0258A7444612S
THE COLOGNE TEAM WILL CONTRIBUTE TO THE FOLLOWINGS PROJECT GOALS. NUMBERINGS REFER TO THE PROPOSAL. AIM 1.1 SELECTION OF VACCINE STRAINS (ŠUKSZA, LäSSIG, LEWIS). WE SELECT REPRESENTATIVE STRAIN PAIRS FOR MOUSE VACCINATION EXPERIMENTS IN THE TIME INTERVAL 2014-2022 BY THE FOLLOWING CRITERIA: (A) THE CORRESPONDING CLADES OF THE STRAINS ARE CLEARLY SEPARATED ON THE STRAIN PHYLOGENETIC TREE (RELEVANT HA AMINO ACID DISTANCES ARE IN THE RANGE 1 - 3%) AND HAVE COMPLEMENTARY CROSS-PROTECTION PROFILES. (B) THE STRAINS OF EACH PAIR CIRCULATE SIMULTANEOUSLY AT SUBSTANTIAL POPULATION FREQUENCY. (C) THE PAIRS COVER A RANGE OF ANTIGENIC DISTANCES, AS COMPUTED FROM AVAILABLE FERRET ANTIGENIC DATA. IN SOME CASES, THE ANTIGENIC DIFFERENCE BETWEEN THE STRAINS ARISES FROM A SINGLE EPITOPE MUTATION; THIS TYPE OF ANTIGENIC DIFFERENCES HAS PREVIOUSLY BEEN STUDIED. THE COMPREHENSIVE FERRET ANTIGENIC DATA THAT WILL INFORM OUR STRAIN SELECTION IS GENERATED AT THE WORLDWIDE INFLUENZA CENTRE, LONDON (A WHO COLLABORATING CENTRE), AND WILL BE PROVIDED BY NICOLA LEWIS. AIM 2.2 IMMUNE REPERTOIRE ANALYSIS (KLEIN). AT THE LAB OF FLORIAN KLEIN, WE WILL PERFORM SINGLE B CELL RECEPTOR ANALYSES, TO IDENTIFY BCRS REPERTOIRES SPECIFIC TO EACH OF THE ANTIGENS AND THEN TRACK THEIR DISTRIBUTION TO TRACK THEIR DYNAMICS IN THE DUAL VACCINATION SCENARIO. WE WILL BUILD ON OUR EXPERIENCE IN ISOLATING ANTIGEN SPECIFIC B CELLS AGAINST NUMEROUS DIFFERENT PATHOGENS FROM HUMAN AS WELL AS HUMANIZED MICE AND ADAPT OUR HIGH-THROUGHPUT B CELL RECEPTOR CLONING PROTOCOLS TO INFLUENZA-SPECIFIC MURINE REPERTOIRES. SPECIFICALLY, WE WILL PURIFY B CELLS FROM POOLED SPLENOCYTES OF THE 10 MICE IN EACH VACCINATION GROUP AND SEPARATE SINGLE B CELLS REACTIVE TO ONE OR BOTH IMMUNIZING ANTIGENS BY MULTICOLOR FLUORESCENCE-ACTIVATED CELL SORTING (FACS) INTO MULTI-WELL PLATES. AGE AND SEX MATCHED ANTIGEN-NAïVE MICE WILL BE USED AS NEGATIVE CONTROLS. ABOUT 500 TO 600 INFLUENZA-REACTIVE B CELL RECEPTORS PER GROUP WILL BE AMPLIFIED WITH MOUSE SPECIFIC V GENE PRIMERS AND ANALYZED BY SANGER OR ILLUMINA-BASED NEXT GENERATION SEQUENCING TO BUILD GROUP-SPECIFIC BCR REPERTOIRES. AIM 2.3 DATA ANALYSIS AND MODELLING (ŠUKSZA, LäSSIG). WE WILL USE BIOPHYSICAL MODELS AND MACHINE LEARNING TO PREDICT GENERIC COMBINATION TITERS GIVEN STANDARD (MONOVALENT) TITER DATA. THESE MODELS WILL BE INFORMED BY THE NEUTRALIZATION AND IMMUNE REPERTOIRE DATA GAINED IN AIMS 2.1 AND 2.2. HERE WE ASSUME THAT THE