WU230179MOD3S
STATEMENT OF WORK THE RAPID WORLDWIDE SPREAD OF THE SARBECOVIRUS SARS-COV-2 AND COVID-19 HAS EXPOSED OUR INADEQUATE PREPAREDNESS FOR THE EMERGENCE OF NEW CORONAVIRUSES (COV). THE EXISTENCE OF MANY RELATED COV IN ANIMAL RESERVOIRS (E.G., BATS) COUPLED WITH THE POSSIBILITY OF VIRUS RECOMBINATION OR AMINO ACID ADAPTATION PROVIDES A SOURCE OF VIRUSES THAT COULD EMERGE AND LEAD TO FUTURE PANDEMICS. CURRENT VACCINE PLATFORMS (MRNA, VIRAL VECTORED, SUBUNIT, OR INACTIVATED) AGAINST SARS-COV-2, WHILE REMARKABLE FOR THE SPEED IN GENERATION AND EFFICACY, ARE PREDICTED TO HAVE LIMITED, IF ANY EFFECT ON CLOSELY OR DISTANTLY RELATED COVS. THIS NEW P01 APPLICATION IN RESPONSE TO PAR-20-072 IS ENTITLED AAcAcAEURSAA...AEUROETHE DEVELOPMENT AND EVALUATION OF PAN-CORONAVIRUS VACCINESAAcAcAEURSAAAA AND CONSISTS OF THREE INTEGRATED RESEARCH PROJECTS AND TWO CENTRALIZED CORES. THE GOAL OF OUR HIGHLY INTERDISCIPLINARY AND COLLABORATIVE GROUP IS TO DESIGN AND GENERATE OPTIMIZED B AND T CELL ANTIGENS THAT CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES (TWO SUBGENERA IN THE BETACORONAVIRUS GENUS) THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. THE SPECIFIC AIMS OF PROJECT 2 WHICH INCLUDES DR. GALIT ALTER OF MASSACHUSETTS GENERAL HOSPITAL IS TO DISCOVER AND DESIGN VACCINE ANTIGEN CANDIDATES, TO BE TESTED IN THE CONTEXT OF PROJECT 3, THAT CONFER BROAD PROTECTIVE T CELL IMMUNITY TO MULTIPLE CORONAVIRUS (COV) SPECIES WITH PANDEMIC POTENTIAL. THERE IS A STRONG RATIONALE FOR EXPLORING WAYS TO MAXIMIZE INDUCTION OF T CELL RESPONSES IN THE CONTEXT OF VACCINATION AGAINST A BROAD SPECTRUM OF COVS. CROSS-REACTIVITY AT THE T CELL LEVEL WAS UNEQUIVOCALLY DEMONSTRATED BETWEEN SARS-COV-2 AND RELATED SARBECOVIRUSES AS WELL AS WITH SEVERAL OTHER MORE DISTANTLY RELATED COV. THUS, INCORPORATING STRATEGIES THAT ELICIT CELLULAR IMMUNITY INTO VACCINES ALSO MAY RESULT IN CROSS-PROTECTION AGAINST FUTURE PANDEMICS EMERGING FROM COV RESERVOIRS. PRELIMINARY PHYLOGENETIC ANALYSES SUPPORT EXPLORING SARBECOVIRUSES, MERBECOVIRUSES AND BETACORONAVIRUSES AS OUR PRIMARY TARGETS, AND THIS ASSESSMENT IS REINFORCED BY THE WELL CONSERVED POLYPROTEIN DOMAIN ARCHITECTURE OF BETACORONAVIRUSES. RELATED TO THIS, OUR PREVIOUS STUDIES ESTABLISHED THE PATTERNS OF ANTIGEN IMMUNODOMINANCE IN HUMAN CD4+ AND CD8+ T CELL RESPONSES TO SARS-COV-2 ANTIGENS; SIMILAR STUDIES ARE IN PROGRESS TO DETERMINE IMMUNODOMINANT ANTIGENS IN NL63 AND OC43. THE REMARKABLE BREADTH OF EPITOPE REPERTOIRE DATA CURRENTLY AVAILABLE WILL ALLOW US TO ACCURATELY DEFINE REGIONS WITHIN EACH ANTIGEN THAT ARE IMMUNODOMINANT FOR HUMAN CD4+ AND CD8+ T CELL RESPONSES. WE ALSO PREVIOUSLY DEMONSTRATED THAT HUMAN T CELL LINES CAN BE USED TO TEST FOR CROSS-REACTIVITY AMONGST DIFFERENT COVS, AND THUS VALIDATED SPECIFIC ASSAYS CAN BE USED TO ASSESS CROSS-REACTIVITY OF COV EPITOPES IN HUMANS. THE REGIONS IDENTIFIED IN THIS PROJECT WILL BE TESTED FOR IMMUNOGENICITY IN MICE AND HAMSTERS IN PROJECT 3 AND CORE B AND INTEGRATED INTO VACCINES FOR CHALLENGE STUDIES. WE PROPOSE THE SPECIFIC AIMS: SPECIFIC AIM 1 - DEFINE TARGETS OF CD4+ AND CD8+ T CELL REACTIVITY THAT ARE BROADLY CONSERVED ACROSS DIFFERENT SARBECOVIRUSES, MERBECOVIRUSES, AND OTHER BETACORONAVIRUSES OF CONCERN. AIM 1A WILL PERFORM AN ANALYSIS OF HOW THE DEGREE OF CONSERVATION VARIES AS A FUNCTION OF