Understanding T cell immunity to SARS-CoV-2 natural infection and vaccination in healthy and immunocompromised individuals

新出现的病毒，严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）是COVID-19大流行的原因，对全球健康和社会产生了巨大影响。SARS-CoV-2感染导致多种疾病结局，从无症状感染到可能需要住院治疗甚至可能导致死亡的严重疾病。决定感染结果的一个关键因素是免疫系统-身体对感染的天然防御机制。自2019年以来，我们已经做了大量工作，开始了解免疫系统在COVID-19结果中的作用，并研究免疫反应的哪些部分对于适当的感染保护是重要的。到目前为止，免疫系统的两个特定部分的核心作用：B细胞和抗体反应，以及T细胞，已经被证明。T细胞似乎在清除感染中的作用特别有趣-然而，由于实验探索这些反应相对困难（与其他免疫反应如抗体相比），关于它们在免疫保护中的作用仍有很多需要了解。因此，在特定背景下观察这些反应-例如观察预先存在的免疫力的影响，可能是由先前感染引起普通感冒的非常相似的冠状病毒引起的，这对我们理解COVID-19的结果可能非常有趣和重要。SARS-CoV-2免疫力的另一个非常重要的方面仍然知之甚少，这是在大量服用药物或患有抑制免疫系统的潜在疾病（如癌症，慢性肝病等）的人群中感染的结果。对这一人群的关键是了解他们对SARS-CoV-2疫苗的反应能力，看看他们的反应是否足以保护他们免受感染。通过观察不同的免疫抑制人群，我们可以开始了解某些疾病或药物对疫苗反应的影响，这将是指导这些人的政策和治疗选择的关键。因此，我的项目的目的和目标是：1。研究SARS-CoV-2自然感染和SARS-CoV-2疫苗的T细胞免疫。探索免疫受损对SARS-CoV-2疫苗应答的影响，并确定T细胞在这些应答中的作用。3.）第三章研究SARS-CoV-2免疫系统对感染应答的潜在作用。重要性作为一种不仅对人类健康而且对全球社会和经济都具有巨大危害的新出现的病毒，建立对SARS-CoV-2免疫系统作用的更详细的了解是关键。全面了解T细胞在SARS-CoV-2免疫反应中的作用是建立这种理解的关键。探索潜在的非常重要的因素的作用，如预先存在的免疫SARS-CoV-2对疾病的结果是关键，可能会对我们理解免疫SARS-CoV-2感染，可能会有很大的影响交叉到其他家庭的病毒。除此之外，研究免疫功能低下人群的免疫力非常重要，因为这是一个巨大的知识缺口，对于保护全球大量高度临床脆弱人群是不可或缺的。由于这些人免疫抑制，他们对疫苗的反应可能比那些免疫系统健康的人更差，因此这些人的保护可能会减少。然而，到目前为止，关于特定疾病和药物对SARS-CoV-2感染或疫苗接种反应的影响的确切信息很少。通过收集免疫功能低下人群对疫苗的反应证据，我们可以指导政策和临床建议的制定，这将在未来保护患者，并了解免疫功能低下人群的疫苗反应。

The emergent virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic and has had a huge impact on global health and society. Infection with SARS-CoV-2 leads to a diverse range of disease outcomes, from asymptomatic infection to severe disease which may require hospitalisation or may even lead to death. A key player in deciding the outcome for infection is the immune system - the body's natural defence mechanism against infection. Since 2019, much work has been done to begin to understand the role of the immune system in COVID-19 outcomes and to investigate what parts of the immune response are important for proper protection against infection. So far, the central role of two specific compartments of the immune system: B cells and the antibody response, and T cells, has been shown. T cells seem to be particularly interesting in their role in clearing infection - however, because of the relative difficulty in exploring these responses experimentally (compared to other immune responses such as antibodies), there remains much to be understood about their role in immune protection. Viewing these responses in specific contexts - such as looking at the effect of pre-existing immunity, potentially caused by previous infection with very similar coronaviruses which cause the common cold, is therefore potentially very interesting and important in our understanding of COVID-19 outcomes. Another very important aspect of SARS-CoV-2 immunity which remains poorly understood is the outcome of infection in the large population of people that are on medication or have underlying conditions (such as cancer, chronic liver disease and more) which suppress their immune system. Key in this group of people is understanding their ability to respond to SARS-CoV-2 vaccines and see if their response is sufficient to protect them against infection. By looking at different groups of immunosuppressed people, we can begin to understand the effect of certain diseases or medication on vaccine response which will be key in guiding policy and treatment options for these people. The aim and objectives of my project therefore are to:1.) Investigate T cell immunity in natural SARS-CoV-2 infection and against the SARS-CoV-2 vaccines.2.) Explore the impact of compromised immunity on responses to SARS-CoV-2 vaccines and to determine the role that T cells play in these responses. 3.) Investigate the potential role of pre-existing T cell immunity to SARS-CoV-2 on responses to infection.ImportanceAs an emergent virus that has been hugely detrimental not only to human health but to global society and economy, building more detailed understanding of the role of the immune system in SARS-CoV-2 is key. Comprehensive knowledge of T cells in the immune response to SARS-CoV-2 is key in building this understanding. Exploring the role of potentially hugely important factors such as pre-existing immunity to SARS-CoV-2 on disease outcomes is key and may have a great impact on our understanding immunity to SARS-CoV-2 infections which may have cross-over to other families of viruses. As well as this, investigating immunity in immunocompromised people is hugely important, as this is a large knowledge gap which is integral to the protection of a very large global population of highly clinically vulnerable people. As these people are immunosuppressed, it is likely that their response to vaccines will be worse than those with healthy immune systems and therefore protection in these people may be decreased. So far however, there is very little definitive information on the effect of specific diseases and medications on responses to SARS-CoV-2 infection or vaccination. By gathering evidence of the responses that immunocompromised people make to vaccines, we can guide the development of policy and clinical advice which will protect patients in the future and develop understanding of vaccine responses in immunocompromised people.