Investigating Host and Viral Factors for Improved Design of Future Live Attenuated Vaccines for IBV

研究宿主和病毒因素以改进未来 IBV 减毒活疫苗的设计

• 批准号: BB/V016067/1
• 负责人: Graham Freimanis
• 金额: $ 85.16万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016067%2F1
• 关键词: Investigating; Host; Viral; Factors; Improved

Vaccination against endemic pathogens is an essential component of the poultry industry, without which chickens would become infected at an early age. This would reduce productivity and push food security beyond sustainable levels. Infectious bronchitis virus (IBV) is a coronavirus that causes respiratory disease in chickens, making them more susceptible to bacterial infections. After infection, they achieve lower weights and produce fewer high-quality eggs. It has been estimated that a 10% reduction in IBV incidence globally would be worth £654million to the poultry industry.An effective vaccine to IBV is therefore critical for both welfare and economic reasons. The best vaccine strategies for IBV are "live attenuated" types, meaning a weakened form of the disease-causing virus is used to vaccinate chickens, generating good immunity. These vaccines are produced by growing disease-causing (pathogenic) viruses in eggs up to one hundred times, during which multiple genome changes can occur. Our understanding of how this process works is limited. Whilst these vaccines have lost their ability to cause symptoms, they still retain the ability to induce protective immune responses in chickens, thereby protecting them from disease. However, some vaccine strains have been reported to evolve, causing outbreaks of disease in flocks after vaccination. This occurs as vaccine virus genomes change and there is a risk, they may regain their pathogenic capability (reversion), producing disease in vaccinated birds i.e. the vaccine virus causes new outbreaks. Understanding better how both vaccine viruses are weakened and the host pressures after vaccination drive reversion are key to designing more stable vaccines.In a previous project (BB/L003988/1) 2 IBV viruses were weakened (a commercial vaccine and a lab-adapted strain) by passaging in eggs to identify how the viruses changed. We deep sequenced these viruses every 10 passages to understand how they change. We know from existing datasets that some changes are shared between both weakened and pathogenic viruses. We also know that some changes are exclusive to each type. Moreover, sequence changes are influenced by factors including restricted diversity and dilution factors during egg passaging. We do not know how these changes will impact reversion after vaccination.The overall aim of the project is to produce a detailed profile of the viral dynamics-host interactions of IBV vaccination in chickens to gain major insights into the virus biology and host responses. This will answer 3 research questions:1. Are there changes in the virus during this weakening process that can be used to improve future vaccines?2. How do vaccine virus's genomes changes after vaccination into chickens and do these changes make them more likely to cause reversion?3. What host genes are expressed, and do they help drive vaccine viruses to evolve in chickens?We will use deep learning will identify genomic patterns in viral genomes during the weakening process. We will characterise how vaccine viruses change after vaccination into chickens, comparing changes to those in pathogenic viruses, to measure the likelihood of reversion. We will characterise cellular gene expression, after vaccination and use machine learning to identify cellular responses driving changes in the vaccine virus genomes. Finally, we will combine datasets and use machine learning to make predictions on which sequence changes are important in the processes of weakening viruses, and reversion. These predictions will be re-inserted back into a virus and their impact on chicken cells measured.This research will identify genome changes involved in the occurrence and likelihood of reversion and reveal how they will change post-vaccination. These results will further our understanding of processes impacting virus genomes both during attenuation and after vaccination, that can be used in future next generation vaccines.