POTENCY DROPS CAN BE COMPUTED IN UNIVERSAL FORM FROM A SUITABLY DEFINED ANTIGENIC DISTANCE, WHICH, IN TURN, IS GIVEN IN TERMS OF TITER DATA. IN PARALLEL, WE WILL USE THE DATA TO DEVELOP MODELS OF IMMUNE ACTIVATION AND AFFINITY MATURATION UNDER SIMULTANEOUS PRESSURE FROM TWO ANTIGENS, USING EVOLUTIONARY RESOURCE-CONSTRAINT MODELS. TOGETHER WITH THE EXPERIMENTAL AND SEQUENCING ANALYSIS, THIS WILL IDENTIFY ORIGIN AND EXPECTED CONDITIONS OF INTERFERENCE EFFECTS FOR SIMULTANEOUS AND SEQUENTIAL IMMUNIZATION. AIM 3.1. MODEL-BASED ANALYSIS (ŠUKSZA, LäSSIG). WE WILL EVALUATE COMPUTATIONAL CROSS-PROTECTION LANDSCAPES FOR ALL COMBINATIONS OF RELEVANT CANDIDATE VACCINE STRAINS. WE WILL COMBINE THESE LANDSCAPES WITH PREDICTIVE ANALYSIS OF VIRAL EVOLUTION BASED ON ESTABLISHED ANTIGENIC FITNESS MODELS. THIS ANALYSIS WILL RANK COMBINATION VACCINE CANDIDATES BY EXPECTED MEAN PROTECTION AGAINST THE NEXT-YEAR VIRAL POPULATION. AIM 3.2 VALIDATION (GARCà A-SASTRE, LEWIS, ŠUKSZA, LäSSIG). TO TEST MODEL PREDICTIONS FOR PRO-ACTIVE VACCINE SELECTION, WE WILL CHOOSE A NEW SET OF VACCINE STRAIN PAIRS WITH CROSS-IMMUNITY AGAINST CURRENTLY CIRCULATING STRAINS, FOR WHICH THE EXPERIMENTAL PROTOCOL DESCRIBED UNDER AIM 1.1 IS REPEATED. MODEL PREDICTIONS FOR THE PROTECTION OF COMBINATION VACCINES WILL BE COMPARED TO THE OBSERVED PROTECTION, AS MEASURED WITH THE NEUTRALIZATION ASSAY TITERS AGAINST THE PANEL OF TEST VIRUSES.
None
Definitive Contract 75N93021C00014
$184.7k 11/11/24 0258A7384609S
OPTION 12B: DESCRIPTION OF WORK: IN SUPPORT OF THE MUCOSAL SAMPLING CONSORTIUM TO INFORM PROJECT NEXTGEN, THE CENTER FOR VACCINE DEVELOPMENT AND GLOBAL HEALTH (CVDGH) AT UMB WILL COLLECT MUCOSAL AND BLOOD SAMPLES THROUGH AN EXISTING DONOR PROTOCOL (CVD 4000). SAMPLES WILL EITHER BE SHIPPED DIRECTLY TO A CENTRAL REPOSITORY OR WILL BE PROCESSED AT UMB AND THEN SHIPPED TO THE REPOSITORY. NASAL AND SALIVA SAMPLES FROM ALL FOUR CONSORTIUM SITES WILL BE SHIPPED FROM THE CENTRAL REPOSITORY TO DR. MARCELA PASETTIÂ S APPLIED IMMUNOLOGY LABORATORY (AIL) FOR MUCOSAL ANTIBODY ANALYSES. A. CVDGH CLINIC: THE CLINIC WILL BE RESPONSIBLE FOR CONSENTING AND ENROLLING ELIGIBLE DONORS IN THE BLOOD DONOR CVD 4000 PROTOCOL. AFTER ENROLLMENT AND SCREENING, MUCOSAL AND BLOOD SAMPLES (TABLE 1) WILL BE COLLECTED FROM 10-15 PARTICIPANTS ON DAY 1, DAY 3, AND DAY 15 USING HARMONIZED SAMPLING PROTOCOLS. THE CLINIC WILL COLLECT AND SECURELY MAINTAIN DEMOGRAPHIC AND BASELINE MEDICAL DATA. I. UP TO 270 