R01AI165505

Development of a Novel Adjuvant Strategy Enabled by Modulation of the Physical Properties of Fungal Mannans - Project Summary

Vaccines represent a highly effective public health measure to protect individuals from infectious diseases. Many vaccines work by inducing antigen-specific antibodies that neutralize the pathogen or its products and promote their clearance. Vaccines based on protein antigens usually require the addition of adjuvants to enhance potency, breadth, and duration of the antigen-specific adaptive immune response.

Adjuvants promote vaccine antigen immunogenicity by activating receptors of the innate immune system called pattern-recognition receptors (PRRs) and/or modulating antigen pharmacokinetics. Aluminum salts are the most common adjuvants in FDA-approved vaccines. Recently, vaccines including adjuvants that target specific PRRs, in particular Toll-like receptor (TLR)4 and TLR9, have also been approved by the FDA, paving the way for the development of molecularly defined adjuvants.

Investigating the potential of additional PRRs as adjuvant targets is of paramount importance to expand our vaccine toolbox and probe how different modalities of innate immune cell activation impact the adaptive immune response. Here, we propose to use the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein as a model antigen to test a new adjuvant formulation that contains fungal ligands that target the PRR Dectin-2.

Our preliminary results show that mannans (fungal cell wall polysaccharides isolated from Candida albicans) alone or formulated with aluminum hydroxide enhance the immunogenicity of pre-fusion stabilized spike trimers in mouse models of immunization. In particular, mannan formulations, compared to aluminum hydroxide only, induce an early increase in anti-spike antibody levels, potentiate the induction of SARS-CoV-2 neutralizing antibodies, broaden the spike epitopes that are targeted, and favor the switch towards immunoglobulin subclasses associated with higher effector functions and reduced risk of vaccine-associated enhanced respiratory disease (VAERD).

Here, we hypothesize that mannans formulated with alumoh induce a potent and durable adaptive immune response to SARS-CoV-2 spike by inducing specific innate immune pathways and activation programs. By combining detailed immunogenicity and mechanistic analyses, our proposal will define a novel adjuvant formulation for SARS-CoV-2 spike and potentially other viral glycoproteins as well as shed new light on the biology of Dectin-2.

Children's Hospital Corporation

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]

Boston, Massachusetts 021155724 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 383% from $777,874 to $3,755,681.