R01AI155804

Novel Immunogens to Elicit Broadly Cross-Reactive Antibodies that Target the Hemagglutinin Head Trimer Interface - Abstract

Novel vaccines are needed that have higher efficacy and that provide long-lasting protection against emerging influenza viruses. An attractive approach towards developing a "universal" vaccine is focused on eliciting antibodies that target conserved regions of the hemagglutinin (HA) protein on the surface of the virus.

The receptor binding site and the stem are two such HA regions, and the elicitation of humoral responses focused on these sites has been the subject of multiple studies. Recently, a new class of antibodies has been discovered that targets the highly conserved HA head trimer interface. Antibodies against this epitope were found in multiple individuals, have broad heterosubtypic cross-reactivity, and provided protection against viral challenges in animal models. Therefore, induction of these types of antibodies as part of a universal influenza vaccine would be valuable.

The head trimer interface epitope is occluded in crystal structures of HAs and likely becomes exposed just transiently through molecular "breathing". This limited accessibility may explain, at least in part, why natural humoral responses against this site are rare.

In this proposal, we will engineer immunogens that present unobstructed the HA head trimer interface epitope in molecular contexts devoid of other immunodominant sites. Using computational protein modeling and high throughput library screening, HA-derived as well as non-influenza-based immunogens will be developed that:

1) Expose the HA head trimer interface to facilitate immune recognition;
2) Preferentially interact with broadly cross-reactive, but not with strain-specific, antibodies that target this site; and
3) Occlude immunodominant regions to focus the immune responses on the epitope.

Designed immunogens will be used to vaccinate small animals to assess their ability to protect against live virus. Detailed analysis of the B cell receptor repertoires of vaccinated animals will reveal the developmental pathways that lead to the activation and maturation of humoral responses against the conserved HA head trimer interface.

This proposal will provide candidate immunogens towards the development of a universal influenza vaccine, lead to a better understanding of molecular features that control HA conformation and immunogenicity, and establish general approaches for immunogen design.

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]

North Carolina United States

State-Wide

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

Amendment Since initial award the End Date has been extended from 07/31/25 to 07/31/26 and the total obligations have increased 379% from $812,575 to $3,892,523.