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

以合成复制核糖核酸为基础的多价出血热疫苗将提供从源头阻止病毒爆发的最快和最具成本效益的方法之一。与病毒载体和减毒病原体等更传统的疫苗方法相比，这提供了显著的优势，并且对于无法接种减毒活疫苗的个人(例如儿童和免疫受损的人)来说将更加安全。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。靶点的选择是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预防感染。这种疫苗还可用作加强剂，可与现有疫苗(如rVSV-EBOV)结合使用。完全人工合成的制造和生产的简便性提供了在几周内生产数十万剂疫苗的可能性，在这种情况下，针对不同出血性病毒的单个疫苗成分可以很容易地组合在一起。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暴发的性质。在这方面，拟议的多价疫苗不仅有可能预防多种已知的出血性病毒，而且更有可能对未来可能出现的新变种表现出交叉保护。在这个项目的第一部分(现已完成)，我们成功地完成了将我们的RNA平台从研究过程转移到完全建立的稳健和经过验证的制造过程所需的繁重工作，确认了生产的产品在临床前模型中的有效性。在这个第二部分的项目中，我们将生产临床级别的材料(GMP)，进行所需的临床前毒理学和疫苗的早期评估，进行I期人体临床试验，以评估我们的泛出血热疫苗的安全性和免疫原性。我们能够在两年拨款期限内完成从生产到完成第一项人类临床试验所需的积极时间表，这只是因为我们制造过程的健壮性和速度，以及组装的团队在将疫苗概念从试验台转化到床边方面的独特能力。最终，我们的愿景是利用我们的疫苗平台确保英国为任何最终的大流行做好准备，并在任何疫情爆发的情况下在全球范围内提供疫苗。我们的方法将确保为低收入和中等收入国家进行适当的成本计算，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/或应对疫情的群体，因此处于协助实施任何疫苗接种战略的理想地位。我们的目标产品简介(TPP)是一种稳定的多价疫苗，可以在所有人群中接种一到两次疫苗后，对最常见的人类病毒性出血热产生保护性免疫，在没有抗媒介免疫的情况下具有增强的潜力，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.