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

连续出现的SARS-CoV-2疫苗逃逸变体突出表明，需要更广泛的保护性“抗变体”疫苗，以防止当前和未来可能更有害的变体。我们的目标是识别和利用人体自身自然的广泛保护性免疫反应，为这种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，但大多数人的病情都很轻微，这表明自然免疫反应可以成功地控制病毒并限制症状，就像保护性刹车一样。此外，超过50%的家庭接触者尽管大量接触SARS-CoV-2，但仍未被感染。这意味着即使没有接种疫苗，人体的防御系统也能像防护盾一样防止感染。然而，由于迄今为止的研究主要集中在住院的重症COVID-19患者身上，人们对这些天然保护机制知之甚少。因此，下列重要问题还有待回答：(a)什么机制保护人体不受感染？(b)如果发生感染，什么早期机制能使身体成功地控制病毒和限制症状？为了解决这些问题，我们需要在暴露于SARS-CoV-2时测量身体的免疫状况，并研究感染的后续“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(b)控制病毒并限制感染者的症状，然后我们可以将这些天然保护机制的好处带给那些没有天然保护机制的人，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，防止当前和未来逃避当前疫苗提供的狭隘保护的“逃逸”变异。另一种应用可能是鼻腔喷雾剂，它可以增强鼻子和喉咙内壁的自然免疫机制，在感染恶化之前进行预防或治疗。本提案利用了暴露于COVID-19病例的180个独特人群的临床样本综合库（生物库）。从SARS-CoV-2暴露开始，每位接触者完成每日症状问卷，并经常提供血液样本、咽拭子和鼻粘膜液（NLF）。NLF反映了“上呼吸道”的状态，即SARS-CoV-2降落在体内建立感染的地方。这是病毒和身体之间的关键战场，在很大程度上决定了接触的结果，但此前尚未在接触过SARS-CoV-2的人群中进行过研究。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，我们将测量我们怀疑可能介导保护的广泛免疫机制。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到的反应，我们将通过测量有价值的NLF样本中许多不同的蛋白质和许多基因的表达来广泛撒网。临床症状数据和咽拭子病毒载量结果匿名存储在安全的链接数据库中。它们共同构成感染的“结果”，例如，抵抗感染或感染，但病毒载量低，症状很少或没有症状。虽然我们的项目是高度原创的，并解决了影响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：建立生物库和相关参与者数据2。在我们的实验室里，所有测量免疫机制的必要方法都在运转。我们世界领先的专家项目团队拥有丰富的经验，提供所有必要的技能。最后，建立生物银行的成本（150万英镑）已经到位，这使得这个提议物有所值。

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.