SAMPLES WILL BE COLLECTED. TWO NASAL AND TWO SALIVA SAMPLES WILL BE COLLECTED AT EACH VISIT FROM EACH PARTICIPANT (LEFT AND RIGHT SIDES). ONE MID-TURBINATE SWAB WILL BE COLLECTED FROM EACH PARTICIPANT AT ALL TIMEPOINTS. AT ONE TIMEPOINT, VENOUS BLOOD WILL BE COLLECTED FROM PARTICIPANTS FOR PBMCS, SERUM, AND/OR PLASMA. B. APPLIED IMMUNOLOGY LABORATORY: THE AIL (PASETTI LAB) SPECIMEN PROCESSING GROUP WILL BE RESPONSIBLE FOR PROCESSING (PBMCS, SERUM, PLASMA), LABELING, STORING, AND SHIPPING ALL SAMPLES COLLECTED BY THE CLINIC. ADDITIONALLY, THE AIL WILL CONDUCT ANALYSES ON NASAL AND SALIVARY SAMPLES TO QUANTIFY BINDING ANTIBODIES SPECIFIC TO SARS-COV-2 ANTIGENS AND TOTAL ANTIBODIES. I. SPECIMEN PROCESSING AND MANAGEMENT: THE AIL SPECIMEN PROCESSING GROUP WILL RECEIVE THE OUTLINED SAMPLES (TABLE 1) FROM THE CVDGH CLINIC. NASAL SECRETIONS (NASOSORPTION), SALIVA (ORACOL+), AND NASAL CELL (MID-TURBINATE SWAB) SAMPLES WILL BE LABELED, DOCUMENTED, RECORDED IN GLOBALTRACE, AND STORED PER THE PROTOCOL. BLOOD SAMPLES WILL BE PROCESSED BY THE SPECIMEN PROCESSING GROUP TO COLLECT SERUM, PBMCS, AND/OR PLASMA ACCORDING TO THE STUDY PROTOCOL. SAMPLES WILL BE ALIQUOTED, LABELED, AND STORED AS INSTRUCTED. ALL SAMPLES WILL BE STORED AND MONITORED UNTIL THEY ARE SHIPPED TO THE CENTRAL REPOSITORY ONCE DIRECTED. II. SAMPLE TESTING: THE AIL WILL ALSO MEASURE MUCOSAL ANTIBODIES SPECIFIC TO SARS-COV-2 ANTIGENS OF INTEREST IN NASAL SECRETIONS (NASOSORPTION) AND SALIVA (ORACOL+) USING A CUSTOMIZED MULTIPLEXED BINDING ANTIBODY ASSAY FROM MESO SCALE DISCOVERY (MSD). TOTAL IGG AND IGA CONTENT WILL ALSO BE QUANTIFIED WITH THE MSD HU/NHP ISOTYPING PANEL 1 MULTIPLEXED ASSAY. NASOSORPTION AND ORACOL+ SAMPLES COLLECTED FROM ALL PARTICIPANTS AT ALL SITES WILL BE SHIPPED TO THE AIL FROM THE CENTRAL REPOSITORY FOR TESTING. UP TO 360 MUCOSAL SAMPLES WILL BE EVALUATED FOR SARS-COV-2-SPECIFIC AND TOTAL IGG AND IGA (TABLE 2). I. THE MSD V-PLEX SARS-COV-2 CUSTOM 10-SPOT PLATE INCLUDES EIGHT SARS-COV-2 ANTIGENS. SEVERAL ANTIGENS MAY BE PRIORITIZED AND ANTIBODY DATA AGAINST THE OTHER ANTIGENS WILL BE ANALYZED AND REPORTED LATER. PRIORITY ANTIGENS ARE TBD. II. INDIVIDUAL NASAL FLUID SAMPLES COLLECTED FROM THE LEFT OR RIGHT NOSTRILS MAY BE EVALUATED AND/OR POOLED SAMPLES MAY BE TESTED. THE CONSTRUCT OF THE SAMPLE SET IS TO BE DETERMINED BUT SHOULD NOT EXCEED 360 SAMPLES. III. SARS-COV-2-SPECIFIC ANTIBODIES MAY BE MEASURED IN SERUM. TESTING OF SERUM IS TO BE DETERMINED.
