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.
Public Health Relevance Statement: PROJECT NARRATIVE Klebsiella pneumoniae frequently causes healthcare-associated infections and deadly community-acquired infections. In addition, K. pneumoniae is often resistant to multiple antibiotics, like carbapenems, which makes treating these infections extremely difficult. In this project, we propose to develop a vaccine that targets the capsular polysaccharide of the most clinically relevant K. pneumoniae isolates.
Project Terms: Klebsiella pneumoniae; K pneumoniae; K. pneumoniae; Americas; Amino Acid Sequence; Primary Protein Structure; protein sequence; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Bacterial Pneumonia; bacteria pneumonia; capsule; Capsules; Carbapenems; Carrier Proteins; Transport Protein Gene; Transport Proteins; Transporter Protein; Chemistry; Clinical Trials; Communities; Cessation of life; Death; Disease; Disorder; Enzymes; Enzyme Gene; Escherichia coli; E coli; E. coli; Europe; glycosylation; Metabolic Glycosylation; Goals; Human; Modern Man; Immunoglobulin G; 7S Gamma Globulin; IgG; Immunization; Immunologic Sensitization; Immunologic Stimulation; Immunological Sensitization; Immunological Stimulation; Immunostimulation; Infection; mortality; Mus; Mice; Mice Mammals; Murine; Names; Patents; Legal patent; Glycans; Polysaccharides; Production; Proteins; Development and Research; R & D; R&D; research and development; Serotyping; Southern Europe; Syndrome; Technology; Testing; Vaccination; Vaccines; Immunocompromised Host; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; base; improved; Site; Clinical; Encapsulated; Phase; Community-Acquired Infections; Conjugate Vaccines; Individual; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; programs; Colony-forming units; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; Modeling; immunogenic; Prevenar; Prevnar; Genomics; Nosocomial pneumonia; healthcare-associated pneumonia; hospital acquired pneumonia; hospital associated pneumonia; preventing; prevent; Dose; Data; in vivo; Small Business Technology Transfer Research; STTR; Vaccinated; Vaccine Production; produce vaccines; Virulent; Characteristics; Development; developmental; Pneumococcal conjugate vaccine; cost; virtual; vaccine efficacy; immunogenicity; pathogenic bacteria; bacteria pathogen; bacterial pathogen; Resistance; resistant; clinically relevant; clinical relevance; mouse model; murine model; prototype; commercialization; carbapenem resistance; carbapenem resistant; resistance to carbapenem; resistant to carbapenem; Antibody Response; Formulation; healthcare-associated infections; health care-associated infections; placebo group; sham group; human pathogen; resistant Klebsiella pneumoniae; resistance in K pneumoniae; resistance in K. pneumoniae; resistance in Klebsiella pneumoniae; resistant K pneumoniae; resistant K. pneumoniae; vaccine access; access to vaccination; access to vaccines; vaccination access; vaccination availability; vaccine availability; COVID-19 patient; COVID infected patient; COVID patient; COVID positive patient; COVID-19 infected patient; COVID-19 positive patient; COVID19 patient; COVID19 positive patient; SARS-CoV-2 infected patient; SARS-CoV-2 patient; SARS-CoV-2 positive patient; coronavirus disease 2019 infected patient; coronavirus disease 2019 patient; coronavirus disease 2019 positive patient; coronavirus disease infected patient; coronavirus disease patient; coronavirus disease positive patient; coronavirus disease-19 patient; coronavirus patient; patient infected with COVID; patient infected with COVID-19; patient infected with SARS-CoV-2; patient infected with coronavirus disease; patient infected with coronavirus disease 2019; patient infected with severe acute respiratory syndrome coronavirus 2; patient with COVID; patient with COVID-19; patient with COVID19; patient with SARS-CoV-2; patient with coronavirus disease; patient with coronavirus disease 2019; patient with severe acute respiratory distress syndrome coronavirus 2; severe acute respiratory syndrome coronavirus 2 infected patient; severe acute respiratory syndrome coronavirus 2 patient; severe acute respiratory syndrome coronavirus 2 positive patient; COVID-19 pneumonia; COVID associated pneumonia; COVID induced pneumonia; COVID pneumonia; COVID related pneumonia; COVID-19 associated pneumonia; COVID-19 induced pneumonia; COVID-19 related pneumonia; SARS-CoV-2 associated pneumonia; SARS-CoV-2 induced pneumonia; SARS-CoV-2 pneumonia; SARS-CoV-2 related pneumonia; coronavirus disease 2019 associated pneumonia; coronavirus disease 2019 induced pneumonia; coronavirus disease 2019 pneumonia; coronavirus disease 2019 related pneumonia; coronavirus disease associated pneumonia; coronavirus disease induced pneumonia; coronavirus disease pneumonia; coronavirus disease related pneumonia; coronavirus disease-19 pneumonia; pneumonia due to COVID; pneumonia due to COVID-19; pneumonia due to SARS-CoV-2; pneumonia due to coronavirus disease; pneumonia due to coronavirus disease 2019; pneumonia due to severe acute respiratory syndrome coronavirus 2; pneumonia in COVID; pneumonia in COVID-19; pneumonia in SARS-CoV-2; pneumonia in coronavirus disease; pneumonia in coronavirus disease 2019; pneumonia in severe acute respiratory syndrome coronavirus 2; severe acute respiratory syndrome coronavirus 2 associated pneumonia; severe acute respiratory syndrome coronavirus 2 induced pneumonia; severe acute respiratory syndrome coronavirus 2 pneumonia; severe acute respiratory syndrome coronavirus 2 related pneumonia; community acquired pneumonia; community associated pneumonia; opportunistic pathogen
