U01AI160338

Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines

In full response to RFA-AI-20-004, we propose to study the mechanisms of cooperativity between NKT cell and TLR adjuvants. We have previously shown that we could use a combination of NKT cell and TLR7 adjuvants to produce high affinity protective anti-bacterial glycan vaccines. Our goal is now to understand the mechanisms of this cooperative effect between the two adjuvants to optimize it and produce a vaccine formulation that promotes protection after a single administration. In addition, we contend that mechanistic studies will also allow the limitation of the potential side effects of adjuvants.

To this end, our proposal is built on two separate and complementary specific aims:

Aim 1: Evaluate endosomal TLR ligands for their ability to enhance NKT cell responses and their B cell helper activities. We have produced nanomolar affinity anti-glycan antibodies by combining NKT cell and TLR7 agonists. This response was dependent on NKT and CD4 T cell help. We hypothesize that each endosomal TLR ligand may have a different enhancing effect in a combinatorial usage. We will investigate NKT, T follicular helper, dendritic, and B cell responses by single cell technologies for RNA and protein expression in animal models of vaccination for each TLR/NKT cell pair that we will study. B cell receptor sequencing and pathogen challenges will be used to measure the efficacy of each combination.

Aim 2: Evaluate the importance of the co-delivery of the two adjuvants to particular cell types and endosomal/lysosomal compartments. We hypothesize that the physical aspects of adjuvanticity with respect to antigen uptake and delivery to processing compartments are critical. By co-delivering antigen and adjuvants to particular cells and within chosen compartments, using synthetic chemistry to control their pairing and separation, mechanisms of adjuvant activity will be examined. The biological consequences of this molecular-based design of adjuvant combinations will be evaluated with respect to dosage, toxicity, and efficacy. We expect to develop robust formulations that induce protection after a single vaccine administration.

Our entire proposal is focused exclusively on vaccines aimed at developing protective B cell immunity, and our model system is a conjugate vaccine against Streptococcus pneumoniae.

Scripps Research Institute

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]

La Jolla, California 920371000 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 391% from $699,766 to $3,438,006.