DIFFERENT POTENTIAL ANTIGENS ENCODED IN THE PROTEOME OF SARBECOVIRUSES, MERBECOVIRUSES, AND BETACORONAVIRUSES IN GENERAL, AND WITHIN EACH ANTIGEN, IDENTIFY WHICH PARTICULAR PROTEIN REGIONS SHOW THE HIGHEST LEVELS OF CONSERVATION ACROSS THE DIFFERENT VIRAL SPECIES. THIS ANALYSIS WILL DEFINE SETS OF ANTIGENS AND ANTIGEN SUBREGIONS THAT SHOW THE HIGHEST LEVELS OF OVERALL SEQUENCE CONSERVATION. AIM 1B WILL PERFORM AN UPDATED META-ANALYSIS OF IMMUNOGENICITY DATA TO CATALOG THE KNOWN T CELL EPITOPES FOR THE DIFFERENT ANTIGENS ENCODED IN THE NON-STRUCTURAL PROTEINS (NSP) AND OPEN READING FRAMES (ORFS) FROM DIFFERENT SARBECOVIRUSES AND MERBECOVIRUSES, AND OTHER BETACORONAVIRUSES OF CONCERN. THIS WILL DEFINE WHICH ANTIGENS AND ANTIGEN SUBREGIONS ARE RECOGNIZED FOLLOWING NATURAL INFECTION ACROSS DIFFERENT COV SPECIES. AIM 1C WILL INTEGRATE THE RESULTS FROM AIMS 1A AND 1B TO SELECT A SET OF CANDIDATE CONSERVED T CELL EPITOPE REGIONS FROM EACH OF THE THREE TAXONOMIC GROUPS FOR THE EXPERIMENTAL EVALUATIONS DESCRIBED IN AIM 2. SPECIFIC AIM 2 - TEST HUMAN T CELLS THAT RECOGNIZE EXPERIMENTALLY DEFINED EPITOPES FROM AIM 1C FOR THEIR CAPACITY TO CROSS-RECOGNIZE HOMOLOGOUS SEQUENCES FROM DIFFERENT SARBECOVIRUSES, MERBECOVIRUSES AND OTHER BETACORONAVIRUSES OF CONCERN. AIM 2A WILL SYNTHESIZE THE EXPERIMENTALLY DEFINED EPITOPES FROM AIM 1C ABOVE, DERIVED FROM THE MOST PROMISING REGIONS OF THE PROTOTYPE VIRUSES, AND CORRESPONDING ALIGNED HOMOLOGOUS PEPTIDES FROM EACH OF THE DIFFERENT TAXONOMIC GROUPS EVALUATED IN AIM 1A. SARS-COV-2 EPITOPES WILL BE USED TO ELICIT T CELL LINES FROM COVID-19 CONVALESCENT HUMAN DONORS. NL63 AND OC43-DERIVED EPITOPES WILL BE USED TO SIMILARLY ELICIT T CELL LINES FROM HUMAN SUBJECTS WITH NL63 AND OC43-REACTIVE MEMORY T CELLS. AIM 2B WILL TEST EPITOPE-SPECIFIC T CELL LINES FOR CROSS-REACTIVITY WITH CORRESPONDING HOMOLOGOUS PEPTIDES FROM EACH OF THE THREE TAXONOMIC GROUPS USING AN APPROACH DEVELOPED IN OUR LABORATORY TO DEMONSTRATE CORONAVIRUS CROSS-REACTIVITY1. THIS ACTIVITY WILL ESTABLISH WHETHER IMMUNIZATION WITH THE CANDIDATE ANTIGENS OR ANTIGEN REGIONS ARE LIKELY TO ELICIT CROSS-REACTIVE T CELL RESPONSES. AIM 2C WILL PERFORM BIOINFORMATIC ANALYSES TO PREDICT IMMUNOGENICITY IN H-2B STRAIN MICE, USED FOR PRECLINICAL TESTING. NO PREDICTIVE TOOL IS CURRENTLY AVAILABLE FOR THE OTHER HOST SPECIES OF INTEREST, THE GOLDEN SYRIAN HAMSTER, AND IN THIS CASE, WE WILL GENERATE OVERLAPPING PEPTIDE POOLS FOR EMPIRICAL TESTING. OVERALL EXPECTED OUTCOMES. BASED ON THE WORK DESCRIBED ABOVE, WE WILL PERFORM BIOINFORMATIC ANALYSES TO ASSIGN TO VARIOUS ANTIGENS AND PROTEINS SUBREGIONS SPECIFIC QUANTITATIVE SCORES, INCLUDING SEQUENCE CONSERVATION SCORES, HUMAN IMMUNOGENICITY SCORES, AND CROSS-REACTIVITY FOR HUMAN T CELLS SCORES. WE EXPECT THAT BASED ON THE ANALYSIS ABOVE AND ADDITIONAL CONSIDERATIONS (E.G., SIZE, MANUFACTURABILITY, ETC.), WE WILL PRIORITIZE POTENTIAL CANDIDATES, AND DELIVER LISTS OF CANDIDATES TO THE OVERALL PROGRAM LEAD AND PROJECT 3. WE ANTICIPATE THAT THIS WILL BE A AAcAcAEURSAA...AEUROELIVING DOCUMENTAAcAcAEURSAAAA WHERE THE LISTS OF POTENTIAL CANDIDATES WILL BE REVISED AND UPDATED REGULARLY, AS NEW AND MORE COMPLETE DATA SETS, IN TERMS OF DESCRIBED EPITOPES, COMPLETION OF IMMUNOGENICITY AND CROSS-REACTIVITY TESTING, AND AVAILABILITY OF NEW VIRAL SEQUENCES, BECOME AVAILABLE.
