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

基本信息

批准号：
10097963
负责人：
Christian Harding
金额：
$ 99.3万
依托单位：
VAXNEWMO, LLC
依托单位国家：
美国
项目类别：
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/10097963
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 vaccination outcome vaccine development

项目摘要

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.

项目概要肺炎球菌结合疫苗 (PCV)，由肺炎球菌多糖与载体蛋白是用于预防肺炎球菌疾病的挽救生命的预防剂，重要的是，PCV 可提供。所有年龄段的人都具有免疫力，包括婴儿和两岁以下的儿童，而纯粹的情况并非如此与所有结合疫苗一样，PCV 是通过化学结合来制造的。这是出了名的复杂、劳动密集型，并最终阻碍了更好版本的开发提供对更多致病血清型的免疫力例如，PCV Prevnar 13 已获得许可。 2010 年，只能预防 13 种肺炎球菌血清型；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。然而，它并没有为婴儿和儿童提供保护，因此，三十多年来，婴儿和儿童尚未获得可预防 20 多种引起肺炎球菌的疫苗为了提供适用于所有年龄段的 20+ 价 PCV，VaxNewMo 一直在开发一种制造肺炎球菌和其他结合疫苗的方法，绕过了依赖性化学缀合，而是在称为生物缀合的过程中利用原核糖基化系统。 VaxNewMo 的专有生物共轭平台依靠共轭酶来转移细菌将多糖（如肺炎球菌荚膜多糖）转化为载体蛋白，所有这些都在实验室内安全进行由于生物缀合是一种酶驱动技术，因此产生的缀合物是重要的是，生物共轭可用于快速生产大量的。只需引入不同血清型的遗传信息编码即可结合多种血清型将肺炎球菌血清型转化为具有生物缀合能力的大肠杆菌菌株。因此，生物缀合可用于在该项目的第一阶段，我们简化了涵盖 20 多种血清型的 PCV 的开发。成功建立了 VaxNewMo 的生物共轭平台可以生成 PCV 的原理证明此外，VaxNewMo 的 PCV 具有免疫原性和保护性。 II 期 SBIR 应用中拟议的研究将重点关注（目标 1）。建立大规模生产 VNM8（一种血清型 8 肺炎球菌）的生物加工能力建立单一血清型生物结合物的生物加工程序是重要的第一步。商业规模生产并将有助于简化其他人未来的上游加工随后，（目标 2）我们将确认 VNM8 在大体积中产生。使用体外和体内模型，生物过程具有保护性。此外，（目标 3）我们将生成大肠杆菌库。能够产生 24 价 PCV 的菌株对于 IIB 期，将寻求配制 24 价 PCV (24vPneumo)。进行药代动力学和毒性研究，并为与 FDA 的 IND 前会议做准备。