GOOD AFTERNOON TO OUR COUNCIL MEMBERS AND MEMBERS OF THE PUBLIC. I'M DANIEL ROTROSEN, THE DIRECTOR OF THE DIVISION OF ALLERGY, IMMUNOLOGY AND TRANSPLANTATION AND IT'S MY PLEASURE TO WELCOME YOU TO THIS AFTERNOON'S OPEN SESSION OF OUR COUNCIL SUBCOMMITTEE. WE HAVE THREE VERY INTERESTING AND TIMELY TALKS. THE FIRST WILL BE AN OVERVIEW OF THE HEROES STUDY PRESENTED BY PATTY FAULKER SON IN OUR ALLERGY, ASTHMA AIRWAY BIOLOGY BRANCH, AND SHE WILL BE INTRODUCING OUR TWO SPEAKERS DR.S TINA AND DR. MAX FROM VANDERBILT UNIVERSITY AND NATIONAL JEWISH HEALTH, TALKING ABOUT THE DESIGN AND CONDUCT AND EARLY RESULTS FROM THE HERO'S STUDY. AND THEN WE'LL FOLLOW THAT WITH THREE RESEARCH CONCEPT CLEARANCES THAT WE'LL NEED COUNCIL APPROVAL TO MOVE AHEAD AND HOPEFULLY WRAP UP AND ADJOURN AS SCHEDULED BY 3 P.M. BEFORE WE BEGIN, I NEED TO GIVE YOU A REMINDER. THAT IS THAT ANY INTERESTED MEMBER OF THE PUBLIC MAY FILE WRITTEN COMMENTS WITH THE EXECUTIVE SECRETARY OF THE COMMITTEE WITHIN 15 DAYS OF THIS MEETING AND THOSE COMMENTS WILL BE INCLUDED IN THE MINUTES TO THE EXTENT THAT IS PRACTICAL, AND THE MAILING INFORMATION TO DO THAT WAS PUBLISHED IN THE FEDERAL REGISTER NOTICE ANNOUNCING THIS MEETING. ALSO, I WANT TO REMIND COUNCIL MEMBERS AND OUR STAFF THAT WE WOULD PREFER YOU NOT USE THE CHAT FEATURE ON ZOOM TO MAKE COMMENTS OR BRING QUESTIONS FORWARD BECAUSE IF YOU DO, THE CHAT FEATURE WILL BECOME PART OF THE FACA RECORD AND CREATE A LOT MORE WORK FOR EVERYBODY INVOLVED IN KEEPING THOSE RECORDS. YOUR COMMENTS WILL BE RECORDED, THOUGH, AND WE HOPE THAT THE ZOOM VIDEO AND SOUND WORK WELL. I WILL JUST REMIND YOU, IF YOU SPEAK, THE EXPECTATION IS YOU ARE ON CAMERA. SO TURN YOUR CAMERAS BACK ON IF THEY WERE SET TO BE OFF. MAKE SURE THAT YOU'RE UNMUTED. AND FOR PEOPLE WHO WANT TO MAKE A COMMENT OR ASK QUESTIONS, YOU CAN USE THE RAISE HAND FUNCTION AND YVETTE WILL BE MONITORING THAT, OR JUST UNMUTE YOURSELF AND CHIME IN AND WE'LL EXPECT THAT WILL WORK AS WELL. SO WITH THAT, LET'S GET ON TO THE AGENDA AND PATTY, YOU'RE UP WITH THE OVERVIEW OF THE HERO'S STUDY. >> THANK YOU, DAN. CAN YOU ALL SEE THAT ALL RIGHT? >> YES. >> GOOD. IT LOOKS GOOD. >> ALL RIGHT, WELL, I'M PATTY FAULKER SON, I'M A MEDICAL OFFICER IN THE ALLERGY, ASTHMA AND IMMUNOLOGY BRACH AND I WAS A MEDICAL OFFICER FOR THE STUDY OF HUMAN EPIDEMIOLOGY AND RESPONSE TO SARS-COV-2 HEROES. HEROES WAS A PUBLIC HEALTH SURVEILLANCE STUDY THAT SURVEYED HOUSEHOLDS WITH CHILDREN, PRIMARILY THROUGH NASAL SWABS FOR SARS-COV-2 INFECTIONS. WHEN IT WAS INITIALLY CONCEDE EARLY IN THE PANDEMIC, THE EFFECT OF ALLERGY ON RISK OF INFECTION WAS UNKNOWN. TO ADDRESS THIS UNANSWERED QUESTION, HEROES RECRUITED FROM A POOL THAT INCLUDED CHILDREN AND THEIR FAMILY MEMBERS THAT WERE OR HAD BEEN ENROLLED IN NIH FUNDED STUDIES THAT HAD AN EMPHASIS ON OTHER ALLERGIC DISEASE. BECAUSE OF THIS RECRUITMENT STRATEGY, OUR HEROES COHORT WAS HIGHLY ENRICH FOR ALLERGIC DISEASE, MEMBERS WITH ALLERGIC DISEASE, SO WE WERE ABLE TO LOOK AT THE IMPACT OF ALLERGY AND ASTHMA ON INFECTION INCIDENCE AS WELL AS ON RISK FACTORS AS WELL AS ON DISPARITY. WE DID NOT REQUIRE INITIAL INFECTION IN THE FAMILY FOR ENROLLMENT. INSTEAD WE DESIGNED THE STUDY TO INCLUDE LONGITUDINAL TESTING OF HOUSEHOLD MEMBERS FOR INFECTION. AS A RESULT, WE - DUE TO RESTRICTIONS ON ACCESS TO HEALTH CARE AND SAFETY MEASURES THAT WERE IN PLACE, TO ENCOURAGE FAMILIES TO STAY AT HOME DURING THE PANDEMIC, WE NEEDED TO CONDUCT HEROES ENTIRELY BY REMOTE METHODS. SO ALL SAMPLES HAD TO BE COLLECTED BY THE FAMILIES IN THEIR HOMES. THESE THREE FEATURES IS WHAT MAKES HEROES UNIQUE COMPARED TO OTHER COVID STUDIES. TODAY, WE HAVE THE OPPORTUNITY TO HEAR TWO TALKS ON THE DATA WE HAVE TODAY, WHAT WE HAVE LEARNED SO FAR FROM THE HEROES STUDY DATA. FIRST TALK IS GOING TO BE GIVEN BY TINA HARTERT, THE ASSISTANT VICE PRESIDENT FOR TRANSLATIONAL SCIENCE AS WELL AS THE DIRECTOR OF ASTHMA RESEARCH AT VANDERBILT UNIVERSITY SCHOOL OF MEDICINE AND HE WAS SHOO THE HEROES PROTOCOL CHAIR. THE SECOND TALK WILL BE GIVEN BY MAX SEE BOLD, WHO IS THE DIRECTOR OF REGENERATIVE MEDICINE AND GENOME EDITING PROGRAM AT NATIONAL JEWISH HEALTH. AND HE WAS A LEAD MECHANIST I COULD INVESTIGATOR FOR HEROES. WE ARE GOING TO TALK ABOUT RISK FACTORS FOR SARS-COV-2 IN THE HOUSEHOLD AND THEN MAX WILL TALK ABOUT TRANSMISSION OF SARS-COV-2 IN THE HOUSEHOLDS WITH CHILDREN. AND WITH THAT, I WILL STOP SHARING SO DR. HARTERT CAN START. >> SO I CONFIRM YOU ALL SEE MY SLIDES AND THE SLIDES PRESENTATION? >> YES, THEY LOOK GOOD, TINA. >> THANK YOU, DAN. THANK YOU, PATTY AND THANK YOU FOR THE INVITATION TO SPEAK ON BEHALF OF THE HEROES STUDY TEAM AS PATTY SAID. I'VE HAD THE HONOR OF SERVING AS THE PROO COLCHAIR FOR THIS NIAID STUDY. I'M A RESPIRATORY EPIDEMIOLOGIST BY TRAINING AND HAVE BEEN INTERESTED FOR OVER TWO DECADES ON THE ROLE OF RESPIRATORY VIREY INFECTIONS AND ASTHMA INCEPTION AND CONTROL. AND I'M ALSO A PULMONARY CRITICAL CARE PHYSICAL SO I HAVE BEEN ON THE FRONT LINE OF SEEING THE DISEASE FIRSTHAND AND AS MANY HAVE ALLUDED TO WHO MADE COMMENTS TODAY, THIS IS REALLY WHAT WE HAVE TRAINED OUR ENTIRE CAREERS TO DO. SO IT REALLY HAS BEEN AN HONOR TO PIVOT TO USE THE TOOLS AND KNOWLEDGE OF OUR TEAM TO TACKLE THIS RAPIDLY-SHIFTING EVERYONE'S EFFORTS AS EVERY INVESTIGATOR AND COLLEAGUE THAT WAS ASKED TO HELP WITH THIS STUDY DID TO ADDRESS THIS GLOBAL CRISIS. THIS TALK WILL BE DIVIDED INTO TWO PARTS. I'LL GIVE THE FIRST SECTION ABOUT WHAT MOTIVATED THIS STUDY, THE STUDY OBJECTIVES AND STUDY METHODOLOGY, DISCUSS THE RESULTS OF THE RISK FACTORS FOR SARS-COV-2 INFECTION AND INCIDENTS AND I'LL END WITH IMPLICATIONS AND FUTURE DIRECTIONS AND MAX WILL GIVE THE SECONDS PORTION FOCUSING ON HOUSEHOLD FINDINGS, TRANSMISSION AND RISK FACTORS FOR TRANSMISSION AS WELL AS ASYMPTOMATIC INFECTION. WE ASK IF YOU COULD PLEASE HOLD YOUR QUESTIONS UNTIL AFTER BOTH TALKS BECAUSE MAX AND I WILL TAKE THE QUESTIONS TOGETHER FOLLOWING THE SECTION OF HIS TALK. SO WHAT DID WE KNOW EARLY ON? WE KNEW FIRST OF ALL THAT THE MAJORITY OF CASES HAVE BEEN ASSOCIATED WITH FAMILY CLUSTERS AND THERE WERE OUTBREAKS REPORTED IN INSTITUTIONAL SETTINGS. WE ALSO KNEW THAT PRE SYMPTOMATIC SARS-COV-2 INFECTIONS AND TRANSMISSION HAD BEEN DOCUMENTED IN SKILLED NURSING FACILITIES AND VIABLE VIRUS HAD BEEN ISOLATED FROM SPECIMENS AS MANY AS SIX DAYS BEFORE AND UP TO NINE DAYS AFTER THE FIRST EVIDENCE OF TYPICAL SYMPTOMS. SO AT LEAST A NINE DAYTIME WINDOW WE KNEW EARLY ON. SO IT WAS VERY CLEAR THAT ASYMPTOMATIC TRANSMISSION OF THIS VIRUS WILL BE ONE OF THE ACHILLES HEELS. SO WHAT DID WE NEED TO LEARN? AT THE START OF THE PANDEMIC, REALLY THE FOCUS WAS ALMOST EXCLUSIVELY ON CRITICALLY ILL COVID PATIENCE AND THOSE WHO WERE DYING, FOR OBVIOUS REASONS. THIS WAS USUALLY THE STARTING POINT FOR PRETTY MUCH EVERY TRANSMISSION STUDY THAT WAS DONE EARLY ON AND REALLY FOR MANY MONTHS INTO THE PANDEMIC. SO THIS MEANS THAT THE REPORTED SECONDARY ATTACK RATES WERE REALLY LIKELY TO MISS INDEX INFECTIONS, PARTICULARLY IF ASYMPTOMATIC, WHICH MEANT CHILDREN, AND UNDERREPORTED HOUSEHOLD MEMBER ATTACK RATE. SO WE NEEDED TO UNDERSTAND THE ROLE OF CHILDREN AND INFECTION TRANSMISSION AND WE ALSO NEEDED TO UNDERSTAND THE ROLE OF ASTHMA AND ALLERGIC DISEASES BECAUSE THERE WAS SPECULATION EARLY ON THAT THESE ASTHMATICS AND ALLERGIC, THOSE WITH ALLERGIC CONDITIONS MIGHT BE PROTECTED FROM SARS-COV-2 INFECTION BUT THERE WAS CONFLICTING INFORMATION WITH EARLY STUDY THAT CAME OUT OF THE U.K. THAT SUGGESTED AT LEAST SEVERE ASTHMATICS WERE AT INCREASED RISK FOR INFECTION. SO IF WE REMEMBER THE TIMELINE AT THE PANDEMIC, ON JANUARY 9, THE WORLD HEALTH ORGANIZATION ANNOUNCED THIS MYSTERIOUS CORONAVIRUS RELATED PNEUMONIA IN CHINA. WE WOULD LEARN THAT THIS VIRUS HAD ALREADY BEEN CIRCULATING IN THINTHE U.S. BY MID-MARCH ALL 50 STATES WOULD CONDUCT ACTIVITYING WITH THE PHYSICIAN APPROVAL BUT THESE WERE LARGELY TARGETED TO SYMPTOMATIC INDIVIDUALS. WE WOULD EXPERIENCE SEVERAL PEAKS AT THE HEIGHT, NEARLY 300,000 NEW CASES DAILY, AND UPDATED AS OF JUNE 3, WE ARE AVERAGING FEWER THAN 20,000 POSITIVE TESTS DAILY. WHILE WE WERE AT THE PEAK, WE WERE REPORTING VERY HIGH RATES AND THERE WAS MORE VARIABILITY OVER THIS PERIOD. THE HEROES STUDY IS EMBEDDED ACROSS THE ENTIRE PANDEMIC PERIOD WHICH WAS REALLY MADE IT UNIQUE. WE HAD OUR FIRST STUDY ON MARCH 16 AND WE ENROLLED OUR FIRST STUDY PARTICIPANT ON MAY 1. SO THE ENTIRE STUDY RAN THROUGHOUT THE ENTIRE PANDEMIC, INCLUSIVE OF THE PORTION OF THE WINTER PEAK AND ALSO THROUGHOUT THE PERIOD WHERE VACCINE WAS NOT AVAILABLE TO NON-HEALTH CARE WORKERS. SO WHAT WERE THE QUESTIONS THE STUDY AIMED TO ADDRESS? PATTY ALLUDED TO THEM BUT I'M GOING TO BRIEFLY REVIEW THEM AGAIN. THE FIRST WAS LOOKING AT INFECTION. IT WAS TO DETERMINE THE INCIDENCE AND RISK FACTORS FOR SARS-COV-2 AMONG THE PARTICIPANTS, PARTICULARLY CHILDREN. BECAUSE WE HAD LONGITUDINAL SAMPLING, WE COULD LOOK AT INCIDENCE. BUT ALSO TO STUDY TRANSMISSION TO, DESCRIBE THE TRANSMISSION RATES WITHIN HOUSEHOLDS AND THE RISK FACTORS FOR HOUSEHOLD TRANSMISSION. TO UNDERSTAND THE ROLE OF ASTHMA AND ARE THESE RISK FACTORS FOR DISEASE IN SOME WAY PROTECTIVE FROM DISEASE DEVELOPMENT? AND LASTLY WAS TO COMPARE THE NASAL EPITHELIAL AND IMMUNE GENE EXPRESSION TO TRY TO UNDERSTAND IF THERE IS A ROLE FOR TYPE II INFLAMMATION OR ATOPY IN THE EXPRESSION OF THIS VIRAL ILLNESS AMONG INDIVIDUALS WITH ASTHMA AND ALLERGIC DISEASES. WHAT WERE THE MOTIVATING REASONS TO FOCUS ON ASTHMA AND ALLERGY COHORTS? THE FIRST AS PATTY MENTIONED, THESE ARE CHILDHOOD COHORTS. AND IT WOULD CLEARLY GAPS IN OUR UNDERSTANDING OF THIS INFECTION, INCIDENCE OF INFECTION AND TRANSMISSION AMONG CHILDREN. AND NEXT WAS THAT VIRAL RESPIRATORY INFECTIONS ARE ASSOCIATED WITH MAJORITY OF ASTHMA EXACERBATIONS. SO HAVING A RESPIRATORY VIRUS THAT ACTUALLY DIDN'T WREAK HAVOC AMONG ASTHMATICS WOULD BE QUITE UNUSUAL. BECAUSE