U01AI160418

Molecular Mechanisms of Adjuvant Triplet Combinations - Abstract:

Molecular mechanisms of adjuvant triplet combinations. The immune system makes decisions in response to complex combinations of microbial inputs. Live vaccines that are empirically attenuated from pathogens have been a powerful means to yield life-long immunity against many deadly pathogens because they mimic immune responses to combinations of microbial signals.

However, the rational design of non-live vaccines using immunomodulatory agents such as adjuvants has remained an elusive task in many cases where live vaccination is not efficacious or feasible, in part because identifying potent adjuvant combinations and associated molecular mechanisms that explain cross talk remains a major challenge.

Based on our recent findings and extensive preliminary data, we propose to define the molecular mechanisms through which two adjuvant triplets – containing agonists for Toll-like receptor (TLR), C-type lection receptor (CLR), RIG-I-like receptor (RLR), and cytosolic dsDNA sensor (CDS) pathways – induce protective CD4+ and CD8+ T cell responses in mice.

We will use an innovative approach which is (i) comparative – by contrasting the quantitative effects of adjuvant triplets and matching singles and pairs as means to accurately pinpoint molecular mechanisms explaining cross talk; and (ii) multiscale – by studying molecular mechanisms at play in cells, tissues, and the whole body.

First, we will determine the molecular mechanisms of intra-cellular signaling cross talk by adjuvant triplets by testing hypotheses at the level of protein complexes proximal to adjuvant receptors, phosphorylation cascades and kinase-substrate relationships, and gene regulatory networks.

Second, we will identify the molecular mechanisms through which adjuvant combinations impact inter-cellular signaling between dendritic cells (DCs) and T cells by testing hypotheses on the regulatory mechanisms shaping the cellular, surface, and secreted proteome of DCs.

Third, we will test hypotheses on the effects of adjuvant triplets on the organism-wide spreading and seeding of effector and memory T cells, and the underlying cell circuits of the skin (vaccination site) and draining lymph node that explain the induction of protective, long-term T cell immunity.

Results from this work will produce critical insights at the forefront of adjuvant combination research by characterizing higher-order combinations of adjuvants that can mimic the effects of well-established, potent live attenuated vaccines and inform future vaccine designs against infection.

University Of Chicago

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]

Chicago, Illinois 606375418 United States

Single Zip Code

Molecular Mechanisms of Combination Adjuvants (MMCA) (U01 Clinical Trial Not Allowed) (RFA-AI-20-004)

Amendment Since initial award the total obligations have increased 395% from $623,649 to $3,084,459.