R01AI175038

Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella - Project Summary

This project will enhance our understanding of the humoral immune response to Klebsiella pneumoniae (KP) and its polysaccharide antigens with the long-term goal of guiding and optimizing broad vaccine development.

KP infections, including pneumonia, urinary tract infection, and bacteremia, are sharply on the rise among hospitalized patients; CDC has declared infections with KP and other carbapenem-resistant Enterobacteriales (CRE) demand a threat level of urgent.

Beyond classical KP typically seen in the US, emerging hypervirulent KP strains, capable of causing liver abscess, bacteremia, and meningitis in healthy hosts, are spreading globally.

This work builds on the PI's background in bacteriology, gram-negative bacterial pathogenesis, and modeling of host adaptive immune responses, to investigate antibodies targeting KP's polysaccharide capsule (K-type) and O-antigen.

We have found that, while mice are able to produce antibodies targeting KP capsule and O-antigen, capsule may directly interfere with O-antibody binding and killing of KP.

With our collaborators at Omniose, we have developed and are testing novel bioconjugate vaccines targeting the most prevalent K- and O-types.

Bioconjugation is an alternative manufacturing process that uses recombinant E. coli strains to concurrently produce the capsule or O-antigen and an engineered carrier protein, and to enzymatically link the two.

We have produced multiple K- and O-bioconjugates that have demonstrated promising efficacy in mice.

As both O- and K-vaccines are under development, we will use our novel bioconjugate vaccines in murine protection experiments to determine the relative effectiveness of O-antigen or K-antigen bioconjugates against classical and hypervirulent KP isolates.

Further, we will challenge O-immunized mice with strains of closely related O-antigen structural subtypes that have not been included to date in vaccine formulations being developed commercially.

Potential masking of O-antigen by capsule will be determined through mouse serum IgG ELISAs.

Serum bactericidal assays (SBAs) and opsonophagocytic killing assays (OPKAs) will be developed and correlated with murine protection.

Further, with bacterial mutants, complemented strains, and capsule inhibitors, we will determine the specificity of KP O-antibody inhibition by capsule, utilizing multiple techniques including biolayer interferometry, immunofluorescence microscopy, and transmission immunoelectron microscopy.

Finally, we will perform a first-ever longitudinal study of human patients with KP infection, analyzing their sera for antibodies specific to KP polysaccharides and their functional activity against the inciting KP strain.

At the conclusion of these studies, the relative efficacy of both K- and O-type bioconjugate vaccines will be determined, cross-protection among O-antigen subtypes will be resolved, correlates of protective immunity will be established, and mechanisms of O-antigen masking will be defined.

Our results will illuminate human antibody responses to KP infection and guide vaccine development to target this worrisome pathogen.

Washington University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Saint Louis, Missouri 631101010 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 421% from $668,998 to $3,483,730.