Novel biotherapeutics for the prevention and control of Campylobacter spp. in chickens

用于预防和控制弯曲杆菌属的新型生物治疗药物。

• 批准号: BB/V015044/1
• 负责人: Andrew Grant
• 金额: $ 67.3万
• 依托单位: University of Cambridge
• 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%2FV015044%2F1
• 关键词: Novel; biotherapeutics; prevention; control; Campylobacter

The most important food-poisoning bacterium both in terms of incidence and in the damage that it causes is Campylobacter. In the UK, out of an estimated one million cases of foodborne disease each year, Campylobacter is responsible for up to 750,000 cases, 22,000 hospitalisations and 110 deaths. Current estimates by the Food Standards Agency indicate that the cost of human campylobacteriosis in the UK is around £1B, out of a total of around £1.5B for all foodborne infections. Campylobacter is found in the gastrointestinal tracts of animals destined for human consumption, with faecal contamination of meat during processing a recognised route of transmission to humans. Up to 80% of raw chicken sold in the UK is contaminated with Campylobacter, and studies suggest that the consumption of poultry is responsible for 50-70% of all endemic infections that are reported. The current level of contamination of raw poultry on sale in the UK presents an unacceptably high public health burden, and the number of human campylobacteriosis cases continues to increase. Alternative strategies are needed to reduce Campylobacter in chickens and the associated disease burden in humans.Once a chicken is colonised with Campylobacter, antibodies against the bacterium are generated and a decrease in the number of Campylobacter colonising the intestinal tract has been observed. These data suggest that passive immunotherapy using anti-Campylobacter antibodies could be an approach for interfering with colonisation in chickens. The approach could also benefit humans and other animals. This is supported by the evidence that, in the general population, humoral immune response to a number of Campylobacter antigens is developed in most people upon infection, and epidemiological studies indicate that the immunity is crucial for the development of protection against Campylobacter disease.Antibody fragments or similar small peptide molecules are under-used as therapeutics. We contend that they have potential as therapeutic and prophylactic treatments for chickens, humans and other animals against Campylobacter. We propose to use antibody library technologies, protein-directed panning and early engagement of functional screens to identify single-chain Fvs (scFvs) that block or impair the activity of Campylobacter proteins. We plan to deliver the molecules via a harmless probiotic bacterium, Bacillus subtilis, either in vegetative cell or spore form, that has been genetically altered to synthesise or release the antibody fragment in situ within the chicken gastrointestinal tract, thus providing a continuous source of scFv in vivo for therapeutic and prophylactic applications. This local in situ production of scFv has many advantages over delivery of the same reagent by conventional means. For example, removing downstream processing steps, reducing the cost of goods, and doing away with any requirement for complex dosing regimens or delivery vehicles. Such a therapeutic could be delivered in food or drink. Alternatively, the bacteria and/or bacterial spores could be used to produce the scFv(s) cheaply and easily for more traditional methods of drug delivery.

从发病率和造成的损害来看，最重要的食物中毒细菌是弯曲杆菌。在英国，每年估计有 100 万例食源性疾病，其中有多达 75 万例病例、22,000 例住院病例是由弯曲杆菌引起的。食品标准局目前估计有 110 人死亡，英国人类弯曲菌病造成的损失约为 10 亿英镑。所有食源性感染的总价值约为 1.5B 英镑，在供人类食用的动物的胃肠道中发现，加工过程中的粪便污染是公认的传播给人类的生鸡肉的途径。英国受到弯曲杆菌污染，研究表明，目前报告的所有地方性感染中有 50-70% 是由食用家禽造成的。英国销售的生禽肉受到的污染造成了令人难以接受的高公共卫生负担，并且人类弯曲杆菌病病例数量持续增加，需要采取替代策略来减少鸡中的弯曲杆菌以及人类的相关疾病负担。一旦鸡被定殖。使用弯曲杆菌，会产生针对该细菌的抗体，并且观察到定植于肠道的弯曲杆菌数量减少。这些数据表明使用被动免疫疗法。抗弯曲杆菌抗体可能是干扰鸡体内定植的一种方法，该方法也可能使人类和其他动物受益，这一点得到了证据的支持，即在一般人群中，对多种弯曲杆菌抗原的体液免疫反应是在鸡中产生的。大多数人在感染后，流行病学研究表明，免疫力对于预防弯曲杆菌病至关重要。我们认为，抗体片段或类似的小肽分子未充分用作治疗剂。我们建议使用抗体库技术、蛋白质定向淘选和早期参与功能筛选来识别阻断或损害弯曲杆菌活性的单链 Fv (scFv)。我们计划通过无害的益生菌枯草芽孢杆菌（以营养细胞或孢子形式）传递分子，该细菌已通过基因合成。例如，在鸡胃肠道内原位释放抗体片段，从而为治疗和预防应用提供体内scFv的连续来源。 ，消除下游加工步骤，降低商品成本，并消除对复杂给药方案或递送载体的任何要求。或者，可以使用细菌和/或细菌孢子。廉价且轻松地生产 SCFv，用于更传统的药物输送方法。