ASTHMA IS ALMOST ALWAYS A RISK FACTOR FOR INCREASED RESPIRATORY VIRAL ILLNESSES. AND AS MENTIONED EARLY IN THE PANDEMIC, THERE WERE CONFLICTING OBSERVATIONAL DATA ON THE ROLE OF ASTHMA AND ATOPIC DISEASES ON SARS-COV-2 INFECTION RISK. AND LASTLY, NIAID FUNDED ASTHMA AND ALLERGY COHORT PARTICIPANTS HAVE EXPERIENCED WITH RESEARCH, EXPERIENCE WITH NASAL COLLECTIONS AND THEY HAVE ESTABLISHED RELATIONSHIPS WITH IN-PLACE STUDY STAFF WHICH ALLOWED US FOR RAPID STUDY RAMP UP AND TRAINING AND STUDY IMPLEMENTATION. SO WHAT MOTIVATED US TO STUDY HOUSEHOLDS? HOUSEHOLDS ARE OBVIOUSLY PLACES WHERE MASKING AND SOCIAL DISTANCING ARE NOT ROUTINELY PRACTICED. PROBLEM WITH A LOT OF MODELING STUDIES IS THAT IT ASSUMES EVERYONE BEHAVES IN THE SAME WAY. THAT IS PROBABLY A SAFER ASSUMPTION IN HOUSEHOLDS ALTHOUGH OBVIOUSLY THERE ARE AGE DIFFERENCES WITHIN HOUSEHOLDS. SO THEY ARE REALLY AN IDEAL STETTING TO STUDY INCIDENTS TRANSMISSION ON VIRUSES. THERE IS A GREATER INTIMACY, PARTICULARLY AMONG YOUNGER CHILDREN AND ADULTS, ONE OF THE KEY QUESTIONS IN UNDERSTANDING TRANSMISSION AND SCHOOLS HAVE BEEN VERY INTERESTED IN THIS DATA. AND IF THERE IS GOING TO BE TRANSMISSION, THIS IS THE HIGH-RISK SETTING. SO IDEAL SETTING TO UNDERSTAND RISK FACTORS FOR TRANSMISSION AND NON-TRANSMISSION. SO THE APPROACH TO THIS STUDY WAS A CONVENIENT STAMP. IT INCLUDED 20 NIH-FUNDED ASTHMA AND ALLERGIC DISEASE COHORTS. THE LOCATION WERE IN 12 U.S. CITIES AS SHOWN ON THE GEOGRAPHIC LOCATION ON THIS SLIDE. AND PARTICIPANTS WERE THE ENROLLED CHILD FROM NIH-FUNDED COHORTS AND AT LEAST ONE ADULT MEMBER OF THE HOUSE HOLD. SO THERE HAD TO BE AN ADULT AND CHILD FROM THE HOUSEHOLD ENROLLED. THERE COULD BE A SECOND CHILD IN THE HOUSEHOLD AND THESE WERE CHILDREN 2-21 YEARS. AND THERE COULD BE A SECOND ADULT FROM THE HOUSEHOLD. SO THERE WAS A REQUIREMENT FOR TWO PARTICIPANTS, ADULT AND CHILD. AND A MAXIMUM OF 4 INDIVIDUALS THAT COULD BE ENROLLED ACROSS FAMILIES. THE STUDY WAS CONDUCTED ENTIRELY REMOTELY BECAUSE OF THE PANDEMIC. FAMILIES WERE TRAINED VIA VIDEOCONFERENCING AND INSTRUCTIONS WERE INCLUDED IN THE BIOSPECIMEN COLLECTION KITS SENT TO THEIR HOUSE. AND THIS WAS CONDUCTED VERY SIMILAR TO THE CENSUS WITH WHICH THESE INDIVIDUALS WOULD HAVE BEEN QUITE FAMILIAR AS WE JUST FINISHED A CENSUS, WHICH IS THAT A PRIMARY CAREGIVER ANSWERED THE QUESTIONS FOR ALL OF THE PARTICIPANTS IN THE HOUSEHOLD WITH THEIR INVOLVEMENT. SO COHORT PARTICIPANTS ACROSS THE COUNTRY AND THESE COHORTS WERE CONTACTED BY THEIR STUDY TEAMS AND MOST WERE ENROLLED ELECTRONICALLY OR OVER THE PHONE. THE ENROLLMENT VISIT INCLUDED A REGISTRATION AND ENROLLMENT QUESTIONNAIRE THAT WAS COMPLETED BY THE PRIMARY CAREGIVER ON BEHALF OF ALL HOUSEHOLD MEMBERS WITH THEIR INVOLVEMENT. AND ALL HOUSEHOLD MEMBERS THAT THE POINT OF ENROLLMENT COLLECTED A NASAL SAMPLE, A CAPILLARY BLOOD SAMPLE AND A STOOL SAMPLE. AND SPECIMENS WERE EITHER SELF COLLECTED BY THE ADULTS OR THE OLDER TEENAGERS OR COLLECTED BY THE PRIMARY CAREGIVER ON ALL HOUSEHOLD PARTICIPANTS. AND FOR EIGHT MONTHS, EVERY OTHER WEEK AN ILLNESS QUERY WAS SENT ASKING ABOUT WHETHER INDIVIDUALS WERE SICK AND EVERY OTHER WEEK ALTERNATING AN ILLNESS SURVEY WAS SENT AND NASAL BIOSPECIMENS WERE COLLECTED ON ALL ENROLLED HOUSEHOLD MEMBERS REGARDLESS OF WHETHER THEY HAD SYMPTOMS OR NOT. FAMILIES WERE CONTACTED EVERY WEEK AND EVERY TWO WEEKS, THERE WAS A TRIGGER TO COLLECT NASAL SAMPLES REGARDLESS OF SYMPTOMS. THIS TWO-WEEK SURVEILLANCE WINDOW WAS SELECTED TO BALANCE ISSUES OF FEASIBILITY AND STUDY FATIGUE WITH WHAT WAS KNOWN AT THE TIME REGARDING THE DURATION OF VIRAL SHEDDING. ADDITIONALLY, IF ON ALLOTTEDDERINATING WEEKS, ANYONE DEVELOPED SYMPTOMS, AN ADDITIONAL ILLNESS EVENT TRIGGER WAS PROMPTED AND COLLECTIONS ON ALL HOUSEHOLD MEMBERS WERE TRIGGERED FOR THE FIRST ILLNESS EVENT TO INCLUDE A NASAL SAMPLE, A STOOL SAMPLE AND A BLOOD SAMPLE. AND ADDITIONAL HOUSEHOLD MEMBERS EVEN IF NOT ENROLLED IN THE STUDY, COULD COLLECT DURING THIS ILLNESS VISIT. AND THEN LASTLY, THERE WAS AN END OF STUDY SURVEY WHICH REGARDLESS OF SYMPTOMATOLOGY AND A BLOOD SAMPLE. SO UNIQUE ASPECT OF THIS STUDY IS THAT WE ACTUALLY HAVE NASAL SAMPLING TO LOOK AT IMMUNE RESPONSE PROFILES, NASAL MUCOSAL GENE EXPRESSION PRIOR TO, DURING AND POST-SARS-COV-2 INFECTIONS. SO FAMILIES COULD CHOOSE WHICH MODE OF CONTACT THEY PREFERRED WITH THE MAJORITY OF OUR PARTICIPANTS SELECTING TEXTING. BUT PHONE SURVEY COMPLETION FOR THE STUDY WAS OFFERED TO ALLOW HOUSEHOLDS THAT DIDN'T HAVE SMARTPHONES OR DIDN'T HAVE INTERNET ACCESS TO PARTICIPATE. SO WEEKLY SURVEYS WERE BUILT INTO A DATABASE SYSTEM DEVELOPED AND MANAGED AT VANDERBILT AND SHARED FREELY WORLDWIDE AND INCLUDES THESE AUTOMATED TEXTING FUNCTIONS AND REMINDERS TO COMPLETE SURVEYS AND REMINDERS AND INSTRUCTIONS TO COMPLETE SAMPLES WERE SENT OUT THROUGH THE PLATFORM. AS I SAID, NASAL SAMPLES WERE COLLECTED REGARDLESS OF SYMPTOMS BUT REQUIRING MORE THAN ONE SYMPTOM DEFINING AS A MINOR ILLNESS TRIGGERED AN ADDITIONAL ILLNESS COLLECTION. THE DEFINITION OF SYMPTOMATIC OR ASYMPTOMATIC REQUIRED THE REPORTING OF A SINGLE SYMPTOM AMONG THE 20-PLUS SYMPTOMS THAT WERE ASKED ABOUT. IN ALL HOMES WERE SENT BYO SPECIMEN COLLECTION KITS WITH A COLOR-CODING SYSTEM. EVERYONE IN THE FAMILY WAS ASSIGNED A COLOR FOR ALL THE BIOSPECIMEN COLLECTIONS TO MORE EASILY DIFFERENTIATE PARTICIPANT SAMPLES. SO WHAT DID WE DO WITH THESE SAMPLES? OVER A 41,000 SAMPLES HAVE BEEN COLLECTED AND RUN BY THE LABORATORY AND WE USE THE STANDARD WELL-DEFINED CRITERIA TO DEFINE INFECTION USING PCR WITH A CYCLE THRESHOLD OF LESS THAN 40 TO DEFINE INFECTION. IN ADDITION, SELECT SAMPLES AMONG THOSE WITH AND WITHOUT ASTHMA AND ATOPIC DISEASES AND IDENTIFIED RISK FACTORS WILL UNDERGO RNA-SEQ PRIOR TO AND DURING SARS-COV-2 INFECTION TO UNDERSTAND THE NASAL, MEW KOSAL AND IMMUNE CELL RESPONSES. AND THIS WILL ALSO BE DONE IN MAX'S LAB. IN ADDITION, WE COLLECTED CAPILLARY BLOOD SAMPLES AT THE START OF THE STUDY, THREE WEEKS FOLLOWING THE TRIGGERED ILLNESS VISIT AND AT THE STUDY EXIT. AND THESE WILL BE ASSAYED FOR SARS-COV-2 SEROLOGY BY AN NIH INTRAMURAL LAB AND WE'LL ALSO DO SPECIFIC ITE FOR ERROR AIR ALLERGENS AND FOOD ALLERGENS USING A COMMERCIALLY AVAILABLE CHIP. AND STOOL SAMPLES WILL BE RUN BY THE FDA LABORATORY OF PAULE CARLSON FOR SARS-COV-2 PCR. SO PRETTY COMPREHENSIVE SAMPLING OF NASAL BIOSPECIMENS, BLOOD AS WELL AS STOOL SAMPLING. SO THE FIRST PORTION OF THE RESULTS THAT I'M GOING TO TALK ABOUT ARE THE DESCRIPTIVE DATA AND INCIDENCE OF SARS-COV-2 INFECTION. SO JUST TO DIFFERENTIATE THIS FROM THE NEXT SECTION MAX IS GOING TO TALK ABOUT, I'M GOING TO TALK HERE ABOUT EVERYTHING ON THE INDIVIDUAL LEVEL. SO IN THIS ANALYSIS, THERE ARE 4100 PARTICIPANTS ENROLLED FROM NEARLY 1400 FAMILIES. AND I'M GOING TO TALK ABOUT INDIVIDUAL INFECTIONS, SOME OF WHICH MAY BE CLUSTERED IN FAMILIES. THE AVERAGE HOUSEHOLD SIZE WAS ABOUT 4.4 MEMBERS AND THE AVERAGE NUMBER ENROLLED PER HOUSEHOLD WAS 2.9 IN THESE FAMILIES. THE AVERAGE AGE OF OUR CAREGIVERS WAS 41 YEARS. THE AVERAGE AGE OF CHILDREN IN THE COHORT WAS 10 YEARS AND 61% OF OF THE FAMILIES HAD MEMBERS WITH A COVID HIGH-RISK CONDITION. 31% OF THE OVERALL COHORT HAD ASTHMA, AGAIN ENRICHED FOR FAMILIES WITH ASTHMA AND ALLERGIC DISEASE. SOMEWHERE POPULATION BASED. SOME OF THESE COHORTS THE CHILDREN HAD TO BE BORN TO FAMILY MEMBERS AND SOME OF THESE COHORTS TO GET INTO THE COHORT, YOU HAD TO HAVE THE DISEASE. SO HIGHLY ENRICHED BASELINE PREVALENCE OF ASTHMA AND POPULATIONS ABOUT 8%. AND AMONG THE CHILDREN, 2-21 YEARS, 37% AND AMONG THE ADULTS, 22%. ALLERGIC RHINITIS IN 48% OF THE COHORT AND 48% OF CHILDREN, 47% OF ADULTS AND FOOD ALLERGY IN NEARLY 18% OF ALL PARTICIPANTS, 21% IN CHILDREN AND 10% IN THE ADULT PARTICIPANTS. AMONG THE 41,000 NASAL SWABS, NEARLY 39,000 WERE FROM THE BIWEEKLY SURVEILLANCE COLLECTIONS THAT WEREN'T TRIGGERED BY A SYMPTOM. AND THE POSITIVITY OF THE BIWEEKLY COLLECTIONS AS YOU CAN SEE HERE, WAS LESS THAN 1% AND WAS ABOUT 6% OR NEARLY 7-FOLD HIGHER DURING THE ILLNESS EVENTS. BUT AMONG THE 261 INDIVIDUAL CASES, IT'S IMPORTANT TO RECOGNIZE THAT 92% OF THE CASES WERE DETECTED THROUGH BIWEEKLY SURVEILLANCE AND 8% OF CASES WERE DETECTED BY AN ILLNESS-TRIGGERED COLLECTION. SO MOST OF THE RECOGNIZED ILLNESSES IN THIS STUDY WERE THROUGH BIWEEKLY SURVEILLANCE AND NOT TRIGGERED THROUGH ILLNESS VISIT, WHICH WOULD HAVE PROMPTED OUR ROUTINE TESTING DURING MOST OF THE PANDEMIC. THIS IS THE DEMOGRAPHIC CHARACTERISTICS OF THE COHORT, THE COSHORT SLIGHTLY MORE CHILDREN THAN CAREGIVERS BUT NEARLY 50/50. THE LARGEST GROUP OF CHILDREN IS 11-21 YEARS FOLLOWED BY THOSE 6-11 YEARS AND THE SMALLEST PERCENT ARE THOSE IN THE GROUP THAT ARE 2 TO LESS THAN 6 YEARS OF AGE. THERE WERE SLIGHTLY MORE MALE CHILDREN THAN FEMALE CHILDREN BUT PRETTY CLOSE TO 50/50. AND 80% OF THOSE WHO WE DEFINED AS THE PRIMARY CAREGIVER, THE PERSON WHO SIGNED UP FOR THE STUDY AND COMPLETED ALL THE COLLECTIONS AND SURVEYS WERE WOMEN AND THE VAST MAJORITY OF THE SECOND HOUSEHOLD MEMBERS WERE MALE. IN TERMS OF THE RACE AND ETHNICITY BREAKDOWN, THE COHORT WAS 58% NON-HISPANIC WHITE, FOLLOWED BY 22% NON-HISPANIC BLACK, HISPANICS MADE UP 13% OF THE COHORT AND REMAINDER WERE OTHER RACES OR NOT REPORTED. AMONG THE NEARLY 41,000 NASAL SWABS THAT WERE COLLECTED, ABOUT A THIRD HAD MISSED SAMPLING AT SOME POINT IN THE BIWEEKLY COLLECTIONS AMONG THE COHORT. AND THEN THE PORTION WITH SARS-COV-2 POSITIVITY IN THESE GRAPHS IS NEARLY IDENTICAL IN CHILDREN AND ADULTS COMPARED TO THE PARTICIPANT ENROLLMENT. AND THIS WAS TRUE IN THAT THE INCIDENTS WAS IDENTICAL ACROSS ALL OF THESE REPORTED AGE GROUPS AS WELL. SO THE ACCUMULATIVE INCIDENTS AND THIS FIGURE REPRESENTS SEVEN-DAY ROLLING INCIDENTS, WAS 6.3%. THE INCIDENCE ON THE LAST SLIDE WAS SIMILAR IN ALL OF THE AGE GROUPS RANGING FROM 6-6.3% IN ALL THE AGE GROUPS. BUT THIS IS AN UNDERREPRESENTATION OF THE