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Principal Investigator: Ivan Zanoni
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2022
Award: $751,928
Funding agency: National Institute of Allergy and Infectious Diseases
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
important 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 Candia 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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Ab response><Address><Adjuvant><Adjuvanticity><Al element><Aluminum><Aluminum Hydroxide><Antibodies><Antibody Formation><Antibody Production><Antigenic Determinants><Antigens><Automobile Driving><Benchmarking><Best Practice Analysis><Binding Determinants><Biology><Bone Marrow><Bone Marrow Reticuloendothelial System><C Type Lectin Receptors><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Body><Cell Wall><Cells><Chimera><Chimera organism><CoV-2><CoV2><Communicable Diseases><Cytokine Receptors><DNA><Deoxyribonucleic Acid><Development><Drug Kinetics><Epitopes><Experimental Models><FDA approved><Formulation><Fungus Diseases><Glycans><Glycoproteins><Goals><Homolog of Drosophila TOLL><Human><Hydrated Alumina><IFN><Immune><Immune Cell Activation><Immune Globulins><Immune response><Immunes><Immunity><Immunization><Immunize><Immunoglobulins><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><In Vitro><Inbreeding><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Injections><Innate Immune System><Interferons><KO mice><Knock-out Mice><Knockout Mice><Ligands><Light><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocytic><Mannan><Mannans><Measures><Mediating><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular><Molecular Mechanisms of Action><Mouse Strains><Murine><Mus><Mycoses><Myeloid Cells><Null Mouse><Pathway interactions><Pattern recognition receptor><Phagocytes><Phagocytic Cell><Pharmacokinetics><Photoradiation><Play><Polysaccharides><Process><Proteins><Public Health><Receptor Protein><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salts><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Site><Specificity><Spike Potential><Surface><TLR protein><TLR4><TLR4 gene><Testing><Th-1 Cell><Th1 Cells><Toll Homologue><Toll-Like Receptor Family Gene><Toll-like receptors><Type 1 Helper Cell><Vaccine Adjuvant><Vaccine Antigen><Vaccines><Viral><Work><Wuhan coronavirus><adaptive immune response><adaptive immunity><amebocyte><antibody biosynthesis><base><beta-Glucans><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><dectin 1><dectin-2><developmental><driving><fungal infection><fungus infection><hCoV19><host response><immune activation><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vitro Model><in vivo><innate immune pathways><innovate><innovation><innovative><lymph cell><lymph gland><lymph nodes><lymphnodes><microbial antigen><microorganism antigen><mouse dectin-2><mouse model><murine model><nCoV2><neutralizing antibody><novel><pathogen><pathway><physical property><programs><receptor><sensor><toll-like receptor 4><tool><β-Glucans>