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; 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.

病毒举办一场竞争激烈的竞赛，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到赢得比赛，因此无法防止病毒在我们的细胞之间传播并传播给他人。因此，必须使用更有效的疫苗训练我们的免疫系统，以使其在个人和人口水平的立足点之前就可以关闭病毒。在过去的20年中，冠状病毒从动物到人类的冠状病毒引起了3种全球大流行：SARS，MERS和COVID-19。即使是针对SARS-COV-2的疫苗的加速发育也不够快，无法以灾难性的发病率和死亡率来防止该病毒的传播。现有的疫苗在预防感染方面的有效性降低了，因为它们靶向迅速突变以逃避免疫力的峰值蛋白。针对最新变体进行新的疫苗意味着我们将永远是病毒的一步。因此，作为主动pandemic准备的关键组成部分，我们正在开发一种泛氧化病毒疫苗，其能力具有广泛的保护，以防止扩散到人类的新动物冠状病毒，以及针对当前和未来的，可能更致命的SARS-COV-COV-2变体。我们的疫苗“ pancovax”将产生靶向病毒复制区域的免疫力。我们发现，这些区域在动物界的所有变体和所有版本的冠状病毒中都是高度保守的。因此，我们的疫苗将是“未来的变体证明”，并为来自动物传播的新冠状病毒的大流传学提供保护。现有的SARS-COV-2疫苗的另一个局限性是，它们不会诱导能够在病毒倍增之前关闭病毒并可以将其传播给其他人。但是，pancovax模仿了我们在能够迅速“流产” SARS-COV-2的一个个体中观察到的一种免疫反应，以至于该病毒永远无法检测到。为了实现这一目标，我们将靶向病毒生命周期中产生的第一种蛋白质，并将疫苗直接输送到气道（鼻子和肺部），即免疫系统和病毒之间竞赛之间的部位。通过将疫苗运送到气道中，我们可以扩大专门提供非常快速的“前线防御”的局部免疫反应。由于我们的疫苗旨在刺激T细胞和抗体，因此它将提供更长的保护。因此，应该非常适合促进易受伤害的人的保护，其抗体产生因免疫抑制药物或慢性肝脏或肾脏疾病而受到损害。为了测试并选择Pancovax的最佳版本，我们组装了一支高度协同的病毒免疫学家团队，并在SARS-COV-2和疫苗开发方面拥有世界领先的专业知识。我们已经建立了疫苗并产生了有希望的初始结果，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会有效刺激局部免疫力，理想位置可在感染部位提供增强的前线保护。该DPFS应用程序的资金对于使我们能够通过选择最佳设计和输送方法来促进pancovax至关重要，并确认它会产生持久的感染障碍。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变体和其他冠状病毒（包括与人类供体的细胞和目前的模型中的细胞），通过测试诱导的T细胞和抗体对不同冠状病毒提供保护的预期能力。在本赠款资金结束时，我们将组装一包数据，以使Pancovax快速发展为人类测试。