ACCUMULATIVE INCIDENCE, REALLY FOR A NUMBER OF DIFFERENT REASONS. SOME ARE RELATED TO LIMITATIONS WITH THE STUDY. THERE WAS SIGNIFICANT DROPOUT IN THE STUDY. WE MISSED INFECTIONS, WE MISSED SAMPLING IN ABOUT A THIRD OF THE SAMPLES. THERE WERE POSITIVE SAMPLES THAT COULDN'T BE LINKED BACK TO A PARTICIPANT BECAUSE OF MISLABELING AND THEN THE 14-DAY COLLECTION WINDOW WHICH WE SELECTED TO BALANCE FEASIBILITY AND STUDY FATIGUE, BUT WE KNOW NOW COULD HAVE MISSED INFECTIONS. AND THEN THE DATA WE ARE PRESENTING TODAY IS NON INCLUSIVE OF THE SEROLOGY AS WELL AS THE STOOL TESTING. BUT AS YOU CAN SEE HERE, THESE ILLNESSES NEAR THE U.S. NATIONAL TREND AS SEEN IN THE OVERLAID NATIONAL DATA BUT THE SIMILAR PEAKS SEEN AND JUST TRENDING OFF THE END OF THE STUDY, BECAUSE PEOPLE EXITED OR COMPLETED THE STUDY OVER A TWO-MONTH TIME WINDOW. SO BECAUSE OF SOME OF THE LIMITATIONS OF LOOKING AT ROLLING INCIDENCE, WE USED KAPLAN-MEIER ESTIMATED TO DETERMINE THE PROBABILITY OF INFECTION ACROSS THE STUDY TIME FREQUENTLY MAY 15 THE FIRST INFECTION, THROUGH THE END OF JANUARY OF 2021. AND IT'S UNIQUE IN CAPTURING INFECTION PROPERTIES IN AND AMONG ASYMPTOMATIC INDIVIDUALS. IT USES A COUNTING PROCESS THAT ALLOWS FOR DELAYED ENTRY AND FOLLOWS OVER CALENDAR TIME. AND IT INCLUDES ALL SUBJECTS REGARDLESS OF THEIR SAMPLING DENSITY AND IN ADDITION PERFORMED ALL THESE ANALYSIS AT NATIONAL JEWISH. SHE CONDUCTED A SENSITIVITY ANALYSIS EXCLUDING PARTICIPANTS WHO HAD LARGE GAPS IN SAMPLING DENSITY AND YIELDED NEARLY SIMILAR RESULTS. SO ABOUT 14% PROBABILITY OF INFECTION OVER THE STUDY TIME WINDOW. THIS IS THE DATA ON REINFECTIONS AMONG COHORT PARTICIPANTS. SO, THIS IS ACTUALLY QUITE CONSERVATIVE. WE DEFINED REPEAT INFECTIONS AS REQUIRING A NEGATIVE PCR FOLLOWING INFECTION. SO IN OTHER WORDS CONFIRMING THE INFECTION ENDED. AND EACH OF THESE REPRESENTS THE TWO-WEEK TIME WINDOW. THIS IS THE ROUND CIRCLE IS BIWEEKLY. IF IT'S RED, IT MEANS IT WAS SARS-COV-2 POSITIVE F IT'S BLACK AND SAYS NEGATIVE AND IT WAS NEGATIVE, THIS REPRESENTS SYMPTOMATIC ILLNESS AND THE GREEN REPRESENTS SYMPTOMATIC ILLNESS, INCLUDING GASTROINTESTINAL SYMPTOMS. SO TO DEFINE THE REINFECTION, YOU HAD TO HAVE A NEGATIVE FOLLOWING THE FIRST INFECTION AND THERE HAD TO BE AT LEAST 50 PLUS DAYS BETWEEN THE LAST POSITIVE AND SECOND POSITIVE PCR DEFINING THE NEW REPEAT INFECTION. SO THIS IS INFECTION IN THE FIRST HOUSEHOLD CASE. THIS IS AN 18-YEAR-OLD INDIVIDUAL. YOU CAN SEE HERE THAT THE FIRST INFECTION IS SIMPLE MATTIC AND THE SECOND INFECTION WAS ALSO SYMPTOMATIC IN THIS INDIVIDUAL. SO WE WILL BE SEQUENCING THESE VIRUSES AGAIN SOMETHING WE HAD DONE IN MAX'S LAB. SO WE'LL KNOW IF THESE VIRUSES ARE THE SAME OR THEY REPRESENT DIFFERENT STRAINS. THE SECOND REINFECTION WAS IN A 43-YEAR-OLD AND INFECTIONS WERE SYMPTOMATIC. 83 DAYS APART. AND THE THIRD AND FORTH INFECTIONS OCCURRED IN THE SAME HOUSEHOLD, ONE AMONG A 6-YEAR-OLD CHILD AND THE SECOND AMONG THE 6-YEAR-OLD CHILD'S 35-YEAR-OLD CAREGIVER. SO IT'S IMPORTANT TO KNOW HERE A COUPLE OF INTERESTING POINTS. OBVIOUSLY THESE ARE REALLY SMALL NUMBERS AND VERY CONSERVATIVE IN HOW WE DEFINE REINFECTIONS BUT 50% OF THESE WERE AMONG CHILDREN AND REINFECTIONS WERE SYMPTOMATIC. AND VERY HIGH PORTION OF THESE SYMPTOMATIC INFECTIONS WERE ASSOCIATED WITH GASTROINTESTINAL SYMPTOMATOLOGY. SO I'LL TURN NEXT TO THE SYMPTOM-LEVEL RISK FACTORS FOR SARS-COV-2 INFECTION. ANOTHER NOVEL ASPECT OF THIS STUDY. SO PERHAPS MOST NOTABLE WAKEUP CALL FOR ALL OF US HAS BEEN THE INEQUALITY AND INFECTION RATES AND MORBIDITY OF SARS-COV-2 INFECTIONS AND SIMILAR TO THAT OF OTHER STUDIES AMONG PARTICIPANTS, THE HERO STUDY WAS NO DIFFERENT IN WHICH MINORITY PARTICIPANTS DEFINED AS HIS SPANNIC AND BLACK STUDY PARTICIPANTS, WERE SIGNIFICANTLY MORE LIKELY TO BE INFECTED COMPARED WITH NON-HISPANIC WHITES SHOWN IN THIS SURVIVAL ANALYSIS. AND A FINDING WAS CONSISTENT ACROSS THE ENTIRE STUDY PERIOD. ONE OF THE MORE NOVEL RISK FACTORS IDENTIFIED WAS BEING ORPHAN WEIGHT OR OBESE. THIS RELATIONSHIP WAS SEEN -- OVERWEIGHT -- THIS WAS SEEN ACROSS THE STUDY PERIOD. THE NORMAL BMI IS IN GREEN AS THE OVERWEIGHT OR OBESE GROUP -- NORMAL BMI IS IN RED. THERE WAS A WEIGHT-DEPENDENT RELATIONSHIP AS YOU SEE IN THIS GRAPHIC BUT INCREASING BMI WITH INCREASING RISK OF SARS-COV-2 INFECTION. SO A DOSE DEPENDENT RELATIONSHIP AND WITH EVERY 10 POINT INCREASE IN BMI PERCENTILE, IT RESULTED IN 9% INCREASE RISK OF INFECTION T IS IMPORTANT TO POINT OUT THIS REPRESENTS INFECTION NOT SEVERITY OF INFECTION. A INTRIGUING FINDING OF WHY THOSE WHO ARE ORCH WEIGHT OR OBESE ARE AT INCREASED RISK OF ESTABLISHING INFECTION OR TESTING POSITIVE FOR INFECTION. SO WHAT ARE THE MAIN HYPOTHESES WAS TESTING IN RELATIONSHIP BETWEEN ASTHMA AND ALLERGIC DISEASE AND THE RISK OF SARS-COV-2 INFECTION. WE SAW NO RELATIONSHIP BETWEEN ASTHMA WHETHER IT WAS ADULT ON SAID, CHILD ONSET, OR BY AGE WITH RISK OF SARS-COV-2 INFECTION COMPARED TO THOSE WITHOUT ASTHMA. IN CONTRAST, SHOWN HERE IN THE RIGHT, WE SAW VERY STRONG PROTECTIVE EFFECT OF FOOD ALLERGY ON INFECTIONS AND THESE FINDINGS WILL BE FOLLOWED UP USING REMAINING PLASMA SAMPLES THAT WE HAVE TO ASSESS SPECIFICKINGS TO CONFIRM AIR ALLERGEN AND FOOD SENSITIZATION GIVEN PROBLEMS WITH THE SELF REPORT OF FOOD ALLERGY AS WELL AS THE ASSESSMENT OF NASAL MUCOSAL AND IMMUNE CELL GENE EXPRESSION BOTH PRIOR TO AND POST I BELIEVE FECKS TO TRY TO UNDERSTAND THE BIOLOGIC REASONS THAT MAY UNDERPIN THE PROTECTIVE EFFECT OF FOOD ALLERGY OR TYPE II INFLAMMATION. SO THIS IS A SUMMARY OF THE RESULTS OF THE RISK FACTORS THAT I HAVE JUST SHOWN YOU FROM THE MULTIVARIATE EXTENDED COX PROPORTIONAL HAZARDS MODEL WITH RANDOM EFFECTS THAT ACCOUNTED FOR CLUSTERING OF SUBJECTS WITHIN FAMILIES AND STUDY SITES AND CONTROLLING FOR AGE, SEX AND RACE AND ETHNICITY. SO FIRST THOSE EXPOSED TO SYMPTOMATIC COVID INDIVIDUAL HAD THE HIGHEST RISK FOR INFECTION AND RECOGNIZED THERE IS INTERRUPTION OF THIS Y AXIS HERE BECAUSE OF HAZARD RATIO IS 87 FOR BEING EXPOSED TO ASYMPTOMATIC COVID PATIENT BEING EXPOSED TO AN ASYMPTOMATIC COVID PATIENT, ALSO MARKED INCREASED RISK WITH A HAZARD RATIO OF 28. THERE WAS NO RELATIONSHIP AS I SAID, BETWEEN ASTHMA AND INFECTION RISK. HOWEVER, FOOD ALLERGY WAS HIGHLY PROTECTIVE ON ESTABLISHING SARS-COV-2 INFECTION. AND AS IN ALL OTHER STUDIES, INDIVIDUALS OF HISPANIC AND BLACK RACE HAD THIS MARKED INEQUALITY WITH HIGHEST RISK OF INFECTION AND VERY INTERESTINGLY OVERWEIGHT AND OBESE INDIVIDUALS HAD A WEIGHT-DEPENDENT RISK OF INFECTION. SO THIS FINDING OF OBESE SITA RISK FACTOR FOR ESTABLISHING INFECTION AND FOOD ALLERGY BEING PROTECTED ARE VERY INTERESTING RISK FACTORS FOR ESTABLISHING SARS-COV-2 INFECTION. SO WHY MIGHT FOOD ALLERGY BE PROTECTIVE AND OBESITY BE APE RISK FACTOR FOR ESTABLISHING SARS-COV-2 INFECTION? THE NEXT SET OF STUDIES WILL MEASURE NASAL AND MUCOSAL IMMUNE GENE CELL AND GENE EXPRESSION THAT MAY HELP ANSWER THESE QUESTIONS BUT WE CAN SPECULATE BASED ON SOME PUBLISHED LITERATURE ON WHY THIS MAY BE AND WHAT WE KNOW ABOUT OTHER RESPIRATORY VIRAL INFECTIONS. SO THIS FIRST PANEL JUST DEPICTS A NORMAL AIRWAY WITH ACE 2 RECEPTORS FOR THE SARS-COV-2 VIRUS. AND THE START OF THE STUDY EARLY ON, STUDIES LED BY MAX AND HIS GROUP AS WELL AS DAN JACKSON AND THE SACKER INITIATIVE, SEVERAL STUDIES DEMONSTRATED DECREASED ACE TWO EXPRESSION AMONG INDIVIDUALS WITH TYPE II AIRWAY INFLAMMATION THAT MAY EXPLAIN WHY THERE COULD BE A PROTECTIVE EFFECT. AND THERE WAS ALSO DATA FROM THE SEVERE ASTHMA RESEARCH NET THAT STEROIDS MIGHT BE ASSOCIATED WITH DECREASED AIRWAY EP PEELIAL ACE 2 EXPRESSION. INTRIGUING AND WILL BE FOLLOWED UP ON THE STUDY SPECIFICALLY DESIGNED TO CAPTURE VERY DETAILED INFORMATION ABOUT THE MEDICATIONS THESE ASTHMA AND ALLERGIC INDIVIDUALS WERE ON AS TO WHETHER THERE COULD BE SOME PROTECTIVE EFFECT. THE MEDICATIONS USED TO TREAT THESE CONDITIONS. AND THEN LASTLY, WE KNOW THAT OBESITY IS OFTEN ASSOCIATED WITH NEUTROPHILIC INFLAMMATION AND MUCOSAL NEUTROPHILIC INFORMATION BEFORE VIRAL EXPOSER IS ASSOCIATED WITH INCREASED VIRAL REPLICATION AND ESTABLISHMENT OF INFECTION FOR SEVERAL RESPIRATORY VIRUSES INCLUDING ADENOVIRUS AND RSV AND RSV IN PARTICULAR, MOWICOSEAL AND NEUTROPHILIC INFORMATION BEFORE VIRAL INFECTION, APPEARS TO BLUNT EARLY TYPE 17 EARLY INFLAMMATORY RESPONSE WHICH COULD INHIBIT INFECTION. THESE ARE FINDINGS TO FOLLOW-UP ON BECAUSE WE HAVE NASAL SAMPLING PRIOR AND DURING INFECTION. SO IN SUMMARY, AMONG 4000 OR OVER 4100 TOTAL HEROES PARTICIPANTS, THERE WERE 261 CONFIRMED SARS-COV-2 CASES AMONG 147 FAMILIES. 