An mRNA vaccine for Plague: design to clinical efficacy testing

鼠疫 mRNA 疫苗：临床功效测试设计

• 批准号: 10088249
• 金额: $ 253.07万
• 依托单位: NEOVAC LTD
• 依托单位国家: 英国
• 项目类别: Small Business Research Initiative
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10088249
• 关键词: mRNA; vaccine; Plague; design; clinical

The purpose of this project is to develop a mRNA vaccine against the Plague that is easy and suitable for distribution and use in lower- and middle-income countries (LMICs). Plague is a deadly disease caused by bacteria called _Yersinia pestis_(_Y. pestis_). Plague has caused millions of deaths throughout recorded history, most notoriously in the 1300s the 'Black Death' Pandemic that ravaged in western Eurasia killing up to 60% of the population., Nowadays endemic outbreaks are still experienced in many LMICs today. _Y. pestis_ is also recognised as a serious bioterrorism threat. Only if diagnosed early, plague can be effectively treated with antibiotics. However, antibiotic-resistant strains of _Y. pestis_ have emerged and human to-human transmission of such strains was recently reported in the 2017 Madagascar outbreak raising concerns about the future effectiveness of antibiotics against plague. Therefore, a plague vaccine could be very useful in preventing future endemic/epidemic outbreaks in LMICs.The Pfizer/BioNTech and Moderna COVID-19 LNP-mRNA vaccines demonstrated effective vaccines against contagious viruses, but mRNA is yet to be used in as antibacterial vaccine in humans. The first report of full protection against a highly lethal bacteria by a single dose of mRNA-LNP vaccine, has been recently published by NeoVac Co-founder Professor Peer and IIBR with the study demonstrating that one dose of a novel mRNA-LNP vaccine in mice provided full protection against plague.Current problem with existing mRNA-LNP vaccines is long-term storage and transportation at below-freezing temperatures. This makes their distribution and use in LMICs very challenging and expensive. To tackle this, NeoVac has developed a large library of proprietary LNPs which are designed to be stable at fridge temperatures (2-8 oC), that can be easily distribute and reduce the cost of vaccines for LMICs.In this project, NeoVac will employ Prof. Peer group's published mRNA encoding for _Y. pestis_ antigens, which have recently been demonstrated as effective in a preclinical plague model. The mRNA will be used to produce a thermostable mRNA-LNP vaccine that can be stored in the fridge. The project will start with the manufacturing of mRNA sequences followed by encapsulation in to the LNPs and efficacy studies both in vitro and in vivo. The vaccine will then be manufactured on a larger scale sufficient for first-in-human clinical trials. The large-scale batch will be further evaluated for stability, toxicity and immunogenicity required to support a clinical trial application.

该项目的目的是开发一种针对鼠疫的mRNA疫苗，这种疫苗容易且适合在中低收入国家（LMIC）分发和使用。鼠疫是一种由鼠疫耶尔森氏菌引起的致命疾病。pestis_）。在有记载的历史中，鼠疫已造成数百万人死亡，最臭名昭著的是在14世纪肆虐欧亚大陆西部的“黑死病”大流行，造成高达60%的人口死亡。如今，许多中低收入国家仍发生地方性疫情。是的。鼠疫也被认为是一种严重的生物恐怖主义威胁。只有及早诊断，鼠疫才能用抗生素有效治疗。然而，Y.鼠疫已经出现，最近在2017年马达加斯加爆发的疫情中报告了这种菌株的人际传播，引发了人们对抗生素对抗鼠疫的未来有效性的担忧。辉瑞/BioNTech和Moderna COVID-19 LNP-mRNA疫苗证明了针对传染性病毒的有效疫苗，但mRNA尚未用作人类的抗菌疫苗。NeoVac联合创始人Peer教授和IIBR最近发表了第一份关于单剂量mRNA-LNP疫苗对高致死性细菌的完全保护的报告，该研究表明，一剂新型mRNA-LNP疫苗在小鼠中提供了对鼠疫的完全保护。现有mRNA-LNP疫苗的问题是在低于冰点的温度下长期储存和运输。这使得它们在中低收入国家的分发和使用非常困难和昂贵。为了解决这个问题，NeoVac开发了一个大型的专有LNP库，这些LNP被设计成在冰箱温度（2-8 ℃）下稳定，可以很容易地分配并降低LMIC疫苗的成本。在这个项目中，NeoVac将使用Peer Group教授发表的_Y的mRNA编码。pestis_ antigens，其最近被证明在临床前鼠疫模型中有效。mRNA将用于生产可储存在冰箱中的热稳定mRNA-LNP疫苗。该项目将从mRNA序列的制造开始，然后封装到LNP中，并进行体外和体内的功效研究。然后，该疫苗将以足以进行首次人体临床试验的更大规模生产。将进一步评价大规模批次的稳定性、毒性和免疫原性，以支持临床试验申请。