>>MY NAME IS CESAR BOGGIANO, PRONOUNS ARE HE HIM HIS, FROM NATIONAL INSTITUTE OF ALLERGY INFECTIOUS DISEASES, I WOULD LIKE TO WELCOME YOU TO THE SUMMIT ON ANTI-SARS COV-2 ANTIBODIES FOR TREATMENT AND PREVENTION OF COVID-19. LESSONS LEARNED AND REMAINING QUESTIONS. WE OPEN THE SUMMIT WITH REMARKS FROM DR. FRANCIS COLLINS DIRECTOR OF NATIONAL INSTITUTES OF HEALTH FOLLOWED BY DR. JANET WOODCOCK, ACTING COMMISSIONER OF THE U.S. FOOD AND DRUG ADMINISTRATION AND DR. ANTHONY FAUCI, DIRECTOR OF NATIONAL INSTITUTE OF ALLERGY INFECTIOUS DISEASE. DR. COLLINS, PODIUM IS YOURS. >> THANK YOU VERY MUCH CAESAR AND THANKS TO THOSE WHO PUT TOGETHER THIS REALLY INTERESTING AND IMPORTANT MEETING, THE SME EXPERTS AS THEY ARE CALLED AND WILL BE ACKNOWLEDGED TOGETHER AT THE END OF THE MEETING SO I WON'T TRY TO READ OFF THEIR NAMES BECAUSE THERE ARE A LOT OF PEOPLE INVOLVED IN MAKING THIS LAST SUMMER AND I CONVENED A SUMMIT TO EXPLORE THE CURRENT STATE AND FUTURE OPPORTUNITIES FOR THE USE OF NEUTRALIZING ANTI-BOUGH KYES TO TREAT -- ANTIBODIES TO TREAT COVID-19 BEFORE WE HAD SAFE EFFECTIVE VACCINES OR MANY IN THE WAY OF THERAPEUTICS. BACK HEN THE GOAL WAS TO REVIEW THE CONSIDERATIONS FOR ASSESSING NEUTRALIZING ANTIBODIES, TO TREAT COVID-19 AND TO GENERATE A CONSOLIDATED KNOWLEDGE BASE THROUGH DEVELOPMENT OF A WHITE PAPER TO DISCUSS THE CURRENT STATE OF NEUTRALIZING ANTIBODIES AND POTENTIAL AREAS OF OPTIMIZATION FOR FUTURE WORK AND TO SHARE KEY LEARNINGS FROM OTHER DISEASES AND IMPLICATIONS FOR PREVENTION. AND VACCINE DEVELOPMENT. WHILE A LOT HAS HAPPENED IN THE COURSE OF THAT YEAR, ALL OF US I THINK CONSUMED BY THE EFFORTS THAT NIH HAS BEEN IN THE MIDDLE TO TRY TO DEVELOP EFFECTIVE MEANS OF PREVENTION AND TREATMENT OF THIS WORSE PANDEMIC IN 103 YEARS. THIS ACTIVE PUBLIC PRIVATE PARTNERSHIP CAME TOGETHER AND ESPECIALLY IN ITS PROTOCOLS A MASTER PROTOCOLS CALLED ACTIVE 2 AND ACTIVE 3 FOR OUTPATIENTS AND IN PATIENTS RESPECTIVELY, HAD THE OPPORTUNITY TO TEST A NUMBER OF MONOCLONAL ANTIBODIES THAT WERE PUT FORWARD BY COMPANIES THAT WITH VERY INTERESTING CONCLUSIONS THAT I'M SURE WE'LL TALK ABOUT IN THE COURSE OF THIS MEETING TODAY. FDA AND SEVERAL COMPANIES GOT DEEPLY ENGAGED IN THIS AS A MEANS OF BOTH TRYING TO TREAT AND PROF LACKS COVID-19. OF COURSE A LOT OF EFFORT HAD TO BE MADE TO ASSESS THOSE PRODUCTS IN PRE-CLINICAL AND CLINICAL TRIALS, PARALLEL EFFORTS UNDERWAY, TO TRY TO SEE WHAT COULD BE LEARNED FROM CONVALESCENT PLASMA AND HYPERIMMUNE GLOBULIN WHICH WE WILL ALSO HEAR ABOUT THIS. AS TIME WENT ON, MORE AND MORE INFORMATION BEGAN TO EMERGE ABOUT VARIANTS IN THE SARS COV-2 VIRUS THAT MIGHT CHANGE THE NATURE OF THE SPIKE PROTEIN ANTIGEN AND MIGHT THEREFORE HAVE AN EFFECT ON WHETHER OR NOT PARTICULAR MONOCLONAL ANTIBODIES WERE SUCCESSFUL IN BINDING AND PROVIDING THIS KIND OF PREVENTION OR TREATMENT. THAT HAS BECOME A VERY BIG DEAL OF COURSE IN THE COURSE OF THE LAST MANY MONTHS SINCE ABOUT LAST FALL AND SURE WE WILL ALSO BE TALKING ABOUT THAT TODAY. SO WHERE ARE WE? WE HAVE HAPPILY THREE VACCINES APPROVED AND WE HAVE A NUMBER OF -- THAT HAVE ALSO BEEN IMPROVED ON THE BASIS OF EMERGENCY USE FOR MONOCLONALS TO BE UTILIZED PARTICULARLY IN OUTPATIENT SETTINGS. AND ONE OF THE LESSONS WE HAVE LEARNED IS HOW QUICKLY ONE NEEDS TO GET STARTED WITH THIS PASSIVE IMMUNIZATION IF IT IS GOING TO BE SUCCESSFUL. AGAIN, THE EMERGENCE OF VARIANTS HAS CAUSED US TO RETHINK A BIT WHETHER SINGLE MONOCLONALS VERSUS COCKTAILS ARE GOING TO BE THE WAY TO GO FORWARD AND I'M SURE WE WILL HAVE A LOT TO SAY ABOUT THAT ISSUE. SO WE MADE A LOT OF PROGRESS. BUT AS WE NOW SURVEY WHAT WE HAVE ACCOMPLISHED SO FAR AND THINK ABOUT WHAT WE STILL HAVE IN FRONT OF US AS FAR AS THE ULTIMATE SUCCESS AGAINST COVID-19 AND THE PLANNING FOR SOME FUTURE PANDEMICS WHICH WE ALL BELIEVE ARE OUT THERE SOMEWHERE, LET US SEE IF WE CAN IN THE COURSE OF THESE HOURS WITH SOME OF THE MOST REMARKABLE WORLD EXPERTS JOINING US SEE WHAT LESSONS CAN BE LEARNED BOTH SHORT AND LONG TERM AND PARTICULARLY TO DEAL WITH THE CONTINUING EVOLVING THREAT POSED BY VARIANTS OF SARS COV-2. MY HOPE IS THIS GROUP WILL IDENTIFY WHAT NEEDS TO GET DONE AND THEN WE WILL ALLOW US TO CONTINUE THE GOOD WORK GOING ON WITH THE INCREDIBLE DEDICATED EFFORTS THOUSANDS AND THOUSANDS OF SCIENTISTS WORKING IN THIS SPACE TRYING TO IDENTIFY WAYS TO SAVE LIVES AND WE COULD HARDLY OVERSTATE HOW CRITICAL THAT IS WITH OUR HAVING HIT 600,000 LOST LIVES JUST IN THE UNITED STATES AND OF COURSE MUCH MORE TROUBLE STILL HAPPENING BOTH HERE AND ESPECIALLY ABROAD. SO THE IMPORTANCE OF OUR DISCUSSIONS TODAY CAN HARDLY BE OVERSTATED. DELIGHTEDDED THAT I'M ABLE TO GIVE YOU THESE WORDS OPENING WELCOME AND ENCOURAGEMENT WITH MY COLLEAGUES DR. JANET WOODCOCK AND DR. TONY FAUCI, LET ME TURN TO IT JANET FOR HER WELCOMING REMARKS NOW. >> THANKS VERY MUCH, FRANCIS. I WOULD LIKE TO WELCOME EVERYONE TO THIS SUMMIT AND THANK THE ORGANIZERS FOR GIVING ME THE OPPORTUNITY TO SAY A FEW WORDS. I THINK IT IS REALLY IMPORTANT TO TAKE THE TIME TO GATHER TOGETHER AND SYNTHESIZE WHAT WE HAVE LEARNED ABOUT THE USE OF PASSIVE IMMUNITY IN THE SETTING OF SARS COV-2 PANDEMIC. I BELIEVE IT HAS LESSONS FOR FURTHER TREATMENT IN THIS DISEASE AS WELL AS POTENTIAL FUTURE OUTBREAKS. EARLY IN THE PANDEMIC THERE WAS GREAT INTEREST IN PASSIVE IMMUNE APPROACH AS A FASTEST METHOD TO BRING VIRUS SPECIFIC INTERVENTIONS TO BEAR. OTHER EARLY CANDIDATES SUCH AS MOLECULE ANTI-VIRALS WERE BY NECESSITY REPURPOSED AGENTS ENVELOPED AGAINST OTHER PATHOGENS. AS SOON AS CONVALESCENT PLASMA BECAME AVAILABLE IT WAS USED WIDELY IN THE SICKEST PATIENTS SINCE AT THAT TIME SUPPORTIVE CARE WAS THE ONLY OTHER OPTION IN THOSE EARLY DAYS. WHEN I JOINED OPERATION WARP SPEED AS IT WAS THEN CALLED IN THE SPRING OF 2020 AS A THERAPEUTICS LEAD, ONE OF THE MODALITIES I FOCUSED ON WAS NEUTRALIZING ANTIBODIES. AS CANDIDATES WITH VERY STRONG MECHANISTIC AND HISTORICAL PLAUSIBILITY. AS DR. COLLINS SAID LAST SUMMER OWS AND NIH JOINTLY HELD A SUMMIT TO DISCUSS THE SCIENCE OF ANTIBODY TREATMENT OF VIRUS INFECTIONS. MAJOR CONCERNS AND INTEREST INTERESTING RAISED AT THAT TIME WERE THE RISK OF ANTIBODY MEDIATED DISEASE ENHANCEMENT AND THE LIKELY POSSIBILITY OF TREATMENT EMERGENT RESISTANT VARIANTS PARTICULARLY WITH USE OF SINGLE MONOCLONAL ANTIBODY. THE POSSIBILITY OF EXOGENOUS RESISTANT VARIANTS ARISING WAS ACKNOWLEDGED BUT THAT WASN'T THE ISSUE OF THE DAY. SO THERE WAS MUCH DISCUSSION ABOUT USING A SINGLE ANTIBODY VERSUS COMBINATION OF POLYCLONAL ANTIBODIES. POTENTIAL FOR USING ANTIBODIES AS PRE-OR POST EXPOSURE PROPHYLAXIS IS TREATMENT FOR EARLY DISEASE OR AS AN INTERVENTION HOSPITALIZED PATIENTS WAS DISCUSSED SINCE AND OTHER VIRAL DISEASES PASSIVE IMMUNITY HAVE BEEN SUCCESSFUL IN EACH OF THESE SCENARIOS. ALTHOUGH BY NO MEANS UNIFORMLY. SO IT DEPENDED ON THE DISEASE, AND THE SETTING AND SOMETIMES PRE-EXPOSURE PROPHYLAXIS WAS SUCCESSFUL, SOMETIMES TREATMENT WAS SUCCESSFUL EVEN OF SICK PATIENTS. AS CLINICAL DATA BEGAN TO EMERGE ON USE OF MONOCLONAL ANTIBODIES IN COVID-19 TREATMENT OF EARLY INFECTION LOOKED PROMISING WHILE INTERVENTIONS USING MONOCLONAL ANTIBODIES IN MANY HOSPITALIZED PATIENTS DIDN'T APPEAR TO IMPACT THE DISEASE. SEEMS THAT PERHAPS ONCE PATIENTS HAVE MOUNTED THEIR OWN HUMORAL IMMUNE RESPONSE ADDING ADDITIONAL ANTIBODY MAY NOT THAT USEFUL THOUGH CONJECTURE AT THIS POINTS. ANTIBODIES ADMINISTERED EARLY APPEAR TO SLOW DISEASE PROGRESSION BY SYMPTOMS, REDUCE SYMPTOM DURATION AND GIVING PATIENTS IMMUNE SYSTEM A CHANCE TO FULLY CLEAR THE VIRUS. ULTIMATELY, TRIAL SHOWING HIGHLY POSITIVE EFFECT OF MONOCLONAL ANTIBODIES ON SEVERE OUTCOMES OF HOSPITALIZATION AND MORTALITY WERE COMPLETED AND SIMILAR RESULTS ARE STILL COMING OUT, SOME WERE JUST RECENTLY ANNOUNCED OF ANOTHER TRIAL. DECIDE RESULTS ADMINISTRATION ANTIBODY INFUSION TO HIGH RISK INFECTIOUS OUTPATIENTS WAS DIFFICULT FOR THE HEALTHCARE SYSTEM TO ACCOMPLISH AND ONLY MINORITY OF RISK INDIVIDUALS IN THE U.S. RECEIVE THIS TREATMENT. THE RISING PREVENIENCE OF SARS COV-2 VARIANTS SOME WHICH WERE NOT WELL NEUTRALIZED BY CERTAIN MONOCLONALS ALSO DIMINISHED THE UTILITY OF SOME OF THE ANTIBODIES THAT HAVE BEEN DEVELOPED. BUT NOT ALL OF THEM. INVESTIGATIONS OF THE USE OF MONOCLONAL ANTIBODIES FOR PRE-OR POST EXPOSURE PROPHYLAXIS OR COMPLETED OR ONGOING. SUCH USES ARE LIKELY TO REDUCE DISEASE ACQUISITION OR PROGRESSION, HOWEVER THESE THERAPIES REMAIN CHALLENGING TO DEPLOY WIDELY AND MAYBE MOST APPROPRIATE FOR INDIVIDUALS WITH CONDITIONS THAT DIMINISH RESPONSES TO VACCINATION. AS I SAID, CONVALESCENT PLASMA WAS USED IN HOSPITALIZED PATIENTS. IT'S EFFECTS ARE STILL NOT WELL ESTABLISHED, I BELIEVE DR. MARKS WILL COVER THIS BUT WITH ANTIBODY THERAPY I IT IS CLEAR USE AS EARLY AS POSSIBLE IS DESIRABLE. CONVALESCENT PLASMA WOULD BE EVEN MORE DIFFICULT TO USE IN OUTPATIENTS THAN MONOCLONAL ANTIBODIES BECAUSE BLOOD TYPE MATCHING IS REQUIRED. HYPERIMMUNE GLOBULIN MIGHT BE USEFUL IN OUTPATIENTS BUT NECESSARY STUDIES HAVE NOT BEEN COMPLETE AND TRIALS OF INPATIENTS HAVE YIELDED NEGATIVE RESULTS THAT ARE SIMILAR TO THOSE SEEN FROM MONOCLONAL ANTIBODIES. MANY QUESTIONS REMAIN ABOUT USE OF ANTIBODIES AND SARS COV-2 INFECTION. SOME ARE CURRENTLY INVESTIGATED SUCH AS RESPONSE TO VACCINATION AFTER ANTIBODY TREATMENT. ADDITIONALLY HOW COULD USE OF THESE THERAPIES BE SCALED BROADLY. IS IM OR SUB Q ADMINISTRATION FEASIBLE AND EFFECTIVE? HOW MUCH UTILITY WOULD BE LOST BY DELAY IN C MAX GIVEN THESE ROOTS OF ADMINISTRATION. ALSO THE LACK OF EFFECTIVENESS I BELIEVE OF MONOCLONALS IN LATER STAGE OF DISEASE, HAS MUCH TO TEACH US ABOUT THE PATHOGENESIS OF THIS INFLAMMATORY STAGE OF THE INFECTION. AS THE PANDEMIC STILL RAGES IN MUCH OF THE WORLD AND PEOPLE CONTINUE TO FALL ILL IN THE U.S. ANTIBODY THERAPY WILL CONTINUE TO BE TOOLS IN THE ARMAMENTARIUM. WE HAVE LEARNED IF WE REFLECT A GREAT DEAL IN A VERY SHORT AMOUNT OF TIME TODAY SUMMIT WILL BE IMPORTANT TO CONSOLIDATE AND BUILD ON OUR UNDERSTANDING. THANK YOU, VERY MUCH AND I WILL TURN IT TO THE NEXT SPEAKER. >> GREETINGS. IT IS A REAL PLEASURE TO BE HERE WITH YOU TODAY ALBEIT VIRTUALLY TO GIVE JUST A COUPLE OF INTRODUCTORY REMARKS FOR THIS SUMMIT ON ANTI-SARS COV-2 ANTIBODIES TO THE TREATMENT AND PREVENTION OF COVID-19. I LIKE TO THINK ABOUT IT WHEN YOU THINK IN TERMS OF THE INDIVIDUAL PATIENT AT RISK OR INFECTED WITH SARS COV-2 AND TO SIX CATEGORIES. ONE IS THE AT RISK UNINFECTED PERSON, THE OTHER IS AN ASYMPTOMATIC BUT INFECTED PERSON, THE OTHER IS A SYMPTOMATIC BUT LOW RISK FOR PROGRESSION, THE OTHER IS A SYMPTOMATIC PERSON BUT HIGH RISK FOR PROGRESSION. AND THOSE WHO HAVE PROGRESSED WITH END ORGAN DISEASE, END ORGAN DISEASE PLUS ABERRANT INFLAMMATORY OR IMMUNOLOGICAL RESPONSE. EACH OF THESE HAS A SEPARATE THERAPEUTIC APPROACH. AS YOU KNOW THE AT RISK UNINFECTED PERSON ONE OF THE THINGS THAT THAT PERSON CAN TAKE IS SOMETHING THAT WOULD DIRECTLY PROPHYLACTICALLY ADDRESS THE VIRUS. THAT COULD BE EITHER A DIRECT ANTI-VIRAL OR SMALL MOLECULE, A DRUG AS IT WERE OR ANTIBODY, MONOCLONAL ANTIBODY. THE ASYMPTOMATIC INFECTED PERSON WHICH 30 AND 40% OF PATIENTS YOU ISOLATE THEM USUALLY AT HOME AND DON'T DO REALLY ANY SPECIFIC THERAPEUTIC INTERVENTION. SYMPTOMATIC BUT LOW RISK PERSON FOR PROGRESSION GIVE SYMPTOMATIC TREATMENT NOT DIRECTED AT THE VIRUS OR ANY OTHER ASPECT OF THE INFLAMMATORY IMMUNOLOGICAL RESPONSE. BUT THE SYMPTOMATIC BUT HIGH RISK PERSON FOR PROGRESSION, YOU TARGET THE VIRUS AGAIN SIMILAR TO PREVENTION OF INFECTION FOR THE TREATMENT OF INFECTION, DIRECTING IT AT THE VIRUS FOR THOSE WITH PROGRESSIVE END ORGAN DISEASE WE HAVE ORGAN SYSTEM SUPPORT. FOR THOSE WITH END ORGAN DISEASE PLUS IN ABERRANT INFLAMMATORY OR IMMUNOLOGICAL RESPONSE WE HAVE A NUMBER OF IMMUNOMODULATORS INCLUDING THE COMMONLY USED DEATH METH ZONE. FOR THE PURPOSE OF -- DEX METH ZONE. FOR TODAY'S CONGRESS WE WILL TALK PREVENTION AND TREATMENT WITH ANTIBODIES. ONE THINKS OF O ANTIBODY THERE'S SEVERAL APPROACH. THERE'S CONVALESCENT PLASMA, MONOCLONAL ANTIBODIES HYPERIMMUNE GLOBULIN OR POLYCLONAL ANTIBODIES. FORT MATILY WE HAVE BEEN SUCCESSFUL PARTICULARLY IN THE ARENA OF MONOCLONAL ANTIBODIES WHICH HAVE BEEN SHOWN UNDER CERTAIN SIX HAVE GIVEN EARLY ENOUGH -- CIRCUMSTANCES IF GIVEN EARLY IN TREATMENT TO PREVENT PROGRESSION OF HOSPITALIZATIONS AND THERE'S BEEN A NUMBER OF CANDIDATES THAT HAVE SHOWN THAT. SO CLEARLY WE ARE DEALING WITH A VIABLE THERAPEUTIC INTERVENTION THAT NEEDS TO BE PERFECTED AND NEEDS TO BE WORKED ON TO MAKE IT BETTER. THAT IS WHAT THIS CONFERENCE IS ABOUT. WE WILL TALK OPTIMIZATION INCLUDING THE USE OF ANIMAL MODELS TO STUDY THIS APPROACH, THERE'S ALSO THE BARRIERS TO THE IMPLEMENTATION IN A REAL WORLD SETTING WHICH WE ALL KNOW ABOUT SO PAINFULLY NAMELY THE LOGISTICS OF IV ADMINISTRATION, AND WHAT WE NEED TO DO TO GET ROUTES OF ADMINISTRATION BEYOND IV ADMINISTRATION. THE USE OF ANTIBODIES IN CONTEXT OF SOMEONE WHO MAY BE VACCINATED AS WELL AS IDENTIFICATION AND OPTIMIZATION OF PAN CORONA VIRUS ANTIBODIES. ALL VERY IMPORTANT ISSUES THAT WE HOPE THIS CONFERENCE WILL BRING US CLOSER TO RESOLUTION OF SOME OF THE UNKNOWN, RESOLUTION OF SOME OF THE PROBLEMS SO LOOKING FORWARD WE WILL BE ABLE TO USE THESE MODALITIES OF THERAPY IN THE OPTIMAL WAY. THANK YOU VERY MUCH. LOOKING FORWARD TO A PRODUCTIVE MEETING. >> THANK YOU VERY MUCH DR. COLLINS, WOODCOCK AND FAUCI. NEXT SECTION OF THE SUMMIT INCLUDES FIVE STATE OF THE SCIENCE PRESENTATIONS WE WILL BEGIN WITH DR. PETER MARKS, DIRECTOR OF THE CENTER OF BIOLOGICS EVALUATION AND RESEARCH, AT THE US DRUG ADMINISTRATION AND HE WILL DISCUSS USE OF CONVALESCENT PLASMA AND HYPERIMMUNE GLOBULIN. THE MIC IS YOURS DR. MARKS. >> THANK YOU FOR INVITING ME TODAY. I ASSUME YOU WILL ADVANCE THE SLIDES SO IF I WILL TALK ABOUT CONVALESCENT PLASMA AND HYPERIMMUNOGLOBULINS FOCUSING ON CONVALESCENT PLASMA. NEXT SLIDE I WILL TRY TO GIVE YOU A SUMMARY OF EXPERIENCE TO DATE WITH CONVALESCENT PLASMA IN COVID-19 TALK ABOUT THE DATA FROM THE U.S. EXPANDED ACCESS PROGRAM AND THEN TOUCH UPON COVID-19 HYPERIMMUNE GLOBULIN FROM HUMANS. I HAVE HAD THE NEXT SLIDE. WHAT WE KNEW GOING INTO THIS AND CONVALESCENT PLASMA STARTED TO BE USED IN CHINA IN LATE JANUARY EARLY FEBRUARY OF 2020 AFTER THE CHINESE CONTACTED US AT FDA AND ALSO WHO ABOUT TRYING TO HAVE A LOW HANGING FRUIT THERAPEUTIC TO USE FOR INDIVIDUALS INFECTED WITH SARS COV-2. THE RATIONALE HERE WAS THE FACT THAT RESPIRATORY ILLNESSES HAD BEEN TREATED WITH CONVALESCENT PLASMA WITH SOME EVIDENCE OF EFFICACY GRANTED NOT WITH DEFINSIVE EFFICACY WITH THE EXCEPTION OF HEMORRHAGIC FEVER WHICH THERE ARE TWO RANDOMIZE CONTROL TRIALS THAT APPEAR TO SHOW THE BENEFIT OF CONVALESCENT PLASMA IN THAT ENTITY. IF ONE LOOKS AT A VARIETY OF RESPIRATORY ILLNESS INFLUENZA OR OTHER SARS CORONA VIRUSES IT SEEMED TO BE A TREND THAT PERHAPS CONVALESCENT PLASMA MIGHT BE A BENEFIT. IMPORTANTLY THE BEST EFFICACY WAS SEEN WHEN PLASMA WITH KNOWN ANTIBODY TITERS WAS USED AND GREATEST EFFECT ON MORTALITY WAS SEEN WHEN CONVALESCENT PLASMA ADMINISTERED EARLY AFTER SYMPTOM ONSET. SO JUST TO TAKE -- REITERATE WHAT WE KNEW FROM THE PAST GOING INTO THIS, THE BEST EFFICACY WAS SEEN WHEN CONVALESCENT PLASMA WITH NO ANTIBODY TITER WAS USED AN EFFECT ON MORTAL I WAS SEEN WHEN PEOPLE TREATED EARLY. EFFECTS WHEN PEOPLE HAD MULTI-ORGAN SYSTEM FAILURE WAS NOT REPORTED SO EARLY ANTIBODY TREATMENT WAS KNOWN, THIS WAS KNOWN BY THE WAY, THIS SLIDE, THE INFORMATION ON THE SLIDE WAS KNOWN IN THE 70s AND 80s AND EVEN BEFORE THAT. REPORTED IN LITERATURE AS EARLY AS 50s AND 60s SO GOING INTO THIS WE HAD KNOWLEDGE. WHAT HAPPENED? WE LOOKED AT DATA TO SUPPORT THE USE OF CONVALESCENT PLASMA AND SOME OBTAINED WHILE THE INITIAL CONVALESCENT PLASMA WAS BEING USED ON EMERGENCY SINGLE PATIENT IND BASIS AND SUPPORT NON-CLINICAL DATA INCLUDED DATA FROM HAMSTERS AND FROM CASE 2 TRANSDUCE MICE WHICH SHOWED THAT ADMINISTERING CONVALESCENT PLASMA SEEMED TO HAVE SOME BENEFICIAL EFFECT EARLY REPORTS OF USE OF COVID-19 CONVALESCENT PLASMA WERE SUGGESTIVE SO THERE WAS AN EARLY CASE SERIES FROM INITIAL OUTBREAK IN CHINA THAT WAS PUBLISHED, VERY SOON AFTER SERIES OF 5, 10 PATIENTS STUDIED MOST OF THEM WERE MORE SERIOUSLY ILL, THERE WAS NOTHING DISPOSITIVE SHOWN BUT THERE WAS THIS FEELING OR TREND TOWARDS BENEFIT THAT WAS FELT TO BE THERE. SUBSEQUENTLY WE HAD A NUMBER OF STUDIES THAT HAVE BEEN DONE INCLUDING RANDOMIZE CONTROL TRIALS, MAJORITY WHICH HAVE BEEN NEGATIVE I WILL TELL YOU IN A MOMENT. CONTROL TRIALS BASED ON PLASMA AVAILABILITY WE ARE NOT TRULY RANDOMIZED RETROSPECTIVE COHORT AND CASE SERIES. NEXT SLIDE. SO THE RETROSPECTIVE MATCH COHORT STUDIES THIS IS AN EXAMPLE OF ONE THAT WAS PERFORMED IN TEXAS WHERE THE LOOKING HERE MATCHING TO INDIVIDUALS WERE AS REASONABLY WELL MATCHED HERE. THEY DIVIDED THIS INTO THOSE THAT WERE TREATED RELATIVELY SOON AFTER ADMISSION, 72 HOURS AND ONES TREATED LATER. IN GENERAL, WHAT BECAME CLEAR IS THAT THERE SEEMED TO BE SOME BENEFIT TO INDIVIDUALS TREATED EARLY ON WITH CONVALESCENT PLASMA AND THAT SEEMED TO INDICATE AT LEAST IN THIS RETROSPECTIVE STUDY A POSSIBLE SURVIVAL BENEFIT BUT WE KNOW POTENTIAL DOWN SIDES OF UNCONTROLLED STUDIES. NEXT SLIDE PLEASE. SO ANY NUMBER OF RANDOMIZE TRIALS WERE CONDUCTED IN HOSPITALIZED PATIENTS AND THOSE WERE PEOPLE WITH MORE ADVANCE DISEASE TREATED GENERALLY THOSE INTUBATED OR THOSE WHO WERE SOON ON THEIR WAY TO BE INTUBATED. REALLY DID NOT SHOW BENEFICIAL EFFECT ON CONVALESCENT PLASMA WITH THE EXCEPTION PERHAPS OF THOSE WHO HAD UNDERLYING IMMUNOCOMPROMISE SUCH AS HEMOLOGIC MALIGNANCIES OR AUTOIMMUNE DISEASE WITH EXCEPT OF THAT GROUP WHICH SEEMED TO BENEFIT ACROSS THE SPECTRUM, TEMPORAL SPECTRUM TO TEAK THEM, NON-IMMUNOCOMPROMISED PATIENTS NO SIGNAL IN A VARIETY OF TRIALS CONDUCTED IN NETHERLANDS TO THE RECOVERY TRIAL, WHICH IS PROBABLY THE MOST NOTABLE OF THESE. THOUGH THERE ARE METHOD LOGIC FLAWS HERE I THINK THAT IT IS STILL REASONABLE TO CONCLUDE THAT LATE ON IN THE GAME TREATING PEOPLE WITH CONVALESCENT PLASMA WAS NOT OF BENEFIT AT LEAST FROM WHAT WE CAN SEE NOW. THERE WERE A FEW RANDOMIZE TRIAL AND SEVERAL UNCONTROLLED TRIALS REPORTED EARLIER WHEN PEOPLE BEFORE STUDIED IN EARLIER STAGE DISEASE. THOSE INCLUDED THE RANDOMIZE TRIALS CONDUCTED IN ARGENTINA, WHICH SEEMED TO SHOW BENEFIT GRANTED DID NOT LOOK AT SURVIVAL IN ONE OF THE TRIALS BUT DID SEEM TO SHOW CLINICAL BENEFIT WHEN INDIVIDUALS WERE TREATED EARLY ON AND THERE HAVE BEEN A FEW TRIALS NOW REPORTED OUT IN THE UNITED STATES WHERE IT WOULD APPEAR IF YOU TREAT PEEP AT THE RIGHT PLACE, THAT IS WHEN -- PEOPLE AT THE RIGHT PLACE WHEN THEY ARE NOT SICK AS TO BE ON THE WAY TO INTO BIG BUT NOT SO HEALTHY AS TO BE ALMOST ABLE TO WEATHER COVID-19 WITHOUT MEDICAL INTERVENTION, YOU CAN POTENTIALLY DEMONSTRATE SOME BENEFIT, GO TO THE NEXT SLIDE. ONE OF THE WAYS THAT THIS TO GIVE AN EXAMPLE OF U.S. CONVALESCENT PLASMA EXPANDED ACCESS PROTOCOL, FDA WAS INVOLVED IN COLLABORATION WITH BARTA AND THE MAYO CLINIC AND JOHNS HOPKINS, THIS IS A SINGLE ARM PROTOCOL THAT WAS PUT IN PLACE TO ALLOW ACCESS. AT THE TIME THIS PROTOCOL WAS PUT IN PLACE FDA WAS RECEIVING HUNDREDS OF INDIVIDUAL PATIENT IND REQUESTS ON A DAILY BASIS AND WE NEEDED TO GET THINGS ORGANIZED WE TRIED TO GET RANDOMIZE TRIALS SET UP BUT THAT WAS NOT TO HAPPEN QUICKLY. SO THE EXPANDED ACCESS PROTOCOL WAS INITIATED ENTERTAINED FROM THE MAYO, WITH COLLABORATION FROM JOHNS HOPKINS. IT WAS A SIMPLE DEMOGRAPHICS CAP CAPTURE SIMPLE OUTCOMES WITH THE KNOWLEDGE WE CAN GO BACK AT THE END OF THE DAY AND TRY TO UNDERSTAND THE TITLERS OF THE UNITS GIVEN. THE TITER OF ANTIBODY TITER OF THE UNITS WAS NOT KNOWN UP FRONT BECAUSE AT THE TIME WHEN THIS WAS STARTED IN APRIL OF 2020 WE DID NOT HAVE A WAY OF GETTING HIGH THROUGH PUT TITERS. 2700 PLUS SITES, OVER 70,000 PEOPLE TREATED. BECAUSE OF THE AMOUNT OF TIME FROM APRIL THROUGH AUGUST, THIS PROTOCOL WENT, PEOPLE HAD A LOT OF TREATMENT, SO TEASING OUT A SIGNAL HERE, A LITTLE CHALLENGING BECAUSE WE WENT FROM TIMES WHEN THERE WAS INEFFECTIVE INTERVENTION HYDROXY HYDROXYCHLOROQUINE TO EFFECTIVE SUCH AS DEXAMETHASONE AND RECOMMEND DECEMBER VEER. WHAT -- REMDESIVIR. SOME CLEAR THINGS IN APRIL IF I CAN GO BACK IS INSIST FINDING SOME WAY TO FIND ANTIBODY TITER UP FRONT BECAUSE WHAT WE LEARNED WAS THAT THIS WAS NOT AN EASY THING TO DO. IT TOOK US SEVERAL TRIES TO FIND A RELIABLE TEST TO UNDERSTAND WHAT THE NEUTRALIZING CAPACITY OF THE PLASMA WAS OR ANTIBODY TITERS WERE. WE SETTLED ON AUTOMATED DSL 3 NEUTRALIZATION ASSAY DONE BY THE BROAD MIT BY LONG LEADING THAT EFFORT. SO THE RANGE OF TITERS IN THE BROAD NEUTRALIZING TITERS IN THE BROAD ASSAY WERE SPREAD ACROSS A WIDE VARIETY FROM 0 TO OVER A THOUSAND AND THERE WAS A RELATIVELY EASY DISTRIBUTION OF TITERS ACROSS THAT RANGE. THAT PROVIDED US WITH SOME BENEFIT BUT -- NEXT SLIDE, BECAUSE WE WERE ABLE TO ESSENTIALLY DIVIDE THE GROUP INTO A HIGHER TITER AND A LOWER TITER GROUP, AND WHEN ONE LOOKED AT THAT AND COMPARED, SHORT TERM SURVIVAL, 28 DAY SURVIVAL ONE SHOULDAL COULD SHOW IN THOSE PARTICULARLY THOSE NOT INTUBATED THAT IS WHERE THE EFFECT WAS SO THE EARLIER STAGE PATIENTS THERE WAS AN ABSOLUTE IMPROVEMENT IN MORTALITY THAT WAS VERY MODEST. NO ONE WILL SAY THIS IS INCREDIBLE BUT RELATIVE IMPROVEMENTS IN SEVEN DAYS WERE 10, 15%. THE OVERALL SURVIVAL BENEFIT AT 17, OR 28 DAYS IS DRIVEN BY PATIENTS NOT INTUBATED. NEXT SLIDE. THIS IS TO SHOW YOU THERE DOES APPEAR TO BE A HINT OF A DOSE EFFECTIVE, DIRECT YOUR ATTENTION THE ORANGE BARS ON THE RIGHT HAND SIDE WHERE YOU CAN SEE THAT AT THE LOWEST ANTIBODY TITERS, 0 TO 62 THESE WERE PEOPLE DOCUMENTED BY AN -- BY A PCR TEST TO HAVE HAD COVID-19 SO THESE ARE NEUTRALIZING ANTIBODY TITERS SO THE LOWEST GROUP FROM 0 TO 62 COMPARED TO THE HIGHEST GROUP 1,000 PLUS YOU CAN SEE THERE WAS DIFFERENCE IN SURVIVAL AT THAT SEVEN DAY TREATMENT INTERVAL AND DOES APPEAR, IT IS A HINT OF A DOSE RESPONSE HERE. AGAIN, VERY MODEST EFFECTS. NEXT SLIDE PLEASE. THIS IS COURTESY OF COLLEAGUES AT NIH WHO ASSISTED IN THIS ANALYSIS, THIS IS A A A KAPLAN MIRE ANALYSIS THAT SHOWED IF YOU LOOK AT THOSE NOT INTUBATED THEY DROVE A STATISTICALLY SIGNIFICANT VERY SMALL DIFFERENCE IN SURVIVAL BUT AGAIN DETECTABLE WHEN YOU START TO HAVE THOUSANDS OF PATIENTS YOU CAN SEE AT THE BOTTOM HERE YOU HAVE 10,000 PATIENTS IN A GROUP. NEXT SLIDE PLEASE. THE TAKE AWAY MESSAGE, HIGH TITER VERSUS LOW TITER CONVALESCENT PLASMA ASSOCIATED WITH A MODEST SURVIVAL BENEFIT MOST APPARENT EARLIER IN THE DISEASE COURSE. MODEST RELATIVE IMPROVEMENTS HERE. NOT LIKE THE MONOCLONALS YOU WILL HEAR ABOUT IN A FEW MINUTES BUT IT WAS A NOISY STUDY BECAUSE IT WASN'T INTENDS, IT WAS AN ACCESS PROTOCOL WHICH WE TRIED TO DERIVE INFORMATION. WHAT HAVE WE LEARNED? NEXT SLIDE. WHAT WE LEARN IS EVERYTHING YOU KNEW YOUR MOTHER TOLD YOU YOU SHOULD KNOW YOU SHOULD HAVE LEARNED EARLIER ON. WHAT WE FOUND OUT AFTERWARDS IS THE BEST EFFICACY WAS SEEN WITH CONVALESCENT PLASMA WITH KNOWN ANTIBODY TITERS WERE USED AN GREATEST EFFECT ON MORTALITY WERE GENERAL GENERALLY OBSERVED WHEN CONVALESCENT PLASMA WAS ADMINISTERED EARLY AFTER SYMPTOM ONSET SOMETHING WE KNEW PROBABLY SHOULD HAVE LISTENED MORE CLOSELY TO AND IN THE HEAT OF THE MOMENT IN ALL HONESTY WHEN EVERYONE WAS DESPERATE TO HELP TERRIBLE SITUATION THE WORST SITUATION IN A CENTURY PEOPLE WERE DOING THEIR BEST. SO WHAT ABOUT HYPERIMMUNE GLOBULIN? THEY WERE STARTED LIGHT IN THE PANDEMIC BECAUSE IT REALLY TOOK A TREMENDOUS AMOUNT AND THE MANUFACTURERS HERE THE COLLABORATION OF THEIR INDICATED BIOTEST AND OTHERS, TOOK A LOT TO GET -- HAD TO OVERCOME ACTIVATION TO MAKE THE PRODUCT IN THE FIRST PLACE AND STUDY IT. IT IS CLEAR THAT THERE IS NO CLEAR BENEFIT IN ONE RANDOMIZED STUDY HOSPITALIZED PATIENTS GOES TOWARDS LATER ON IN DISEASE, HARD TO SEE A BENEFIT OUTPATIENT STUDIES ONGOING WE DON'T HAVE ANSWERS TO YOU MAY HEAR MORE ABOUT OTHER IMMUNE POLYCLONALS. NEXT SLIDE RUNNING OUT OF TIME HERE, IF WE HAVE ANOTHER PANDEMIC LIKE THIS AND DECIDE TO GO FORWARDS CONVALESCENT PLASMA, THE KEY LEARNING HERE IS REMEMBER WHAT WE KNOW ALREADY, THIS ACTS MOST LIKE A CONVENTIONAL ANTI-VIRAL SO EARLY ON IF IT'S GOING TO WORK IT WILL WORK EARLY ON AND HAS TO HAVE THE RIGHT POTENCY AND BE HIGH TITER. I'LL STOP THERE. THANKS VERY MUCH. >> THANK YOU, VERY MUCH, DR. MARKS FOR YOUR PRESENTATION AND BEING ON TIME. NOW I WOULD LIKE TO TURN THE VIRTUAL PODIUM TO DR. BUY I DON'T KNOW COHEN, -- BYRON COHEN, UNIVERSITY OF NORTH CAROLINA CHAPEL HILL, HE WILL DISCUSS SARS COV-2 ANTIBODIES TO PREVENT COVID-19. SO I THINK IT WAS STATE IN THE THE INTRODUCTION DECADES OF SCIENCE CREATED AN ENVIRONMENT THAT SET THE STAGE FOR THINKING ABOUT MONOCLONAL ANTIBODIES FOR PREVENTION AND TREATMENT OF SARS COV-2. DENNIS BURDEN WELL KNOWN FOR LEADERSHIP IN HIV RESEARCH IN A SCIENCE PAPER HAS A WONDERFUL SLIDE INDICATING IF B CELLS HARVESTED FROM PEOPLE RECOVERING FROM COVID THAT PARADIGM