Bat influenza virus chimeras as basis for the development of a new type of vaccine backbone

甲型流感病毒（IAV）是动物的重要病原体，从农场动物向人类溢出的IAV是发生新流行病的主要危险因素。疫苗接种可能是控制家畜和伴侣动物感染禽流感的一种选择。然而，目前还缺乏有效和安全的禽流感病毒活疫苗来保护家禽。这主要是由于疫苗毒株与野生型iav毒株之间存在重配事件的风险，部分是由于与疫苗毒株相关的致病性，例如在非常年幼的动物中。然而，我们最近成功地产生了含有8个蝙蝠H17N10病毒基因中的6个的嵌合病毒，其余两个基因编码原型甲型流感病毒（IAV）的血凝素（HA）和神经氨酸酶（NA）蛋白。这些病毒在哺乳动物细胞中生长，但在禽细胞和鸡细胞中复制有限。最重要的是，这些蝙蝠嵌合病毒不能与其他病毒重组。因此，蝙蝠嵌合病毒可能是开发新型、安全的家禽活疫苗的理想病毒骨架。为了实现这一目标，我们希望更详细地研究这些蝙蝠嵌合病毒在鸡胚胎中经过几轮适应后在不同年龄等级的鸡中复制的能力。我们还想用高致病性（H5、H7）和低致病性（H1、H5、H7、H9）的禽流感病毒HA和NA装备这些病毒，并测定鸡的生长特性和相关的免疫反应。作为一种防止疫苗株物种传播的新策略，物种特异性siRNA靶序列将嵌入病毒基因组中。最后，我们希望获得用蝙蝠嵌合体接种疫苗可以防止高致病性禽流感病毒感染的主要证据。从这些研究中，我们期望开发出新的、安全的家畜疫苗接种病毒载体。

Influenza A viruses (IAV) are important pathogens for animals and spillover of IAV from farm animals to humans is a major risk factor for new pandemics. Vaccination could be an option for controlling IAV-infections in both livestock and companion animals. However, effective and safe IAV live vaccines to protect poultry are missing. This is mainly due to the risk of reassortment events between vaccine strains and wild type IAV-strains, and partly to the pathogenicity associated with vaccine strains e.g. in very young animals. However, we recently succeeded to generate chimeric viruses containing six out of the eight bat H17N10 virus genes, with the remaining two genes encoding the haemagglutinin (HA) and neuraminidase (NA) proteins of a prototypic influenza A virus (IAV). These viruses grow in mammalian cells but show limited replication in avian cells and chicken. Most importantly, these bat chimeric viruses fail to reassort with other IAV. Thus bat chimeric viruses might represent ideal viral backbones to develop novel and safe live vaccines for poultry. To achieve this, we want to study the capacity of these bat chimeric viruses to replicate in chickens of different age classes after several rounds of adaptation in chicken embryos in more detail. We also want to equip these viruses with HA and NA of high (H5, H7) and low (H1, H5, H7, H9) pathogenic avian IAV and determine the growth properties and associated immune responses in chicken. As a novel strategy to prevent species transmission of the vaccine strain, species-specific siRNA target sequences will be embedded in the viral genome. Finally, we want to obtain proof of principal that vaccination with bat chimeras can protect from IAV-infection with highly pathogenic avian influenza viruses. From these studies we expect the development of novel and safe viral vectors for livestock vaccination.