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 疫苗逃逸变体凸显了对更广泛保护性“防变体”疫苗的需求，以预防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自然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 在许多人中引起严重疾病，但大多数人病情较轻，这表明自然免疫反应可以成功遏制病毒并限制症状，就像保护性刹车一样。此外，尽管大量接触 SARS-CoV-2，但超过 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，身体的防御能力也可以预防感染，就像防护罩一样。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主要集中在重症住院的 COVID-19 患者身上。因此，以下重要问题尚待解答： (a) 尽管暴露，但什么机制可以保护身体免受感染？ (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，我们需要测量人体在接触 SARS-CoV-2 时的免疫状况，并研究随后的感染“结果”。这使我们能够梳理出哪些特征：（a）预测感染保护（b）包含病毒并限制感染者的症状然后我们可以将这些自然保护机制的好处带给那些天生没有这些机制的人，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，以针对当前和未来的“逃逸”变种提供广泛的保护，这些变种逃避了当前疫苗提供的狭隘保护。另一种应用可能是鼻喷雾剂，它可以增强鼻子和喉咙内壁的自然免疫机制，在感染进展之前预防或治疗感染。该提案利用了 180 个接触过 COVID-19 病例的 HHC 的独特群体的临床样本综合存储库（生物库）。从接触 SARS-CoV-2 起，每个接触者都完成了每日症状调查问卷，并经常提供血液、咽拭子和鼻腔粘液 (NLF) 样本。 NLF 反映了“上呼吸道”的状态，SARS-CoV-2 在此降落在体内形成感染。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 - 但此前尚未在暴露于 SARS-CoV-2 的人群中进行过研究。血液和 NLF 样本被冷冻在安全的索引生物库中。在 NLF 和血液中，我们将测量多种我们怀疑可能介导保护的免疫机制。其中包括化学信使、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。它们共同构成了感染的“结果”，例如，抵抗感染或被感染，但病毒载量较低，症状很少或没有症状。尽管我们的项目具有高度原创性，并解决了具有深远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。建立了生物样本库和关联的参与者数据2。测量免疫机制的所有必要方法都在我们的实验室中启动并运行3。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，建立生物库的成本（150 万英镑）已经得到满足，使该提案物超所值。