8% OF INFECTIONS WERE IDENTIFIED FOLLOWING AN ILLNESS AND RECOGNIZED 92% WERE IDENTIFIED THROUGH BIWEEKLY SURVEILLANCE. THESE WOULD HAVE BEEN TESTING THAT WOULD PROBABLY NEVER HAVE BEEN DONE AS PART OF CLINICAL PRACTICE. OVERALL, A 14% PROBABILITY OF SARS-COV-2 INFECTION ACROSS THE STUDY PERIOD REPRESENTING MOST OF THE PANDEMIC, THE PEAKS AND REPRESENTING NON-VACCINE PERIODS. IMPORTANT ALSO IS THE PROPORTION OF ADULTS AND CHILDREN INFECTED OVER THIS PERIOD WERE IDENTICAL. CHILDREN WERE NOT LESS LIKELY TO BE INFECTED. ALTHOUGH THEY WERE LESS LIKELY TO BE HAVE SYMPTOMATIC INFLECTION. AND THEN LASTLY, THERE WERE VERY FEW REINFECTIONS THAT BOTH CHILDREN AND ADULTS. THERE WERE ONLY 4 REINFECTIONS, TWO IN CHILDREN, TWO IN ADULTS, REPEAT INFECTIONS AND THEY WEREN'T NECESSARILY ASYMPTOMATIC ASYMPTOMATIC. RISK FACTORS FOR SARS-COV-2 INFECTION INCLUDED EXPOSURE TO AN INFECTED INDIVIDUAL, SYMPTOMATIC GREATER RISK FACTOR THAN ASYMPTOMATIC. THE INEQUITIES OF MINORITY, RACE AND ETHNICITY DEMONSTRATED ALSO IN THIS STUDY. BUT THERE WERE NOVEL RISK FACTORS FOR SARS-COV-2 INFECTION, THE FIRST BEING OBESITY AND THE SECOND OBESITY BEING A RISK FACTOR AND FOOD ALLERGY BEING A PROTECTIVE FACTOR FOR ESTABLISHING SARS-COV-2 INFECTION. AND WE BELIEVE THAT THE AIRWAY MUCOSAL NICHES ARE LIKELY LINKED WITH VIRAL REPLICATION SYMPTOMS AND SPREAD AND UNDERSTANDING MUCOSAL INFLAMMATION MAY REVEAL TARGETS FOR INFECTION PREVENTION NEXT PHASE OF THIS STUDY. SO I'M JUST GOING TO END HERE WITH WHAT I CALL THE HEROES OF THE HEROES STUDY. AND ACKNOWLEDGE MANY PEOPLE, INCLUDING THE NIAID WHO LED THIS STUDY, [ READING ] I'LL TURN IT OVER TO MAX AND WE ASK YOU HOLD QUESTIONS UNTIL MAX FINISHES HIS TALK. >> ALL RIGHT, CAN EVERYBODY SEE MY SLIDES? CAN YOU SEE IT AND HEAR ME? >> YES, MAX, THIS IS DAN. THEY ARE SHOWING ON MY SCREEN SO I HOPE THAT IS TRUE OF EVERYBODY ELSE. >> GOOD. ALL RIGHT, SO I'LL GET RIGHT IN. SO WE ARE ON TIME. FIRST ITR. I'D LIKE TO THANK DAIT IT'S BEEN REALLY EXCITING. AND I'M EQUALLY EXCITED TO TELL YOU ABOUT SOME OF THE RESULTS TODAY. SO AS YOU JUST HEARD FROM TINA, THE HEROES STUDY IS ALREADY IDENTIFIED SOME IMPORTANT INDIVIDUAL-LEVEL RISK FACTORS FOR INFECTION AND THE PROBABILITY OF INFECTION REGARDLESS OF A PERSON'S HOUSEHOLD SYMPTOMS. BUT IN REALITY, A SIGNIFICANT COMPONENT OF THE RISK WE ALL ACQUIRE FOR INFECTION AND THROUGH OUR HOUSEHOLDS AND INTERACTIONS WITH OUR HOUSEHOLD MATES. TO UNDERSTAND INFECTION AT THE LEVEL OF THE HOUSE HOLD, THERE ARE SEVERAL THINGS WE WOULD WANT TO KNOW. FIRST IS, HOW DOES THE FIRST MEMBER OF THE HOUSE HOLD THAT BECOMES INFECTED ACQUIRE THAT INFECTION WHETHER THE EXPOSURE IS RELATED TO THAT? AND WHAT ARE THE HOUSEHOLD RISK FACTORS INVOLVED IN AN INFECTION COMING INTO THE HOUSEHOLD? ADDITIONALLY, WE WANT TO KNOW AFTER AN INFECTION HAS COME INTO THE HOUSEHOLD, WHAT ARE THE RISK FACTORS THAT ADD INFECTION TO SPREAD TO OTHER HOUSEHOLD MEMBERS, CHARACTERISTIC OF THE HOUSE HOLD AND INDEX AND THEN OF THAT INITIAL INFECTION. AND THESE ARE EXACTLY SOME OF THE QUESTIONS THAT WE TRY TO ADDRESS IN HEROES AND THE RESULTS THAT I'LL BE REVIEWING TODAY. SO IN TERMS OF PROBABILITY OF INFECTION AT HOUSEHOLD LEVEL, SO WE SAW 10% OF THE HOUSEHOLDS REPORTED AN INFECTION BUT AS RELATED TO THIS, WE KNOW THESE NUMBERS IS AN OVERESTIMATE NOT THE LEAST OF WHICH IS BECAUSE THERE WAS A LOT OF DROPOUT IN THE STUDY. AND SO INSTEAD WE MODELED THE PROBABILITY OF INFECTION WITH THE KAPLAN-MEIER TIME TO EVENT ANALYSIS AND WHEN WE DO THIS, WE SEE THAT THE PROBABILITY THAT A HOUSEHOLD BECOMES INFECTED IS ABOUT 26%. SO QUITE A BIG NUMBER ACROSS THIS EARLY PANDEMIC TIME PERIOD. SO THEN WE WANTED TO LOOK AT WHAT ARE THE HOUSEHOLD EXPOSURES THAT ARE ASSOCIATED WITH INTRODUCTION OF THE VIRUS INTO A HOUSEHOLD? AND SO HEROES COLLECTED SELF REPORTS OF A VARIETY OF DIFFERENT EXPOSURES OF WHICH I'M SHOWING YOU. THE PERCENTAGE OF HOUSEHOLDS THAT REPORTED ONE OF THESE EXPOSURES AT LEAST WENT ACROSS STUDY TIME. AND AS EXPECTED, MOST HOUSEHOLDS EXPERIENCE MANY OF THESE EXPOSURES AT LEAST ONCE AND YOU'RE PROBABLY MOST INTERESTED IN THESE THREE WHETHER THERE WAS A PERSON IN THE HOUSEHOLD THAT HAD IN-PERSON WORK -INE-PERSON SCHOOL OR DAY CARE. AND YOU CAN SEE THAT NUMBER WAS 80% FOR WORK, 46% FOR SCHOOL, 19% FOR DAY CARE. AGAIN, THIS IS JUST THE PERCENTAGE OF HOUSEHOLDS THAT REPORTED THIS AT ANY ONE POINT IN TIME. NOW IF WE LOOK AT THE AVERAGE PERCENTAGE OF HOUSEHOLDS EXPERIENCING THIS EXPOSURE ACROSS TIME, WE CAN SEE IT HOVERED AROUND 60% FOR WORK. AND ONCE SCHOOL BEGAN, IT HOVERED AROUND 30% FOR SCHOOL, WITH THE NUMBER AROUND 10% FOR DAY CARE. AND SO WITH THIS INFORMATION THEN WE GET TIME TO INFECTION EXTENDED COX REGRESSION ANALYSIS TO LOOK AT THE RELATIONSHIP BETWEEN EXPOSURES AND HOUSEHOLDS BECOMING INFECTED. THE MOST SIGNIFICANT THEY THINK WE SAW WAS THAT IN-PERSON SCHOOL WAS ASSOCIATED WITH RISK OF THE HOUSE HOLD BECOMING INFECTED. IN FACT, HOUSEHOLDS THAT HAD AT LEAST ONE MEMBER ATTENDING IN-PERSON SCHOOL HAD A 67% INCREASE RISK OF BECOMING INFECTED. YOU CAN SEE THE CONFIDENCE INTERVAL AND ESTIMATE FOR WORK, IT WAS TRENDING TOWARDS THE ASSOCIATION WITH RISK BUT DIDN'T QUITE REACH SIGNIFICANCE AND THE OTHER FACTORS, INCLUDING DAY CARE WERE REALLY NOT ASSOCIATED WITH THE HOUSEHOLDS BECOMING INFECTED. SO WE NEXT WANTED TO LOOK AT THE FAMILY CHARACTERISTICS THAT WERE ASSOCIATED WITH THE INTRODUCTION OF SARS-COV-2 INTO THEIR HOUSEHOLD. SOME OF THE FACTORS WE LOOKED AT WERE THE RACE AND ETHNICITY OF THE HOUSE HOLD, WHETHER A SMOKER, AND THEN IMPORTANTLY WE WANTED TO SEE IF THERE WAS AGE EFFECTS SO WE LOOKED AT THE AVERAGE AGE OF THE CAREGIVERS AND THE AVERAGE AGE OF THE CHILDREN. AND ONE THING I WANT TO NOTE, AND IT'S IMPORTANT THROUGHOUT THE STUDY, IS THAT THERE WAS A DEFINITE STRATIFICATION IN TERMS OF AGE GROUP DISTRIBUTION OF CHILDREN ACROSS THE HOUSEHOLD. SO MOST OF THE HOUSEHOLDS EITHER HAD CHILDREN THAT WERE YOUNGER THAN 13 YEARS OF AGE OR OLDER THAN 13 YEARS OF AGE AND FEW HOUSEHOLDS HAD A MIX OF THOSE TWO AGE GROUPS. SO WHEN WE RAN THESE ANALYSIS, WE FOUND SIMILAR TO THE INDIVIDUAL LEVEL ANALYSIS THAT IS MINORITY, RACE AND ETHNICITY HOUSEHOLDS WERE AT 52% HIGHER RISK OF BECOMING INFECTED COMPARED TO WHITE NON-HISPANIC HOUSEHOLDS. AND THEN WE ALSO SAW A REALLY STRONG AGE ASSOCIATION. WE SAW THIS FOR BOTH CAREGIVERS AND CHILDREN. WE FOUND THAT THERE WAS A 15% INCREASE RISK OF INFECTION FOR EVERY 5-YEAR DECREASE IN THE AVERAGE AGE OF THE CAREGIVER. SO YOUNGER CAREGIVER HOUSEHOLDS WERE AT HIGHER RISK. WE ALSO SAW THAT THE HOUSEHOLDS THAT HAD OLDER KIDS WERE AT HIGHER RISK FOR INFECTION. WE SAW 7% INCREASE INFECTION RISK FOR EVERY YEAR INCREASE IN THE AVERAGE AGE OF THE CHILDREN. SO WE MIGHT SPECULATE HERE THAT THE YOUNGER CAREGIVERS AS THE OLDER CHILDREN HAD MORE REASONS TO EXIT THE HOUSEHOLD, MAYBE THE YOUNGER CAREGIVERS TO ATTEND IN-PERSON WORK, AND THE OLDER KIDS POTENTIALLY HAD MORE OUTSIDE ACTIVITIES THAT THEY WERE ATTENDING THAT PUT THEM AND THEIR HOUSEHOLDS AT HIGHER RISK. SO NOW I'M GOING TO MOVE ON AND SHOW YOU SOME OF THE HOUSEHOLD TRANSMISSION DATA. AND SO WHEN WE LOOKED AT HOUSEHOLD TRANSMISSION, WE REALLY HAD 146 FAMILIES WE COULD EVALUATE. AND WHEN YOU TALK ABOUT WHETHE THERE IS A TRANSMISSION OR NOT, IT'S VERY CLEAR TO SEE HOUSEHOLDS THAT THERE WAS NOT A TRANSMISSION. AND THOSE ARE THE HOUSEHOLDS WITH THE SINGLE INFECTED FAMILY MEMBER. AND THEN WE ASSUMED THE HOUSEHOLDS THAT HAVE MORE THAN ONE INFECT THE FAMILY MEMBER, THERE WAS LIKELY A TRANSMISSION EVENT. NOW, THE EVENT WE MIGHT HOPE TO CAPTURE IS THESE CLEAR TRANSMISSIONS WHERE WE HAVE A SINGLE PERSON INFECTED, INDEX CASE THAT THEN PASSES THE INFECTION ON TO ANOTHER FAMILY MEMBER. BUT IN REALITY, IN HEROES, WE SAW IN MANY CASES, WHEN WE FIRST DETECTED THE INFECTION IN THE FAMILY, THERE WERE ALREADY MULTIPLE MEMBERS INFECTED. AND THIS IS, WE BELIEVE BECAUSE OF TRANSMISSION TIME IT'S MUCH SHORTER THAN THE STUDY SAMPLING TIME THAT WE HAD IN HEROES WHICH WAS EVERY TWO WEEKS. AND SO WE MAKE AN ASSUMPTION GOING FORWARD THAT IF THERE IS MORE THAN ONE INFECTED MEMBER IN A HOUSEHOLD THAT THERE WAS A LIKELY HOUSEHOLD TRANSMISSION EVENT. AND SO WE MODELED THE PROBABILITY OF TRANSMISSION AGAIN WITH THE TIME TO TRANSMISSION KAPLAN-MEIER ANALYSIS AND WHEN WE DO THAT, WE GET A TRANSMISSION PROBABILITY OF 56%. SO HERE THE DENOMINATOR IS THE NUMBER OF INFECTED HOUSEHOLDS. AND THEN IF WE LOOK AT THE SUBJECT LEVEL, WE SEE THE PROBABILITY OF TRANSMISSION IS 41%. HERE THE DENOMINATOR IS NUMBER OF SUSCEPTIBLE INDIVIDUALS IN THOSE INFECTED HOUSEHOLDS. SO YOU SEE THERE IS A VERY HIGH LIKELIHOOD THAT THE VIRUS WILL BE TRANSMITTED ONCE IT ENTERS THE HOUSEHOLD. SO YOU MIGHT BE ASKING HOW QUICKLY DOES THIS TRANSMISSION OCCUR? AS I MENTIONED BEFORE, MOST OF THE HOUSEHOLDS THAT WE FOUND INFECTIONS IN, THERE WERE MULTIPLE PEOPLE INFECTED WHEN WE FIRST SAW THE HOUSEHOLD WAS INFECTED. SO CONCURRENT INFECTIONS CONTRIBUTED TO 25% OF THE RISK OF THE HOUSE HOLD TRANSMISSION. WE THEN SAW ANOTHER 11% PROBABILITY OF TRANSMISSION OCCURRING OVER THE NEXT 14 DAYS. AND THEN BEYOND 14 DAYS, WE SAW VERY MINIMAL RISK LOOKING TOUT 50 DAYS IN ANOTHER TRANSMISSION OCCURRING IN THE HOUSEHOLD. SO NOT ONLY ARE THE TRANSMISSION OCCURRING AT A HIGH RATE IN THE HOUSEHOLD, THEY ARE OCCURRING VERY QUICKLY. SO WE NEXT WANTED TO LOOK AT WHAT ARE THE HOUSEHOLD CHARACTERISTICS THAT ARE ASSOCIATED WITH THE HOUSEHOLD TRANSMISSION OF SARS-COV-2? HOUSEHOLDS THAT WERE NON TRANSMITTING OVER A SINGLE INFECTION VERSUS THE TRANSMITTING HOUSEHOLD. AND WE LOOKED AT THE SAME CHARACTERISTICS. WE LOOKED AT THE HOUSEHOLD INFECTION, AVERAGE AGE, RACE, ETHNICITY AND OTHER FACTORS. AND HERE I'M SHOWING YOU THE ODDS RATIOS FOR THE DIFFERENT FACTORS. AND IT BOILS DOWN TO THE MOST STRONG ASSOCIATION THAT WE OBSERVED IN TERMS OF THE HOUSE HOLD CHARACTERISTICS WAS THAT HOUSEHOLDS WITH OLDER CHILDREN ARE LESS LIKELY TO HAVE A HOUSEHOLD TRANSMISSION. IN FACT, WE SEE A 21% DECREASE IN ODDS OF TRANSMISSION FOR EVERY YEAR INCREASE IN THE AVERAGE AGE OF THE CHILDREN IN THAT HOUSEHOLD. AND IF YOU REMEMBER, THE AGE GROUPS WITHIN THE HOUSEHOLDS ARE VERY STRATIFIED BETWEEN YOUNGER KIDS, TEENAGERS. SO YOU MIGHT BE WONDERING HOW MUCH THIS IS DRIVEN BY THOSE DIFFERENT AGE GROUPS. AND YOU MIGHT ASSUME AGAIN THAT THE INTERACTION BETWEEN CHILDREN OF DIFFERENT AGE GROUPS MIGHT INFLUENCE THIS TRANSMISSION RISK. AND SO WHEN WE STRATIFY HOUSEHOLD STATES ON WHETHER THEY DO OR DO NOT HAVE A TEENAGER, WE SEE HOUSEHOLDS WITH TEENAGERS ARE AT MUCH LOWER RISK OF TRANSMISSION. AND THIS BRINGS US THE QUESTION OF WHETHER THE TEENS ARE ACTUALLY THE INFECTED SUBJECTS THAT ARE NOT TRANSMITTING. AND AGAIN WHETHER THIS NON TRANSMISSION IS DUE TO LESS HOUSEHOLD INTERACTIONS BETWEEN THE TEENS AND THE OTHER HOUSEHOLD MEMBERS. IF WE BELIEVE THAT, THEN WE MIGHT ALSO ASSUME THAT VERY YOUNG CHILDREN WOULD HAVE INCREASED HOUSEHOLDS WITH THOSE YOUNG CHILDREN WOULD HAVE INCREASED RISK OF TRANSMISSION. AND THAT IS EXACTLY WHAT WE SEE. IF WE STRATIFY HOUSEHOLDS BASED ON ONES THAT HAVE CHILDREN THAT ARE UNDER THE AGE OF FIVE WORKSY SEE THOSE HOUSEHOLDS ARE AT MUCH HIGHER RISK OF HAVING A HOUSEHOLD TRANSMISSION. SO WE NEXT WANTED TO LOOK AT SUBJECT-LEVEL RISK FACTORS