WAS POSSIBLE WHICH CELLS MAY BE ISOLATED POTENCY TESTED IN VITRO IN ANIMALS AND RESULT ULTIMATELY IN HUMAN CLINICAL TRIALS. SO THIS PARADIGM AND AS ME PETER SAID, AS CONVALESCE SENTENCE PLASMA CAME INTO PLAY, MANY COMPANIES STARTED USING A PARADIGM LIKE THIS TO GENERATE WHAT THEY THOUGHT THE MOST POTENT MONOCLONAL ANTIBODIES. NEXT SLIDE PLEASE. SO IN ORDER TO CONDUCT GET THIS WORK DONE, PEOPLE HAD TO BE REDEPLOYED AND RETOOLED. OPERATION WARP SPEED WAS A CRITICAL SOURCE OF FORWARD MOVEMENT, THAT DID ACTIVE PLATFORM YOU WILL HEAR MORE ABOUT TODAY. AND THE ACTIVE PLATFORM IS DONE MANY TRIALS DIFFERENT SPACES. BUT IN ADDITION, C SEVERAL NIAID NETWORKS WERE -- THAT WERE DOING OTHER THINGS WERE ASKED TO COME TOGETHER TO FORM THE COVID PREVENTION TRIALS, COVID-19 THE VTN PTN, INFECTIOUS DISEASE CLINICAL RESEARCH CONSORTIUM, WE WERE CHARGED WITH WORKING CONCOMITANTLY AND SYNERGISTICALLY ON VACCINES AN MONOCLONAL ANTIBODIES. M&A THIS WAS WITH THOUSANDS OF PARTICIPANTS AND SITES AND INVESTIGATORS AND WONDERFUL COLLABORATION WITH INDUSTRY BEYOND ANYTHING I EXPERIENCED AS MONOCLONALS BECAME AN IDEA OUT OF THE GATE WE WERE THEN ABLE TO IDENTIFY COMPANIES THAT WERE HEAD STARTS AND AGGRESSIVELY PURSUING THIS. THERE IS AN EXTENSIVE LIST OF COMPANIES, NOT REASONABLE, I'M FOCUSING ON A FEW, THE ONES WE STARTED WITH, BECAUSE I'M TALKING THE COVID PREVENTION NETWORK DID LAST YEAR, THERE ARE MANY COMPANIES THAT DESERVE RECOGNITION. THEY HAVE MADE AND ARE MAKING BUT WE WORK WITH LILLIAN AND REGENERON OUT OF THE GATE BECAUSE OF HOWEVER ALONG THEY WERE. AT THE END OF THE DAY AS ALREADY POINTED OUT EUAs WERE GRANTED TO MONOCLONAL LILY GENERATED WHICH ULTIMATELY EXTERNAL VARIANTS BECAME RESISTANT TOO AND THEY GENERATED COMBINATION OR COCKTAIL IF YOU WILL ON THIS SLIDE AND REGENERON ALWAYS WAS FOCUSED ON COMBINATION, COMMITTED TO THAT FROM THE BEGINNING AND THEIR COMBINATION WE'LL REFER TO AS REGENCOV. (INAUDIBLE) ACHIEVED -- HARD TO PRONOUNCE THESE NAMES, THERE ARE MANY OTHER MONOCLONALS IN DEVELOPMENT. MY COLLEAGUE DR. CHEW WILL TALK MORE DETAIL ABOUT THE DEVELOPMENT OF THESE DRUGS AND THEIR USE -- UA AND TREATMENTS. I WILL FOCUS ON WHAT WE HAVE DONE WITH PREVENTION. SO IN THE PREVENTION SPACE WE SAID TO OURSELVES WHY WOULD WE DO THIS? DR. COLLINS ELUDED TO THIS. WE WERE LOOKING FOR PEOPLE WHO -- THERE WAS NO VACCINE AND WE DIDN'T KNOW WE EVER MAKE THE VACCINE BUT WE KNEW THERE WERE THOSE EXPOSED WHO WOULD DO POORLY SHOULD THEY ACQUIRE COVID AND SO WE WERE FOCUSED ON THAT ABOUT THOSE POPULATIONS WITH THE -- PROVIDE IMMEDIATE IMMUNITY YOU WOULDN'T NEED VACCINE RESPONSE AND SOME UNLIKELY TO RESPOND TO VACCINES BE ALLERGIC, WE THOUGHT THAT WE WOULD CONTRIBUTE TO THE TREATMENT SPACE OR TREATMENT PEOPLE BY LOOKING AT VIRAL REPLICATION AND THOUGHT WE COULD PREDICT WHAT KINDS OF CONCENTRATION OF ANTIBODIES MIGHT BE REQUIREDDED IN THE VACCINE FIELD. SO NOT SURPRISINGLY WE HAD TO DECIDE WHO ARE THE TARGET POPULATION AND QUICKLY DECIDED ELDERLY PEOPLE, ESPECIALLY THOSE LIVING IN LONG TERM CARE FACILITIES U SUCH AS NURSING HOMES, HOUSEHOLDS BECAUSE WE KNEW VERY QUICKLY THAT HOUSEHOLD CONTACTS WERE IMPORTANT FOR TRANSMISSION EVENTS, COMPROMISED FOLKS WHICH REMAIN A DIFFICULT POPULATION TO WORK WITH AND THEN SOME HIGH INCIDENCE WORKPLACES ESPECIALLY THE PROTEIN INDUSTRY, IE MEAT PACKING PLANTS AND TRANSPORT FACILITIES. IN THE TRIAL WE FOCUSED ON THE FIRST TWO GROUPS. WE DID SPEND A LOT OF TIME STALKING TO OTHER GROUPS. NEXT SLIDE. SO NURSING HOMES. IT WAS OBVIOUS FROM THE BEGINNING FROM THIS NEW YORK TIMES ARTICLE WHILE ONLY ABOUT SOME PERCENTAGE OF PATIENTS IN NURSING HOMES WOULD ACQUIRE COVID DEATH WOULD BE REMARKABLE AND DISTURBING TRAGIC RATE. NEXT SLIDE. I HAD THE OPPORTUNITY TO TALK TO CEOS IN NURSING HOMES TO DECIDE WOULD IT BE POSSIBLE TO DO CLINICAL TRIALS IN NURSING HOMES PROSPECTIVE RANDOMIZE CONTROL TRIALS OF ANTIBODIES IN NURSING HOMES AND IT WAS QUITE AN AMAZING EXPERIENCE BECAUSE RATHER THAN RESISTANCE TO THE IDEA IT WAS LIKE CAN YOU BE HERE TOMORROW. THIS IS BEFORE THE DRUGS WERE AVAILABLE. SO THEN THE FIRST REALLY BIG EVENT WAS AVAILABILITY OF (INDISCERNIBLE) LILY DID THIS REMARKABLE JOB. THEY SAID WE WANT TO DO THIS, WE WILL ANTIBODY IN SUFFICIENT CONCENTRATION FOR TRIALS AND OUTFIT VANS THAT ARE GOING TO CRISS CROSS THE UNITED STATES AND WORK AS A SWAT TEAM TO GO TO A PLACE WHERE OUTBREAK OF SARS COV-2 IN A NURSING HOME MAY BE OCCURRING. WE ARE GOING TO PROVIDE BAMLANLVIMAB TO ANYONE A RESIDENT IN THE NURSING HOME OR STAFF OF THE NURSING HOME. THESE VANS WERE AMAZING AND THEY BUILT MORE DURING THE COURSE OF THE STUDY AND I JUST CAN'T SAY ENOUGH GOOD THINGS ABOUT MY COLLEAGUES AT THAT COMPANIES AND THE WORK THEY DID. THESE ARE THE PEOPLE ON THE VANS, ON CALL WITH THE DRIVER AND SECURITY AID, A NURSE, A PHARMACIST, JUST FACILITIES AMAZING TO DRIVE AROUND THE UNITED STATES AND ULTIMATELY WENT TO 140 FACILITIES ACROSS MANY CHAINS IN OTHER WORDS TO ACCOMPLISH WHAT I'M ABOUT TO SHOW YOU. NEXT SLIDE PLEASE. SO THE END OF THE DAY THIS IS A SLIDE OF WHAT HAPPENED WHEN WE TOOK PLACEBO TO THE ANTIBODY IN RESIDENTS OF LONG TERM CARE FACILITIES SO MEDIAN AGE AROUND 75 TO 80. AND YOU WILL SEE THAT VERY QUICKLY WE SAW THAT THIS ANTIBODY IS PROOF OF CONCEPT WORKED. REDUCED INCIDENT COVID INFECTION THAT IS SYMPTOMATIC COVID INFECTION BY 80% AMONG THOSE WHO RECEIVE ANTIBODY AND THERE WERE NO DEATHS IN THOSE WHO RECEIVED THE ANTIBODIES COMPARED TO FOUR DEATHS AMONG RESIDENTS AND TRAGICALLY WHO DID NOT RECEIVE THE ANTIBODY. SO WE SAW THIS AS A PRETTY STRONG PROOF OF THE CONCEPT THAT THESE ANTIBODIES COULD SERVE THE PASSIVE IMMUNITY WE THOUGHT WE WOULD SEE. IT IS IMPORTANT TO POINT OUT FROM THE BEGINNING WE HAD A COHORT A AND COHORT B. COHORT A ARE PEOPLE WHO ARE PCR NEGATIVE BASELINE PROVEN RETROSPECTIVELY WHO DID NOT HAVE COVID. COHORT B ARE PEOPLE WE INADVERTENTLY REITED EARLY ASYMPTOMATICALLY FOR COVID. ALL ANY TIME I USE THE WORD COHORT B REFERS TO INFECTED ASYMPTOMATIC POPULATION INADVERTENTLY BUT WISELY RECEIVED MONOCLONAL ANTIBODIES COCKTAIL. THIS SHOWS WHAT MIGHT BE ANTICIPATED THE NOSE PART OF THE WINDOW NEUROOF THE DISEASE THAT SHOWS AMONG RESIDENTS AND STAFF, WHO ULTIMATELY DEVELOP COVID INFECTION THE CONCENTRATION OF VIRUS IN THE NOSE IS HIGHER AMONG THOSE WHO DID NOT RECEIVE ANTIBODY COMPARED TO THOSE WHO DID RECEIVE ANTIBODY AND DURATION OF SHEDDING IS LONGER THAN THOSE WHO DID NOT RECEIVE ANTIBODY. AS I SAID THIS IS ONTOLOGY TALK, THESE RESULTS ARE IN JAMA RECENT WILL I SO THOSE INTERESTING ALL DETAILS CAN PULL UP THIS ARTICLE. SAME TIME DOING THE STUDY WE WERE WORKED ON REGENERON AND REGEN COV COMBO AND THERE WE HAVE A DIFFERENT MODEL GOING TO GO TO HOUSEHOLDS AND TRY TO GET THERE WITHIN A QUICK PERIOD OF TIME JUST LIKE LILY A FEW DAYS LESS THAN FIVE, FOUR TO FIVE DAYS IF WE COULD AND AGAIN THERE IS A COHORT A AND COHORT B WHO WILL RECEIVE THE COCKTAIL, A ARE PCR NEGATIVE NOSE BASELINE COHORT B TREATED FOR ASYMPTOMATIC INFECTION. IMPORTANTLY, WE GAVE THIS DRUG SUB Q SO NOW HAVING REALIZED I THINK FROM OUR DISCUSSION THE LOGISTICAL CHALLENGE THE FACT WE ARE GIVING SUB Q IS IMPORTANT. NEXT SLIDE PLEASE. THE FIRST 400 SUBJECTS OF THIS TRIAL WERE REPORTED PRELIMINARY RESULTS BECAUSE WE HAD NO IDEA WHAT WE WERE GOING TO SEE N SUMMARY WE SAW THAT WHEN HOUSEHOLD CONTACTS RECEIVE THE ANTIBODY THERE WERE NO SYMPTOMATIC CASES AND THERE WAS A 50% REDUCTION OF ACQUISITION OF SARS COV-2 IN THE NOSE. SO IT WAS A BIG SUCCESS IN THE FIRST 400 CASES. NEXT SLIDE PLEASE. AS MIGHT BE EXPECTED THE NOSE AGAIN THE WINDOW OF OUR UNDERSTANDING OF THIS DISEASE, IF YOU LOOK AT THE CONCENTRATION OF RECOVERY OF ACUTE PCR OF COPIES IN THE NOSE YOU SEE AMONG THOSE WHO RECEIVE ANTIBODY THERE WERE ONLY SMALL CONCENTRATIONS OF SARS COV-2 COMING FROM THE NOSE. AND IF WE LOOK AT THE NUMBER OF WEEKS YOU CAN DETECT VIRUS BY QPCR IN THE NOSE, IT IS MUCH SHORTER WHEN ANTIBODY WAS DELIVERED AS PROPHYLAXIS SO AGAIN SUCCESS FOR PROOF OF CONCEPT THAT ANTIBODY CAN PREVENT SYMPTOMATIC SARS COV-2 AND CAN ALSO REDUCE ACQUISITION OF ASYMPTOMATIC INFECTION IN THE NOSE. NEXT SLIDE PLEASE. FOR COMPLETENESS IT WOULD BE -- IT IS WORTH THE FOLLOWING, THAT WE REPORTED AT MEETING EARLIER IN THE YEAR 400 SUBJECTS BUT 1,505 SUBJECTS IN THE FULL STUDY. THAT DATA IS NOW ON LINE OR WILL BE ON LINE TODAY IN MEDRX AND SUBMITTED FOR PUBLICATION AND PRESENTED AT THE ACCMID MEETING. THE OTHER THING TO POINT OUT WHAT ABOUT THE PEOPLE WHO TREAT ASYMPTOMATICALLY COHORT B, THAT IS ALSO ONLINE NOW, IN MED RX AND SUBMITTED FOR PUBLICATION, INVOLVES 207 PARTICIPANTS RANDOMIZED TO PLACEBO OR ACTIVE AGENT AND RECEIVED -- THEN ATTEMPTING TO SEE WHAT BENEFIT WE WOULD REALIZE BY TREATING ASYMPTOMATIC SARS COV-2 AND MAYBE THAT WILL BE DISCUSSED LATER TODAY. NEXT SLIDE PLEASE. SO THE VARIANTS ARE GOING TO BE A HUGE TOPIC OF CONVERSATION, WE AS DR. WOODCOCK INDICATED CONCERNED AND MONITORED DID WE INDUCE VARIANTS AMONG THOSE WHO RECEIVE OUR ANTIBODY, THAT IS A RARE EVENT BUT DO VARIANTS EXOGENOUSLY DEVELOP RESISTANT TO ANTIBODIES, OBVIOUSLY YES. AND OUR EVOLUTION OF BETTER ANTIBODIES AND DIFFERENT COCKTAILS AND COMBINATIONS IS A RESULT OF THE EVOLUTION OF THE VIRUS AND I THINK WE ARE SUCCEEDING SOME LEVEL TRYING TO MEET THIS CHALLENGE. NEXT SLIDE PLEASE. SO THIS WHOLE PAST YEAR I HAVE NOW PRESENTED TWO COMPLETED TRIALS BY COVID PREVENTION MET WORK. MORE WORK THAT I DON'T HAVE TIME TO TALK ABOUT. AND TRY TO EMPHASIZE THE SUCCESS OF THE PROOF OF CONCEPTS THE PASSIVE IMMUNITY IDEA DOES WORK, A GIANT WAVE WASHED OVER US, SEEMS TO ME IT IS WASHED US TO SHORE TO THE EXTENT THE IDEAS ARE CORRECT AND POSSIBLE TO MAKE MONOCLONALS QUICKLY, THAT CAN MAKE A CONTRIBUTION. NEXT SLIDE PLEASE. SO TRYING TO STAY ON TIME, I'M GOING TO SLOW DOWN A LITTLE MORE THE CONCLUSION THAT I DRAW FROM THE PAST YEAR. MONOCLONAL ANTIBODIES NEUTRALIZE THIS VIRUS WERE RAPIDLY GENERATED, QUITE AMAZING WHEN WE GOT THERE THAT THE COMPANIES ARE MAKING THESE SUCCESSFULLY, EUA FOR SEVERAL AGENTS DR. CHEW WILL TALK ABOUT. WE COMPLETED TWO NIH INDUSTRY COLLABORATIVE TRIALS TO DATE ONE WITH LILY AND ONE WITH REGENERON AND BOTH POSITIVE RESULTS. THE EFFECT OF ASYMPTOMATIC EPIPEEK TREATMENT, I WILL CALL COHORT B, THAT -- THOSE RESULTS ARE STILL BEING EVALUATE AND STILL ABSTRACT FORM. WE BELIEVE THAT WE CAN MAKE A CONTRIBUTION TO THE TREATMENT OF ASYMPTOMATIC INFECTION BUT THAT REQUIRES MORE ANALYSIS. IN ADDITION A QUESTION THAT IS SURFACED IS WHAT HAPPENS IF YOU ARE GOING TO -- WHEN DO YOU GIVE A VACCINE WITH RESPECT TO MONOCLONAL ANTIBODIES? IF YOU GIVEN SOMEBODY A MONOCLONAL AND TRY TO VACCINATE THEM WILL YOU GET A VACCINE TAKE? CONVERSELY IF YOU GIVE VACCINE IN MONOCLONAL DO YOU WIPE OUT VACCINE TAKE? BEARE TRYING TO EVALUATE THAT QUESTION NOW. THE ANTIBODIES I PRESENTED TO YOU DO NOT HAVE ANY ALTERATION IN THE FC PORTION SO THEIR HALF LIVES ARE NATIVE HALF LIVES BUT OTHER MONOCLONALS ASTRA ZENECA, COMBINATIONS HAVE MODIFICATION THAT PROLONG THE HALF LIFE THAT MIGHT MAKE THESE ANTIBODIES ATTRACTIVE FOR LONG LONG TERM USAGE. FOR PEOPLE WHO CAN'T BENEFIT FROM A VACCINE. SO I WOULD END MY TALK BY ONCE AGAIN THANKING -- THIS HAS BEEN A REMARKABLE YEAR TO GET -- TO BE ABLE TO PRESENT THESE RESULTS. IT WAS A YOUNG TEAM EFFORT WITH INDUSTRY AND NIAID AND NIH AND OTHER INVESTIGATORS I CAN'T THANK THEM ALL, I LEAVE THE YEAR THINKING MONOCLONALS ARE GOING TO PLAY AN IMPORTANT ROLE IN PUBLIC HEALTH MEDICAL MANAGEMENT OF COVID-19 INFECTIONS. I THINK THE LOGISTICAL CHALLENGES ARE OBVIOUS. MANY ORGANIZATIONS HAVE SET UP INFUSION CENTERS OR DONE OTHER THINGS IN ORDER TO MAKE THIS POSSIBLE AND SUB Q IS A OBVIOUSLY PROVEN ANOTHER POTENTIAL ROOT TO GO. THANK YOU FOR LISTENING AND INVITING ME THIS MORNING. >> THANK YOU, VERY MUCH, DR. COHEN. MOVING FORWARD IT IS MY PLEASURE TO INTRODUCE DR. KARA CHEW FROM THE DAVID GEFEN SCHOOL OF MEDICINE AT UCLA. THE STAGE IS YOURS DR. CHEW. >> GREAT. THANK YOU. THANKS TO THE PLANNING COMMITTEE FOR THE OPPORTUNITY TO SPEAK TODAY. SO I'M GOING TO TALK WITH YOU ABOUT MONOCLONAL ANTIBODIES FOR OUTPATIENT TREATMENT AND WILL HEAR THE SAME MONOCLONALS AS DR. COHEN REVIEWED. JUST A POINT ALONG WITH DAVID SAMANTHA, I'M CO-CHAIR OF ACTIVE 2, ADAPTIVE PLATFORM TRIAL FOR EVALUATION OF THERAPEUTICS IN THE OUTPATIENT SETTINGS FOR COVID-19. SO JUST BRIEFLY SUMMARIZING MONOCLONAL ANTIBODIES AN TARGETS IN SPECTRUM YOU WILL HEAR MORE ABOUT THEIR MECHANISM OF ACTION IN SUBSEQUENT SESSION BUT THESE ARE NEUTRALIZING HUMAN IGG ANTIBODIES, MOST COMMONLY TARGET THE RECEPTOR BINDING DOMAIN, WHICH INTERACTS WITH THE H 2 RECEPTOR. AND AS SUCH IN TERMS OF MECHANISM OF ACTION THEY DO BLOCK VIRAL ENTRY BUT THEY MAY ALSO BE EFFECTIVE IN TREATMENT BY ENHANCING CLEARANCE OF INFECTED CELLS THROUGH NC MEDIATED EFFECTIVE MECHANISMS SUCH AS DBCC, ANTIBODY DEPENDENT CYTOSIS OR PLATFORMMENT PATHWAYS. THERE WERE A LARGE NUMBER OF MONOCLONAL ANTIBODIES IN DEVELOPMENT FOR TREATMENT AND PREVENTION, THESE ARE SINGLE AND COMBINATION OR COCKTAIL REGIMENS ANYWHERE FROM PRE-CLINICAL TO BASE 3 AND ALSO OF COURSE AS EVERYONE KNOWS, IN REAL WORLD USE THROUGH EMERGENCY USE AUTHORIZATION. THESE ANTIBODIES VARY IN EPITOPES THEY TARGET AND THIS HAS AN IMPACT ON THEIR POTENTIAL SUSCEPTIBILITY TO VARIANTS, SOME OF THE MONOCLONAL ANTIBODIES TARGET THE RECEPTOR BINDING MOTIF AND OTHERS HAVE TARGETS OUTSIDE OF PHASE 2 BINDING REGION, RECEPTOR BINDING WHICH IS A CONSERVED REGION LESS SUSCEPTIBLE TO MUTATION. SOME ALSO AS DR. COHEN MENTIONED FC DOMAIN MODIFICATION THAT EXTEND HALF LIFE AND THESE MODIFICATIONS MAY HAVE IMPACT ON EFFECTOR MECHANISMS. IN TERMS OF ROUTE OF ADMINISTRATION, THERE ARE LARGELY GIVEN RIGHT NOW THROUGH INTRAVENOUS INFUSION BUT ALSO UNDER EVALUATION ARE INTRAMUSCULAR ROUTES OF ADMINISTRATION IN SUB Q AS WELL AS INHALED ROUTES OF ADMINISTRATION. NEXT SLIDE. SO WE STARTED WITH BAMLIV,NAB FROM LILY, THIS IS INTERIM ANALYSIS WHERE THEY RANDOMIZE PARTICIPANTS TO ONE O THREE DOSE, 700, 2800 AND 7,000 MILLIGRAMS OR PLACEBO, THE PRIMARY ENPOINT, WE HAVE LEARNED A LOT SINCE THIS TIME, BUT SOME OF THE PRIMARY END POINT WAS CHANGED FROM BASELINE TO DAY 11 IN THESE VIRAL LOAD. THIS POPULATION ENROLLED INCLUDED SIMILAR RISK IN INDIVIDUALS, 70% HAD RISK FACTOR FOR SEVERE COVID, AT THAT TIME OLDER OR CO-MORBIDITIES. BMI 35 OR HIGHER. PARTICIPANTS WERE ENROLLED IN THE MEDIAN FOUR DAYS SO YOU CAN SEE THAT WAS VERY EARLY ON IN THEIR DISEASE COURSE AND AS DR. COHEN MENTIONED THIS REALLY REQUIRED HERCULEAN EFFORT I THINK IN TERMS OF GETTING PARTICIPANTS TESTED AND ENROLLED RAPIDLY. TO STUDY INTERVENTION. AS FAR AS THE PRIMARY END POINT THAT CHANGED BASELINE TO DAY 11 SARS COV-2 VIRAL LOAD VIR LOGIC OUTCOME WAS FOR 28-MILLIGRAM DOSE ONLY OUT OF THE THREE, DID APPEAR CROSS DOSES THAT IT REDUCED VIRAL LOAD FASTER AND SECONDARY ANALYSIS LOOKING AT THE HOSPITALIZATION, THESE ARE COVID RELATED HOSPITALIZATION OR ED VISITS, THE RATES OF THAT OUTCOME POOLED ACROSS THE DIFFERENT KOASES OF BAMLIBM MARKS THE RATE OF OUTCOME WAS LOWER IN RECIPIENTS COMPARED TO PLACEBO, 1.6% VERSUS 6.3%, THIS LED TO FIRST USE AUTHORIZATION FOR MONOCLONAL ANTIBODY. ALSO OF INTEREST AS WE CONTINUE TO LEARN MORE ABOUT SARS COV-2 RNA KINETICS IN INDIVIDUAL SARS COV-2 INFECTION WHAT THEY SAW WAS SOMETHING INTERESTING IN GIVEN IN THE SHOWN IN THE PANEL IN THE BOTTOM RIGHT HAND CORNER WHICH IS THAT INDIVIDUALS WHO ENDED UP HOSPITALIZED TENDED TO HAVE PERSISTENTLY HIGH VIRAL LOADS, LOAD THRESHOLDS, POST ENTRY. WHEREAS YOU CAN SEE IN THE BOX PLOTS THOSE NOT OPT HOSPITALIZED STUFF STEADY DECLINES OVER COURSE OF THEIR INFECTION. NEXT SLIDE. WHAT FOLLOWED WAS EVALUATION EXTENSION OF THE SAME BLAZE 1 STUDY. THE FIRST SO YOU CAN SEE LEFT HAND FIGURE, THE VIRAL LOAD THE THRESHOLD OCCURS NASO PHARYNGEAL, THREE DOSES OF BAMLIBMAM MENTIONED PREVIOUSLY IN THE ANALYSIS AND COMBINATION OF (INAUDIBLE) GIVEN 2800 MILLIGRAMS EACH. PLACEBO IN REDD, YOU CAN SEE BIGGER DIVERGENCE IN THE VIRAL LOAD CURVE AND THRESHOLD CURVES FOR COMBINATION IN BLUE. COMPARED TO PLACEBO AND BIGGER DIVERGENCE COMPARED TO THE BAMLIMAB ALONE. THE CHANGE IN BASELINE AT DAY 11 WAS SIGNIFICANT COMPARED TO PLACEBO FOR THE BAM ANY COMBINATION BUT NOT SIGNIFICANT FOR INDIVIDUAL MONOTHERAPY ARMS. IN THE TABLE WHAT IS GIVEN ARE RATES OF COVID RELATED HOSPITALIZATION OR ED VISITS AT DAY 28 FOR THE DIFFERENT ARMS, WHAT YOU CAN SEE IS OVERALL VERY LOW RATES WITH BAMLIBMAB, BUT FEW EVENTS IN THIS STUDY WITH SMALL POPULATION SMALL SAMPLE SIZE. EVICTING TO THE HIGHEST RISK DEFINED IN ANALYSIS POST HOCK WAS 65 OR OLDER BMI 35 OR OLDER THE DIFFERENCE IN HOSPITALIZATION AND EMERGENCY DEPARTMENT EVENT RATES WAS MUCH GREATER, AND SIGNIFICANT FOR BAMSIBMAM. I WANT TO MAKE ONE POINT HERE THINKING ABOUT THE TARGETS OF -- OF THESE DIFFERENT MONOCLONAL ANTIBODIES HELP US UNDERSTAND POTENTIAL REDUCES SUSCEPTIBILITY TO VARIANTS SO FOR THAT BOTH TARGET THE RECEPTOR BINDING MOTIF. NEXT SLIDE. THEN WHAT WE SAW WERE CONFIRMATORY DATA FOR THE BENEFIT OF BAMBIBMAB ON HOSPITALIZATION DEATH AND OUTPATIENT COVID. THIS IS PAGE 3 DATA FOR 2800-MILLIGRAM DOSE FOR EACH COMPONENT. THERE WAS A 70% REDUCTION IN EVENT RATES FOR THE COMBINATION COMPARED TO PLACEBO. SIMILAR FINDINGS FOR BAMLANIVAMAB WHICH ARE THE DOSES AUTHORIZED FOR EMERGENCY USE. ALSO OBSERVE WERE SAME REDUCTION IN VIRAL LOAD DAY 11 UNSTEAD OF DAY 7, EARLY TRIAL CHANGES SEEN WHERE THE ANTI-VIRAL EFFECT IS BEING OBSERVED. WHAT WAS ALSO REPORTED IN THIS PHASE 3 STUDY WAS REDUCTION IN TIME TO SUSTAINED SYMPTOM RESOLUTION. IN THIS CASE THIS WAS ABSENCE OF SYMPTOMS ALLOWING FOR MILD COUGH OR FATIGUE. THAT REDUCTION TIME SUSTAIN ISOLATION WAS MODEST, ONE DAY, 8 VERSUS 9 DAYS IN THE BAM COMBINATION COMPARED TO PLACEBO. NEXT SLIDE. SO MOVING TO HAVE (INAUDIBLE) HAS EPITOPE TARGET IN RECEPTOR BINDING MOTIF AND DEEMEMAB IS IN THE CORE AND YOU WILL SEE LATER THAT THERE ARE DIFFERENCES IN TERMS OF SUSCEPTIBILITY. OF VARIOUS VARIANTS TO THE INDIVIDUAL MONOCLONALS HERE SO THIS IS FROM REGENERON AND WHAT IS PRESENTED ON THIS SLIDE ARE THE PHASE 2 DATA WHICH ALSO LED THEM TO THE EMERGENCY USE AUTHORIZATION FOR THIS COMBINATION. SO WHAT THEY STUDIED WERE TWO DOSES OF (INAUDIBLE) AND PLACEBO 93-YEAR-OLD PER ARM AND MEDIAN THREE DAYS OF SYMPTOMS AT STUDY ENTRY RANDOMIZATION SO VERY EARLY IN DISEASE COURSE. AGAIN, AND 64% HAD AT LEAST ONE RISK FACTOR FOR HOSPITALIZATION, THEY USE SLIGHTLY DIFFERENT CUT OFFS FOR AGE, 50 AND OLDER, SIMILAR CO-MORBIDITIES, BMI OF 30. THE PROGRAM WAS VIR LOGIC, THEY DID LOOK AT AS FAR AS CLINICAL OUTCOME AT MEDICALLY ATTENDED VISITS. AND IN TERMS OF VIRAL LOGIC OUTCOME YOU CAN SEE IN THE LEFT HAND PANEL ARE THE VIRAL LOAD CURVES, TWO RNA WITH TWO REGENERON COMBINATION MONOCLONAL ANTIBODY DOSES IN GREEN AND BLUE COMPARED TO PLACEBO IN GRAY YOU CAN SEE THAT DIVERGENCE IN THE CURVES FROM PLACEBO. AND THEN WHAT THEY DID WAS AN INTERESTING ANALYSIS LOOKING AT THOSE WHO -- SORRY AT SERO STATUS, 4 STARTS WITH TWO BASELINE AND ANTI-LEADS VIRAL LOAD RESULTS IN THE TWO POPULATIONS SEPARATELY. AND THE DIFFERENCE IN VIRAL LOAD CURVES, ANTI-VIRAL EFFECT WAS MUCH MORE OBVIOUS IN THOSE ANTIBODY NEGATIVE AT STUDY ENTRY COMPARED TO THOSE WHO WERE ANTIBODY POSITIVE. THEY DID SEE POTENTIAL CLINICAL BENEFIT, IN TERMS OF THE MEDICALLY ATTENDED VISITS AS OUTCOME, 6% MEANING THAT IN THE PLACEBO GROUP VERSUS 3% IN TWO DOSE ARMS COMBINED. NEXT SLIDE. SO THEN THE PHASE 3 CONFIRMATORY DATA AS WITH (INAUDIBLE) COMBINATION MONOCLONAL ANTIBODIES IN OUTPATIENT COVID IN TERMS OF REDUCING HOSPITALIZATIONS AND DEATH. SO THESE ARE THE KAPLAN MIRE CURVES FOR THE 1200-MILLIGRAM TOTAL DOSE OF CAUSEIRIVIMAB COMPARED TO PLACEBO AND ALSO STUDY 2400-MILLIGRAM TOTAL DOSE AND THE FIRST WAVE WAS 2400-MILLIGRAM DOSE. ANALYSIS SPECIFIED TO INCLUDE INDIVIDUALS THAT HAD POSITIVE FAY SEW PHARYNGEAL PCR RANDOMIZATION AND ONE RISK FACTOR FOR COVID. THEY SAW BENEFITS IN HOSPITAL AND DEATH, REDUCTIONS THERE, OBSERVED ACROSS SUB GROUPS PARTICULARLY THOSE VIRAL LOAD OVER 10 AND SIX COPIES PER ML AT ENTRY AND SERO NEGATIVE. SIMILAR POINTS ESTIMATES IN THE DIRECTION OF BENEFIT, IN THOSE WITH LOWER VIRAL LOAD AND SERO POSITIVE WITH THE CONFIDENCE INTERVAL AROUND THIS POINT WERE VERY WIDE. WHAT WAS IMPRESSIVE HERE WAS GRAYER REDUCTION IN SYMPTOM DURING RATION, SYMPTOM TO RESOLUTION OF FOUR DAYS NOW, 10 VERSUS 14 DAYS FOR COMBINATION OF THEM COMPARED TO PLACEBO AND THAT WAS RESERVED FOR BOTH 1200-MILLIGRAM AND 2400-MILLIGRAM DOSE. RELATIVE RISK REDUCTION OF 70, 70% IN HOSPITALIZATION AND DEATH IN THIS POPULATION. JUST AS WAS OBSERVED WITH BAMLIMIMAB MENTION SLIDE. YOU MENTIONED WE ARE LEARNING A LOT STILL ABOUT VIROLOGY, THAT IS AN AIRIA MORE DATA WILL EMERGE AND WE HOPE THE SHARE MORE WITH YOU SOON FROM ACTIVE 2. THESE WERE SARS COV-2 RNA, NASO PHARYNGEAL LEVEL IN REGENERON PHASE 3 STUDY 2067. HERE THE SARS COV-2 RNA LEVELS ARE GIVEN BY HOSPITALIZATION AND DEATH, IN SERO NEGATIVE GROUP MIDDLE ROWS AND THOSE SERO POSITIVE, IN PLACEBO RECIPIENTS. SIMILAR TO WHAT WAS OBSERVED IN BLAZE 1 I WE SEE PERSISTENCE TENSE OF HIGH VIRAL LOADS FOLLOW-UP DAY 7 IN THOSE INDIVIDUALS WHO ENDED UP HOSPITALIZED AND DIFFERENT FROM THOSE NOT HOSPITAL HOSPITALIZED, MORE RAPID DECREASE IN SARS COV-2 RNA. EVOLVING IN TERMS OF VIROLOGY, DON'T HAVE A GREAT SURROGATE FOR HOSPITALIZATION AND DEATH IN TERMS OF VIROLOGY. NEXT SLIDE PLEASE. SO JUST SUMMARIZING HERE THE VIRAL LOAD CURVES AGAIN CAUSERUBIMAB, FOR THE IV FORMULATION DAY 3 AND NOW WE HAVE WAY FOR THE SUB Q FORMULATION FOR 1200-MILLIGRAM DOSE, WE DON'T HAVE OUTCOMES IN THE TREATMENT STUDY FOR SUB Q ADMINISTRATION BUT WHAT IS ANNOUNCED IS THERE ARE SIMILAR VIRAL LOAD REDUCTION WITH THAT DOSING AND WITH THE SUB Q ROUTE AS WITH IV. NEXT SLIDE. SO (INAUDIBLE) IS ANOTHER THAT HAS SINGLE MONOCLONAL ISOLATED FROM A SARS COV-2 SURVIVOR, IT HAS TARGET OF IN THE RBD CORE CONSERVED AND IS EXPECTED THEN TO HAVE MUTUALIZATION ACROSS SARS COV-2 VIRUS. SO THE CLINICAL DATA FOR THAT ARE FROM THE PHASE 3 ANALYSIS. THIS IS INTERIM ANALYSIS PRE-PLANNED AND THE TRIALS FOR EFFICACY WITH EVIDENT REDUCTION IN HOSPITALIZATION, IN THOSE WHO RECEIVE -- COMPARED TO PLACEBO. THIS IS GIVEN IV. HERE WHAT WAS OBSERVED WAS 85% RELATIVE REDUCTION. WE HAVE LESS CLINICAL OUTCOMES DATA LESS EXPERIENCE WITH THIS MONOCLONAL. NEXT SLIDE. SO BRIEFLY THIS IS FROM THE STANFORD SARS COV-2 DATABASE BUT SUMMARIZES ACTIVITY OF THE DIFFERENT MONOCLONALS, AGAINST DIFFERENT VARIANTS AND INDIVIDUAL MUTATION INTRODUCED IN VIRTUALIZATION ASSAYS. THROUGH THE DARK BLUE AND LIGHT BLUE IS WHERE THE ACTIVITY OF THESE MONOCLONALS IS EFFECTED. AND THE LOSS OF ACTIVITY WITH BAMLIMAB AND SUB VARIANTS AND ALSO FORAYSRUBIMA -- FOR CASRUBIMAB BUT RETAIN ACTIVITY FOR OTHERS IN DEVELOPMENT INCLUDING ASTRA ZENECA COMBINATION AND COMBINATION OF (INDISCERNIBLE). NEXT SLIDE. THIS IS REALLY INTENDED TO SHOW OTHER MONOCLONALS IN THE PIPELINE, THREE THAT ARE CURRENT WILL I IN PHASE 3 EVALUATION ACTIVE 2, ROCKEFELLAR BMS MONOCLONAL, ALSO WITH RETAINED ACTIVITY IN 20 WHICH IS AN INTERESTING MONOCLONAL. TARGETING CONSERVED REGION. THERE IS MORE DATA I THINK AVAILABLE THAN PRESENTED HERE ON THE ACTIVITY OF -- RETAINED FOR THESE MONOCLONALS ACROSS VARIANTS. SO I I I WILL SKIP TO MY FINAL SLIDE. SO THE LESSONS LEARNED, I DID PRESENT A LOT OF SAFETY DATA. BUT WHAT WE HAVE SEEN IS THAT THESE MONOCLONAL ANTIBODY THERAPIES ARE SAFE AND THEY ARE EFFECTIVE IN PREVENTING HOSPITALIZATION AND DEATH IN SYMPTOMATIC SARS COV-2 INFECTION AND EARLIER THE BETTER IN TERMS OF ADMINISTRATION. THEY HAVE VULNERABLE TO VIRUS EVOLUTION SO WE NEED THERAPIES THAT ARE GOING TO BE MORE STABLE AND ROBUST TO FUTURE VARIANTS. WHAT ARE THE UNKNOWN RISKS WE DON'T YET KNOW ABOUT TREATMENT RESISTANCE AND IMPLICATIONS PARTICULARLY ON PUBLIC HEALTH LEVEL. THEN UNKNOWN OR UNESTABLISHED BENEFITS STILL ARE ON THE SYMPTOMATIC IN DIFFERENT POPULATION AND POST ACUTE SEQUELAE. YOU WILL HEAR MORE ABOUT CHALLENGES WITH DELIVERY AND PERHAPS THESE RATS WILL MAKE THINGS EASIER ON SUB Q. SO JUST ONE MORE. SORRY. SO A PLUG FOR ACTIVE 2 WHERE WE ARE AS I MENTIONED THREE MONOCLONALS PHASE 3, THE EMS MONOCLONALS ADMINISTERED SUB Q IN PHASE 2 AND POLYCLONAL ANTIBODIES FROM BOVINE INHALED INTERFERON BETA. REGIMEN. THANKS VERY MUCH. >> THANK YOU VERY MUCH, DR. CHEW. MOVING FORWARD DR. JENS LUNDGREN FROM HOSPITAL OF COPE HAGAN WILL DISCUSS ANTIBODIES FOR TREATMENTS IN HOSPITALIZED PATIENTS. A HI, EVERYBODY. I'M DOING THIS PRESENTATION ON BEHALF OF THE ISAAC STUDY GROUPS AND PEOPLE HAVE BEEN WORKING HARD THE LAST 18 MONTHS. NEXT SLIDE PLEASE. AS YOU KNOW COVID-19 PATIENTS THE SITE OF THE DISEASE CAUSING VIRAL REPLICATION IS THE PULMONARY COMPARTMENTS IN THE LUNG AND NASAL, THAT'S A TESTAMENT TO THAT VIREMIA OR PROCESS HERE, PROGNOSTIC OUTCOMES AMONG PATIENTS. STANDARD OF CARE IS ALSO DIFFERENT FROM OUTPATIENTS. WE GIVE THEM ANTI-VIRAL REMDESIVIR