Universal protection against Streptococcus pneumoniae by recombinant glycoconjugate vaccines

重组糖复合物疫苗对肺炎链球菌具有普遍保护作用

• 批准号: MR/R001871/1
• 负责人: Jeremy Brown
• 金额: $ 115.4万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR001871%2F1
• 关键词: Universal; protection; against; Streptococcus; pneumoniae

Vaccines are a critical component of defence against infectious disease, and have eliminated some of the most dangerous diseases that have faced humanity. This is increasingly the case in low income countries, where vaccines can transform the likelihood of healthy childhoods. Streptococcus pneumoniae can cause life-threatening diseases such as pneumonia, septicaemia and meningitis. S. pneumoniae is responsible for significant morbidity and mortality worldwide with over one million deaths of children annually. The emergence and rapid spread of antibiotic-resistant S. pneumoniae strains has further emphasised the need for prevention of S. pneumoniae infections. An inexpensive, broad-range, long-lasting pneumococcal vaccine is a current global imperative, and be of most impact to LMIC countries as this is where existing vaccines are often under utilised and S. pneumoniae infections remain a significant cause of childhood mortality and morbidity. A defining characteristic of a successful vaccine is the ability to evoke long-lasting protective immunity with minimal side effects. The most successful human vaccines are often glycoconjugates, which are combinations of a protein coupled to a sugar glycan, as these provide multiple triggers for the immune system, and increases the lifetime of the vaccine. Examples of current human glycoconjugate vaccines include vaccines against Haemophilus influenzae, Neisserria meningitidis and S. pneumoniae strains. These vaccines are made chemically which is time consuming and expensive. Furthermore, the current pneumococcus glycoconjugate vaccines only protect against a fraction of all S. pneumoniae strains. Ideally, to improve the proportion of all S. pneumoniae strains that the vaccine protects against, a glycoconjugate vaccine against S. pneumoniae should link the sugar component to S. pneumoniae proteins that are present in all strains, but to date this has proved technically challenging to achieve.Recently, we have developed a new approach for constructing glycoconjugate vaccines involving genetically altering the bacterium E. coli so that they act as cellular factories for the production of glycoconjugate vaccines. This is termed Protein Glycan Coupling Technology (PGCT), and involves making an E. coli strain that can produce the candidate protein and glycan, along with an enzyme that couples the protein and glycan together to produce an inexhaustible and inexpensive supply of vaccine. PGCT can produce purified vaccine in a one-step purification procedure, which reduces costs, and because multiple combinations of protein and glycans can be produced, a greater flexibility in the range of vaccines can be generated and tested. However, as yet we do not know the best S. pneumoniae proteins to use in a vaccine made using PGCT that are able to induce the highest level of protection against S. pneumoniae infections. In this study we will use new technologies to systematically screen all S. pneumoniae proteins to identify the best candidates for a "double hit" glycoconjugate vaccine consisting of a S. pneumoniae protein coupled to S. pneumoniae glycan (capsular polysaccharide). We will select the top 50 candidates from the screen to test which can be linked using PGCT to S. pneumoniae capsule glycan to make effective recombinant glycoconjugates. The most promising vaccines will then be tested in mouse models of S. pneumoniae infection to find which ones are best able to prevent infections. The new vaccines generated will also be compared to the efficacy of market leading vaccines such as Prevenar13. These experiments will identify the most suitable proteins for inclusion in a novel S. pneumoniae vaccine made using PGCT, or for other novel vaccine approaches. Additionally, the development of PGCT in this study will provide the expertise and knowledge base to make the technology more widely applicable for making glycoconjugate vaccines against other important infectious agents.

