P01AI162242

Impact of Antibody Effector Function Diversity on Antiviral Activity in Situ - Abstract

Overall, preventing HIV-1 acquisition and extinguishing virus replication is a key goal for vaccine and immunoprophylaxis strategies. Diverse antibody (Ab) Fc receptor (FcR)-mediated functions and multiple effector cell populations engage in vivo in a joint merger to thwart infection. An improved understanding of specific functional and qualitative features of the humoral response and how they contribute to protective efficacy is needed.

Results from immune correlates analyses of vaccine efficacy trials, immunoprophylaxis trials, and preclinical studies indicate that antibody constant (Fc) region-mediated antiviral activity is an untapped source of antiviral functions to afford broad and potent protection against HIV infection. Full exploitation of this potential demands a more complete understanding of Fc-mediated immune mechanisms in humans and animal models. Rational design of prevention methods requires more information regarding epitope targets, cognate polyclonal antibody (Ab) isotypes and subclasses, diverse FcR and effector cell populations, and most importantly, how these elements can be pulled together for the greatest antiviral impact.

The goal of this program is to define how Fc-mediated immunity can be used for preventing, treating, and curing HIV infection. We propose to determine the combined impact of antibody Fc and effector cells on antiviral outcomes in situ, thus informing how antibody Fc effector functions can be used to improve antibody-based vaccine strategies, increase the relative antiviral activity of HIV-1 specific antibody subclasses, and augment broadly neutralizing antibody (bnAb)-based prophylactic and therapeutic approaches.

Our central hypothesis is that antibody antiviral potency is maximal when multiple antibody specificities and subclasses are combined and that their antiviral functions are modulated by the in vivo localization of Fc-bearing effector cells and host genetic determinants of Fc-FcR engagement. Harnessing Fc function will improve bnAb vaccine strategies given the need to increase the antiviral functions of neutralizing antibodies (NAbs) at sub-efficacious levels.

Toward this end, we propose three synergistic, inter-related projects supported by two cores and an administrative core to achieve the following overall aims:

1. Identify combinations of bnAb and non-neutralizing antibody (nnAb) antibody specificities with maximal antiviral activity.
2. Define the contribution of antibody Fc domain (subclass, allotype) on antiviral functions.
3. Determine FcR and effector cell populations responsible for maximal Ab Fc antiviral functions in situ.

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 277012047 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-20-072)

Amendment Since initial award the total obligations have increased 411% from $4,343,297 to $22,206,461.