R01AI169619

Flipped Germinal Centers - Project Summary

Developing universal vaccines to influenza and HIV-1 is an urgent global goal. A critical challenge is that immune responses to native HIV-1 envelope (ENV) and influenza hemagglutinin (HA) are dominated by non-neutralizing and highly strain-specific antibodies.

Discoveries that some individuals produce broadly neutralizing antibodies (BNABs) invigorated hope that, while not naturally dominant, broadly protective antibody responses are possible. Antibodies mature during through somatic hypermutation (SHM) and affinity-based selection in germinal centers (GCs) in competition with other antibodies that recognize different parts of the same virus.

It is widely believed that a prime and boost vaccine tactic can effectively elicit BNAB precursors and strategically guide SHM trajectory can produce BNABs. Challenges to this process are that native envelope proteins may not bind well to the BNAB precursor antibodies and may be poorly represented in the antibody repertoire.

A strategic prime and boost strategy requires generation of designer viral envelope variants that bind well to BNAB ancestor antibodies acting as a primer, followed by modified variants to function as boosting immunogen(s) to shepherd BNAB maturation. This promising approach is hindered by time and effort required to identify ENV or HA variants as immunogens, which traditionally require mutation library generation, in vitro static selection, cloning, expression, and validation testing. This extensive hands-on trial and error process greatly hinders the pace of progress.

Here a new technology is proposed with power to explosively accelerate the pace of immunogen discovery by creatively harnessing the full spectrum of automated mutation and selection inherent in one of nature's innovations in hyperevolution - namely the GC SHM and affinity maturation system - an automated in vivo dynamic mutation process coupled to parallel selection activity that dynamically shuttles superior binding variants back for further diversification and selection.

In addition to dramatically improving binding affinity, the GC system can be engineered to generate new recognition. The objective is to create flipped GC systems in which antibody genes are replaced with viral envelope proteins - and deploy them for immunogen design. In contrast to dynamic antibody evolution to viral envelope protein in normal GCs, flipped GCs dynamically evolve viral envelope protein toward user-defined antibodies (e.g. select BNAB precursors and intermediates).

The overall hypothesis is that, in the context of key modifications, the GC/affinity maturation system is sufficiently flexible to permit bioengineered viral envelope proteins to affinity mature toward user-defined BNAB precursors and intermediates. The objective will be pursued with two aims: 1) to establish parameters to engineer GCs as a platform for non-IG protein evolution, and 2) to generate HIV-1 and influenza envelope variants from flipped GC mice.

Completion of this work has the potential to result in both scientific and technological breakthroughs of broad impact because it is expected to define parameters enabling the extension of the power of GC evolution beyond IG to essentially any protein-protein interaction.

Brigham & Womens Hospital

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.

93.310 - Trans-NIH Research Support

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

NIH Directors Transformative Research Awards (R01 Clinical Trial Optional) (RFA-RM-20-013)

Amendment Since initial award the total obligations have increased 400% from $740,268 to $3,701,340.