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Principal Investigator: Erica Ollmann Saphire
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2023
Award: $2,060,891
Funding agency: National Institute of Allergy and Infectious Diseases
Project 3 Summary
Coronaviruses will likely remain a persistent threat to human health. However, whether the next significant
disease outbreak will be caused by a known coronavirus, another novel coronavirus, or continued surges from
variant(s) of SARS-CoV-2 is unknown. The goal of this project is to develop novel, improved immunogens to
elicit broader anti-coronavirus immunity, to structurally evaluate resulting pan-coronavirus or broad-coronavirus
antibodies, and to evaluate efficacy of broad coronavirus vaccines in animal models. We will begin with novel
third-generation spikes that better remain in a pre-fusion quaternary assemblies relative to earlier versions of
spike that have been described in the literature. These novel spike proteins, termed “VFLIP”, retain a trimeric
conformation even in the absence of exogenous trimerization motifs, are resistant to thermal denaturation,
feature glycan structures that better reflect those on authentic virions and offer receptor-binding domain positions
and conformation that also better reflect those on native virions. These molecules further feature slower “off”
rates for a wide panel of anti-coronavirus antibodies. In this program, we will develop novel immunogens from
these improved spikes alone and as part of innovative multimeric vaccine particles. Our collaborating projects
will evaluate these immunogens for their ability to elicit broad B- and T-cell immune responses. We will then
evaluate the efficacy of the best candidate immunogens in mouse and hamster models of infection using multiple
relevant coronaviruses. This project represents the beginning and end of the collaborative, iterative circle of
immunogen design and evaluation. Cycles of in-depth evaluation and iteration will shepherd vaccine efforts for
broad protection against the growing threat posed by coronaviruses.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bats><Binding Determinants><COVID-19 transmission><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus transmission><COVID19 virus><Chiroptera><CoV S protein><CoV emergence><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Collaborations><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus glycoprotein S><Coronavirus spike protein><Cricetinae><Detection><Development><Disease Outbreaks><Dissociation><Ebola><Engineering><Ensure><Epitopes><Evaluation><Generations><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic defect><Glycans><Goals><HCoV><HIV-2><HIV-II><HIV2><HTLV-IV><Hamsters><Hamsters Mammals><Hand><Health><Human><Human Immunodeficiency Virus Type 2><Human T-Lymphotropic Virus Type IV><Human immunodeficiency virus 2><Immune Targeting><Immune response><Immunity><Immunological response><Infection><LAV-2><Literature><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Measures><Mediating><Metabolic Glycosylation><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Murine><Mus><Mutation><Outbreaks><Pathogenicity><Pattern><Polysaccharides><Position><Positioning Attribute><Proteins><Resistance><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 transmission><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 related corona virus 2><Structure><T-Cells><T-Lymphocyte><Testing><Vaccinated><Vaccines><Variant><Variation><Virion><Virus><Virus Particle><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><cold temperature><combat><conformation><conformational><conformational state><conformationally><conformations><corona virus><corona virus emergence><coronavirus S protein><coronavirus disease 2019 transmission><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease-19 virus><coronavirus emergence><coronavirus spike glycoprotein><coronavirus vaccine><cross immunity><cross protection><cross reactivity><cross-species spillover><cross-species transmission><design><designing><determine efficacy><developmental><diagnostic tool><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><evaluate efficacy><examine efficacy><genome mutation><glycosylation><hCoV19><hands><host jump><host response><host switching><human CoV><human corona virus><human coronavirus><immune system response><immunogen><immunogenicity><immunoresponse><improved><innovate><innovation><innovative><interspecies transmission><low temperature><model of animal><nCoV><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><particle><pressure><programs><receptor binding><receptor bound><resistant><response><severe acute respiratory syndrome coronavirus 2 transmission><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe acute respiratory syndrome-CoV><thermolability><thermostability><thymus derived lymphocyte><transmission across species><transmission between species><transmitted COVID-19><transmitted SARS-CoV-2><transmitted across species><transmitted between species><transmitted coronavirus disease 2019><transmitted cross-species><transmitted severe acute respiratory syndrome coronavirus 2><vaccine against coronavirus><vaccine candidate><viral fitness>