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Principal Investigator: Anthony Bowen
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $193,644
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT: Rationale: Continued evolution of Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) has led to immune-evasive variants that pose a persistent threat to global public
health. Updated vaccines are needed to provide improved immune responses against emerging variants, but
current approaches targeting the Omicron BA.4/5 variant may have limited effectiveness due to immune
imprinting caused by prior immune system exposure to ancestral D614G variant antigens. Our preliminary data
suggests that bivalent boosters targeting BA.4/5 do not provide superior neutralizing antibody (NAb) responses
to SARS-CoV-2 variants compared to the original monovalent vaccine. This mentored career project aims to
elucidate the impact and molecular basis of immune imprinting following primary D614G vaccination on
subsequent humoral responses to variant antigens. Candidate: As an Infectious Diseases physician with a PhD
in Microbiology and Immunology, I am uniquely positioned to bridge the gap between biomedical research and
patient care to advance our knowledge of humoral immune responses to SARS-CoV-2. Further training in
virology, structural biology, bioinformatics, and monoclonal antibody characterization will be crucial for
completion of the proposed research and my development as an independent physician-scientist specializing in
humoral immunity to pathogens of global importance. I have a globally recognized mentor in Dr. David Ho and
benefit from an outstanding multidisciplinary team of experts to guide my training and research progress.
Environment: The Ho laboratory at the Columbia University Irving Medical Center (CUIMC) is a leading group
in the study of SARS-CoV-2, with expertise in the characterization of viral variants and monoclonal antibodies.
This enriching environment provides access to a large network of collaborators including experts in cryo-electron
microscopy, single cell sequencing, and antibody repertoire analysis. CUIMC also has a strong track record of
enabling junior physician-scientists to develop independent and successful careers in academic medicine.
Approach: Our central hypothesis is that primary vaccination targeting the SARS-CoV-2 D614G strain induces
immunological imprinting that restricts antibody responses to subsequently encountered viral variant antigens.
In Aim 1, we will test the impact of imprinting on NAb responses following BA.4/5 boosting strategies in a
humanized mouse model. In Aim 2, we will characterize the antibody repertoires of immunized mice to identify
imprinting effects using single B cell sequencing and bioinformatic approaches. In Aim 3, we will use high-
throughput techniques to produce monoclonal antibodies, determine their neutralizing activity, and identify
epitopes associated with imprinting responses though structural and binding assays. Through these aims, we
will expand understanding of the immunologic and structural basis underlying imprinting in SARS-CoV-2. Our
results should inform novel strategies for structure-based vaccine design to circumvent imprinting responses and
produce broader immunity to SARS-CoV-2 variants and possibly other antigenically variable pathogens.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Repertoire><Antibody Response><Antibody titer measurement><Antigen Variation><Antigenic Determinants><Antigenic Variability><Antigenic Variation><Antigens><Assay><B blood cells><B cell><B cell repertoire><B cells><B-Cells><B-Lymphocytes><B-cell><B.1.1.529><B.1.617.2><BNT 162b2><BNT162b2><Binding><Binding Determinants><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biomedical Research><Blood Serum><COVID-19 S protein><COVID-19 antigen><COVID-19 immunity><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccination><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19 virus><Cessation of life><Clinical Treatment 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