WITH AGENTS. WE KNOW FROM OTHER VIRAL DISEASE IT IS COMBINATION OF TWO OR MORE LEADS TO BETTER OUTCOME AND THEREFORE WE EXAMINE WHETHER NEUTRALIZING ANTIBODIES IN ADDITION TO STANDARDS OF CARE ARE SAFE AND APPROVED OUTCOME SO THIS TWO STUDIES I'M DISCUSSING IS ACTIVE 3 ALSO KNOWN AS TICO IN SITU 14, A PLATFORM 3 TRIAL OF NOVEL ANTI-VIRAL AGENTS. EARLY SAFETY AND UTILITY ASSESSMENT USING THE OUTCOMES THE PRIMARY END POINT THAT IS SUSTAINED RECOVERY DURING (INAUDIBLE). WE HAVE STUDYING FIVE AGENTS. THE FIRST THREE FAILED EARLY UTILITY ASSESSMENT HENCE UNBLINDED. THE FOURTH MONOCLONAL ANTIBODY D 7442 DID PASS EARLY FUTILITY AS WELL AS SUBSEQUENT DSMB MEETING WE HAD YESTERDAY AND STUDY IS STILL BLINDED, THE ROLE IS AROUND 5150 AS WE SPEAK. IN ADDITION TO THAT INSIDE 13 ALSO KNOWN AS ITAC THAT STUDY IS COMPLETED, WAS POWERED TO ASSESS PRIMARY END POINTS USING DAY 7 ORDINAL PULMONARY OUTCOME AND WE ARE STUDYING STANDARDIZED GAMMA GLOBULIN PRODUCT PROVIDED BY FOUR COMPANIES. THE ORGANIZATION AROUND THESE FILES INCITE WAS THE -- INSIGHT WAS THE LEAD TRIAL NETWORK COMPOSED OF THE SDMC UNIVERSITY OF MINNESOTA IN NATIONAL COORDINATING SENSES, WE WERE HAPPY TO HAVE EXTRAORDINARY FRUITFUL COLLABORATION WITH TWO NHLBI CONNECTS TRIAL NETWORK CTSN AS WELL AS VA. THE VISION OF CLINICAL RESEARCH FUNCTIONS AS FOR BOTH TRIALS. NEXT SLIDE. SO THE PRINCIPLE OF STUDY DESIGN FOR THESE TRIALS WERE TO STUDY HOSPITALIZED PATIENT COVID-19 WITHIN 12 DAYS OF SYMPTOM ONSET. AND VERY CLASSICALLY RANDOMIZATION TO THE INVESTIGATIONAL AGENT, COMBINATION OF STANDARD OF CARE WHICH INCLUDED REMDESIVIR STUDIES PROVIDED AS WELL AS IMMUNE MODULATORY TREATMENT ALL MATCHING THE CFO COMBINATION STANDARD OF CARE. NEXT SLIDE. WE HAVE BEEN ASKED WHAT IS THE RATIONALE FOR STARTING FIVE ANTIBODY AGENTS. PARTLY THIS IS BECAUSE OF AVAILABILITY WHEN THE TRIAL WAS UP AND RUNNING, FOR BAM BOTH OF THEM WERE SINGLE MONOCLONAL ANTIBODIES, OBVIOUSLY (INAUDIBLE) WAS DIFFERENT FROM BAM BECAUSE OF CONSERVED EPITOPE AND HARVESTED FROM A COV 1 PATIENT. THE NEXT TWO COMBINATION OF TWO MONOCLONAL ANTIBODIES, NON-NOVEL EPITOPES SHOWN TO HAVE ADDITIVE EFFECTS ON WHAT DIFFERS FROM BRII IS THE SECTION IS GENETICALLY MODIFIED TO REDUCE RISK OF ANTIBODY DEPENDENT ENHANCEMENT. THE HYPERIMMUNE IVIG HAVE ANTI-ANTIBODIES AANGST MULTIPLE EPITOPES FROM RECOVERED PATIENTS, DIFFERENT FROM CONVALESCENT PLASMA, IT IS A STANDARDIZED MEDICINE PRODUCT WITH RELIABLE HIGH TITER, AND OBVIOUSLY TARGET CELLS AND HAVE BEEN SHOWN ALSO TO BE EFFECTIVE AGAINST ALL TESTED VARIANTS IN CELLS. NEXT SLIDE. SO THIS GIVES YOU A SENSE OF THE TYPICAL HOSPITALIZED PATIENT WITH COVID-19, AGE AROUND 60 YEARS, AGE 40 TO 50% FEMALE, AROUND HALF THE POPULATION WITH -- PEOPLE HAVE HAD SYMPTOMS AROUND A WEEK WHEN THEY COME INTO THE HOSPITAL THOUGH THERE IS QUITE A BIG SPREAD YOU CAN SEE THE LOWER RANGE WAS ABOUT 5 TO 6 DAYS. REMDESIVIR STANDARDS OF CARE ALREADY STARTED IN PATIENTS, FOR THOSE NOT JET STARTED THEY WOULD START AT TIME OF RANDOMIZATION AND AROUND 70% WERE NEED OF VARIOUS DEGREES OF SUPPLEMENTARY OXYGEN AT TIME OF ENROLLMENT. SO THIS GIVES YOU THE FIRST OF THE AGENTS WE ARE STARTING WE PUBLISHED WITH CELLS IN THE JOURNAL LAST DECEMBER THIS IS THE FINAL RESULTS LOOKING HERE PULMONARY ORDINAL OUTCOME DAY FIVE AND OF COURSE INTENT HERE IS FOR THE THIS CATEGORY TO BE BETTER IN THE EXIT ARM COMPARED TO PLACEBO, THE ARTS IS EXPRESSING THE BEING IN A BETA CATEGORY LESSER CATEGORY IF YOU ARE RANDOMIZED TO ACT AS PLACEBO. AND SHOULD BE ABOVE ONE IF THERE IS A BENEFIT. OBVIOUSLY IN THIS SENSE IT WAS BELOW ONE THOUGH OVERLAPPING NOT SIGNIFICANTLY. IMPORTANTLY WE REDESIGN PRAY MARE ENPOINT OF TRIAL COMPARED TO EARLIER TRIAL BECAUSE WE REALIZE SOME PATIENTS AFTER HOSPITAL DISCHARGE HAD TO BE READMITTED OR DIED AFTER DISCHARGE THEREFORE DISCHARGE WAS NOT CONSIDERED RECOVERY. SUSTAINED RECOVERY YOU NEED TO RETURN TO PRE-HOSPITALIZATION FOR AT LEAST 14 CONSECUTIVE DAYS. VERY GOOD ASSOCIATION RECOVERY AND CLEARLY NO DIFFERENCE BETWEEN THE TWO ARMS OF THE STUDY. NEXT SLIDE PLEASE. THIS GIVES YOU THE TOP LINE RESULTS OF FOUR COMPLETED TRIALS LOOKING AT DAY FIVE FOR THE MONOCLONALS AND DAY 7 FOR HYPERIMMUNE IVID OR OUTCOME, REMEMBER ODDS RATIO BELOW ONE WERE FAVORING PLACEBO AND ABOVE ONE FAVOR THE AGENT. YOU CAN SEE HEALTHY NUMBER OF PATIENTS THAT WAS INCLUDED PARTICULARLY FOR HYPERIVID STUDY, NONE OF THESE ODDS RATIOS (INAUDIBLE). NEXT SLIDE. THIS POSE THE CRITICAL QUESTION WHY ANTIBODY TREATMENT TO DATE USED IN HOSPITAL ICED PATIENTS NOT -- HOSPITALIZED PATIENTS NOT EFFECTIVE? THREE POTENTIAL EXPLANATION, ANY ACTIVE VIRAL REPLICATION WILL SOON TO BE STOPPED INDICATION FUTURE OF REMDESIVIR, THERE WOULD BE BENEFIT FROM FURTHER ANTI-VIRAL ACTIVITY BUT ANTIBODY IS NOT SUFFICIENTLY ACTIVE TO ADD MEANINGFULLY INTRINSIC LACK OF INTEGRITY IN VIVO OR RAPID EMERGENCE OF DRUG RESISTANCE. FINALLY, THERE ARE HARMFUL EFFECT FROM THE ANTIBODY THAT COUNTER ACT ANY BENEFICIAL IMPACT, FOR EXAMPLE ANTIBODY ENHANCEMENT OR THE ADVERSE EFFECTS. WE WOULD ARGUE THAT IT COULD BE THAT FOR SOME OF THESE EXPLANATIONS THEY MAY APPLY IN SOME SUBGROUP OF PATIENTS AND NOT OTHERS. NEXT SLIDE PLEASE. THE FACTS AS WE HAVE CONSIDERED TO ADDRESS THESE THINKING IS OBVIOUSLY CLINICAL FACTORS INCLUDING DURATION OF INFECTION, DURATION OF INFECTION DIDN'T CHANGE THE OUTCOME ON PREVIOUS SLIDES AND THEREFORE NOT SOMETHING WE ARE ABLE TO TO REPRODUCE COMPARED TO EARLIER FINDINGS. CONVERSELY STUDYING ANTIBODIES AGAINST ACCEPTOR BINDING DOMAIN, WE HAVE USING A ASSAY NEUTRALIZING ANTIBODIES EPITOPES ON THIS PART OF THE SLIDE. PLASMA NUCLEAR CAPSID ANTIGEN WHICH IS ESSENTIALLY A SANDWICH IMMUNOASSAY DEVELOPED BY -- VERY SENSITIVE WITH LOW LEVEL DETECTION OF 3 PICO GRAMS PER MILLILITER. WE ARE STUDYING POST INFLAMMATORY INFLATION MARKERS INCLUDING IL 6 DIMER AS WELL AS DEEP SEQUENCING OF VIRAL RNA FROM NATIVE SWABS. WE HAVE ONLY COMPLETED THE FIRST TRIAL, THAT IS THE DATA I'M GOING TO SHARE WITH YOU SOME OF THE PRELIMINARY FINDINGS WITH THAT. NEXT SLIDE PLEASE. SO THIS GIVES YOU THE CHANGE IN MEAN BINDING FROM ASSAY BETWEEN DAY ZERO AND DAY FIVE. FOR THOSE WHO CAME INTO THE TRIAL WITHOUT DETECTABLE ANTIBODIES USING THIS ASSAY ON THE LEFT AND THOSE WHO HAVE DETECTABLE ANTIBODY ON THE RIGHT. AS WE EXPECT INFUSING WITH NEUTRALIZING MONOCLONAL ANTIBODIES, THE MEAN BINDING FOR THOSE WHO RECEIVE INFUSION VERSUS GETS TO AROUND HUNDRED. BUT EQUALLY CLEAR THAT IN THOSE WHO DID NOT HAVE ANTIBODIES IN STUDY ENROLLMENT THERE IS GRADUAL PRODUCTION OR ENDOGENOUS NEUTRALIZING ANTIBODIES OVER THE FIVE DAY PERIOD. YOU CAN SEE A SIMILAR TREND THOUGH THE SEPARATION BETWEEN ACTIVE VERSUS PLACEBO IS LESS CLEAR FOR THOSE WHO ALREADY HAVE ANTIBODY WHEN THEY CAME INTO THE STUDY. IN TERMS OF PLASMA ANTIGEN WE FIND IS AT LEAST A REASONABLE PROXY FOR TOTAL BODY VIRAL REPLICATION YOU CAN SEE THE DISTRIBUTION OF ANTIGEN AT TIME OF ENROLLMENT ON THE LEFT SIDE, THERE IS A WIDE RANGE OF PLASMA ANTIGEN LEVELS IN PATIENTS COMING IN. THE MEDIAN LEVEL IS AROUND THOUSAND. SOME ALSO HAS HIGH PLASMA ANTIGEN LEVELS WHAT IS EQUALLY STRIKING IS THAT IF YOU LOOK AT PROPORTION WITH HIGH ANTIGEN ABOVE THE MEDIAN BY VISIT FOR BOTH THOSE RECEIVING ACTIVE AGENT AND PLACEBO YOU CAN SEE A DECLINE IN PARTICULAR BETWEEN DAY ONE AND DAY THREE AND HARDLY ANYBODY HAD ANTIGEN LEVELS ABOVE HUNDRED AT DAY FIVE. NO DIFFERENCE IN KINETICS ACTIVE VERSUS PLACEBO. IN TERMS OF THE PROGNOSTIC IMPORTANCE OF THESE PARAMETERS, NOW FOCUSING ON PLACEBO ARM OF THAT FIRST TRIAL, YOU ARE LOOKING AT THE PERCENTAGE WITH SUSTAINED RECOVERY EACH DAY ONE ANTIBODY STATUS. IT SHOULD BE CLEAR THOSE WHO CAME INTO THE STUDY WITHOUT DETECTABLE ANTIBODIES HAD LOWER CHANCE OF SUSTAINED RECOVERY COMPARED TO TO THOSE WHO DIDN'T HAVE ANTIBODY. YOU CAN SEE AS AS WELL PEOPLE WITH HIGH ANTIGEN HAD LOWER CHANCE OF SUSTAINED RECOVERY COMPARED TO THOSE WITH LOW ANTIGEN LEVELS. IF YOU DO THE PERMUTATION OF THE TWO, IT WAS IN PARTICULAR THOSE WHO CAME INTO THE STUDY, AND ANTIBODY NEGATIVE WITH HIGH ANTIGEN THAT HAVE LOWEST RISK OF ACHIEVING SUSTAIN RECOVERY. THESE DIFFERENCES ARE SIGNIFICANT. NEXT SLIDE PLEASE. SO THIS WILL LED US TO DO A SUBGROUP ANALYSIS ACCORDING TO THE PRESENCE OR ABSENCE OF DIFFERENT PERMUTATION. WHAT HOPEFULLY IS CLEAR FROM THIS SLIDE, I CAN SEE MOVED ITSELF TRANSITION OVER THE ATLANTIC BUT THE GROUP OF PATIENTS THAT APPEARS TO HAVE POTENTIAL BENEFIT BOTH NUMERICALLY AS WELL AS LOOKING AT P VALUE FOR INTERACTION WHICH HOVERS AROUND 0.05, FOR THOSE WHO CAME INTO THE STUDY ANTIBODY NEGATIVE THOSE WHO CAME INTO THE STUDY HIGH ANTIGEN AND IN PARTICULAR IF THEY HAD NO ANTIBODIES AND HIGH ANTIGEN WITH A RELATIVE RATE RATIO OF 1.48. NEXT SLIDE PLEASE. FINALLY STUDYING POST IMMUNE RESPONSE, WE ARE FOCUSING FOR THE INTEREST OF TIME ON LINE 6. ON THE LEFT SIDE YOU SEE THAT FOR PEOPLE IN THE PLACEBO GROUP, THE RELATIVE RATES OF SUSTAIN RECOVERY FOR NOSE WHO CAME INTO THE STUDY WITH HIGH VERSUS LOW DAY ZERO FIVE SIX LEVELS HIGH AND LOW ABOVE AND/OR BELOW MEDIAN LEVEL AT STUDY ENTRY WHICH WAS 8.7 PICO GRAMS PER MILL LITTER. THOSE WITH HIGH IL 6 LEVELS HAD AROUND 50% LOWER CHANCE OF ACHIEVING SUSTAINED RECOVERY COMPARED TO THOSE IN STUDY WITH LOW. LOOK AT THE PROPORTION WITH HIGH LEVELS BY VISIT YOU CAN SEE THAT THERE IS A DECLINE THAT HAPPENS MORE QUICKLY FOR PEOPLE IN THE PLACEBO ARM COMPARED TO THOSE RECEIVING ACTIVE AGENT. THIS IS PRELIMINARY INFORMATION WE ARE DOING ADDITIONAL INVESTIGATION TO FURTHER UNDERSTAND POTENTIAL SIGNAL. OF NOTE IL 6 LEVELS ALSO IN ENSUING DAYS AFTER STUDY ENTRY WAS HIGHLY PROGNOSTIC. SO IN SUMMARY WE HAVE TRIALS RAPIDLY DEPLOYED AND QUICK TURN AROUND OF RESULTS WHICH I BELIEVE HAVE BEEN PERFORMED ON FIELD OF USE OF THESE AGENTS. WE FEEL IT IS COMFORTABLE TO CLIENT THERE IS A LOW LIKELIHOOD 196198 HYPERIMMUNE IBIT IMPROVES OUTCOME OVERALL OF HOSPITALIZED PATIENTS WITH COVID-19. 7442 AND OTHER COMBINATION MONOCLONAL REMAINS UNDER EVALUATION. WE MENTION 550 PATIENTS AND THE TARGET SAMPLE IS 1,000. (INAUDIBLE) PROS CONTROL. -- PROTOCOL. BASED ON BIOMARKER RESULTS OF RUN OF THE RILES RECEIVED A PLAUSIBLE SUBGROUPS WITH BLUNTED RESPONSE, THIS IS WHAT WE HYPOTHESIZED BEFORE LOOKING AT THE DATA. ESPECIALLY UNCONTROLLED VIRAL REPLICATION TO INFECTION WHICH MAKE SENSE AS WELL. THIS OBVIOUSLY NEEDS TO BE CONFIRMED IN OTHER TRIALS AND INTEGRATED DATA FROM FROM ACROSS TRIALS GIVEN THE FACT THAT WE ARE STUDYING SUBSTANTIAL DATABASE TO ANALYZE THE FACT IT DOES NOT APPEAR TO BE EXPLAINED BY INFECTION WITH VIRUS RESISTANCE WITH NEUTRALIZED MONOCLONAL ANTIBODY, NO CHANGES IN KINETICS,ERS NOR UNDESIRED CHANGE IN BIOKINETICS FROM USE IN MONOCLONAL ANTIBODIES. THERE IS A QUESTION AROUND WHETHER THE NEUTRALIZING ANTIBODIES WAS INDUCING SOME TYPE OF HYPERINFLAMMATION THAT THIS CLEARLY NEEDS ADDITIONAL INVESTIGATION AND CONFIRMATION. I WANT TO THANK THE PEOPLE WHO HAVE BEEN INVOLVED, THERE'S TOO MANY ON THIS SLIDE TO ACKNOWLEDGE ALL BUT IT HAS BEEN A TREMENDOUS TEAM EFFORT I I AM HUMBLED TO BE THE ONE WHO WAS ALLOWED TO DO THE PRESENTATION IN THAT REGARD. THANK YOU VERY MUCH. >> THANK YOU SO MUCH, DR. LUNDGREN. NOW BETTY KORBER FROM LOSS ALAMOS LABORATORY P SARS COV-2 MUTATION FIND VARIANTS ACROSS THE GLOBE. DR. KOR BEAR, THE STAGE IS YOURS. >> THANK YOU VERY MUCH. I APPRECIATE THE OPPORTUNITY TO GIVE MY PERSPECTIVE ON THIS ISSUE. I'M GOING TO GIVE UPDATES SO IF I CAN HAVE THE FIST SLIDE. I ALSO WANT TO THANK THE ENTIRE SOURCE OF THE DATA THAT I'M GOING TO SHOW YOU AND THEY HAVE BEEN WONDERFUL FACILITATING EFFORTS FROM THE VERY BEGINNING OF PANDEMIC IN 2020. THEY PROVIDED US WITH DATA FEEDS, ALL THE DATA WE NEED, AND ANY QUESTIONS WE HAVE THEY HELP US RESPOND QUICKLY AND ANSWER THEM. SO THEY HAVE BEEN REALLY GREAT TO PARTNER WITH. I THINK SOMETHING REMARKABLE HAPPENED SO REDD CIRCLE ON THE THE RIGHT THIS WAS FROM THE 11TH, NOW CLOSE TO 2 MILLION ENTRIES, I NEVER WOULD HAVE ANTICIPATED THIS IN 2020 BUT INCREDIBLE GLOBAL EFFORT SO PEOPLE ALL OVER THE WORLD CLINICS AN SCIENTISTS CONTRIBUTING THEIR SEQUENCES PRIOR TO PUBLICATION AND ENABLE THE GLIMPSE OF GLIMPSE OF PANDEMIC VARIATION IN A WAY WE NEVER HAD AVAILABLE TO US BEFORE THIS SCALE OF COOPERATIVE EFFORT. I'M GOING TO NAME SOME COUNTRIES IN PARTICULAR AS I GO INTEREST VARIANTS CROPPING UP AND I WANT TO THANK THE PEOPLE WHOSE COUNTRIES I NAME FOR THEIR CONTRIBUTIONS. NEXT SLIDE. SO WE HAVE DEVELOPED TOOLS FOR TRIAGING VARIANTS, I'M GOING TO QUICKLY TALK ABOUT THEM. FIRST ONE WE CALL -- HISTORICALLY IDENTIFIED VARIANTS IN EPITOPE REGIONS BECAUSE I'M PARTICULARLY INTERESTED IN VACCINE SUCCESS, I WANT TO KNOW WHAT VARY I CAN'T WANT ALSO EACH CONTINENT. WE PICK UP MOST COMMON FORMS OF MTV AND RDB REGION, IMPLANTS THOSE IN THE MOST COMMON SPIKE PROTEIN PRESENTED TO THEM AND THESE TURN OUT TO BE THE VARIANTS THAT WE ARE SO USED TO TALKING ABOUT NOW. SOME ARE COMMON ONES VERY FAMILIAR WITH AND SOME LESS COMMON THAT ARE SHOWING UP SOMEPLACE IN THE WORLD. WE HAVE SOMETHING CALLED X SPIKE WHICH EXPLORES THE WHOLE OF SPIKE METHOD THEN PICKING PRIMARILY ON EPITOPE REGION VARIATION. WE USE THIS TO IDENTIFY CO-VARIATION AMONG MUTATION AND THE TOP RIGHT THERE IS A CO-VARIATION THAT OF THE MOST COMMON MUTATION IN THE SPIKE. USEFUL FOR ANTICIPATING VACCINE SIGN. WE USE THIS TO IDENTIFY WHERE THE UNUSUAL VARIANTS WHICH WOULD BE WITH TARGETS FOR EXPLORATION FOR IMMUNE ESCAPE AND WE USE THIS TO TRACK EMERGING VARIANTS OF VARIANTS. MOST OF THE PLOTS YOU SEE ARE JUST A DYNAMIC TRACKING TOOL TO LOOK AT VARIANT FORMS AT ANY GEOGRAPHIC LEVEL. NEXT SLIDE. SO THIS HORRIBLY DENSE SLIDE OR VARIANTS CURRENTLY TRACKING, BASED ON THE TOOLS I TALKED TO YOU ABOUT. A LOT OF THEM ARE QUICK AND YOU CAN SEE THE WHO DESIGNATION OF THE SECOND COLUMN AT THE TOP. THE RECURRING THIRD CATEGORY ARE LESS COMMON BUT STILL INTERESTING VARIANTS. DECLINING VARIANTS THAT CROPPED UP SOMETIME 2021 BUT NOW REALLY RECEIVING AND SAMPLING. SO I FIND THESE STILL INTERESTING BECAUSE THEY ARE FORMS OF THE VIRUS THE VIRUS IS ABLE TO TAKE AND THEY OFTEN HAVE POTENTIAL IMMUNE RESISTANCE IN MUTATION. SO YOU SEE COMMON SPIKE VARIANT FORMS, I HAVE TWO COLORS THAT STAND OUT. ONE IS GREEN, AND THOSE ARE MUTATIONS WITHIN THE SUPER SITE AND ONE IS A PINK COLOR, RBD MUTATION. THESE MUTATIONS ARE HIGHLY RECURRENT. THEY OCCUR IN ALL THESE VARIANTS AND IN BOTH REGIONS IN ALL THESE VARIANTS. I THINK THIS SPEAKS TO THE FACT THAT BOTH OF THESE REGIONS ARE EVOLVING SIMULTANEOUSLY AND ADVANTAGES TO MOVE OUT AND EXPAND THEY TEND TO HAVE MUTATIONS IN BOTH REGIONS WHICH WHICH IMPACT BETTER FORCES FACING THESE VIRUSES BECAUSE IT IS CONSISTENT YOU GET MULTIPLE MUTATIONS IN BOTH REGION IT IS BLACK LETTERS ARE JUST MUTATION NOT IN EITHER REGION. THE BLUE ARE INTERESTING ALMOST ALWAYS POSITIVELY CHARGE AND VERY OFTEN LITTLE OVER HALF TIME EMERGING FORMS CARRY POSITIVE CHARGE INTERFERON CLEAVAGE SITE SO CONSISTENT PATTERNS AND THEY OFTEN RESISTANCE MUTATION SO NEXT SLIDE. THIS IS SHOWING YOU RECURRENT MUTATIONS MAP, THEY ARE FOCUSED AND DEEPER THE COLOR HERE, THE MORE TIMES WE OBSERVE LINEAGE, THIS FIGURE WAS MADE IN EARLY MAY SO LESS LINEAGES THAN I JUST SHOWED YOU BUT THINGS THAT RECRUIT IN 7 LINEAGES ARE DEEP BLUE AND YOU CAN SEE THOSE IN THE RBD SPECIFIC SITES AND YOU CAN SEE A DENSE CLUSTERING NTD OF SPRINKLING OF DIFFERENT MUTATION BUT REALLY FOCUSED ON EPITOPE REGIONS AND INTERFERON LOOP. IF I COULD HAVE THE NEXT SLIDE. SO WE ARE ALL AWARE OF THE DELTA VIRUS THAT SHOWING INTERESTING PATTERNS I WANT TO TALK BRIEFLY. I WASN'T SURE MID SPRING HOW EVOLUTION OF THE VIRUS WAS GOING TO UNFOLD WHAT HAPPENED WAS UNITED KINGDOM PLOTS OVER TIME STARTING FROM DECEMBER 1 GOING THROUGH LAST FRIDAY. THE ORANGE ALWAYS INDICATING THE B 11 P OR ALPHA VARIANT. AND WHAT HAPPENED IN THE UK WAS SHOWED UP IN SEPTEMBER, BY DECEMBER DOMINATING THE UNITED KINGDOM PANDEMIC, REPLACING THE GENE THAT WAS THERE BEFORE AND STAYED THROUGHOUT THE SPRING AND DELTA VARIANT CAME IN AND THAT'S THE BRIGHT PURPLE, YOU CAN SERA -- SEE, RAPIDLY THE VARIANT OVERTOOK. THOSE ARE WEEK ENROLLING AVERAGE AND ON THE RIGHT IT IS JUST THE PROPORTION IN THE FRACTION. SO SAME DATA TWO WAYS YOU CAN SEE THE PURPLE TAKING OVER THE HIGHEST FRACTION SAMPLING IN THE UK. NORTH AMERICA SHOWED A DIFFERENT PATTERN OF EVOLUTION WHERE EARLY SPRING THERE WERE VARIANTS CIRCULATING OVERTAKING G CLADE AND VIRUS THAT HAD POSITIVE CHARGE INTERFERON THAT WAS THEIR ONLY LIMITATION ABOVE D 614 GENE MUTATION. SO THOSE ARE THE BRIGHT PINK GUYS. THOSE WERE COMMON IN NORTH AMERICA, BUT WE STARTED SEEING VARIANTS IN CALIFORNIA, NEW YORK OTHER PLACES IN THE COUNTRY, THE DEEP BLUE IS VARIANT OUT OF CALIFORNIA. HOLDING THEIR OWN THROUGHOUT MUCH OF THE SPRING BUT THE ALPHA B 1 # 17 STARTED TO TAKE OVER IN NORTH AMERICA. IT IS GETTING COMPETITION FROM NEWER VARIANTS. AND IN PARTICULAR THE P 1 VARIANT FROM BRAZIL WHICH IS GAMMA VARIANT, IT IS THAT REDD COLOR. THIS IS A BREAK DOWN AND YOU CAN SEE THE SAMPLING OF THE DELTA VARIANT HAS INCREASED DEEPLY GLOBALLY. THIS TRANSITION SEEMS FASTER THAN THE TRANSITION TO THE ALPHA VARIANT. SO IF YOU LOOK AT THE SLOPE GOING FROM GRAY TO ORANGE YOU CAN SEE TAKING MANY MONTHS BUT THIS ONE SEEMS TO BE A MUCH MORE RAPID EXCHANGE. LOOK AT THE CONTINENTS ON THE RIGHT AND AGAIN COUNTS ON THE LEFT AND PERCENTAGE ON THE RIGHT YOU CAN SEE HERE IT FOLLOWS THE UK AND THE GLOBE AND MOST SAMPLES ARE FROM EUROPE AND THE U.S.. AND THE UK, DOMINATED BY NOSE TWO PLACES. IN ASIA THERE IS (INAUDIBLE) FROM INDIA. THAT IS PART OF WHY (INAUDIBLE) PURPLE STRAIN BUT IT HAS ITS OWN VARIANT QUITE INTERESTING, BRIGHT PINK ONE THAT IS CALLED P 1 AND THEN WE SEE MUCH MORE COMPLEX EPIDEMICS IN SOUTH AMERICA AND AFRICA DOWN TOWARDS THE BOTTOM SO WE CAN SEE TRANSITION TO THIS P 2 VARIANT, THE BRICK REDD ONE IN AFRICA THE STRAIN THAT WAS DISCOVERED IN IN SOUTH AFRICA BETA IS THAT LAVIN DOOR COLOR. IT IS STILL HOLD -- HAVE THE NEXT SLIDE SO I WANT TO SHOW YOU THE MORE LOCAL PLACES WHERE THE DELTA VARIANT IS TRANSITIONING QUITE QUICKLY. YOU CAN SEE ON THE LEFT WHAT IS HAPPENING IN LOCALITIES IN ENGLAND AND THEY HAVE THESE FOUR LETTER CODES LIKE MILK, THERE IS SCOTLAND. YOU CAN SEE THEY ARE RAPID TRANSITION FROM ONE STREAM TO THE OTHER AND -- HAS TRACKING VARIANT SITE WHICH IS VERY NICE AND IT SHOWS YOU THAT THIS DELTA FORM IS ALL OVER THE WORLD NOW, SO IT IS INITIATED SAMPLING IN PRETTY MUCH ALL CONTINENT AND MANY COUNTRIES. THESE WERE SOME OF THE PLACES WHERE IT IS CO-CIRCULATING SO AGAIN THE PURPLE IS THE DELTA, ORANGE IS ALPHA. CO-CIRCULATING AND YOU SEE A TRANSITION SO RUSSIA, INDIA, AUSTRALIA ARE EXAMPLES OF THIS. INDIA THEY ARE TWO OF THESE VARIANTS COMING OUT, THERE'S THE B 6.7.1 WHICH CAME UP FIRST AND THE DEEPER PURPLE COLOR AND THE BRIGHTER PURPLE IS THE .2 VARIANT, THE ONE THAT IS REALLY DOMINATING THE GLOBAL SAMPLING IN TERMS OF NEW VARIANTS COMING UP. NEXT SLIDE. I WANT TO MAKE THE POINT ABOUT TIMING OF TRANSITION. THE ONLY TIME I HAVE SEEN SOMETHING LIKE THIS HAPPEN BEFORE WAS THE D 614G TRANSITION SO EVEN IN WELL ESTABLISHED COMMUNITIES WITH THE ANCESTRAL VARIANT IN SPRING OF 2020, ONCE THE CHIEF FORM IN 614 ENTERED THE POPULATION THERE IS RAPID SWITCH ON THE ORDER OF SIX WEEKS TO THE NEW FORM. AND YOU CAN SEE THAT REALLY STEEP SLOPE WITH THE GREEN ARROW. YOU CAN SEE SAME STEEP TRANSITION HAPPENING WITH THE B .1.6.7.2 DELTA. IT WAS SLOWER AT TIME OF TRANSITIONS WE WERE SEEING WITH THE VARIANT, THE ALPHA VARIANT AND THE ORANGE. SO NEXT SLIDE. MY VIDEO HAS APPARENTLY GONE OFF. SO I WANTED TO SHOW YOU -- GOSH, MY CO-HOST IS BLOCKING MY VIEW OF THE SLIDES. THERE WE GO. SO I WANTED TO SHOW YOU HOW THE VARIANT -- BETA VARIANT BE B .1.531 IS COMPARED TO THE B 117 ALPHA VARIANT. THAT IS THE VARIANT OUT OF SUB AFRICA -- SOUTH AFRICA. AND THAT IS LEVENDAR VERSUS ORANGE, PLACE THEY CO-CIRCULATE, I THINK SOUTH AFRICAN VARIANT WAS HOLDING ITS OWN STEADILY AND HOLDING ON TO THE PREDOMINANT FORM IN THE EPIDEMIC. BUT NOW WE HAVE THE BRIGHT PURPLE COMING IN AGAIN, THE DELTA IN THOSE REGIONS THAT SEEMS TO BE OUTGROWING BOTH OF THOSE TWO FORMS WHEN IT COMES IN YOU DON'T HAVE A LOT OF DATA YET IN SUCH REGIONS WITH CO-CIRCULATION GOING ON. NEXT SLIDE. THE OTHER VARIANT THAT REALLY SEEMS TO BE COMING UP IN FREQUENCY, IS THE P 1 VARIANT THAT STUDIED AND -- IT REPLACED THE P 2 VARIANT ON THE TOP LEFT YOU CAN SEE THE BRIGHT REDD THE BRICK REDD, THE P 2 VARIANT WAS SAMPLED ALL OVER THE WORLD BUT IS RAPIDLY DECLINING. THIS ONE SEEMS TO BE INCREASING A LITTLE BIT AND SEEMS TO BE INCREASING OVER THE ALPHA VARIANT, THE ORANGE VARIANT. THERE IS ANOTHER VARIANT THAT I FIND QUITE INTERESTING COMING OUT OF SOUTH AMERICA AND MERITING FURTHER STUDY, THE C 37. FIRST CAME MANY THE SPRING DURING AGGRESSIVE EARLY VACCINE PROGRAM AND THE SIMULTANEOUS EXTREMELY SERIOUS OUTBREAK. SO THEY WERE -- THEY WANT TO BUILD COUNTRIES IN TERMS OF VACCINES THROUGHOUT THE SPRING AND THEY ARE HAVING THIS TERRIBLE OUTBREAK AND THAT WAS THE MOMENT THAT THIS VARIANT BEGAN TO EMERGE AND BECOME DOMINANT, THE DARK GREEN ON THE BOTTOM. ALSO SHOWING UP IN ARGENTINA. SO IT SEEMS TO BE GETTING WAY (INAUDIBLE) IN CHILE BUT THAT STORY IS STILL OPEN. IT IS GOT VERY LARGE DELETIONS IN THE NTD AND MULTIPLE MUTATIONS THAT COULD BE RESISTANT, SO H IS IS THE VARIANT THAT MERITS FURTHER STUDY. P 1 IS BEGINNING TO GAIN GROUND IN OTHER PARTS OF THE WORLD, WE'LL HAVE TO SEE WHAT HAPPENS WHEN EF THE COMMUNITY DELTA CO-CIRCULATING WITH THE P 1 SO BRICK REDD UP ON THE FAR RIGHT YOU CAN SEE AND ENTERED ALL THESE COMMUNITIES, VERY RECENTLY WITH 135, 89 OR 137 SAMPLES, SO NOW THEY OVER THE NEXT MONTH WILL BEGIN TO GET A FEEL FOR WHAT IS RELEVANT THERE. SOMETHING INTERESTING TO LOOK AT WISH WE COULD MAKE A CONCERTED EFFORT TO LOOK BETTER, HIGHLY VACCINATED COMMUNITIES SO FAR, WHERE ARE WE HAVING RELEASE OF OUT-- REALLY SEVERE OUTBREAK? TURNS OUT THE SAY SHELLS IS THE SMALL PLACE, BUT IT IS HIGHLY VACCINATED. IT IS IN THE MIDST OF A VERY SEVERE OUTBREAK. IT IS THE BROWN LINE VACCINATION RATE ON THE RIGHT YOU CAN SEE THE OUTBREAK. WE DON'T HAVE SEQUENCE FROM THE SAY SHELLS SO WE DON'T KNOW WHAT THAT MEANS. I THINK IT WOULD BE GREAT TO TRY TO PARTNER WITH A PLACE LIKE THAT TO SEE SEQUENCES WORTH EXPLORING. BAHRAIN IS ANOTHER EXAMPLE OF OUTBREAK. YOU CAN SEE ON THE GREEN ON THE RIGHT IS A SEVERE OUTBREAK AND VERY HIGHLY VACCINATED POPULATION. THERE IS NOT A LOT OF SEQUENCES. 