U19AI174999

Vanderbilt Antibody and Antigen Discovery for Clostridioides Difficile Vaccines - Overall Project Summary

Vanderbilt Antibody and Antigen Discovery for Clostridioides Difficile Vaccines (VANDY-CDV)

Clostridioides difficile is a spore-forming anaerobic bacterium that is the leading cause of hospital-acquired gastrointestinal infection in the United States. The rising incidence of community-acquired C. difficile infection (CDI) in otherwise healthy adults is linked to increased antibiotic use and the emergence of new strains. CDI symptoms and pathology are mediated by two large homologous toxins, TCDA and TCDB, and therefore the toxins represent attractive targets for prevention and therapeutic strategies.

While efforts centered around the use of toxoids for immunization have shown promise in reducing the severity of symptoms, the toxoid approach has not resulted in a decreased incidence of CDI in clinical trials. There are several opportunities to improve upon existing vaccine strategies. First, large-scale genomic studies show that TCDB is undergoing rapid evolutionary change; the identification of conserved toxin epitopes can be used to direct the immune response toward the production of broadly neutralizing responses.

Second, the identification of conserved antigens on the surface of the vegetative bacteria or spores that can serve as immunogens will allow the host to elicit mucosal immune responses that prevent bacterial colonization. The inclusion of mucosal immunization routes is expected to further enhance vaccine efficacy and durability.

The overarching goal of the VANDY-CDV program is to identify toxin subunits and novel cell surface antigens that, when combined, promote durable protection against C. difficile infection and symptoms. Among many innovative strengths, the approach includes the use of human CDI patient samples as a resource for understanding what antigens promote IgG, IgA, and sIgA responses in natural infection. The approach also includes the use of powerful single B cell sorting and sequencing methods. The ability to identify paired heavy and light chain sequences from individual memory B cells binding toxins and/or bacteria allows for the production of unique antibodies that can then be used as tools for epitope mapping and novel antigen discovery.

A third highlight of the approach involves the use of a newly created C. difficile transposon library which will be used to identify novel antigens in an in vivo vaccination/challenge experiment. Other innovations include a structure-guided approach to identifying potent, neutralizing epitopes and a systematic evaluation of how intestinal lymphocyte responses vary with routes of immunization. Vaccine efficacy and the mucosal correlates of protection will be evaluated in pre-clinical models of colonization, infection, and recurrence.

At the end of five years, we expect to have the pre-clinical data needed to advance a novel antigen cocktail and immunization strategy forward into human safety and efficacy trials.

Vanderbilt University Medical Center

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]

Nashville, Tennessee 37203 United States

Single Zip Code

Host Immunity and Novel Immunization Strategies for Clostridioides difficile Infection (CDI) (U19 Clinical Trial Not Allowed) (RFA-AI-22-001)

Amendment Since initial award the total obligations have increased 50% from $3,140,094 to $4,710,141.