A novel self-adjuvanting vaccine platform

背景：疫苗接种是控制传染病最有效的公共卫生措施。传统疫苗由不引起疾病的整个病原体或病原体的一部分组成，而大多数新型疫苗利用遗传物质直接在接种者中引起保护性反应，例如mRNA疫苗和重组病毒载体。mRNA疫苗制造相对简单，但它们产生的免疫反应往往是短暂的，需要定期增强。相反，非复制病毒载体，如MVA，具有良好的安全性，并诱导长期的免疫反应。然而，MVA仅具有中等免疫原性，因此需要高病毒剂量才能产生这些长期反应。我们将解决的挑战：制造高滴度的MVA具有挑战性，成本高，是限制其广泛使用的主要瓶颈。使MVA具有更强的免疫原性，将允许使用更低剂量的疫苗来达到相同水平的长期免疫保护，从而减轻生产负担并降低成本。以前试图使MVA更具免疫原性的方法包括从MVA基因组中去除已知会抑制免疫反应的病毒蛋白，但这些方法只取得了有限的成功。相反，我们的新策略旨在通过用通常感知感染的宿主蛋白武装疫苗载体来提高MVA的免疫检测，从而在接种部位产生更多的内源性“佐剂”。佐剂是一种已知的分子，可以激活人体的免疫反应，从而提高免疫原性的潜力，我们的方法利用了细胞自然产生的佐剂，避免了与其他化合物相关的毒性。我们称这项发明为“自我调节”MVA或SAMVA。目的和目标：利用MRC先前的转译拨款，我们已经证明SAMVA的产生是可能的，并且它确实比目前的MVA在细胞中激活更强的免疫反应。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调节性能？2) SAMVA在临床前模型中是否更具免疫原性？为了实现第一个目标，我们将利用我们关于细胞如何感知MVA的知识和专业知识，从疫苗平台改善宿主传感器的表达，从而增加内源性佐剂的产生。对于第二个目标，我们将给小鼠接种疫苗，以测试SAMVA和在目标1中产生的改良SAMVA是否会对当前的MVA产生优越的免疫反应。解决这些问题是必要的，以证明未来的临床试验，并吸引进一步投资的翻译平台。应用和益处：MVA已被批准作为天花和猴痘疫苗。它的广泛分布受到制造挑战的极大限制，SAMVA的目标是克服这些挑战。因此，SAMVA可以立即用作猴痘疫苗。MVA还作为许多其他感染原的疫苗平台进行了广泛的测试，SAMVA具有迅速应用于这些感染原的潜力。例如，目前已批准或正在评估MVA用于预防丝状病毒（如埃博拉病毒）、冠状病毒（如中东呼吸综合征、SARS）和流感病毒的疫苗接种。由于SAMVA是一种改进的媒介，无论将对哪种疾病产生免疫力，它都可以应用于目前正在开发的任何基于mva的疫苗体系。

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.