The General Hospital Corporation
Project Grant P01AI168347
$31.5k 1/30/25 WU230178MOD2S
STATEMENT OF WORK THE RAPID WORLDWIDE SPREAD OF THE SARBECOVIRUS SARS-COV-2 AND COVID-19 HAS EXPOSED OUR INADEQUATE PREPAREDNESS FOR THE EMERGENCE OF NEW CORONAVIRUSES (COV). THE EXISTENCE OF MANY RELATED COV IN ANIMAL RESERVOIRS (E.G., BATS) COUPLED WITH THE POSSIBILITY OF VIRUS RECOMBINATION OR AMINO ACID ADAPTATION PROVIDES A SOURCE OF VIRUSES THAT COULD EMERGE AND LEAD TO FUTURE PANDEMICS. CURRENT VACCINE PLATFORMS (MRNA, VIRAL VECTORED, SUBUNIT, OR INACTIVATED) AGAINST SARS-COV-2, WHILE REMARKABLE FOR THE SPEED IN GENERATION AND EFFICACY, ARE PREDICTED TO HAVE LIMITED, IF ANY EFFECT ON CLOSELY OR DISTANTLY RELATED COVS. THIS NEW P01 APPLICATION IN RESPONSE TO PAR-20-072 IS ENTITLED AAcAcAEURSAA...AEUROETHE DEVELOPMENT AND EVALUATION OF PAN-CORONAVIRUS VACCINESAAcAcAEURSAAAA AND CONSISTS OF THREE INTEGRATED RESEARCH PROJECTS AND TWO CENTRALIZED CORES. THE GOAL OF OUR HIGHLY INTERDISCIPLINARY AND COLLABORATIVE GROUP IS TO DESIGN AND GENERATE OPTIMIZED B AND T CELL ANTIGENS THAT CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES (TWO SUBGENERA IN THE BETACORONAVIRUS GENUS) THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. DR. AARON G. SCHMIDT OF MASSACHUSETTS GENERAL HOSPITAL WILL SERVE AS A PROJECT LEAD ON PROJECT 1 AAcAcAEURSAA...AEUROESTRUCTURE-GUIDED IMMUNOGENS TO ELICIT PAN-CORONAVIRUS B CELL RESPONSES.AAcAcAEURSAAAA UNDER THIS PROGRAM PROJECT GRANT (DIAMOND AND WHELAN, PIS). DR. SCHMIDT AND HIS TEAM WILL HELP IN THE SELECTION, DESIGN AND CHARACTERIZATION OF CORONAVIRUS SPIKE AND RECEPTOR BINDING DOMAIN (RBD)-BASED IMMUNOGENS. THESE DESIGNS WILL BE ADVANCED TO PROJECT 3 AND THE RELEVANT CORES WITHIN THE P01 FOR SUBSEQUENT FORMULATION IN VARIOUS VACCINE PLATFORMS. THE SCHMIDT LAB WILL HELP REDESIGN AND OPTIMIZE CONSTRUCTS AS NECESSARY. ADDITIONALLY, THEY WILL AIDE IN BIOCHEMICAL AND BIOPHYSICAL CHARACTERIZATION OF THE ELICITED ANTIBODY RESPONSES OBTAINED FROM THE VECTORED IMMUNOGENS FROM PROJECT 3 AND IN VIVO TESTING FROM THE CORES. THE SCHMIDT LAB WILL SYNERGIZE WITH OTHER PROJECTS AND CORES TO HELP ACHIEVE THE OVERALL SCIENTIFIC GOALS OF THIS P01. THE AIMS OF PROJECT 1 ARE TO DESIGN AND EVALUATE IMMUNOGENS THAT ELICIT HUMORAL RESPONSES TO CONSERVED SITES ON S PROTEIN THAT ARE RECOGNIZED BY NEUTRALIZING ANTIBODIES AND BY NON-NEUTRALIZING ANTIBODIES THAT ENGAGE FC EFFECTOR FUNCTIONS FOR PROTECTION. THEY WILL IMPLEMENT STRUCTURE-GUIDED IMMUNOGEN DESIGN STRATEGIES TO FOCUS IMMUNE RESPONSES ON KEY ANTIGENIC REGIONS USING ANTIGENICALLY DISTINCT COVS AS MOLECULAR SCAFFOLDS. SPECIFIC AIMS. THE EMERGENCE OF SEVERE ACUTE RESPIRATORY SYNDROME VIRUS 2 (SARS-COV-2) CORONAVIRUS (COV) HAS HIGHLIGHTED THE CRITICAL NEED FOR FRAMEWORK(S) TO DEVELOP VACCINES TO FUTURE SARBECOVIRUSES AND MERBECOVIRUSES OF CONCERN. ONE APPROACH