Towards a New Generation of Glycoengineered Pneumococcal Bioconjugate Vaccines

迈向新一代糖工程肺炎球菌生物结合疫苗

• 批准号: 9906398
• 负责人: Christian Harding
• 金额: $ 93.11万
• 依托单位: VAXNEWMO, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-22 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906398
• 关键词: Adjuvant; Advanced Development; Age; Air; Antibody Response; Applications Grants; Bacteria; Bacterial Polysaccharides; Bypass; Carrier Proteins; Chemicals; Chemistry; Child; Childhood; Complex; Conjugate Vaccines; Dependence; Development; Disease; Dose; Drug Addiction; Drug Kinetics; Elderly; Engineering; Enzymes; Escherichia coli; Formulation; Foundations; Future; Generations; Glucose; Glycoconjugates; Immunity; Immunologic Memory; In Vitro; Infant; Infection; Libraries; Life; Link; Methodology; Methods; Mus; Pharmaceutical Preparations; Phase; Pneumococcal Infections; Pneumococcal conjugate vaccine; Polysaccharides; Polyvalent pneumococcal vaccine; Positioning Attribute; Prevnar; Procedures; Process; Production; Proteins; Recombinants; Research; Sales; Savings; Serotyping; Serum; Small Business Innovation Research Grant; Streptococcus pneumoniae; System; Technology; Toxic effect; Vaccine Production; Vaccines; age group; bioprocess; clinically relevant; cost; genetic information; glycosylation; immunogenic; immunogenicity; in vivo; in vivo Model; meetings; mortality; mouse model; prevent; prophylactic; research clinical testing; sugar; vaccine development

PROJECT SUMMARY Pneumococcal conjugate vaccines (PCVs), composed of a pneumococcal polysaccharide covalently linked to a carrier protein, are life-saving prophylactics used to prevent pneumococcal disease. Importantly, PCVs provide immunity for all age groups, including, infants and children under the age of two, which is not the case for purely polysaccharide vaccines. Like all conjugate vaccines, PCVs are manufactured using chemical conjugation, which is notoriously complex, labor intensive, and ultimately hinders the development of better versions that provide immunity to more disease-causing serotypes. As an example, the PCV, Prevnar 13, was licensed in 2010 and only protects against 13 pneumococcal serotypes; whereas, the purely polysaccharide vaccine, Pneumovax 23, was licensed in 1983 and protects against 23 serotypes. Pneumovax 23 is approved for use in the elderly; however, it does not provide protection to infants and children. Thus, for more than three decades, infants and children have not had a vaccine option that protects against 20+ disease causing pneumococcal serotypes. In order to provide a 20+ valent PCV for use in all age groups, VaxNewMo has been developing a method for manufacturing pneumococcal and other conjugate vaccines that bypasses the dependency of chemical conjugation and instead exploits prokaryotic glycosylation systems in process termed bioconjugation. VaxNewMo’s proprietary bioconjugation platform relies on a conjugating enzyme to transfer a bacterial polysaccharide, like a pneumococcal capsular polysaccharide, to a carrier protein all within the lab safe bacterium E. coli. Since bioconjugation is an enzyme driven technology, the conjugates produced are homogenous and readily purified. Importantly, bioconjugation can be used to rapidly produce a plethora of conjugates against many serotypes simply by introducing the genetic information encoding for a different pneumococcal serotype into a bioconjugation competent strain of E. coli. Thus, bioconjugation can be used for the streamlined development of a PCV covering more than 20 serotypes. In Phase I of this project, we successfully established proof of principle that VaxNewMo’s bioconjugation platform could generate PCVs containing conventional vaccine carriers. Moreover, VaxNewMo’s PCVs were both immunogenic and protective against pneumococcal disease. The proposed research in this Phase II SBIR application will focus on (Aim 1) establishing bioprocessing capabilities for large volumetric production of VNM8, a serotype 8 pneumococcal bioconjugate. Establishing bioprocessing procedures for a single serotype bioconjugate is an important first step towards commercial scale production and will help streamline future upstream processing for other pneumococcal bioconjugates. Subsequently, (Aim 2) we will confirm that VNM8 produced in a large volumetric bioprocess is protective using in vitro and in vivo models. In addition, (Aim 3) we will generate a library of E. coli strains capable of producing a 24 valent PCV. For Phase IIB, will seek to formulate a 24 valent PCV (24vPneumo) for pharmacokinetic and toxicity studies and prepare for pre-IND meetings with the FDA.

项目摘要 肺炎球菌结合疫苗（PCV），由肺炎球菌多糖共价连接到 载体蛋白是用于预防肺炎球菌疾病的救命药物。重要的是，PCV提供 所有年龄组，包括婴儿和两岁以下儿童，都享有豁免权， 多糖疫苗与所有结合疫苗一样，PCV使用化学结合来制造， 这是众所周知的复杂，劳动密集型，并最终阻碍了更好的版本的开发， 提供对更多致病血清型的免疫力。例如，PCV，Prevnar 13，在2009年获得许可。 2010年，并且仅针对13种肺炎球菌血清型提供保护;而纯多糖疫苗， Pneumovax 23于1983年获得许可，可预防23种血清型。Pneumovax 23被批准用于 它保护老年人，但不保护婴儿和儿童。因此，三十多年来， 婴儿和儿童还没有一种疫苗可以预防20多种引起肺炎球菌的疾病。 血清型为了提供20+价PCV用于所有年龄组，VaxNewMo一直在开发一种 制造肺炎球菌和其它结合疫苗的方法 化学缀合，而是在称为生物缀合的过程中利用原核糖基化系统。 VaxNewMo的专有生物结合平台依赖于结合酶来转移细菌 多糖，像肺炎球菌荚膜多糖，到载体蛋白，都在实验室安全 菌E.杆菌由于生物缀合是一种酶驱动的技术，所产生的缀合物是 均质且易于纯化。重要的是，生物缀合可用于快速产生过多的 通过简单地引入编码不同血清型的遗传信息， 肺炎球菌血清型转化为E.杆菌因此，生物缀合可用于 涵盖20多种血清型的PCV的简化开发。在本项目的第一阶段，我们 成功证明了VaxNewMo的生物结合平台可以产生PCV的原理 含有常规的疫苗载体。此外，VaxNewMo的PCV具有免疫原性和保护性。 对抗肺炎球菌疾病。第二阶段SBIR应用中的拟议研究将集中在（目标1） 建立大体积生产VNM 8（一种血清型8肺炎球菌）的生物处理能力 生物结合物建立单一血清型生物结合物的生物处理程序是重要的第一步 这将有助于简化未来的上游加工， 肺炎球菌生物结合物。随后，（目标2）我们将确认VNM 8以大体积生产， 使用体外和体内模型，生物过程具有保护性。此外，（目标3）我们将产生一个E.杆菌 能够产生24价PCV的菌株。对于IIB期，将寻求配制24价PCV（24伏） 进行药代动力学和毒性研究，并准备与FDA的IND前会议。