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Principal Investigator: Barton F. Haynes
Organization: DUKE UNIVERSITY
Fiscal Year: 2021
Award: $1,904,952
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract - Project 1
Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including
Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and Middle East Respiratory coronavirus (MERS-
CoV) in 2012. In Dec 2019, a third novel coronavirus (CoV) designated SARS-CoV-2 emerged in Wuhan China
and in the space of 11 months, has caused over 85 million cases, >1.8 million deaths in >217 countries. Over
1/5 of these total cases have been reported in the US, resulting in over 350,000 deaths. In humans, virus
infection results in COVID-19 disease, characterized by pneumonia and severe acute respiratory distress
syndrome (ARDS), an often-fatal end-stage lung disease. In addition to SARS-CoV2, multiple other SARS-like
and MERS-like CoV strains reside in bats and other species and are poised to emerge at some point in the
future. The threat posed by these viruses creates a need for the development of broadly efficacious antivirals
and vaccines that will protect against this heterogeneous family of highly pathogenic emerging viruses. In
response, our assembled team in this P01 of leading virologists with complementary expertise in viral immunity,
CoV pathogenesis, antibody repertoire mapping, vaccinology and structure-based vaccine design have
developed an integrated program designed to develop panbetaCoV vaccines that protect against the
Merbecoviruses (MERS-like group 2c) and Sarbecoviruses (SARS-like group 2b CoV). Project 1, led by the
Baric and Heise laboratories at UNC, will develop and test panels of wildtype and chimeric vaccines developed
in the context of a well-established alphavirus replicon particle (VRP) vaccine platform. They will interface with
other projects and cores to map the location of broadly neutralizing antibody epitopes that will inform panCoV
vaccine design. They will also produce killed and live attenuated viruses as vaccine gold standards and models
for vaccine induced immune pathology phenotypes (VARED). Project 1 also provides mouse models of human
disease, including the first lethal mouse adapted SARS-CoV-2 MA10 variant that replicates efficiently and
produces ARDS like disease phenotypes in standard laboratory mice. They also provide novel mouse models
of human disease for other SARS-like and MERS-like CoV. Project 1 also provides reporter viruses expressing
nLUC, that span the group 2 and group 1 CoV that provide precise measures of neutralizing antibody titer,
breadth and magnitude following natural infection and vaccination. Finally, they provide robust heterologous
challenge models for evaluating the breadth and performance of emerging coronavirus vaccines. The overall
goal is to develop a panCoV vaccine that will universally protect against group 2b and 2c CoV. Aim 1
deciphers the antigenic structure of the BetaCoV. Aim 2 measures group 2b and 2c vaccine performance after
virus challenge. Aim 3 develops and tests panbetaCoV vaccine candidates.
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Arboviruses><Hamsters><Hamsters Mammals><Human><Humoral Immunities><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inactivated Vaccines><Inactivated Virus Vaccine><Individual><Infection><Inflammatory Infiltrate><Killed Vaccines><Laboratories><Laboratory mice><Location><Lung diseases><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mainland China><Maps><Measures><Messenger RNA><Mice><Mice Mammals><Middle East><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 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><Mosaicism><Murine><Mus><Outcome><Pathogenesis><Pathogenicity><Pathologic><Pathology><Performance><Phase><Phenotype><Pneumonia><Population><Primates><Primates Mammals><Pulmonary Diseases><Pulmonary Disorder><Recombinants><Replication Unit><Replicon><Reporter><Reporting><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><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 Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shock><Shock Lung><Stiff lung><Stroke><Structure><Syndrome><T-Cells><T-Lymphocyte><Testing><Vaccination><Vaccine Design><Vaccines><Variant><Variation><Viral><Viral Diseases><Virulent><Virus><Virus Diseases><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><aged><anti-viral agents><anti-viral drugs><anti-virals><antibody titering><antibody-based immunity><base><beta CoV><beta coronavirus><beta coronavirus vaccine><betaCoV><betacoronavirus><betacoronavirus vaccine><bleeding disorder><brain attack><cerebral vascular accident><cerebrovascular accident><circulatory shock><clotting disorder><corona virus><corona virus disease 2019><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus emergence><coronavirus vaccine><cytokine><design><designing><develop a vaccine><development of a vaccine><developmental><disease of the lung><disease phenotype><disorder of the lung><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><hCoV19><host response><human disease><human model><immune system response><immunogen><immunogenicity><immunoresponse><in vivo><lung disorder><mRNA><model of human><mosaic disorders><mouse model><murine model><nCoV><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><panbetaCoV vaccine><pandemic><pandemic disease><particle><programs><respiratory><response><severe acute respiratory syndrome-CoV><thymus derived lymphocyte><vaccine against coronavirus><vaccine candidate><vaccine development><vaccine formulation><vaccinology><vector><viral infection><virology><virus infection><virus-induced disease><wet lung><zoonotic CoV><zoonotic coronavirus><β CoV><β coronavirus><β coronavirus vaccine><βCoV>