IS TO PRIORITIZE IMMUNOGEN DESIGN STRATEGIES THAT ELICIT HUMORAL RESPONSES TO CONSERVED SITES ON THE SURFACE-EXPOSED SPIKE GLYCOPROTEIN SUCH AS THE RECEPTOR BINDING MOTIF (RBM), MORE GENERALLY, THE RECEPTOR BINDING DOMAIN (RBD). TARGETING SUCH SITES WILL INTERFERE WITH RECEPTOR ENGAGEMENT AND VIRAL ENTRY POTENTIALLY CONFERRING BROAD PROTECTION. ADDITIONALLY, THERE MAY BE A ROLE FOR NON- NEUTRALIZING YET STILL PROTECTIVE ANTIBODIES RECOGNIZING CONSERVED EPITOPES ON THE SPIKE (S) PROTEIN OUTSIDE OF THE RBD. THIS PROJECT WILL COMBINE COMPUTATIONAL, STRUCTURAL, BIOPHYSICAL, AND SINGLE B CELL ANALYSES TO DESIGN S AND RBD IMMUNOGENS THAT ELICIT BROAD-SPECTRUM HUMORAL IMMUNITY AGAINST COVS. AS EVOLUTIONARY ANALYSIS OF COVS SUGGESTS THAT NO SINGLE ANTIGEN WILL CONFER BROAD ENOUGH IMMUNITY AGAINST THE ENTIRE BETACORONAVIRUS GENUS, WE ANTICIPATE GENERATING A POLYVALENT S OR RBD CONTAINING VACCINE (WITH PROJECT 3). WE WILL PRIORITIZE ACE2-RECEPTOR USING COVS AS A PROOF-OF-CONCEPT BUT ENVISION THAT OUR DESIGN PRINCIPLES CAN BE EXTRAPOLATED MORE BROADLY FOR OTHER EMERGING COVS WHERE ACE2 IS NOT THE RECEPTOR. THE SCHMIDT LABORATORY WILL IMPLEMENT STRUCTURE-GUIDED IMMUNOGEN DESIGN STRATEGIES TO FOCUS IMMUNE RESPONSES TOWARDS THE RBM AND RBD. WE WILL USE ANTIGENICALLY DISTINCT COV RBDS AS MOLECULAR SCAFFOLDS TO SELECTIVELY PRESENT SELECTED ACE2-BINDING COV RBMS AND FURTHER IMMUNE FOCUS USING ENGINEERED GLYCANS TO MASK NON-CONSERVED EPITOPES. THE SCHEUERMANN LABORATORY WILL USE EVOLUTIONARY ANALYSES TO AID IN COV ANTIGEN SELECTION, AS WELL AS ANCESTRAL RECONSTRUCTIONS TO IDENTIFY EXTANT COV AS ADDITIONAL S-BASED IMMUNOGENS. THE ELLEBEDY LABORATORY WILL ISOLATE MONOCLONAL ANTIBODIES (MABS) GENERATED FROM NATURALLY INFECTED, VACCINATED, OR NAAAE'A'AVE HUMAN SUBJECTS TO DEFINE COV CROSS-REACTIVE, CONSERVED EPITOPES ON S RECOGNIZED BY NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES. WE WILL DEFINE THE BREADTH OF MAB CROSS-REACTIVITY, CROSS-NEUTRALIZATION, AND EFFECTOR FUNCTIONS (WITH PROJECT 3). STRUCTURAL ANALYSIS BY X-RAY CRYSTALLOGRAPHY AND CRYO-ELECTRON MICROSCOPY (FREMONT LABORATORY) OF THE ISOLATED MABS WILL BE PERFORMED TO DEFINE THE TARGETED EPITOPES ON S; THIS INFORMATION WILL AID IN ITERATIVE IMMUNOGEN OPTIMIZATION TO ELICIT RESPONSES TO THESE NEWLY DEFINED, CROSS-REACTIVE EPITOPES. AIM 1: TO DEVELOP RBD-BASED IMMUNOGENS USING MOLECULAR SCAFFOLDS AND GLYCAN ENGINEERING. HYPOTHESIS: CONSERVED, CROSS-REACTIVE EPITOPES WITHIN AND OUTSIDE THE RBM ARE RECOGNIZED BY PROTECTIVE MABS; IMMUNE FOCUSING TO THESE SITES CAN CONFER BROAD NEUTRALIZING IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES. AIM 1.1. WE WILL USE MOLECULAR SCAFFOLDS SELECTIVELY PRESENTING THE RBM AT A HIGHER FREQUENCY OVER OTHER EPITOPES TO FOCUS THE IMMUNE RESPONSE TO THE RBM. WE WILL GRAFT THE ACE2 RBM ONTO OTHER STRUCTURALLY HOMOLOGOUS, BUT