Next generation vaccines for bovine respiratory disease (BRD) complex utilizing virus vaccine vectors to target both bacterial and viral pathogens.

下一代牛呼吸道疾病 (BRD) 疫苗利用病毒疫苗载体来靶向细菌和病毒病原体。

• 批准号: BB/X017532/1
• 负责人: William Golde
• 金额: $ 91.57万
• 依托单位: Moredun Research Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX017532%2F1
• 关键词: Next; generation; vaccines; bovine; respiratory

Bovine respiratory disease (BRD) is a complex condition influenced by a combination of environmental stressors, host immune responses, and multiple pathogens. It is most prevalent in young cattle that are housed in close quarters and was called shipping fever due to its association with animal movements. The economic consequences of BRD are significant worldwide, for example, one feed lot study showing more than one in six cattle being affected by BRD and over 2% mortality, with a reduction in net return of 50% in affected cattle. BRD is initiated in susceptible cattle by respiratory virus infections, with bovine herpesvirus 1 (BoHV-1), bovine respiratory syncytial virus (BRSV) and parainfluenza virus 3 (PI3) being among the most prevalent. Secondary infections with bacterial pathogens, in particular Mannheimia haemolytica and Pasteurella multocida, follow leading to clinical disease.Moredun Research Institute (MRI) and Ceva Sante Animale (Ceva) have active programs developing new vaccines for the pathogens that cause BRD. At Moredun, we have developed vaccine vectors to deliver antigen payloads from the virus pathogens using four of our vaccine vector platforms. Concurrently, Ceva has identified antigens from the same viral pathogens as well as 2 bacterial pathogens as potential vaccine payloads for a multivalent recombinant protein vaccine. These are presently being tested at Moredun, specifically by the contract research organization (CRO), Moredun Scientific, Ltd. In this proposal, we have selected (from the Ceva antigens) one protein from bacteria and one protein from a virus to test in all of the vector formats. These will both be cloned into each of the vectors under study, specifically, replication defective human adenovirus 5 (Ad5), Maedi visna virus (MV), Alcelaphine herpesvirus 1 (AlHV-1), and Orf virus. All vaccine vectors made expressing the targeted antigens (A from a virus and B from a bacterium, from the Ceva antigens) will be tested in vitro as a pre-screen before conducting animal trials. If, as expected, all express the protein payload in vitro, they will be tested in cattle. We will assay for serum antibody responses, mucosal antibody responses, and the comparative levels of CD4 T helper cell responses. Results will provide data to determine if one or more of these vectors out-perform the others in the delivery of the selected antigens. Further, we will demonstrate whether these vectors induce stronger and more protracted immune responses than the recombinant proteins in adjuvant as well as presently available commercial vaccines. If any of the vectored vaccines are superior performers, this will advance the development of more effective BRD vaccines. These vector systems allow for delivery of multiple proteins in a single payload, providing multivalent vaccines. They also allow rapid change of the payload if new, antigenically divergent strains of either bacteria or virus pathogens are identified. Additionally, these vectors do not require adjuvants for delivery, removing that expense and reducing injection reactions often seen with strong adjuvants.

牛呼吸道疾病 (BRD) 是一种复杂的疾病，受环境应激源、宿主免疫反应和多种病原体的共同影响。它在饲养在近距离的幼牛中最为普遍，由于它与动物运动有关，因此被称为运输热。 BRD 的经济后果在世界范围内影响重大，例如，一项饲料场研究显示，超过六分之一的牛受到 BRD 的影响，死亡率超过 2%，受影响牛的净回报减少了 50%。 BRD 在易感牛中由呼吸道病毒感染引发，其中最常见的是牛疱疹病毒 1 (BoHV-1)、牛呼吸道合胞病毒 (BRSV) 和副流感病毒 3 (PI3)。细菌病原体的继发感染，特别是溶血性曼海姆菌和多杀性巴氏杆菌，会导致临床疾病。Moredun 研究所 (MRI) 和 Ceva Sante Animale (Ceva) 正在积极开展针对引起 BRD 的病原体开发新疫苗的计划。在 Moredun，我们开发了疫苗载体，利用我们的四个疫苗载体平台从病毒病原体中传递抗原有效负载。同时，Ceva 已鉴定出来自相同病毒病原体和 2 种细菌病原体的抗原作为多价重组蛋白疫苗的潜在疫苗有效负载。这些目前正在 Moredun 进行测试，特别是由合同研究组织 (CRO) Moredun Scientific, Ltd. 进行测试。在这项提案中，我们（从 Ceva 抗原中）选择了一种来自细菌的蛋白质和一种来自病毒的蛋白质来测试所有蛋白质。的矢量格式。这些病毒都将被克隆到所研究的每个载体中，特别是复制缺陷型人类腺病毒 5 (Ad5)、Maedi visna 病毒 (MV)、Alcelaphine 疱疹病毒 1 (AlHV-1) 和 Orf 病毒。所有表达目标抗原（A 来自病毒，B 来自细菌，Ceva 抗原）的疫苗载体都将在进行动物试验之前进行体外测试作为预筛选。如果正如预期的那样，它们都在体外表达蛋白质有效负载，那么它们将在牛身上进行测试。我们将检测血清抗体反应、粘膜抗体反应以及 CD4 T 辅助细胞反应的比较水平。结果将提供数据以确定这些载体中的一种或多种在递送所选抗原方面是否优于其他载体。此外，我们将证明这些载体是否比佐剂中的重组蛋白以及目前可用的商业疫苗诱导更强和更持久的免疫反应。如果任何一种载体疫苗表现优异，这将推动更有效的 BRD 疫苗的开发。这些载体系统允许在单个有效负载中递送多种蛋白质，从而提供多价疫苗。如果发现新的、抗原性不同的细菌或病毒病原体菌株，它们还可以快速改变有效负载。此外，这些载体不需要佐剂来递送，从而消除了费用并减少了强佐剂常见的注射反应。