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

• 批准号: 10544164
• 负责人: Christian Harding
• 金额: $ 29.31万
• 依托单位: VAXNEWMO, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544164
• 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; Hospitalization; Human; Immunization; Immunocompromised Host; Immunoglobulin G; Individual; Infection; Klebsiella pneumoniae; Legal patent; Licensing; Modeling; Multi-Drug Resistance; Mus; Names; Nosocomial pneumonia; Phase; Pneumococcal conjugate vaccine; Polysaccharides; Prevnar; Production; Protein Glycosylation; Proteins; Resistance; Serotyping; Site; Small Business Technology Transfer Research; Southern Europe; Syndrome; Technology; Testing; Vaccinated; Vaccination; Vaccine Production; Vaccines; Virulent; capsule; carbapenem resistance; clinically relevant; commercialization; community acquired pneumonia; cost; glycosylation; healthcare-associated infections; human pathogen; immunogenic; immunogenicity; improved; in vivo; manufacture; 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

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.

项目摘要 肺炎克雷伯氏菌是一种包囊的人类病原体，能够引起无数的人类感染。 最近，K。肺炎也已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，K。肺炎已演变成两种不同的病理类型，已知 经典K pneumoniae（cKp）和高毒力K. pneumoniae（hvKp）。cKp通常作为 在住院或免疫受损个体中引起疾病的机会性病原体。实际上，cKp是 每年占所有医疗相关感染的5%，是医院感染的主要原因。 肺炎在美国此外，cKp分离株通常对碳青霉烯类耐药（CR），限制了治疗选择。 在美国，K。肺炎多位点序列型258（ST 258）菌株约占所有碳青霉烯的70%。 抗性K.肺炎感染。相反，hvKp通常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ST 258感染一样，hvKp感染具有 死亡率高达40- 60%。目前，没有获得许可的疫苗可用于预防K。 肺炎感染，临床试验中没有。然而，初步数据表明，cKp和hvKp 感染可以通过靶向其荚膜多糖（CPS）的疫苗来预防。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 疫苗是有据可查的，新的结合疫苗靶向克雷伯氏菌的发展。肺炎是滞后的， 这可能是由于进入的高技术壁垒和与结合疫苗生产相关的高成本。 此外，大多数缀合物疫苗是多价的，进一步增加了制造复杂性。为了 为了简化偶联疫苗生产，我们开发了一种称为生物偶联的体内偶联平台。 生物缀合允许同时产生CPS、载体蛋白和它们的后续产物。 共价键都在E.杆菌我们生物结合平台的关键是我们的专利结合酶PglS， 其实际上将任何多糖连接到与载体蛋白融合的独特氨基酸序列上。 此外，生物缀合是模块化的，允许快速生产多种不同的CPS蛋白质。 结合物。利用我们的生物结合平台，我们正在开发一种基于CPS的多价生物结合疫苗 为了防止大多数K。肺炎感染。在这个I期STTR项目中，最初检测了四种血清型。 选择（K1、K2、KL 106、KL 107），因为这些血清型与>80%的所有hvKp（K1和K2）分离株相关 在全球范围内，超过70%的ST 258（KL 106和KL 107）分离株在美国。在目标1中，我们将产生一种四价的 (K1、K2、KL 106、KL 107）生物缀合物疫苗，所述生物缀合物疫苗在内部位点糖基化的修饰载体蛋白上， 预期改善缀合物的特性，例如稳定性和免疫原性。在目标2中，我们将测试 四价生物缀合物疫苗在剂量递增研究中用于确定最佳剂量。在目标3中，我们 将用ST 258菌株（KL 106和KL 107）攻击安慰剂或生物缀合物接种小鼠组 或hvKp菌株（K1和K2），并评估存活率作为疫苗效力的替代物。