A novel self-adjuvanting vaccine platform

接种疫苗是控制传染病最有效的公共卫生措施。虽然传统的疫苗由不会引起疾病的完整病原体或部分病原体组成，但大多数新型疫苗利用遗传物质直接在接种者中产生保护性反应，例如mRNA疫苗和重组病毒载体。mRNA疫苗的生产相对简单，但它们产生的免疫反应往往是短暂的，需要定期加强。相反，非复制型病毒载体，如MVA，具有良好的安全性，并诱导长期免疫应答。然而，MVA只有中等免疫原性，因此需要高剂量的病毒才能产生这些长期的反应。我们将解决的挑战：生产高滴度的MVA具有挑战性，成本高，是限制其广泛使用的主要瓶颈。使MVA更具免疫原性将允许施用较低的疫苗剂量以实现相同水平的长期免疫保护，从而减轻生产负担并降低成本。以前使MVA更具免疫原性的尝试涉及从MVA基因组中去除已知抑制免疫应答的病毒蛋白，但这些尝试只取得了有限的成功。相反，我们的新策略被设计为通过用通常感测感染的宿主蛋白质武装疫苗载体来改善MVA的免疫检测，从而在疫苗接种部位产生更多的内源性“佐剂”。佐剂是已知激活身体免疫反应的分子，从而增强免疫原性潜力，我们的方法利用了我们细胞天然产生的佐剂，避免了与其他化合物相关的毒性。我们将本发明称为“自辅助”MVA或SAMVA。目的和目标：使用来自MRC的先前翻译授权，我们已经表明SAMVA的产生是可能的，并且它确实比当前MVA在细胞中激活更强的免疫应答。我们现在要解决的两个重要问题是：1）SAMVA能否进一步优化，以最大限度地提高自佐剂性能？2)SAMVA在临床前模型中是否更具免疫原性？为了解决第一个目标，我们将利用我们关于MVA如何被细胞感知的知识和专业知识来改善宿主传感器从疫苗平台的表达，从而增加内源性佐剂的产生。对于第二个目的，我们将接种小鼠以测试SAMVA和目的1中产生的修饰的SAMVA是否导致对当前MVA的上级免疫应答。解决这些问题对于证明未来临床试验的合理性和吸引对平台翻译的进一步投资是必要的。应用和好处：MVA已经被批准作为天花和猴痘的疫苗。它的广泛分布受到制造挑战的极大限制，SAMVA旨在克服这些挑战。因此，SAMVA可以立即用作猴痘疫苗。MVA也已被广泛测试作为许多其他传染性病原体的疫苗平台，SAMVA有可能快速应用于这些病原体。例如，MVA目前被批准或正在评估用于针对丝状病毒（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是一种改进的载体，无论针对何种疾病都会产生免疫力，因此它可以应用于目前正在开发的任何基于MVA的疫苗方案。

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.