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

汉城病毒(SEOV)和汉滩病毒(HTNV)是广泛存在于啮齿动物体内的病原体，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至150,000例之间。虽然存在其他汉坦病毒，但它们会引起更罕见的疾病类型或仅限于美洲，对它们的疫苗干预需求没有SEOV和HTNV那么迫切。在12个月的Stream 1资助项目中，我们开发了一种多价疫苗，命名为MVA-HantaVacc，该疫苗基于含有SEOV和HTNV重组马赛克核蛋白的载体改良的Vaccinia Ankara(MVA)。以MVA为基础的疫苗效率高、成本效益高；它们提供了许多优点，包括已证实的安全记录、诱发细胞和体液免疫的能力、热稳定性和易于制造。然后，我们证明了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，观察到了强烈的抗原特异性召回T细胞反应。在缺乏合适的SEOV或HTNV感染的实验室疾病模型的情况下，对可以实验感染SEOV的I型干扰素受体基因敲除小鼠(菌株A129)的疫苗效力进行了评估。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。这是成功的研究级MVA汉坦病毒疫苗的第一次演示。为了使MVA-HantaVacc通过一期人体临床试验进一步发展，我们将首先将汉坦病毒核蛋白抗原重组为符合GMP的MVA载体。然后，我们将展示新疫苗与“研究级”疫苗的生物等效性，然后再生产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将进入第一阶段临床试验，在健康的人类志愿者中测试安全性和免疫原性。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