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Principal Investigator: Kevin Wiehe
Organization: DUKE UNIVERSITY
Fiscal Year: 2023
Award: $2,828,814
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract – Project 2
Animal betacoronaviruses (betaCoVs), such as those that gave rise to SARS-CoV-1, MERS, and now SARS-
CoV-2, represent a significant, continuous threat to human health. Vaccines can provide pre-existing immunity
to future zoonotic coronaviruses. A major limitation of the current effective vaccines to SARS-CoV-2 is that they
likely will only protect SARS-CoV-2 isolates that are nearly identical to the Wuhan isolate used in the
vaccines. Thus, the world remains vulnerable to SARS-CoV-2 mutational escape variants
and from future animal betacoronavirus spillover events that have pandemic potential. Vaccine development
that addresses this vulnerability is urgently needed. Project 2 will support this Program’s overall goal to develop
vaccines that will prevent future betaCoV pandemics and SARS-CoV-2 escape variants by
designing vaccine immunogens that elicit broadly neutralizing antibodies (bnAb) to provide protective
immunity across the betaCoV genus. Structurally conserved neutralizing epitopes exist
on betaCoV spike proteins, and we hypothesize that vaccines that elicit broadly protective antibodies to these
sites can be developed. In preliminary studies, we have isolated cross-reactive neutralizing antibodies from
SARS-CoV-1 or SARS-CoV-2-infected or recovered humans and used structural determination to precisely
define their betaCoV bnAb epitopes. Our vaccine design strategy involves using computational and structural-
based design techniques to develop immunogens that preferentially present these and additionally
identified bnAb epitopes. Each immunogen design will be displayed on the surface of nanoparticles to enhance
antigen avidity and antigen trafficking to germinal centers and follicular dendritic cells. We have demonstrated a
proof-of-concept for our strategy using a multimerized SARS-CoV-2 receptor binding domain (RBD)-
ferritin nanoparticle that induces high titers of antibodies that neutralize diverse human and
animal Sarbecoviruses (group 2b) in immunized macaques. In Aim 1, we will isolate new antibodies to define
additional bnAb epitopes and establish the full spectrum of regions on the surface of betaCoV S proteins that
are capable of inducing bnAbs to animal betaCoVs in groups 2b and 2c. In Aim 2, we will utilize cutting-edge
computational immunogen design methods to design broadly neutralizing epitope-focused immunogens. These
immunogens have the spike protein fixed in conformations that expose neutralizing epitopes or are spike
subunits that are truncated or resurfaced to remove irrelevant, non-neutralizing, or betaCoV strain-specific
neutralizing epitopes while retaining broadly neutralizing epitopes. In Aim 3, we will immunize wild-type mice
with these novel immunogens and evaluate their ability to induce human betaCoV bnAbs that can protect
animals from viral challenge. Project 2 will impact the field by generating cross-reactive neutralizing antibodies
that could be translated into therapeutics, elucidating new broadly neutralizing epitopes on the betaCoV spike
protein, and defining the design principles for epitope-focused immunogens that elicit protective immunity
to betaCoVs.
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defect><Germinal Center><Goals><Grippe><Group A Arboviruses><HIV><HIV vaccine><HIV/AIDS Vaccines><Health><Human><Human Immunodeficiency Viruses><Immune Monitoring><Immunity><Immunize><Immunologic Monitoring><Immunological Monitoring><Immunomonitoring><Influenza><Influenza Vaccines><LAV-HTLV-III><Lymphadenopathy-Associated Virus><MERS><MERS coronavirus disease><MERS-CoV disease><Macaca><Macaque><Mediating><Merbecovirus><Messenger RNA><Methods><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Mutation><Outbreaks><Peptides><Persons><Proteins><SARS Virus><SARS corona virus><SARS corona virus 2><SARS 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