Advancement of a cost-effective MVA-based Hantavirus vaccine (HantaVacc).

首尔病毒（SEOV）和汉滩病毒（HTNV）是啮齿动物体内广泛存在的病原体，并通过啮齿动物排泄物的气溶胶传播给人类。人类感染导致肾综合征出血热（HFRS），这是许多低收入和中等收入国家的主要疾病负担，全世界每年记录的病例在100，000 - 150，000之间。虽然存在其他汉坦病毒，但它们引起的疾病类型更为罕见，或者在地理上局限于美洲，因此对它们进行疫苗干预的需求不如SEOV和HTNV那么迫切。 在为期12个月的Stream 1资助项目中，我们开发了一种多价疫苗，称为MVA-HantaVacc，基于含有SEOV和HTNV重组嵌合核蛋白的载体Modified Vaccinia Ankara（MVA）。基于MVA的疫苗是有效的和具有成本效益的;它们提供了许多优点，包括经证实的安全记录、引发细胞和体液免疫的能力、热稳定性和易于制造。然后，我们证明MVA-HantaVacc在小鼠中具有免疫原性。随着汉坦病毒特异性抗体的产生，观察到强烈的抗原特异性回忆T细胞应答沿着。在缺乏合适的SEOV或HTNV感染的实验室疾病模型的情况下，在I型干扰素受体敲除小鼠（A129株）中评估疫苗效力，所述小鼠可以实验性感染SEOV。与对照组相比，用MVA-HantaVacc免疫的动物显示病毒从关键组织中清除。这是第一个成功的研究级MVA汉坦病毒疫苗的演示。 为了进一步推进MVA-HantaVacc通过I期人体临床试验，我们将首先将汉坦病毒核蛋白抗原重新设计成符合GMP的MVA载体。然后，我们将证明新疫苗与“研究级”疫苗的生物等效性，然后生产GMP批次，该批次将经过严格的质量控制和毒性测试。一旦完成，MVA-HantaVacc将进入I期临床试验，以测试健康人类志愿者的安全性和免疫原性。我们已经开始讨论了。

Seoul virus (SEOV) and Hantaan virus (HTNV) are widespread pathogens maintained in rodents and transmitted to humans in aerosols of rodent excreta. Human infection results in Haemorrhagic Fever with Renal Syndrome (HFRS), a key burden of disease in many low and middle income countries with between 100,000-150,000 cases documented worldwide per year. Whilst other Hantaviruses exist, they cause more infrequent types of disease or are geographically restricted to the Americas, the need for vaccine intervention against them is less urgent than for SEOV and HTNV. During the 12 month Stream 1 funded project, we developed a multi-valent vaccine, termed MVA-HantaVacc, based on the vector Modified Vaccinia Ankara (MVA) containing a recombinant mosaic nucleoprotein of SEOV and HTNV. MVA-based vaccines are efficient and cost-effective; they offer many advantages including a proven safety record, the ability to elicit both cellular and humoral immunity, thermostability and ease of manufacture. We then demonstrated that MVA-HantaVacc is immunogenic in mice. A strong antigen-specific recall T-cell response was observed along with production of Hantavirus-specific antibodies. In the absence of a suitable laboratory disease model of SEOV or HTNV infection, vaccine efficacy was assessed in type-I interferon receptor knockout mice (strain A129) which can be experimentally infected with SEOV. Animals immunised with MVA-HantaVacc demonstrated clearance of virus from key tissues in contrast to control groups. This is the first demonstration of a successful research grade MVA Hantavirus vaccine. In order to further progress MVA-HantaVacc through a Phase I human clinical trial, we will first re-engineer the Hantavirus nucleoprotein antigens into a GMP-compliant MVA vector. We will then demonstrate bioequivalence of the new vaccine with the 'research grade' vaccine, before manufacturing a GMP batch which will undergo stringent quality control and toxicity testing. Once complete, MVA-HantaVacc will enter into a Phase I clinical trial to test safety and immunogenicity in healthy human volunteers. We have already started discussi