University Of Maryland, Baltimore
Definitive Contract 75N93021C00014
$458.3k 5/22/24 0258A7284612S
OPTION 22B: 0258-A728-4612 TOWARDS UNIFIED QUANTITATIVE ASSAYS OF MUCOSAL IMMUNITY MUCOSAL ANTIBODIES ARE CRITICAL FOR PROTECTION FROM SARS-COV-2 INFECTION. THE FIELD IS CURRENTLY USING DIFFERENT COLLECTION METHODS AND ASSAYS TO QUANTIFY MUCOSAL SARS-COV-2 ANTIBODIES. PUTTING TOGETHER A SET OF MATCHED SALIVA AND NASAL SECRETION SAMPLES THAT CAN BE USED BY A LARGER GROUP OF INVESTIGATORS, AS WELL AS BY NIAID, TO TEST AND BENCHMARK THEIR MUCOSAL ANTIBODY ASSAYS WOULD GREATLY ADVANCE THE FIELD. MOREOVER, IT WOULD INFORM ON THE STRENGTHS AND WEAKNESSES OF EACH COLLECTION METHOD; INFORMATION, WHICH IS CRITICAL FOR THE DEVELOPMENT OF STUDY PROTOCOL FOR LARGE-SCALE MUCOSAL VACCINE STUDIES. DRS. KRAMMER AND SIMON DISCUSSED AND DEVELOPED THE FOLLOWING INTEGRATED TWO SPECIFIC AIMS WITH THEIR COLLEAGUES DRS. GOMMERMAN (UNIVERSITY OF TORONTO, CANADA) AND THÃ¥LIN (KAROLINSKA INSTITUTE, SWEDEN). EACH OF THE THREE SITES HAS BANKED BIOSPECIMEN AND ONGOING COLLECTION PROTOCOLS SUITABLE TO IMPLEMENT TO PROPOSED COLLECTIONS AND EVALUATIONS. SPECIFIC AIM 1: TO SHARE EXISTING BANKED SALIVA, NASAL AND SERUM SAMPLES TO GENERATE BIOSPECIMEN POOLS TO BE DISTRIBUTED TO SAVE LABORATORIES DR. THÃ¥LINÂ S LAB AT KAROLINSKA INSTITUTET WILL BANK MATCHED NASAL SECRETION (ANTE NARES SWAB), SALIVA (DROOLING) AND SERA (VENIPUNCTURE) FROM 20 PARTICIPANTS. SPECIFIC AIM 2: TO COLLECT SALIVA AND NASAL SECRETIONS FOLLOWING HARMONIZED PROTOCOLS TO MEASURE THE QUANTITY OF MUCOSAL SARS-COV-2 ANTIBODY (SUBTYPES, SECRETED IGA). NASAL SECRETIONS, SALIVA AND SERA WILL BE PROVIDED FROM 20 PARTICIPANTS TWICE A YEAR. THE SAMPLES WILL BE SHARED BETWEEN THE THREE PARTNERING LABS TO COMPARE AND MEASURE SARS-COV-2 ANTIBODIES WITH EACH LABS UNIQUE TESTING PLATFORM. METHODS NASAL SECRETIONS: LEFT AND RIGHT ANTE NARES WILL EACH BE SWABBED WITH A COTTON SWAB WHICH WILL BE RESUSPENDED IN 1ML PBS (YIELD: 2ML TOTAL FOR BOTH NOSTRILS). SALIVA WILL BE COLLECTED FROM THE SAME PARTICIPANT AT THE SAME VISIT USING THREE DIFFERENT PROTOCOLS: PASSIVE DROOLING (YIELD: 2ML SALIVA), SALIVETTE (YIELD: 1ML SALIVA) AND DIPPING OF A COTTON SWAB FOLLOWED BY RESUSPENSION IN 0.5ML PBS. OF NOTE, THE COMPLEXITY OF THE COLLECTION METHOD IS INVERSELY CORRELATED WITH THE EASE OF COLLECTION AS WELL AS THE VOLUME OF SPECIMEN COLLECTED (E.G., THE EASIEST WAY TO COLLECT SALIVA IS TO USE A COTTON SWAB BUT THIS METHOD ALSO PROVIDES THE SMALLEST AMOUNT OF SPECIMEN). SERUM: 3-5ML SERUM WILL BE COLLECTED BY VENIPUNCTURE AT THE SAME STUDY VISIT. APPROACH THE THÃ¥LIN LAB WILL COLLECT AND SHARE WITH BEI RESOURCES PAIRED BLOOD, NASAL AND SALIVA SAMPLES FROM A TOTAL OF 40 STUDY PARTICIPANTS (HIGH AND LOW MUCOSAL ANTIBODY LEVELS), WHICH CAN THEN BE ACCESSED BY SAVE INVESTIGATORS AND SELECTED NIAID INVESTIGATORS FOR CONCORDANCE TESTING. DATA ON THE SAMPLES FROM THE THÃ¥LIN LAB WILL BE COMBINED WITH DATA FROM THE GOMMERMAN, KRAMMER AND SIMON LABORATORIES AND WILL FORM THE BASIS FOR A MANUSCRIPT DESCRIBING CONCORDANCE BETWEEN METHODS AND CORRELATIONS OF MUCOSAL ANTIBODIES IN DIFFERENT SAMPLES.