ANTIGENICALLY DISTINCT COV RBDS. WE WILL PRIORITIZE MERS-COV AND HKU9 AS INITIAL SCAFFOLDS TO PRESENT ACE2 RBMS FROM POTENTIALLY EMERGENT WIV-1, RATG13, AND SHC014 COVS. WE WILL USE STRUCTURE-GUIDED IMPROVEMENT OF THESE AAcAcAEURSAA...AEUROERESURFACEDAAcAcAEURSAAAA SCAFFOLDS BY OBTAINING STRUCTURES IN COMPLEX WITH CONFORMATIONALLY-SPECIFIC MABS. AIM 1.2. ENGINEERING NON-NATIVE GLYCANS ON THE RBD PROTEIN CAN SHIELD IMMUNODOMINANT OR NON-PROTECTIVE EPITOPES AND ENHANCE IMMUNE RESPONSES TO CONSERVED SITES OF INTEREST. TO FOCUS ON CONSERVED EPITOPES, WE WILL ENGINEER PREDICTED N-LINKED GLYCOSYLATION SITES OUTSIDE OF THESE REGIONS. WE WILL USE CONFORMATIONALSPECIFIC MABS WITH DEFINED EPITOPES TO CONFIRM THE EFFECTS OF GLYCAN SHIELDING. AIM 2. TO DEVELOP SPIKE-BASED IMMUNOGENS TO ELICIT NEUTRALIZING AND NON-NEUTRALIZING RESPONSES HYPOTHESIS: CONSERVED COV EPITOPES IDENTIFIED OUTSIDE THE RBD CAN INDUCE NEUTRALIZING AND NONNEUTRALIZING, PROTECTIVE RESPONSES. AIM 2.1 RECONSTRUCTING THE EVOLUTIONARY HISTORY OF SARBECOVIRUSES AND MERBECOVIRUSES CAN IDENTIFY EXTANT VIRUSES FOR USE AS IMMUNOGENS TO ELICIT BROADLY PROTECTIVE RESPONSES TARGETING CONSERVED NEUTRALIZING AND NON-NEUTRALIZING SITES ON S. WE WILL USE AVAILABLE SARBECOVIRUS AND BETACORONAVIRUS SEQUENCES TO IDENTIFY ANCESTRAL S PROTEIN VARIANTS. WE WILL EXPRESS RECOMBINANTLY THESE ANCESTRAL S PROTEINS AND ASSAY FOR REACTIVITY TO KNOWN BROADLY NEUTRALIZING AND PROTECTIVE MABS. AIM 2.2. WE WILL IDENTIFY NON- NEUTRALIZING, CROSS-REACTIVE MABS TARGETING CONSERVED SITES (E.G., S2) FROM INFECTED OR VACCINATED INDIVIDUALS. WE WILL ASSAY MABS FOR RECOGNITION OF CELLASSOCIATED FORMS OF S AND THEN PERFORM SYSTEMS SEROLOGY (PROJECT 3) TO DEFINE THOSE WITH OPTIMAL FC EFFECTOR FUNCTION PROFILES. WE WILL CHARACTERIZE ISOLATED MABS BIOCHEMICALLY AND STRUCTURALLY TO IDENTIFY THE TARGETED CONSERVED EPITOPE(S). WE WILL USE THE RATIONAL IMMUNOGEN DESIGN STRATEGIES DESCRIBED IN AIM 1 TO ENGINEER IMMUNOGENS THAT SELECTIVELY ELICIT THESE CROSS-REACTIVE AND PROTECTIVE MABS. AIM 3. TO OLIGOMERIZE RATIONALLY DESIGNED IMMUNOGENS TO ELICIT BROAD, PROTECTIVE RESPONSES THROUGH POTENT STIMULATION OF BCRS. HYPOTHESIS. MULTIMERIC DISPLAY OF AN ANTIGEN WILL LEAD TO MORE EFFICIENT CROSSLINKING OF B-CELL RECEPTORS (BCRS) AND INCREASED IMMUNOGENICITY. OPTIMIZED IMMUNOGENS FROM AIMS 1 AND 2 WILL BE VECTORED INTO THE CHAD AND VSV PLATFORMS (PROJECT 3). TO INCREASE AVIDITY OF OUR RATIONALLY DESIGNED RBD-BASED IMMUNOGENS THAT WILL BE SECRETED AS NON-MEMBRANE ANCHORED ANTIGENS, WE WILL DEVELOP PLATFORMS FOR HIGHER-ORDERED MULTIVALENT DISPLAY USING (I) CONCATENATION (I.E., RBDS LINKED IN TANDEM) AND (II) NANOPARTICLE-BASED CONSTRUCTS (E.G., LUMAZINE SYNTHASE). CONCLUSION: THE OUTPUT OF PROJECT 1 WILL BE OPTIMIZED RBD AND S GENES TO TRANSFER TO PROJECT 3 FOR VACCINE FORMULATION IN VSV OR CHAD VACCINE PLATFORMS.
