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Principal Investigator: Bryce C Chackerian
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2021
Award: $511,894
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary / Abstract
This proposal describes the framework of an R01 grant by Dr. Daniel Lingwood, an Assistant Professor at
Harvard Medical School and faculty member of the Ragon Institute of MGH, MIT and Harvard, and Dr. Bryce
Chackerian, an Associate Professor in the Department of Molecular Genetics & Microbiology at the University
of New Mexico School of Medicine. Their research centers on B cell receptor (BCR) antigen recognition
biology (Lingwood) and directed evolution of virus-like particle (VLP) vaccine platforms (Chackerian). Together
they propose to develop a new strategy for universal influenza vaccine design. Most vaccine-elicited antibody
responses to this virus are dominated by immunodominant off-target, non-neutralizing activities. However,
recent work from Dr. Lingwood indicates that human BCRs assembled using the antibody gene IGHV1-69
possess V region-encoded (innate-like) specificity for a functionally conserved site of vulnerability, the stem-
epitope of the influenza spike protein hemagglutinin (HA) and target of broadly neutralizing antibody (bnAb)
responses. To experimentally evaluate this as a gene-encoded template for building a universal vaccine, Dr.
Lingwood has generated transgenic mice in which antibody development proceeds via normal human VDJ
recombination, but where V region use is constrained to IGHV1-69. Preliminary data indicate that IGHV1-69
usage itself refocuses the antibody response to the stem epitope, a feature that Dr. Lingwood finds is
dependent on a single gene-encoded amino acid in the stem-contacting CDRH2 of IGHV1-69. To now
transduce this into bnAb elicitation, Dr. Lingwood proposes to immunize his humanized mice with rationally-
designed trimeric and nanoparticle displays of influenza HA stem which trigger innate-like stem-epitope
signaling by the reconstituted germline IGHV1-69 BCR. Through these experiments Dr. Lingwood will provide
a major paradigm shift in rational vaccine design, namely that broad protection may be generated through
`activation' and `amplification' of gene-encoded antibody responses. To define a pathway for clinical
development, Drs. Lingwood and Chackerian have applied RNA bacteriophage peptide display and affinity
selection technology to derive a VLP vaccine with multivalent affinity to the V region of IGHV1-69 germline
BCR, in essence a V region-specific primer to selectively expand innate-like stem targeting activity that is
otherwise normally diluted by human BCR diversity. Selective IGHV1-69 priming will be evaluated in the
Trianni mouse, the latest industry-standard humanized mouse vaccine model. V region priming will then be
boosted with IGHV1-69-engaging HA stem immunogens, to stimulate a now immunodominant innate-like HA
stem sensing antibody response. Exploiting a genetic basis for bnAb elicitation aims to overcome the failure of
traditional approaches to influenza vaccination and is consistent with the purpose of this funding opportunity
and broader mission of the NIH.
Terms: <Adaptive Immune System><Affinity><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Repertoire><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Biology><Cell Communication and Signaling><Cell Lineage><Cell Signaling><Clinical Pathways><Complementarity Determining Regions><Complimentarity Determining Region><DNA Recombination><Data><Development><Directed Molecular Evolution><Epitopes><Evolution><Failure><Flu vaccination><Funding Opportunities><Gene Amplification><Genes><Genetic><Genetic Recombination><Genetic Template><Grant><Grippe><Hemagglutinin><Heterozygote><Human><Hypervariable Loop><Hypervariable Regions><Immunity><Immunization><Immunize><Immunoglobulin Hypervariable Region><Immunoglobulin V(D)J Rearrangement><Immunologic Receptors><Immunologic Sensitization><Immunologic Stimulation><Immunological Receptors><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Industry Standard><Influenza><Influenza HA><Influenza Hemagglutinin><Influenza Virus><Influenza immunization><Influenza vaccination><Institutes><Instruction><Intracellular Communication and Signaling><Medical Faculty><Mice><Mice Mammals><Microbiology><Mission><Modeling><Modern Man><Molecular Genetics><Murine><Mus><NIH><National Institutes of Health><New Mexico><Pathway interactions><Pattern><Pattern Recognition><Peptides><Phenylalanine><Position><Positioning Attribute><Prophylactic vaccination against influenza><Proteins><RNA Bacteriophages><RNA Phages><Receptor Protein><Recombination><Regimen><Research><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Site><Specificity><Structure><System><Technology><Testing><Transgenic Mice><United States National Institutes of Health><Universities><V(D)J Rearrangement><V(D)J Recombination><VDJ rearrangement><VDJ recombination><Vaccination><Vaccine Design><Vaccines><Viral><Virus><Virus-like particle><Work><acquired immune system><aminoacid><antigen binding><antigen bound><associate faculty><associate professor><base><biological signal transduction><clinical development><design><designing><developmental><directed evolution><discover vaccines><experiment><experimental research><experimental study><flu HA><flu hemagglutinin><flu immunisation><heterozygosity><humanized mice><humanized mouse><immune receptor><immunogen><in vivo><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><influenza virus vaccination><influenzavirus><medical college><medical schools><member><mid-career faculty><midcareer faculty><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><natural gene amplification><neutralizing antibody><pathway><preservation><prevent><preventing><professor><receptor><reconstitute><reconstitution><response><school of medicine><sensor><single nucleotide variant><stem><tool><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine><universal vaccine against flu><universal vaccine against influenza><vaccination against influenza><vaccine discovery><virus-like nanoparticles><viruslike particle>