Karolinska Institutet
Definitive Contract 75N93021C00014
$72.5k 4/18/24 0258A7304609S
OPTION 9B: 0258-A730-4609 RECOVERY AND IMMUNOLOGIC COMPARISONS ACROSS THE GROUP B MERBECOVIRUSES USING ANTIGENIC CARTOGRAPHY INTRODUCTION: MERBECOVIRUSES INCLUDE A DIVERSE ARRAY OF POSITIVE STRANDED RNA VIRUSES WITHIN THE BETACORONAVIRUS GENUS AND INCLUDE THE HIGHLY PATHOGENIC MERS-COV STRAIN THAT CAUSED 2604 LABORATORY-CONFIRMED CASES OF MIDDLE EAST RESPIRATORY SYNDROME (MERS) INCLUDING 936 ASSOCIATED DEATHS AT A CASE-FATALITY RATIO (CFR) OF 36% SINCE 2012. IMPORTANTLY, NUMEROUS ZOONOTIC BAT MERS-LIKE VIRUSES CIRCULATE IN NATURE INCLUDING SEVERAL STRAINS THAT CAN USE THE HUMAN DIPEPTIDYL PEPTIDASE RECEPTOR (HDPP4) FOR DOCKING AND ENTRY. SOME REPLICATE EFFICIENTLY OR ARE ANTICIPATED TO REPLICATE EFFICIENTLY IN PRIMARY HUMAN AIRWAY EPITHELIAL CELLS (E.G., MERS-422, MJHKU4R -COV-1, NEO, ), WHILE MOST HAVE NOT BEEN STUDIED. CURRENTLY, THERE ARE NO APPROVED VACCINES OR THERAPEUTICS FOR USE AGAINST MERS-COV INFECTION OR ANY OTHER MERBECOVIRUS. GIVEN THE EXTREME PATHOGENIC POTENTIAL OF MERS-COV, COUPLED WITH THE PRESENCE OF MERBECOVIRUSES THAT CAN USE DPP4 OR ANGIOTENSIN 1 CONVERTING ENZYME 2 (ACE2) AS RECEPTORS FOR DOCKING AND ENTRY, THE DEVELOPMENT OF PANMERBECOVIRUS VACCINES IS STILL CONSIDERED HIGH PRIORITY TARGETS FOR COUNTERMEASURE INVESTMENTS BY HEALTH AGENCIES ACROSS THE WORLD (HTTPS://WWW.WHO.INT/TEAMS/BLUEPRINT). THE OVERARCHING GOAL OF THIS PROPOSAL IS TO DETERMINE THE ANTIGENIC DISTANCE BETWEEN HIGHLY HETEROGENEOUS MERBECOVIRUSES, CREATE AN ANTIGENIC CARTOGRAPHY MAP, AND PRODUCE DEFINED SERA AND RECOMBINANT VIRUS REAGENTS THAT WILL ENHANCE GLOBAL PREPAREDNESS AGAINST FUTURE MERBECOVIRUS EPIDEMICS AND PANDEMICS. THE PROPOSAL HAS THREE AIMS: AIM I) PRODUCTION AND CHARACTERIZATION OF MERBECOVIRUS SPIKE ANTIGENS AND PRODUCTION OF MURINE ANTISERUM. FROM PUBLISHED SEQUENCES, MERBECOVRIRUS SPIKE GENES WILL BE SYNTHESIZED AND EXPRESSED AT UNCÂ S PROTEOMIC CORE. RECOMBINANT PROTEINS PLUS ADJUVANT WILL BE INJECTED INTO RODENTS FOR THE PRODUCTION OF SERUM NEUTRALIZING ANTIBODIES. AIM II) RECOVERY OF RECOMBINANT MERBECOVIRUSES AND DERIVATIVE VIRUSES ENCODING NANOLUCIFERASE. (FOR LIVE VIRUS