EML-VAC: Multivalent replicon vaccine against Ebola, Marburg and Lassa viruses

基于合成复制核糖核酸的多价出血热疫苗将提供从源头上阻止病毒爆发的最快和最具成本效益的方法之一。这提供了比更常规的疫苗方法（例如病毒载体和减毒病原体）更显著的优点，并且在不能接受活减毒疫苗的个体（例如儿童和免疫功能低下者）中更安全。我们的计划旨在开发一种针对最常见的人类病毒性出血热（埃博拉病毒、马尔堡病毒和拉沙热病毒）的多价疫苗。靶点的选择基于强有力的科学证据，即基于基因的方法可以在临床前模型中保护免受感染。该疫苗也可用作可与现有疫苗（例如rVSV-EBOV）组合使用的加强剂。全合成制造和易于生产提供了在几周内生产数十万剂的潜力，其中针对不同出血性病毒的单个疫苗组分可以很容易地组合。这可能对全球应对新出现的出血性病毒感染至关重要，因为无法可靠地预测下一次疫情的性质。在这方面，所提出的多价疫苗不仅有可能预防多种已知的出血性病毒，而且更有可能显示出对未来可能出现的新变体的交叉保护。在该项目的第1部分（现已完成）中，我们成功完成了将我们的RNA平台从研究过程转移到完全建立的稳健和经验证的生产过程所需的繁重工作，证实了生产的产品在临床前模型中的效力。在第2部分项目中，我们将生产临床级材料（GMP），在I期人体临床试验中进行所需的临床前毒理学和疫苗的早期评估，旨在评估我们的泛出血热疫苗的安全性和免疫原性。我们有能力在两年的资助期内从生产到完成首次人体临床试验所需的积极时间表上交付，这是由于我们生产过程的稳健性和速度以及组装团队在将疫苗概念从实验室翻译到床边的独特能力。最终，我们的愿景是利用我们的疫苗平台，确保英国对任何最终的大流行病做好准备，并在任何疫情爆发的情况下在全球提供疫苗。我们的方法将确保低收入和中等收入国家的适当成本，并随时提供给专注于全球卫生的组织（例如无国界医生组织和世卫组织）：这些组织历来是第一个发现和/或应对疫情的组织，因此非常适合协助实施任何疫苗接种策略。我们的目标产品概况（TPP）是一种稳定的多价疫苗，在所有人群中进行一次或两次免疫接种后，可引发针对最常见的人类病毒性出血热的保护性免疫，在缺乏抗载体免疫的情况下具有加强免疫的潜力，并且可以低成本快速生产。

A multivalent haemorrhagic fever vaccine based on synthetic replicating ribonucleic acid would provide one of the fastest and most cost-effective approaches to stop viral outbreaks at their source. This affords significant advantages over more conventional vaccine approaches such as viral vectors, and attenuated pathogens and would be safer in individuals unable to receive live attenuated vaccines (e.g. children and the immunocompromised ). Our program aims to develop a multivalent vaccine against the most common human viral haemorrhagic fevers ( Ebola, Marburg and Lassa fever virus). The choice of targets is based on strong scientific evidence that gene-based approaches can protect against infection in preclinical models. This vaccine may also find utility as a booster that can be used in combination with existing vaccines (e.g. rVSV-EBOV). The fully synthetic manufacture and ease of production provides the potential to produce hundreds of thousands of doses within a matter of weeks where the individual vaccine components targeting different haemorrhagic viruses can easily be combined. This may be critical to the global response against emerging haemorrhagic viral infections, as the nature of the next outbreak cannot be reliably predicted. In this respect the proposed multivalent vaccine has potential not only to protect against multiple known haemorrhagic viruses but is also more likely to show cross-protection against novel variants that may arise in the future. In Part 1 of this project (now complete) we successfully completed the heavy lifting required to move our RNA platform from a research process through to fully established robust and validated manufacturing process, confirming the potency of the produced product in preclinical models. In this Part 2 project we will manufacture clinical grade material (GMP), conduct the required preclinical toxicology and early evaluation of the vaccine in a phase I human clinical trial designed to assess the safety and immunogenicity of our pan-haemorrhagic fever vaccine. Our ability to deliver on the aggressive timelines required to move from manufacture through to completion of a first in human clinical trial within two-year grant funding period is only possible due to the robustness and speed of our manufacturing process and the unique competency of the assembled team in translating vaccine concepts from the bench to the bedside . Ultimately our vision is to use our vaccine platform to ensure UK preparedness for any eventual pandemic and to make vaccines globally available in the event of any outbreak situation. Our approach will ensure appropriate costing for low and middle-income countries and be readily available to organizations focused on global health (e.g. MSF and WHO): these groups have historically been the first to detect, and/or respond to an outbreak, and are therefore ideally positioned to assist in implementing any vaccination strategy. Our Target Product Profile (TPP) is a stable multivalent vaccine that can elicit protective immunity against the most common human viral haemorrhagic fevers following one or two immunisation across all populations, has potential for boosting in the absence of anti-vector immunity, and can be rapidly manufactured at low cost.