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

新出现的严重急性呼吸综合征冠状病毒2型是新冠肺炎大流行的原因，对全球卫生和社会产生了巨大影响。感染SARS-CoV-2会导致一系列不同的疾病结局，从无症状的感染到可能需要住院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--人体对感染的天然防御机制。自2019年以来，人们已经做了很多工作来开始了解免疫系统在新冠肺炎结局中的作用，并调查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，免疫系统的两个特殊部分：B细胞和抗体反应以及T细胞的核心作用已经被证明。T细胞在清除感染方面的作用似乎特别有趣--然而，由于在实验上探索这些反应相对困难(与抗体等其他免疫反应相比)，关于它们在免疫保护中的作用仍有许多需要了解。因此，在特定背景下观察这些反应，例如观察先前存在的免疫的影响，可能是由先前感染非常相似的导致普通感冒的冠状病毒引起的，对于我们理解新冠肺炎的结果可能非常有趣和重要。SARS-CoV-2免疫的另一个非常重要的方面仍然知之甚少，那就是大量服用药物或有潜在疾病(如癌症、慢性肝病等)的人感染的结果会抑制他们的免疫系统。这群人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.调查SARS-CoV-2自然感染和SARS-CoV-2疫苗接种后的T细胞免疫功能。探索免疫受损对SARS-CoV-2疫苗应答的影响，并确定T细胞在这些应答中所起的作用。3.)研究先前存在的对SARS-CoV-2的T细胞免疫在应对感染中的潜在作用。重要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紧急病毒，对SARS-CoV-2免疫系统的作用建立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，如先前存在的对SARS-CoV-2的免疫力对疾病结局的影响是关键，并可能对我们理解对SARS-CoV-2感染的免疫力有很大影响，因为SARS-CoV-2感染可能会交叉到其他病毒家族。除此之外，研究免疫受损人群的免疫力非常重要，因为这是一个巨大的知识鸿沟，对于保护全球非常庞大的高度临床脆弱人群是不可或缺的。由于这些人受到免疫抑制，他们对疫苗的反应可能会比免疫系统健康的人更差，因此对这些人的保护可能会减弱。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。通过收集免疫缺陷人群对疫苗反应的证据，我们可以指导制定政策和临床建议，以保护未来的患者，并加深对免疫缺陷人群疫苗反应的了解。

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.