NEUTRALIZATION ASSAY DEVELOPMENT). A SELECT PANEL OF RECOMBINANT MERBECOVIRUSES WILL BE ISOLATED FROM PUBLISHED SEQUENCES, INCLUDING DERIVATIVES THAT ENCODE THE NANOLUCIFERASE GENE IN REPLACE OF A KNOWN ACCESSORY ORF. LIVE VIRUS NEUTRALIZATION ASSAYS WILL BE DEVELOPED USING A 96 WELL FORMAT AS PREVIOUSLY DESCRIBED BY OUR GROUP. AIM III) PERFORM LIVE VIRUS CROSS NEUTRALIZATION ASSAYS AND ANTIGENIC CARTOGRAPHY. USING CELLS EXPRESSING HDPP4, WE WILL PERFORM LIVE VIRUS NLUC NEUTRALIZATION ASSAYS ACROSS EACH MEMBER OF THE PANEL, USING MURINE ANTISERUM (N=3/EACH SPIKE). THE RESULTS WILL BE SHARED WITH DR. DEREK SMITH, WHO WILL PERFORM ANTIGENIC CARTOGRAPHY STUDIES ON THE DATA. DELIVERABLES: RECOMBINANT MERBECOVIRUS SPIKES, RECOMBINANT WILDTYPE AND DERIVATIVE VIRUSES ENCODING NLUC, REFERENCE SERA, ANTIGENIC CARTOGRAPHY MAPS, IDENTIFICATION OF BNAB FROM EXISTING PANELS OBTAINED FROM COLLABORATORS ACROSS THE US AND ELSEWHERE.
University Of North Carolina At Chapel Hill
Definitive Contract 75N93021C00014
$771.1k 3/22/24 0258C5044609S
OPTION 3: 0258-C504-4609 OPTION 4: 0258-D504-4609 THE WORK PERFORMED BY DR. MEDINA AND HIS COLLABORATORS WILL INCLUDE: 1. SURVEILLANCE OF HUMAN INFLUENZA VIRUS IN THE METROPOLITAN AREA OF SANTIAGO. 2. ENROLMENT OF HUMAN SUBJECTS UNDER AN APPROVED IRB PROTOCOL ALLOWING THE COLLECTION OF INFLUENZA CLINICAL SAMPLES AND METADATA. 3. COLLECTION OF 250 INFLUENZA CLINICAL SAMPLES FOR VIRUS ISOLATION AND TO ANALYZE IMMUNE RESPONSES. 4. ESTABLISHING A CLINICAL SAMPLE DATABASE. 5. CHARACTERIZATION (SUBTYPING) OF VIRAL STRAINS AND HOST IMMUNE RESPONSES DURING ACUTE INFECTION FROM 250 VIRAL SAMPLES OBTAINED FROM INDIVIDUALS. 6. SUBMITTING BI-MONTHLY, SEMI-ANNUAL AND ANNUAL CLINICAL PROGRESS REPORTS. 7. SURVEILLANCE OF SWINE INFLUENZA VIRUSES IN THE CENTRAL REGIONS OF CHILE. 8. CHARACTERIZATION OF SWINE VIRAL STRAINS AND GENOTYPES. 9. PERFORMING ANTIGENIC CHARACTERIZATION OF SELECTED ANIMAL STRAINS. 10. COLLABORATING AND EXCHANGING RESEARCH MATERIALS WITH MEMBERS OF THE CENTER. 11. ATTENDING THE CEIRS NETWORK ANNUAL MEETING. 12. ATTENDING SCIENTIFIC ADVISORY BOARD MEETINGS AND CLINICAL SITE VISITS.
Emory University
Definitive Contract 75N93021C00014
$427.7k 3/18/24