30A WENT FROM ALPHA EPIDEMIC TO INDIAN FORMS WITH SEQUENCES BUT WE HAVEN'T GOT A PICTURE SINCE APRIL SO WOULD BE NICE TO PARTNER AND HELP OUT AND SEE WHAT IS GOING ON IN THOSE COMMUNITIES IF NOT ABLE TO DO THAT. ISRAEL TURNED OUT TO BE INTERESTING. THE GRAY LINE ON THE LEFT, HIGHLY VACCINATED. VARIANTS MOVING IN, AND ONE HAPPENS TO BE THE C 37 VARIANT, DARK GREEN COMING IN, YOU CAN SEE THAT DARK GREEN PATCH. THE DELTA VARIANT FROM INDIA IS COMING IN ALSO A B 117 VARIANT THAT CARRIES 490S MUTATION IN ISRAEL. THAT IS ALSO FOUND MANY C 37. SO IF I COULD HAVE THE NEXT SLIDE. SO THIS IS JUST TO COMPARISON OF WHAT IS GOING ON IN INDUSTRY TO LOOK AT THIS SORT OF THING. C 37490S CARRY B 117 CARRY THAT MUTATION. AND THEY ARE BOTH COMING UP IN ISRAEL, ISRAEL IS ONE OF THE MOST HIGHLY VACCINATED COUNTRIES ON EARTH SO IT IS KIND OF INTERESTING TO KEEP AN EYE ON THESE. THIS DOESN'T PROVE ANYTHING BUT RAISES HYPOTHESES FOR FURTHER TESTING AND SUGGEST THAT MAYBE THESE VARIANTS SHOULD MOVE UP IN THE LIST FOR SEEING HOW WELL THE VACCINE SERA HOLD AGAINST THEM SO TRYING TO USE THIS TO HELP GUIDE EXPERIMENTAL TESTS THIS KIND OF REASONING. NEXT SLIDE. BSR -- THESE ARE SOMETHING I CALL EMBER, EMBER PLOTS SO THEY ARE JUST CASES WHERE YOU FIND IN A LOCAL REGION OR COUNTRY, YOU FINDS A NEW FORM SHOWING UP. COOING TO RATHER HIGH FREQUENCY AND SOMETIMES TEMPORARY AND DIE OUT, SOMETIMES THEY FLAIR UP AND START BEING TRANSMITTED. ALL THESE HAVE THE PROPERTY OF HAVING MULTIPLE MUTATIONS, BOTH RBD AND NTD MUTATIONS. MANY HAVE THE POSITIVE CHARGE INTERFERON. THERE IS ALSO THINGS TO DISTINGUISH. SO LOOK AT JAPAN, THE SECOND COLUMN YOU CAN SEE BUYING BLUE COMMON IN JAPAN, MORE COMMON PRIOR TO DECEMBER 1 BUT REALLY GONE AWAY YOU DON'T SEE IT ANY MORE. THIS BRIGHT PINK FORM R 1 WE DON'T KNOW WHAT WILL HAPPEN, MAYBE GIVING WAY TO UK BUT ALSO FOUND IN THE U.S. AND THERE IS AN NMWR ABOUT THAT PARTICULAR STRAIN WHERE IT SHOWED IN THE MUSTING FACILITY AMONG VACCINATED PATIENTS SO THAT INFORMATION IS SOMETHING I THINK SHOULD RAISE PRIORITIES FOR STUDYING TO SEE IMPLICATIONS THESE MUTATIONS FOR VACCINE SERA. IT HAS THE 484K MUTATION WE ALL KNOW IS -- RESISTANCE. NEXT SLIDE. SO VARIANTS OF VARIANTS. THIS IS SOMETHING THAT I'M TRACKING REGULARLY AS ARE MANY COLLEAGUES. BUT THERE WERE OBVIOUSLY HAVE THE MOST INFORMATION IS THE ALPHA. B 117 THAT STARTED IN THE UK LAST FALL. SO IN THE LAST FEW MONTHS I WAS ABLE TO FIND OUT -- WE HAVE THIS IS LONGER LOOK, WE HAVE 45% OF THE DATA CONTAIN THE MOST COMMON FORM OF THE SPIKE OF THAT LINEAGE. OF THESE, ABOUT 65% EXACTLY HAVE THAT MOST COMMON FORM BUT 35% DON'T. THERE ARE 12790 SPIKES THAT SHARE THAT BACKBONE AND ADDITIONAL CHANGES SO THESE ARE HUGE NUMBER OF VARIANTS OF VARIANTS, EVOLVING LINEAGES SO OF COURSE THEY WILL DOING THINGS LIKE THIS IF YOU THINK ABOUT IT. THEY ARE MOVING TARGETS AND CONTINUING TO EVOLVE. THERE'S 16 -- 1594 OF THESE FOUND TEN FILES OR MORE ESTABLISHED SO THE TOP TEN SHOWN HERE ON THE LEFT HAD PRIORITIZE AMONG THESE FOR MAKING THESE FOR TESTING AND THINKING ABOUT FUTURE VACCINES. SO I THINK COMMONALITY ISN'T THE BEST SCALE BUT POTENTIAL RESISTANT STANCE MUTATION, NOT JUST FREQUENCY, AND IF I CAN HAVE THE NEXT SLIDE. THE OTHER THING WE CAN DO IS TAKE EACH OF THESE AND SEE ALL OVER THE WORLD IF DECREASE OR INCREASING, THEY MIGHT BE THERE BECAUSE OF FOUNDER EFFECTS SO THE MOST COMMON VARIANT OF THE B 117 FORM CARRIES THE K 1191 N MUTATION. THERE'S 53 REGIONS IN THE WORLD WHERE THIS VARIANT HAS AN ESTABLISHED PRESENCE. INCREASING SOME OF THESE AND DECREASING SOME OF THESE. DECREASING TWICE THE NUMBER. TURNS OUT ONE CAN SEE FOUNDER EFFECTS. I WILL SHOW YOU THAT MORE EXPLICIT MANY THE NEXT SLIDE BUT THIS VARIANT IS DECREASING IN FLORIDA, FLORIDA IS THE STATE WHERE IT IS MOST COMMONLY FOUND AND LOCAL COMMONLY FOUND IN THE WORLD SO IT IS NOT APPARENTLY TRANSMITTING FASTER THAN THE PARENT LINEAGE OF B 117. OBJECT RIGHT THE 490S MUTATION THE ONE WE WERE TALKING ABOUT, THE CHILE VARIANT AND ALSO THE WHAT IS GOING ON IN ISRAEL RIGHT NOW THAT 490S IS INCREASING MOST OF THE TIME WHEN YOU LOOK AT IT SO IT'S FOUND IN 22 REGIONS AND SIGNIFICANTLY INCREASING IN 14 OF THOSE, THE POLAND IS THE PLACE MOST COMMONLY FOUND, YOU CAN THINK PORTRAIT OF THE INCREASE. WHAT THESE PLOTS ARE, THEY ARE DAILY PLOTS OF SAMPLES, SITES OF THE CIRCLE INDICATES HOW MANY SEQUENCES WERE CHECKED THAT DAY. THE -- COLLECTED THAT DAY. FREQUENCY OF MUTATION IS PLOTTED ON Y AXIS SO GOING FROM QUITE A FEW SAMPLES ON THE FIRST TIME POINTS, QUITE A FEW SAMPLES IN ALL TIME POINTS IN FLORIDA AND DECREASE PROPORTION OF MUTATION ON THE LEFT AND INCREASING PROPORTION OF THE MUTATION ON THE RIGHT. THESE ARE STATISTICALLY SIGNIFICANT BY PERMUTATION TEST. NEXT SLIDE. I LIKE TO LOOK AT THESE IN TERMS OF OTHER CO-VARIANTS TO SEE WHAT'S GOING ON AND SEE IF I CAN'T SEE FOUNDER EFFECTS. THE 1191 I FIND NOT INTERESTING, THE MOST PREVALENT VARIANT OF B 117 WAS INTRODUCED INTO FLORIDA PRIOR TO THE GENERIC FORM. IT NOW IS DECREASING RELATIVE FOSI NARY OWE SO IT IS THE BLIGHT BLUE LINE, ORANGE IS STANDARD ALPHA B 117 LINEAGE. YOU CAN SEE THAT THAT'S INCREASING RELATIVE TO THE MUTANT FORM OVER TIME. THERE'S OTHER LINES ARE WHEN OTHER VARIANTS ARE INTRODUCED AND I'M FLOWING P 1 AND B .1.6.7.2 DELTA, AND YOU CAN SEE THAT THOSE ARE BEGINNING TO COME UP, P 1 ESPECIALLY, SO YOU CAN SEE THIS IS GOING ON YOU CAN ALSO SEE OTHER VARIANTS OF VARIANTS AND THEY ARE SHOWING UP IN THOSE COMMUNITIES. ON THE OTHER HAND YOU CAN SEE THAT THE 490S AND B 117 IS INCREASING. AND IT IS INCREASING RELATIVE TO OTHER VARIANTS IN THOSE COMMUNITIES BUT WE HAVE INTRODUCED THE DELTA FORM SO WE HAVE TO SEE HOW THAT GOES AND DIFFERENT FORM T 20I IN THE UK BACKBONE IS INCREASING QUITE RAPIDLY AND NEW ENTRIES SO THIS IS THE THING WE MIGHT KEEP AN EYE ON TO FLOW OF REAGENTS TO TEST FOR EFFECT OF MUTATION. NEXT SLIDE. >> DR. KOR KORBER, HOW MANY SLIDES LEFT? WE ARE OVER FIVE MINUTES. >> I WILL TALK (INAUDIBLE) AND THEN GO TO THE END. >> THANK YOU SO MUCH. >> I WANT TO SHOW YOU COUPLE OF PLACES MUTATIONS ARE CONCENTRATED. AND THE -- THIS IS PLOT OF THE LAST FEW MONTHS OF SEQUENCES TWO MONTHS OF SEQUENCES THE HIGH ENTRY SITES ARE ONES B 117 BUT YOU CAN SEE A LOT OF CHANGE IN SIGNAL PEPTIDE SO THAT IS AN INTERESTING REGION. 5 AND 18 HAVE BEEN CHANGING SINCE THE VERY BEGINNING OF THE EPIDEMIC AND THEY FLICKER ON AND OFF IN ALL LINEAGES. I DON'T KNOW WHAT THAT MEANS. BUT THEY ARE QUITE INTERESTING SITES AND I DON'T THINK WE HAVE A FULL UNDERSTANDING OF THEM YET. THERE ARE MANY RECURRENT MUTATIONS IN THE NTD AND RBM ASSOCIATED KNOWN TO BE ASSOCIATED EXPERIMENTALLY WITH RESISTANCE. AND THEN POSITIVE CHARGE COMPLETED SO YOU CAN SEE THE CONCENTRATION IN WHAT THESE SITES ARE AND THEY TEND TO BE REALLY FOCUSED ON A HANDFUL OF SITES AND PROBABLY DUE TO FITNESS CONSTRAINTS THESE ARE THE ONES THAT CAN MUTATE SO THEY DO. NEXT SLIDE. THIS IS JUST APPEARING SERENE NEGATIVELY CHARGED SO POSITIVELY CHARGED CAN ENHANCE ACTIVITY. NEXT SLIDE. WE HAD A LOT OF RECOMBINATION GOING ON. THAT INFLUENCE IT IS TREES AND THAT'S ALL I WILL SAY ABOUT THAT. SKIP THE NEXT TWO SLIDES. AND I JUST CONCLUSIONS. EMERGING WITH CHARACTER SICS BLI CARRY ONE OR MORE MUTATION IN EACH MAJOR EPITOPE REGION, NTDSS SUGGESTING IMMUNOLOGICAL SELECTION MAYBE HAPPENING BOTH BOTH REGIONS AS A CONSEQUENCE CONVALESCENT SERA AND NOW VACCINE SERA PUT FURTHER AND DIFFERENT PRESSURES ON. B LI CARRY INFECTION ENHANCE MUTATION, THIS IS VERY COMMON. SEEING COMPLEX FORMS REPLACING SIMPLER FORMS. SO THIS IS JUST HAPPENING OVER AND OVER, SIMILAR MUTATIONS ARE CLAIMING UP, N TELLS ARE BECOMING A PROMINENT PART, ARISING FROM THE NTD. BIGGER AND MORE COMPLEX AND GETTING TO BE MORE OF THEM. SO THESE ARE IMPORTANT THINGS TO BE LOOKING INTO. RECOMBINATION IS DEFINITELY OCCURRING AMONG THE VIRUSES. WE DON'T KNOW A LOT ABOUT MUCH OF THE WORLD SO WE HAVE LIMITED SAMPLING OUT OF AFRICA ASIA AND SOUTH AMERICA. COORDINATED EFFORTS GETTING PEOPLE IN THESE PLACES THE RESOURCES THEY NEED TO SEQUENCE IS GOING TO BE CRITICAL GOING FORWARDS. NEXT SLIDE. THE CURRENT EVIDENCE SUGGESTS THIS VIRUS MAY BE EVOLVING IN SUITES AND CERTAINLY WHAT HAPPENED IN THE UK AND THEN ECHOED IN THE REST OF THE WORLD G CLADE GOING TO B 16172. THIS TRANSITION CAN BE VERY FAST, SIX TO TEN WEEKS AND I WANT TO POINT OUT THAT'S ABOUT THE TIME IT TAKES TO ORDER A PSEUDOVIRUS FOR TESTING AND SEEMS TO BE ABOUT TIME IT TAKES TO ORGANIZE A ZOOMCAL SO I THINK WE HAVE TO BE -- ZOOM CALL SO WE HAVE TO BE CAREFUL TO STAY AHEAD OF THE VIRUS AND BE SURE IF WE DO SEE RESISTANCE THAT WE ARE ON TOP OF IT SO TRANSITIONS CAN BE MADE QUICKLY. I THINK THE PATTERNS OF MUTATION ARE HIGHLY CONVERGENT. THERE IS LOTS OF CO-VARIATION. SO EVEN IF WE DO SAY SWITCH TO THE DELTA FORM, THE HISTORIC PATTERNS INFORM WHERE B 1.617.2 CAN GO SO WE CAN THINK ABOUT MAKING POLYVALENT VACCINES TO HAVE IN OUR BACK POCKET SHOULD WE NEED THEM AND THE VARIANTS START PROPOSE MORE CHALLENGE FOR THE VACCINES. I DID WANT TO SAY A CONFLICT OF INTEREST DISCLOSURE WORKING WITH (INAUDIBLE) AND WE HAVE SOME IP ON VARIAN VACCINATIONS. >> THANK YOU SO MUCH, DR. KORBER, FASCINATING PRESENTATION. AND WE NOW MOVE WITH THE NEXT PART OF THE SUMMIT. THREE DIFFERENT SESSIONS ADDRESSING ANN BODY DESIGN DEVELOPMENT AND IMPLEMENTATION. STARTING WITH SESSION 1 TITHED MECHANISM OF ACTION, A FUNCTIONAL ANTIBODIES THAT NEUTRALIZE SARS COV-2 OR SARS COV-2 INFECTED CELLS. THE SESSION WILL BE WITH A PRESENTATION BY DR. ERICA SAPHIRE FROM THE LA JOLLA INSTITUTE FOR FOR IMMUNOLOGY FOLLOWED BY A -- MODERATOR ADRIAN MCDERMOTT. DR. SAPHIRE, THE STAGE IS YOURS, YOU CAN START SHARING YOUR SCREEN. >> THANK YOU TO THE ORGANIZERS FOR THE INVITATION TO SPEAK. I'M HERE ON BEHALF OF A LARGE CONSORTIUM, THE CORONA VIRUS IMMUNOTHERAPEUTIC CONSORTIUM LAUNCHED WITH DUAL FUNDING FROM THE BILL MELINDA GATES FOUNDATION AND SUPPLEMENT TO OUR CENTER FOR EXCELLENCE AND TRANSLATIONAL RESEARCH U 19 OF NIAID. SPIKES, COMPETITION WITH EACH OTHER. THEIR ABILITY TO NEUTRALIZE PSEUDOVIRUS AND LIVE VIRUS SYSTEMS, ABILITY TO BRING ABOUT EFFECTOR FUNCTION AND SYSTEMS LEVEL AND CELLULAR ASSAYS. STRUCTURES, LOCATION OF PROPENSITY OF ESCAPE AND ABILITY TO DELIVER IN VIVO PROTECTION. THE ANTIBODIES COME FROM FOUR CONTINENT, TWO-THIRDS FROM INDUSTRY, ONE-FOURTH ACADEMIA, 8% FROM GOVERNMENT LABORATORY. AND A LOT OF THE MOLECULES COME FROM SMALL START UPS NOT GET ATTENTIONON MOLECULE ANOTHER WAY. 8% FROM MULTI-MAJOR MULTI-NATIONAL CORPORATIONS AND ALSO ANALYZING THERAPEUTICS THAT ARE BEING CONSIDERED BY THE ACTIVE CLINICAL TRIALS WHEREBY INDEPENDENT ANALYSIS AND STANDARDIZED PLATFORMS THE ARRAY OF COMPANIES SIZE HERE REFLECTS ARRAY OF COMPANIES IN THE UNITED STATES ANDES BROAD, LOT OF SMALL COMPANIES. THIS IS WHAT IT LOOKS LIKE FROM OVER HERE. EVERY ANTIBODY IS CODE NAMED BLINDED AND THEY ARE ALL GIVEN THE SAME FAIR SHAKE. WHAT HAPPENS WHEN THE ANTIBODY COME IN AND THEY ARE GIVEN THE CODE NAME, THE DONOR KNOWS WHICH ANTIBODY IS THEIRS AND THEY GET THE DATA BACK AND CAN USE IT FOR IND FILING. THE DATA ARE ANONYMIZED SO I CAN LOOK AT AGGRAVATED DATA OF WHAT THEY DO AND TELL US. SO WE ALLOQUAT AND DISTRIBUTE THESE AND SEND TO DIFFERENT EXPERTS IN THE FEEL EACH DOING A DIFFERENT KIND OF ASSAY TO EVALUATE THE FUNCTION OF ANTIBODIES. THE DATA IS THEN AGGRAVATED INTO A DATABASE CALLED COVID DB. THERE ARE NUMBER OF PEOPLE WRITING THE ASSAYS. VERY MUCH LIKE TO THANK THESE GROUPS OF PEOPLE THAT ARE DOING A LOT OF THE HEAVY LIFTING TO BUILD THIS PUBLICLY AVAILABLE DATABASE. IN THAT DATABASE, YOU CAN SEE DATA FOR YOUR OWN ANTIBODY AND UNBLINDED DATA FOR EVERYBODY ELEMENT COVID.LG.ORG YOU CAN CLICK THE DAY BASE IT LOOK LIKE THISSER, IF YOU ARE INTERESTED IN COVID 2 YOU CAN SEE HOW IT RANKS IN NEUTRALIZATION IN THE POOL, WHERE IT RANKS IN NEUTRALIZATION AMONG OTHERS OF EPITOPE GROUPS SO COVID 2 IS AMONG THE MOST POTENT IN GROUP TWO AND LOOK AT ITS FOOTPRINT BY STRUCTURAL BIOLOGY. IF YOU ARE INTERESTED IN ANTIBODY 96 YOU CAN FIND THAT INFORMATION HERE. ANTIBODY 96 IS INTERESTING. IT IS NOT THE MOST POTENT NEUTRAL NEUTRALIZER, IT IS TOWARD BOTTOM OF EPITOPE BUT IT DOES DELIVER POTENT PROTECTION IN VIVO. THAT IS A STUDY WE WERE RUNNING IN THIS BROAD DATABASE AND SIX MONTHS AGO THE VARIANTS OF CONCERN EMERGE AND WE WERE ASKED TO PIVOT STUDIES TO FIND OUT WHICH COVID ANTIBODIES RESISTANT TO THE VARIANTS OF CONCERN. SO THE FIRST THING WE DID TOWARD THAT EFFORT IS COMPETITION ANALYSIS. THIS IS DONE BY DAN BET,TINGER USING THE HIGH THROUGH PUT PLASMA RESONANCE PLATFORM. SO WE HAVE ANTIBODIES IN COVID AGAINST RECEPTOR BINDING DOMAIN, S 2 EVERYTHING ELSE THE MAJORITY ARE RECEPTOR BINDING DOMAIN, ACHIEVING POTENT MUTUALIZATION. LOOK AT THE FIRST 250, RECEPTOR BINDING DOMAIN REACTIVE ANTIBODIES WE FIND THEY DIVIDE INTO SEVEN MAJOR GROUPS. WE CALL THESE COMMUNITIES. SEVEN MAJOR COMPETITION BINS OR FOOTPRINTS WHERE THEY BIND. NOW OTHER STUDIES THAT DIVIDED THERAPEUTIC ANTIBODIES INTO CLASSES OR GROUPS LOOK AT THEM BY STRUCTURE, OR LOOK AT THEM BY GERM LINE, THIS IS A SLIGHTLY DIFFERENT COMPLIMENTARY APPROACH, THIS IS BY COMPETITION, WHICH IS INTERFERE WITH EACH OTHER, WE CHOSE THIS METHOD BECAUSE WE KNEW WE WERE GOING TO LOOK FOR A COCKTAIL. SO THE SEPARATION HERE IS BY DEGREE OF PHYSICAL COMPETITION TO BIND RBD. THE FIRST MAJOR DIVISION HERE REMOVES GREEN AND SIGH YEN GROUPS FROM OTHERS, THE SECOND MAJOR DIVISION OVER HERE TAKES GROUPS 1 THROUGH 3 AND SEPARATES FROM 6 AND 7. YOU CAN DRAW AS MANY DIVISIONS AS YOU WANT. ANTIBODIES BIND ACROSS THE SPIKE IN A COMPLETE SPECTRUM. AND THE CUT OFF, REDD BAR ACROSS THE CENTER RAISE OR LOWER AS YOU WISH. YOU CAN HAVE FEW GROUPINGS, ALL THE WAY DOWN TO 350 DIFFERENT INDIVIDUAL GROUPS. BUT WE PLACED THIS CUT OFF BAR WHERE IT MAKES SENSE IN DIVISIONS OF DIFFERENT ANTIBODY BEHAVIOR. SO WE HAVE SEVEN MAJOR COMMUNITIES THAT MAP PLACES IN SPACE, BUT WITHIN THEM WE CAN NAME 17 SMALLER CLUSTERS SO GROUP 2 HAS A AND B AND B CAN BE DIVIDED TO ONE, TWO, THREE. SO YOU MIGHT THINK OF THESE IN CONTINUUMS LIKE A CITY. SO FOR EXAMPLE, THE RBD IS NEW YORK CITY IT IS DIVIDED TO BORROWS. THEY ARE DIVIDED TO NEIGHBORS. AND THEN THERE'S INDIVIDUAL STREETS AND INDIVIDUAL HOUSES ON THOSE STREETS. SO YOU KNOW THE LINE BETWEEN ONE NEIGHBORHOOD AND ANOTHER BLURS AND ONES ON THE EDGE HAS CHARACTERISTICS OF ONE NEIGHBORHOOD AND SOME OF THE THE OTHER. THIS IS HOW WE DIVIDED BASED ON BEHAVIOR IN MANY BIOLOGY. WE HAVE SOLVED STRUCTURE OF COUPLE MEMBERS OF THE EACH OF THESE GROUPS AND SUB DIVISIONS TO MAP WHERE THEY ARE, FOR EXAMPLE THESE THREE ARE DIRECTED AGAINST THE RBM. RECEPTOR BINDING MOTIF, EXACTLY WHERE ACE 2 BINDS, SO ACE 2 STRUCTURE HERE IN REDD, WE HAVE THREE DIFFERENT FOOTPRINTS WITHIN THAT RBM. RBD 1 WHICH OVERLAPS PRECISELY WITH THE ACE 2 BINDING SITE, RBD # 2 ONE WAY, RBD 3 SHIFTED THE OTHER WAY. WE CAN MAP FOOTPRINTS AND ANGLES SO WE HAVE TWO CLASSES AGAINST THE OUTER FACE OF RECEPTOR BINDING DOMAIN, ALWAYS EXPOSED WHETHER RBD IS DOWN OR UP. AND TWO CLASSES AGAINST THE INTERFACE, ONLY BIND RBD WHEN IT IS UP AND NOT WHEN DOWN. SO THIS DIVISION IS BACKED UP BY A LOT OF STRUCTURE, SO WE ARE BUILDING THIS DATA BATES HERE, THIS WILL BE AVAILABLE IN THE EM DATABASE AND ALSO IN BIOARCHIVE VERY SOON. MAPPING LOTS OF STRUCTURES FOR EACH DOMAIN AND WE ARE SHOWING YOU EXAMPLE IMAGES 2D CLASS, LOOKING AT THE SAB FRAGMENT ANTIBODY AND THE COMPLETE IGG WHERE YOU SEE THESE SO THIS IS BASED ON STRUCTURE AND BIOPHYSICAL ANALYSIS. WE ARE LOOK AT EACH OF THESE ANTIBODY GROUPS, BY THEIR FOOTPRINT. THEIR FOOTPRINT TERMS WHICH MUTATIONS THEY MAY OR MAY NOT BE SUSCEPTIBLE TO. FOR EXAMPLE EACH OF THESE STRUCTURE, THE FOOTPRINT OF ACE 2 ITSELF IS OUTLINED IN THE BLACK DOTTED LINE, THE FOOTPRINT OF THAT APPS REMARKABLY CONSISTENT, 2B 1 HIT THE SAME SPOT, THEY OVERLAP WITH THE ACE 2 FOOTPRINT. SO RBD 1 IS REPRECISE THE ACE 2 BINDING SITE, OVERLAPSES THAT BLACK DOTTED LINE CLOSELY. ON THE RIGHT EM STRUCTURE OF SPIKE AND SIDE VIEW AND TOP VIEW, OF THE THREE FAB E COVID 259 ANTIBODY 259 WHICH FALLS INTO GROUP RBD 1 OVERLAPPING THE ACE 2 BINDING SITE. RBD 2 SHIFTED TO ONE SIDE. YOU ARE LOOK AT ANTIBODY 252. FAB FRAGMENTS. RBD 3 IS SHIFTED DOWN A LITTLE BIT TO LOWER ANTIBODY NUMBER 8 THEN THE INTERFAITH AND OUTER FACE ANTIBODIES ARE SHIFTED SOMETIMES ENTIRELY OUTSIDE THE ACE 2 BINDING FOOTPRINT. IF YOU LOOK AT THESE IN MORE DETAIL HERE IS A MODEL OF SPIKE ORIENTED IN A SIDE VIEW SO THE VIRAL MEMBRANE TOWARD THE BOTTOM AND TARGET CELL WILL BE TOWARD THE TOP. THIS HAS ONE RECEPTOR BINDING DOMAIN, RBD IN TO THE UP POSITION AS IF IT WERE GOING TO INTERACT WITH ACE TWO RECEPTOR. THE NEXT VIEW WILL BE FROM PERSPECTIVE OF TARGET CELL LOOKING DOWN ON TO SPIKE SO IF YOU WERE ACE 2 ON TO SPIKE, THIS IS WHAT YOU SEE, ZOOM INTO THAT SINGLE RECEPTOR BINDING DOMAIN AND THE RESIDUES OF COLORING ARE HIGH FREQUENCY MUTATIONS THAT HAVE EMERGED ALONE OR IN VARIANTS OF CONCERN SO MAP WHERE THEY ARE. NOW COMPETITION MAKES PERFECT SENSE WITH STRUCTURAL BIOLOGY. YOU CAN ROUGHLY DIVIDE RECEPTOR BINDING DOE MANE IN HALF BETWEEN THE ONES THAT HAVE INTERFACE OWN EXPOSED RBD AND THE OUTER FACE ALWAYS EXPOSED RBD IS DOWN OR UP. THIS IS THE ACES 2 BINDING SITE. THERE ARE MOLECULES IN COVID WHICH ARE ACE 2. RBD 2 SHIFTED TOWARD INTERFACE, RBD 3 SHIFTED DOWNWARD, 4 AND 5 ON THE OUTER FACE, SHIFTED UP AND SHIFTED DOWN. RBD 6 AND 7 OVERLAP BUT BEHAVE DIFFERENTLY ON THE INTERFACE. HOW DOES THIS COMPARE TO WHAT YOU HAVE SEEN BEFORE? PAMELA'S LAB CHRIS BARNES DEFINED FOUR CLASSES. CLASS ONE RECEPTOR BINDING MOTIF ONE TWO THREE, WHAT WE SEE ABOUT THESE IN COVID IS THEY NEARLY COMPLETELY OR COMPLETELY BLOCK BINDING OF ACE 2. WHEN WE LOOK AT THE IGG, INSTEAD OF FAB IT BINDS TO STOICHIOMETRY, ONE FAB TO ONE TRIAL RICK SPIKE. THEY BIND WITH PARALLEL GOAL POSE STICKING UP FROM THERE. THEY REQUIRE RBD UP IN ORDER TO BIND. LOOK AT THE STRUCTURE OF WHAT AN IGG LOOKS LIKE BOUND TO THAT SPIKE YOU CAN SEE THE GOAL POST HERE. SPIKE AT THE BOTTOM, TWO CLEAR FAB WITHHOLDS IN THE CENTER AND THE LITTLE BLUR AT THE TOP. THE BLUR AT THE TOP WAS FLEXIBLE FC ATTACHED TO THE FABs. ANN WILSON'S GROUP PUBLISHED ANOTHER DEFINITION OF SPIKE. RECEPTOR BINDING SITES DIVIDED TO RBS AB AND RB RBS D. (INAUDIBLE) GROUP DEFINE AD CLASS TWO. THIS LOOKS LIKE RBD 4, RBSC. MOST OF THE ONES IN THIS GROUP OF OUTER DOMAIN ARE ACE 2 BLOCKING AND COMBINE SPIKE WHETHER UP OR DOWN. RBD 5 FORMS CLASS 3 WHERE S 309 BINDS. THESE DO NOT BLOCK ACE 2, THEY COMBINE RBD UP OR DOWN, THE INTERESTING THING ABOUT IGGs THEY CAN CROSS LINK SPIKES TOGETHER. THEY CAN THE IGG IN SOLUTION CAN BIND TO SPIKES FACING EACH OVER, THIS WOULDN'T HAPPEN ON THE SAME VIRUS, BUT I SUPPOSE TWO VIRUSES COULD OPPOSE EACH OTHER BUT WE CAN ALSO SEE IS IT NEIGHBORING SPIKES WITHIN THE RANGE THAT IS OBSERVED ONE IDG BRIDGE THESE TWO. 6 AND 7 FORM CLASS FOUR AND REQUIRE TWO RBDs TO BE UP: DIVIDED BECAUSE THEY HAVE DIFFERENT BEHAVIOR BIOLOGY, ONE BLOCKS ACE 2, ONE ONLY SOMETIMES DOES. ACROSS THE -- WE CREATE A COMPETITION GRID WHICH COMPETE WITH EACH OTHER SO DARK BLUE ARE ANTIBODIES THAT COMPETE AND LIGHT BLUE DON'T COMPETE. HARD TO SENSE ACROSS HUNDREDS SO ZOOM IN TO 50 EXAMPLES SHOWING YOU HERE COMPETITION GRID, 50 SAMPLE ANTIBODIES GROUPS RAINBOW COLORING ONE TO 7 ACROSS THE RBD. YOU CAN SEE A COUPLE OF THINGS. THIS IS WHY WE HAVE DIVIDED THIS CLASS INTO GROUP 6 AND 7. 6 EXEATS WITH PRO TENT NEUTRALIZING OF 2A. 7 DO NOT. GROUPS FOUR AND FIVE BIND OUTER DOMAIN BUT FOUR EXEATS WITH 2B AND FIVE DOES NOT. EXHIBITS IN DIFFERENT BEHAVIOR. SO THIS GRID GIVES A WAY WHICH WE CHOOSE COCKTAILS SO FOR EXAMPLE IF YOU WANT TO TAKE ADVANTAGE OF VERY POTENT NEUTRALIZATION OBSERVED IN 2A AND CLINICAL CANDIDATES COME FROM THE ORANGE GROUP, YOU CAN PAIR WITH ONE FROM GROUP 4 OR 5 OR 7. BUT FOUR AND FIVE COMPETE TO YOU HAVE TO PICK. A 2A OF 4 AND 7 WITH ONE. IF YOU WANT TO CHOOSE THERAPEUTIC CANDIDATES IN 2B PAIR IT WITH 5, 6, 7, 2A CAN'T BE WITH 6 ONLY 2B SO YOU MIGHT SEE RECEPTOR BINDING MOTIF BUT NEED TO KNOW WHERE TO CHOOSE THE COKE TAME TO PAIR IT WITH. OF AND 7 COMPETE WITH EACH OTHER. YOU CAN'T CHOOSE BOTH PICK ONE SO 2B WITH FIVE. AND THE 6. THIS MATTERS BECAUSE THE DIFFERENT FOOTPRINTS TYPICALLY HAVE COMMONALITIES WHICH ARE AND ARE NOT SUSCEPTIBLE TO DIFFERENT MUTATION IN VARIANTS OF CONCERN SO 2A THERAPEUTIC CANDIDATES IS SENSITIVE TO THE K 417 MUTATION. 2B IS SENSITIVE TO 84K ON THE FAR RIGHT THE CYENN BLUE AND PURPLE ARE RECESSTANT SO VERY ARACTIVE FOR MAKING DURABLE COCKTAILS MOVING FORWARD. SODS PAIRINGS YOU MIGHT CONSIDER WITH LARGER POOL WE HAVE. ANTIBODIES FROM 50 GROUPS RAISED IN DIFFERENT WAYS SELECTEDDED IN DIFFERENT WAYS, COMBINATIONS YOU WOULDN'T PUT TOGETHER ANY OTHER WAY. SAY YOU WANTED TO FOCUS ON ANTIBODY 249 EXTREMELY POTENT NEUTRALIZATION OR COVID 2 FOR POTENT NEUTRALIZATION. YOU CAN PAIR THEM WITH THESE MOLECULES. THAT GIVES YOU ADVANTAGE OF POTENT NEUTRALIZATION WITH VARIANT RESISTANCE. WE LOOKED AT NEUTRALIZATION ESCAPE BY COMMUNITY. SHOW YOU HOW WE PRESENTED RESULTS. WE LOOK INDIVIDUALLY AND AS ASSEMBLED VARIANTS. TERMINOLOGY 5 AND 5 BY N AND CLUSTER OF FIVE AND MINUS 1, PARTICULAR POINT MUTATION THAT IS INTERESTING AND ENHANCES AVENUE THAT WILLIZATION. LOOKING AT THE FULL CHANGE IN PSEUDOVIRUS NEUTRALIZATION FOR BSD WHERE THE ANTIBODIES THAT ARE GRAY HAVE NO EFFECT BY MUTATION, THOSE THAT ARE TURQUOISE NEUTRALIZE THAT VARIANT BETTER FROM WILD TYPE, THOSE THAT ARE BROWN ARE KNOCK OUTS. SO WHAT YOU CAN SEE ARE THIS ONE HERE COVIC 69 IS ACE 2 LINKED TO XC, NEUTRALIZATION GETS BETTER WITH VARIANTS AS U YOU MIGHT EXPECT. NOT POTENT BUT INTERESTING CONCEPT. TWOA AND B RECEPTOR BINDING MOTIF, THERE ARE EXCEPTIONS BUT UNIVERSALLY KNOCKED OUT BYE-BYE 1351. THE SAME THING WITH RBS GROUP 4 GROUP 5, 6, 7 CAN BE RESISTANT. FOUR AND FIVE FIND THE OUTER PHASE BUT BECAUSE OF DIFFERENT FOOTPRINT AND DIFFERENT SUSCEPTIBILITY TO EMERGE IN VARIANTS. SOME OF INTEREST HERE COVID 268 IS MUTATION RESISTANT. MIGHT BE MORE DURABLE IN TIME AND GIVEN OPTION FOR THERAPY MOVING FORWARD. INTERESTING MOLL EXCUSE THERE THAT CROSS LINK SPIKE. ANTIBODIES 251, 170, 166 ARE ALSO VARIANT RESISTANT. AND WE HAVE DONE THE STRUCTURAL BIOLOGY TWO WAYS WITH AN FAB TO GET RESOLUTION AND WITH AN IGG TO GET RELEVANCE, THINGS MOBILIZED IN VIVO IS IGG. WE HAVE GROWN UP LOOKING AT STRUCTURE OF FAB BECAUSE THIS WAS THE ONLY WAY, HIGH RESOLUTION. WHEN CRYSTALS WAS THE ONLY OPTION THAT WAS THE ONLY WAY TO BUILD A LATTICE. FLEXIBLE OF THE CROSS LINKING OF THE IGG PREVENTED STRUCTURE DETERMINATION NOW THAT WE HAVE CRYOEM WE CAN DO BOTH AND WE CAN THINK ABOUT WHAT HAPPENS WHEN THE IGG BINDS AND WE CAN LEARN A LOT THAT WAY. SO THE FIRST THING TO UNDERSTAND IS SPIKE SURFACE OF THE VIRUS IS NOT RIGIDLY UP RIGHT. THIS WORK HERE THIS BEAUTIFUL TOMOGRAPHY SHOWS SPIKE MORE OFTEN LIENS ONE WAY OR ANOTHER. MAYBE 40 DEGREES THIS WAY OR 40 DEGREES THAT WAY SO THEY TILT ON THE SURFACE OF THE VIRUS. AND THE BEHAVIOR HOW THE IGG INTERACTS WITH SPIKE, HAS TO DO WITH ITS FOOTPRINT ON SPIKE. COMMUNITY. RBD 1 HUMAN ANTIBODY OVERLAP WITH ACE 2 BINDING SITE FREQUENTLY BINDS 3 SEPARATE FABs ON THE TRIMER AND ANGLED OUT OUTWARD SUCH THAT THAT IT IS THREE DIFFERENT IGGs, LOOK AT THE TWO D CLASS YOU CAN SEE THE HAIL LOW ACROSS THE TOP, REST OF THE I GO,G IN SPACE. YOU CAN SEE THE FABs IN MANY REDD DOWN HERE. THAT GROUP IS DIRECT ACE 2 COMPETITION. GROUP RBB 2, THESE ARE THERAPEUTIC CANDIDATES, POTENCY NEUTRALIZATION, TEND TO BIND ONE IGG FOR SPIKE. UP RIGHT GOAL POSTS YOU CAN SEE THE TWO FABs CLEARLY RIGIDLY AND ONE SINGLE SMALL BLUR ABOVE IS FC. SO THEY BIND ON TO TWO RBDs, LEAVE THE THIRD ONE UNOCCUPIED BUT THEY MIGHT STERICALLY BLOCK ACCESS TO ACE 2 WITH THAT BULK OF THE IGG SO THESE BINDS BIVALENTLY INTRASPIKE 1 IGG TO ONE SPIKE. GROUP 5 IS INTERESTING, GROUP 5 ALWAYS LINKS SPIKES TOGETHER. WE RARELY, NEVER SEE A SINGLE IGG BOUND TO SINGLE SPIKE. SO WHAT YOU -- LET ME SHOW YOU THE STRUCTURE MODELS ON THE RIGHT. YOU ARE LOOKING AT TWO SPIKES FACING EACH OTHER. THIS WON'T HAPPEN ON SINGLE VIRUS, IT HAPPENS WHEN THE SPIKES ARE SOLUBLE ECTO DOMAINS AND TUMBLE ANY DEGREE IN SOLUTION OR MAYBE TWO COME TOGETHER BUT THE WAY THESE FABs ARE ORGANIZED, IGG IS ANCHORING TWO DIFFERENT SPIKES TOGETHER. A LOT OF CLASSES WE SEE ARE THE PICTURE ON THE BOTTOM RIGHT WITH TWO TILTED SPIKES LINKED WITH ONE IGG. THIS ANTIBODY HERE NUMBER 96 IN GROUP 5 IS INTERESTING. YOU WOULD NEVER HAVE CHOSEN BY NEUTRALIZATION ALONE BUT AS PROTECTION IS AMONG THE BEST SO PUNCHING ABOVE ITS WEIGHT FOR SOME MECHANISM. IT IS POSSIBLE THAT WHAT IT IS DOING IS ACHIEVING LINKAGE OF SITES GREAT HER S 2 STERIC HINDRANCE BY CROSSING SURFACE, WE DON'T KNOW YET BUT IT IS INTRIGUING AND WE SHOULD THINK HOW THE DIFFERENT TYPES OF ANTIBODIES BEHAVE AS IGGs. SO THOSE RBD 1 TEND TO BIND THREE PER SPIKE, SOMETIMES CROSS LINK RBD 2 BIVALENTLY ON ONE AND BEHAVIOR AROUND (INAUDIBLE) CATEGORIES. NDDs BIND IN EVERY ORIENTATION ACROSS THE CLOCK, SHOWING THREE EXTREMITIES HERE. THEY AREs -- THEY EASILY ESCAPE BY DIVERGENCE AMONG THE VARIANTS. THAT WHAT WE HAVE DONE BUILD CONSORTIUM, CONTRACT THE MOLECULES ORGANIZE OURSELVES WITH CONTRIBUTORS AND PEOPLE AT THE ASSAYS WHO DEVELOP THIS DATABASE TO LOOKING AT THE VARIANTS CONCERN. WHAT YOU CAN EXPECT FROM THIS CONSORTIUM THE NEXT YEAR IS COMPLETE THE ANALYSIS ON THE ENTIRE COVID PANEL SO IN DEPTH ANALYSIS OF 50, GO THROUGH ALL OF THEM. WE ARE GOING TO EXPAND TO MORE S 2 REACTIVE AND ADDITIONAL VARIANT RESISTANT CANDIDATES PEOPLE DISCOVER OUT IN THE COMMUNITY. WE WILL COMPLETE IN VIVO STUDIES AND USING THAT DATA AND THE ONES IN THE STUDY WHICH THERE'S HUMAN CLINICAL DATA AVAILABLE USE THAT BODY OF DATA TO UNDERSTAND THE CAPACITY OF DIFFERENT IN VITRO ASSAYS FORECAST PROTECTION. OFTEN FOR EMERGING VIRUSES, WE HAVE TO EVALUATE THINGS IN PLASTIC IN RODENTS THEN IN PRY MATES AND VERY FEW SEEK CLINICAL FUTILITY. WE HAVE THE OPPORTUNITY FOR THE FIRST CLINICAL DATA TO IN INFORM THE NEXT GENERATION OF THERAPIES. WE WILL ALSO BE DOING IS USING A BROAD ARRAY OF ANTIBODIES, 350 FROM FOUR CONTINENT TO MAKE MORE VARIANT RESISTANTS POTENT COCKTAILS, NOT HAVE COME TOGETHER ANY OTHER WAY. ALSO WHAT WE ARE BUILDING IS DATABASE. A VERY BROAD DEEP ANALYSIS OF THERAPEUTIC CANDIDATES ACROSS THE LANDSCAPE OF SPIKE SHOWS IN A DIFFERENT WAY AND SELECT DIFFERENT WAY. THE STANDARD BASE BEING BUILT WITH FAIR IDEOLOGY SO THE DATA IS FINDABLE ACCESSIBLE INTEROPERABLE AND REUSABLE. BECAUSE IT IS ANONYMIZED YOU CAN DOWNLOAD YOURSELF AN EXCEL SPREADSHEET WHAT TO LEARN ABOUT ANTIBODIES IN GENERAL. IF YOU HAVE AN ANTIBODY IN COVID YOU CAN SEE HOW IT IS THERE. IN THIS DATA BASE YOU WILL LIST RESIDUES THAT COMPRISE THE FOOTPRINTS AND LINKS TO THE EM STRUCTURE AND HOW TOs AND MAKE THIS BROADLY APPLICABLE FOR FOR THE ANTIBODIES YOU ARE DISCOVERING NOW AND OTHERS TO COME AND WE WILL BE USE THE INFORMATION FROM THE DATABASE TO ADVANCE VARIANT RESISTANT COCKTAILS. AND COME UP WITH THE INFORMATION THAT WILL INFORM THE NEXT GENERATION OF VACCINES BECAUSE LOOK AT MONOCLONALS NOT ONLY GIVES THAT THERAPEUTIC OR PROPHYLACTIC, IT ALSO TELLS WHAT ANTIBODIES REALLY LIKE VACCINE TO ELICIT SO BY STUDYING WHERE THESE BIND, WHAT PROCESSES GIVE RISE TO THEM, WE CAN MAKE NEXT GENERATION VACCINES. SO THIS IS A LARGE CONSORTIUM, THANKS