Glycoengineering of Veterinary Vaccines

兽用疫苗的糖工程

• 批准号: BB/N001591/1
• 负责人: Brendan Wren
• 金额: $ 548.6万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN001591%2F1
• 关键词: Glycoengineering; Veterinary; Vaccines

A healthily maintained livestock is essential for the economy and prosperity of the UK. Additionally some infected livestock are the source of human diseases, particularly through foodborne infections. Historically, vaccines have been the most successful and effective intervention to reduce the burden of infectious diseases in humans. By contrast, the application of vaccines in veterinary medicine is rudimentary, mainly due to the economic necessity for reduced costs to vaccinate animals and because our knowledge of the pathogens that cause animal diseases lags behind that of human counterparts. A defining characteristic of a successful vaccine is the ability to evoke long-lasting protective immunity with minimal side effects. Many of the most successful human vaccines are glycoconjugates, a combination of a protein coupled to a glycan, which induces both a T-cell dependent and independent immune response generating a protective and lasting immunity. Examples of currently licensed human glycoconjugate vaccines include those against Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae, in which glycans (lipopolysaccharides or capsular polysaccharides) are chemically coupled to immunogenic carrier proteins. However, the production of these vaccines requires multistep procedures that are often complex and expensive, and can exhibit batch-to-batch variation.We recently developed Protein Glycan Coupling Technology (PGCT) that can overcome the complex procedures required for chemically synthesising glycoconjugate vaccines by expressing the vaccine in an Escherichia coli cell in a single-step procedure. The advantages of applying PGCT to veterinary vaccines are (i) glycoconjugate vaccines can be produced at low cost, (ii) the flexibility of coupling "any glycan" with "any protein" facilitates the production of vaccine combinations providing the opportunity to evaluate a greater variety of vaccine candidates, and (iii) combination vaccines against more than one disease can be produced, further reducing cost and obviating the need to administer multiple vaccines (or antibiotics).In this study we will use PGCT to produce inexpensive triple combination poultry vaccines to reduce infection from E. coli, Salmonella, Campylobacter jejuni/coli and C. perfringens. This will not only protect poultry flocks from severe disease but would also protect the human population from the most common foodborne infections including those caused by Salmonella and Campylobacter. In addition we will construct and evaluate a dual Coxiella/C. perfringens vaccine to protect cattle, sheep and goats against severe disease. This vaccine would also prevent the spread of Q-fever to humans, which is caused by the highly infectious Coxiella burnetii pathogen. The principles developed in this proposal could subsequently be widely applied to produce inexpensive efficacious vaccines against most animal species and promise to break new ground in veterinary vaccine production.

健康的牲畜对英国的经济和繁荣至关重要。此外，一些受感染的牲畜是人类疾病的来源，特别是通过食源性感染。从历史上看，疫苗一直是减少人类传染病负担的最成功和最有效的干预措施。相比之下，疫苗在兽医学中的应用是初级的，主要是由于降低动物接种成本的经济必要性，以及因为我们对导致动物疾病的病原体的了解落后于人类。成功疫苗的一个决定性特征是能够以最小的副作用唤起持久的保护性免疫。许多最成功的人类疫苗是糖缀合物，即蛋白质与聚糖偶联的组合，其诱导T细胞依赖性和非依赖性免疫应答，产生保护性和持久的免疫力。目前许可的人糖缀合物疫苗的实例包括针对流感嗜血杆菌、脑膜炎奈瑟氏菌和肺炎链球菌的那些，其中聚糖（脂多糖或荚膜多糖）与免疫原性载体蛋白化学偶联。然而，这些疫苗的生产需要多步骤的程序，往往是复杂和昂贵的，并可以表现出批次间的变化。我们最近开发的蛋白质聚糖偶联技术（PGCT），可以克服化学合成糖缀合物疫苗所需的复杂程序，通过表达疫苗在大肠杆菌细胞在一个单一的步骤程序。将PGCT应用于兽用疫苗的优点是（i）可以低成本生产糖缀合物疫苗，（ii）将“任何聚糖”与“任何蛋白质”偶联的灵活性促进了疫苗组合的生产，从而提供了评估更多种类的疫苗候选物的机会，以及（iii）可以生产针对多于一种疾病的组合疫苗，在本研究中，我们将使用PGCT生产廉价的三联组合家禽疫苗，以减少E.大肠杆菌、沙门氏菌、空肠弯曲菌/大肠杆菌和C.产气荚膜杆菌这不仅可以保护家禽群免受严重疾病的影响，还可以保护人类免受最常见的食源性感染，包括沙门氏菌和弯曲杆菌引起的感染。此外，我们将构建和评估一个双重Coxiella/C。产气荚膜杆菌疫苗，以保护牛，绵羊和山羊免受严重疾病。这种疫苗还可以防止Q热传播到人类，这是由高度传染性的贝氏柯克斯体病原体引起的。该提案中提出的原则随后可广泛应用于生产针对大多数动物物种的廉价有效疫苗，并有望在兽医疫苗生产方面开辟新天地。

项目成果

Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

• DOI: 10.1016/j.jbc.2022.101903
• 发表时间: 2022-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Cross, Alice R.;Roy, Sumita;Vega, Mirella Vivoli;Rejzek, Martin;Nepogodiev, Sergey A.;Cliff, Matthew;Salmon, Debbie;Isupov, Michail N.;Field, Robert A.;Prior, Joann L.;Harmer, Nicholas J.
• 通讯作者: Harmer, Nicholas J.

Characterization of Posttranslationally Modified Multidrug Efflux Pumps Reveals an Unexpected Link between Glycosylation and Antimicrobial Resistance.

• DOI: 10.1128/mbio.02604-20
• 发表时间: 2020-11-17
• 期刊: mBio
• 影响因子: 6.4
• 作者: Abouelhadid S;Raynes J;Bui T;Cuccui J;Wren BW
• 通讯作者: Wren BW

Patterns of antimicrobial resistance in Streptococcus suis isolates from pigs with or without streptococcal disease in England between 2009 and 2014.

• DOI: 10.1016/j.vetmic.2017.06.002
• 发表时间: 2017-08
• 期刊: Veterinary microbiology
• 影响因子: 3.3
• 作者: Hernandez-Garcia J;Wang J;Restif O;Holmes MA;Mather AE;Weinert LA;Wileman TM;Thomson JR;Langford PR;Wren BW;Rycroft A;Maskell DJ;Tucker AW;BRADP1T Consortium
• 通讯作者: BRADP1T Consortium

Zoonoses under our noses.

• DOI: 10.1016/j.micinf.2018.06.001
• 发表时间: 2019-01
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Cross AR;Baldwin VM;Roy S;Essex-Lopresti AE;Prior JL;Harmer NJ
• 通讯作者: Harmer NJ

Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

抗原生物合成中的旋转糖：伯内特柯克斯体和灰色链霉菌 TDP-糖差向异构酶的直接研究

• DOI: 10.1101/2021.10.25.465559
• 发表时间: 2021
• 作者: Cross A