Developing an infection-blocking pan-coronavirus vaccine

开发阻断感染的泛冠状病毒疫苗

• 批准号: MR/Y019466/1
• 负责人: Mala Maini
• 金额: $ 241.92万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY019466%2F1
• 关键词: Developing; infection; blocking; pan; coronavirus

Viruses run a highly competitive race to outpace our immune system and establish infection. Our immune responses can't usually expand fast enough to win the race so are unable to prevent viruses spreading amongst our cells and being transmitted on to others. Therefore, it is essential to train our immune systems with more effective vaccines to allow them to shutdown viruses before they gain a foothold, both within an individual and at a population level. In the last 20 years, there have been 3 global pandemics caused by coronaviruses passing from animals to humans: SARS, MERS and COVID-19. Even the accelerated development of vaccines against SARS-CoV-2 was not fast enough to prevent worldwide spread of the virus, with devastating morbidity and mortality. Existing vaccines have become less effective at preventing infection because they target the spike protein that rapidly mutated to escape immunity; making new vaccines against the latest variant means we will always be a step behind the virus. As a crucial component of proactive pandemic preparedness, we are therefore developing a pan-coronavirus vaccine with the capacity to provide broad protection against new animal coronaviruses spreading into humans, as well as against current and future, potentially more lethal, SARS-CoV-2 variants. Our vaccine, 'PanCoVax', will generate immunity that targets regions that are essential for virus replication. We found these regions to be highly conserved across all variants and also all versions of coronaviruses in the animal kingdom. Our vaccine will therefore be 'future variant proof' and offer protection against pandemics from new coronaviruses transmitted from animals. Another limitation of existing SARS-CoV-2 vaccines is that they do not induce immunity able to shut down the virus before it multiplies and can be transmitted on to others. However, PanCoVax mimics a type of immune response we observed in a subset of individuals who were able to 'abort' SARS-CoV-2 so rapidly that the virus never became detectable. To achieve this, we will target the first proteins produced in the viral lifecycle and deliver the vaccine directly into the airways (nose and lungs), the site where the race between the immune system and the virus starts. By delivering the vaccine into the airways, we can expand local immune responses that are specialised to provide very rapid 'frontline defence'. Because our vaccine is designed to stimulate T-cells as well as antibodies, it will provide longer-lasting protection. It should, therefore, be well-suited to boost protection in vulnerable individuals whose antibody production is impaired because of immunosuppressive medication or chronic liver or kidney diseases, for example. To test and select the optimal version of PanCoVax, we have assembled a highly synergistic team of viral immunologists with world-leading expertise in SARS-CoV-2 and vaccine development. We have already constructed our vaccines and generated promising initial results showing that they can generate excellent immune responses. Our preliminary data show that delivering vaccine directly into the airways potently stimulates local immunity, ideally positioned to provide enhanced frontline protection at the site of infection. Funding from this DPFS application will be crucial to allow us to progress PanCoVax by selecting the optimal design and delivery method and confirming it generates durable, infection-blocking immunity. We will investigate the anticipated ability of PanCoVax to provide protection against different coronaviruses by testing whether induced T-cells and antibodies cross-react with a range of different SARS-CoV-2 variants and other coronaviruses, including with cells from human donors and in state-of-the-art models. At the end of this grant funding, we will have assembled a package of data to allow rapid progression of PanCoVax into human testing.

病毒进行着一场高度竞争的竞赛，以超过我们的免疫系统并建立感染。我们的免疫反应通常不能足够快地扩展以赢得比赛，因此无法阻止病毒在我们的细胞中传播并传播给其他人。因此，必须用更有效的疫苗训练我们的免疫系统，使它们能够在病毒站稳脚跟之前将其关闭，无论是在个人还是在群体水平上。在过去的20年里，有3次全球性大流行病是由冠状病毒从动物传播到人类引起的：SARS，MERS和COVID-19。即使是加速开发SARS-CoV-2疫苗的速度也不足以防止该病毒在世界范围内传播，造成毁灭性的发病率和死亡率。现有的疫苗在预防感染方面已经变得不那么有效，因为它们针对的是迅速突变以逃避免疫力的刺突蛋白;针对最新变种制造新疫苗意味着我们将永远落后于病毒。因此，作为积极防范大流行的重要组成部分，我们正在开发一种泛冠状病毒疫苗，该疫苗能够提供广泛的保护，防止新的动物冠状病毒传播到人类，以及防止当前和未来可能更致命的SARS-CoV-2变种。我们的疫苗“PanCoVax”将产生针对病毒复制所必需的区域的免疫力。我们发现这些区域在动物王国的所有变体和所有版本的冠状病毒中高度保守。因此，我们的疫苗将是“未来的变种证明”，并提供保护，防止从动物传播的新冠状病毒的大流行病。现有SARS-CoV-2疫苗的另一个局限性是，它们不能诱导免疫力，从而在病毒繁殖并传播给他人之前关闭病毒。然而，PanCoVax模拟了我们在一部分人中观察到的一种免疫反应，这些人能够如此迅速地“中止”SARS-CoV-2，以至于病毒从未被检测到。为了实现这一目标，我们将瞄准病毒生命周期中产生的第一批蛋白质，并将疫苗直接输送到气道（鼻子和肺部），这是免疫系统和病毒之间竞争的开始。通过将疫苗输送到气道，我们可以扩大局部免疫反应，这些免疫反应专门提供非常快速的“前线防御”。由于我们的疫苗旨在刺激T细胞和抗体，它将提供更持久的保护。因此，它应该非常适合于加强对由于免疫抑制药物或慢性肝脏或肾脏疾病而导致抗体产生受损的脆弱个体的保护。为了测试和选择PanCoVax的最佳版本，我们组建了一个高度协同的病毒免疫学家团队，他们在SARS-CoV-2和疫苗开发方面具有世界领先的专业知识。我们已经构建了我们的疫苗，并产生了有希望的初步结果，表明它们可以产生出色的免疫反应。我们的初步数据表明，将疫苗直接输送到气道中可以有效地刺激局部免疫力，这是在感染部位提供增强的前线保护的理想位置。来自DPFS申请的资金将是至关重要的，使我们能够通过选择最佳设计和交付方法并确认它产生持久的感染阻断免疫力来推进PanCoVax。我们将通过测试诱导的T细胞和抗体是否与一系列不同的SARS-CoV-2变异体和其他冠状病毒交叉反应，包括与来自人类供体的细胞和最先进的模型，来研究PanCoVax提供针对不同冠状病毒的保护的预期能力。在这笔拨款结束时，我们将收集一系列数据，以使PanCoVax能够快速进入人体测试。