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: 10379720
• 负责人: Christian Harding
• 金额: $ 30万
• 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 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

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.

项目总结