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

最近接触过的家庭接触者免受 SARS-CoV-2 感染和疾病的相关性 (COPASID)

• 批准号: MR/X004058/1
• 负责人: Ajit Lalvani
• 金额: $ 129.45万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX004058%2F1
• 关键词: Correlates; protection; against; SARS; CoV

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.

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，“防变体”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的天然广泛保护性免疫反应，为开发这种第二代通用疫苗提供信息。虽然SARS-CoV-2在许多人中引起严重疾病，但大多数人都有轻微的疾病，这表明天然免疫反应可以成功地遏制病毒并限制症状，就像保护性刹车一样。此外，尽管严重暴露于SARS-CoV-2，但超过50%的家庭接触者（HHC）仍未感染。这意味着身体的防御可以防止感染，即使没有接种疫苗，就像一个保护盾。然而，人们对这些自然保护机制知之甚少，因为迄今为止的研究都集中在严重的住院COVID-19患者身上。因此，以下重要问题尚待回答：（a）尽管接触，哪些机制可保护身体不受感染？(b)如果发生感染，使身体能够成功遏制病毒并限制症状的早期机制是什么？为了解决这些问题，我们需要在接触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概况：（a）预测免受感染的保护（B）包含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，这些新知识将为第二代疫苗的开发提供信息，以提供针对当前和未来的“逃逸”变体的广泛保护，这些变体逃避了当前疫苗提供的狭隘保护。另一个应用可能是鼻喷雾剂，它可以增强鼻腔和喉咙内壁的天然免疫机制，在感染进展之前预防或治疗感染。该提案利用了180个暴露于COVID-19病例的独特HHC人群的全面临床样本库（生物库）。从SARS-CoV-2暴露开始，每个接触者都完成了每日症状问卷调查，并提供了频繁的血液、咽拭子和鼻粘膜液（NLF）样本。NLF反映了“上呼吸道”的状态，SARS-CoV-2在体内降落以建立感染。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-但以前没有在暴露于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索引生物库中。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，我们将通过测量宝贵的NLF样品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。它们共同构成了感染的“后果”，例如，抵抗感染或被感染，但病毒载量低，症状轻微或无症状。虽然我们的项目是高度原创性的，并解决了具有深远医学和科学意义的问题，成功执行的风险非常低，因为：1.建立生物库和相关的参与者数据2。测量免疫机制的所有必要方法都已在我们的实验室中启动并运行3。我们的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，以交付最后，建立生物库的成本（150万英镑）已经得到满足，使这项建议物有所值。