A novel self-adjuvanting vaccine platform

一种新型的自我辅助疫苗平台

• 批准号: MR/Z503885/1
• 负责人: Carlos Maluquer De Motes
• 金额: $ 29.61万
• 依托单位: University of Surrey
• 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%2FZ503885%2F1
• 关键词: novel; self; adjuvanting; vaccine; platform

Context: Vaccination is the most effective public health measure to control infectious disease. While traditional vaccines consist of either whole pathogens that do not cause disease or parts of them, most novel vaccines employ genetic material to raise a protective response directly in vaccinees, such as mRNA vaccines and recombinant virus vectors. mRNA vaccines are relatively simple to manufacture but the immune responses they produce tend to be short-lived, requiring regular boosting. Conversely, non-replicating virus vectors, such as MVA, have excellent safety profiles and induce long-lived immune responses. MVA is only moderately immunogenic however, therefore high viral doses are required to generate these long-lived responses.The challenge we will address: Manufacturing MVA to high titres is challenging, costly and a major bottleneck that limits its widespread use. Making MVA more immunogenic would allow administration of lower vaccines doses to achieve the same levels of long-lived immune protection, thus relieving manufacture burden and reducing costs. Previous attempts to make MVA more immunogenic have involved removing viral proteins from the MVA genome that are known to suppress the immune response, but these have yielded only limited success. Instead, our novel strategy is designed to improve immune detection of MVA by arming the vaccine vector with the host protein that normally senses infection, resulting in greater production of endogenous 'adjuvants' at the site of vaccination. Adjuvants are molecules known to activate the body's immune response, thus boosting immunogenic potential, and our approach exploits the ones naturally made by our cells, avoiding the toxicity associated with other compounds. We have termed this invention 'self-adjuvanting' MVA or SAMVA.Aims and objectives: Using a previous translational grant from the MRC we have shown that generation of SAMVA is possible and that it indeed activates a stronger immune response in cells than the current MVA. Two important questions that we will now address are: 1) Can SAMVA be further optimised to maximise the self-adjuvanting properties? 2) Is SAMVA more immunogenic in a pre-clinical model? To address the first aim we will use our knowledge and expertise on how MVA is sensed by cells to improve expression of the host sensor from the vaccine platform and hence increase endogenous adjuvant production. For the second aim we will vaccinate mice to test whether SAMVA and the modified SAMVAs generated in aim 1 lead to superior immune responses to current MVA. Addressing these questions is necessary to justify future clinical trials and to attract onward investment for translation of the platform.Applications and benefits: MVA is already approved as a vaccine against smallpox and monkeypox. Its widespread distribution has been greatly limited by manufacturing challenges, which SAMVA aims to overcome. SAMVA could therefore be used immediately as a monkeypox vaccine. MVA has also been extensively tested as a vaccine platform for many other infectious agents and SAMVA has the potential to be rapidly applied to these. For example MVA is currently approved or under evaluation for vaccination against filoviruses (e.g. Ebola virus), coronaviruses (e.g. MERS, SARS) and influenza virus. As SAMVA is an improved vector regardless of the disease against which immunity will be generated, it can be applied to any MVA-based vaccine regime currently in development.

环境：疫苗接种是控制传染病的最有效的公共卫生措施。虽然传统的疫苗由不引起疾病的整个病原体组成，或者大多数新型疫苗都采用遗传物质来直接在疫苗中提高保护性反应，例如mRNA疫苗和重组病毒载体。 mRNA疫苗的生产相对简单，但是它们产生的免疫反应往往是短暂的，需要定期提升。相反，非复制病毒载体（例如MVA）具有出色的安全性并诱导长期的免疫反应。 MVA仅是中等免疫原性的，因此，需要高病毒剂量才能产生这些长期寿命的反应。我们将要应对的挑战：制造MVA到高滴度是充满挑战，成本高昂的且主要的瓶颈，这限制了其广泛使用。使MVA更加免疫原性将使较低的疫苗剂量施用以达到相同水平的长寿命免疫保护，从而减轻制造负担并降低成本。以前的尝试使MVA更具免疫原性的尝试涉及从MVA基因组中去除病毒蛋白，这些病毒蛋白已知可以抑制免疫反应，但这些蛋白质仅产生有限的成功。取而代之的是，我们的新型策略旨在通过使用通常感染感染的宿主蛋白武装疫苗载体来改善MVA的免疫检测，从而在疫苗接种部位增加内源性“辅助”的产生。佐剂是已知可以激活人体免疫反应的分子，从而提高了免疫原性，我们的方法利用了我们的细胞自然产生的免疫原性，避免了与其他化合物相关的毒性。我们已经称这项发明的“自我加快” MVA或SAMVA.AIM和目标：使用MRC的先前翻译赠款，我们表明SAMVA的产生是可能的，并且它确实激活了与当前MVA相比，细胞中的免疫反应更强。我们现在将要解决的两个重要问题是：1）SAMVA是否可以进一步优化以最大化自我支持的属性？ 2）在临床前模型中，SAMVA是否更容易免疫原性？为了解决第一个目标，我们将使用我们的知识和专业知识来了解细胞如何感知MVA，从而改善疫苗平台的宿主传感器表达，从而增加内源性辅助生产。对于第二个目标，我们将接种小鼠，以测试SAMVA和在AIM 1中生成的修饰的SAMVA是否导致对当前MVA的优势免疫反应。解决这些问题是为了证明未来的临床试验的合理性并吸引平台翻译的投资是必要的。应用程序：MVA已被批准为针对天花和蒙基托克斯的疫苗。 SAMVA旨在克服这一挑战，其广泛的分布受到了制造挑战的极大限制。因此，SAMVA可以立即用作猴子疫苗。 MVA也已作为许多其他传染剂的疫苗平台进行了广泛的测试，SAMVA有可能快速应用于这些疫苗。例如，目前，MVA已批准或评估针对FILOVIRES（例如埃博拉病毒），冠状病毒（例如MERS，SARS）和流感病毒的疫苗接种。由于SAMVA是一种改善的载体，无论将产生免疫力的疾病如何，都可以应用于目前正在开发的任何基于MVA的疫苗状态。