R01AI172156

Human Monoclonal Antibodies for Encephalitic Alphaviruses - Summary:

Eastern Equine Encephalitis Virus (EEEV) is a re-emerging mosquito-borne alphavirus that causes a debilitating encephalitic illness in humans. About a third of human cases of EEEV infection die and many survivors have long-term, debilitating neurologic problems. The virus is maintained in an enzootic cycle between Culiseta melanura mosquitoes and avian hosts but can be transmitted to humans and horses by some Aedes, Coquilettidia, and Culex species.

The infection is unusual in humans but increasing in frequency in recent years, likely secondary to climate changes, vector expansion, and other uncharacterized factors. EEEV also is regarded as a potential bioterrorism threat due to spread via aerosol route.

Despite the highly pathogenic nature of the virus, no specific treatment or vaccine for EEEV is available. A primary goal of this project is to define the molecular, genetic, immunologic, and structural characteristics of ultra-potent neutralizing human monoclonal antibodies (MAbs) with broad activity in vivo against EEEV.

Additional goals include defining the mechanistic correlates of protection by these ultra-potent neutralizing MAbs and determining ways to optimize function and deliver to the brain. In these studies, we will elucidate how antiviral antibodies with exceptional inhibitory activity exert their action in cell culture and in vivo.

The approach will include high efficiency isolation of human MAbs, coupled with innovative antibody gene repertoire studies based on next-gen sequencing. Several hypotheses will be tested, including the concept that ultra-potent neutralizing activity results from features of both the antibodies (selection of optimal V-D-J clonotypes and accumulation of critical somatic mutations) and the antigen (binding to quaternary epitopes on multiple adjacent envelope proteins and blockade of structural transitions critical for virus entry or release).

We also will apply new technologies for receptor-mediated transfer of molecules across the blood-brain barrier using engineered sequence changes in the Fc region. Although our focus is to understand how and why ultra-potent human MAbs inhibit EEEV, the studies likely will be relevant to general principles of antibody neutralization of many different encephalitic viruses.

In addition to defining the molecular and structural basis of antibody neutralization of EEEV and deploying new strategies for delivery of biologics to the brain, these studies will generate a group of fully human MAbs that can prevent and treat EEEV infection, which could be developed in the near future as a possible therapeutic for humans.

Studies in this project, while targeted against EEEV, likely will inform future antibody-based and/or vaccine efforts against other arboviruses that cause human brain infections.

We have assembled a unique group of investigators, including a human antibody expert, a molecular virologist with experience in antibody-virus interactions, an animal model and pathogenesis expert with specific expertise in encephalitic alphaviruses, including EEEV, and brain-targeting scientists to pursue these studies.

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 372152691 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 278% from $858,139 to $3,248,015.