A capsule-based bioconjugate vaccine to prevent Klebsiella pneumoniae infections

一种预防肺炎克雷伯菌感染的胶囊生物结合疫苗

基本信息

批准号：
10379720
负责人：
Christian Harding
金额：
$ 30万
依托单位：
VAXNEWMO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379720
关键词：
Americas Amino Acid Sequence Antibiotics Antibody Response Bacterial Pneumonia COVID-19 patient COVID-19 pneumonia Carbapenems Carrier Proteins Cessation of life Characteristics Chemistry Clinical Clinical Trials Colony-forming units Communities Community-Acquired Infections Conjugate Vaccines Data Development Disease Dose Encapsulated Enzymes Escherichia coli Europe Formulation Genomics Goals Human Immunization Immunocompromised Host Immunoglobulin G Individual Infection Klebsiella pneumoniae Legal patent Modeling Multi-Drug Resistance Mus Names Nosocomial pneumonia Phase Pneumococcal conjugate vaccine Polysaccharides Prevnar Production Proteins Resistance Serotyping Site Small Business Technology Transfer Research Southern Europe Syndrome Technology Testing Vaccinated Vaccination Vaccine Production Vaccines Virulent base capsule carbapenem resistance clinically relevant commercialization community acquired pneumonia cost glycosylation healthcare-associated infections human pathogen immunogenic immunogenicity improved in vivo mortality mouse model opportunistic pathogen pathogenic bacteria placebo group prevent programs prototype research and development resistant Klebsiella pneumoniae vaccine access vaccine development vaccine efficacy virtual

项目摘要

PROJECT SUMMARY Klebsiella pneumoniae is an encapsulated human pathogen capable of causing a myriad of human infections. Recently, K. pneumoniae has also emerged as one the most common causes of secondary bacterial pneumonia in COVID-19 patients. Over the last 40 years, K. pneumoniae has evolved into two distinct pathotypes, known as classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp). cKp commonly acts as an opportunistic pathogen causing disease in hospitalized or immunocompromised individuals. In fact, cKp is annually responsible for 5% of all healthcare-associated infections and is the leading cause of nosocomial pneumonia in the US. Furthermore, cKp isolates are often carbapenem-resistant (CR), limiting treatment options. In the US, K. pneumoniae multilocus sequence type 258 (ST258) strains account for ~70% of all carbapenem- resistant K. pneumoniae infections. Conversely, hvKp usually cause community-acquired infections in healthy hosts that frequently manifest as community-acquired pneumonia. Like ST258 infections, hvKp infections have high mortality rates approaching 40-60%. Currently, there are no licensed vaccines available to prevent K. pneumoniae infections and none in clinical trials. Nevertheless, preliminary data demonstrate both cKp and hvKp infections can be prevented by vaccines that target their capsular polysaccharide (CPS). Conjugate vaccines consist of a CPS covalently attached to an immunogenic carrier protein. While the clinical benefits of conjugate vaccines are well documented, the development of new conjugate vaccines targeting K. pneumoniae is lagging, likely due to the high technological barriers to entry and high costs associated with conjugate vaccine production. In addition, most conjugate vaccines are multivalent, further increasing manufacturing complexities. In order to simplify conjugate vaccine production, we have developed an in vivo conjugation platform termed bioconjugation. Bioconjugation allows for the simultaneous production of the CPS, the carrier protein and their subsequent covalent linkage all within E. coli. Key to our bioconjugation platform is our patented conjugating enzyme, PglS, which attaches virtually any polysaccharide to a unique amino acid sequence fused to the carrier protein. Furthermore, bioconjugation is modular, allowing for rapid production of multiple, different CPS-protein conjugates. Using our bioconjugation platform, we are developing a multivalent CPS-based bioconjugate vaccine to prevent the majority of K. pneumoniae infections. In this Phase I STTR program, four serotypes were initially selected (K1, K2, KL106, KL107) as these serotypes are associated with >80% of all hvKp (K1 and K2) isolates worldwide and >70% of ST258 (KL106 and KL107) isolates in the US. In Aim 1, we will produce a tetravalent (K1, K2, KL106, KL107) bioconjugate vaccine on a modified carrier protein glycosylated at an internal site, which is expected to improve conjugate characteristics such as stability and immunogenicity. In Aim 2, we will test the tetravalent bioconjugate vaccine in a dose-escalation study to determine an optimal dose. Finally, in Aim 3, we will challenge groups of placebo- or bioconjugate-vaccinated mice with either a ST258 strain (KL106 and KL107) or a hvKp strain (K1 and K2) and assess survival as a surrogate for vaccine efficacy.