疫苗是防御传染病的重要组成部分，并消除了人类面临的一些最危险的疾病。在低收入国家，这种情况越来越普遍，疫苗可以改变健康童年的可能性。肺炎链球菌可引起肺炎、败血症和脑膜炎等危及生命的疾病。肺炎链球菌在全世界范围内造成严重的发病率和死亡率，每年有超过一百万儿童死亡。抗生素耐药性肺炎链球菌菌株的出现和快速传播进一步强调了预防肺炎链球菌感染的必要性。廉价、广泛、持久的肺炎球菌疫苗是当前全球的当务之急，并且对中低收入国家影响最大，因为在这些国家，现有疫苗往往未得到充分利用，而肺炎链球菌感染仍然是儿童死亡和发病的一个重要原因。成功疫苗的一个决定性特征是能够以最小的副作用激发持久的保护性免疫力。最成功的人类疫苗通常是糖复合物，它是蛋白质与糖聚糖的组合，因为它们为免疫系统提供了多种触发因素，并延长了疫苗的使用寿命。目前的人复合糖疫苗的例子包括针对流感嗜血杆菌、脑膜炎奈瑟氏菌和肺炎链球菌菌株的疫苗。这些疫苗是通过化学方法制成的，既耗时又昂贵。此外，目前的肺炎球菌糖复合物疫苗只能预防所有肺炎链球菌菌株中的一小部分。理想情况下，为了提高疫苗预防的所有肺炎链球菌菌株的比例，针对肺炎链球菌的糖复合物疫苗应将糖成分与所有菌株中存在的肺炎链球菌蛋白连接起来，但迄今为止，这在技术上已被证明具有挑战性最近，我们开发了一种构建糖复合物疫苗的新方法，涉及对大肠杆菌进行基因改造，使其充当生产糖复合物疫苗的细胞工厂。这被称为蛋白聚糖偶联技术 (PGCT)，涉及制造能够产生候选蛋白和聚糖的大肠杆菌菌株，以及将蛋白质和聚糖偶联在一起的酶，以生产取之不尽、用之不竭且廉价的疫苗供应。 PGCT 可以通过一步纯化程序生产纯化疫苗，从而降低成本，并且由于可以生产蛋白质和聚糖的多种组合，因此可以生产和测试疫苗范围的更大灵活性。然而，迄今为止，我们还不知道在使用 PGCT 生产的疫苗中使用哪种最佳肺炎链球菌蛋白能够诱导针对肺炎链球菌感染的最高水平的保护。在这项研究中，我们将使用新技术系统地筛选所有肺炎链球菌蛋白，以确定由肺炎链球菌蛋白与肺炎链球菌聚糖（荚膜多糖）偶联组成的“双重打击”糖复合物疫苗的最佳候选者。我们将从筛选中选择前 50 名候选者进行测试，这些候选者可以使用 PGCT 将其与肺炎链球菌荚膜聚糖连接起来，形成有效的重组糖缀合物。然后，最有希望的疫苗将在肺炎链球菌感染的小鼠模型中进行测试，以找出哪些疫苗最能预防感染。生产的新疫苗还将与市场领先的疫苗（如 Prevenar13）的功效进行比较。这些实验将确定最适合包含在使用 PGCT 制造的新型肺炎链球菌疫苗或其他新型疫苗方法中的蛋白质。此外，本研究中 PGCT 的发展将提供专业知识和知识基础，使该技术更广泛地应用于制造针对其他重要传染原的糖复合物疫苗。

项目成果

Corrected and Republished from: "A Novel, Multiple-Antigen Pneumococcal Vaccine Protects against Lethal Streptococcus pneumoniae Challenge".

更正并重新发布自：“一种新型多抗原肺炎球菌疫苗可防止致命的肺炎链球菌挑战”。

• DOI: http://dx.10.1128/iai.00846-18a
• 发表时间: 2022
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Chan WY

Post-resolution macrophage-derived lipids shapes long-term tissue immunity and integrity

解析后巨噬细胞衍生的脂质塑造长期组织免疫和完整性

• DOI: http://dx.10.21203/rs.3.rs-2162680/v1
• 发表时间: 2022
• 作者: Feehan K

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System.

锌转运蛋白 AdcAII 的缺失会导致与 I 型限制性修饰系统的不同等位基因相关的肺炎链球菌的过度封装。

• DOI: http://dx.10.1128/mbio.00445-20
• 发表时间: 2020
• 期刊: mBio
• 影响因子: 6.4
• 作者: Durmort C

Opportunistic bacterial, viral and fungal infections of the lung

肺部机会性细菌、病毒和真菌感染

• DOI: http://dx.10.1016/j.mpmed.2023.08.002
• 发表时间: 2023
• 期刊: Medicine
• 影响因子: 1.6
• 作者: Pates K

Spirometric Classifications of Chronic Obstructive Pulmonary Disease Severity as Predictive Markers for Clinical Outcomes: The HUNT Study.

慢性阻塞性肺疾病严重程度的肺活量分类作为临床结果的预测标志物：HUNT 研究。

• DOI: http://dx.10.1164/rccm.202011-4174le
• 发表时间: 2021
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Bhatta L