A multivalent O-antigen bioconjugate vaccine for the prevention of Klebsiella pneumoniae infections

用于预防肺炎克雷伯菌感染的多价 O 抗原生物结合疫苗

• 批准号: 10480371
• 负责人: Christian Harding
• 金额: $ 29.92万
• 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: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480371
• 关键词: Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Awareness; Bacteria; Bacterial Infections; Bacterial Polysaccharides; Biological Assay; Bioreactors; Carbapenems; Carrier Proteins; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Cessation of life; Chemicals; Clinic; Clinical; Communities; Complex; Conjugate Vaccines; Development; Disease; Dose; Drug resistance; Encapsulated; Enzyme-Linked Immunosorbent Assay; Enzymes; Epitopes; Escherichia coli; Europe; Formulation; Future; Generations; Genetic; Glean; Goals; Healthcare; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunologics; Individual; Infection; Infection prevention; Inferior; Investments; Klebsiella; Klebsiella pneumoniae; Life; Light; Link; Lipopolysaccharides; Meta-Analysis; Methods; Minor; Mus; O Antigens; Oryctolagus cuniculus; Ozone; Patients; Phase; Placebos; Polysaccharides; Prevention; Process; Production; Resistance; Savings; Scheme; Serotyping; Serum; Structure; Surface; System; Technology; Testing; Vaccinated; Vaccination; Vaccine Design; Vaccine Production; Vaccines; Work; bactericide; carbapenem resistance; combat; cross immunity; genetic information; glycosylation; healthcare community; immunogenicity; microbial; novel; pathogen; pathogenic bacteria; pre-clinical; preclinical development; prevent; response; vaccine candidate; vaccine development; vaccine efficacy; vaccine immunogenicity

PROJECT SUMMARY Klebsiella pneumoniae is a leading cause of healthcare- and community-associated infections. Moreover, K. pneumoniae is frequently resistant to last line antibiotics like third generation cephalosporins and carbapenems. In fact, carbapenem-resistant Klebsiella is considered an Urgent Threat by the CDC requiring aggressive, immediate action. One of the five core actions proposed by the CDC to combat antibiotic resistance is for continued investment and development of vaccines to prevent K. pneumoniae as well as other drug resistant bacterial infections. As such, VaxNewMo developed a multivalent conjugate vaccine targeting the majority of K. pneumoniae clinical isolates. Conjugate vaccines, composed of a polysaccharide covalently linked to a carrier protein, are life-saving vaccines used to prevent disease from multiple bacterial pathogens. Conventionally, conjugate vaccines are manufactured using chemical conjugation, which is notoriously complex, labor intensive, and imprecise, hindering the development of new conjugate vaccines against existing and emerging bacterial threats, like K. pneumoniae. Well aware of these drawbacks, VaxNewMo has been advancing an alternative method for manufacturing conjugate vaccines that utilizes prokaryotic glycosylation systems in a process termed bioconjugation. VaxNewMo’s proprietary bioconjugation platform relies on a conjugating enzyme to transfer a bacterial polysaccharide to a carrier protein all within the lab safe bacterium E. coli. Moreover, since bioconjugation is an enzyme driven process, the conjugates produced are non-derivatized and are therefore structurally identical to those presented to immune cells by the pathogen itself. Bioconjugation can be used to rapidly produce many conjugates simply by introducing new genetic information encoding for a different polysaccharide serotype into a bioconjugation competent strain of E. coli. As an example of this, we developed a multivalent O-antigen bioconjugate vaccine targeting >80% of K. pneumoniae isolates encountered in the clinic. In this Fast-Track application, we will validate the vaccine for immunogenicity and subsequently determine optimized doses in mice and rabbits, assess functional antibody responses as well as vaccine efficacy by performing challenge studies. In Phase I, we will assess immunogenicity of monovalent and multivalent O- antigen bioconjugate formulations by performing dose-escalation studies in mice. Immunogenicity will be assessed by ELISA for serotype-specific total IgG and IgG subtype antibody concentrations pre- and post- immunizations to each O-antigen formulated into the vaccine. Once validated for immunogenicity, we will proceed to Phase II. In Phase II, we will produce the vaccine in larger batches using a scalable microbial bioreactor system. Subsequently, we will assess functional antibody responses via a serum bactericidal assay (SBA) and an opsonophagocytic killing assay (OPKA) as well as perform challenge studies in mice vaccinated with a mouse optimized dose of the multivalent O-antigen bioconjugate vaccine. Finally, we will confirm immunogenicity and functional antibody responses (SBA and OPKA) of monovalent and multivalent O-antigen bioconjugate formulations in rabbits, a widely utilized animal model for conjugate vaccine development.

项目总结