THE GATES FOUNDATION, NIH FOR THE FUNDING THAT LAUNCHED IT. GHR, OVERTON FAMILY FOR EMERGENCY SUPPORT WHEN WE NEEDED IT. VARIANT ANALYSIS. LIKE THE THANK PROGRAM OFFICERS FOR SHEPHERDING THE PROGRAM ALONG AND THE CONTRIBUTORS OF SAMPLES AND CONTRIBUTORS OF DATA. THE DATA SHOWING YOU TODAY WAS LED BY THE EFFORTS OF A PROGRAM MANAGER DR. SHARON SCHENDEL AND DR. KATHERINE HASTIE DAN BEDINGER TIM GERMANN AND DATABASE AND LIKE TO THANK YOU FOR YOUR ATTENTION. >> THANK YOU SO MUCH, DR. SAPHIRE, WE WILL CONTINUE WITH THE PANEL. DR. MCDERMOT ARE YOU READY? >> YES. CAN THE PANEL LIGHT HAIR CAMERAS UP SO YOU CAN START OUR CONVERSATION? OBVIOUSLY CHRIS WILL GET THE FIST QUESTIONS BECAUSE ERICA WON'T POINTED OUT ALL THE BRILLIANT WORK HE'S DOING. AS I SAID IN OUR PRE-MEETING I COME TO THIS VERY MUCH AS AN ACT LIGHT AND NOT A GURU. SO WILLING TO LEARN THE NEXT 20 MINUTES OR SO. THE ASSEMBLED EXPERTISE WAS IMPRESSIVE SO I'M GOING TO ASK CHRIS CHRIS TO INTRODUCE HIMSELF BRIEFLY. >> CHRISTOPHER BARNES IN CAL TECH, SOON TO BE ASSISTANT PROFESSOR BIOLOGY AT STANFORD. >> TERRIFIC. MIKE DIAMOND. >> I'M MIKE DIAMOND, PROFESSOR WASHINGTON SCHOOL UNIVERSITY OF MEDICINE. >> DAVID MONTEFIORI. >> I'M PROFESSOR IN THE DEPARTMENT OF SURGERY DUKE UNIVERSITY. >> PENNY. >> PENNY MOORE FROM THE NATIONAL INSTITUTE FOR COMMUNICABLE DISEASE AND -- SOUTH AFRICA. >> RACHEL. >> HI, RACHEL LIBERATORE DIRECTOR OF RESEARCH DEVELOPMENT AT BOO FOCUS CANNING ON ANTIBODY THERAPEUTIC. >> LAURA. >> I'M LAURA WALKER DIRECTOR OF THE ANTIBODY SCIENCES DEPARTMENT AT -- AND CHIEF SCIENTIFIC OFFICER AT (INAUDIBLE) THERAPEUTICS. >> FANTASTIC. SO CLEARLY ERICA GAVE SUCH A FANTASTIC TALK THAT SHE'S RAISED A LOT OF QUESTIONS OFF THE BACK. SO INITIALLY I THINK WE SHOULD TALK ABOUT WHAT IS THE PROSPECT OF COMBINATION THERAPY? AND IN THE DIFFERENT SITES CHRIS IDENTIFIED MAYBE HE CAN EXPAND A LITTLE BIT ON WHAT HIS PREDICTION OR INSIGHT WOULD BE MOVING FORWARD AND WHICH KIND OF ANTIBODIES WE WOULD NEED. >> DR. SAPHIRE PRESENTED A GREAT TALK RECAPITULATING OUR WORK. YOU THINK OF THE VARIANTS OF CONCERN AND WHERE THE MUTATIONS RESIDE. THAT'S THE FOCUS MOVING FORWARD TRYING TO UNDERSTAND EXACTLY WHICH CLASS OF ANTIBODIES CAN WE COMBINE BASED OFF OF WHERE THESE VARIANTS OR THESE COMMONLY REOCCURRING MUTATIONS ARE OCCURRING IN THE RBD. SO BACK TO HER CLASSIFICATION MY CLASSIFICATION, CLASS ONE AND CLASS 2 ARE THOSE THAT BINDS TO THESE TOWARDS APEX OF RBD OVERLAP WITH ACE 2 BINDING SITES. THE E 4A 4 K MUTATION COMMON AMONG A LOT OF CIRCULATING VARIANTS, KNOCKS OFF NUMBER OF THESE OR MAKES THESE ANTIBODIES SENSITIVE TO THE VIRUS. SO IN THIS SENSE YOU DEFINITELY WANT TO ADD ANTIBODIES THAT BIND TO THESE OTHER REGIONS OUTSIDE THE ACE 2 BINDING SITE AND SO THIS IS TYPICALLY A CLASS 3 OR CLASS 4 IN MY DEFINITION AND ERICA'S DEFINITION. IT WAS CLASS 5 OR GROUP 5, 6, 7. THE GROUP CLASS 3 OR GROUP 5 ANTIBODIES YOU SHOWY CROSS LINK ENTER CROSS LINK SPIKES IS AN INTERESTING CLASS BECAUSE THEY CAN BE VERY POTENT ANTIBODIES. SO YOU THINK ABOUT COMBINING THOSE ANTIBODIES WITH THOSE FROM DIFFERENT CLASSES THAT DON'T OVERLAP YOU CAN DO IT BASED ON WHAT WE UNDERSTAND STRUCTURALLY FROM THESE ANTIBODIES. >> I DON'T KNOW IF ANYBODY ELSE HAS ANY QUESTIONS FOR CHRIS. WOULD YOU COMBINE WHAT ABOUT ANTIBODIES THAT ARE OUTSIDE THE RBD? WOULD YOU COMBINE THOSE AS WELL LIKE THE NTD? >> DEFINITELY LOOK AT COMBINING NTD ANTIBODIES, S 2 WITH THOSE THAT BIND TO THE RBD. OBVIOUSLY DAVID HAS DONE WORK AS WELL AS VRC ON DEFINING THE NEUTRALIZING ANTIBODIES WITH THE END TERMINAL DOMAIN. ONE SUPER SITE PEOPLE POINTED OUT EASILY ESCAPED BY VARIANTS THROUGH MUTATIONS IN THIS ONE EPITOPE BUT NTD PROVIDES ADDITIONAL REGION TO COMBINE MAYBE TWO OR THREE ANTIBODIES. SO MAYBE TWO RBD VIRUS PLUS NTD BINDER THAT WOULD GIVE YOU MORE COVERAGE OF THE SPIKE AND ALLOW BETTER THERAPEUTIC COCKTAILS. I THINK ONE THING YOU HAVE TO BE CAREFUL WITH NTD ANTIBODIES IS CAN YOU COMBINE THEM WITH RBD ANTIBODIES THAT BIND DIFFERENT ORIENTATION THAT MAY NOW BE HINDERED BY NTD BINDER SO TEASING OUT EXACTLY HOW THE NTD ANTIBODIES TARGET AND ORIENT ON THE NTD IS IMPORTANT THINKING ABOUT COMBINING THEM IN THAT THE SUPER SITE IS THOSE THAT CONFLICT WITH THE RBD. >> FROM A ANTIBODY DEVELOP. MORE INDUSTRIAL POINT OF VIEW, POSE A QUESTION TO RACHEL AND LAUREN, DO KIND OF THE GROUP 5 LIKE ANTIBODIES DO THEY REPRESENT A VERY GOOD TARGET AS A SPECIFIC ANTIBODY OR TRISPECIFIC ANTIBODIES AND ARE YOU WORKING ANY OF THOSE IF YOU CAN TELL US. >> THE SHORT ANSWER IS YES, THEY REPRESENT VERY INTERESTING TARGETS. AND I THINK THAT IS REALLY KEY POINT OF A LOT OF WHAT IS DISCUSSED TODAY A REAL FOCUS ON THINKING ABOUT CONSERVED EPITOPES AN THERAPEUTICS THAT GET AT THOSE EPITOPES IS QUITE IMPORTANT WITH CONCERNS OR VARIANTS AND TO GET AT ONE OF THE POINTS THAT CHRIS WAS MAKING, WITH RESPECT TO BY SPECIFICS THE SAME PRINCIPLES THAT APPLY WHEN THINKING ABOUT PAIRING THE ARMS, SO IN A BISPECIFIC EACH ARM IS BINDING A DISTINCT EPITOPE ON THE SARS COV-2 SPIKE SAME THAT A COCKTAIL WOULD HAVE TWO ANTIBODIES BINDING DIFFERENT SITES. NOT ALL WORK TOGETHER. WITH BY SPECIFIC PERHAPS EVEN MORE STRUCTURAL CONSTRAINTS BECAUSE THESE TWO DIFFERENT BINDING SITES ARE PHYSICALLY LINKED. SO THERE ARE PROS TO THAT BUT ALSO CONS SO WHEN DESIGNING BY SPECIFICS, IT IS VERY MUCH NOT THE CASE THAT YOU JUST ARE THINKING ABOUT TWO SITES COMPATIBLE IN TERMS OF THESE SORT OF BINDING CLASSES. BUT THEY ALSO HAVE TO WORK AT SOME LEVEL WHEN PHYSICALLY LINKED TOGETHER SO THERE'S SOME ADDITIONAL CONCERNS THERE. >> WE ARE NOT DEVELOPING A BISPECIFIC ANTIBODIES AS EVERYBODY PROBABLY KNOWS THERE'S SOME MANUFACTURING CHALLENGES ASSOCIATED WITH T THAT. RATHER FOCUSING ON DEVELOPMENT OF BROADLY NEUTRALIZING ANTIBODIES AND COCKTAILS OF BROADLY NEUTRALIZING ANTIBODIES BECAUSE THAT MIGHT BE OPTIMAL LONG TERM SOLUTION TO THE PROBLEM. SOME OF THE ANTIBODIES BUSINESS DIG COVERED LIKE THE SO CALLED CHRIS NOMENCLATURE TYPE 3 ANTIBODIES RESISTANT TO A SCAPE -- ESCAPE, MIGHT NOT BE TRUE IN THE FUTURE, AS BENNY SHOWED, WE ARE SEEING THE EMERGENCE OF VARIANTS EVERY WEEK SO START DEVELOPING THESE COCKTAILS YOU MIGHT DEVELOP NEW COCKTAILS BUT THE FOLLOWING YEAR, I THINK BROADLY NEUTRALIZING ANTIBODIES BECAUSE THEY GENERALLY TARGET EPITOPES NOT TARGETED BY ENDOGENOUS IMMUNE SITES, TARGET CONSERVE RESIDUES THAT MIGHT BE MORE DIFFICULT FOR THE VIRUS TO MUTATE WITHOUT SUFFERING FITNESS COST. THAT IS WHAT WE ARE FOCUSING ON. >> WHILE I HAVE YOU ON VARIANTS OF CONCERN, HOW CONCERNED ARE YOU ABOUT THE VARIANT OF A Y 1 OR EVEN 617.2. DOES THAT CREATE A CHALLENGE IF YOU TRY TO PUT THESE INTO CLINICAL TRIALS BEFORE YOU GET THERAPY? >> DO YOU MEAN CONCERN FROM MONOCLONAL PERSPECTIVE OR GENERALLY IN TERMS OF VACCINE? >> MONOCLONAL PERSPECTIVE. >> I THINK FROM THE PERSPECTIVE OF PEOPLE DEVELOPING BROADER ANTIBODIES, COMPANY WE HAVEN'T SEEN EVIDENCE TO DATE OR WE HAVEN'T IDENTIFIED VARIANTS THAT ARE RESISTANT TO ANTIBODY OR THE VERE ANTIBODY FOR THAT MATTER. WHEN WE LOOK AT OTHERS THAT ARE SARS 2 SPECIFIC WE ARE SEEING THAT THERE ARE MANY MUTATIONS ARISING RELATIVE WILL I HIGH FREQUENCY THAT'S SCAPE SOME OF THOSE ANTIBODIES. SO I'M NOT CONCERNED YET BUT HAVING A COCKTAIL OF TWO THAT ARE BROADLY NEUTRALIZING REALLY INCREASE THE BARRIER SO THAT IS THE DIRECTION WE ARE MOVING NOW. YOU CAN NEVER BE 100%, CLOSER AN CLOSER HIGHER LEVELS IN THE POPULATION UNCLEAR WHERE THINGS ARE GOING TO GO. MAYBE AS PRESSURE SURE ON THE VIRUS, THESE COMMON SITES WILL SHIFT TO CONSERVE SITES AND PRESSURE ON OUR SITE, HARD TO PREDICT THAT. COCKTAILS MIGHT OVERCOME SOME OF THAT. >> I THINK HOW DO YOU DOWN SELECT -- I MAY ASK MIKE DIAMOND THIS, IN THE SELECTION OF SOME OF THESE MONOCLONALS, I KNOW WE HAVE HAMSTERS AND WE HAVE GOT MICE AND WE HAVE GOT NON-HUMAN PRY MATES. WHERE DO YOU START WITH THIS, MIKE? >> I THINK THE FIRST THING IS WHAT LAURA AND RACHEL ECHOED AND THIS RELATES TO BETTY'S COMMENT IN THE SETTING OF THESE VARIANTS AND VARIANTS THAT WILL EMERGE. I COME TO THE CONCLUSION ONE OF THE KEY COMPONENTS IS TRYING TO IDENTIFY IDENTIFIES -- ANTIBODIES THAT BIND VERY MUCH CONSERVED SITES AND HAVE GREAT POTENCY. IN IN ERICA'S CLASS SHE HAS ALL THESE GREAT POTENCY DATA. SHE HAS COMPETITION DATA AND STRUCTURAL DATA ON MANY BUT NOT ALL. BUT IDENTIFYING IN THOSE CLASSES THOSE THAT BIND TO CONSERVED EPITOPES AND FIGURING OUT ASSAYS THAT YOU CAN DO THAT, LOOK FOR CROSS TO SARS 1 BUT DOESN'T HAVE TO GO TO SARS 1, CAN STILL BIND CONSERVED EPITOPE FOR SARS 2 WITHOUT NECESSARILY BINDING SARS 1. THAT IS ONE ASPECT GOING FORWARD. I WOULDN'T HAVE SAID THAT AT THE BEGINNING OF THE PANDEMIC BUT CERTAINLY NOW IN THE SETTING OF THE OUR UNDERSTANDING OF VARIATION AND RECOMBINATION IN CHANGE THAT THE VIRUS PROBABLY IS GOING TO HAVE UNDER NEW SELECTION PRESSURE. THE SECOND ISSUE FOR ME WHAT WE LEARNED OVER TIME IS EVEN THOUGH MONOCLONAL ANTIBODIES DON'T APPEAR TO GENERATE ESCAPE EASILY I HAVE A FEELING THAT IN THE SAME WAY THAT WAS ECHOED MORE COMFORTABLE HAVING MORE BROADLY NEUTRALIZING ANTIBODY, A SECOND ANTIBODY TO CONTROL RESISTANCE. WE HAVE SEEN IN VIVO RESISTANCE DOESN'T HAPPEN AS REGENERON DID EARLY ON AGAINST VARIANTS OR AGAINST HISTORICAL STRAINS AS LONG AS THEY HAVE ACTIVITY IN A COMBINATION. WHEREAS YOU DO GET RESISTANCE IN WAYS THAT ARE UNPREDICTABLE AS MONOTHERAPY. FOR EXAMPLE YOU GET RESISTANCE THOUGH MAY MAY NOT BE RESISTANT TO A GIVEN VARIANT AT TIME A YOU MAY SEE RESISTANCE TO THAT VARIANT BUT NOT ANOTHER, THOUGH THERE IS THE SAME SELECTION PRESSURE. IN OTHER WORDS SEQUENCE IS IN HOW YOU GET THERE MAY CHANGE THE WAY MUTATION OCCUR, HOW MANY NUCLEOTIDES OR WHICH CHANGE TO BECOME RESISTANT IN THAT PARTICULAR VARIANT. SO I DO THINK THAT BEING COGNIZANT OF EVOLUTION OF THE VIRUS IN DIFFERENT BACKGROUNDS IS IMPORTANT. YOUR OTHER QUESTION RELATES TO IN VIVO ASSAY WHICH IS MOST PREDICTIVE. I THINK THE SMALLER ANIMAL MODELS ARE MODELS. AND WE USE THEM ALL THE TIME. THEY NEED TO BE CORROBORATED, AS YOU GO UP. BUT I DO THINK THERE'S UTILITY IN THE HAMSTER MODEL, SEEMS TO HAVE PREDICTIVE ABILITY AND MOUSE MODELS ARE STRINGENT, ESPECIALLY THE THERAPEUTIC MODELS AND MY FEELING IS IF YOU CAN SHOW EFFICACY IN THOSE MODELS, THAT MAY BE ONE WAY TO MOVE UP TO THE NEXT MODEL AND DOWN SELECT. I THINK THERE'S UTILITY (NO AUDIO) FROM ANIMAL TO ANIMAL BECAUSE OF DIFFERENCES IN ISOTYPE AND FC RECEPTORS SO WE ARE LEARNING HOW TO MAKE THOSE PREDICTIONS BASED ON ACTIVITY SO I THINK THE LONG AND SHORT IS HIGHLY CONSERVED MULTIPLE ANTIBODIES, PROBABLY MULTIPLE MODELS AND DOING THEM IN COMBINATIONS THAT ARE RATIONALLY DESIGNED AS ERICA SAID. >> YOU ARE MUTED ADRIAN. >> I CAME UPOR UP ON SOMETHING ELSE ERICA SAID. MAYBE YOU WILL SEE PROTECTION IN ANIMAL MODEL THAT DOESN'T ECHO WHAT IS FOUND IN VITRO NEUTRALIZATION. AND SO THAT WOULD INDICATE SOME SORT OF SC FUNCTION. I KNOW THAT LEADS HAS DONE BEAUTIFUL WORK ON THIS BUT HAS ANYBODY ELSE BEEN LOOKING AT THIS, DAVID OR PENNY LOOK AT FC FUNCTION IN ANY OF THE ASSAYS IN HUMAN? >> YOU ARE ASKING ME THE QUESTION? >> PENNY AND DAVID TO LEAD OFF ON THAT AND THEN MIKE. SURE YOU ACTUALLY GOT DATA ON IT. >> I'LL WAIT TO HEAR. >> ADRIAN I WILL START OUT MY LAB IN PARTICULAR IS NOT LOOKING AT FC EFFECTOR FUNCTION BUT OTHER LABS ARE AND I THINK THAT THEY ARE VERY IMPORTANT. REALLY GLAD TO HEAR THEY ARE PART OF THE PROGRAM THAT ERICA PUT TOGETHER. >> WE ARE LOOKING AT EFFECTOR FUNCTION MOST IN THE CONTEXT OF INFECTION RATHER THAN MONOCLONAL ANTIBODIES BUT IT MIGHT BE INTERESTING, I THINK ONE OF THE THINGS WE DON'T REALLY UNDERSTAND IS WHAT TARGETS OF THE MOST POTENT FC EFFECTOR FUNCTION ANTIBODIES MIGHT BE AND THEY MAY NOT NECESSARILY OVERLAP WITH ANTIBODIES WE FOCUS ON ISOLATING WHICH ARE MORE THOSE WITH NEUTRALIZING ACTIVITY. SO I THINK THERE IS SOME UNKNOWNS IN THE SENSE THAT WE PROBABLY DON'T KNOW WHAT THE TARGETS ARE OF THE BEST FC EFFECTOR ANTIBODIES NOR DO WE I THINK WE ARE ONLY BEGINNING TO UNDERSTAND HOW THAT RELEVANT THAT MIGHT BE. SO I I THINK EFFORTS TO ANTIBODIES WITH FCFF FUNCTION MAY GIVE A DIFFERENT ANSWER TO THE SET OF NEUTRALIZING ANTIBODIES. >> DO YOU HAVE ANY DATA THAT REFLECTS THIS? >> WE DO. I WOULD SAY ALSO THE FC EFFECTOR FUNCTIONS NEED TO BE BROKEN DOWN AND CERTAINLY HAS A TOOL KIT OF ASSAYS AS TO OTHERS. ONE ARE GOING TO BE THE ANTIBODIES THAT BIND TO THE VIRION AND YET ENGAGE FC EFFECTOR FUNCTION FOR COMPLIMENT MEDIATED AUGMENTATION VIA COMPLIMENT DEPOSITION OR CELLS TARGETED DESTRUCTION. THERE'S THE ANTIBODIES THAT ARE RECOGNIZING SPIKE ON THE SURFACE OF INFECTED CELLS. AND ENGAGING IMMUNE CELLS DIRECTLY. THOSE ARE DIFFERENT EVENTS AND MAY HAVE DIFFERENT QUALITY OF THE ANTIBODIES YOU NEED TO DO TO ENGAGE THE PARTICULAR COMPONENTS. ONE OF THE THINGS WE NOTICED IS THAT ALL ANTIBODIES DON'T BIND SPIKE ON THE SURFACE EQUIVALENTLY. SOME ANTIBODIES BIND WITH HIGH AVIDITY AND AT HIGHER LEVELS SO THE EC 50 BINDING IS DIFFERENT AND THEN THE MAGNITUDE THE AMOUNT FROM FLOW CYTOMETRY OR OTHER VISUALIZING ASSAY IS DIFFERENT. THIS MAY BE A CORRELATE OF PROTECTION, IN FACT WE HAVE SEEN IT IN LIMITED DATA, THAT SOME OF THIS INFORMATION CORRELATES WITH THE ABILITY TO HAVE EFFECTOR FUNCTION MEDIATED PROTECTION. THE SECOND ISSUE IS AND IT IS DIFFERENT FOR DIFFERENT REGIONS. FOR EXAMPLE NTDA BODIES MAY BIND DIFFERENTLY THAN RBM ANTIBODIES IN TERMS OF AMOUNT OF SPIKE THAT'S ACTUALLY BEING SEEN. THE SECOND WE HAVE SEEN IN VIVO IN THE MOUSE AND HAMSTER, THE ONLY TWO ANIMALS WE HAVE LOOKED THAT THERAPEUTIC ACTIVITY OF NEUTRALIZING ANTIBODIES IS AUGMENTED SUBSTANTIALLY BY FC MEDIATED FUNCTION. IF YOU TAKE A VARIANT OF ANTIBODIES THEY DON'T DO NEARLY AS WELL AS INTACT ANTIBODY. AND WE HAVE MEASURED PKPD, NOT DUE TO THAT BUT THEY DON'T HAVE THE ADDED ACTIVITY AND WE HAVE BEEN ABLE TO SHOW IN THE MOUSE CERTAIN CELL TYPES ARE IMPORTANT. MONOCYTES ARE IMPORTANT FROM MODULATING INFLAMMATION AND ANTIBODY HELPING PRIMING FUNCTION. THEY PUBLISHED A PAPER EARLIER LAST YEAR I BELIEVE ON FLU WHERE THEY SAW FC RECEPTOR MEDIATED CLEAR MORE RAPID PACE. SO THERE IS DATA FOR IT IN THE THE SMALLER ANIMAL MODEL WHERE WE DON'T HAVE GOOD DATA FOR THIS YET IS IN MONKEYS, NOT THAT I HAVE SEEN, MAYBE IT EXISTS BUT I HAVEN'T SEEN DATA ON THIS. I'M CERTAINLY NOT IN HUMANS YET BECAUSE WE HAVEN'T DONE PAIRED ANALYSIS. OF ONES MODULATED BUT I THINK THERE IS AN OPPORTUNITY ONE TO LEARN ABOUT THE BIOLOGY, ABOUT HOW ANTIBODY ENGAGE DIFFERENT ANTIBODIES ENGAGE SPIKE WHETHER ON THE VIRION OR SURFACE. THEN POTENTIALLY OPTIMIZING THOSE FUNCTIONS IN A WAY WHERE YOU CAN GET ENHANCED ACTIVITY OVER TIME. SO STILL A LOT TO LEARN. >> SPEAK TO WHETHER YOU HAVE ANY DATA TO SUGGEST ANTIBODIES ARE ABLE TO DO SHEDDING OF THE S 1 SUBUNITS, TARGETING ANTIBODY SHED S 1 IF THOSE ARE HAVE REDUCED EFFECTOR FUNCTION. >> YEAH. >> WE DON'T HAVE ANY DIRECT DATA TO ADDRESS THAT. I BELIEVE THERE ARE PEOPLE IN THE FIELD THAT HAVE LOOKED AT IT MORE CAREFULLY. WE HAVE NOT LOOK AT SHEDDING PER SE. WILL IS A CONCEPT THAT CERTAIN ANTIBODY WILL BIND AND THE S WILL GET S 1 WILL DROP OFF. IF IT DROPS THE CELL SURFACE THEN IT IS NOT GOING TO HAVE EFFECTOR FUNCTION. SOME GROUPS DO HAVE THIS DATA. WE DON'T HAVE IT BUT I BELIEVE THAT IF IT IS OCCURRING CERTAINLY WILL IMPACT THIS. YES. >> I HAVE SEEN IN VITRO BUT NOT IN VIVO. UNCLEAVEED ON THE SURFACE OF INFECTED CELLS FOR EXAMPLE. A LOT OF THESE IN VITRO ARE PERFORMED WITH STABILIZED SO THEY MIGHT BE MISSING THIS AS WELL. >> CORRECT. IT IS DIFFERENT IF YOU TRANSDUCE ON THE SURFACE AS POPESSED TO VIRAL INFECTION. I DON'T THINK WE HAVE DATA TO SUGGEST Ss ARE NOT DISPLAYED EXACTLY THE SAME IN TERMS OF THE LEVEL THAT MIGHT HAVE BEEN GIVEN ONE SO THERE'S CERTAINLY UTILITY BUT THERE HAS TO BE VALIDATION COMPARING TO SPIKE TRANSDUCED VERSUS ACTUAL SPIKE COMING FROM INFECTED CELL. >> WE HAVE FIVE MINUTES LEFT I'M TOLD. SO I WOULD ALSO LIKE TO KNOW, ANYBODY TRYING TO -- TAKEN ANTIBODY AND TRYING TO IMPROVE FOR FC FUNCTION OR IMPROVE BY MODIFICATION AT CDRH 3. CHRIS HAVE YOU TRIED TO DO THAT? OR LAURA, RACHEL, ANYBODY ELSE? >> SO I SHOULD HAVE MENTIONED EARLIER, ONE OF THE PROBLEMS WITH BROADLY NEUTRALIZING ANTIBODIES THAT COME FROM HUMANS THE ONES THAT WE HAVE IDENTIFIED IS THERE SEEMS TO BE A TRADE OFF BETWEEN BREADTH AND POLICY. SOME OF THESE CLASS 4 ANTIBODIES ACROSS THE SUB GENUS, THEY ARE DEFINITELY NOT AS POTENT. SO WE HAVE OVERCOME THAT BY ENGINEERING SO THEY HAVE THAT COMBINE WITH THAT SEEN WITH OTHER ANTIBODY BUT NOT SURE THOSE ARE ARISING NATURALLY OR AT LEAST WE HAVEN'T BEEN ABLE TO FIND ANY. SO WE HAVE OVERCOME WITH ENGINEERING WE HAVE NOT ENGINEERED FC BEYOND EXTENSION MODIFICATION THOUGH. >> WE FOUND ONE MOUSE ANTIBODY THAT IS CLASS 4 I GUESS WHICH NEUTRALIZES IN THE SINGLE DIGIT NANOGRAM PER ML OF ALL VIRAL STRAINS WE HAVE TESTED ALL VSCs WE HAVE TESTED AND INGAUGES WITH LIGHT CHAIN. NOT HEAVY CHAIN AS DOMINANT MODE OF ENGAGEMENT STRUCTURALLY. BUT I AGREE WHAT WE HAVE NOTICED IS THAT MANY OF THESE WITH GREAT BREADTH DON'T QUITE HAVE THE SAME POTENCY BUT THERE ARE SOME EXCEPTIONS WHICH LEADS ME TO BELIEVE THAT THROUGH ENGINEERING OR THROUGH JUST SELECTION CAMPAIGNS THE WAY ERICA HAS I WOULDN'T CALL BRUTE BECAUSE IT IS ELEGANT BUT LARGE NUMBERS OF THESE YOU MAY BE ABLE TO FIND NEEDLES IN THE HAY STACK WHICH ENGAGE IN A CERTAIN WAY WHICH ALLOW YOU TO GIVE YOU BOTH QUALITIES. SO THEY CAN EXIST, JUST THAT THEY ARE RARE. >> AND YOU MIGHT BE IDENTIFYING ANTIBODIES IN MICE THAT WOULDN'T A ARISE IN HUMANS DUE TO GERM LINE REPERTOIRE. >> TOTALLY POSSIBLE. >> WE HAVE NOT BEEN ENGINEERING IN A SEQUENCE BASED WAY BUT THROUGH THE ENGINEERING OF THE BY SPECIFIC ONE THING I DIDN'T MENTION BEFORE IS THOUGH THERE ARE SOME CONS TO LIMITATION IN THE TARGETING DOMAINS YOU CAN PAIR SUCCESSFULLY ONE OF THE BENEFITS THAT SEEN WITH SOME BISPECIFICS NOT ALL, YOU GET A SYNERGISTIC EFFECT OF THE BINDING. SO THE BISPECIFIC WILL HAVE A BETTER POTENCY THAN THE COCKTAIL OF MONOCLONALS. SO IN SOME CASES YOU CAN IF YOU ARE TARGETING CONSERVED DOMAINS WITH BOTH ARMS OF YOUR BISPECIFIC YOU CAN GET A BOOST IN POTENCY JUST BY PHYSICALLY LINKING THEM TOGETHER AND SOMETIMES GETTING THIS SYNERGISTIC EFFECT. >> I WAS GOING TO ADD WE HAVE BEEN EXPLORING LIBRARIES OF ANTIBODIES TO IMPROVE THEM BUT I GUESS THE TRADE OFF ALSO WAS FOR ONES THAT ARE USUALLY BROAD THEY ARE POTENT SO WE CAN IMPROVE THOSE BUT THOSE POTENT CAN WE IMPROVE THAT BREADTH, THAT IS HARD TO DO. A LOT OF THE TAKE AWAY WAS THAT A LOT OF ANTIBODIES COMING OUT OF HUMANS ARE PRETTY HAVE HIGH AFFINITY TOWARDS TARGET TOWARD RBD. REALLY WHEN YOU LOOK AT METRICS TO IMPROVE ANTIBODY, WHEN IT COMES TO DISPLAY MECHANISMS IN THE MATURATION, THAT IS SOMETHING THAT HUMAN BODY IS DOING BETTER SO NOW BACK TO EXPLORING CLONAL VARIANTS FOUND AT SIX MONTHS NOW ONE YEAR THAT HAVE ACQUIRED MORE MUTATIONS. THOSE ARE BEING PULLED OUT BY COLLABORATOR MICHELLE BY ROCKEFELLAR THEY SHOW THESE HAVE BETTER AFFINITIES AND ARE BECOMING MORE RESISTANT TO SOME OF THE VARIANTS WHICH IS REALLY GOOD FROM NATURAL INFECTION SO THAT IS GOING TO BE SOMETHING WE EXPLORE IN THE VACCINATED PEOPLE MOVING FORWARD, LOOKING AT TIME POINTS DOWN THE ROAD ANTIBODIES THAT WERE EXPANDED UPON VACCINATION ARE ALSO REQUIRING MUTATION TO COME TOGETHER OVER TIME. WHICH IS GOING TO BE IMPORTANT FOR PROTECTION MOVING FORWARD. >> I THINK CAESAR WILL APPRECIATE IF WE WRAP UP NOW. APOLOGIZE FOR DAVID AND PENNY FOR NOT -- I WAS GOING TO ASK NEUTRALIZATION BUT NO TIME. THANK YOU, VERY MUCH TO THE PANEL. THANK YOU FOR ERICA FOR OUTLINING HER PAPER AND OVER TO CEASAR. THANK YOU VERY MUCH. >> THANKS, EVERYONE, AGAIN FOR THE GREAT PRESENTATION AND THE PANEL DISCUSSION. WE ARE GOING TO TAKE -- WE NEED TO RECOVER TIME SO WE ARE GOING TO TAKE A FIVE MINUTE BREAK. WE WILL CONTINUE WITH SESSION 2, CLINICAL DELIVERY PHARMACOLOGY OF SARS COV-2 ANTIBODIES. THE SESSION WILL BEWIN WITH A PRESENTATION FOLLOWED BY PANEL DISCUSSION MODERATED BY DR. CONNIE SCHMALJOHN FROM THE NATIONAL INSTITUTE OF ALLERGY INFECTIOUS DISEASE. TAKE IT AWAY. >> PLEASURE TO BE HERE, THANK YOU TO THE ORGANIZING COMMITTEE FOR INVITING ME TO SPEAK. NOTICE ON THE LOWER RIGHT HAND SIDE OF MY SLIDE, I NOTED VARIOUS COMPANIES WE HAVE COLLABORATION WITH. THE GOAL IS TO REVIEW ANIMAL MODELS TO REVIEW IN VITRO ASSAYS FOR PRE-CLINICAL EVALUATION AND CHARACTERIZATION OF COVID-19 19 ANTIBODY. SO THE TO STIMULATE DISCUSSION ON VALUE OF EXISTING MODELS FOR ANTIBODY DEVELOPMENT, AND EVALUATING THE PERFORMANCE. THINK TIME YOU THINK ABOUT DEVELOPING ROBUST ANIMAL MODELS OF HUMAN DISEASE, ONE OF THE THINGS YOU WANT TO THINK ABOUT IS FEATURES PRESENT IN TERMS OF PATHOGENESIS. THINK ABOUT SARS CORONA VIRUS 2 REGULAR LATED BY COMPLEX POLYGENIC TRAITS, HIGH RISK SUSCEPTIBILITY LOCI THAT REGULATE DISEASE SEVERITY, THE PRIMARY INFECTION IS LUNG WITH MULTI-ORGAN SYSTEMIC COMPLICATIONS AND ACUTE CHRONIC DISEASE PHENOTYPES OCCUR AS CONSEQUENCE OF INFECTION. LOOK AT THE VIRAL LOAD BAR ON THIS SLIDE, FOUR DAYS PRIOR TO SYMPTOMATIC DISEASE IN INDIVIDUALS BECOME INFECTED, INFECTION IS ASSOCIATED WITH HIGH VIRUS TITERS EARLY IN INFECTION SYMPTOMATIC DISEASE STARTS ABOUT FOUR DAYS LATER. THE WINDOW IS SHORT, SIX OR SEVEN DAYS MAX DURING WHICH TIME THERE'S HIGH LEVELS OF VIRUS REPLICATION, VIRUS BEGINS TO CLEAR, YOU LOSE THE ABILITY TO DETECT VIRUS AFTER ABOUT SEVEN TO TEN DAYS POST INFECTION. WHEN ACUTE RESPIRATORY DISTRESS SYNDROME, THAT THE PROGRESS FOR SOME TIME AND ORGANIZE INTO VARIOUS POST ACUTE SEQUELAE COMPLICATIONS IN THE LUNG LIKE PULMONARY FIBROSIS. SO WHAT WE NEED ARE MODEL SYSTEMS THAT CAPTURE OR ALLOW TO EVALUATE THE ABILITY OF THERAPEUTICS THAT EXTEND THERAPEUTIC WINDOW. THE ABILITY TO LOOK AT IMMUNE MODULATORS WHICH MAY CHANGE AS FUNCTION OF TIME. AFTER THE DEVELOPMENT OF OURS AND PROCOMPRESSION TO LATE PHASE DISEASE PHENOTYPES AS WELL AS MODELS THAT CAPTURE LATE STAGE COMPLICATIONS OF DISEASE. THERE IS A VARIETY BY THE THANK YOUTY INCLUDE THE MOUSE HAMSTER FER IT AND PRIMATE. THAT IS TYPICALLY A REPLICATION MODEL WITH MILD DISEASE TRANSMISSION MODELS INCLUDE THE FER IT AND HAMSTER WITH MORE SEVERE DISEASE AND WEIGHT LOSS IN THE HAMSTER COMPARED TO THE FERRET. THERE IS A INVESTIGATE OF MOUSE MODELS TO TAKE ADVANTAGE OF SYSTEMS PERHAPS WITH THE K 18 MODEL OR TRANSGENIC MYSELF AND RELATED FORM. THAT WERE DEVELOPED BY STAN AND OTHERS. IN ADDITION WE HAVE KNOCK IN MOUSE MODELS TRANSDUCTION SYSTEMS ADENOVIRUS DELIVER MOLECULES TO MOUSE ADAPTIVE STRAINS AND THEN YOU HAVE REFERENCE POPULATION THAT ALLOW FOR ACQUIRING ROLE OF SUSCEPTIBILITY LOCI IN DISEASE SEVERITY AND HUMAN LUNG ONLY MODELS IN WHICH LUNG TISSUE IS IMPLANTED ON BACK OF MICE A KEY FEATURE IN CELL TYPES IN THE CASE OF SARS CORONA VIRUS 2 IT AFFECTS CILIARE CELLS IN CONDUCTING AIRWAYS AND PRIMARY TARGET IN THE ALVEO LIE. YOU SEE OCCASIONAL INFECTION OF AT 1 CELLS OR AT 2 CELLS IN THE PROCESS OF TRAN -- TRANSITIONING AND ENDOTHELIAL CELLS MAYBE INFECTED WITH VIRUS. SO THE BEST MODEL FOR RECAPITULATE THESE DISEASE PHENOTYPES AND TROPISMS SEEN IN HUMAN POPULATION. STAN NEXT SLIDE PLEASE STAN AND PAULA PROVIDED WE WITH SLIDES ON THE BOTTOM RIGHT HAND SLIDE SECTION OF THE SLIDE, THE K 18 MODEL USES A EPITHELIAL CELL PROMOTER TO DRIVE EXPRESSION OF ACE 2 WHICH THERE ARE EIGHT COPIES. PRIMARILY IN EPITHELIAL CELLS SILLIATED CELLS, AT 1 AND AT 2 CELLS AS WELL AS OTHER CELLS, IN THE LUNG. THE SEVERITY THE MITIGATED BY DOSE SO HIGH DOSE VIRUS ALL ANIMALS DICE, 10 TO 5 IN PURPLE, INTERMEDIATE DOSE HALF ANIMALS DIE AND LOW DOSE FEWER DIE. IN GENERAL HIGH DOSE INFECTION RESULT IN FATAL DISEASE VIA SPREAD TO THE CENTRAL NERVOUS SYSTEM AND ENCEPHALITIS. BUT THIS CNS PHENOTYPE IS MITIGATED IN SOME EXTENT BY REDUCING TITER OR INCREASING AGE OF ANIMAL WHICH HAS TENDENCY TO KEEP MORE LOCALIZED IN THE LUNG. THIS HAS BEEN USED BY MANY GROUPS TO STUDY PATHOGENESIS AND VACCINE PERFORMANCE, SMALL MOLECULE PERFORMANCE, AND THE ABILITY OF ANTIBODY TO PROTECT AGAINST DISEASE. AND IN THIS MODEL YOU SEE EXTENSIVE REPLICATION PROXIMAL TO DISTAL LUNG. YOU SEE PATHOLOGY AND DIFFUSE ALVEOLAR DAMAGE AND INFILL TRAITS IN THE PARYNCHEMAL OF THE LUNG BY DAY 6 AND 4 OF THE INFECTION. THIS MODEL CAUSES INFECTION IN THE OLFACTORY EPITHELIUM, TARGETING CELLS WHICH PROVIDE A SUPPORT ROLE FOR OLFACTORY FUNCTION, THE VIRUS DOESN'T EFFECT NEURONS BUT DOES RESULT IN LOSS OF SMELL MEASURED HERE DESCRIBED IN NATURE PAPER. NEXT SLIDE, ALTERNATIVE MODEL, FROM PAPER FROM MIKE DIAMOND'S LAB IN CELL USES ADENOVIRUS TO TRANSDUCE MICE AND EXPRESSION HUMAN ACE 2 RESTOP THIS WAS DEVELOPED BY STAN CROMIN FOR MAKING RAPIDLY -- PRODUCING A MOUSE MODEL NOR PERCENT CORONA VIRUS INFECTION. ADENOVIRUSES WERE USED TO DELIVER TO DELIVER MOLECULE TO THE LUNG OF NAIVE MICE AND IN THE PRESENCE OR ABSENCE OF ANTIBODIES AGAINST THE INTERFERON RECEPTOR THE ANIMAL IS INFECTED AND YOU CAN SEE WEIGH LOSS PHENOTYPES