项目概要肺炎克雷伯菌是一种封装的人类病原体，能够引起多种人类感染。最近，肺炎克雷伯菌也成为继发性细菌性肺炎的最常见原因之一在 COVID-19 患者中。在过去的 40 年里，肺炎克雷伯菌已进化成两种不同的致病型，即已知的典型肺炎克雷伯菌 (cKp) 和高毒力肺炎克雷伯菌 (hvKp)。 cKp 通常充当在住院或免疫功能低下的个体中引起疾病的机会性病原体。事实上，cKp 是每年造成所有医疗保健相关感染的 5%，是医院内感染的主要原因美国肺炎。此外，cKp 分离株通常具有碳青霉烯类耐药性 (CR)，限制了治疗选择。在美国，肺炎克雷伯菌多位点序列 258 型 (ST258) 菌株约占所有碳青霉烯类菌株的 70% 耐药肺炎克雷伯菌感染。相反，hvKp 通常会在健康人群中引起社区获得性感染经常表现为社区获得性肺炎的宿主。与 ST258 感染一样，hvKp 感染也具有死亡率高达 40-60%。目前，尚无获得许可的疫苗可用于预防 K. 肺炎感染，但临床试验中没有发现。尽管如此，初步数据表明 cKp 和 hvKp 可以通过针对其荚膜多糖（CPS）的疫苗来预防感染。结合疫苗由共价连接至免疫原性载体蛋白的 CPS 组成。虽然结合物的临床益处疫苗已有充分记录，针对肺炎克雷伯菌的新结合疫苗的开发滞后，可能是由于技术进入壁垒高以及结合疫苗生产相关的成本高。此外，大多数结合疫苗是多价的，进一步增加了生产的复杂性。为了为了简化结合疫苗的生产，我们开发了一种称为生物结合的体内结合平台。生物共轭允许同时生产 CPS、载体蛋白及其后续产品共价键都在大肠杆菌内。我们的生物共轭平台的关键是我们的专利共轭酶 PglS，它将几乎任何多糖附着到与载体蛋白融合的独特氨基酸序列上。此外，生物共轭是模块化的，可以快速生产多种不同的 CPS 蛋白共轭物。利用我们的生物共轭平台，我们正在开发一种基于 CPS 的多价生物共轭疫苗预防大多数肺炎克雷伯菌感染。在第一阶段 STTR 计划中，最初确定了四种血清型选择（K1、K2、KL106、KL107），因为这些血清型与所有 hvKp（K1 和 K2）分离株中 >80% 相关全球范围内有超过 70% 的 ST258（KL106 和 KL107）在美国分离。在目标 1 中，我们将产生四价（K1、K2、KL106、KL107）生物结合疫苗，基于内部位点糖基化的修饰载体蛋白，预计将改善缀合物特性，例如稳定性和免疫原性。在目标 2 中，我们将测试四价生物结合疫苗用于剂量递增研究以确定最佳剂量。最后，在目标 3 中，我们将用 ST258 菌株（KL106 和 KL107）挑战安慰剂或生物共轭疫苗接种的小鼠组或 hvKp 毒株（K1 和 K2），并评估存活率作为疫苗功效的替代指标。