R01AI163857

Rational development of a vaccine against tick-borne rickettsioses - Abstract

Rickettsiae are a group of arthropod-associated, obligately intracellular gram-negative bacteria that are closely related but potentially cause life-threatening infection in humans. Tick-borne rickettsioses (TBRS) are increasingly posing serious threat to the public health in the US due to increased incidence and lack of commercially available vaccine for prevention.

Therefore, a safe and effective vaccine against TBRS will be an important resource that will ensure the nation’s capability to prevent this group of diseases. Our long-term goal is to develop novel approaches for safe and effective immunoprophylaxis of TBRS.

Our recently published and pilot studies demonstrated that live-attenuated R. parkeri mutant 3A2 conferred full protection against lethal challenge of two highly virulent rickettsiae in mouse models, accompanied by generating high titers of IgG antibodies reactive against several pathogenic rickettsial species and significantly elevated type 1 T cell memory immunity.

These findings support the proof-of-concept that live-attenuated vaccine candidate serves a feasible and effective approach to prevent TBRS and study vaccine-induced memory immunity against TBRS. Thus, the objectives of this R01 application are to generate a safe and efficacious live-attenuated vaccine (LAV) against TBRS, define the protective efficacy of LAV against homologous and heterologous rickettsial strains, and mechanistically determine the immune correlates of vaccine-elicited protection against tick transmission of TBRS.

To achieve these objectives, we propose three specific aims to test the central hypothesis that the LAV will elicit high quality CD8+ T memory cells and rickettsiae-specific neutralizing antibodies to confer complete protection against natural acquisition of TBRS as a safe and efficacious polyvalent vaccine candidate.

Aim 1 will optimize R. parkeri mutants genetically to reduce virulence, enhance safety while maintaining immunogenicity. Aim 2 will define the efficacy of genetically optimized R. parkeri mutants in protecting against TBRS in both needle-challenge and tick transmission animal models. Aim 3 will identify the immunological correlates of vaccine-induced protection against TBRS.

Upon the completion of the proposed research, we expect to define the first multivalent vaccine candidate for TBR and reveal the novel elements of host immunity responsible for prevention from natural transmission of TBRS. This will have significant positive effects on human health because it will provide the basic information required to ultimately develop a safe, effective, and tractable vaccine against TBRS.

University Of Texas Medical Branch At Galveston

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]

Galveston, Texas 775555302 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 287% from $818,015 to $3,166,318.