THAT ARE ASSOCIATED WITH A SARS-COV-2 HOUSEHOLD TRANSMISSION. AND OF COURSE WE'D LIKE TO DO AN INDEX CASE ANALYSIS, CHARACTERISTICS OF THE INDEX THAT ARE ASSOCIATED WITH TRANSMISSION BUT AGAIN, AS I MENTIONED IN MOST CASES WHERE THERE WAS A TRANSMISSION, THE INDEX CASE IS UNCLEAR. BUT WHAT IS CLEAR IS WHO THE NON TRANSMITTER IS IN THESE NON TRANSMITTING HOUSEHOLDS SINCE THEY ARE THE ONLY INFECTED INDIVIDUALS. SO WE TRIED TO DO AN ANALYSIS COMPARING NON TRANSMITTERS TO ALL POSSIBLE TRANSMITTERS THAT IS INFECTED INDIVIDUALS WITHIN TRANSMITTING HOUSEHOLDS. AND SO WE LOOKED AT SUBJECT-LEVEL CHARACTERISTICS IN THIS ASSOCIATION ANALYSIS SUBJECT HEALTH CHARACTERISTICS AND THEN ALSO CHARACTERISTICS OF THE INFECTION ITSELF. AND THE FACTORS WE SAW MOST ASSOCIATED WITH NON TRANSMITTERS IS FIRST WEIGHT. SO LANE INDIVIDUALS WERE 55% MORE LIKELY TO BE NON TRANSMITTERS AS COMPARED TO OVERWEIGHT OR OBESE SUBJECTS. AND THEN WE SAW THE AGE ASSOCIATION WE FIGURED MIGHT BE THERE. TEENAGERS ARE MORE LIKELY TO BE NON TRANSMITTERS COMPARED TO EITHER CHILDREN, YOUNGER CHILDREN OR ADULTS. THEY ARE SIX TIMES MORE LIKELY TO BE NON TRANSMITTERS THAN KIDS AND 3.5 TIMES MORE LIKELY TO BE NON TRANSMITTERS COMPARED TO ADULTS. THEN WE WANTED TO LOOK AT WHAT ARE THE CHARACTERISTICS OF THE INFECTION THAT ARE ASSOCIATED WITH NON TRANSMISSION. SO YOU MIGHT ASYL SYMPTOMS AND VIRAL LOAD COULD BE ASSOCIATED. SO WHEN WE TESTED SYMPTOMS AND THIS IS CORRECTED FOR VIRAL LOAD, WE FOUND A TREND BUT FAILURE TO REACH SIGNIFICANCE FOR SYMPTOMS. IT WAS IN THE DIRECTION WE EXPECTED, LESS SYMPTOMS MORE LIKELY TO BE A NON TRANSMITTER. WHAT WE DID FIND TO BE ASSOCIATED IS VIRAL LOAD. AND YOU CAN SEE THE VIRAL LOAD AND POSSIBLE TRANSMITTERS IS MUCH HIGHER THAN IN NON TRANSMITTERS. WE FIND A 14% INCREASE IN THE CHANCE OF BEING A NON-TRANSMITTER FOR EVERY 10-FOLD INCREASE IN VIRAL LOAD. SO PROBABLY A LOT OF THIS TRANSMISSION IS RELATED TO WHETHER AN INFECTION IS SYMPTOMATIC OR NOT. WE WANTED TO LOOK AT RISK FACTORS FOR SYMPTOMATIC VERSUS ASYMPTOMATIC INFECTIONS. AND SO AS YOU HEARD, THIS IS UNIQUE IN PERSPECTIVE, IT HAS REGULAR SAMPLING, EVERY TWO WEEKS REGARDLESS OF SYMPTOMS AND THERE IS ALSO A DETAILED SYMPTOM QUESTIONNAIRE THAT FILLS OUT WEEKLY BY ALL PARTICIPANTS. SO WE HAVE TWO ASPECTS WE NEED, REGULAR SAMPLING AND THEN SEMP REPORT OF SYMPTOMS TO TRY TO JUDGE THIS. AND THEY ARE VERY EXTENSIVE SYMPTOM DATA THAT IS COLLECTED. EVERYTHING YOU WOULD EXPECT WITH THE VIRAL ILLNESS, INCLUDING THINGS THAT YOU COULD HAVE REGARDLESS OF WHETHER YOU'RE SICK WITH SARS-COV-2, LIKE HEADACHES AND BODY ACHES. WE WANTED TO BE PRETTY CONSERVATIVE BEFORE WE CALLED AN INFECTION EVENT TRULY ASYMPTOMATIC. SO WE FIRST HAD TO DELINEATE THE FULL RANGE OF THE INFECTION EVENT AND LOOK AT SYMPTOMS ACROSS THAT RANGE. FOR US, THAT WAS OF COURSE THE ENTIRE TIME PERIOD THE SUBJECTS TESTED POSITIVE, INCLUDING TWO WEEKS UPSTREAM OF THE FIRST POSITIVE AND DOWNSTREAM OF THE LAST POSITIVE. THEN WE ALSO WANTED TO HAVE A VERY HIGH LEVEL OF COMPLETE INNOCENCE THEIR SYMPTOM SURVEYS BEFORE WE CALLED THEM ASYMPTOMATIC. WE SET THAT NUMBER AT 25% COMPLETENESS. SO THIS GAVE US 151 INFECTION EVENTS THAT WE HAD REASONABLE COMPLETENESS IN SYMPTOM SURVEY DATA. AND WHEN WE LOOKED AT IT, WE FOUND OVER HALF OF ALL OF THE INFECTIONS WERE ASYMPTOMATIC. 55%. QUITE A HIGH NUMBER. SO THIS BRINGS UP WHAT FACTORS ARE ASSOCIATED WITH THIS RATE OF ASYMPTOMATIC ILLNESS. AND THE FACTOR THAT IS MOST STRONGLY ASSOCIATED IS AGE GROUP. WHEN WE LOOKED AT KIDS UNDER THE AGE OF 13, TEENAGERS VERSUS ADULTS WORKSY SAW THIS STEP-WIDE INCREASE IN THE PROPORTION OF INFECTIONS THAT WERE SYMPTOMATIC. ONLY 25% OF INFECTIONS WERE SIMPLE MAT NICK KIDS, 41% IN TEENAGERS AND ALMOST 63% OF THE INFECTIONS IN ADULTS WERE SYMPTOMATIC. THIS GIVES US AN ODDS RATIO FOR ASYMPTOMATIC ILLNESS IN TEENAGERS VERSUS CHILDREN OF ALMOST 3 AND ALMOST 6.5 FOR ADULTS COMPARED TO KIDS. NOW THIS BRINGS UP ANOTHER QUESTION, WHICH IS, HOW THE VIRAL LOAD RELATES TO THIS. AND WE FOUND THAT VIRAL LOAD WAS STRONGLY ASSOCIATED WITH WHETHER AN INFECTION WAS SYMPTOMATIC. IN FACT, WE FOUND FOR EVERY 10-FOLD INCREASE IN VIRAL LOAD, THE ODDS OF SYMPTOMS INCREASED BY 30%. YOU CAN SEE THAT BY THIS PLOT SHOWING THE VIRAL LOAD IS MUCH HIGHER IN THE SYMPTOMATIC INDIVIDUALS. BUT THIS RAISES A VERY INTERESTING QUESTION THAT WE HAVE ALREADY SHOWN YOU THAT CHILDREN ARE MUCH LESS LIKELY TO BE SYMPTOMATIC BECAUSE OF THIS ASSOCIATION WE MIGHT ASSUME THEIR VIRAL LOADS ARE ALSO LOWER LOWER. AND SO HERE I'M SHOWING YOU THE VIRAL LOAD DISTRIBUTION IN ASYMPTOMATIC ILLNESSES, STRATIFIED BY CHILDREN, TEENS AND ADULTS. ALL AGE GROUPS EXHIBIT A VERY SIMILAR VIRAL LOAD DISTRIBUTION SKEWED TOWARDS LOWER VIRAL LOAD WHEN THEY ARE ASYMPTOMATIC. HOWEVER, IF WE OVERLAY HERE THE VIRAL LOAD DISTRIBUTION IN THE AGE GROUP IN SYMPTOMATIC ILLNESSES, YOU CAN SEE BOTH THE TEENS AND THE ADULTS HAVE MUCH HIGHER VIRAL LOAD ON AVERAGE WITH THEIR SYMPTOMATIC ILLNESSES THAN THEIR ASYMPTOMATIC. WHEREAS THERE IS LARGE OVERLAP IN THE VIRAL LOAD DISTRIBUTION AMONG KIDS BETWEEN THEIR SYMPTOMATIC AND ASYMPTOMATIC ILLNESSES. YOU CAN MAYBE PERHAPS SEE THIS MORE CLEARLY IF WE PLOT VIRAL LOADS ACROSS THE AVERAGE RANGE AND YOU CAN SEE IN THAT AGE RANGE FROM 0-13 THERE IS VERY STRONG OVERLAP IN VIRAL LOAD BETWEEN SYMPTOMATIC AND ASYMPTOMATIC ILLNESSES BUT AT THE AGE OF THE INFECTED INDIVIDUAL INCREASES THERE IS AN INCREASE IN THE VIRAL LOAD THAT WE SEE WITH SYMPTOMATIC VERSUS THE ASYMPTOMATIC ILLNESSES. AND THIS IS PERHAPS SEEN MOST STARKLY IF WE LOOK AT THE RISK OF HAVING ASYMPTOMATIC INFECTION VERSUS THE VIRAL LOAD STRATIFIED BY THE AGE GROUPS. YOU CAN SEE THAT BOTH TEENS AND ADULTS HAVE THIS DRAMATIC INCREASE AND RISK OF ASYMPTOMATIC ILLNESS AS VIRAL LOAD INCREASES. WHEN WE LOOK AT CHILDREN THERE IS NO RELATIONSHIP BETWEEN VIRAL LOAD AND ODDS OF SYMPTOMS. SO THIS BRINGS US THE IDEA THAT CHILDREN CAN TOLERATE A MUCH HIGHER VIRAL LOAD WITHOUT BECOMING SYMPTOMATIC. AND SO TO CONCLUDE WHAT WE SEEN THUS FAR IN HEROES, FIRST WE SEE HOUSEHOLDS THAT ARE HIGHEST RISK OF INFECTION ARE MINORITY HOUSEHOLDS, ONES WITH YOUNGER CAREGIVERS, OLDER CHILDREN PERHAPS THROUGH INCREASED OUTSIDE INTERACTIONS, AND THAT HOUSEHOLDS WITH A MEMBER ATTENDING IN-PERSON SCHOOL ARE AT HIGH RISK FOR BECOMING INFECTED AS WELL. WE SEE ONCE THE HOUSEHOLD BECOMES INFECTED, THE HOUSEHOLD AND SUBJECT LEVEL, THERE IS A VERY HIGH RISK THAT THE INFECTION WILL BE TRANSMITTED TO OTHER INDIVIDUALS AND THIS TRANSMISSION RISK IS VERY HIGH AT START OF INFECTION AND WAYNES QUICKLY. IN TERMS OF HOUSEHOLD TRANSMISSION WE SEE THAT IT IS HIGHLY RELATED TO AGE OF CHILDREN. IF THERE IS YOUNGER KIDS IN THE HOUSEHOLD, THERE IS LIKELY TO BE A TRANSMISSION EVENT. OLDER KIDS, TEENAGERS, THERE IS LOWER RISK. THE TEENAGERS THEMSELVES ARE MORE FREQUENTLY NON TRANSMITTERS THAN WE FIND THAT VIRAL LOAD IS MORE IMPORTANT THAN SYMPTOMS IN TERMS OF TRANSMISSION RISK. WE ALSO SEE IN HOUSEHOLDS WITH YOUNG KIDS LIKE HEROES, THERE IS A VERY HIGH RATE OF INFECTIONS THAT ARE ASYMPTOMATIC AND THIS IS DRIVEN BY THE FACT THAT CHILDREN ARE SO MUCH MORE LIKELY TO HAVE ASYMPTOMATIC ILLNESS. WE SEE VIRAL LOAD IS VERY RELATED TO THE PRESENCE OF SYMPTOMS IN BOTH TEENS AND ADULTS SO WE SEE A BREAKDOWN IN THAT RELATIONSHIP WITHIN CHILDREN. SO IN THERE, AGAIN, I'LL THANK THE AMAZING HEROES TEAM, INCLUDING AT NIAID AND THEN ALL OF THE INVESTIGATORS, TINA, EVERYONE IN OUR TEAM. I REALLY WANT TO GIVE A LOT OF THANKS TO THE LABORATORY TEAM THAT TURNED OUR LAB UPSIDE DOWN TO PROCESS THESE SAMPLES, PLAC AND CAMILLE, WHO BLAKE HANDLED ALL THE DATA IN THE LAB AND CAMILLE HAS BEEN LEADING THE ANALYSIS WITH OUR GROUP AND WE ARE JUST REALLY EXCITED TO BE A PART OF THIS AND TO GET THESE RESULTS OUT. SO TINA AND I CAN TAKE QUESTIONS NOW. THANK YOU. >> SO HOW FAR ARE YOU ALONG IN ANALYZING THE LABORATORY DATA? I SAW YOU MENTIONED IGE. HAVE YOU DONE THAT AND MEASURED SARS-COV-2 SPECIFIC IGE? WHICH YOU DON'T REALLY SEE ANYBODY MEASURE. >> SO, THE SPECIFIC IGE WE ARE DOING A PILOT RIGHT NOW WITH THE COMMERCIAL LAB WHO WILL RUN THAT ISAC CHIP. WE SENT THE SAMPLES LAST TUESDAY. WE EXPECT TO GET THE DATA BACK FROM THEM TODAY TO CONFIRM THAT WE'LL GET VALID RESULTS ON THE RELATIVELY SMALL CAP LARRY PLASMA SAMPLES THAT WE HAVE REMAINING AND THEN ALL THOSE SAMPLES WILL BE SHIFT IF THE DATA FROM THAT PILOT LOOKS GOOD. IT WILL BE MONTHS BEFORE WE HAVE THAT DATA. AND WE ARE NOT MEASURING SARS-COV-2 IGE. >> I HAVE A QUESTION. SO I HEARD TWO THINGS. ONE IS THE YOUNGER KIDS OBVIOUSLY ARE UNAFFECTED BY VIRAL LOAD YET THE HOUSEHOLDS WITH YOUNGER KIDS ARE MORE LIKELY TO BE INFECTED. SO I GUESS FROM MY -- I'M ASSUMING THEN THAT MEANS THAT YOUNGER KIDS ARE STILL JUST AS LIKELY TO PASS ON THE VIRUS AS ANYONE ELSE. IS THAT ACCURATE? >> YES, SO IT'S DIFFICULT TO SAY WHO IS PASSING HERE. BUT IT APPEARS THAT THERE IS A PAIR -- LIKELY CAREGIVER/CHILD IN THESE TRANSMISSION EVENTS. WE MIGHT ASSUME THAT THE INFECTION IS BEING BROUGHT IN BY THE CAREGIVERS AND THEN EASILY PASSED TO THE CHILD. REGARDLESS OF WHETHER THEY ARE HAVING SYMPTOMS. WE ARE ABLE TO SEE ALL OF THAT SINCE WE ARE SCREENING FOR INFECTION REGARDLESS OF SYMPTOMS. BUT IT'S DIFFICULT. WE COULDN'T DO A FORMAL INDEX ANALYSIS AND SEE WHO THE ACTUAL TRANSMITTERS ARE. THAT'S MY SPECULATION. >> OKAY. THAT IS GOOD TO KNOW. BECAUSE IT'S JUST HARD TO KIND OF MAKE THAT ASSUMPTION. I AGREE WITH YOU. BUT IT'S HARD TO SAY WITH CERTAINTY WHETHER OR NOT THERE IS A RISK IN THE SCHOOL SETTING SINCE KIDS ARE BEING SENT BACK TO SCHOOL AND THEY ARE ALSO BEING -- THE SPACE AROUND THEM IS ALSO BEING LESS THAN THREE FEET. THERE ARE LOTS OF DIFFERENT THINGS THAT AS PARENTS WE THINK ABOUT WHEN WE ARE ASSESSING THAT RISK. SO I WONDERED IF YOU HAD ANY THOUGHTS THERE. >> WELL, I THINK THERE IS SUCH A GREAT OPPORTUNITY WITH KIDS LACKING SYMPTOMS THAT THEY CAN BE