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Principal Investigator: Neil King
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $9,065,441
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY – OVERALL: Structure-based design of broadly protective coronavirus vaccines
We propose a highly synergistic research Program focused on developing two broadly protective coronavirus
vaccine candidates: a pan-sarbecovirus vaccine at the end of Year 2, and a pan-betacoronavirus at the end of
Year 5. Our Program brings together six research groups with complementary and synergistic expertise in
structure-based vaccine design, coronavirus structural biology and immunity, the immunology of vaccines,
animal model development, and viral evolution. This team emerged in response to the SARS-CoV-2 pandemic
to rapidly develop an ultrapotent protein nanoparticle vaccine that is currently in Phase I/II clinical trials, with
funding secured for Phase III. Our Program comprises three Scientific Projects supported by four Scientific Cores
and an Administrative Core. This structure will allow maximal synergy between our groups in pursuit of the three
central outputs of our Program: Tools, Antibodies, and Vaccines. Tools: we will develop reverse genetic platforms
for producing panels of wild-type and indicator viruses and new animal models of human coronavirus disease
that can be used to assess neutralizing and protective breadth. We will also develop platforms for deep
mutational scanning of spike proteins spanning the betacoronavirus phylogeny to inform antigen design and
model development and assess the breadth and mutational resistance of vaccine-elicited antibodies. Antibodies:
our Program will identify conserved epitopes in betacoronavirus spike proteins targeted by cross-reactive
antibodies, and characterize the structural basis for broad neutralization and protection at high resolution. This
information will be used to iteratively inform structure-based antigen and vaccine design and will generate
antibody therapeutics that could blunt the effects of future zoonotic spillovers. Vaccines: we recently showed that
co-displaying multiple hemagglutinin antigens on the same self-assembling protein nanoparticle, an approach
termed mosaic nanoparticle display, induced broadly protective humoral immunity against influenza. We will
combine this approach with cutting-edge computational methods for stabilizing glycoprotein antigens and
designing nanoparticle scaffolds tailored to display coronavirus spikes in optimal geometries. We expect the
resultant nanoparticle vaccine candidates to elicit potent and broadly protective antibody responses against
conserved epitopes in betacoronavirus spikes. We will mechanistically and functionally evaluate the performance
of these vaccine candidates formulated with clinically relevant adjuvants in relevant animal models, including
nonhuman primates. To facilitate successful transfer to industry partners, we will prepare technology transfer
packages for the two lead vaccine candidates that will be produced by our Program: a pan-sarbecovirus vaccine
at the end of Year 2, and a pan-betacoronavirus vaccine at the end of Year 5.
Terms: <Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Binding Determinants><COVID><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><CoV disease><Communities><Computing Methodologies><Coronaviridae><Coronavirus><Development><Epitopes><Evolution><Funding><Future><Geometry><Glycoproteins><Goals><Grippe><HIV-1><HIV-I><HIV1><Hemagglutinin><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Humoral Immunities><Immunity><Immunology><Influenza><Influenza HA><Influenza Hemagglutinin><Intervention><Intervention Strategies><Knowledge><Lead><Modern Man><Mosaicism><Output><Pb element><Performance><Phase><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Phylogeny><Proteins><Public Health><Research><Resolution><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sarbecovirus><Science><Secure><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Structure><Technology><Technology Transfer><Therapeutic antibodies><Vaccine Design><Vaccines><Viral><Virus><Work><Zoonoses><Zoonotic><Zoonotic Infection><animal model development><antibody-based immunity><base><beta CoV><beta coronavirus><beta coronavirus vaccine><betaCoV><betacoronavirus><betacoronavirus vaccine><clinical relevance><clinically relevant><computational methodology><computational methods><computer based method><computer methods><computing method><corona virus><corona virus disease><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus of pandemic concern><coronavirus of pandemic potential><coronavirus vaccine><coronavirus with pandemic potential><cross reactivity><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><flu HA><flu hemagglutinin><heavy metal Pb><heavy metal lead><human model><immunogen><industrial partnership><industry partner><industry partnership><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><interventional strategy><model development><model of animal><model of human><model organism><mortality><mosaic disorders><multidisciplinary><mutation scanning><mutation screening><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><non-human primate><nonhuman primate><novel><panbetaCoV vaccine><pandemic><pandemic coronavirus><pandemic disease><pandemic threat coronavirus><programs><public health priorities><resistance mutation><resistant mutation><response><reverse genetics><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><structural biology><support tools><synergism><tool><tool development><vaccine against coronavirus><vaccine candidate><vaccine development><virology><zoonotic spillover><β CoV><β coronavirus><β coronavirus vaccine><βCoV>