FROM 5 TO 20% OR MORE DEPENDING O AGE OF ANIMAL AND OTHER FACTORS. MIKE'S GROUP USED THIS AS HIGH THROUGH PUT AND RAPID APPROACH TO I -- ASSESS VALUE OF ANTIBODIES TO PREDICT SEVERE OR LETHAL INFECTION. THIS IS AN EXAMPLE OF EARLIER WORK SHOWN HERE, WHERE TRANSDUCE ANIMAL WITH HUMAN A 2 RECEPTOR. IN BLUE 10% BODY WEIGHT IN PRESENCE OF ANTIBODY AGAINST THE RECEPTOR YOU CAN SEE THAT THERE'S MUCH MORE EXTENSIVE WEIGHT LOSS AND IN THE GRAPH SHOWN IN GREEN AND THERAPEUTIC ANTIBODIES ON THE RIGHT SIDE PROTECT AGAINST LETHAL INFECTION. IN THE LUNG OF PANELS THERE IS EXTENSIVE INFLAMMATION, THERE IS EXTENSIVE FLUID ACCUMULATION IN THE PARYNCHEMAL OF THE LUNG AND CLEAR EVIDENCE OF EXTREME DIFFUSE DAMAGE. OUR GROUP HAS BEEN PRIMARILY FOCUSED ON MOUSE ADAPTED STRAINS OF SARS CORONA VIRUS OF THIS WAS SOMEWHAT PROBLEMATIC BECAUSE THE ORIGINAL WUHANND SEATTLE STRAINS DIDN'T REPLICATE MANY MICE SO MUTATION HAD TO BE INTRODUCED TO THE VIRUS TO PROMOTE GROWTH FOLLOWED BY SERIAL PASSAGE TO SELECT FOR LETHAL STRAINS. THE MA 10 FORM RESULTED IN A VIRUS THAT SHOWED AGE RELATED DISEASE GRADIANT FROM YOUNG TO OLDER ANIMALS. INFECTION OF OLDER ANIMALS WITH 10 TO THIRD DOSE OF VIRUS RESULTS IN 30% WEIGHT LOSS AND 85% MORTALITY. THERE IS PROLONG HIGH LEVEL VIRUS TITERS, CONGESTION IN THE LUNG MAXIMAL LEVELS BY DAY FOUR AND MAINTAINED THROUGH DANE 7 TO 10. POST INFECTION HIGH VIRUS TITERS ARE RECORDED IN THE LUNGS AND NAVAL THROUGH DAY 6 WITH CLEARANCE OCCURRING AT DAY 6 OR 7 POST INFECTION IN THE MODELED THE VIRUS TARGET IT IS OLFACTORY EPITHELIUM, THE CELLS ARE THE PRIMARY TARGET NO EVIDENCE OF INFECTION NEURONS. IN THE TERMINAL BRONCHI THE (INAUDIBLE) IS PRIMARY TARGET IS SILL YETED CELL IS INFECTED IN THE AIRWAYS. TO LESSER EXTENT. THAT REFLECTS A CHANGE IN THE DISTRIBUTION OF THE HUMAN ACE TWO RECEPTOR COMPARING MICE IN HUMANS WHERE THEY HAVE MORE ACE 2 IN THE SILLIATED CELLS OF THE AIRWAY EPITHELIUM BUT IN THE MOUSE IN THE CLEAR CELL. THE MODEL TARGETS AT 2 CELLS LOWER LUNG AND RAPIDLY CAUSES AT 2 CELL LOSS. THE CAUSE OF MORTALITY IS THE ELEVATED CYTOKINES AK 2 CELL LOSS AND ASSOCIATED SURFACTANT DEFICIENCY. WE HAVE TESTED MANY DIFFERENT MONOCLONAL ANTIBODIES IN THIS MODEL AS WELL AS OTHER MODEL SYSTEMS THAT I HAVE JUST TALKED ABOUT IN THE MOUSE AND THERE'S SIMILARITIES IN GENERAL THERE IS SHORT THERAPEUTIC WINDOW FOR THERAPEUTIC ANTIBODIES. COMBINATION THERAPY MULTIPLE ANTIBODIES OR ANTIBODIES WITH DIRECT ANTIVIRUSES LIKE REMDESIVIR. REPRESENT WILL RESULT IN 24 HOUR INCREASE IN PROTECTIVE WINDOW. SO DISEASE COURSE IS SET VERY EARLY IN THESE MODELS AND IT IS HARD TO HAVE VERSE. THERE IS A PROGRESSED DISEASE COURSE, THIS IS ONE OF THE COMPLICATIONS TO DEMONSTRATE ANTI-INFLAMMATORIES WILL HAVE A BIG IMPACT ON THE MOUSE MODEL IN TERMS OF REVERSING DISEASE. DEXAMETHASONE DOESN'T WORK AND SIMILAR FINDINGS THAT WORK WITH HAMSTERS IN K 18. NOW, IN COLLABORATIONS AND WORK THAT REALLY WAS DIRECTED BY JEFF (INAUDIBLE) LAB HIS GROUP BEGAN TO ASK IMPORTANCE OF FC GAMMA RECEPTORS, IN ANTIBODY PERFORMANCE SO HE DID A SIMPLE EXPERIMENT SHOWN HERE, LET'S FOCUS ON THE LOWER PART OF THE SLIDE. HE LOOKED AT THE REGENERON COCKTAIL TO PROTECT FC GAMMA RECEPTOR NULL MICE SHOWN WITH THE DOTTED LINES OR FCR GAMMA RECEPTOR POSITIVE MICE SHOWN WITH THE SOLID LINES. YOU CAN SEE IN THE NULL MICE REGENERON ANTIBODY DOES NOT PROTECT AT ALL, BUT IN THE FCR RECEPTOR FUNCTIONAL RECEPTOR ANIMAL THERE WAS COMPLETE PROTECTION SHOWN BY THE BLUE LINE. ONE ADVANTAGE OF THE SARS MA 10 MODEL IS YOU CAN TAKE ADVANTAGE OF GENETICALLY DEFINED KNOCKOUT MICE TO LOOK AT EFFECT IN PERFORMANCE OF ANTIBODIES IN REGULATING DISEASE SEVERITY. WHAT THE IMPACT OF FC DOMAIN VARIANT ENGINEERED VARIANTS MIGHT HAVE ON ANTIBODY PERFORMANCE UNDER PROPHYLACTIC AND THERAPEUTIC CONDITIONS. SO HE INTRODUCED MUTATIONS THAT VARIANTS AND THEN ASKED IN THE MA 10 MODEL HOW WELL THIS ENGINEERED ANTIBODY WOULD PROTECT PROPHYLACTICALLY THERAPEUTICALLY SO THE BOTTOM IS PROPHYLACTIC, WHERE THEY TREATED WITH THE WILD TYPE ANTIBODY COCKTAIL OR THE FC MUTATED ANTIBODY COCKTAIL. INFECTED A DAY LATER IN THE ABSENCE OF ENGINEERING THEY FAIL TO PROTECT AGAINST LETHAL INFECTION BUT HIGH DOSE REGENERON ANTIBODY DETECTED. IF YOU TAKE LOWER DOSE AMOUNT .5 MGs PER KILOGRAM SHOWN ON THE MID SLIDE OF THE PANEL, ONCE THE FC RECEPTORS ENGINEERED IT PROTECTS AGAINST CONTINUED WEIGHT LOSS, THERE IS 100% SURVIVAL IN THESE ANIMALS. THIS NOT ONLY WORKS PROPHYLACTICALLY ON BOTTOM BUT THERAPEUTICALLY. IT DEFINITELY DEMONSTRATES IMPORTANCE OF FC RECEPTOR IN PROMOTING PROTECTION FROM LETHAL DISEASE ESPECIALLY UNDER THERAPEUTIC CONDITIONS. THIS MIGHT HELP TO EXTEND THE PERFORMANCE OF ANTIBODIES UNDER HUMAN USE. MA 10 MODEL CAN BE REDERIVED TO DEAL WITH OTHER VARIANTS OF CONCERN IN THIS CASE, THIS IS THE B 1351 VARIANT. WHERE THEY SPIKE GENE OF THAT VIRUS WHICH CONTAINS A CAN BE DROPPED THE THE BACKBONE OF THE OTHER MA 10 MUTATION PRODUCING A WEIGHT LOSS MODEL AT ONE TIMES TEN TO FOURTH DOSE IN YOUNGER ANIMALS OR THE ANIMALS WILL LOSE 10% BODY WEIGHT AND RECOVER. OR LETHAL MODEL IN 20 WEEK OLD MOUSE WITH SLIGHTLY HIGHER DOSE VIRUS. IN THIS PARTICULAR SET OF EXPERIMENTS WE USED A MONOCLONAL ANTIBODY DERIVED IN COLLABORATION WITH PEOPLE AT DUKE INCLUDING BART HAYNES GROUP KEVIN SANDERS AND OTHERS. THIS ANTIBODY IN PARTICULAR IS A BROAD-BASED ANTIBODY THAT NEUTRALIZES ALL CLADE 1 AND 2 CLADE 1 AND 3 SARS CORONA VIRUS INCLUDING 2003 AND 2019 STRAIN. IT TARGETS A CONSERVED REGION IN THE RBD AND UNDER THERAPEUTIC CONDITIONS THE ANTIBODY DOESN'T HAVE A HUGE EFFECT ON WEIGHT LOSS BUT PROPHYLACTICALLY PROTECTS AGAINST INFECTION WITH THE VARIANT. UNDER THERAPEUTIC AND PROPHYLACTIC TICK CONDITIONS ON THE RIGHT SIDE OF THE SLIDE YOU CAN SEE THAT THE ANTIBODY PROTECTS AGAINST PROLIFERATION, IT PROTECTS AGAINST ACUTE LUNG INJURY MEASURED BY PARAMETERS USED BY THE PROPOSED BY THE AMERICAN THORACIC SOCIETY. SO AGAIN IT ARGUES TWO THINGS ONE IS ANTIBODIES TARGET CONSERVED REGIONS ACROSS THE CORONA VIRUSES HAVE A GOOD CHANCE WORKING AGAINST VARIANTS OF CONCERN THAT MIGHT EMERGE IN THE FUTURE. ALSO PROVIDES A APPROACH TO EVALUATE OTHER ANTIBODIES AN VACCINES. THE OTHER MODELS THE TRANSDUCED MODEL HAVE ADVANTAGE OVER THE SYSTEM I JUST TALKED ABOUT. WHICH REQUIRES RECOMBINANT ENGINEERING THEY CAN IMMEDIATELY GO INTO THOSE MODELS TO ASSESS PERFORMANCE OF ANTIBODIES ALMOST IMMEDIATELY. ONE THING I MENTIONED COMMON ACROSS THE SMALL ANIMAL MODELS INCLUDING HAMSTERS, IS IN GENERAL THERE IS A SHORT THERAPEUTIC WINDOW AND WE HAVE NO IDEA WHETHER SUSCEPTIBILITY LOCI IN THESE MODEL SYSTEMS REFLECTS SUSCEPTIBILITY LOCI THAT ARE PRESENT IN HUMANS THAT REGULATE DISEASE. THIS COULD HAVE A BIG EFFECT ON THE ABILITY AND THE PERFORMANCE OF IMMUNOTHERAPEUTICS THAT ARE DESIGNED TO TARGET AND DAMPEN DOWN SPECIFIC IMMUNOPATHOLOGIC COMPONENTS ASSOCIATED WITH DISEASE. ONE WAY TO GET AT THIS IS TO DEVELOP NEW ANIMAL MODELS, SO I JUST WANT TO BRIEFLY INTRODUCE THE COLLABORATIVE MOUSE WHICH IS SHOWN ON THE LEFT SIDE. INBREADS MICE, DOMESTIC DISEASE MODELS, C 626 BLACK MICE AND SEVERAL WILDS DERIVED STRAINS. THEY ARE ORGANIZED AT THE TOP OF THE FUNNEL AND BREAD TO PRODUCE A RECOME RECOMBINANT STRAIN THAT HAS SCRAMBLED THE SUSCEPTIBILITY LOCI. OF THE FOUNDERS. CHANGING THE PARENTS AT THE TOP OF THE FUNNEL YOU END UP WITH DIFFERENT COMBINATION OF SUSCEPTIBILITY LOCI IN ABOUT 80 RECOMBINANT INBRED LINES SO IF YOU INFECT 20 LINES ON THE RIGHT SIDE OF THE SLIDE YOU CAN SEE SOME GAIN WEIGHT, SOME LIKE REDD AND PURPLE DON'T LOSE WEIGHT, OTHERS LOSE 30% BODY WEIGH, OTHERS DIE EITHER DAY THREE OR FOUR AND MORTALITY IS SHOWN HERE. SO YOU CAN EXTEND THE WINDOW AND THE DISEASE WINDOW IN THESE MODELS BY VARYING THE GENETICS IN THE BACKGROUND. LOCI, 22 IN THE MOUSE WHICH IMPORTANT TAKE HOME MESSAGE IS THAT (INAUDIBLE) IS MULTI-GENIC TRAIT. NOTICE THIS MULTI-LOCUST TRAIT ON CHROMOSOME 9 THAT AFFECTS MULTIPLE FEATURES LIKE WEIGHT LOSS MORTALITY, RESPIRATORY FUNCTION AND OTHERS. IF YOU INFECT THIS DERIVED FROM F 2 CROSS BETWEEN CCL 1 THAT DOESN'T LOSE WEIGHT FROM SARS OR O 74 WHICH LOSES WEIGHT AND DIES SARS 2 CAUSES EXTENSIVE MORTALITY IN THIS LINE AS WELL, THE C 74 LINE BUT NOT 11 LINE. SET UP AN F 2 CROSS YOU CAN IDENTIFY GENES THAT REGULATE THIS PHENOTYPE AND THIS IS WHAT IS SEEN HOON CHROMOSOME 9. IF YOU DO GENETIC MAPPING YOU FIND A STRONG QUANTITATIVE TRAIT ON CHROMOSOME 9. LOOK AT AT THE PEAK OF PHENOTYPES YOU THINK SEE NEUTRA FILLS LYMPHOCYTES, RESPIRATORY FUNCTION, LONG SCORES MORTALITY AN WEIGHT LOSS CLUSTER AT THE END OF CHROMOSOME 9 AND IN FACT THE SAME SIX GENES PRESENT WITHIN THE REGION ARE IDENTICAL TO THE SAME SIX GENES THAT ARE WITH SIX GENES ON CHROMOSOME 3 IDENTIFIED IN HUMAN GWAS STUDIES. IN COLLABORATION WITH MIKE'S GROUP AND OTHERS WE HAVE SHOWN THE KNOCK OUT ONE OF THE GENES UNDER THE LOCUST AFFECT MORTALITY RESPIRATORY DOES STRESS RESULT IN INCREASE INFLAMMATION AND PROLONG DISEASE PHENOTYPES. SO YOU CAN USE COLLABORATIVE PROCESS STANDARD APPROACH TO USE COMMON SUSCEPTIBILITY LOCI BETWEEN HUMANS AN MICE TO ASK THE QUESTION WHETHER THESE PROVIDE BETTER MODEL SYSTEMS ESPECIALLY FOR PROBING THE ROLE OF ANTI-INFLAMMATORY DRUGS LATER IN INFECTION. NEXT SLIDE. I WANT TO FINISH ONE FINAL SLIDE THE MA 10 MODEL RESULTS IN CHRONIC DISEASE PHENOTYPE THAT PROGRESSES TO FEATURES OF EARLY SUB PLURAL FIBROSIS PHENOTYPE WITH PROLONGED INFLAMMATORY INFILL TRAITS AT DAY 30 YOU CAN SEE HERE. THIS IS ACTIN STAINING OR SERA REDD STAINING FOR COLLAGEN DEPOSITION. THESE EARLY SUB PLURAL FIBROSIS LESIONS BECOME MORE ORGANIZED BY DAY 60 AND WE USED A LARGE NUMBER OF MARKERS TO SHOW THAT THIS IS A MODEL THAT LOOKS LIKE PROGRESSING TO A PULMONARY FIBROSIS MODEL PROVIDING CHRONIC PHENOTYPE MODEL. NOW WE CAN ASK QUESTIONS WHETHER THEY PREVENT CHRONIC LONG TERM DISEASE SEQUELAE, WHAT IS ROLE OF ANTI-INFLAMMATORY DRUGS PREVENTING THE PHENOTYPE ANTI-FIBROTIC DRUGS AND WHETHER THEY ARE DRUGS THAT REVERSE LATE STAGE FIBROSIS SEQUELAE IN COVID-19 PATIENTS. I JUST WANTED TO SHOW TWO SLIDES REGARDING THE HAMSTER MODEL IN THE -- AT LOW DOSE AND YOUNG ANIMALS THAT CAUSE ABOUT A FIVE TO 8 PERCENT BODY WEIGHT PHENOTYPE, HIGHER DOSE MORE WEIGHT LOSS AS SHOWN LEFT SIDE OF THE SLIDE WITH DARK COLORS REDD AND BLUE COLORS, THE LIGHTER BLUE COLORS SHOW HIGH DOSE IN AGE ANIMALS MORE SEVERE DISEASE AND MUCH MORE SEVERE PATHOLOGY IT IS VULNERABLE TO DIFFERENT WILD TYPE VARIANTS OF CONCERN SO YOU CAN DO RAPID TESTING. AND ALSO YOU HAVE THE ADVANTAGE OF LOOKING AT TRANSMISSION PHENOTYPE. THIS IS WORK WE DID IN COLLABORATION WITH YOSHI, SHOWING THE VARIANT WAS TRANSMITTED MUCH MORE EFFICIENTLY TO EXPOSED ANIMALS ACROSS A GAP BETWEEN INFECTED RECIPIENT ANIMALS. I WAS ASKED TO SUMMARIZE THE NEUTRALIZATION ASSAYS THAT ARE USED, THEY FALL INTO THREE CATEGORIES. PSEUDOTYPE LENTIVIRUS THAT USES NANOLUKE AS READ OUT, THE VSV VIRUS ENGINEERED TO EXPRESS THE SARS SPIKE. GFP AS READS OUT AND LIVE ASSAYS THAT USE CPE LO SHIV RACE ASSAYS TO MEASURE NEUTRALIZATION PHENOTYPES. AND A VARIETY OF GROUPS HAVE SHOWN THAT TITERS ARE IMPACTED BY VARIETY INCLUDING THE ASSAY PERFORMANCE PLATFORM, THE HOST CELL, THE HUMAN ACE 2 LEVELS OF EXPRESSION, THE LEVEL EXPRESSION OF VARIOUS PROTEASES. THIS IS A STUDY LOOKING AT NEUTRALIZATION RESULTS ACROSS 57 LABS. I DON'T WANT TO RUN THROUGH THE RESULTS EXCEPT SHOW YOU ONE TO TWO LOG DIFFERENCE IN NEUTRALIZATION TITER AND AS YOU MIGHT EXPECT SOME -- SUCH VARIATION IN RESULTS ACROSS LAB CAN RESULT IN PREDICTING OVERPREDICTING OR UNDERPREDICTING IMPACT OF VARIANTS OF CONCERN ON NEUTRALIZATION POTENCY OF POLYCLONAL OR MONOCLONAL SERA AND ALSO IN IDENTIFYING CLEAR CORRELATES OF PROTECTION. ESPECIALLY OUTBREAD POPULATIONS. SO JUST JUMP TO THE END. ONE MORE. SO FOR LIBERATION BY THE GROUP, IMPORTANT QUESTIONS TO CONSIDER ONE OF THE MOST IMPORTANT KNOWLEDGE GAPS IN ANIMAL MODELS, WHAT ARE THE MOST IMPORTANT CORRELATES FOR SARS CORONA VIRUS 2 ESPECIALLY REGARD TO BROAD PROTECTION OF VARIANTS OF CONCERN. WHAT ARE THE MOST IMPORTANT ASPECTS OF ANTIBODIES WITH PROVIDING LONG TERM PROTECTION. HOW DOES THE BIODISTRIBUTION OF ANTIBODY IMPACT THERAPEUTIC PROPHYLACTIC PERFORMANCE AND TRANSMISSION DYNAMICS. ESPECIALLY IN OTHER ORGANS AND WHAT ARE THE REGULATORY ASPECTS OF ANTIBODIES TO BE CONSIDERED. SORRY I RAN OVER A LITTLE BIT. >> DR. SCHMALJOHN. >> HELLO, EVERYBODY. I'M CONNIE SCHMALJOHN, DIRECTOR OF THE NIAID INTEGRATED RESEARCH FACILITY. IN FREDERICK MARYLAND, MY PLEASURE TO MODERATE THIS SESSION. TO REMIND YOU THE GOAL IS TO REVIEW THE STATUS OF AVAILABLE ANIMAL MODELS IN VITRO ASSAYS FOR PRE-CLINICAL EVALUATION AN CHARACTERIZATION OF ANTIBODIES AND ASSESS VALUE TO INFORM ANTIBODY DEVELOPMENT AND PREDICT CLINICAL OUTCOMES. OUR PANELISTS HAVE DIVERSE BROAD EXPERTISE, I EXPECT A LIVELY INFORMATIVE DISCUSSION. WHAT I'M GOING TO DO IS TO INTRODUCE THESE MEMBERS MYSELF TO SAVE A LITTLE TIME AND THEN BEGIN THE QUESTIONS. ON THE PANEL WE HAVE DR. EMMIE DE WIT, CHIEF MOLECULAR PATHOGENESIS UNIT AT ROCKY MOUNTAIN LABS. DR. SKIP VIRGIN EXECUTIVE VICE PRESIDENT OF RESEARCH CHIEF SCIENTIFIC OFFICER FOR VERE BIOTECHNOLOGY, DR. KEVIN SAUNDERS, ASSOCIATE PROFESSOR OF SURGERY, DIRECTOR OF RESEARCH AT THE DUKE HUMAN VACCINE INSTITUTE DUKE UNIVERSITY MEDICAL CENTER. DR. TOM HOPE DEPARTMENT OF CELLULAR AND DEVELOPMENTAL BIOLOGY FINEBURG SCHOOL OF MEDICINE NORTHWESTERN UNIVERSITY. AND DR. CHRISTOPHER ELLIS, PHARMACOLOGY TOXICOLOGY TEAM LEAD DIVISION OF PHARMATOX OR INFECTIOUS DISEASE AT CDER FDA. I WILL ASK THESE PANELISTS A QUESTION IN TURN AND IF ANY OF THE OTHER PANELISTS WOULD LIKE TO COMMENT ON THAT QUESTION OR FOLLOW ON THAT QUESTION TO FELLOW PANELISTS FEEL FREE TO DO SO. I WILL START WITH DR. DE WIT. AND ASKING EMMIE FROM YOUR ANIMAL STUDIES, WHAT -- OR ANIMAL STUDIES WHAT ARE THE MOST IMPORTANT CORRELATES OF PROTECTION FROM SARS COV-2 ESPECIALLY WITH REGARD TO BROAD PROTECTION FROM NEWLY APPEARING VARIANTS? >> I GUESS IN LINE WITH THE TOPIC OF TODAY, I THINK THE MOST IMPORTANT CORRELATE OF PROTECTION ARE ANTIBODIES ESPECIALLY NEUTRALIZING ANTIBODIES. OF COURSE A LOT OF ANIMAL STUDIES HAVE BEEN DONE TO SHOW THEIR EFFECT PROPHYLACTICALLY WHERE THEY PREVENT INFECTION AS WELL AS THERAPEUTIC ADMINISTRATION, AS RALPH SHOWED IT IS IMPORTANT TO TREAT EARLY AFTER INFECTION. THESE PRE-CLINICAL DATA HAVE BEEN REALLY NICELY CORROBORATED BY REAL WORLD DATA AS WE SAW EARLIER TODAY. SO TO GO SPECIFICALLY BACK TO VARIANTS E MERGING, IT IS VERY CONCERNING THAT THERE ARE VARIANTS AND IN VITRO DATA ARE NOT AS EFFICIENT AS NEUTRALIZING THE VARIANTS THAT ARE EMERGING BUT THERE IS ALSO REASSURING DATA THAT EVEN THOUGH IN VITRO THE NEUTRALIZATION IS NOT AS EFFICIENT OF THESE NEW VARIANTS THAT AT LEAST THERE ARE SEVERAL OF THE ANTIBODIES THAT ARE ALREADY IN USE THAT CAN STILL PREVENT SEVERE DISEASE FROM DEVELOPING. THAT IS THE MAIN GOAL. WOULD BE NICE IF WE CAN PREVENT ANY DISEASE BUT OF COURSE I WANT TO PREVENT AND THINK IT IS ALSO BECOMING MORE CLEAR THESE CELLS ARE GOING TO BE IMPORTANT WITH EMERGING VARIANTS BECAUSE A LOT OF T-CELL EPITOPES ARE MORE A LOT OF EPITOPES WOULD BE SEEN BUT THAT ONLY HELPS YOU IF YOU HAVE BEEN INFECTED OR VACCINATED. SO I THINK FOR THE POPULATION THAT IS NOT VACCINATED OR PREVIOUSLY INFECTED THESE ARE IMPORTANT. >> OTHER PANEL MEMBERS LIKE TO FOLLOW-UP BEFORE THE NEXT QUESTION? THEN DON'T. THE NEXT QUESTION THEN COME COMES FROM DR. VIRGIN. WHAT ARE MOST IMPORTANT ASPECTS PROVIDING LONG TERM PROTECTIVE IMMUNITY AGAINST SARS COV-2 IN YOUR OPINION? >> THE FIRST WE HAVE HEARD FROM ERICA AND OTHERS OUTLINE. IT IS CONSERVE EPITOPES, WHAT HASN'T BEEN EMPHASIZED YET IS THE RBM PART OF THE SPIKE IS IMMUNODOMINANT BUT NOT PARTICULARLY SURPRISING THAT THAT IS HIGHLY VARIABLE UNDER IMMUNE SELECTED PRESSURE. IT -- SEEMS LIKE A GOOD AVENUE FORWARD AND YOU HEARD THERE ARE A COUPLE OF ANTIBODIES IN TRIALS FOR THAT ONE WHICH IS SHOWN TO BE EFFECTIVE WHICH IS SETROBIMAB ANTIBODY. THE OTHER THING NOT FULLY STATED CLEARLY, IS EVERYONE SHOULD LOOK AT ERICA SAPHIRE'S AND HER CONSORTIUMS EXTREMELY COMPLETE WORK ON EBOLA. AND DATA FROM FLU AND NOW EMERGING DATA FROM ROCKEFELLAR IN WASHINGTON UNIVERSITY. >> IN ANSWER TO ONE OF THE QUESTIONS FROM THE PREVIOUS SESSION THERE IS ALREADY ONE CLINICAL TRIAL INITIATED TO FC ENHANCED ENGINEERED MONOCLONAL ANTIBODY IN HUMANS TO TAKE FORWARD THAT MUTATION RALPH SHOWED YOU, AN ANTIBODY CALLED 7832. THE LAST THING -- TWO THINGS I WOULD SAY IS THAT DOSES REALLY IMPORTANT. DOSE IS REALLY IMPORTANT. DOSE HAS TO DO WITH POTENCY OF PROTECTIVE EFFECT AND BASICALLY THERE'S NO SYSTEM WHERE POE POTENCY IN VIVO CORRELATES WITH NEUTRALIZATION. ADDITIONALLY THERE'S THE ISSUE OVERBUY DISTRIBUTION WHICH I THINK IS A REALLY IMPORTANTISH HUMAN AND TOM HOPE IS ONE OF THE PEOPLE ON DISCUSSION THAT HAS DONE FORMATIVE WORK SHOWING YOU CAN ENGINEER THE, IFC PORTION TO GET IT TO DIFFERENT PLACES AND HIGHER CONCENTRATIONS. SO THERE IS FUTURE ENGINEERING THE FC AS LONG AS YOU HAVE THE RIGHT FAB GOING FORWARDS FOR POTENCY AND LONGEVITY OF PERFECTION. >> WE WILL GET TO TOM WHO WILL SHOW BIODISTRIBUTION INFORMATION AT THE BUT NOT JUST YET. DID ANY PANELISTS WANT TO FOLLOW-UP ON THAT QUESTION? >> IF I CAN JUMP IN. >> PLEASE DO. >> WE PERFORMED FC ENHANCED IN VIVO STUDIES AT THE VRC. WE WERE WORKING TO DEVELOP HIV EPIFUSING ANTIBODIES, WE DID INFUSION TO NON-HUMAN PRY MATES AND FOUND IF WE OPTIMIZE FC BY INTRODUCING MUTATION INCREASE AFFINITY FOR FC GAMMA RECEPTOR, WE ALSO SAW INCREASE IN AND VRC RESPONSE THE MONKEYS GENERATED SO WHEN WE COMPARE AGAINST WILD TYPE ANTIBODY, TENDED TO BE LOWER. IF IT WAS A WILD TYPE FC VERSUS IF IT WAS THE MODIFIED VERSION. SO WONDERING IF ANYONE ELSE HAD SIMILAR EXPERIENCES OR ANY KNOWLEDGE ABOUT WHEN THE ANTIBODIES HAS BEEN ENGINEERED TO INTERACT WITH FC GAMMA RECEPTORS IF THERE IS HIGHER INCIDENCE OF ANTI-DRUG ANTIBODY. >> THERE IS A LOT OF DATA FOR LS MUTATION I THINK SO FAR MY INTERPRETATION OF THAT IS THAT IT IS NOT A MAJOR CLINICAL PROBLEM, OTHERS KNOW MORE. THERE IS LESS INFORMATION ON. >> SO WE FOUND LS MUTATION COMPARABLE TO WILD TYPE. BUT IN PARTICULAR WE INTRODUCE DLE, WHEN WE INTRODUCE THAT IN COMBINATION WITH LS THAT'S WHERE WE SAW THE MONKEYS TENDED TO HAVE A HIGHER RESPONSE AGAINST GENERATE ANTIBODIES AGAINST IT MORE READILY. WE NEVER WORKED OUT MECHANISM, WE ASSUMED THE FC RECEPTOR AFFINITY SO PERHAPS ANTIBODIES WERE BEING TAKEN UP BY INNATE CELLS AND PRESENTED MORE READILY AND GETTING SOME KIND OF RESPONSE THERE. I THOUGHT THAT WAS A CONSIDERATION TO PUT OUT AS FOLKS START TO ENGINEER THE FC TO HAVE GREATER FUNCTION. ANTI-DRUG ANTIBODY MAYBE SOMETHING TO LOOK AT. >> THAT LEADS TO WHAT I WAS GOING TO ASK AND MAYBE YOU DON'T WANT TO HAVE MORE TO SAY BUT THE QUESTION WAS -- IS, WHAT FUNCTION OF ANTIBODY DO YOU BELIEVE ARE MOST IMPORTANT FOR PREDICTING OR CORRELATING THE PROPHYLACTIC OR THERAPEUTIC EFFICACY? >> NEUTRALIZATION POTENCY IS A KEY ONE. WE FOUND IN OUR IN VIVO ASSAY IF THE ANTIBODY IS HIGHLY POTENT WE PEND TENDED TO SEE LOW LEVELS OF VIRUS REPLICATION OR UNDETECTABLE LEVELS. NOT BE ABLE TO DETECT ANTIGEN IN THE LUNGS PARTICULARLY ANTIBODIES IN THE LEVEL OF TWO NANOGRAM SINGLE DIGIT LEVELS NEUTRALIZATION POTENCY IN ASSAYS PERFORMED BY DAVID MONTEFIORI'S LAB. SO WE FOCUSED ON NEUTRALIZATION POTENCY. WITH THAT SAID, I HAVE SEEN THE WORK BY RALPH BURK AND SOME OF THE WORK PRESENTED FROM JEFF'S LAB, WHERE POTENCY DOESN'T CORRELATE WITH IN VITRO PROTECTION THAT U WHERE SEE. SO I THINK AS YOU MOVE UP THE SPECTRUM OF NEUTRALIZATION POTENCY THE EFFECTER FUNCTION BECOMES CRITICAL SO IF YOU ARE NOT AT THE SINGLE DIGIT NANOGRAM PER ML LEVEL OF NEUTRALIZATION WHICH MAYBE DIFFICULT FOR MANY ANTIBODIES PARTICULARLY AS VARIANTS OF CONCERN COME ACROSS, AS THEY CONTINUE TO ESCAPE FROM THESE ANTIBODIES, HAVING THAT LEVEL OF POTENCY MAYBE DIFFICULT. EFFECTOR FUNCTIONS ARE CRITICAL IN THAT SPACE PARTICULARLY CURRENTLY TRYING TO FIGHT AGAINST VARIANTS OF CONCERN. >> THANK YOU. I'M GOING TO SWITCH THE TOPIC JUST A LITTLE BIT HERE. MOVE TO OUR REGULATORY EXPERT DR. ELLIS. CHRIS, FROM A REGULATORY PERSPECTIVE, WHAT IS THE VALUE OF DATA OBTAINEDED FROM ARE AVAILABLE ANIMAL MODELS TO HELP SUPPORT THE CLINICAL DEVELOPMENT OF ANTI-SARS COV-2 ANTIBODIES? >> THANK YOU FOR THE QUESTION SO THE DATA SUBMITTED TO THE AGENCY FROM THESE ANIMAL MODELS HAVE BEEN USED TO SUPPORT MONOCLONAL ANTIBODIES PRODUCT DEVELOP DEVELOPMENT FOR COVID-19. HOWEVER, GIVEN THE TIMING OF ANIMAL MODEL AVAILABILITY WITH THESE MODELS, NOT AVAILABLE FRANKLY TO SUPPORT PRODUCT DEVELOPMENT IN THE -- EARLY IN T PANDEMIC. THE DATA USED TO SUPPORT INITIAL PRODUCT ADMINISTRATION AND DOSE SELECTION. IN COVID-19 PATIENTS. SO DATA FROM THE MONOCLONAL ANTIBODIES PRODUCTS EVALUATED IN THESE MODELS HAVE OFTEN BEEN COLLECTED IN PARALLEL. WITH THE CONDUCT OF CLINICAL TRIALS FOR MANY PRODUCTS. SO GIVEN INITIAL ISSUES WITH MONOAVAILABILITY AS WELL AS SOME STUDY DESIGN LIMITATIONS, THE OVERALL UTILITY OF MONOCLONAL ANTIBODY PRODUCT SPECIFIC DATA IS INVESTMENTED TO SUPPORTING INITIAL ASSESSMENT OF ACTIVITY AND FOR EVALUATING POTENTIAL FOR ANTIBODY DEPENDENT ENHANCEMENT. OF INFECTION. I'LL STOP THERE, THANKS. >> ANYBODY HAVE ANY OTHER REGULATORY ASPECT OF THIS THEY WOULD LIKE TO ASK CHRIS WHILE HE'S SITTING THERE? IF NOT WE'LL GET BACK LATER. NOW I'M GOING TO MOVE TO DR. HOAK. TOM AS MENTIONED YOU HAVE A LOTTED DATA ON BIODISTRIBUTION AND WONDERING IF YOU CAN COMMENT HOW THE BIODISTRIBUTION OF SARS COV-2 AND TISSUES AND ORGANS RELATED TO ABILITY OF THERAPEUTIC ANTIBODIES TO PREVENT OR TREAT INFECTION OR DISEASE. TOM HAS BEEN GIVEN PERMISSION TO SHOW US A COUPLE OF SLIDES. >> THANK YOU FOR THE OPPORTUNITY TO PARTICIPATE IN THE PANEL AND SHARE OUR THOUGHTS ABOUT BIODISTRIBUTION. THE BOTTOM LINE IS THAT WE ARE LOOKING AT ANTIBODIES THAT ARE LABELED RADIO ACTIVELY OR WITH FLUORESCENCE. THEN WE CAN DO A PET SCAN TO LOOK AT DISTRIBUTION OVER TIME, FLUORESCENCE, WE CAN LOOK AT CELLS AND TISSUES AND SECTIONS AND THEN RECENTLY WE HAVE BEEN LOOKING AT RELEVANT FLUIDS WHICH GIVE PRETTY ACCURATE READINGS. I JUST WANTED TO SHOW THIS EXAMPLE FROM SOME WORK WE DID WITH OPERATION WARP SPEED AND CONVALESCENT IGG. 30 DONORS POOLED TOGETHER, FAIRLY HIGH TITER NORMAL IGG FROM SINGLE DONOR AND TWO MONOCLONAL ANTIBODIES DISCUSSED EARLIER. THIS IS A TIME COURSE AND SO THE FIRST PART IS HOURS SO 0 IS FIRST 20 MINUTES WE INJECT PUT ANIMAL IN SCANNER TWO HOURS FOUR HOURS BY 24 HOURS YOU HAVE THIS SITUATION WHERE YOU GET THIS MOVEMENT FROM THE CIRCULATION IN TO THE TISSUES. AND THEN YOU ACHIEVE A STEADY STATE HERE AND WHAT YOU CAN SEE IS LARGE CLEAR DIFFERENCES BETWEEN THESE ANTIBODIES, ONE OF THE MORE OBVIOUS DIFFERENCES IS IN THE LIVER AND WITHIN THE FIRST 20 MINUTE IT IS CONVALESCENT IGG IS CONCENTRATING WITHIN THE LIVER. WE CAN QUANTIFY ALL OF THIS AND YOU CAN SEE THAT HAPPENING. CONVERSELY THIS 144 LS IS NOT REALLY ACCUMULATING IN THE LIVER. I THINK THAT ANTIBODY FOR THIS VIRUS WE DON'T NEED ANTIBODY IN THE LIVER. SO THE TIME THAT IT SPENDS IN LIVER COULD CAUSE DELAYS. WE CAN QUANTIFY THE DIFFERENT TISSUES AND SEE HERE, WE CAN ISOLATE PET SCAN TO GET AT DETAILS OF SITES AND FINALLY COMPARE CHALLENGE AT DAY 3 DIFFERENT SWABS CHECKED AND THE BOTTOM LINE, -- COLLECTED. THE SAME AS WHAT WAS MENTIONED EARLIER. THE IG -- CONVALESCENT IGG WHICH HAD A TITER COUPLE LOGS LESS THAN THE MONOCLONAL ANTIBODIES WE TESTED DID SEEM TO HAVE AN IMPACT, THIS IS SHOWN IN THIS HEAT MAP NICELY AND THIS ONE SPECIFICALLY ONE ANIMAL GROUPED WITH THE MONOCLONAL. BOTTOM LINE IS THAT EACH OF THESE ANTIBODIES SEEMS TO HAVE UNIQUE CHARACTERISTICS, THEY CAN ISOLATE -- ACCUMULATE DIFFERENT PLACES AND THIS CASE THE ONE OF THE CHARACTERISTICS OF THE CONVALESCENT IGG WAS TO APPEAR IN FLUIDS BEFORE MONOCLONAL ANTIBODIESES PEEKING SO HAVING OUR CHALLENGE ON DAY 3 WHEN THEY WERE PEEKING IN RESPIRATORY TRACT FLUIDS MIGHT HAVE BEEN PART OF THE REASON FOR THE PROTECTION WE OBSERVED. THEN THIS IS JUST TO ACKNOWLEDGE ALL THE COLLABORATORS HERE. DISTRIBUTION IS VERY IMPORTANT ONE POTENTIAL ASPECT THAT HASN'T BEEN CONSIDERED IS TO HAVE ANTIBODY WITH GREAT CHARACTERISTICS OF INACTIVATION OF DIFFERENT BINDING MECHANISMS AND UNDERSTAND HOW THEY ARE DISTRIBUTED AND FOCUS ON THOUSAND THOSE ACCUMULATING IN RELEVANT AREAS THAT WOULD BLOCK THE VIRUS EARLY ON IN ACQUISITION AND PROGRESSION. >> THANK YOU, TOM, DOES ANYBODY WANT TO COMMENT ON ANY OF THE THINGS HE SHOWED? >> ONE THING THAT MAKES THIS REALLY INTERESTING AT LEAST TO ME IS THAT POTENTIALLY YOU COULD MAYBE USE LOWER DOSE OF ANTIBODY AND ESPECIALLY EARLY ON IF SUPPLIES LIMITED TO TARGET TO ANTIBODY THROUGH THE SITE WHERE YOU NEED IT. THAT COULD HELP SENTING TO THE LIVER. >> EMMIE SINCE WE ARE GOING TO RUN OUT OF TIME I'M GOING TO LUMP THESE QUESTIONS TOGETHER YOU CAN ANSWER WHATEVER YOU WANT TO. THE QUESTION REALLY -- ARE THERE ANY CLEAR INDICATORS THAT YOU SEE THAT WILL GIVE A BETTER OUTCOME TO INFECTION IN YOUR MODELS AND DO YOU THINK WE STILL NEED A MODEL FOR ANTIBODY DEPENDENT ENHANCEMENT OR IS THAT WORRY GONE NOW? FINALLY DO YOU HAVE ANY THOUGHTS ON HOW WE MIGHT MODEL HUMAN SEQUELAE TO COVID-19 SUCH AS LONG COVID? YOU DON'T HAVE TO ANSWER ALL BUT SOME. >> I'M JUST GOING TO TALK FOREVER. I THINK ONE OF THE MAYBE TO GIVE PERSPECTIVE ON THIS FROM A MORE PRACTICAL POINT OF VIEW, THIS PANDEMIC WE HAVE BEEN FOLLOWING EVERYTHING THAT HAPPENED AND REACTING TO IT. AS FAST AS WE COULD. ONE ISSUE I THINK ESPECIALLY WITH THE LONG COVID BUT ALSO UNDERSTANDING TRULY PATHOGENESIS IS WE DEVELOPED ANIMAL MODELS CHARACTERIZE THEM TO SEE IF THEY ACTUALLY REFLECT THAT WHAT HAPPENS IN PEOPLE. AND THEN WE MOVED ON TO QUICKLY TESTING VACCINES AND ANTIVIRUS. SO BY THE TIME WE HAD SOME OF THAT GOING FROM THE PRE-CLINICAL TO THE CLINICAL STAGE AND WE WOULD HAVE TIME TO MAYBE FOCUS ON THINGS LIKE PATHOGENESIS AND LONG COVID STORY, THOSE VARIANTS EMERGED SO WE ALL DECIDED WE NEED TO FIGURE OUT WHAT'S GOING ON WITH THESE VARIANTS. SO I THINK THIS IS A LOT OF THIS IS REALLY A LONG TERM THING TO STUDY NOW THAT HOPEFULLY IF WE HAVE THIS PANDEMIC MORE UNDER CONTROL WE CAN START FOCUSING ON SOME OF THESE QUESTIONS MORE. I THINK THE QUESTIONS ABOUT THE ANTIBODY DEPENDENT ENHANCEMENT IS PROBABLY MORE SUITABLE FOR -- FROM A REGULATORY PERSPECTIVE AND ALSO I THINK KEVIN WHO IS WORKED WITH THESE MODELS EXTENSIVELY PROBABLY ANSWER THOSE. >> DOES ANYBODY WANT TO COMMENT ON THAT? I DON'T HEAR MUCH ABOUT ANTIBODY DEPENDENT ENHANCEMENT ANY MORE AS WORRY FOR TREATMENT WITH ANTIBODIES BUT IT DOES REAR ITS HEADS NOW AND THEN. >> IT IS IMPORTANT TO DISTINGUISH WHAT EDE MEANS. THERE IS CLEARLY YOU CAN MAKE IN VITRO MODEL WHERE YOU HAD ANTIBODY YOU CAN GET INCREASED UPTAKE OF VIRUS AND SOME MEDIATED ENHANCEMENT. I THINK PEOPLE CONFLATE THAT WITH ANTIBODY MEDIATED ENHANCEMENT OF DISEASE. WHICH IS WHAT YOU WORRY ABOUT. THERE IS NOW A LOT OF DATA FROM COVID PANDEMIC SOME EXTENT PREDICTABLE FROM A CAREFUL LOOK AT LITERATURE BEFORE BIOLOGY OF DENGI WHERE THE CONCEPT HAS GOTTEN ITS ROOTS, IT IS QUITE A DIFFERENT VIRUS. SO IT MAY BE VIRUS SPECIFIC. >> I WILL ASK YOU ONE SO DO YOU HAVE ANY SUGGESTIONS FOR STRATEGIES THAT MIGHT BE USED TO INTEGRATE REDUCED ANTIBODY POTENCY TO THE VARIANTS WITH PK PD DOSE SELECTION OR ROOT OF ANTIBODY DELIVERY? >> I THINK WHAT LAURA SAID IN THE BEGINNING AND MIKE DIAMOND COMMENTED ON, I THINK THE BEST PROTECTION AGAINST THE VARIANTS IS TO FOCUS ON CONSERVED EPITOPES. THE HEAD OF THE FLU HEMAGGLUTININ IS SIMILAR TO RBM, IT IS VARIABLE, IT IS A FUNCTIONALLY FLEXIBLE PROTEIN. AND SO THE VIRUS HAS LOT OF SOLUTIONS TO STILL MAINTAINING FITNESS WHILE MUTATING THERE. WITH REGARD TO YOUR OTHER QUESTIONS THINGS LIKE HALF LIFE EXTENSION WHICH CAN YIELD HIGHER LEVEL FOR LONGER TIME AND FC EFFECTER FUNCTION WHICH CAN GIVE GREATER POTENCY AT LOWER DOSE, ALL THOSE MITIGATE, AND IF YOU HAVE ANTIBODIES WHICH CAN INDIVIDUALLY RAPIDLY SUSCEPTIBLE TO CIRCULATING VARIANTS, THEN COMBINATIONS CAN HELP OBVIOUSLY. RALPH BROUGHT THAT UP IN HIS TALK TOO ABOUT EPITOPES FOR SARS COV-2 VIRUSES. >> THEY ARE THERE AND THEY ARE ACROSS MANY OF THE ECO VIRUSES. THE OTHER THING IS THAT CONCEPT IS EXTREMELY IMPORTANT FOR PANDEMIC PREPAREDNESS. SO THE ANTIBODIES THAT ARE SARS COV-2 SPECIFIC HAVE BEEN PROVEN TO BE QUITE USEFUL AND SAVE LIVES PREVENT DISEASE IN PEOPLE WITH SARS COV-2. YOU CAN ALSO HAVE ANTIBODY WITH THAT FUNCTION AND PROTECTS AGAINST SARS OR OTHER VIRUSES IN FUTURE. SO IF WE ARE GOING TO LOOK FOR THINGS WE SHOULD PROTECT AGAINST THIS PANDEMIC WITH AN EYE TOWARDS THE FUTURE. BECAUSE IT MAY NOT BE THE LAST ONE. >> KEVIN, I WILL ASK YOU THE LAST QUESTION I HAD FOR YOU SKIPPING OVER OTHERS AND ASK IF YOU CAN COMMENT ON WHAT IS KNOWN ABOUT PREDICTIVE VALUE OF CURRENT IN VITRO ASSAYS AND WHAT WE NEED TO DO TO MAKE BETTER ASSAYS OR MAKE ONES WE HAVE MORE EFFECTIVE. >> THANK YOU FOR THE QUESTION. THAT IS RELATED TO THE POINT THAT EMMIE MADE EARLIER. WE HAVE DONE WORK LOOKING AT VIRUS UPTAKE AND WE CAN SEE YOU CAN SEE RBD DIRECTED ANTIBODIES MEDIATE VIRUS UPTAKE. WHEN WE MOVE IN VIVO MODELS EVEN THOSE SPOKEN ABOUT, OR MACAQUE MODELPS WITH MARK LOUIS TO USE, WE FOUND THERE THAT WE DIDN'T SEE EVIDENCE OF INFECTION ENHANCEMENT SO EITHER ENHANCEMENT OF ACTUAL VIRUS LOAD, VIRUS REPLICATION, OR DISEASE SEVERITY, MEANING INFLAMMATION, CYTOKINES, PRO INFLAMMATORY CYTOKINES, DIFFERENT LEVELS OF THOSE. IN THE LUNG. SO LOOKED LIKE THERE IN VITRO WE WERE ABLE TO MEASURE THESE -- THIS TYPE ENHANCED INFECTION, HOWEVER WHEN YOU MOVE IN VIVO WE DIDN'T SEE THAT TYPE OF RESPONSE. WITH THAT SAID THERE ARE CAVEAT TO MACAQUE MODELS AND MOUSE MODELS WE USE, THINGS LIKE FC RECEPTOR AFFINITIES BETWEEN MACAQUE FC GAMMA RECEPTOR VERSUS HUMAN ANTIBODY FC WE ARE USING. SOME OTHER THINGS YOU CAN COME UP WITH WHERE DATA COULD -- DATA IS STILL IN MODEL SYSTEM AND THERE ARE STILL QUESTIONS WHAT HAPPENS TO HUMANS BUT AT LEAST WITH THE DATA SET WE HAD, WE DIDN'T SEE ANY EVIDENCE THAT IN VITRO ASSAYS DETECTING VIRUS UPTAKE WERE TRANSLATED TO IN VIVO ANTIBODY DEPENDENT ENHANCEMENT. SO AS FAR AS NEUTRALIZATION GOES, IF YOU LOOK AT THOSE ASSAYS, I THINK THAT AT LEAST IN OUR HANDS WE HAVE SEEN PSEUDOVIRUS ASSAYS AND LIFE VIRUS ASSAYS WORK WELL AND THE DATA WE HAVE DONE WITH DAVID MONTEFIORI AND RALPH BARIC WE SEE TWOFOLD DIFFERENCE IN THEIR TITERS USING REPLICATION VIRUSES. PSEUDOVIRUSS. SO WHEN I COMES TO ANTIBODY EFFECTOR FUNCTIONS, NEUTRALIZATION ASSAYS, WE TEND TO SEE GOOD CONCORDANCE ACROSS GROUPS AND DIFFERENT ANTIBODIES. SO I THINK THOSE AS FAR AS I CAN TELL FAIRLY PREDICTIVE. THE ONE THING I WILL PUT OUT THERE THAT IT IS POSSIBLE THAT YOU CAN HAVE ANTIBODIES THAT HAVE DIFFERENT FUNCTIONS THAT ARE IN A POLYCLONAL MIXTURE. SO WHEN YOU LOOK AT THAT POLYCLONAL MIXTURE IN VITRO YOU CAN GET DIFFERENT TYPES OUTCOME COMES COMPARED TO IN VIVO SO IN PARTICULAR WE HAVE SEEN STUDY WHERE IS WE GET GREAT PROO TEXT BUT DON'T PROTECT NEUTRALIZING ANTIBODIES IN VITRO SO NOW WE ARE WORKING ON EXACTLY WHAT THOSE MECHANISMS OF PROTECTION ARE. SO LIKELY MIXTURE OF DIFFERENT ANTIBODY FUNCTION THAT ARE CONTRIBUTING TO PROTECTION. >> THANK YOU. WELL, LET ME SEE, LET'S MOVE BACK TO REGULATORY THEN, DR. ELLIS, FROM A REGULATORY PERSPECTIVE WHAT ARE YOUR THOUGHTS ON POTENTIAL CLINICAL IMPACT OF MONOCLONAL ANTIBODIES WITH REDUCED SUSCEPTIBILITY TO CIRCULATING SARS COV-2 VARIANTS BASED ON PSEUDOVIRUS AND/OR AUTHENTIC VIRUS NEUTRALIZATION ASSAYS. >> THIS CONCERN OF COURSE WITH POTENTIAL CLINICAL IMPACT THAT REDUCE SUSCEPTIBILITY TO CIRCULATING VARIANTS. MANY ASSAYS, HOWEVER WE DON'T HAVE SUFFICIENT DATA TO KNOW IF REDUCTION IN NEUTRALIZATION AND CELL CULTURE CORRELATES WITH LOSS OF CLINICAL ACTIVITY. THIS WOULD DEPEND ON MANUFACTURERS INCLUDING MONOCLONAL ANTIBODY POTENCY, DOSES BEING USED, DISTRIBUTION, AS WELL AS SPECIFIC ASPECT OF THE VARIANTS NOT CAPTURED BY NEUTRALIZATION ASSAYS SUCH AS IMPACTED VARIANTS ON REPLICATION DISTRIBUTION, ET CETERA. SO REALLY IN THE ABSENCE OF CLINICAL DATA ON CIRCULATING VARIANTS OR PERHAPS AS WE HAVE HEARD SOME APPROPRIATE DATA FROM ANIMAL MODEL, WE JUST DON'T KNOW CLINICAL IMPACT OF SUSCEPTIBILITY IN THESE ASSAYS. >> THIS IS FOR TOM. FOLLOWING UP ON YOUR BIODISTRIBUTION SLIDES AND WHAT EMMIE MENTIONED ARE THERE NEW DEVELOPMENTS THAT SUGGEST IT IS POSSIBLE TO TARGET ANTIBODIES TO SPECIFIC TISSUE AND FLUID TO PROVIDE BETTER PROTECTION OR TREATMENT AND WHERE PARTICULARLY WOULD YOU LIKE TO TARGET THEM? >> EMERGING DATA IS SUGGESTS THAT THERE ARE ASPECTS OF THE ANTIBODIES INCLUDING GLYCO FORM FOR INSTANCE THAT CAN IMPACT ABILITY ANTIBODY TO SHOW IN CERTAIN MUCOSAL FLUIDS. THERE IS WORK AHEAD TO TRY TO UNDERSTAND WHICH OF THESE ANTIBODIES ARE REACHING BECAUSE THESE ARE MIXED POPULATIONS. WHAT IS EMERGING IS IT WILL BE POSSIBLE TO DO THIS, IT IS JUST GOING TO BE A COMPLICATED EQUATION THAT INCLUDES GLYCO FORM OVERALL CHARGE ANTIBODIES, OTHER CHARACTERISTICS THAT IMPACT WHERE THAT ANTIBODY CAN BE DISTRIBUTED. ONE MORE THING CHIMED IN TALKING ABOUT THE LONG LONG SEQUELAE THINGS WE HAVE DEVELOPED AN FAB 2 PROBE TO SPIKE WITH THE FIRST ANTIBODIES WOE GET OUR HANDS ON CR 3022 TO ALLOW US TO IDENTIFY SITES OF CORONA VIRUS REPLICATION IN A RHESUS MACAQUE USING PET SCAN GUIDED NECROPSY. SO THAT IS GOING TO BE A HANDY TOOL MOVING FORWARD ANIMAL MODELS. >> NEARING THE END OF TIME BOUNDARY IF ANYBODY ON THE PANEL HAS THOUGHTS ON THE NEW TECHNOLOGIES COMING OUT FOR ANTIBODY SUCH AS NUCLEIC ACID DELIVERY OF ANTIBODIES, IS THAT GOING TO BE A PRACTICAL METHOD OR STILL REALM OF DARPA? >> YOU NEED TO BE CONFIDENT IN YOUR ANTIBODY BECAUSE THAT IS A ONE WAY STREET AT LEAST FOR WAYS. WHEN YOU PUT THOSE ANTIBODIES IN AND THEY PERSIST A WHILE. IF VIRUS CHANGES IT MIGHT BE PROBLEMATIC. >> OKAY. WELL, I WOULD LIKE TO INVITE THE PANEL MEMBERS TO FOLLOW-UP ON ANY OF THE QUESTIONS THEY HAVE OR ASK EACH OTHER A QUESTION BEFORE I GO TO MY LESSER IMPORTANT QUESTIONS UNLESS YOU WOULD LIKE US TO STOP NOW. I DIDN'T GET A CHAT STOP NOW SO I DIDN'T. >> WE ARE RUNNING A LITTLE BIT LATE SO IF WE CAN WRAP UP IN THE NEXT FIVE MINUTES WILL BE AWESOME. >> THEN I WILL ASK THE PANELISTS, DO YOU HAVE ANY FINAL THOUGHTS, ANYTHING THAT OUR SESSION SHOULD HAVE FOCUSED ON BUT DIDN'T OR JUST HIGHLIGHT SOMETHING THAT YOU HEARD? SKIP HAS HIS HAND UP. >> I WANT TO CALL OUT THINGS ABOUT THE ANIMAL MODELS AS A GREAT FUNDAMENTAL IMPORTANCE. STATED YOU SAW THAT YOU PARTICIPATED IN BUT ALSO THAT RALPH MENTIONED THE AGING ANIMALS BEING DIFFERENT WHEN WE TALK ABOUT ANIMAL MODEL VACCINE OR SMALL MOLECULE, THOSE CHANGES IN BIOLOGY THAT REFLECT THE HUMAN MECHANISM ARE IMPORTANT. BECAUSE THE PEOPLE WHO WE WANT TO HELP ARE THE MOST VULNERABLE ANIMAL MODEL MIMICS THEIR NEEDS BETTER THAN ANOTHER ANIMAL MODEL. SO I THINK THE FUNDAMENTAL WORK TO RELATE TO HUMAN BIOLOGY WHICH WILL OCCUR OVER THE NEXT YEARS SOONER THE BETTER WILL HELP US UNDERSTAND HOW THE ANIMAL MODELS THEN MAY CORRELATE SO WE GET AWAY FROM THINGS LIKE MEASURING NEUTRALIZATION POTENCY AND TISSUE CULTURE DISH WITH OVERT EXPRESS Z ACE 2 OR ARTIFICIAL CELL LINE AND START TO GET MORE PHYSIOLOGICALLY RELEVANT MODELS. I'M ENCOURAGED BY THOSE DATA AND THERE'S OBVIOUSLY A LOT OF WORK TO DO. THAT IS IMPORTANT. >> LIKE MANY OF THE NON-HUMAN PRIMATE STUDYS WE ALL DO ARE WITH YOUNG HEALTHY ANIMALS THAT WOULD BE LIKE TEENAGE HUMANS OR ATHLETES. IT ISN'T THAT SURPRISING WE ARE NOT REALLY GETTING THE SAME DISEASE IN 80-YEAR-OLD PERSON THAT HAS MULTIPLE PROBLEMS. FINAL THOUGHTS THEN WE'LL TURN IT BACK TO CESAR. >> WE MIGHT NEED TO HAVE ANIMAL MODELS THAT ARE GOING TO HELP US WE GET VACCINE UNDER CONTROL PANDEMIC WE WILL HAVE YEARS OF CHALLENGES OF INDIVIDUALS INFECTED AND ARE HAVING HEALTH PROBLEMS BECAUSE OF THAT, THAT WILL BE A NEW PROBLEM AND WE WILL HAVE ANIMAL MODELS THAT HELP WITH THAT. >> WE BARELY TOUCHED ON THIS SEQUELAE IN THE LONG COVID AND ALL THE OTHER THINGS JUST STARTING TO LEARN CAN BE NEUROLOGICAL, AFTER COVID. SO YOU ARE RIGHT THERE. I THINK WE'LL WRAP IT UP AND GIVE BACK TO YOU. >> THANK YOU VERY MUCH FOR THE EXCELLENT PRESENTATION AND THE GREAT PANEL DISCUSSION. SO WE CONTINUE WITH AGENDA. AND NEXT WILL BE THE SESSION ON FINAL SESSION TITLED REAL WORLD CLINICAL USE OF ANTI-SARS COVE ANTIBODIES, THIS WILL BE KICKED OFF BY PRESENTATION FROM KATHERINE BAR, UNIVERSITY OF PENNSYLVANIA AND FOLLOWED BY A PANEL DISCUSSION MODERATED BY DR. RAJESH GANDHI FROM MASSACHUSETTS JUNIOR HOSPITAL AT HARVARD. THE PODIUM IS YOURS, DR. BAR. >> THANK YOU FOR THE OPPORTUNITY TO SPEAK TODAY. MY GOAL IS TO ATTEMPT TO FRAME SOME OF THE ISSUES AT THE INTEREST SECTION BETWEEN THE SCIENCE SO BEAUTIFULLY DISCUSSED UP TO THIS POINT, AND THE CHALLENGES OF IMPLEMENTING THESE ANTIBODIES IN THE REAL WORLD FOR CLINICAL AND PUBLIC HEALTH USE. SO MY COMMENTS HAVE BEEN -- ARE GUIDED BY DISCUSSIONS THAT I HAVE HAD WITH THE OTHER MEMBERS OF THE SESSION 3 PANEL LISTED BELOW AND HOPEFULLY WILL SET THE STAGE FOR SOME OF THE DISCUSSIONS THAT WILL FOLLOW. NEXT SLIDE PLEASE. SO I DON'T -- I THINK IT GOES WITHOUT STATING WITHOUT REPEATING, THE COVID-19 PANDEMIC HAS BEEN INCREDIBLY DEVASTATING. AS WELL AS RAPIDLY EVOLVING. WE HAVE HAD CONTINUAL CHANGE IN OUR UNDERSTANDING OF HOW VIRUS IS TRANSMITTED, MECHANISMS OF PATHOGENESIS. THE DETERMINANTS OF SEVERE DISEASE, AND THAT HAS INFLUENCED THE BEST PRACTICES FOR PREVENTION AN TREATMENT AND INFECTION CONTROL. FROM A CLINICAL STANDPOINT THERE'S A REAL WORLD DILEMMA OF THE DESIRE TO BOTH TREAT THE PATIENT IN FRONT OF YOU WITH POTENTIAL DEVASTATING ILLNESS BUT RIGOROUSLY EVALUATE EFFICACY OF CANDIDATE THERAPIES. THAT IS HIGHLIGHTED THIS TENSION BETWEEN THE RAPID PACE OF THE EPIDEMIC AND SLOWER PACE OF ACCRUING HIGH QUALITY EVIDENCE. I THINK WHEN WE APPLY THIS TENSION OR THIS CONSIDERATION OF TENSION TO ANTIBODY BASED APPROACH WE CAN SEE THERE IS A COUPLE OF PATHWAYS CHOSEN FROM OUR TWO MAJOR ANTIBODY APPROACH, CONVALESCENT PLASMA AND MONOCLONAL ANTIBODIES. SO IN TERMS OF COVID-19 CONVALESCENT PLASMA WHAT WE HAVE SEEN EARLY ON WAS EXTENSIVE USE WITH RELATIVELY UNCLEAR BENEFITS. NEXT SLIDE PLEASE. SO AS WAS DESCRIBED BY DR. MARKS EARLIER COVID-19 CONVALESCENT PLASMA WAS RECOGNIZED EARLY AS POTENTIAL MEANS OF DELIVERING ANTIBODY OR ANTI-VIRAL, STRONG BIOLOGICAL PLAUSIBILITY GIVEN HISTORICAL USE OF PLASMA INFECTIOUS DISEASE AS SHOWN BY THIS CLIPPING OF GIRL GETTEN ANTI-POLIO IMMUNE GLOBULIN INJECTION AS WELL AS OBSERVATIONAL DATA FROM SARS COVE 1, ALL OBSERVATIONAL DATA AND NOT RIGOROUS CLINICAL TRIALS DATA. IN ADDITION THE EARLY PANDEMIC IN CHINA BROUGHT OBSERVATIONAL STUDIES THAT SUGGESTED THAT PLASMA WAS SAFE AND POSSIBLY BENEFICIAL WITH THAT SEEN IN THE UNITED STATES THERE IS HUGE MOBILIZATION TO USE CONVALESCENT PLASMA SO WE MOBILIZED BLOOD BANKS TO RECRUIT DONORS THE NIH, FGA ET CETERA TO PROVIDE COMPASSIONATE USE OF IN PLASMA. SO CONVALESCENT PLASMA WAS INSTITUTED AS AND EXPANDED ACCESS PROGRAM, THEN THROUGH EMERGENCY USE, THESE HAVE ENABLED WIDESPREAD USE OF PLASMA IN TOTAL MORE THAN 500,000 DOSES OF PLASMA TO HOSPITALS THROUGHOUT THE UNITED STATES. WHAT YOU CAN SEE IS THESE TOOK OFF IN EARLY APRIL AND PEAKED DURING PANDEMIC INTO THE FALL WITH 40% INPATIENTS IN FALL OF 2020 RECEIVING CONVALESCENT PLASMA. THESE NUMBERS HAVE COME DOWN SUBSTANTIALLY SINCE THEN BUT EMERGENCY USE AUTHORIZATION FOR PLASMA REMAINS. HIGH TITER PLASMAS ARE AVAILABLE EARLY IN STAGE OF DISEASE SO NOT ON MECHANICAL VENTILATION OR INDIVIDUALS IMMUNOCOMPROMISED UNABLE THE MAKE THEIR OWN ANTIBODY RESPONSES. BUT THIS WIDESPREAD USE OF PLASMA PARTICULARLY EARLY ON HAD AN OPPORTUNITY COST AND THAT IT LIMITED THE RIGOROUS GATHERING OF EFFICACY DATA THROUGH CONTROL TRIALS PARTICULARLY IN THE UNITED STATES. RANDOM SIZE CONTROL TRIAL DATA HAVE BECOME AVAILABLE IN THE PUBLIC AND THESE TRIALS CONDUCTED OUTSIDE OF THE UNITED STATES AND SORT OF BEST REPRESENTED BY RECOVERY STUDY BUT SEVERAL OTHERS SIMILAR LARGE RANDOMIZE CONTROL TRIALS HAVE GENERALLY SHOWN THAT PLASMA IS SAFE BUT APPEARS TO HAVE IN THESE LARGE COHORT MINIMAL EFFECT ON CLINICAL SEVERITY SCORES DAY 14 OR DAY 28 OR OVERALL MORTALITY. SO THESE LARGE RANDOMIZE CONTROL TRIALS HAVE NOT SUGGESTED SIGNIFICANT BENEFIT. HOWEVER THERE ARE NOTABLE EXCEPTION. SO THERE'S SEVERAL STUDIES SHOWING THAT EARLY TREATMENT WITH HIGH TITER PLASMA TO HIGH RISK INDIVIDUALS IN OUT PATIENT SETTING CAN BE BENEFICIAL, THAT IS HERALDED IN NEW ENGLAND JOURNAL EARLIER THIS YEAR. ADDITIONAL STUDIES COMING THROUGH PRE-PUBLICATION SERVERS THOUGH NOT YET PEER REVIEWED SEVERAL CONTROL TRIALS IN UNITED STATES AND ELSEWHERE WITH BENEFITS SHOWN IN THESE OPTIMIZED STUDIES AND MORE ONGOING. AND ONE THING THAT'S SUGGESTED IS THIS MAY -- THE DIFFERENCE BETWEEN THESE COHORT AND SMALLER STUDIES IS HETEROGENOUS EFFECTS SEEN WITH PLASMA. SO IN PARTICULAR THERE'S QUITE A LOT OF VARIABILITY WHEN WE THINK OF MAJOR COMPONENTS INVOLVED IN PLASMA TREATMENT SO AS HAS BEEN DISCUSSED BY DR. MARKS AND OTHERS, PLASMA CAN BE QUITE VARIABLE. SOME HAS QUITE HIGH TITER ANTIBODY, OTHERS LOWER ANTIBODIES. TIMING OF ADMINISTRATION IS VERY IMPORTANT. EARLIER BEING BETTER. WHERE SOME OF THESE PATIENTS ARE GETTING PLASMA QUITE EARLY AFTER SYMPTOM ONSET AND OTHERS ARE GETTING PLASMA MUCH LATER IN DISEASE STATE. BUT I THINK ONE OF THE MORE RECENT DISCOVERIES IS THE IMPORTANCE OF THE SPECIFICS OF THE PATIENT POPULATION. SO INDIVIDUALS WITH RISK FACTORS FOR SEVERE DISEASE, WITH CO-MORBIDITIES, AND POTENTIALLY IMMUNOSUPPRESSION THAT PREVENTS THEIR OWN IMMUNE RESPONSES OR DISREGULATES IMMUNE RESPONSE, THESE INDIVIDUALS MAY IN FACT HAVE A GREATER BENEFIT FROM PLASMA THAN OTHER INDIVIDUALS. SO THERE ARE MANY NEW TRIALS COMING OUT TO DATE BUT SOME THAT WE CAN LOOK TO ARE LARGE META ANALYSES AND COMPILATION STUDIES THAT TEASE OUT CONTRADICTIONS OR CONTROVERSY AROUND BENEFIT OF PLASMA. LARGE META ANALYSIS SHOWING OVERALL MORTALITY BENEFIT IN RECIPIENTS OF PLASMA COMPARED TO ALTERNATIVE TREATMENTS. ON THE RIGHT IS FIGURE OF STUDIES IN DEVELOPMENT NOW LET BY ANDREA AND ADRIAN PET COVA FROM NEW YORK LOOK AT PATIENT SPECIFIC DATA FROM 2000 INDIVIDUALS ENROLLED IN RANDOMIZED CONTROL TRIALS AND UNDERSTAND OVERALL BENEFIT AS WELL AS SPECIFIC COMPONENTS OF PLASMA THERAPY BASED ON PARTICIPANTS AND TIMING THE SPECIFIC COMPONENTS THAT COULD LEAD TO A GREATER BENEFIT. SO THESE ARE ONGOING AND UNDER REVIEW, THESE WILL BE IMPORTANT IN OUR FINAL ASSESSMENT HOW WE USE CONVALESCENT PLASMA. AS OF RIGHT NOW, I WOULD SAY THAT WE ARE IN AN UNCLEAR PLACE OF HOW TO ADMINISTER CONVALESCENT PLASMA. WE HAVE EMERGENCY USE AUTHORIZATION FOR EARLY HOSPITALIZED PATIENTS BUT THE USE GENERALLY DECREASED AND MY INSTITUTION WE ONLY GIVE CONVALESCENT PLASMA IN THE SETTING OF IMMUNOCOMPROMISED PATIENTS WHO ARE SEVERE VEER LILL AND UNABLE TO MOUNT OWN ANTIBODY RESPONSE. THE EUA THAT EXISTS SPECIFICALLY RECOMMENDS ENROLLMENT WITHIN RANDOMIZE CONTROL TRIALS AS MUCH AS POSSIBLE FOR PARTICIPATING HOSPITALS AND ANTICIPATES CONTINUED EVALUATION OF THE DATA AS THESE NEW STUDIES ARE PRESENTED. CERTAINLY THERE ARE OUTPATIENT STUDIES AND HOSPITALIZED STUDIES THAT ARE GOING TO BE PRESENTING THEIR DATA IN THE NEAR FUTURE TO INFORM OUR UNDERSTANDING. IT SEEMS THE OVERALL PICTURE IS COMPLICATED AND THE BEST APPROACH TO USE OF CCP IN HOSPITALIZED PATIENTS OR OTHERWISE IS STILL SOMEWHAT UNCLEAR. IN CONTRAST TO CONVALESCENT PLASMA MONOCLONAL ANTIBODIES HAS A DIFFERENT -- RIGHT NOW WE HAVE HAD EMERGENCE FOR EARLY TREATMENT BUT THERE'S SUBSTANTIAL IMPLEMENTATION CHALLENGES TO OVERCOME AND TO MAXIMIZE THE USE OF THESE ANTIBODIES IN THE REAL WORLD. NEXT SLIDE PLEASE. AS BEEN -- HAS BEEN DISCUSSED BY MIKE COHEN AND OTHER INDIVIDUALS SO FAR, THERE IS UNPRESS DENNED USE OF RESOURCES, SCIENCE RESOURCES AND PARTNER SHIPS TO DEVELOP AND TEST MONOCLONAL ANTIBODIES. THESE AGENT SITS LED TO THE CLINICAL TRIALS THAT BRING US TO THE CURRENT STATE OF BEING ABLE TO USE SOME OF THESE ANTIBODIES. SO AS ITS STANDS NOW THERE IS AN EMERGENCY USE AUTHORIZATION FOR MONOCLONAL ANTIBODIES TREATMENT OF MILD TO MODERATE COVID-19 DISEASE IN ADULTS AND PEDIATRIC PATIENTS. THESE INDIVIDUALS MUST HAVE A RECENT COVID TEST AND THEY MUST BE AT HIGH RISK PROGRESSION TO SEVERE COVID-19. IMPORTANTLY THIS IS ONLY AVAILABLE FOR OUTPATIENT USE. THERE ARE THREE PRODUCTS AT OUR DISPOSAL PER THIS EUA. THERE ARE LILY COMBINATION ANTIBODIES REGENERON COMBINATION ANTIBODIES AS WELL AS THIS RECENTLY INTRODUCED SOTROBAMAB. THESE ARE AVAILABLE BY IV ADMINISTRATION WHICH POSES CHALLENGE AND THE REGENERON ANTIBODIES HAVE BEEN INDICATED OR OR AUTHORIZED FOR SUBCUTANEOUS USE SO THAT OPENS NEW POSSIBILITIES HOW WE MIGHT ADMINISTER THESE ANTIBODIES. IN ADDITION TO THE TREATMENT DATA, THERE ARE PREVENTION DATA THAT HAVE BEEN PRESENTED PUBLICLY AT CONFERENCES AND ARE CURRENTLY UNDER REVIEW AND THE FDA IS ALSO REVIEWING THESE FOR POTENTIAL AUTHORIZATION FOR USE. SO THESE DATA HAVE PRESENTED -- BEEN PRESENTED IN NURSING HOME RESIDENTS AND STAFF AND HOUSEHOLD CONTEXT BUT THE FIELD IS ANTICIPATING THE AVAILABILITY TO USE THESE ANTIBODIES IN THE FUTURE HOPEFULLY FOR PREVENTION AS WELL. THE WAY WE GOT HERE IS BY THIS REALLY WELL ORCHESTRATED COLLABORATIVE CLINICAL TRIAL FRAMEWORK THAT ENABLED US TO TEST IN PARTICULAR ANTIBODIES FOR OUTPATIENT TREATMENT. THIS HAS BEEN A SUCCESS BUT TOOK OVERCOMING MULTIPLE CHALLENGES THAT ARE RELEVANT AS WE MOVE FORWARD AND CONSIDER CONTINUAL ASSESSMENT OF NEW THERAPIES DEVELOPED AND THINK ABOUT IMPLEMENTATION. THESE ARE CONCEPTS THAT WILL BE DISCUSSED IN THE CONCEPTS FOLLOWING THIS BUT IN PARTICULAR WE CAN TALK CHALLENGES TO RECRUITING TO THESE TRIALS, AS WELL AS INFRASTRUCTURE. THERE A NARROW WINDOW BETWEEN DIAGNOSIS OF PATIENT AND THAT EARLY TIME POINT WE USE ANTI-VIRAL TREATMENT FOR BEST EFFECT. THIS FLIES IN THE FACE OF MESSAGING THAT PATIENTS RECEIVE SO PEOPLE ARE TOLD IF YOU GET A DIAGNOSIS IF YOU ARE SICK STAY HOME. SELF-ISOLATE. WE NEED TO BE ABLE TO INFLUENCE THEM TO UNDERSTAND OPTION FOR THEM TO SEEK TREATMENT TO GO TO THEIR HEALTHCARE PROVIDER AND ASK ABOUT ENROLLING IN A TRIAL BUT AS WE MOVE FORWARD SEEKING EARLY TREATMENT WITH MONOCLONAL ANTIBODIES. SO IN ADDITION TO HAVING TRIAL CENTERS SPECIFIC LANGUAGES, THERE WOULD BE BENEFIT FOR CENTRALIZED MESSAGING FROM EITHER THE GOVERNMENT OR NATIONAL PROGRAMS TO LET PATIENTS DIAGNOSED KNOW THERE IS AN OPTION FOR CLINICAL TRIAL OR TREATMENT OF EARLY DIAGNOSIS. I THINK ANOTHER MAJOR CHALLENGE FOR THESE TRIALS WAS TO RECRUIT INDIVIDUALS FROM UNDER-REPRESENTED GROUPS SO AS WE ARE ALL AWARE, COVID-19 HAS HAD A VERY HIGH BURDEN ON MINORITIES IN PARTICULAR AFRICAN AMERICANS, NATIVE AMERICANS AND LATIN X POPULATIONS SO IT WAS A MAJOR GOAL OF THESE TRIALS AND ONE THAT HAD TO BE FOCUSED ON TO MAKE SURE THAT WE RECRUITED AND ENGAGED THOSE COMMUNITIES WITHIN CLINICAL TRIAL FRAME WORKS. THE DEVELOPMENT OF THE CLINICAL TRIAL INFRASTRUCTURE WAS ALSO A MAJOR LIFT. SO JUST THE ABILITY TO FIND APPROPRIATE FACILITIES TO ADMINISTER THESE ANTIBODIES DURING THE MIDDLE OF THE PANDEMIC WAS REALLY CHALLENGING. YOU HAD OUTPATIENT SETTING WITH GOOD FLOW THROUGH, VENTILATION APPROPRIATE SPACING AND STAFFING AND THAT WAS A REAL OBSTACLE. IN ADDITION THERE ARE MANY COMPETING PRIORITIES DURING THIS THIS PANDEMIC. IN THE OUTPATIENT AND PREVENTION SETTING WE WE ARE PRIORITIZING VACCINE TRIALS. WHERE DO PREVENTIVE THERAPIES FIT WITHIN THAT MODEL? MANY CLINICAL TRIAL UNITS ARE LINKED TO HOSPITALS AND MANY HOSPITALS OF COURSE HAD TO PRIORITIZE THE TREATMENT OF THEIR INPATIENT POPULATION OR THE TESTING OF INPATIENT THERAPIES. SO OFTEN THERE WAS COMPETING PRIORITIES WITHIN THE COVID-19 PANDEMIC. SO THROUGH ALL THIS I THINK WE ARE WELL AWARE HEALTHCARE WORKERS AND CLINICAL TRIAL STAFF WORKED INCREDIBLY HARD OVER THE PAST YEAR. DEALING WITH STAFF BURN OUT, TURN OVER, IS A MAJOR CHALLENGE AS WE MOVE FORWARD CONTINUING TO SUPPORT THIS TRIAL INFRASTRUCTURE. THAT IS A MESSAGE MYSELF AND OTHERS WANT TO COMMUNICATE, TO CONTINUE TO MAINTAIN SUPPORT AND MOMENTUM FOR THESE COLLABORATIVE TRIAL NETWORKS TO BE ABLE TO TEST NEW PRODUCTS AS THEY BECOME AVAILABLE, POISED IF THERE'S SURGES FROM THE VARIANTS OF CONCERN OR THE NEXT PANDEMIC THAT WE ARE ABLE TO EQUALLY QUICKLY REACT TO THOSE AS WE HAVE FOR THIS PREVIOUS PANDEMIC. # '01 # SIMILARLY TO CLINICAL TRIAL DEVELOPMENT IMPLEMENTATION OF ANTIBODIES HAS CHALLENGES. RIGHT NOW THE DEPARTMENT OF HEALTH AND HUMAN SERVICES DISTRIBUTES THERE'S TO ORGANIZATIONS THAT REQUEST. THERE ARE MORE THAN 3500 DISTRIBUTION SITES WITHIN THE UNITED STATES. WE HAVE ADMINISTERED MORE THAN 500,000 COURSES OF THESE MONOCLONALS TO PATIENTS WITH COVID-19 THE PAST FEW MONTHS. THAT IS REMARKABLE AND SHOULD BE SEEN AS VICTORY WHEN WE THINK OF THE NUMBER OF DEATHS PREVENTED, AND THE NUMBER OF HOSPITALIZATION AVERTED. HOWEVER THERE IS A GENERAL AGREEMENT THESE ANTIBODIES ARE CURRENTLY UNDER USED AND WE NEED THE ADDRESS THESE IMPLEMENTATION CHALLENGES IN ORDER TO OPTIMIZE THEIR USE IN THE RAIL WORLD. ONE MAY -- REAL WORLD. TIMELY IDENTIFICATION OF ELIGIBLE PATIENT AFTER DIAGNOSIS AND LINKAGE OF THEM TO A FACILITY THAT CAN REFER OR PRESCRIBE ANTIBODIES. THE WAY OUR HEALTHCARE SYSTEM WORKS NOW THERE IS A DISCONNECT BETWEEN THE AGENCIES OR THE GROUPS PROVIDED DIAGNOSIS OF COVID-19 ACUTE CARE CENTERS, PHARMACIES EMERGENCY DEPARTMENTS AND INSTITUTIONS THAT ARE ABLE TO ACTUALLY PROVIDE PRESCRIPTION OR INFUSION OF ANTIBODIES. SO THERE NEEDS TO BE MORE COMMUNICATION AND NETWORKING AND REFERRAL NETWORKS BETWEEN THESE DIFFERENT GROUPS BECAUSE IT IS A SHORT PERIOD OF TIME TO GET THAT PATIENT LINKED. IN ADDITION THERE NEEDS TO BE BETTER MESSAGING TO BOTH PATIENTS AND PROVIDERS ABOUT WHAT THE POTENTIAL BENEFITS OF THESE MONOCLONAL ANTIBODIES ARE. MANY INDIVIDUALS ARE