R01AI153250

Development of mRNA-Platform Vaccines - Project Summary

Pertussis is a respiratory disease caused by the obligate human pathogen Bordetella pertussis. Two generations of pertussis vaccines have been developed and licensed: whole cell pertussis (DTP) and acellular pertussis (DTaP/Tdap). Pertussis was thought to be a disease of the past but has recently re-emerged. The number of cases of pertussis in 2012 was 48-fold over the lowest year on record (1976), which was also a 50-year high.

While the increase of pertussis has multiple potential reasons, epidemiological studies clearly suggest that the duration of immunity of both DTaP and Tdap wanes quickly each year after a booster, and regresses to non-protective levels in humans. Each dose of whole cell vaccine contains hundreds of antigens, of which numerous are immunodominant. Whole cell vaccines also induce T helper 1 and 17 (Th1/Th17) cellular immune responses. On the other hand, acellular vaccines focus Th2-mediated humoral responses exclusively to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae.

We aim to develop a vaccine that would induce Th1 responses and include a greater number of antigens than acellular vaccines. mRNA vaccines provide a platform that can be easily modified for the targeted antigen/pathogen and they induce Th1 responses. mRNA vaccines encode the antigen, which once expressed, results in immunity mediated by TFH responses. We used an mRNA platform to screen antigens of B. pertussis and identified a protective multivalent formulation (mRNA-DTP10; 8 pertussis antigens with diphtheria and tetanus antigens) in a murine challenge model.

In this project, we will further extend our studies and investigate the correlates of protection of the mRNA-pertussis vaccine in the murine model with longevity studies and examine DTaP prime / mRNA-boost effects (SA1). Next, we will utilize the coughing rat model of pertussis with whole body plethysmography to compare mRNA, whole cell, and acellular immunity for protection against cough (SA2). We will study the mRNA pertussis vaccine in immunogenicity and challenge experiments using the baboon model of pertussis (SA3). Lastly, we will aim to develop a suite of assays to phenotype antibodies produced by mRNA pertussis vaccines and bridge each of the pertussis models, which will facilitate clinical development.

Through these studies, we aim to characterize the mRNA-pertussis immunity and develop a clearer understanding of how this vaccine platform can be used to overcome "complex or difficult" pathogens that employ numerous virulence factors. We expect the data acquired in each aim will result in a deeper understanding of pertussis immunity as well as illuminate the mRNA platform for bacterial vaccines.

West Virginia University Research Corporation

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]

Morgantown, West Virginia 265069177 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 399% from $826,282 to $4,121,318.