The General Hospital Corporation
Project Grant P01AI168347
$165.5k 1/30/25 WU230175MOD3S
SCOPE OF WORK THE RAPID WORLDWIDE SPREAD OF THE SARBECOVIRUS SARS-COV-2 AND COVID-19 HAS EXPOSED OUR INADEQUATE PREPAREDNESS FOR THE EMERGENCE OF NEW CORONAVIRUSES (COV). THE EXISTENCE OF MANY RELATED COV IN ANIMAL RESERVOIRS (E.G., BATS) COUPLED WITH THE POSSIBILITY OF VIRUS RECOMBINATION OR AMINO ACID ADAPTATION PROVIDES A SOURCE OF VIRUSES THAT COULD EMERGE AND LEAD TO FUTURE PANDEMICS. CURRENT VACCINE PLATFORMS (MRNA, VIRAL VECTORED, SUBUNIT, OR INACTIVATED) AGAINST SARS-COV-2, WHILE REMARKABLE FOR THE SPEED IN GENERATION AND EFFICACY, ARE PREDICTED TO HAVE LIMITED, IF ANY EFFECT ON CLOSELY OR DISTANTLY RELATED COVS. THIS NEW P01 APPLICATION IN RESPONSE TO PAR-20-072 IS ENTITLED AAcAcAEURSAA...AEUROETHE DEVELOPMENT AND EVALUATION OF PANCORONAVIRUS VACCINESAAcAcAEURSAAAA AND CONSISTS OF THREE INTEGRATED RESEARCH PROJECTS AND TWO CENTRALIZED CORES. THE GOAL OF OUR HIGHLY INTERDISCIPLINARY AND COLLABORATIVE GROUP IS TO DESIGN AND GENERATE OPTIMIZED B AND T CELL ANTIGENS THAT CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES (TWO SUBGENERA IN THE BETACORONAVIRUS GENUS) THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. THE AIMS OF ADMINISTRATIVE CORE A INCLUDING DR. RICHARD SCHEUERMANN AND STAFF AT J CRAIG VENTER INSTITUTE WILL PROVIDE DIRECTION, OVERSIGHT, AND QUALITY CONTROL FOR EACH PROJECT/CORE AND MAXIMIZE COLLABORATION AND EXCHANGE FROM ALL PARTICIPATING GROUPS. IT ALSO WILL PROMULGATE DATA MANAGEMENT AND SHARING, INTEGRATION OF PROJECTS, AND COMMUNICATION. CORE A WILL BE RESPONSIBLE FOR THE ITERATIVE MACHINE LEARNING ANALYSIS THAT WILL BE USED FOR ANTIGEN DOWNSELECTION AND TO IDENTIFY THE CORRELATES OF IMMUNE CROSS-PROTECTION WITH FEEDBACK TO ALL PROJECT DESIGNS. SPECIFIC WORK INCLUDES: AAcAcAEURSAA'Ac CONFIGURE AN INSTANCE OF THE LABKEY SERVER USING THE IMMPORT DATA STANDARD FOR USE BY P01INVESTIGATORS. AAcAcAEURSAA'Ac WORK WITH PROJECT AND CORE INVESTIGATORS TO CAPTURE THEIR EXPERIMENTAL DATA IN A STANDARDIZED FORMAT. AAcAcAEURSAA'Ac PROJECT DATA INTO THE LABKEY SERVER DATA MANAGEMENT INFRASTRUCTURE IN NEAR REAL TIME. AAcAcAEURSAA'Ac TRANSFERRING THE DATA TO THE IMMPORT AND IMMUNE EPITOPE DATABASE RESOURCES FOR DISSEMINATION OF THE DATA TO THE BROADER RESEARCH COMMUNITY AT THE TIME OF PUBLICATION. AAcAcAEURSAA'Ac ASSIST IN THE PREPARATION OF PROGRESS REPORTS BY SUMMARIZING THE DATASETS GENERATED AND DISSEMINATED INTO THE PUBLIC DOMAIN. AAcAcAEURSAA'Ac ASSIST IN THE STATISTICAL ANALYSIS OF THE EXPERIMENTAL DATA.
J. Craig Venter Institute, Inc.
Project Grant P01AI168347
$54.9k 10/29/24 WU230174MOD3S
SCOPE OF WORK AAcAcAEURSAAcA'A" JCVI PROJECT 2 THE RAPID WORLDWIDE SPREAD OF THE SARBECOVIRUS SARS-COV-2 AND COVID-19 HAS EXPOSED OUR INADEQUATE PREPAREDNESS FOR THE EMERGENCE OF NEW CORONAVIRUSES (COV). THE EXISTENCE OF MANY RELATED COV IN ANIMAL RESERVOIRS (E.G., BATS) COUPLED WITH THE POSSIBILITY OF VIRUS RECOMBINATION OR AMINO ACID ADAPTATION PROVIDES A SOURCE OF VIRUSES THAT COULD EMERGE AND LEAD TO FUTURE PANDEMICS. CURRENT VACCINE PLATFORMS (MRNA, VIRAL VECTORED, SUBUNIT, OR INACTIVATED) AGAINST SARS-COV-2, WHILE REMARKABLE FOR THE SPEED IN GENERATION AND