Developing an infection-blocking pan-coronavirus vaccine

病毒进行了一场激烈的竞争，以超越我们的免疫系统并建立感染。我们的免疫反应通常不能迅速扩大到足以赢得竞争，因此无法阻止病毒在我们的细胞中传播并传播给其他细胞。因此，有必要用更有效的疫苗来训练我们的免疫系统，使它们能够在病毒在个人和群体层面站稳脚跟之前关闭病毒。在过去的20年里，由动物传播给人类的冠状病毒引发了三次全球大流行：SARS、中东呼吸综合征和COVID-19。即使是针对SARS-CoV-2的疫苗的加速开发，也不足以防止该病毒在全球范围内的传播，造成了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的刺突蛋白；研制针对最新变种病毒的新疫苗意味着我们将永远落后于病毒一步。因此，作为积极防范大流行的关键组成部分，我们正在开发一种泛冠状病毒疫苗，能够提供广泛的保护，防止新的动物冠状病毒传播给人类，以及防范当前和未来可能更具致命性的SARS-CoV-2变种。我们的疫苗“PanCoVax”将产生针对病毒复制所必需区域的免疫力。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都是高度保守的。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型冠状病毒的大流行。现有的SARS-CoV-2疫苗的另一个限制是，它们不能诱导出能够在病毒繁殖和传播给他人之前将其关闭的免疫力。然而，PanCoVax模拟了我们在一小部分个体中观察到的一种免疫反应，这些个体能够如此迅速地“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呼吸道（鼻子和肺部），这是免疫系统和病毒之间竞争开始的地方。通过将疫苗注入呼吸道，我们可以扩大局部免疫反应，专门提供非常快速的“一线防御”。因为我们的疫苗被设计为刺激t细胞和抗体，它将提供更持久的保护。因此，它应该非常适合于增强对抗体产生受损的脆弱个体的保护，例如，由于免疫抑制药物或慢性肝脏或肾脏疾病。为了测试和选择最佳版本的PanCoVax，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和疫苗开发方面拥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，将疫苗直接注入气道可以有效地刺激局部免疫，理想的定位是在感染部位提供增强的一线保护。通过选择最佳设计和交付方法，并确认其产生持久的感染阻断免疫，来自DPFS申请的资金对于我们推进PanCoVax至关重要。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（包括来自人类供体的细胞和最先进的模型）发生交叉反应，研究PanCoVax对不同冠状病毒提供保护的预期能力。在这项拨款资助结束时，我们将收集一整套数据，以便将PanCoVax快速推进到人体试验中。

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.