Correlates of protection against SARS-CoV-2 infection and disease in recently exposed household contacts (COPASID)

接连出现的SARS-CoV-2疫苗逃逸变种突显了对更广泛的保护性、抗变种的疫苗的需求，以保护当前和未来可能更有害的变种。我们的目标是识别和利用人体自身天然的广泛保护性免疫反应，为此类第二代通用疫苗的开发提供信息。虽然SARS-CoV-2会导致许多人患上严重疾病，但大多数人病情轻微，这表明自然免疫反应可以成功地遏制病毒，并限制症状，如保护性刹车。此外，尽管严重暴露于SARS-CoV-2，超过50%的家庭接触者(HHC)仍未受到感染。这意味着，即使没有接种疫苗，人体的防御系统也可以防止感染，就像保护盾一样。然而，人们对这些自然保护机制知之甚少，因为到目前为止，研究主要集中在重症住院的新冠肺炎患者身上。因此，下列重要问题尚未得到回答：(A)尽管暴露在空气中，什么机制仍能保护身体免受感染？(B)如果发生感染，使人体能够成功控制病毒并限制症状的早期机制是什么？为了解决这些问题，我们需要测量接触SARS-CoV-2病毒时人体的免疫状况，并研究随后感染的“结果”。这使我们能够梳理出哪些特征：(A)预测免受感染的保护措施(B)控制病毒并限制感染者的症状然后我们可以将这些自然保护机制的好处带给那些不是天生具有这些机制的人，防止传播和严重疾病。例如，这一新知识将为第二代疫苗的开发提供信息，以提供广泛的保护，防止当前和未来的“逃逸”变种逃避现有疫苗提供的狭隘保护。另一个应用可能是鼻喷雾，它可以增强鼻子和喉咙衬里的自然免疫机制，在感染进展之前预防或治疗感染。这项建议利用了接触新冠肺炎病例的180HHC独特人群的临床样本(生物库)的综合信息库。自SARS-CoV-2接触后，每个接触者完成每日症状问卷调查，并经常提供血液、咽拭子和鼻腔液(NLF)样本。NLF反映的是“上呼吸道”的状况，即SARS-CoV-2病毒落在体内以确定感染的地方。这是病毒和身体之间的关键战场，在很大程度上决定了暴露的结果--但之前还没有对接触SARS-CoV-2的人进行研究。血液和NLF样本被冷冻在一个安全的、有索引的生物库中。在NLF和血液中，我们将测量一系列我们怀疑可能介导保护的免疫机制。这些包括化学信使、抗体和不同类型的免疫细胞。为了确保我们不会错过我们没有考虑过的反应，我们将通过测量许多不同的蛋白质和许多有价值的NLF样本中许多基因的表达来撒下我们的网。临床症状数据和咽拭子病毒载量结果被匿名存储在一个安全的、链接的数据库中。尽管我们的项目具有很高的原创性，解决了具有深远的医学和科学重要性的问题，但成功执行的风险非常低，因为：1.生物库和相关参与者数据已建立2.所有测量免疫机制的必要方法都已在我们的实验室中启动并运行。我们世界领先的专家项目团队拥有丰富的经验，提供交付所需的所有技能最后，建立生物库的成本(150万GB)已经满足，使这项建议物有所值。

The emergence of successive SARS-CoV-2 vaccine escape variants highlights the need for more broadly protective, 'variant-proof' vaccines that protect against current and future, potentially more harmful, variants. We aim to identify and harness the body's own natural broadly protective immune responses to inform development of such 2nd generation universal vaccines.While SARS-CoV-2 causes severe disease in many people, most have mild illness, indicating that natural immune responses can successfully contain the virus and limit symptoms, like a protective brake. Additionally, over 50% of household contacts (HHCs) remain uninfected despite heavy exposure to SARS-CoV-2. This implies the body's defences can prevent infection, even without vaccination, like a protective shield. However, little is known about these natural protective mechanisms because research to date has focused on severe, hospitalised COVID-19 patients. Hence, the following important questions are yet to be answered: (a) What mechanisms protect the body from infection despite exposure? (b) If infection occurs, what are the early mechanisms that enable the body to successfully contain the virus and limit symptoms? To address these, we need to measure the body's immune profile at the time of exposure to SARS-CoV-2 and study the subsequent 'outcomes' of infection. This allows us to tease out which profiles:(a) predict protection from infection(b) contain the virus and limit symptoms in those who get infectedWe can then bring benefits of these natural protective mechanisms to people who do not naturally have them, preventing transmission and severe disease. For example, this new knowledge will inform development of 2nd generation vaccines to provide broad protection against current and future 'escape' variants which evade the narrow protection provided by current vaccines. Another application could be a nasal spray that enhances natural immune mechanisms in the lining of the nose and throat, preventing or treating infection before it progresses.This proposal leverages the comprehensive repository of clinical samples (biobank) of a unique population of 180 HHCs exposed to COVID-19 cases. From the time of SARS-CoV-2 exposure onwards, each contact completed daily symptom questionnaires and provided frequent samples of blood, throat swabs and nasal lining fluid (NLF). NLF reflects the status of the 'upper respiratory tract,' where SARS-CoV-2 alights in the body to establish infection. This is the pivotal battlefield between the virus and the body that largely decides outcome of exposure - but it has not previously been researched in people exposed to SARS-CoV-2.The blood and NLF samples were frozen in a secure, indexed biobank. In both NLF and blood we will measure a wide range of immune mechanisms that we suspect may mediate protection. These include chemical messengers, antibodies and different types of immune cells. To ensure we do not miss responses that we have not considered, we will cast our net wide by measuring many different proteins and the expression of many genes in the valuable NLF samples. The clinical symptom data and throat swab virus load results were stored anonymously in a secure, linked database. Together they comprise the 'outcomes' of infection, e.g., resisting infection or getting infected but with low viral load and minimal or no symptoms.Although our project is highly original and addresses questions of far-reaching medical and scientific importance, the risk to successful execution is very low because:1. The biobank and linked participant data are established 2. All the necessary methods for measuring immune mechanisms are up-and-running in our lab3. Our world-leading expert project team has a diverse range of experience providing all the requisite skills to deliverLastly, the cost to establish the biobank (£1.5 million) has already been met, making this proposal excellent value for money.