Document text
Principal Investigator: Samuel David Stampfer
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $181,764
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Current COVID-19 vaccines fail to induce strong cross-reactive neutralizing antibodies against circulating SARS-
CoV-2 variants, which have undergone extensive mutation in the neutralizing epitopes of spike protein. Booster
vaccinations with variant-matched vaccines primarily strengthen immunity towards epitopes shared with the
original strain, leading to poor neutralizing activity against variants and failing to induce strong protection. This
biased immune response towards the ancestral strain is termed “original antigenic sin”. It results in repeated
infections with new variants regardless of vaccination status.
The overall goal of this proposal is to develop an improved SARS-CoV-2 vaccine that can induce broadly cross-
reactive neutralizing antibody responses against current and future variants by targeting a highly conserved
epitope in the heptad repeat 1 (HR1) region of the spike protein. When presented on spike protein, it is poorly
immunogenic and anti-HR1 antibodies rarely form naturally. Dr. Stampfer has developed an engineered antigen,
composed only of the HR1 epitope, that induces high titer anti-HR1 antibodies in mice. This immunogen also
functions as a scaffold when linked to an additional epitope, the receptor binding motif (RBM), which mutates
frequently between different SARS-CoV-2 variants and can induce very potent neutralizing antibodies. The HR1
portion of such a vaccine has the potential to induce broadly neutralizing antibodies against all variants, while
the RBM portion can function as a seasonal component targeting current circulating strains, all without boosting
non-neutralizing cross-reactive epitopes on spike protein. Three Aims are proposed. Aim 1 investigates the
immunogenicity and protection of the HR1 and RBM-HR1 vaccines against the current circulating SARS-CoV-2
variants in naïve mice, while Aim 2 evaluates their efficacy as boosters in mice with prior mRNA COVID-19
vaccination. Aim 3 will isolate vaccine-induced HR1-specific B-cells to generate broadly-active anti-HR1
monoclonal antibodies for prophylactic and therapeutic evaluation in mouse challenge experiments. Long term,
this lays the groundwork for future larger projects testing the optimized vaccine and anti-HR1 therapeutics in
nonhuman primates and humans, and in designing HR1-based vaccines for other viruses.
The research will be conducted at the Emory Vaccine Center, with multiple vaccinology labs whose close
proximity encourages new collaborations and the sharing of methodology and equipment, along with on-site
nonhuman primates for future preclinical vaccine testing. Dr. Stampfer’s career goal is to develop better
vaccines for viral pathogens by using protein structure data to design antigens that induce strong immunity to
critical epitopes. His career development plan includes hands-on training in vaccine development, neutralization
assays, and monoclonal antibody isolation, along with didactic and online courses in immunology, antibody
engineering, biostatistics, and grant-writing. The mentorship team of physician-scientists and viral vaccinologists
will ensure productive research and training, helping him launch his career as an independent researcher.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><Absenteeism at work><Adoptive Transfer><Amino Acid Receptors><Amino Acids><Animals><Anti-viral Agents><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Area><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B.1.351><Binding><Binding Determinants><Bioassay><Biological Assay><Biometrics><Biometry><Biostatistics><Booster Immunization><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccination><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cessation of life><Chimera Protein><Chimeric Proteins><Clinical Treatment Moab><CoV emergence><CoV-2><CoV2><Collaborations><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Data><Death><Development><Development Plans><E-course><ELISA><Economics><Employee Absenteeism><Engineering><Ensure><Enzyme-Linked Immunosorbent Assay><Epitopes><Equipment><FDA approved><Family><Funding><Fusion Protein><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Grippe><Human><Immune><Immune response><Immunes><Immunity><Immunize><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunology><Immunosuppressed Host><Individual><Individuals from minority><Individuals of minority><Infection><Infection prevention><Influenza><Investigators><K-18><K-18 conjugate><K18><K18 combination><Learning><Length><Light><Link><Measures><Mentors><Mentorship><Messenger RNA><Methodology><Mice><Mice Mammals><Minority Groups><Minority People><Minority Population><Minority individual><Modern Man><Molecular Interaction><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Murine><Mus><Mutate><Mutation><PASC><Paramyxoviridae><Paramyxovirus><Persons><Photoradiation><Physicians><Population><Position><Positioning Attribute><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Prevent infection><Productivity><Protein Engineering><Proteins><RNA vaccine><RNA-based vaccine><Research><Research Personnel><Researchers><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 B.1.351><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 beta><SARS-CoV-2 infection><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sarbecovirus><Scientist><Seasons><Secondary Immunization><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Site><South Africa strain><South Africa variant><South African strain><South African variant><Spottings><Staining method><Stains><Structure><T cell response><T-Cells><T-Lymphocyte><Techniques><Testing><Therapeutic><Training><Transmission><Update><Vaccinated><Vaccination><Vaccines><Variant><Variation><Viral><Viral Vaccines><Virus><Work><Writing><Wuhan coronavirus><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><aminoacid><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody engineering><asymptomatic COVID-19><asymptomatic SARS-CoV-2 infection><asymptomatic coronavirus disease 2019><booster dose><booster shot><booster vaccination><booster vaccine><career><career development><cell sorting><chronic COVID-19 sequelae><corona virus><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><cross reactivity><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><economic><efficacy testing><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><enzyme linked immunoassay><evaluate vaccines><experiment><experimental research><experimental study><experiments><genetic protein engineering><genome mutation><hCoV19><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><immunosuppressed patient><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><mAbs><mRNA><mRNA vaccine><mRNA-based vaccine><missing work><monoclonal Abs><monoclonal antibody production><nCoV><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><non-human primate><nonhuman primate><novel CoV><novel corona virus><novel coronavirus><online course><online curriculum><pathogenic virus><post COVID-19 sequelae><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><pre-clinical><preclinical><prevent><preventing><prophylactic><protein design><protein structure><protein structures><proteins structure><prototype><receptor binding><receptor bound><response><sarbecovirus vaccine><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><skills><spike proteins on SARS-CoV-2><therapeutic evaluation><therapeutic testing><thymus derived lymphocyte><transmission process><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine antibodies><vaccine boost><vaccine candidates against SARS-CoV-2><vaccine development><vaccine efficacy><vaccine evaluation><vaccine for novel coronavirus><vaccine induced antibodies><vaccine screening><vaccine testing><vaccine-induced antibodies><vaccines against Sarbecoviruses><vaccines preventing COVID><vaccines to prevent COVID><vaccinology><variants of concern><vector><viral pathogen><viral transmission><virus pathogen><virus transmission>