INVOLVED IN THESE TRANSMISSION EVENTS. ALREADY, THERE IS A PRO PESTY FOR A CAREGIVER TO INTERACT WITH A YOUNG CHILD AND THEN IF THEY HEAR THAT THEY ARE NOT SICK, THEN YOU'LL DEFINITELY PROBABLY HAVE YOUR GUARD DOWN AS OPPOSED TO SOMEONE IS COUGHING AND SNEEZING AND SUSPECTED ILL, YOU AVOID THEM. SO I THINK THEY ARE VERY KEY COG IN TRANSMISSION OF THESE HOUSEHOLDS. THAT WOULD BE MY TAKE. >> THANKS. >> I HAVE A QUESTION. TINA, MAX, REALLY ENJOYED YOUR PRESENTATIONS. THIS INTERESTING ASSOCIATION BETWEEN OBESITY AND INCIDENCE OF INFECTION AS WELL AS SEVERITY OF INFECTION. DO YOU SEE THAT ALSO IN YOUR STUDY IN KIDS? AND CAN YOU COMMENT ON WHAT IS KNOWN CURRENTLY? IS IT DUE TO SOME LIPID -- LDL OR CHOLESTEROL OR ANYTHING THAT REALLY ENHANCES THE INFECTIVITY? >> SO IT'S ADULTS AND CHILDREN. THIS WAS NOT JUST OBESITY INCREASES WITH AGE. BUT THIS WAS SEEN INDEPENDENT OF AGE AND THERE WAS A VERY STRONG WEIGHT DEPENDENT OR DOSE DEPENDENT RELATIONSHIP, WHICH EVEN FURTHER STRENGTHENS THE FINDINGS. WE DON'T KNOW. ULTIMATELY WHAT I PRESENTED WAS REALLY PURELY SPECULATION OR THINGS THAT WE KNOW FOR OTHER VIRUSES, WHICH IS THAT NEUTROPHILIC INFLAMMATION DOES ENHANCE ESTABLISHMENT OF INFECTION IN INOCULATION WE KNOW THIS FOR ADENOVIRUS AND RSV. THE THOUGHT IS THAT PERHAPS, AND IT'S BEEN SHOWN WITH RSV THAT NEUTROPHILIC INFLAMMATION IMPACTS TYPE 17 RESPONSES, WHICH COULD BLUNT OR EVEN ABORT THE INITIAL VIRAL INFECTION. BUT IT'S SOMETHING WE'LL BE ABLE TO FIND OUT BECAUSE WHAT IS UNIQUE ABOUT THIS STUDY IS WE ALL HAVE THE BIOLOGY OF THE AIRWAY PRIOR TO THE ESTABLISHMENT OF INFECTION SO WE'LL BE ABLE TO LOOK AT GENE EXPRESSION OF THE IMMUNE CELLS IN THE AIRWAY AS WELL AMONG OBESE AND NON-OBESE INDIVIDUALS. SO PURELY SPECULATION IN TERMS OF ANSWERING YOUR QUESTION BUT HOPEFULLY WE'LL BE ABLE TO ANSWER IT IN PART. >> THANK YOU. >> PERHAPS WE COULD GO BACK TO MARK'S QUESTION. AND MARK, DID YOU HAVE ANYTHING PARTICULAR IN MIND WITH IGE OR ISOTOPE-SPECIFIC RESPONSES TO THE VIRUS? MANY PEOPLE ON THE SESSION TODAY KNOW THERE IS A KIND OF LONG HISTORY, A BIT PATCHY ABOUT A TOPIC INDIVIDUALS HAVING IGE OR TYPE II RESPONSES TO SOME INFECTIOUS AGENTS OR TO CERTAIN VACCINES LIKE PERTUSSIS OR TETANUS? DICK AIDS OLD HISTORY AND I'M WONDERING MARK, HAVE YOU -- DECADES OLD HISTORY -- DO YOU HAVE A HYPOTHESIS ABOUT THIS THAT WOULD SUBSTANTIATE OUR DOING THE WORK AND ADDRESSING THE COST OF DOING THOSE ANALYSIS? WE CERTAINLY HAVE LOTS OF SERUM TO DO IT. BUT WHAT DID YOU HAVE IN MIND? >> THAT IS EXACTLY WHAT I HAD IN MIND. BASICALLY, DO THOSE PEOPLE EXIST AND DO THEY CONSISTENTLY MAKE MORE IGE THAN OTHER PEOPLE? IT JUST SEEMED LIKE GIVEN THE HUGE NUMBER OF SAMPLES AND EVERYONE HAS GOT A SPIKE-SPECIFIC GOING -- THIS COULD BE DONE NOW. I'M NOT SURE WHAT WOULD MEAN ONE WAY OR THE OTHER BUT IT WOULD KIND OF TIE INTO THE -- INTO THE -- I'M IMPRESSED BY CASANOVA'S DISCOVERY THAT AT LEAST 30% OF PEOPLE WHO GOT REALLY NASTY INFECTIONS ARE TYPE I INTERFERON TYPO MOREOVERS IN SOME PART OF THE PATHWAY. SO IT JUST SEEMS LIKE THIS IS AN INTERESTING HEW AMONG USUALLY-SCALED HUMAN IMMUNOLOGY EXPERIMENT TO LOOK FOR GENETIC VARIATION IN HUMAN IMMUNITY. AND SO I'M RAMBLING THERE BUT IT JUST SEEMED LIKE A GOOD CHANCE TO LOOK FOR -- A MICROBE SPECIFIC IGE RESPONSE IN A SETTING YOU MIGHT NOT EXPECT IT. ALONG THOSE LINES, I THINK THOSE FEW PEOPLE WHO HAD GOT REINFECTED ARE INTERESTING CANDIDATES TO HAVE THEIR EXOME SEQUENCED OR START LOOKING AT PEOPLE WHO IN THE -- ALSO THE PEOPLE WHO ARE BREAKING THROUGH AND GETTING A BREAK FROM INFECTION AFTER VACCINATION. I THINK THESE ARE INTERESTING PEOPLE TO LOOK FOR GENES INVOLVED IN HUMAN IMMUNITY. >> YES, FOR SURE. AND TINA, YOU MAY WANT TO COMMENT ON THIS, BUT AS I RECALL, AS WE WERE PUTTING THE STUDY TOGETHER, MANY IF NOT MOST OF THE INDEXED PARTICIPANTS, THAT IS ASTHMATIC CHILDREN OR ATOPIC CHILDREN, ALREADY HAD BEEN SEQUENCED THROUGH THEIR PARTICIPATION IN OTHER NIAID OR NIH-SPONSORED STUDIES. SO WE MAY ALREADY HAVE A GOOD HEAD START ON THAT. >> WOW. >> RIGHT. THAT IS THE CASE. AND MANY OF THESE PARTICIPATE IN ECHO. THERE -- ECHO GENOTYPE OF OF THESE COHORTS. AND WE HAVE FULL EXOME SEQUENCING OF OUR COHORT IT'S ALREADY BEEN COMPLETED. >> THE OTHER THING IS, WE WILL RNA-SEQ DEFINITELY EVERYONE INFECTED AND WE CAN CALL GENETIC VARIANTS FROM THE RNA-SEQ, AT LEAST CODING ONES, WHICH I THINK THE VARIANCE REFERRING TO ARE CODING VARIANCE. >> YES, I THINK -- I'M NOT SURE. MAYBE THE ONES IN CASANOVA STUDY AND THE INTERFERE ON PATHWAY WERE ENCODING SEQUENCES, YES. >> BUT AT THE SAME TIME, MARK, YOU MUST HAVE AS TINA MENTIONED, THERE IS AN INTERESTING RELATIONSHIP, MANY STUDIES INCLUDING OUR OWN WITH US -- ADULTS, NO THE CHILDREN, LAST YEAR THAT AGAIN WITH THE LOW TYPE II, YOU SEE THIS INVERSE CORRELATION BETWEEN AIR EPITHELIAL, THAT'S WE STUDIED -- THE RELATIONSHIP AND WITH TYPE I OR TYPE II INTERFERONS YOU HAVE A VERY HIGH EXPRESSION DIRECT RELATIONSHIP. AND THEN YOU HAVE THE CORRESPONDING GENE SIGNATURES IN THE EPITHELIAL CELLS. SO ON ONE HAND THE INTERFERON RESPONSE, RF7, 3, THAT'S WHAT CASANOVA STUDY SHOWS -- PUT YOU AT HIGH RISK, LESS PROTECTION BUT AT THE SAME TIME A HIGHER INTERFERON RESPONSE WILL ALSO ENHANCE INFECTION. THAT'S THE QUESTION ALSO MANY PEOPLE ARE SEEKING TO ANSWER, HOW WILL IT GO? >> SO GWEN, HU YOUR HAND RAISED. >> YES, MY QUESTION IS A LITTLE BIT MORE RELATED TO THE EARLIER QUESTIONS FROM DR. RAY. BUT I WANTED A CLARIFICATION ON USING THE WORD OBESITY. BUT THE BMI DATE YOU PRESENTED ACTUALLY SHOWED A FUNNY CURVE WHERE WHEN YOU HIT 80 PERCENTILE IT REALLY SPIKED UP. BUT IT ACTUALLY WENT DOWN AGAIN WHEN YOU HIT LIKE WHAT LOOKED LIKE 99%, WHICH IN MY UNDERSTANDING, AT LEAST IN THE CHILDHOOD CHART, THAT IS WHEN YOU REALLY HIT THE DEFINITION OF OBESITY. OR MAYBE BEYOND 95. BUT IT REALLY LOOKED LIKE IT WAS THE CURVE WAS SHAPED IN A WAY THAT OBESITY DIDN'T NECESSARILY BE THE RIGHT WORD. BUT I MIGHT AGREE THAT OVERWEIGHT IS THE RIGHT WORD. AND I LIKE A CLARIFICATION ON IT BECAUSE THE WAY ONE THINKS ABOUT IT, ESPECIALLY IF THERE IS A NUMBER OF LABORATORIES DOING STUDIES ON THE EFFECT OF NOT EATING DURING -- IS THERE A REAL REASON WHY PEOPLE LOSE THEIR APPETITES DURING SICKNESS? IS THERE A LOT OF STUDIES GOING ON THAT IS LINKED TO THE PROGRESSION OF INFECTION. SO I'M CURIOUS IF YOU WOULD REALLY LIKE -- IS OBESITY THE RIGHT WORD? >> WELL, SO I MIGHT ADDRESS THAT THAT. SO WE LOOKED AT A DICHOTOMY AND WHEN WE COMBINED OVERWEIGHT AND OBESE, WE SEE THE ASSOCIATION. WHEN WE LOOK AT BMI ITSELF, WE SEE A LINEAR RELATIONSHIP. NOW WHEN YOU LOOK OUT AT THE FAR END OF THE DISTRIBUTION, THERE IS VERY FEW INDIVIDUALS, AND VERY FEW EVENTS. SO THE CONFIDENCE INTERVAL AROUND THAT PART OF THE CURVE IS EXTREMELY WIDE. SO I WOULDN'T READ INTO THE DISTORTION AT THE END OF THAT CURVE. ACROSS THE RANGE WHERE THE VAST MAJORITY OF PEOPLE WHERE WE HAVE CONFIDENCE, IT IS A LINEAR EFFECT WE SEE WITH INFECTION. >> BUT THEN TO MODIFY THE QUESTION. I CAN BUY INTO THAT IDEA THAT OUTWARD PART OF THE SLOPE IS JUST A SMALL -- BUT IS 80 PERCENTILE OBESE? OR ARE WE REALLY AGAIN JUST TALKING ABOUT OVERWEIGHT AND THEN MAYBE SHOULD BE THINKING ABOUT SOMETHING ELSE BESIDES JUST OBESITY? OR EVEN IN FLORIDAIMATION ASSOCIATED WITH OBESITY, WHICH IS -- INFLAMMATION -- I'M JUST SKEPTICAL. >> WELL, I GUESS IT'S BOTH. SO WE DO SEE THE ASSOCIATION. IF WE GO BASED ON -- AND THIS IS DIFFERENT CUTOFFS FOR DIFFERENT AGE GROUPS IF WE CLASSIFY PEOPLE AS OVERWEIGHT OR OBESE, THERE IS AN ASSOCIATION. BUT THEN WHEN WE LOOK ACROSS THE RANGE OF JUST BMI, REGARDLESS OF WHETHER IT IS CLASSIFIED AS OVERWEIGHT OR OBESE, WE SEE THIS RELATIONSHIP THAT IS DOSE RELATIONSHIP, THE HIGHER THE BMI, THE INCREASE IN RISK. >> I THINK THE REASON WHY WORDS ARE IMPORTANT IS OBESITY IS MAYBE CONNECTED TO TISSUE INFLAMMATION BUT OVERWEIGHT MAY NOT BE. BUT INSTEAD IT MIGHT BE MORE RELATED TO DIET OR POST CRANIAL RESPONSES. SO I DON'T KNOW IF YOU HAVE DIETARY INFORMATION FROM THESE PATIENTS OR IF YOU WOULD ALSO BE LOOKINGA -- YOU COULD PROBABLY GET SOME DIET COMPETITION BY LOOKING AT T13, ET CETERA IN EVEN BLOOD. AND FOR EXAMPLE GET QUITE A CLEAR PICTURE OF FRUCTOSE IN THE DIET, ET CETERA, BY DOING SOMETHING LIKE THAT. AND MY FEELING IS THAT IT'S SOMETHING MORE RELATED TO LIFESTYLE RATHER THAN INFLAMED TISSUE, JUST BECAUSE OF WHERE THE CURVE SUPPORTS MOVE UP. >> -- STARTS TO MOVE UP. >> I WOULD SAY THAT THE COMBINATION IS OVERWEIGHT AND OBESITY COMBINED. AND I THINK AS MAX SAID, THE LINEAR RELATIONSHIP IS REALLY STRIKING. I WOULD ALSO AGREE OF IGNORING THAT DOWN TRENDING SECTION OF THE CURVE WHERE THERE ARE VERY FEW EVENTS. BUT I THINK WE DON'T KNOW WHY. I MEAN, IT'S VERY POSSIBLE THERE IS A BIOLOGIC REASON AND IT'S VERY POSSIBLE THERE ARE ALSO BEHAVIORAL REASONS THAT MAY NOT BE A SINGLE -- THIS COULD BE TRUE FOR FOOD ALLERGY. DO PEOPLE WITH FOOD ALLERGY BEHAVE -- THERE COULD BE A BIOLOGIC REASON. IT COULD BE PEOPLE WITH FOOD ALLERGY BEHAVE IN A VERY DIFFERENT WAY. THEY DON'T GO TO RESTAURANTS AND THEY ARE MUCH MORE CAREFUL ABOUT WHAT THEY TOUCH. SO I THINK FOR ALL OF THESE ASSOCIATIONS THAT WE HAVE DESCRIBED, THERE COULD BE MECHANISTIC AND BIOLOGIC AND BEHAVIORAL REASONS AS WELL. POINT IS WELL TAKEN. >> I ALSO WONDER IF TINA OR MAX YOU CAN ELABORATE ON THE MULTIVARIATE ANALYSIS YOU DID TO BE COMFORTABLE THAT THE ASSOCIATION WITH OBESITY REALLY DOESN'T JUST REFLECT IT BEING AN EPIC PHENOMENON THAT GOES ALONG WITH SOME OTHER SOCIOECONOMIC FACTOR THAT WE COULD EXPLORE OR THAT WE JUST ARE UNABLE TO TEASE OUT AT THIS POINT. JUST ON THE DATA WE HAVE. >> SURE. I CAN ADDRESS THAT. SO THE NUMBERS WE WERE SHOWING THROUGHOUT WERE CORRECTED FOR MULTIPLE FACTORS. SO THOSE ASSOCIATIONS WITH OBESITY ARE IN THE CONTEXT OF CONTROLLING FOR AGE, GENDER, RACE, ETHNICITY, AND EVERYTHING THAT IS SIGNIFICANT, FOOD ALLERGIES, BMI, WHETHER THEY ARE EXPOSED TO SYMPTOMATIC