两种蛋白是通过检测来测量的，可以给我们每种蛋白的数量，也可以测量中和或“消毒”免疫——评估个体血液杀死或中和活的SARS-CoV-2病毒或实验室制造的复制品的能力。t细胞通过释放被称为细胞因子的蛋白质直接杀死被病毒感染的细胞，细胞因子可以向其他细胞发出信号，并向免疫系统提供有关其反应强度和范围的指令。研究重点是：1。为什么有些人在接种疫苗后会再次感染或感染？在接种疫苗后感染的个体中，我们能否确定他们免疫系统的哪些部分不能提供免疫保护？接种疫苗的这种免疫力持续多长时间？不同的疫苗有什么不同？免疫系统对加强剂量的疫苗接种有何反应？SARS-CoV-2病毒基因组成的变化如何导致免疫反应的逃避？在人类遗传密码中，与对病毒和疫苗接种的不同免疫反应相关的差异是什么？我们将使用我们的队列研究中招募的关键人群的血液来评估这些问题，以评估免疫反应。我们将研究：a)再次感染（在先前确认感染后再次感染）和接种一剂或两剂疫苗的个体；b)接种两剂疫苗后再次感染的个体。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进行一次PCR测试，并定期进行血液抗体测试，以备将来分析。此外，对于接种疫苗后发生感染的个体，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存在功能性问题，服用可能阻止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检查，以详细分析他们对COVID的免疫反应。这将包括对他们感染前后的血液测试进行分析，我们将询问他们是否愿意参与对他们的DNA密码进行遗传分析，看看他们的DNA密码中是否存在可能预测疫苗接种不良反应的特定突变。我们将寻求科学地做到这一点，使用特定的研究设计，将疫苗接种后感染的个体与未感染的个体进行比较，并根据年龄、性别、种族和合并症进行匹配。将对T细胞和b细胞免疫反应进行比较，以确定这两组之间是否存在可检测到的关键差异。

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.