R01AI158516

Heterosubtypic immunity to influenza virus mediated by MHC-E-restricted memory NK cells - Seasonal influenza epidemics are a leading cause of morbidity and mortality worldwide. While prophylactic immunization has proven the most efficient way to prevent influenza so far, current vaccines provide limited protection against antigenically distinct influenza strains, notably those with pandemic and/or high pathogenic potential.

Therefore, innovative approaches to provide longer-lasting protection than currently licensed vaccines and against a wider variety of influenza viruses is highly desirable. Mobilization of immune effector cells with potent antiviral activity against conserved influenza antigens represents one strategy to enhance cross-protection.

Classically, natural killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections, including influenza. Unexpectedly, for over a decade, paradigms suggesting that immunological memory is exclusively mediated by T and B cells have been challenged by several independent studies clearly demonstrating that subsets of murine, non-human primate (NHP), and human NK cells are capable of adaptive immune functions, including antigen-specificity and recall responses.

Our new preliminary data now show for the first time that influenza-specific NK cells mediating potent responses against conserved influenza antigens from serologically distinct strains exist in humans and provide mechanistic evidence supporting a role for HLA-E and its activating ligand NKG2C in antigen-specific NK cell responses.

Collectively, these findings suggest that vaccine strategies that concomitantly enhance the breadth, magnitude, and cross-reactivity of influenza-specific memory NK cell, T cell, and B cell responses might significantly improve vaccine-induced cross-protective immunity. However, mechanisms underlying the establishment and maintenance of true antigen-specific NK cell memory are largely undefined, and protection mediated by influenza-specific memory NK cells remains to be determined in primate species.

In this study, we propose to address the overarching hypothesis that MHC-E-restricted memory NK cells can mediate heterosubtypic protection against influenza through three focused independent aims: (I) characterize human influenza-specific memory NK cell responses; (II) assess influenza-specific memory NK cell-mediated cross-protection in macaques; and (III) delineate MHC-E-restricted NK cell antigen specificity against influenza.

We expect these innovative studies to help develop universal influenza vaccines tailored to mobilize influenza-specific memory NK cells.

Duke 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]

Durham, North Carolina 277054640 United States

Single Zip Code

Advancing Research Needed to Develop a Universal Influenza Vaccine (R01 Clinical Trial Not Allowed) (PA-18-859)

Amendment Since initial award the total obligations have increased 462% from $662,843 to $3,727,019.