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Principal Investigator: Darrell J Irvine
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $469,443
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
The majority of licensed vaccines are thought to elicit protection mediated by humoral immunity. A key
determinant of the specificity and affinity of the antibody response is the germinal center (GC) response elicited
by immunization, wherein B cells enter GCs to undergo cyclic rounds of proliferation and somatic hypermutation
to evolve higher-affinity antibodies, followed by exit from the GC to become long-lived plasma cells or memory
B cells. Effective GC responses are thought to be critical for difficult pathogens such as HIV, and even for easily-
neutralized viruses such as SARS-CoV-2, effective and long-lived GC responses are associated with more
effective cross-neutralization of viral variants. Hence, optimizing GC responses is fundamental to vaccines
broadly. In recent work, we have studied how vaccine kinetics– the temporal pattern of antigen and adjuvant
exposure during immunization– impact humoral immunity and GC reaction in particular. Our preliminary studies
have revealed that prolonged delivery of antigen to draining lymph nodes over a period of 2-3 weeks substantially
alters the immune response. One particularly effective immunization approach, which we term “extended
dosing” (ext-dosing) immunization, involves administering a given total dose of vaccine antigen and adjuvant
as a half-dozen injections over two weeks in an escalating-dose pattern. Ext-dosing enhances the magnitude
of the GC response in both small and large animal models and increases the clonality (number of distinct B cell
clones participating in the GC), leading to enhanced neutralizing antibody production. These dramatic effects of
ext-dosing vaccination warrant close study to understand how and why this strategy is so effective. As ext-dosing
through repeat injections is not practical for human immunization, we are also highly motivated to develop
alternate strategies to achieve the same immunologic effects without the need for 6 or more injections. To
address these goals, our specific aims are (1) define how antigen exposure kinetics govern the immune
response elicited by ext-dosing immunization, (2) determine how adjuvant exposure kinetics impact the immune
response in ext-dosing, (3) test strategies to achieve “extended-dosing” effects using bolus subunit vaccine
administration, and (4) to evaluate the potential for ext-dosing-like effects in mRNA vaccines. Altogether, these
studies will both clarify fundamental concepts underlying effective primary immune responses and develop new
translationally-relevant approaches to enhance immune responses elicited by subunit and mRNA vaccines. We
test-bed these concepts using clinically-relevant antigens and adjuvants, and aim to pursue strategies we expect
to be broadly applicable to vaccines independent of disease target.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adjuvant><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Affinity><Antibody Formation><Antibody Production><Antibody Response><Antigens><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Beds><Binding><Blast Transformation><Blastogenesis><Blood Plasma Cell><Bolus><Bolus Infusion><COVID-19 virus><COVID19 virus><Cell Body><Cells><Chemotactic Cytokines><Clonality><Clone Cells><CoV-2><CoV2><Collagen><Complement><Complement Proteins><Computer Analysis><Computer Models><Computerized Models><Cyclicity><Disease><Disorder><Dose><Drug Kinetics><Effectiveness><Feedback><Future Generations><Generations><Germinal Center><Goals><HIV><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Viruses><Humoral Immunities><Ig Somatic Hypermutation><Immune response><Immunity><Immunization><Immunochemical Immunologic><Immunoglobulin Somatic Hypermutation><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inflammation><Injections><Intercrines><Kinetics><LAV-HTLV-III><Licensing><Lymphadenopathy-Associated Virus><Lymphoblast Transformation><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><Mediating><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Modeling><Modern Man><Molecular Interaction><Non-Polyadenylated RNA><Output><Pattern><Periodicity><Pharmacokinetics><Phenotype><Plasma Cells><Plasmacytes><Proliferating><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Reaction><Regimen><Replication Unit><Replicon><Rhythmicity><Ribonucleic Acid><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><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 coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure of germinal center of lymph node><Subunit Vaccines><Testing><Translating><Vaccination><Vaccine Adjuvant><Vaccine Antigen><Vaccines><Variant><Variation><Viral><Virus><Virus-HIV><Work><Wuhan coronavirus><antibody biosynthesis><antibody-based immunity><antigen antibody affinity><cell type><chemoattractant cytokine><chemokine><clinical relevance><clinically relevant><complementation><computational analyses><computational analysis><computational modeling><computational models><computer analyses><computer based models><computerized modeling><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><design><designing><draining lymph node><driving><hCoV19><host response><immune response to vaccination><immune response to vaccines><immune system response><immunogen><immunoglobulin biosynthesis><immunoresponse><in vivo><mRNA><mRNA vaccine><mRNA-based vaccine><model of animal><nCoV2><neutralizing antibody><new vaccines><next generation vaccines><novel vaccines><pathogen><plasmocyte><regional lymph node><response><social role><somatic hypermutation><vaccination study><vaccination trial><vaccine associated immune response><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine study><vaccine trial>