A novel self-adjuvanting vaccine platform

点击翻译按钮获取中文摘要

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.