An mRNA vaccine for Plague: design to clinical efficacy testing

该项目的目的是开发一种易于在中低收入国家分发和使用的抗鼠疫mRNA疫苗。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，瘟疫造成了数百万人死亡，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，导致多达60%的人口死亡。如今，许多中低收入国家仍有地方性疫情。_Y吗。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，才能用抗生素有效治疗鼠疫。然而，耐药菌株_Y。鼠疫已经出现，最近在2017年马达加斯加疫情中报告了这类菌株的人际传播，这引起了人们对未来抗生素治疗鼠疫有效性的担忧。因此，鼠疫疫苗在预防中低收入国家未来的地方性/流行病暴发方面可能非常有用。辉瑞/BioNTech和Moderna的COVID-19 LNP-mRNA疫苗显示出对传染性病毒的有效疫苗，但mRNA尚未用于人类抗菌疫苗。NeoVac联合创始人Peer教授和IIBR最近发表了第一份关于单剂mRNA-LNP疫苗对一种高致命性细菌具有完全保护作用的报告，该研究表明，在小鼠中使用一剂新型mRNA-LNP疫苗可提供对鼠疫的完全保护。现有mRNA-LNP疫苗目前的问题是在冰点以下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具有挑战性和昂贵。为了解决这个问题，NeoVac开发了一个大型的专有LNPs库，这些LNPs被设计成在冰箱温度（2-8摄氏度）下稳定，可以很容易地分发并降低低收入国家的疫苗成本。在这个项目中，NeoVac将采用Peer教授小组发表的_Y mRNA编码。鼠疫抗原，最近在临床前鼠疫模型中被证明是有效的。mRNA将被用来生产一种耐热的mRNA- lnp疫苗，这种疫苗可以储存在冰箱里。该项目将从mRNA序列的制造开始，然后将其封装到LNPs中，并在体外和体内进行功效研究。然后，该疫苗将大规模生产，足以进行首次人体临床试验。大规模批量将进一步评估支持临床试验应用所需的稳定性、毒性和免疫原性。

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.