EFFICACY, ARE PREDICTED TO HAVE LIMITED, IF ANY EFFECT ON CLOSELY OR DISTANTLY RELATED COVS. THIS NEW P01 APPLICATION IN RESPONSE TO PAR-20-072 IS ENTITLED AAcAcAEURSAA...AEUROETHE DEVELOPMENT AND EVALUATION OF PAN-CORONAVIRUS VACCINESAAcAcAEURSAAAA AND CONSISTS OF THREE INTEGRATED RESEARCH PROJECTS AND TWO CENTRALIZED CORES. THE GOAL OF OUR HIGHLY INTERDISCIPLINARY AND COLLABORATIVE GROUP IS TO DESIGN AND GENERATE OPTIMIZED B AND T CELL ANTIGENS THAT CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES (TWO SUBGENERA IN THE BETACORONAVIRUS GENUS) THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. THE AIMS OF PROJECT 2 WHICH INCLUDES DR. RICHARD SCHEUERMANN OF THE J CRAIG VENTER INSTITUTE WILL DESIGN ANTIGEN CANDIDATES THAT CONFER BROAD PROTECTIVE T CELL IMMUNITY TO MULTIPLE COV SPECIES WITH PANDEMIC POTENTIAL. THEY WILL IDENTIFY PROTEIN REGIONS THAT SHOW THE HIGHEST LEVELS OF CONSERVATION ACROSS DIFFERENT BETACORONAVIRUSES. THIS INFORMATION WILL BE ANALYZED IN THE CONTEXT OF A META-ANALYSIS OF IMMUNOGENICITY DATA THAT CATALOGS KNOWN T CELL EPITOPES FOR PROTEIN ANTIGENS AND OPEN READING FRAMES FROM DIFFERENT SARBECOVIRUSES, MERBECOVIRUSES AND BETACORONAVIRUSES. THESE RESULTS WILL BE INTEGRATED TO SELECT A SET OF CANDIDATE CONSERVED T CELL EPITOPE REGIONS FOR EXPERIMENTAL EVALUATION WITH T CELLS DERIVED FROM HUMANS AND ANIMALS (WITH PROJECT 3 AND CORE B). SPECIFIC WORK TO BE PERFORMED INCLUDES: AAcAcAEURSAA'Ac PREPARE DATA SET OF CORONAVIRIDAE SPIKE PROTEIN SEQUENCES FILTERED TO REMOVE POOR QUALITY SEQUENCES AAcAcAEURSAA'Ac CALCULATE POSITION SPECIFIC SEQUENCE VARIATION SCORES OF ALIGNED SPIKE PROTEIN SEQUENCES FROM SELECTED PHYLOGENETIC GROUPS, INCLUDING BETACORONAVIRUSES, SARBECOVIRUSES, MERBECOVIRUSES, AND SARBECO SUBCLADES AAcAcAEURSAA'Ac MAP KNOWN AND PREDICTED ANTIBODY AND T CELL EPITOPES TO ALIGNED SPIKE PROTEIN SEQUENCES TO DETERMINE THE LOCATION OF CONSERVED EPITOPE REGIONS AAcAcAEURSAA'Ac PHYLOGENETIC ANALYSIS OF SPIKE PROTEIN SEQUENCES FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac INFER ANCESTRAL SPIKE PROTEIN SEQUENCES FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac ASSIST IN PEPTIDE POOL DESIGN FROM CONSENSUS SPIKE PROTEIN SEQUENCES FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac PREPARE DATA SET OF CORONAVIRIDAE NON-SPIKE PROTEIN SEQUENCES FILTERED TO REMOVE POOR QUALITY SEQUENCES AAcAcAEURSAA'Ac CALCULATE POSITION SPECIFIC SEQUENCE VARIATION SCORES OF ALIGNED NON-SPIKE PROTEIN SEQUENCES FROM SELECTED PHYLOGENETIC GROUPS, INCLUDING BETACORONAVIRUSES, SARBECOVIRUSES, MERBECOVIRUSES, AND SARBECO SUBCLADES AAcAcAEURSAA'Ac MAP KNOWN AND PREDICTED ANTIBODY AND T CELL EPITOPES TO ALIGNED NON-SPIKE PROTEIN SEQUENCES TO DETERMINE THE LOCATION OF CONSERVED EPITOPE REGIONS AAcAcAEURSAA'Ac PHYLOGENETIC ANALYSIS OF NON-SPIKE PROTEIN SEQUENCES FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac INFER ANCESTRAL NON-SPIKE PROTEIN SEQUENCES WITH CONSERVED EPITOPE REGIONS FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac ASSIST IN PEPTIDE POOL DESIGN FROM CONSENSUS NON-SPIKE PROTEIN SEQUENCES FOR THE SELECTED PHYLOGENETIC GROUPS AAcAcAEURSAA'Ac ASSIST IN THE STATISTICAL AND MACHINE LEARNING ANALYSIS OF THE T CELL RESPONSE DATA
