VACCINE: Development of Novel BRSV Pre-Fusion Protein Recombinant Bovine Vaccine.

疫苗：新型 BRSV 预融合蛋白重组牛疫苗的开发。

• 批准号: BB/P004040/1
• 负责人: Ultan Power
• 金额: $ 48.21万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP004040%2F1
• 关键词: VACCINE; Development; Novel; BRSV; Pre

Bovine respiratory syncytial virus (BRSV) is a respiratory virus associated bovine respiratory disease complex, which is a major problem for the cattle industry. It results in considerable morbidity and mortality in cattle, and particularly young calves, worldwide. Efficacy of current vaccines is limited and there is a major need for a much more effective vaccine. BRSV is highly similar to Human RSV (HRSV) which is the most common cause of hospitalization in young infants and causes severe disease in elderly. No HRSV vaccines are available to date due to poor efficacy and safety issues. No HRSV vaccines are available to date due to poor efficacy and safety issues. In cattle the response of the immune system of current vaccines is compromised by the presence of maternal antibodies which neutralise the vaccine. This current proposal will target the exploitation of a combination of novel technologies to generate novel BRSV vaccines. Specifically, we will bring together world-renowned expertise in paramyxovirus reverse genetics, structure-based vaccine antigen design, and vaccine development to generate a new generation of BRSV vaccines that we are confident will circumvent many of the limitations of current vaccines. This will include the use of Sendai virus (SeV, a mouse virus) and parainfluenza virus type 5 (PIV5, a dog virus) as vehicles (vectors) to deliver a BRSV gene into the cell and produce the protein (antigen) from this. As neither of these viruses is found in cattle, they infect bovine cells but do not cause disease in cattle and there is no known cross-reactivity with bovine antibodies, problems associated with the presence of maternal antibodies will be circumvented. The use of SeV and PIV5 will facilitate development of a prime/boost vaccine regimen, which will circumvent a virus vector-specific immune response induced by the 1st vaccine administration, as both viruses are antigenically distinct. Such a regimen is likely to maximize immune responses to the BRSV antigen. We will develop both replication competent and incompetent viruses for both SeV and PIV5. The latter are produced by producing virus infectious particles that have one of the genes for further replication removed. However, these particles can enter cells and produce BRSV proteins. Our cumulative data, both published and unpublished, confirms that both replication competent viruses are independently highly efficient vectors for human RSV vaccine antigens in animal models. The development of replication-incompetent SeV and PIV5 viral vectors will address some safety concerns related to environmental dissemination of recombinant viruses, and will involve the generation of novel rescue technologies (production of virus from copies of the virus genes) for both viruses. BRSV and HRSV contain a protein called the fusion (F) protein which allows the virus to get into cells and is in a different form on the virion surface (pre-fusion) compared to when it interacts with a cell (post-fusion). The F protein induces a response by the immune system and the pre-fusion form has recently been shown to produce a several fold higher immune response than the post fusion form (in an experimental HRSV vaccine. We will exploit this finding to design and generate the most highly immunogenic BRSV vaccine, based on the use of a pre-fusion stable F protein. Precedence for this was demonstrated for human RSV pre-fusion F-based experimental vaccine, which was shown to be many fold superior to native F as a vaccine antigen. Finally, we will bring all of these complementary but disparate elements together to develop novel BRSV vaccines and vaccine regimens and test their efficacy in the final host target for the use of these vaccines, i.e., calves. These vaccines and the results from their study will also serve as the basis for design of effective human vaccines for HRSV.

牛呼吸道合胞病毒（BRSV）是一种与牛呼吸道疾病相关的呼吸道病毒复合体，是养牛业的一个主要问题。它导致全世界牛，特别是幼牛的发病率和死亡率相当高。当前疫苗的功效有限，迫切需要一种更有效的疫苗。 BRSV 与人类 RSV (HRSV) 高度相似，后者是导致小婴儿住院的最常见原因，并导致老年人出现严重疾病。由于功效和安全性问题较差，迄今为止还没有 HRSV 疫苗可用。由于功效和安全性问题较差，迄今为止还没有 HRSV 疫苗可用。在牛中，当前疫苗的免疫系统的反应因中和疫苗的母体抗体的存在而受到损害。目前的提案将致力于利用新技术的组合来生产新型 BRSV 疫苗。具体来说，我们将汇集副粘病毒反向遗传学、基于结构的疫苗抗原设计和疫苗开发方面世界知名的专业知识，以产生新一代 BRSV 疫苗，我们相信该疫苗将规避当前疫苗的许多局限性。这将包括使用仙台病毒（SeV，一种小鼠病毒）和 5 型副流感病毒（PIV5，一种狗病毒）作为媒介（载体）将 BRSV 基因传递到细胞中并从中产生蛋白质（抗原）。由于这两种病毒在牛体内均未发现，它们会感染牛细胞，但不会在牛体内引起疾病，并且与牛抗体之间没有已知的交叉反应性，因此将避免与母源抗体存在相关的问题。 SeV 和 PIV5 的使用将促进初免/加强疫苗方案的开发，该方案将规避第一次疫苗接种引起的病毒载体特异性免疫反应，因为两种病毒在抗原上是不同的。这样的治疗方案可能会最大限度地提高对 BRSV 抗原的免疫反应。我们将为 SeV 和 PIV5 开发具有复制能力和无复制能力的病毒。后者是通过产生病毒感染性颗粒而产生的，其中去除了用于进一步复制的基因之一。然而，这些颗粒可以进入细胞并产生 BRSV 蛋白。我们已发表和未发表的累积数据证实，两种具有复制能力的病毒都是动物模型中人类 RSV 疫苗抗原的独立高效载体。无法复制的SeV和PIV5病毒载体的开发将解决与重组病毒的环境传播相关的一些安全问题，并将涉及针对这两种病毒的新型救援技术的产生（从病毒基因的副本生产病毒）。 BRSV 和 HRSV 含有一种称为融合 (F) 蛋白的蛋白质，它允许病毒进入细胞，并且与与细胞相互作用时（融合后）相比，病毒粒子表面（融合前）的形式不同。 F 蛋白诱导免疫系统做出反应，最近显示融合前形式产生的免疫反应比融合后形式高几倍（在实验性 HRSV 疫苗中）。我们将利用这一发现，基于使用融合前稳定的 F 蛋白来设计和生成免疫原性最高的 BRSV 疫苗。基于人 RSV 融合前 F 的实验疫苗已证明了这一点的优先性，其中 作为疫苗抗原，其性能比天然 F 优越许多倍。最后，我们将把所有这些互补但不同的元素结合在一起，开发新型 BRSV 疫苗和疫苗方案，并测试它们在使用这些疫苗的最终宿主目标（即小牛）中的功效。这些疫苗及其研究结果也将作为设计有效的 HRSV 人类疫苗的基础。

项目成果

ATAC-Seq identifies regions of open chromatin in the bronchial lymph nodes of dairy calves experimentally challenged with bovine respiratory syncytial virus.

• DOI: 10.1186/s12864-020-07268-5
• 发表时间: 2021-01-06
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Johnston D;Kim J;Taylor JF;Earley B;McCabe MS;Lemon K;Duffy C;McMenamy M;Cosby SL;Waters SM
• 通讯作者: Waters SM