INDIVIDUALS. SO IT STOOD UP TO EVERYTHING WE COULD CONTROL FOR WHETHER THERE IS OTHER SOCIOECONOMIC FACTORS THAT WE DON'T HAVE. MAYBE WE MIGHT AND WE NEED TO LOOK AT THAT. BUT IT STOOD UP TO WHAT WE LOOKED AT. >> AND I THINK THAT IS VERY GOOD THAT IT DOES, THAT THERE WILL ALWAYS BE QUESTIONS ABOUT DEMOGRAPHICS AND THE EMPLOYMENT HISTORY AND EXPOSURE OF FAMILY MEMBERS AND THINGS LIKE THAT. >> OKAY. LET ME JUST ASK BEFORE WE MOVE ON, ARE THERE ANYMORE QUESTIONS OR COMMENTS PEOPLE WANT TO MAKE? IF NOT, THEN LET ME THANK BOTH TINA AND MAX FOR A TERRIFIC PRESENTATION AND ALSO FOR YOUR LEADERSHIP OF THE STUDY. IT'S JUST SPECTACULAR EXAMPLE OF PEOPLE MOVING QUICKLY IN THE MIDST OF A PANDEMIC TO DO SUCH HIGH-QUALITY RESEARCH. >> THANK YOU. >> WE HAVE THREE CONCEPT CLEARANCES FOR CONSIDERATION BY COUNCIL. THE FIRST OF THESE IS THE ANALYSIS AND BIO INFORMATICS CENTER AND DR. GONG WILL BE PRESENTING THAT. CAN YOU GET YOUR SLIDES UP? >> ARE MY SLIDES UP? >> YES. >> OKAY. MY NAME IS GANG DONG, PROGRAM OFFICER ALLERGY, ASTHMA, AIRWAY BIOLOGY BRANCH AND I'M PRESENTING A CONCEPT CLEARANCE SUN BEAM, ANALYSIS AND BIO INFORMATICS CENTER OR ABC. IN WAY OF BACKGROUND, FOOD ALLERGY HAS EFFECTED FROM 8% OF CHILDREN WITH HIGHEST INCIDENCE OF FOOD ALLERGIES IN THE FIRST YEAR OF LIFE. ATOPIC DERMATITIS IS A MAJOR RISK FACTOR FOR FOOD ALLERGY AND OTHER ATOPIC DISORDERS, EARLY EVENTS IN THE IMMUNE SYSTEM OR END ORGANS THAT PRE DISPOSE IN FACTS TO ATOPIC DISEASE ARE POORLY UNDERSTOOD. THEREFORE THERE IS NO RELIABLE WAY TO IDENTIFY THOSE INFANTS DESTINED TO DEVELOP ATOPIC DISEASE WHO WOULD BENEFIT FROM THE TARGETED PREVENTION STRATEGIES. SUN BEAM IS INITIATED EARLY THIS YEAR. STUDIES CONDUCTED BY -- [ READING ] SO THE SUN BEAM STUDY MORE DESCRIPTION. FOR THIS STUDY, 2500 PREGNANT WOMEN FROM GENERAL POPULATION WILL BE RECRUITED ACROSS 12 U.S. SITES. CLINICAL EVALUATION WILL BE CONDUCTED AND QUESTIONNAIRES ARE COLLECTED DURING THE PARTICIPANT VISIT SO DURING THE STUDY PERIOD, THERE ARE 6 CLINICAL VISITS SCHEDULED. 4 TIMES DURING THE FIRST YEAR OF LIFE AND YEARLY THEREAFTER FOR THE REMAINING TWO YEARS. SAMPLES TO BE COLLECTED FROM SUN BEAM STUDIES INCLUDE CORD AND PERIPHERAL BLOOD, SKIN, GUT, AIRWAY SAMPLES, SKIN TAPES AND HOME ENVIRONMENT SAMPLES. SO THERE COMES THE FOLLOW-UP STUDY -- NOT FOLLOW-UP. HERE COMES THE SUN BEAM ABC. THE PURPOSE OF THE SUN BEAM ABC IS TO ESTABLISH AN OMICS ANALYSIS AND BIO INFORMATICS CENTER TO SUPPORT SUN BEAM. [ READING ] FOR THE SUN BEAM ABC, WE PROPOSE TO USE COOPERATIVE AGREEMENT MECHANISM TO SUPPORT A SINGLE UM1 AWARD. SO THIS PROPOSAL CAN COME FROM EITHER SINGLE INSTITUTION OR CONSORTIUM OF THE MULTIPLE INSTITUTION. SO THE PROPOSAL NEED TO BE INCLUDE ADMINISTRATIVE ELEMENT AND -- [ READING ] AND THIS IS MY LAST SLIDE. HAPPY TO ANSWER QUESTIONS. >> OKAY. THANK YOU FOR A CLEAR PRESENTATION. I THINK WE WILL DO WHAT WE OFTEN DO, WHICH IS TO ASK FOR A MOTION AND A SECOND TO APPROVE THESE AT THE END OF DISCUSSION OF THE THREE CONCEPT CLEARANCES. THE NEXT ONE IS LIMITED COMPETITION TO CONTINUE THE PARK CLINICAL TRIAL AND LISA WHEATLEY WILL BE DISCUSSING THAT. LISA? >> GOOD AFTERNOON. CAN YOU SEE THEM? BECAUSE IT SAYS I'M UP. >> I SEE THEM. SO YOU'RE GOOD TO GO. >> OKAY. SO GOOD AFTERNOON. I'M LISA WHEATLEY. I'M THE SECTION CHIEF FOR FOOD ALLERGY, ATOPIC DERMATITIS AND ALLERGIC MECHANISMS AND I'M PRESENTING THIS CONCEPT CLEARANCE TODAY BECAUSE I'M ALSO THE MEDICAL OFFICER FOR THIS PARTICULAR TRIAL. SO WHAT WE ARE ASKING YOU TO CONSIDER IS A LIMITED COMPETITION TO CONTINUE THE PARK CLINICAL TRIAL. SO THE PARK TRIAL IS A TRIAL OF PREVENTION OF ASTHMA IN HIGH-RISK KIDS. IT IS AN ONGOING CLINICAL TRIAL. WE HAVE OVER 100 CHILDREN BETWEEN THE AGES OF TWO AND FOUR AT THE START OF THE TRIAL ENROLLED IN IT. THERE IS A PLANNED ENROLLMENT OF 250 2-3-YEAR-OLDS ALTHOUGH THAT WAS RECENTLY DECREASED TO 200 BASED ON A RE-EVALUATION OF RISK. SO THIS TRIAL ENROLLS SMALL CHILDREN AT HIGH RISK OF ASTHMA DUE TO THE FACT THEY ARE SENSITIZED TO ONE OR MORE ALLERGENS BY SKIN OR SERUM TESTING AND THEY HAVE RECURRENT WEEDS. ALWAYS DIFFICULT TO SAY EXACTLY HOW THIGH THEIR RISK IS BUT WE THINK IT IS SOMEWHERE BETWEEN 60-80%. THE TRIAL INVOLVES TREATING FOR 24 MONTHS WITH OMLIZUMAB ONCE A MONTH AND IT IS AT THE DOSE USED FOR ASTHMA. AND THEN THEY ARE FOLLOWED FOR AN ADDITIONAL TWENTY FOUR MONTHS WITH THE PRIMARY OUTCOMES BEING ASSESSED IN THE FINAL 12 MONTHS OF THIS STUDY. DURING THE STUDY, IN ADDITION TO GIVING THE OHMLIZUMAB, WE WILL BE ALSO -- WE HAVE BEEN AND WILL CONTINUE TO CONTROL THE RESPIRATORY SYMPTOMS BESIDES A PROTOCOLIZED FORMAT SO ACROSS THE 13 SITES IN THE STUDY. WE WILL HAVE SOME AT LEAST UNIFORMY. THERE ARE TWO PRIMARY OUTCOMES, ONE IS THE DIAGNOSIS OF ASTHMA AND THIS IS BASED ON THE DIAGNOSIS WE HAD USED IN THE EUREKA STUDY, PART OF THE -- CONSORTIUM. AND THEN ALSO A SECONDARY PRIMARY OUTCOME OF THE SEVERITY OF ASTHMA BASED ON SOMETHING CALLED THE CASSEY SCORE, ALSO DEVELOPED IN THE INNER CITY ASTHMA CONSORTIUM. SO I SAY TO MYSELF, WHY WOULD OMLIZUMAB PREVENT ASTHMA? THE AFFECTS OF IGE ARE TO CAUSE ALLERGIC INFLAMMATION AND PART OF THAT ALLERGE IN INFLAMMATION IS AIRWAY REMODELING. SO THE EFFECTS OF OMLIZUMAB COULD POTENTIALLY BE TO REDUCE REMODELING TO SUPPRESS THE INFLAMMATORY MILIEU AND TOL PRESERVE LUNG FUNCTION. ADDITIONALLY, WE KNOW THAT IGE INHIBITS ANTI-VALUABLE RESPONSES, PARTICULARLY PDC INTERFERON ALPHA GENERATION. AND SO THE EFFECTS OF OMLIZUMAB MAY BE TO ALLOW FOR FEWER VIRUS INDUCED WHEEZING EPISODES AND WE KNOW THAT THE VIRUS INDUCED WHEEZE IS A STRONG RISK FACTOR FOR ASTHMA. AND THEN IGE MAY PROMOTE ADDITIONAL SENSITIZATIONS AFTER THE ORIGINAL AND IT'S POSSIBLE THAT IF YOU INTERRUPT THAT WITH OMLIZUMAB, YOU WILL HAVE FEWER ALLERGIES IN THE CHILDREN AND THEREFORE LESS ASTHMA. SO THE PARK TRIAL WAS ORIGINALLY SCORED IN THE FIFTH PERCENTILE BY PEER REVIEW AND THE AWARD PERIOD WAS FROM JULY 20, 2016 TO JUNE 30, 2023. HOWEVER, THERE HAD TO BE A CLINICAL TRIAL AGREEMENT BETWEEN GENENTECH, WHO SUPPLIES THE OMLIZUMAB AND GLAXOSMITHKLINE WHICH PROVIDES THE RESPIRATORY MANAGEMENT MEDS AND THAT TOOK UNTIL OCTOBER 8 OF 2018 TO BE FINALIZEDDIZED. THE FIRST SITE WAS ACTIVATED IN NOVEMBER OF THAT YEAR, THE FIRST PATIENT WAS ENROLLED IN DECEMBER OF THAT YEAR. AND THE NUMBER ENROLLED AT THE TIME OF THIS SLIDE PRESENTATION WAS 108, I BELIEVE WE ARE AT 114 RIGHT NOW. AND THE ENROLLMENT IS EXPECTED TO BE COMPLETE IN JULY OF 2022. SO, WHY IS IT THAT THE TRIAL HAS NOT ENROLLED AS EXPECTED? WHEN WAS THE SLOW START UP OUTSIDE OF THE CONTROL OF THE PI. THE INCLUSION AND EXCLUSION CRITERIA WERE FURTHER NARROWD IN RESPONSE TO FDA REQUESTS BECAUSE THE FDA WANTED TO BE SURE WE WERE NOT GIVING CHILDREN MONTHLY OMLIZUMAB INJUNCTIONS UNLESS THEY WERE AT A VERY HIGH RISK OF ASTHMA. SOME OF THE SITES WE STARTED WITH WERE NOT ABLE TO ENROLL PER EXPECTATIONS BASED ON PERFORMANCE IN OTHER CHILDHOOD ASTHMA STUDIES SO ADDITIONAL SITES NEEDED TO BE ADDED. WE HAD A 3-MONTH SHUTDOWN, PROBABLY MOST OTHER STUDIES FOR THE CORONAVIRUS IN THE SPRING. AND THERE HAS BEEN SOME CONTINUING RELUCTANCE OF PEOPLE TO GET INVOLVED IN A STUDY WHERE THEY GO IN EVERY FOUR WEEKS WITH SMALL CHILDREN AND THEN BECAUSE OF THE CORONAVIRUS CHANGES IN SOCIAL INTERACTIONS AND MANY PLACES SCHOOLS WERE CLOSED, PRE-SCHOOLS WERE CLOSED, PARENTS WERE AT HOME, THERE WERE FEWER EPISODES OF WHEEZING IN CHILDREN SO FEWER CHILDREN AT RISK. WE THINK. SO THE REASON WE WANT TO DO THIS LIMITED COMPETITION IS PARK IS A UNIQUE STUDY TO PREVENT ASTHMA IN CHILDREN AT HIGH RISK. THE TIME TO DETERMINE THE DIAGNOSIS IS AT AGE 6 OR 7 IN THE STUDY AND THAT'S BECAUSE IS IT A MUCH MORE RELIABLE DIAGNOSIS AT THAT AGE THAN EARLIER WHEN YOU'RE STILL IN THE TRANSIENT WHEEZING TIME OF LIFE. THAT TRIAL CAN'T BE SHORTENED MUCH BECAUSE OF THE HALF-LIFE OF OMLIZUMAB IS SOMEWHAT LONG AND SO WE NEED TO MAKE SURE THAT OMLIZUMAB IS OUT OF THE SYSTEM AND ALSO THE WAY THE DIAGNOSIS IS SET UP IS IT IS BESIDES IT ENDS OVER A 12-MONTH PERIOD. AND WE ARE ASKING FOR APPROVAL FOR A 3-YEAR AWARD WHICH WILL ALLOW COMPLETION OF THE FINAL TWO YEARS OF OBSERVATION FOR THE LAST ENROLLED CHILD AND SOME TIME FOR DATA CLEANING AND ANALYSIS. AND REALLY THE OVERWHELMING REASON TO REQUEST THE LIMITED COMPETITION IS THAT IT ALLOWS FOR PEER REVIEW TO DETERMINE IF THIS TRIAL IS STILL CONSIDERED HIGH VALUE. SO NAVES MY LAST SLIDE BUT I'M HAPPY TO TAKE QUESTIONS. >> I HAVE A COUPLE OF QUICK SCIENTIFIC QUESTIONS. DOES THE OMLIZUMAB NEUTRALIZE IGM OR -- EXCUSE ME, IGE OR -- [ INAUDIBLE ] >> ESSENTIAL AT THE PREVENTS IT FROM BINDING TO THE HIGH AFFINITY RESPENTOR AND SO IF YOU MEASURE IGE YOU FIND THAT IT'S SKYROCKETED BECAUSE IT'S STILL THERE IN THE SYSTEM. >> INTERESTING. AND DOES THE DRUG GET OUT INTO TISSUE WHERE I WOULD HAVE ANTIBODY PRODUCTION LOCALLY AND MAYBE BIND LOCALLY? OR IS ALL THE DATA COME FROM BLOOD? >> NO, IT DEFINITELY GOES OUT INTO TISSUE. YOU CAN SUPPRESS YOUR SKIN TEST RESPONSES WITH IT. >> OKAY. ALL RIGHT. ANYWAY, THOSE MAY BE WELL-KNOWN, I WAS CURIOUS. I DIDN'T KNOW THE ANSWER. >> SO YOU STILL HAVE 80 CHILDREN TO ENROLL? >> 85-ISH. >> LISA DIDN'T MENTION THIS BUT THIS WAS A TOTALLY NEW KIND OF CONCEPT FOR US. ORDINARILY YOU WOULD NEVER HEAR ABOUT THIS AS A COUNCIL CONCEPT CLEARANCE BECAUSE WE WOULD JUST, AS AN INSTITUTE, APPROVE A TYPE FOR CONTINUATION OF A CLINICAL TRIAL. AND THAT HAPPENS QUITE OFTEN WHEN CLINICAL TRIALS DON'T ENROLL ACCORDING TO THE INITIAL PROJECTIONS. BUT IN THIS CASE, BECAUSE THIS WAS ALREADY A SEVEN-YEAR STUDY, NIH OD POLICY TEAM WOULD NOT APPROVE TYPE 4 APPLICATION. AND WE WERE -- THEREFORE WE WERE REQUIRED TO GO THIS ROUTE WHICH WAS TO OUR EXPERIENCE AND ACROSS THE INSTITUTE TO JUST -- EXCEPTIONAL. THAT'S WHERE WE ARE. IS THERE ANY FURTHER COMMENT? >> NO, I HAVE NOTHING ELSE. >> OKAY. IF WE DON'T HAVE ANY FURTHER QUESTIONS ABOUT THIS OR COMMENTS, WE