针对地方性病原体的疫苗接种是家禽业的重要组成部分，如果没有疫苗，鸡在早期就会受到感染。这将降低生产率，并将粮食安全推到超出可持续水平的水平。传染性支气管炎病毒(IBV)是一种冠状病毒，会导致鸡患呼吸道疾病，使它们更容易受到细菌感染。感染后，它们的体重较轻，产下的高质量鸡蛋较少。据估计，全球IBV发病率减少10%将为家禽养殖业带来6.54亿GB的价值。因此，从福利和经济两个方面考虑，有效的IBV疫苗至关重要。IBV最好的疫苗策略是“活减毒”型，这意味着用一种弱毒的致病病毒给鸡接种疫苗，产生良好的免疫力。这些疫苗是由致病(致病)病毒在鸡蛋中生长100次而生产的，在此期间可能会发生多个基因组变化。我们对这个过程的理解是有限的。虽然这些疫苗已经失去了引起症状的能力，但它们仍然保持着诱导鸡的保护性免疫反应的能力，从而保护它们免受疾病的侵袭。然而，据报道，一些疫苗毒株会进化，导致接种疫苗后在禽群中爆发疾病。这发生在疫苗病毒基因组发生变化并且存在风险时，它们可能会恢复其致病能力(逆转)，在接种疫苗的禽类中产生疾病，即疫苗病毒导致新的暴发。更好地了解这两种疫苗病毒是如何被削弱的，以及接种后的宿主压力是设计更稳定的疫苗的关键。在之前的一个项目(BB/L003988/1)中，通过在鸡蛋中传代来确定病毒是如何变化的，从而削弱了两种IBV病毒(一种商业疫苗和一种实验室适应株)。我们每隔10代对这些病毒进行深度测序，以了解它们是如何变化的。我们从现有的数据集了解到，一些变化在弱毒和致病病毒之间是相同的。我们还知道，某些更改是每种类型所独有的。此外，在卵子传代过程中，序列的变化还受到限制多样性和稀释因子等因素的影响。我们不知道这些变化将如何影响接种疫苗后的回归。该项目的总体目标是对鸡接种IBV疫苗的病毒动力学和宿主相互作用的详细情况进行描述，以获得对病毒生物学和宿主反应的重要见解。这将回答三个研究问题：1.在这个弱化过程中，病毒是否发生了变化，可用于改进未来的疫苗？2.疫苗病毒在接种到鸡体内后，基因组发生了怎样的变化，这些变化是否使它们更有可能导致逆转？3.哪些宿主基因表达，它们是否有助于推动疫苗病毒在鸡体内进化？我们将使用深度学习来识别弱化过程中病毒基因组的模式。我们将描述疫苗病毒在接种到鸡体内后的变化，并与致病病毒的变化进行比较，以衡量逆转的可能性。我们将在接种疫苗后表征细胞基因的表达，并使用机器学习来识别驱动疫苗病毒基因组变化的细胞反应。最后，我们将结合数据集并使用机器学习来预测在削弱病毒和逆转的过程中哪些序列变化是重要的。这些预测将被重新插入到病毒中，并测量它们对鸡细胞的影响。这项研究将确定与发生和逆转有关的基因组变化，并揭示它们在疫苗接种后将如何改变。这些结果将进一步加深我们对在减毒过程中和接种后影响病毒基因组的过程的理解，这些过程可用于未来的下一代疫苗。

项目成果

Porcine Respiratory Coronavirus as a Model for Acute Respiratory Coronavirus Disease.

• DOI: 10.3389/fimmu.2022.867707
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Keep S;Carr BV;Lean FZX;Fones A;Newman J;Dowgier G;Freimanis G;Vatzia E;Polo N;Everest H;Webb I;Mcnee A;Paudyal B;Thakur N;Nunez A;MacLoughlin R;Maier H;Hammond J;Bailey D;Waters R;Charleston B;Tuthill T;Britton P;Bickerton E;Tchilian E
• 通讯作者: Tchilian E

Deletion of the s2m RNA Structure in the Avian Coronavirus Infectious Bronchitis Virus and Human Astrovirus Results in Sequence Insertions.

• DOI: 10.1128/jvi.00038-23
• 发表时间: 2023-03-30
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Keep S;Dowgier G;Lulla V;Britton P;Oade M;Freimanis G;Tennakoon C;Jonassen CM;Tengs T;Bickerton E
• 通讯作者: Bickerton E

A Customizable Suite of Methods to Sequence and Annotate Cattle Antibodies.

• DOI: 10.3390/vaccines11061099
• 发表时间: 2023-06-14
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Ramirez Valdez K;Nzau B;Dorey-Robinson D;Jarman M;Nyagwange J;Schwartz JC;Freimanis G;Steyn AW;Warimwe GM;Morrison LJ;Mwangi W;Charleston B;Bonnet-Di Placido M;Hammond JA
• 通讯作者: Hammond JA

The transcriptomic insight into the differential susceptibility of African Swine Fever in inbred pigs

从转录组学角度了解近交猪对非洲猪瘟的不同易感性

• DOI: 10.21203/rs.3.rs-3522805/v1
• 发表时间: 2023
• 作者: Banabazi M

Establishing an In Vitro System to Assess How Specific Antibodies Drive the Evolution of Foot-and-Mouth Disease Virus.

• DOI: 10.3390/v14081820
• 发表时间: 2022-08-19
• 期刊: Viruses