J. Craig Venter Institute, Inc.
Project Grant P01AI168347
$90.2k 10/24/24 WU230215MOD2S
SCOPE OF WORK THE RAPID WORLDWIDE SPREAD OF THE SARBECOVIRUS SARS-COV-2 AND COVID-19 HAS EXPOSED OUR INADEQUATE PREPAREDNESS FOR THE EMERGENCE OF NEW CORONAVIRUSES (COV). THE EXISTENCE OF MANY RELATED COV IN ANIMAL RESERVOIRS (E.G., BATS) COUPLED WITH THE POSSIBILITY OF VIRUS RECOMBINATION OR AMINO ACID ADAPTATION PROVIDES A SOURCE OF VIRUSES THAT COULD EMERGE AND LEAD TO FUTURE PANDEMICS. CURRENT VACCINE PLATFORMS (MRNA, VIRAL VECTORED, SUBUNIT, OR INACTIVATED) AGAINST SARS-COV-2, WHILE REMARKABLE FOR THE SPEED IN GENERATION AND EFFICACY, ARE PREDICTED TO HAVE LIMITED, IF ANY EFFECT ON CLOSELY OR DISTANTLY RELATED COVS. THIS NEW P01 APPLICATION IN RESPONSE TO PAR-20-072 IS ENTITLED AAcAcAEURSAA...AEUROETHE DEVELOPMENT AND EVALUATION OF PANCORONAVIRUS VACCINESAAcAcAEURSAAAA AND CONSISTS OF THREE INTEGRATED RESEARCH PROJECTS AND TWO CENTRALIZED CORES. THE GOAL OF OUR HIGHLY INTERDISCIPLINARY AND COLLABORATIVE GROUP IS TO DESIGN AND GENERATE OPTIMIZED B AND T CELL ANTIGENS THAT CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES (TWO SUBGENERA IN THE BETACORONAVIRUS GENUS) THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. THE GOAL OF PROJECT 2 INCLUDING, DR. ALBA GRIFONI AT LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY, IS TO DESIGN ANTIGEN CANDIDATES THAT CONFER BROAD PROTECTIVE T CELL IMMUNITY TO MULTIPLE COV SPECIES WITH PANDEMIC POTENTIAL. DR. GRIFONI PLAN IS TO DISCOVER AND DESIGN VACCINE ANTIGEN CANDIDATES, TO BE TESTED IN THE CONTEXT OF PROJECT 3, THAT CONFER BROAD PROTECTIVE T CELL IMMUNITY TO MULTIPLE CORONAVIRUS (COV) SPECIES WITH PANDEMIC POTENTIAL. THERE IS A STRONG RATIONALE FOR EXPLORING WAYS TO MAXIMIZE INDUCTION OF T CELL RESPONSES IN THE CONTEXT OF VACCINATION AGAINST A BROAD SPECTRUM OF COVS. CROSS-REACTIVITY AT THE T CELL LEVEL WAS UNEQUIVOCALLY DEMONSTRATED BETWEEN SARS-COV-2 AND RELATED SARBECOVIRUSES AS WELL AS WITH SEVERAL OTHER MORE DISTANTLY RELATED COV. THUS, INCORPORATING STRATEGIES THAT ELICIT CELLULAR IMMUNITY INTO VACCINES ALSO MAY RESULT IN CROSS-PROTECTION AGAINST FUTURE PANDEMICS EMERGING FROM COV RESERVOIRS. PRELIMINARY PHYLOGENETIC ANALYSES SUPPORT EXPLORING SARBECOVIRUSES, MERBECOVIRUSES AND BETACORONAVIRUSES AS OUR PRIMARY TARGETS, AND THIS ASSESSMENT IS REINFORCED BY THE WELL CONSERVED POLYPROTEIN DOMAIN ARCHITECTURE OF BETACORONAVIRUSES. RELATED TO THIS, OUR PREVIOUS STUDIES ESTABLISHED THE PATTERNS OF ANTIGEN IMMUNODOMINANCE IN HUMAN CD4+ AND CD8+ T CELL RESPONSES TO SARS-COV-2 ANTIGENS; SIMILAR STUDIES ARE IN PROGRESS TO DETERMINE IMMUNODOMINANT ANTIGENS IN NL63 AND OC43. THE REMARKABLE BREADTH OF EPITOPE REPERTOIRE DATA CURRENTLY AVAILABLE WILL ALLOW PROJECT 2 TO ACCURATELY DEFINE REGIONS WITHIN EACH ANTIGEN THAT ARE IMMUNODOMINANT FOR HUMAN CD4+ AND CD8+ T CELL RESPONSES. OUR RESEARCH HAS PREVIOUSLY DEMONSTRATED THAT HUMAN T CELL LINES CAN BE USED TO TEST FOR CROSS-REACTIVITY AMONGST DIFFERENT COVS, AND THUS VALIDATED SPECIFIC ASSAYS CAN BE USED TO ASSESS CROSS-REACTIVITY OF COV EPITOPES IN HUMANS. THE REGIONS IDENTIFIED IN THIS PROJECT WILL BE TESTED FOR IMMUNOGENICITY IN MICE AND HAMSTERS IN PROJECT 3 AND CORE B AND INTEGRATED INTO VACCINES FOR CHALLENGE STUDIES. WE PROPOSE THE SPECIFIC AIMS: SPECIFIC AIM 1 - DEFINE TARGETS OF CD4+ AND CD8+ T CELL REACTIVITY THAT ARE BROADLY CONSERVED ACROSS DIFFERENT SARBECOVIRUSES, MERBECOVIRUSES, AND OTHER BETACORONAVIRUSES OF CONCERN. AIM 1A WILL PERFORM AN ANALYSIS OF HOW THE DEGREE OF CONSERVATION VARIES AS A FUNCTION OF DIFFERENT POTENTIAL ANTIGENS ENCODED IN THE PROTEOME OF SARBECOVIRUSES, MERBECOVIRUSES, AND BETACORONAVIRUSES IN GENERAL, AND WITHIN EACH ANTIGEN, IDENTIFY WHICH PARTICULAR PROTEIN REGIONS SHOW THE HIGHEST LEVELS OF CONSERVATION ACROSS THE DIFFERENT VIRAL SPECIES. THIS ANALYSIS WILL DEFINE SETS OF ANTIGENS AND ANTIGEN SUBREGIONS THAT SHOW THE HIGHEST EVELS OF OVERALL SEQUENCE CONSERVATION. AIM 1B WILL PERFORM AN UPDATED META-ANALYSIS OF IMMUNOGENICITY DATA TO CATALOG THE KNOWN T CELL EPITOPES FOR THE DIFFERENT ANTIGENS EN
La Jolla Institute For Immunology
Project Grant P01AI168347
$549.0k 10/11/24