CAN MOVE ON TO THE FINAL PRESENTATION CONCEPT CLEARS ON DEVELOPMENT OF MICROBIOME APPROACHES FOR DIAGNOSIS AND MITIGATION AND TREATMENT OF RADIATION INJURIES. AND LANYN I THINK YOUR SCREEN IS COMING UP. IT'S SHOWING NOW. >> CAN YOU SEE MY SLIDES? >> YES. >> ALL RIGHT. FANTASTIC. SO I'M THE FINAL ONE AND GIVING YOU A BRIEF OVERVIEW OF THE CONCEPT WE ARE TRYING TO CLEAR. DEVELOPING THE MICROBIOME-RELATED APPROACHES FOR DIAGNOSIS, MISIGATION, TREATMENT OF RADIATION INJURIES. MY NAME IS LANYN AND I'M A PROGRAM OFFICER. SO THE GOAL OF THIS INITIATIVE IS TO SUPPORT RESEARCH THAT IS GOING TO AVAND -- ADVANCE THE UNDERSTANDING OF HOW THE MICROBIOME AFFECTS RADIATION INJURY. ADDITIONALLY WE WANT TO TARGET THE MICROBIOME TO PREVENT OR MITIGATE RADIATION INJURY. THIS IS A NEW CONCEPT. AND WE ARE USING THE U01 CONCEPT AGREEMENT BECAUSE WE WANT TO MAKE SURE WE HAVE OVERSIGHT OF THE RESEARCH THAT IS BEING CONDUCTED. THESE WILL BE 5-YEAR AWARDS. SO JUST TO GIVE YOU A LITTLE BIT OF BACKGROUND ABOUT THE INFORMATION THAT WE HAVE THUS FAR WITH REGARDS TO THIS PARTICULAR AREA OF RESEARCH. RODENT STUDIES WERE DONE WITHIN OUR PORTFOLIO LOOKING AT THE GUT MICROBIOME AND HOW IT FACILITATES EITHER RADIO RESISTANCE FOR PROTECTING THE EPITHELIUM FROM APOPTOSIS AND ALSO HOW THE RADIO -- RADIATION INDUCES ENDOTHELIAL APOPTOSIS THUS FAR GIVING THAT RADIATION SENSITIVITY. WE KNOW THAT THE MICROBIOME DOES CHANGE OVER TIME WHEN ANIMALS ARE EXPOSED TO RADIATION AND THIS HAS BEEN SEEN IN NHP AND MINIPIG. AND WE ALSO WANT TO IDENTIFY ANIMAL MODELS THAT CAN BE USED TO UNDERSTAND THE SIMILARITIES BETWEEN THESE ANIMAL MODELS AND HUMAN PHYSIOLOGY SINCE WE ARE ATTACHED TO THE ANIMAL MODEL RULE FOR A LOT OF THE RESEARCH THAT WE DO. AND THAT REALLY REQUIRES UNDERSTANDING THESE ANIMAL MODELS IN A VERY THOROUGH WAY. SO WE ULTIMATELY WANT TO UNDERSTAND HOW THE MICROBIOME IS EFFECTING THE RADIATION INDUCED TISSUE INJURY AND ALSO HELP PREDICT THE DISEASE PROGRESSION AND UNDERSTANDING THE DEVELOPMENT OF THESE TREATMENTS. INTERESTINGLY, WE HAVE HAD THE OPPORTUNITY TO PUBLISH A PAPER THAT IS SHOWN HERE AND THIS WAS ACCEPTED JUST THIS YEAR AND WE ALSO HAVE AN RFI FOR THIS PARTICULAR AREA SINCE IT IS A NEW AREA WE WANT TO REALLY UNDERSTAND THIS AREA TO THE MAXIMUM POSSIBLE. SO JUST TO KIND OF GIVE YOU A LITTLE BIT MORE OF AN UNDERSTANDING OFF HOW A PORTFOLIO STARTED TO GET INTERESTED IN THIS AREA, I'M GOING TO GIVE YOU A BRIEF OVERVIEW OF THE RESEARCH THAT HAS BEEN DONE. SO UNDER NORMAL CIRCUMSTANCES, WE HAVE A DIVERSE GUT MICROBIOME WHICH RELEASES METABOLITES SUCH AS FATTY ACIDS AND TRYPTOPHAN N THIS CASE, AND THAT LEADS TO EPITHELIAL INTEGRITY THAT IS MAINTAINED AND THERE IS A HARMONY OF KIEM KINES AND CYTOKINES AND THEREFORE LESS DAMAGE IS REPORTED IN THESE SYSTEMS. AND THIS ACTUALLY HAS BEEN NOTED IN SOME MICE WHICH ARE COINED ELITE SURVIVORS AND I'LL DISCUSS THOSE IN THE NEXT SLIDE. HOWEVER, WHEN RADIATION IS INSULTING THE SYSTEM, THIS GUT MICROBIOME BECOMES LESS DIVERSE. YOU GET A LESS METABOLITES. ENDOTHELIAL INTESTINAL INTEGRITY BECOMES COMPLETELY BROKEN -- BROKEN UP AND WE GET A DYSREGULATED CYTOKINE CHEMOKINE REDUCTION. THIS LEADS TO MORE APOPITOSEIS AND SEVERE HEMATOPOIETIC DAMAGE. SO LOOKING AT THIS CONCEPT OF HOW THE MICROBIOME EFFECTS THE GI, SOME OF THE THOUGHTS WERE THAT PERHAPS THERE IS SOME EFFECTS OF THE MICROBIOME THAT ARE PERFECT IN THESE CONDITIONS UNDER THE ELITE SURVIVORS SO WE HAVE A SITUATION HERE WHERE ANIMALS WERE LOOKED AT FOR THEIR ABILITY TO IMPACT RADIATION SURVIVE. IN THIS CASE, WHAT WAS BEING DONE THAT WAS THEY HAD CONTROL ANIMALS FROM NORMAL DONORS AND THEN THOSE ANIMALS THAT WERE ALSO ELITE SURVIVORS THEY HAD THEIR CAGES. SO SPECIFIC PATHOGEN-FREE ANIMALS WERE PLACED IN THESE DIRTY CAGES SO THEY WERE EXPOSED TO THE MICRO BIOME OF THE CONTROL ANIMALS OR ELITE SURVIVOR AND THEN THOSE ANIMALS WERE EXPOSED TO TOTAL BODY RADIATION. SO AS YOU CAN SEE HERE ON THE RIGHT, ANIMALS THAT HAVE BEEN EXPOSED TO THE ELITE SURVIVOR MICROBIOME SURVIVED RADIATION AT A HIGHER EXTENT. SO THE THOUGHT WAS THAT PERHAPS THE MICROBIOME IS HAVING A SIGNIFICANT IMPACT AND PROTECTING THE ANIMALS AGAINST RADIATION. OTHER PARTS OF THE PORTFOLIO LOOKED AT TAKING ADVANTAGE OF THE LACK OF STRAINS IN PARTICULAR THIS ONE, WAS BEING USED TO PRODUCE IL22 AND AS YOU CAN SEE, IN BLUE HERE, THERE IS EFFECT OF IL22 IN HELPING TO PROMOTE THE PROTECTION OR BETTER YET THE EFFECTING THE GUT MICROBIOME IN SUCH A WAY THAT THE SURVIVAL WAS ENHANCED. AND WHEN YOU PROVIDE A LOCALIZED LACTOBACK SILL US PRODUCING BACTERIA, IT INCREASES IT. WE ARE INTERESTED IN THIS AND WE ARE PURSUING THIS AND THIS IS SOMETHING THAT IS NOW BEING LOOKED AT UNDER A CONTRACT. SO THESE DIFFERENT PIECES OF OUR PORTFOLIO GIVEN US A GLIMPSE INTO THE MICROBIOME AN IDEA THAT THERE IS SOMETHING TO BE LOOKED AT HERE AND SOMETHING TO BE HARNESSED AND SO WE ARE HOPING TO OPEN THIS UP TO GET NOT ONLY JUST ANIMAL MODELS AND MICROBIOME BIOMARKERS OF INJURY RESEARCH BUT WE ALSO WANT TO LOOK AT THE RESEARCH THAT IMPACTS THE MICROBIOME AND THE CONTRIBUTION IT HAS TO INJURY FOR ALL TISSUES LISTED HERE. WE ARE ALSO INTERESTED IN THE TREATMENTS WHETHER IT BE PROBIOTICS, PRE BIOTICS, DIETARY MODIFICATIONS OR MICROBIOTIC TRANSPLANT AND SEEING HOW THOSE CAN HELP WITH RADIATION SENSITIVITY. AND WITH THAT, I'LL ASK IF YOU HAVE ANY QUESTIONS. >> MAYBE JUST ONE QUICK QUESTION. WHEN YOU STARTED THE PRESENTATION YOU HAD ALL THE NON-HUMAN PRIME EXPATS PIG LETS AND THEN YOU HIGHLIGHTED A NICE STUDY IN MOUSE -- PRIME MATES -- SO THE MOUSE IS NOT TO BE SOMEHOW -- >> ABSOLUTELY. THEY CAN BE INCLUDED. WE EXPECT THAT BECAUSE THIS IS SUCH A PRELIMINARY AREA OF RESEARCH FOR US. WE'LL PROBABLY START AT THAT LEVEL. WE HAVE HAD SOME THINGS GO INTO NHP JUST BECAUSE OF THE LEVEL OF ACTIVITY THAT HAS GONE DOWN WITH THOSE PARTICULAR ASPECTS OF THE PORTFOLIO. WE CERTAINLY THINK IT PROBABLY WILL START AT THE RESEARCH -- SMALL ANIMAL LEVEL. >> THANK YOU. >> SO WAS JENNY KING'S STUDY, THAT STUDY PUBLISHED IN SCIENCE, WAS THAT FUNDED BY THIS INITIATIVE? >> NO. IT WAS FUNDED BY OUR PROGRAM UNDER ANOTHER U01 INITIATIVE WE HAD PUT IN PLACE. >> OKAY. >> BUT BECAUSE OF THOSE STUDIES, AND SOME OF THE OTHER ONES THAT WE SHOWCASED WE FEEL LIKE THIS IS AN AREA THAT IS RIPE RIGHT NOW AND WE WANT TO REALLY GET AN OPPORTUNITY HERE TO EXPAND IT A BIT MORE. >> HER PAPER HAD SOME REALLY INCREDIBLE STUFF IN IT. >> ABSOLUTELY. >> I WOULD JUST ADD THAT FOR THE SIZE OF THE INVESTMENT, OUR RADIATION COUNTER MEASURE SYSTEM PROGRAM HAS BEEN VERY SUCCESSFUL IN BRINGING NON-HUMAN PRIMATE STUDIES TO THE FDA FOR LICENSURE BIOLOGICS FOR RADIATION COUNTERMEASURES IN HUMANS USING THE ANIMAL MODEL RULE. SO WE REALLY WANT TO GET THE KIND OF DATA IN SMALLER ANIMAL MODELS THAT THIS TYPE OF INITIATIVE WILL HOPEFULLY PRODUCE, RECOGNIZING THAT THINGS LIKE THIS WILL EVENTUALLY PROBABLY COME TO THE FDA AND WE REALLY WANT TO BE CONFIDENT IF AND WHEN THEY DO, THAT THEY ARE WELL GROUNDED. >> ABSOLUTELY. THANK YOU FOR THAT. WE DEFINITELY AGREE. >> IT JUST SEEMS LIKELY THAT PEOPLE WILL START TO LOOK AT THE COMBINED EFFECTS OF THE MICROBIOME PLUS PLATELET PRESERVING TECHNOLOGIES OR NEUTROPHIL ILLICITTING LYINGICS, THINGS LIKE THAT. BECAUSE THERE IS PROBABLY LIKELY TO BE SOME SYNERGY. >> ABSOLUTELY. AND WE ARE TRYING TO PIECEMEAL IT RIGHT NOW BUT EVENTUALLY WE WOULD LIKE TO SEE HOW THEY CAN HARMONIZE TOGETHER TO GET US OVER THE FLESH HOLD OF SURVIVAL AND QUALITY OF LIFE. >> OKAY. NOT HEARING ANY FURTHER COMMENTS OR QUESTIONS, MAY I ASK THEN FOR A BLOCK MOTION AND A SECOND FOR APPROVAL OF THE THREE CONCEPT CLEARANCES. >> SO MOVED. >> SECOND. >> ALL RIGHT. THANK YOU. SO THAT WRAPS UP OUR SUBCOMMITTEE OPEN SESSION FOR THIS AFTERNOON. LET ME JUST WISH YOU ALL WELL AND WE'LL SEE YOU IN A FEW MONTHS. HOPEFULLY WE'LL BE MEETING IN PERSON SOME TIME SOONER THAN LATER. BUT SEPTEMBER IS STILL A LITTLE BIT IFFY REGARDING NIH STAFF TRAVEL OR OUR EXPECTATIONS THAT ANYBODY ELSE WOULD TRAVEL. SO WE'LL SEE HOW THAT UNFOLDS. WE ARE EXPECTING AN UPDATE SOMETIME IN JULY OR AUGUST ABOUT THAT. >> WE ARE SUPPOSED TO VOTE LIKE EVEN IF IT'S ON BLOCK, RIGHT? THERE IS A PLACE IN THE ELECTRONIC COUNCIL BOOK WE NEED TO CHECK ALL THE BOXES? IS THAT RIGHT? >> THAT IS RIGHT. AND I JUST SAW A CHAT ENTRY FROM ANDREA WORCESTER IN OUR DIVISION OF EXTRAMURAL ACTIVITIES ASKING THAT YOU ALL ACTUALLY DO THAT IN THE ECB. >> I'M KIND OF STRUGGLING TO FIND WHERE TO CLICK. IS IT UNDER THE -- NOT OPEN SESSION -- >> STILL UNDER OPEN SESSION MATERIALS AND THERE IS VOTING MATERIALS AND THEN VOTE ON DOCUMENTS LINK. AND THE HAVE THE OPTION TO ADD COMMENTS IF YOU LIKE TO TO ANY OF THE CONCEPTS AS WELL. >> I'M SORRY, CAN YOU SAY WHERE THAT IS AGAIN BECAUSE UNDER OPEN SESSION -- >> OPEN SESSION MATERIALS AND THERE SHOULD BE A, VOTE ON DOCUMENTS LINK. >> IT'S UP AT THE TOP TOWARDS THE TOP. >> SO, WHAT I SEE IS OPEN SESSION AGENDA, WHICH IS CLEARLY NOT IT. >> NO, IT'S THE CODE BLOCK. IF YOU GO TO THE FIRST THINGS WE HAD. DO YOU SEE THE DATE EXTENSION NOMINATIONS, DO YOU SEE THAT LINE WE HAD BEFORE? RIGHT BELOW THAT. SO YOU GO TO THE TOP -- >> GOT IT. SORRY. >> AND YOU SEE THE LINK TO VOTE ON DOCUMENTS. >> YES. ALL RIGHT. I WAS TOO FAR DOWN. SORRY. >> THANK YOU VERY MUCH. I APPRECIATE YOU ORIENTING THAT. THANK YOU VERY MUCH. >> OKAY. YVETTE, IS THERE ANYTHING ELSE WE NEED TO BRING UP BEFORE WE WRAP UP? >> NO, JUST WANTED TO DOUBLE CHOKE MAKE SURE THE COUNCIL MEMBERS VOTE ON THE CONCEPT CLEARANCES. THAT WAS ALL. >> THANKS TO THE WHOLE TEAM FOR THEIR PRESENTATIONS. IT IS REALLY HELPFUL TO HEAR THE PRESENTATIONS. ALL THOSE DIFFERENT PROPOSALS&THAT I HAD QUESTIONS ON BUT -- GREAT PRESENTATIONS. >> THANK YOU FOR THAT. AND WE WILL PROBABLY BE MEETING BY ZOOM ONCE MORE BUT IF NOT, WE'LL LOOK FORWARD TO SEEING YOU IN PERSON SOMETIME IN THE FALL OR WINTER. >> THANK YOU. >> THANKS, ALL. >> THANK YOU.