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Principal Investigator: Lanying Du
Organization: GEORGIA STATE UNIVERSITY
Fiscal Year: 2022
Award: $796,048
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Viral subunit vaccines are safe and convenient, but generally suffer low efficacy. Our overall hypothesis is that
an intrinsic limitation is associated with subunit vaccine designs in which artificially exposed surfaces of subunit
vaccines contain epitopes unfavorable for vaccine efficacy. The receptor-binding domain (RBD) of a
coronavirus spike protein consists of a core subdomain that serves as the structural scaffold and a receptor-
binding motif (RBM) that binds the receptor and contains neutralizing epitopes. The RBDs are prime
candidates for subunit vaccine designs. In preliminary studies, we identified epitopes on the core subdomain of
MERS coronavirus (MERS-CoV) RBD that were buried in the full-length spike protein but became artificially
exposed in recombinant RBDs. We further showed that these epitopes severely reduce vaccine efficacy by
inducing strong non-neutralizing immune responses and distracting the host immune system from reacting to
the neutralizing epitopes on the RBM. This novel finding reveals an intrinsic limitation of viral subunit vaccines
that the vaccine field had been unaware of. In this proposal, we aim to characterize this intrinsic limitation and
establish novel approaches to overcome it. We use the RBDs from highly pathogenic coronaviruses, including
MERS-CoV and SARS coronavirus (SARS-CoV), as the model system. This proposal contains three major
design approaches for coronavirus RBD vaccines. First, we will identify and characterize the artificially
exposed unfavorable epitopes on the core subdomain of coronavirus RBDs. To this end, we introduce a novel
concept, neutralizing immunogenicity index (NII), to evaluate the contribution of each epitope to the overall
vaccine efficacy. We will mask the negative epitopes on the core subdomain through glycan shielding or
resurfacing. This design enhances the efficacy of the individually optimized RBD vaccines. Second, we will
construct chimeric RBDs containing the core subdomain from one coronavirus RBD as the structural scaffold
and the RBM from another coronavirus RBD as the immunogenic sites. The unfavorable epitopes on the core
subdomain should have been silenced from the first design approach. The interface of the core subdomain and
RBM will be optimized to maximize the stability of the chimeric RBD vaccines. This design prepares us for the
emergence of highly pathogenic coronaviruses in the future. Third, we will construct nanoparticle-carried
coronavirus RBD vaccines in a way that artificially exposed unfavorable epitopes on the core subdomain are
re-buried at the molecular interfaces to enhance the RBD vaccine's efficacy. We will use mice to evaluate the
immunogenicity of the above engineered RBD vaccines and will use animal models (including hDPP4-knock-in
(KI)) mice and non-human primates) to assess the selected RBD vaccines against live coronavirus challenge.
Overall, this research establishes the artificially exposed unfavorable epitopes as the intrinsic limitation of viral
subunit vaccines and finds novel approaches to overcome it. Therefore, this research holds the promise of
making subunit vaccines a more successful and widely used strategy in combating virus infections.
Terms: <Affinity><Animal Model><Animal Models and Related Studies><Antigenic Determinants><Binding Determinants><Biochemical><Biologic Models><Biological Models><Clinical Treatment Moab><CoV S protein><CoV emergence><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Data><Development><Engineering><Ensure><Epitopes><Evaluation><Face><Future><Glycans><Goals><Immune response><Immune system><Immunize><Immunochemical Immunologic><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><KI mice><Knock-in Mouse><Length><Life><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Masks><Measures><Mice><Mice Mammals><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Model System><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Monoclonal Antibodies><Murine><Mus><Pathogenicity><Play><Polysaccharides><Proteins><Recombinants><Research><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-1><SARS-Related Coronavirus><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Site><Solid><Structure><Subunit Vaccines><Surface><Vaccine Design><Vaccines><Viral><Viral Diseases><Viral Vector><Virion><Virus><Virus Diseases><Virus Particle><allergic/immunologic body system><allergic/immunologic organ system><base><beta CoV><beta coronavirus><betaCoV><betacoronavirus><combat><conformation><conformational state><corona virus><corona virus emergence><coronavirus S protein><coronavirus emergence><coronavirus receptor><coronavirus spike glycoprotein><coronavirus vaccine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><faces><facial><host response><immune system response><immunogenic><immunogenicity><immunoresponse><improved><indexing><knockin mice><mAbs><model of animal><model organism><nCoV><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><new CoV><new approaches><new corona virus><new coronavirus><non-human primate><nonhuman primate><novel><novel CoV><novel approaches><novel corona virus><novel coronavirus><novel strategies><novel strategy><preservation><protective efficacy><receptor binding><receptor bound><scaffold><scaffolding><severe acute respiratory syndrome-CoV><social role><vaccine against coronavirus><vaccine candidate><vaccine development><vaccine efficacy><viral infection><virus infection><virus-induced disease><β CoV><β coronavirus><βCoV>