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Principal Investigator: Christopher O'Neil Barnes
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $347,463
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Human respiratory viruses not only contribute to substantial morbidity and mortality worldwide but also pose
a massive pandemic threat. This broad range of viruses includes human coronavirus (hCoVs), influenza A,
and human metapneumoviruses (HMPV). Vaccines are among the most powerful means for mitigating viral
epidemics but require significant neutralizing antibody breadth to maximize the probability of effectiveness
against unknown viral threats. While a number of components of a protective immune response could be
targeted to form the basis of a broadly protective coronavirus vaccine, neutralizing antibodies are generally
accepted to be a key component of protective immunity. Although development of effective first-generation
SARS-CoV-2 vaccines that induced protective antibody responses against severe illness has proceeded
with unprecedented speed and seasonal influenza A (IAV) vaccines continue to offer protection, their
effectiveness against emergent seasonal variants (e.g., Omicron) and, importantly, against other potential
zoonotic viruses is less likely. Indeed, risk of zoonotic spillover events of divergent CoVs, such as the
recently documented cases of human transmission from a canine alpha-CoV and a porcine delta-CoV that
led to flu-like symptoms in infected Haitian children, highlights the need for innovative approaches to identify
countermeasures targeting highly-conserved sites on CoV spikes shared among the Orthocoronavirinae
subfamily. Project 2 will prioritize the development of immunogens that elicit neutralizing antibodies
that can be measured in vitro. We will synergize with other Project members to test as many
immunization strategies as possible in human organoid models, where the multifaceted functions of
antibodies, effector cells, and host factors can be used to inhibit viral replication in an exposed host.
Specifically, this proposal will focus on three interrelated aims: 1) identify the structural correlates of broad
and potent antibody neutralization against conserved viral epitopes in CoV-S and IAV-HA trimers, 2) design
multivalent immunogens that stimulate cross-reactive immune responses in human organoid model systems,
and 3) provide insights into the molecular mechanisms of feedback inhibition and immune imprinting that
limit diversification of B cell responses. Overall, this proposal will employ immunology, bioinformatics,
structural biology, protein engineering and immune system models to discover how to elicit antibodies
capable of neutralizing a broad range of emerging pandemic threat RNA viruses. The results will inform our
understanding of broadly-protective anti-CoV and anti-lAV immunity in recovered and vaccinated individuals
and will inform ongoing and future vaccine efforts.
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Moab><CoV-2><CoV2><Collaborations><Complement><Complement Proteins><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus Infectious Disease 2019><Cryo-electron Microscopy><Cryoelectron Microscopy><Development><Diabetes Mellitus><Directed Molecular Evolution><Dogs><Dogs Mammals><Effectiveness><Effector Cell><Electron Cryomicroscopy><Electron Microscopy><Engineering><Epidemic><Epitope Mapping><Epitopes><Evaluation><Event><FOXP3><FOXP3 gene><Family suidae><Feedback><Forkhead Box P3><Future><Generations><Genetic><Germ Lines><Germinal Center><Grippe><HCoV><Haitian><Health><Hemagglutinin><Host Factor><Host Factor Protein><Human><Human Metapneumovirus><Humoral Immunities><IgG><Immune><Immune Complex><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunization><Immunoglobulin G><Immunological response><Immunologically Directed Therapy><Immunology><Immunotherapy><In Vitro><Infection><Influenza><Influenza A><Influenza A virus><Influenza HA><Influenza Hemagglutinin><Influenza Viruses Type A><Influenzavirus A><Integration Host Factors><Intervention><Intervention Strategies><JM2><Lung><Lung Respiratory System><Measures><Memory B Cell><Memory B-Lymphocyte><Model System><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Negative Staining><Obesity><Organoids><Orthomyxovirus Type A><PBMC><Peripheral Blood Mononuclear Cell><Pigs><Plasma><Plasma Serum><Population><Probability><Protein Engineering><RNA Viruses><Resolution><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><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><SCURFIN><Sarbecovirus><Seasons><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 CoV 2 vaccine><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 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 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