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

基本信息

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

项目摘要

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.

疫苗是防御感染疾病的重要组成部分，并且消除了面临人类的一些最危险的疾病。在低收入国家，疫苗可以改变健康童年的可能性。肺炎链球菌会引起威胁生命的疾病，例如肺炎，败血病和脑膜炎。 S.肺炎负责全球范围内的大量发病率和死亡率，每年有超过100万儿童死亡。耐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。一种廉价，宽阔的，持久的肺炎球菌疫苗是当前的全球必需品，对LMIC国家的影响最大，因为这是现有疫苗经常被使用，而肺炎链球菌感染仍然是儿童死亡率和发病率的重要原因。成功疫苗的定义特征是能够以最小的副作用引起长期的保护性免疫。最成功的人类疫苗通常是糖缀合物，它们是与糖聚糖结合的蛋白质的组合，因为这些蛋白质为免疫系统提供了多个触发因素，并增加了疫苗的寿命。当前人类糖缀合物疫苗的例子包括针对流感嗜血杆菌，奈瑟氏菌和肺炎链球菌菌株的疫苗。这些疫苗是化学生产的，这既耗时又昂贵。此外，当前的肺炎球菌疫苗只能防止所有肺炎链球菌菌株的一小部分。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，糖偶联疫苗针对肺炎链球菌的疫苗应将糖成分与肺炎链球菌蛋白联系起来，这些肺炎链球菌蛋白在所有菌株中都存在，但是迄今为止，这种方法在涉及新的方法，我们已经开发出了一种涉及新方法，我们已经建立了gropecon，我们已经建立了ggyconge gropcon，gropecon构建了ggcocon grom gropcon new gropcon groment gropcon，细菌大肠杆菌使其充当糖缀合物疫苗生产的细胞工厂。这被称为蛋白质聚糖偶联技术（PGCT），涉及制造大肠杆菌菌株，可以产生候选蛋白质和聚糖，以及将蛋白质和聚糖耦合在一起以产生不可脱阻且廉价的疫苗供应的酶。 PGCT可以在一步纯化的过程中产生纯净的疫苗，从而降低成本，并且由于可以产生蛋白质和糖的多种组合，因此可以生成和测试的疫苗范围更大的灵活性。但是，到目前为止，我们还不知道使用PGCT制造的疫苗中使用的最佳肺炎链球菌蛋白，该疫苗能够诱导针对肺炎链球菌感染的最高保护水平。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，以鉴定最佳的候选物，用于使用由肺炎链球菌蛋白质组成的S. pneumoniae蛋白与肺炎链球菌糖（S. pneumoniae glycan）（乳糖多糖）组成。我们将从屏幕上选择前50个候选者进行测试，可以使用PGCT将其连接到肺炎链球菌胶囊聚糖，以制造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，以发现哪些最能预防感染。所产生的新疫苗也将与市场领先疫苗（如Prevenar13）的功效进行比较。这些实验将鉴定出最合适的蛋白质，用于纳入使用PGCT制造的新型肺炎疫苗或其他新型疫苗方法。此外，本研究中PGCT的开发将提供专业知识和知识库，以使该技术更广泛地适用于对其他重要感染剂进行糖缀合疫苗。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
10.21203/rs.3.rs-2162680/v1
发表时间：
2022
期刊：
影响因子：
0
作者：
Feehan K
通讯作者：
Feehan K

Maintained partial protection against Streptococcus pneumoniae despite B-cell depletion in mice vaccinated with a pneumococcal glycoconjugate vaccine.

DOI：
10.1002/cti2.1366
发表时间：
2022
期刊：
Clinical & translational immunology
影响因子：
5.8
作者：
Ercoli G;Ramos-Sevillano E;Pearce E;Ragab S;Goldblatt D;Weckbecker G;Brown JS
通讯作者：
Brown JS

The Influence of B Cell Depletion Therapy on Naturally Acquired Immunity to Streptococcus pneumoniae.

DOI：
10.3389/fimmu.2020.611661
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Ercoli G;Ramos-Sevillano E;Nakajima R;de Assis RR;Jasinskas A;Goldblatt D;Felgner P;Weckbecker G;Brown J
通讯作者：
Brown J

Opportunistic bacterial, viral and fungal infections of the lung

肺部机会性细菌、病毒和真菌感染