UNAWARE THAT THERE'S A THERAPY THAT COULD BE BENEFICIAL DURING THESE EARLY STAGES OF DISEASE. IN ADDITION HOW TO RIVER THEM TO THE RIGHT FACILITY. UNAWARE IN THE SETTING OF VARIANTS AND CONSTANTLY CHANGING LOCAL EPIDEMICS, WHAT THE UTILITY AND ROLE FOR MONOCLONAL ANTIBODIESES ARE. THAT DO ADMINISTER ANTIBODIES SO IT TAKES A LOT OF THOUGH THESE ANTIBODIES ARE PROVIDED FREE OF COST FROM THE GOVERNMENT IT TAKES A REAL COMMITMENT FROM THESE INSTITUTIONS IN ORDER TO PROVIDE THESE ANTIBODIES. IT TAKES A LOT OF STAFFING SO YOU NEED A PROVIDER, EITHER PHYSICIAN OR NURSE PRACTITIONER TO ACTUALLY PERFORM THE INFORMED CONSENT PROCESS AND TO SUPERVISE ADMINISTRATION OF ANTIBODY. YOU NEED PHARMACY SUPPORT TO PREPARE THESE MONOCLONAL ANTIBODIES ON A DAILY BASIS AND YOU NEED NURSING STAFF TO PROVIDE THE INFUSION AND TO MONITOR FOR REACTION AFTERWARDS. TOTAL IT TAKES THREE HOURS OF TIME TO DO THE WHOLE PROCESS OF ADMINISTERING AND MONITORING THESE ANTIBODIES SO THINK ABOUT NUMBER OF PATIENTS WE COULD BE TREATING THAT THREE HOUR BLOCK OF TIME IS LIMITING. YOU NEED A CLINICAL SPACE WITH APPROPRIATE VENTILATION, PROVISION OF. PPE, AND THE ABILITY TO GET IN AND OUT FOR THIS RECENTLY INFECTED POTENTIALLY INFECTIOUS PATIENT. IN IN ADDITION THESE INSTITUTIONS NEED TO PROVIDE FOLLOW-UP FOR ANYBODY WHO RECEIVES ANTIBODIES AND THAT IS AN EXTRA ASK FOR THESE GROUPS. NEXT SLIDE PLEASE. SO IN ADDITION TO JUST GETTING THESE ANTIBODIES TO AS MANY PEOPLE AS POSSIBLE IT IS IMPORTANT TO CONSIDER EQUITY. THERE ARE MANY DISENFRANCHISED INDIVIDUAL INDIVIDUAL THE HEALTHCARE SYSTEM MUCH LESS LIKELY TO BE OFFERED ANTIBODY AND WE NEED MESSAGING REFERRAL NETWORKS TO PROVIDE INDIVIDUALS WITH THE KNOWLEDGE OF THESE ANTIBODIES AS WELL AS THESE LINKAGE TO CARE. THE FUTURE THERE WILL BE COST AND INSURANCE ISSUES, AND THAT WILL BE IMPORTANT FOR US TO CONSIDER AS WELL AS -- THIS IS TOTALLY INADEQUATE TO ADDRESS THE ISSUE OF INTERNATIONAL USE OF THESE ANTIBODIES. BUT AS WE LOOK AT THE PANDEMIC RAGING AROUND THE WORLD IT IS IMPORTANT TO CONSIDER WHETHER WE COULD CONTRIBUTE THESE ANTIBODIES TO THE GLOBAL PANDEMIC. NEXT SLIDE PLEASE. I'M NOT GOING TO TOUCH TOO MUCH VARIANTS OF CONCERN JUST TO SAY THIS IS A HUGE ISSUE THAT'S BEEN DISCUSSED, THE CURRENT GOVERNMENT HAS INTERAGENCY GROUP THAT MONITORS VARIANTS ON A WEEKLY BASIS AND CHANGES THE DISTRIBUTION OF THESE ANTIBODIES BASED ON THIS. IT IS OBVIOUS WE NEED CONTINUED SEQUENCING AND SURVEILLANCE, SHORTEN THE LAG TIME BETWEEN INDIVIDUAL REGIONS SEQUENCING AND WE NEED TO COMMUNICATE WITH PROVIDERS SO THEY UNDERSTAND WHAT THE SEQUENCES MEAN FOR THEIR LOCAL EPIDEMICS. NEXT SLIDE PLEASE. AN EXAMPLE FROM MY HOME INSTITUTION AT PENN PROVIDE SEQUENCENING NEAR REAL TIME LOCAL PHILADELPHIA SAMPLES BEING PROVIDED. WHAT WE HAVE SEEN HERE IN THIS PUBLICLY AVAILABLE DASHBOARD OF SEQUENCING IS THAT WE HAVE HAD OVER THE COURSE OF THE SPRING AN INCREASING PREVALENCE OF P 1 VARIANTS. BECAUSE OF THIS, WE ACTUALLY CHANGED -- THIS WAS COMMUNICATED TO THE WIDER PHILADELPHIA REGION AN SPECIFIC HOSPITAL ANTI-MICROBIAL STEWARDSHIP COMMUNITY CHANGE USE OF MONOCLONAL ANTIBODIES BASED ON THESE NEAR REAL TIME SEQUENCING DATA. SO WE NOW ONLY A PRESCRIBE ANTIBODIES THAT SHOULD BE ABLE TO TREAT THE FULL RANGE OF VARIANTS THAT ARE SEQUENCED IN THE OUR COMMUNITY. SO THIS LEVEL OF REGIONAL SURVEILLANCE IS REALLY IMPORTANT TO EMBODY TRUST AND UNDERSTANDING IN PATIENTS FOR THESE ANTIBODIES. NEXT SLIDE PLEASE. SO THE FINAL ISSUE THAT I WANT TO MENTION IN THE REAL WORLD IS A HUGE AMOUNT OF EXCITEMENT FOR POTENTIALLY BEING ABLE TO USE THESE ANTIBODIES FOR PREVENTION IN IMMUNOCOMPROMISED PATIENTS. CURRENTLY IMMUNOCOMPROMISED PATIENTS HAVE THESE AVAILABLE IF HOSPITALIZEDIZED SO CCP IS AVAILABLE BY EMERGENCY USE AND MONOCLONAL ANTIBODIES THROUGH COMPASSIONATE USE PROGRAMS BUT SHOULD THEY BE AVAILABLE FOR PREVENTION? THERE ARE COUNTLESS TRANSPLANT RECIPIENTS OF CANCER PATIENTS AND OTHER IMMUNOSUPPRESSED INDIVIDUALS NOT ABLE TO HAVE VACCINE RESPONSE VERY MUCH SEEKING ABILITY TO PREVENT DISEASE WITH MONOCLONALS. SO WE MAY NOT BE ABLE TO DO CLINICAL TRIALS IN THESE INDIVIDUALS BUT I THINK REGISTRIES OR PRAGMATIC TRIALS MAYBE REALLY INFORMATIVE TO THESE INDIVIALS. NEXT SLIDE. I HI THE REAL WORLD USE OF ANTIBODIES IS IMPORTANT CONSIDERATION AS WE HEAR OF ALL THE AMAZING SCIENTIFIC DISCOVERIES DISCUSSED TOO. I THINK THIS TENSION BETWEEN THE DEVASTATION AND RAPID PACE OF THE PANDEMIC AND SLOWER ACCUMULATION DATA IS IMPORTANT AND WHEN WE THINK ABOUT THESE DIFFERENT ANTIBODY FORMULATION THEY HAVE HAD DIFFERENT PATHS TO GETTING TO WHERE WE ARE CURRENTLY. I JUST MY FINAL MESSAGE, I THINK IT IS VERY IMPORTANT WE MAINTAIN THE SUPPORT AND ENERGY TOWARDS ALL THESE REAL SUCCESSES IN TERMS OF DISCOVERY, CLINICAL TRIAL INFRASTRUCTURE, VIRUS SURVEILLANCE, MONOCLONAL ANTIBODIES DISCOVERY, AS WELL AS ENHANCE OUR MESSAGING AND EDUCATION STRATEGIES SO THAT WE CAN BETTER DELIVER THESE ANTIBODIES TO OUR PATIENTS AND TO PREVENTION FORMAT MOVING FORWARD. NEXT SLIDE. THANK YOU VERY MUCH. I WILL LOOK FORWARD THE TO DISCUSSION ABOUT THIS TOPIC. >> THANK YOU SO MUCH. I WANT TO INVITE DR. GANDHI AND PANELISTS OF SESSION 3 TO TURN THEIR CAMERAS ON AND WELCOME TO THE SESSION 3 PANEL SESSION. I'M PLEASED TO BE JOINED BY THE DISTINGUISHED PANEL DR. ADA ADIMORA UNIVERSITY OF NORTH CAROLINA. DR. JUDY KURRIER, UNIVERSITY OF CALIFORNIA LOS ANGELES, DR. FRED KORLEY UNIVERSITY OF MICHIGAN, DR. MEAGAN O'BRIEN FROM REGENERON, DR. JOHN REDD FROM OFFICE OF ASSISTANT SECRETARY FOR PREPAREDNESS AND RESPONSE AND FINALLY, DR. MARK WILLIAMS, FROM ELY LILLY. MAYBE I WILL JUST ASK ONE OR TWO SLIDES BE PUT UP TO FRAME DISCUSSION. THIS IS WHAT WE HAVE BEEN TALKING ABOUT OVER THE COURSE OF THIS SYMPOSIUM, ROLE OF MONOCLONAL ANTIBODIESES, GO ON TO THE NEXT SLIDE. CLEARLY MONOCLONAL ANTIBODIESs FIT WITHIN THIS EARLY TREATMENT PORTION OF THE SARS COV-2 SPECTRUM WHEN PEOPLE HAVE MILD TO MODERATE ILLNESS AND HA IS WHERE THAT IS SHOWN THEIR CLINICAL BENEFIT. THE GOAL OF THIS PARTICULAR SECTION -- SESSION IS TO GO THROUGH SOME OF THE KEY KNOWLEDGE GAPS IN QUESTIONS AND DR. BAR HIGHLIGHTED THOSE FOR US AS WELL AS POTENTIAL CLINICAL TRIAL STRATEGIES TO PROVIDE ADDITIONAL DATA. SO THE QUESTIONS THAT WE AND THE PANEL ARE GOING TO BE DISCUSSING ARE ON THE LAST SLIDE AND THEN WE WILL TAKE DOWN THE SLIDES AND GO TO OUR PANEL. WE WILL BE TALKING CHALLENGES RELATED TO INFRASTRUCTURE DEVELOPMENT FOR CLINICAL TRIALS ANTIBODY FOR OUTPATIENTS WITH COVID-19. GET DOWN TO SOME OF THE IMPLEMENTATION ISSUES FOR MONOCLONAL ANTIBODIES TREATMENT OF OUTPATIENT WITH COVID-19 MESSAGING ISSUE TO PATIENTS ANDLY IN ADDITIONS. AS WELL AS KEY BARRIERS TO EQUITABLE IMPLEMENTATION. WE WILL TALK SOME ABOUT OVERCOMING BARRIERS TO ADMINISTRATION OF ANTIBODIES INCLUDING IMPACT OF ROUTE OF ADMINISTRATION. TALK ABOUT ROLE OF FEDERAL GOVERNMENT IN ANTIBODY DISTRIBUTION, PRECISION MEDICINE AND RAPID TESTING AND THE ROLE OF ANTIBODIES FOR PREVENTION AND TREATMENT IN IMMUNOCOMPROMISED PATIENTS SO AMBITIOUS AGENDA. WE WILL LAUNCH RIGHT INTO THIS AND I WILL ASK YOU TO TAKE DOWN THE SLIDES SO THAT WE CAN SEE OUR PANELISTS. SO LET'S START WITH THE FIRST QUESTION AND I WILL PUT THIS JUDY KURRIER. YOU HAVE BEEN REALLY IN THE THICK OF IT IN TERMS OF SETTING UP CLINICAL TRIALS OF ANTIBODIES AS WELL AS OTHER INTERVENTION FOR OUTPATIENT. I WOULD LOVE TO HEAR YOUR THOUGHTS ON SOME OF THE CHALLENGES WITH SETTING UP THAT INFRASTRUCTURE, THIS -- IN THE OUTPATIENT SETTING. WHAT YOU SEE THE LESSONS FROM THOSE CHALLENGES OVERCOME AS WELL AS CHALLENGES TO COME. OVER TO YOU, JUDY. >> THANKS SO MUCH, RAJ. AS KATIE OUTLINED THIS WAS A BIG ISSUE SETTING UP OUTPATIENT FA ITS IS FOR MONOCLONALS. WE LEARNED FROM LILY WHO HAD GREAT EXPERIENCE SETTING UP THEIR SITES, TRIAL SITES, BUT IT WAS CRITICAL THIS NEED TO HAVE A PLACE WHERE THE PARTICIPANT COULD BE SAFELY SEEN BUT WHERE THERE WAS ALSO STAFF AVAILABLE. BECAUSE PEOPLE WERE -- WHO HAVE EXISTING SITES WERE BUILDING THESE UNITS OR PLACES BRINGING IN TRAILERS AND TENTS BUT THERE'S NO ONE WHO WORKS THERE. AND THE PEOPLE WHO WORK SOMEWHERE ELSE HAVE TO GO THERE SO I THINK THAT THE STAFFING INFRASTRUCTURE IS SOMETHING WE SHOULD STILL BE BUILDING. NOT MAINTAINING BUT EXPANDING BECAUSE WE HAVE LEARNED A LOT ABOUT WHERE THE FACILITIES ARE NEED TO BE WHERE THEY ARE NOT. WE NEED TO EXPAND CAPABILITY MORE IN TO COMMUNITY SETTINGS AS WELL AS LARGE CENTERS. BUT THE STAFFING WAS REALLY -- WE TOOK PEOPLE WHO WERE CLINICAL TRIAL STAFF WORKING IN HIV AND THEY FLIP TO WORK ON COVID AND DO THIS BUT THE STAFF DOESN'T EXIST IN A LOT OF OUTPATIENT SETTINGS. SO I WOULD SAY STAFFING AND LOCATION WERE TWO OF THE BIGGEST CHALLENGES. WITH OTHER ISSUES KATIE MENTIONED ABOUT THE PRIORITY FOR OUTPATIENTS AND MIDDLE OF A PANDEMIC WHERE PEOPLE ARE DYING IN THE HOSPITAL. GETTING RESOURCES TO OUTPATIENT SETTING WAS A CHALLENGE. MAYBE UX EXPAND YOUR OWN LOCAL EXPERIENCE IN LOS ANGELES. HERE IN BOSTON WE SET UP ANTIBODY TRIALS AND ACADEMIC CENTERS, HAS GENERAL BRIGHAM WOMEN HOSPITAL. BUT THE FORCE OF INFECTION WAS GREATSEST IN COMMUNITIES LIKE CHELSEA WERE NEAR BUT NOT NEAR ENOUGH TO ACADEMIC CENTERS, I WONDER HOW YOU HELD WITH SOME OF THAT IN LOS ANGELES, I WILL INVITE OTHERS TO COMMENT IF LIKE BUT GIVEN US YOUR LOS ANGELES EXPERIENCE. >> THIS WAS A PROBLEM. SOMETHING THAT WE COULD HAVE DONE BERTH AND NEED TO DO BETTER IN THE FUTURE. WE SET UP INITIALLY AT OUR MEDICAL CENTER THE ISSUE IS TRANSPORTATION. PEOPLE AREN'T GOING TO TAKE A BUS WHEN THEY HAVE COVID OR SHOULDN'T TAKE A BUS. SOME OF THE COMMUNITY HEALTH CENTERS DIDN'T HAVE STAFF TO TAKE ON PUTTING THIS IN PLACE BUT IT COULD BE DEVELOPED AND MADE IF WE PRIORITIZE I THINK WE CAN DO BETTER. NEXT TIME. SOME OF OUR PUBLIC HOSPITALS DIDN'T -- THEY JUST DIDN'T -- JUST COULDN'T TAKE IT ON BECAUSE OF STAFFING CONSTRAINTS. T THAT PLAIN AND SIMPLE RESOURCES. WERE THE KEY THING. >> TALK ABOUT TRIALS, INVITE ANYONE ELSE ON THE CALL WHO ANY OF THE OTHER PANELISTS WHO PARTICIPATE IN THESE TRIALS TO SHARE THEIR EXPERIENCES IF THEY HAVE ANYTHING TO ADD. I HAVE THE SAME EXPERIENCE THAT YOU DO. ANY OTHER COMMENTS BEFORE WE TACKLE ANOTHER SET OF CHALLENGES? >> MARK WILLIAMS LILY, AWARE OF SUCCESS STORIES AND ONE THAT INSPIRED ME THE MOST WAS WHAT THEY WOULD CALL STRIKE TEAMS EMERGENCY MEDICAL SERVICES PERSONNEL WERE INVOLVED IN NOT JUST TRANSPORTING PATIENTS TO INFUSION CENTERS BUT MAKING HOME INFUSIONS POSSIBLE IN CERTAIN AREAS, THERE'S REALLY INTERESTING WORK THAT WAS DONE ACROSS THE COUNTRY LED TO SUCCESS. ONE OTHER THING WE LOOKED INTO USING BLOOD MOBILE. WE THOUGHT MAYBE WE COULD REPURPOSE THE BLOOD MOBILE FOR THIS, DIDN'T WORK OUT BUT MOBILE CAPACITY IS SOMETHING TO HAVE STAFF ATTACHED TO IT AND GO TO PLACES WHERE PEOPLE ARE WANDS THEY FEEL COMFORTABLE GOING TO RECEIVE TREATMENT. >> WE WILL TALK DELIVERY MECHANISM AND HOW THAT IMPACTED BUT MAYBE MARK DO YOU WANT TO SAY A LITTLE BIT MORE ABOUT THE HOME INFUSION AND HOW YOU SET THAT UP? I THINK IT IS A MODEL FOR THE FUTURE AS WE ARE ALL SAYING. MAYBE DESCRIBE THAT IN A BIT MORE DETAIL. >> ELY LILLY DID NOT SPONSOR THOSE ACTIVITIES WE SPONSORED THEM IN TERMS OF PROVIDING EDUCATION IN OUR PLAY BOOKS AND KNOW HOWS. UNITED HEALTH GROUP IS ONE ORGANIZATION THAT WAS VERY NOVEL IN IN PROPROVIDING HOME INFUSION EARLY, THERE'S OTHER EXAMPLES AS WELL. CHIEF MEDICAL OFFICER AT ASPR AND RUNNING THE ADMINISTRATION DISTRIBUTION PART OF OPERATION WARP SPEED WITH THESE PRODUCTS AND UPCOMING ONES TOO. WHAT WE ARE HINTING ON IS THE DIFFERENCE BETWEEN THE CLINICAL TRIAL PHASE OF DEVELOPMENT OF A PRODUCT AND THE POST EUA PHASE OF A PRODUCT. WE NEVER HAD EUA PRODUCTS THIS MAGNITUDE BEFORE, NOT EVEN CLOSE. ONE THING THAT WAS DIFFICULT AS YOU RECALL, LILY AND SHORTLY THEREAFTER REGENERON EUA CAME OUT IN NOVEMBER. NUMBER ONE, LEVEL OF EVIDENCE BY DEFINITION WHEN EUA COMES OUT IS OF LOWER LEVEL THAN EXPECT FOR FULL AUTHORIZATION. THAT AGAIN IS BY DEFINITION. THERE IS ONE EDUCATIONAL AND PATIENT INTERACTION PROBLEM BUT THE SECOND PROBLEM THAT RAJ WANTED ME TO SPEAK ABOUT IN A SECOND IS SCARCITY. SO THE -- IT WOULDN'T BE ETHICAL TO HOLD THESE PRODUCTS BACK UNTIL THEY ARE SUFFICIENTLY IN SUPPLY TO GO EVERYWHERE. ON THE OTHER HAND, THERE ARE MANY ON THE OTHER HANDS IN THIS ENTERPRISE, ON THE OTHER HAND WHAT THAT MEANS IS LITERALLY SOMEONE HAS TO GET IT FIRST. THERE HAS TO BE AN EQUITABLE METHOD TO DISTRIBUTE. SO A LOT OF THE ISSUES THAT WE ARE DISCUSSING ARE COMMON TO A LOT OF EUA PRODUCTS BUT LOT OF CASES EXACERBATED BY THE FACT THAT THESE WERE NEW EUA BASED PRODUCTS, IN THE MIDDLE OF A PANDEMIC, THAT WERE OUTPATIENT INFUSED THERAPEUTIC. THEREFORE REQUIRE NEW INFRASTRUCTURE. >> GOOD TRANSITION FROM THE TRIALS CHALLENGES SUBSTANTIAL TO THE IMPLEMENTATION CHALLENGES SO LET'S TURN OUR ATTENTION TO CHALLENGES AND I WANT TO ASK THE CLINICIANS ON THE CALL FOR A MOMENT TO REFLECT MESSAGING ISSUE. WE SPENT THE FIRST YEAR OR ALMOST A YEAR SAYING IF YOU ARE NOT FEELING TOO BAD STAY AT HOME. DO NOT GET ANYWHERE NEAR US, BECAUSE OF THE VARIETY OF ISSUES. BUT THEN WE ON A DIME ESSENTIALLY HAVE TO CHANGE AND SAY NO, IF YOU ARE SICK WITH ANY SYMPTOMS WE WANT YOU TO GET TREATMENT AS EARLY AS POSSIBLE. WONDERED WHAT YOUR OWN EXPERIENCE THOSE OF YOU INVOLVED IN TALKING WITH PATIENTS WITH COVID WHAT YOUR EXPERIENCE WAS ABOUT MAKING THAT RATHER QUICK TRANSITION AS ACCESS TO THESE ANTIBODIES BECAME AVAILABLE FROM EUA. I'M GOING TO ASK BRAD IF YOU OR ADA BEFORE WHICH GO TO CLINICIAN, ANOTHER SIDE OF THE COIN. >> I CAN GO AHEAD AND SAY THAT FROM EMERGENCY DEPARTMENT STANDPOINT WE WERE PRETTY HARD HIT IN THE BEGINNING HOW DO YOU DEAL WITH EXISTING PATIENT SURGES FROM OTHER DISEASE COMPLAINTS AS WELL. SO THOSE ARE HARD BALANCED TO MAKE BUT I THINK THERE IS ONE IMPORTANT POINT THAT I WANT TO MAKE WHICH IS THAT IT IS OUR DUTY AS CLINICIANS WHO ARE MORE COMFORTABLE WITH DEALING WITH UNCERTAINTY TO BE ABLE TO COMMUNICATE THIS MESSAGE CLEARLY TO THE GENERAL PUBLIC THIS IS A PANDEMIC THAT IS UNPRECEDENTED AND DON'T GO O THE HOSPITAL, I THINK WE SHOULD HAVE ALSO BEEN EQUALLY AS LOUD WITH SAYING THAT GET CARE IMMEDIATELY AND NOT NECESSARILY BE EMERGENCY DEPARTMENT, IT COULD BE OUTPATIENT INFUSION CENTER, BUT I THINK THAT AS MUCH EFFORT AS WE PUT INTO THE RESEARCH TO FIGURE OUT THE EFFICACY OF THESE PRODUCTS, WE NEED TO PUT SIMILAR EFFORT INTO MESSAGEING. >> MY OWN EXPERIENCE, WE ADOPTED A SYSTEM FOR INITIALLY CONTACTED PATIENT A CENTRALIZED SYSTEM WHEN THEY TESTED POSITIVE. THERE ARE A NUMBER OF PATIENT WHOSE DIDN'T COME IN AND WHAT THEY WERE LOOKING TO IS THEIR CLINICIAN, PEOPLE THEY TRUSTED TO ENDORSE AND/OR SO THAT CLINICIAN RELY, I FOUND AND I SUSPECT OTHERS AS WELL TO BE CRITICAL AND WITHOUT CLINICIAN BEING INVOLVED IN RECOMMENDED THESE ANTIBODIES A CENTRALIZED SYSTEM JUST LEFT PEOPLE COLD. AND JUST DIDN'T HAVE THAT SHAME TRUSTWORTHINESS. JOHN YOU RAISED YOUR HAND. >> THANKS, RAJ. I WANT TO COMMENT ON SOME EFFORTS WE HAVE MADE TO LINK AS CLOSE AS POSSIBLE TEST TO TREAT. IN THIS INSTANCE IT IS REALLY IMPORTANT, REMINDS ME OF OTHER PUBLIC HEALTH WORK DONE ON STD TREATMENT, RAPID URINE TESTING FOR EXAMPLE FOR STD BUT IN THIS CASE USE OF RAPID ANTIGEN TESTS FOR COVID-19 TESTING WAS EXTREMELY APPROPRIATE BECAUSE YOU WOULD HAVE SOMEONE SYMPTOMATIC WHO HAS A VERY HIGH PRE-TEST PROBABILITY AND THEREFORE COUNT ON POSITIVE. WE MADE EFFORTS IN SEVERAL LOCATIONS TO TRY TO MAKE IT AS ABSOLUTELY CONVENIENT AS POSSIBLE SO LITERALLY SOMEONE TO SAY YOU ARE POSITIVE, WALK DOWN THE HALL, THAT IS WHERE YOU WILL GET YOUR TREATMENT. THAT IS HARD TO DO BUT VERY EFFECTIVE. >> JUST ADD TO THAT, TESTING WAS REALLY DELINKED FROM BOTH -- MOST HEALTH SYSTEMS, SO LOT OF TIMES CLINICIANS DIDN'T KNOW THEIR PATIENT WAS GETTING TESTED. SO TRYING TO LINK THE TESTING TO THE TREATMENT AND BRING CLINICIAN BACK IN TO HAVE INPUT THAT PEOPLE WERE GOING ELSEWHERE TO GET TESTING AND IT WASN'T PART OF THEIR REGULAR MEDICAL CARE. >> ONE OTHER THING -- I WAS GOING TO COMMENT ON AND I GOT MOST INFORMATION FROM UMC WHO HEADED UP THE MONOCLONAL ANTIBODIES EFFORTS THERE. ONE THING HE EMPHASIZED TO ME, EXTENT CLINICIANS ARE UNAWARM ON THE NIH TREATMENT GUIDELINES PANEL WE ARE -- EVERY EVERY WORD AND COMMENT BUT FACT OF THE MATTER A LOT OF CLINICIANS DON'T KNOW ABOUT THE UTILITY OF MONOCLONAL ANTIBODIES, THEY DON'T KNOW WHICH TO USE. THEY ALSO THERE IS A LOT OF CONFUSION ABOUT WHERE TO GO TO SEND THEIR PATIENTS TO GET THEM. THESE ARE JUST I'LL MENTION THAT A LITTLE MORE >> IF I COULD ADD, WE KNEW IT WAS IMPORTANT TO EDUCATE PHYSICIANS AND NURSE PRACTICERS,s ESPECIALLY PRIMARY CARE SO THROUGH INDEPENDENT MEDICAL EDUCATION SYSTEM WE WERE ABLE TO FUND A NUMBER OF IMPACTFUL PROGRAMS THAT HELPED, COULD HAVE BEEN MORE I'M SURE BUT FELT GOOD ABOUT THOSE EFFORTS. >> I KNOW ASPR AND OTHER ORGANIZATIONS GET SIMILAR OUTREACH TO CLINICIANS TO MAKE SURE THAT INFORMATION WAS GETTING OUT. BUT MY WIFE IS A PRIMARY CARE DOCTOR AND I -- SHE HAD TO LISTEN TO ME. BUT THAT POINT IS VERY GOOD ONE. THIS WAS A RAPID RAPIDLY MOVING FIELD, EVIDENCE WAS CHANGING BY THE WEEK KEEPING EVERYONE ABREAST WAS -- OTHER COMMENTS ON THIS CLINICIAN EDUCATION AS SPECIAL BEFORE WE MOVE TO CLINICAL ASPECT OF EQUITY? >> SO ONE OF THE CHALLENGES THAT I HAD AND COLLEAGUES SHARED WAS THE FACT THAT STUDIES PUBLISHED IN THE BEGINNING WERE STUDIES THAT WERE SMALL IN SAMPLE SIZE, THE RESULTS HAD HIGH FRAGILITY INDEX. YOU JUST NEED A COUPLE OF EVENTS TO CHANGE SIDES AND OUTCOME WILL BE DIFFERENT. AND ALSO SOME OF THE INITIAL OUTCOMES, WERE THINGS LIKE CLEARANCE, WHICH IS IMPORTANT, BUT IT IS NOT AS CLINICALLY AS IMPORTANT AS HARD CLINICAL OUTCOMES. SO I THINK ONE OF THE STRUGGLES WAS WHEN PEOPLE WENT BACK TO LITERATURE TO READ FOR THEMSELVES WHAT THE EVIDENCE IS, THE LEFT NOT IMPRESSED. WHEN MORE DATA CAME LATER THEY MAY NOT HAVE GONE BACK TO REREVIEW THAT DATA. AND SO LEFT WITH THAT INITIAL IMPRESSION THAT THE DATA ARE NOT THAT STRONG. >> I WANT TO MAKE SURE WE COVER THE GAMUT OF ASPECTS OF REAL WORLD IMPLEMENTATION. MAYBE I WILL ASK ADA IF YOU CAN COMMENT ON THE THOUGHTS YOU HAVE HAD AROUND EQUITABLE IMPLEMENTATION OF TRIALS BUT ALSO ACCESS TO AUTHORIZED ANTIBODIES. >> THANKS. I WANT TO EMPHASIZE, TALK WITH DAVID WALL ABOUT ACTUALLY DOES THIS UP CLOSE AND IN PERSON ALL THE TIME BUT THERE ARE A NUMBER OF BARRIERS TO EQUITABLE IMPLEMENTATION OF MONOCLONAL ANTIBODIES FOR TREATING COVID. AS YOU CAN IMAGINE ANYTHING BARRIERS TO EVERYONE LIKELY BIGGER BARRIER LESS OF MEANS. FIRST LANGUAGE OF SIGNIFICANT BARRIER WHEN YOU CONVEY NUANCED CONCEPT LIKE NEED FOR INFUSION AND WHY SOME PEOPLE NEED AND OTHERS DON'T. SPANISH SPEAKERS MAY NOT BE THE ONLY PEOPLE WHO TRIER TRANSLATION, OTHER IMMIGRANT POPULATIONS SPEAKING DIFFERENT LANGUAGES AS WELL. BUT HAVING SAID THAT, MANY BARRIERS TO RECEIPT OF MONOCLONAL ANTIBODIES DON'T RELATE TO RACE OF ETHNICITY BUT SOCIOECONOMIC STATUS. ALSO TO THE COMBINATION OF RACE ETHNICITY AND SOCIOECONOMIC STATUS WHICH IN THE UNITED STATES CAN BE FAIRLY PRETTY TOXIC COMBINATION. PEOPLE DIAGNOSED IN ER, URGENT CARIS, CENTERS, ET CETERA, THE INFUSION TIME OBSERVATION TIME REQUIRED FOR MONOCLONAL ANTIBODIES ADMINISTRATION OBVIOUSLY MAKES IT HARD TO DO THEM IN THESE PLACES AS POINTED OUT BEFORE. DON'T HAVE INFUSION CENTERS OR INFUSION CAPABILITY. IN ADDITION, GEOGRAPHIC BARRIERS SOME SETTINGS INFUSION CENTERS ARE IN A DISTANCE FROM WHERE THE PERSON WAS DIAGNOSED OR FROM WHERE THE PERSON LIVES. SO LACK OF TRANSPORTATION CAN BE BARRIER IN RURAL SETTINGS. ALONG THESE CURRENTLY KNOWN CHARGE FOR MONOCLONAL ANTIBODIES SOME PLACES MAY HAVE A FACILITY CHARGE THAT CAN BE SUBSTANTIAL GIVEN REQUIRED INVESTMENT IN TERMS OF STAFFING NURSING ET CETERA. MEDICAID, MEDICARE, COMMERCIAL INSURANCE PAY FOR THESE. BUT THESE E FEES CAN BE A PROBLEM FOR PATIENTS WITH NO INSURANCE OR INADEQUATE INSURANCE. LACK OF PRIMARY CARE PROVIDERS SOMEONE ALLUDED TO ALREADY, WHICH IS NOT UNCOMMON FOR UNINSURED PEOPLE. LACK OF PCP WHO MAKE REFERRAL FOR ANTIBODY TREATMENT IS ANOTHER POTENTIAL BARRIER. THE PERSON SEE THEM IN FOLLOW-UP LACK OF P PCP IN FOLLOW-UP BUT JUST MAKE REFERRAL. MANY PATIENTS AND PROVIDERS, ESPECIALLY THOSE OUTSIDE ACADEMIC CENTERS, SOME PEOPLE LOWER INCOME GET THEIR CARE, WHAT WOULD FACILITATE MORE EQUITABLE DISTRIBUTION OF THIS THERAPY? IM INJECTIONS SUB Q IN A MANAGEABLE VOLUME AND COVID TESTING SO CLINICIANS CAN ACT QUICKLY TO GIVE THE THERAPY RIGHT AWAY. PEOPLE DON'T HAVE TO TRAVEL TO GET EDUCATED. EDUCATING NOT ONLY THE COMMUNITY HEALTHCARE PROVIDERS BUT AS DR. KORLEY POINTED OUT, EDUCATING PEOPLE IN THE COMMUNITY ABOUT UTILITY OF THIS TREATMENT SO THEY KNOW TO ADVOCATE FOR THEMSELVES. EVERYBODY KNOWS THAT VACCINES NOW WHICH IS A GOOD THING BUT PEOPLE ARE MUCH LESS AWARE OF MONOCLONAL ANTIBODIESES. ANOTHER THING IS MAKING SURE REFERRAL NETWORKS AND PARTNERSHIPS ARE IN PLACE TO FACILITATE PATIENTS GETTING TREATED WHEN THEY DON'T HAVE PCP. KATIE MENTIONED IN HER EXCELLENT REVIEW. FINALLY, I CAN'T -- I HAVE TO -- ALWAYS EMPHASIZE, HEALTHCARE COVERAGE IS ESSENTIAL. AND GOING TO BE MORE ESSENTIAL AFTER THEY ARE FDA APPROVED AND THERE IS A CHARGE FOR DRUGS THEMSELVES AS WELL AS FACILITY FEES. I WILL STOP THERE. >> THANK YOU FOR THAT. MAYBE I WILL BRING DR. MEAGAN O'BRIEN IN THE CONVERSATION AROUND THIS ASPECT OF DELIVERY. DEVIN RECENT WILL I HAVE A REVISION TO THE EUA AS ALTERNATIVE MEANS OF DELIVERY USE SUBCUTANEOUS INJECTION. I WOULD LIKE TO HEAR YOUR THOUGHTS ON WHAT THE DATA THAT WENT TO THAT UA AND HOW MUCH YOU CAN SHARE YOU MAY NOT BE ABLE TO SHARE ALL AND HOW YOU THINK THAT MIGHT IMPLEMENT EVERYBODY BUT PARTICULARLY PEOPLE NOT HAVING GOOD ACCESS IN THE PAST. >> I'M MEAGAN O'BRIEN INFECTIOUS DISEASE AND SENIOR MEDICAL DIRECTOR AT REGENERON, CLINICAL LEAD OF PREVENTION TRIAL SO IN TERMS OF THE JUNE 4 EUA, AUTHORIZATION TO INCLUDE SUBCUTANEOUS ADMINISTRATION IF THE IV CAN'T BE GIVEN IN A FEASIBLE WAY FOR EARLY TREATMENT, THIS DECISION WAS BASED ON DATA FROM COUPLE OF STUDIES. ONE WAS A DOSE FINDING STUDY SO WE DID A STUDY IN EARLY TREATMENT OUTPATIENTS AND WE DID MANY IVM SUB KUDOSES AND WE LOOK IN THE NASO FIRST FOR RTQPCR LEVELS OF VIRUS. COMPARING DIFFERENT ADMINISTRATION ROUTES AND DOSES YOU ARE ABLE TO SEE ACROSS EVERY DOSE TESTED THAT WE HAD SIMILAR VIRAL CLEARANCE. SO THAT WAS PRIMARILY WHAT THE DECISION WAS BASED ON AND THAT PAPER IS NEARLY DONE AND SHOULD BE AVAILABLE SOON. WE ARE TRYING TO GET PAPERS OUT ALSO WITH THROUGH PREPRINTS SO EVERYBODY SEE THE DATA BECAUSE THAT IS A LIMITATION PHYSICIANS WANT TO SEE EVIDENCE HEALTHCARE PROVIDERS WANT TO SEE EVIDENCE SO THAT WAS -- I THINK THAT IS WHAT FDA BASED THEIR DECISION ON. WE ALSO HAVE, AVAILABLE TODAY, IN A PRE-PRINT THROUGH MEDRX IN PREVENTION STUDY MIKE COHEN DISCUSSED THATLY RAN WITH US AS WELL AS KATIE BAR, WE WERE ON A TEAM FOR THIS STUDY. WE ENROLLED PARTICIPANTS ASYMPTOMATIC AND WE DID THE NASO PHARYNGEAL SWAB AT BASELINE. THERE WERE A COUPLE OF HUNDRED INFECTED. BUT ASYMPTOMATIC. WE LOOK TO SEE IF WE CAN PREVENT SYMPTOMATIC INFECTION IF GIVEN REGEN COV. WE SAW THE YOU CAN SUBCUTANEOUS ADMINISTRATION OF DRUG PREVENTED PROGRESSION TO SYMPTOMATIC INNEXT AND REDUCE DURATION OF SYMPTOMS. AND REDUCE THE VIRAL LOAD AND WHEN WE LOOK SIDE BY SIDE OF PATIENTS IN OUTPATIENT STUDY WHICH THE EUA IS APPROVED WITH THESE PATIENTS, BOTH IV ADMINISTRATION AND OUTPATIENT STUDY AND SUBCUTANEOUS IN THIS STUDY, THE NUMBERS LOOK SIMILAR IN TERMS OF REDUCING DURATION OF SYMPTOMS AND REDUCING THE VIRAL LOAD. THAT DATA AGAIN IS AVAILABLE PUBLICLY TODAY. THIS IS SORT OF THE BODY OF EVIDENCE ENCOURAGING US THE SUB Q FORMULATION CAN BE REALLY USEFUL, THE LAST POINT IS THAT WHEN YOU GIVE SUB Q MEDICATION YOU THINK THE CMAX IS LATER, YOU ARE NOT GOING TO GET TO LEVELS NEEDED FOR A COUPLE OF DAYS BUT WHAT WE SAW ACTUALLY WAS THAT LEVELS NEEDED TORR NEUTRALIZATION TARGET TISSUES ARE ACHIEVED ONE DAY 24 HOURS AFTER DOSING SO THE DRUG IS ON BOARDS QUITE QUICK AT LEVELS WE THINK ARE NEEDED. THAT IS SUPPORTED BY CLINICAL DATA AND THESE STUDIES. >> FOLLOW-UP WITH QUESTION ABOUT CURRENT INJECTION SUB Q IS 2.5-MILLILITERS FOUR INJECTIONS FOUR DIFFERENT SITES, IS THERE A PROSPECT OF REGENERON OR LILY DECREASING THAT VOLUME TO THE POINT IT IS SINGLE INJECTION THAT MIGHT BE SELF-ADMINISTERED? WHERE DO YOU SEE THAT GOING? MAYBE STARTING WITH DR. O'BRIEN. >> THERE'S LOTS OF OPPORTUNITIES TO IMPROVE WHAT WITH THE WAY WE GIVE NOW BUT WE HAVE BEEN IN A RACE AGAINST TIME TO LOOK FOR EFFICACY FIRST BUT CERTAINLY THERE ARE OPPORTUNITIES TO IMPROVE UPON THE PRESENTATION OF THE ANTIBODIES. ALL THESE DISCUSSIONS ABOUT VARIANTS OF CONCERN AND NEXT GENERATION ANTIBODIES, MAYBE INTERESTING TO THINK ABOUT CO-FORMULATING VERSUS HAVING ANTIBODY SEPARATE SO THAT YOU CAN MIX AND MATCH OR SWAP OR IF YOU DON'T WANT TO COME IN WITH A NEW COMBINATION. SO ALL THESE ARE POSSIBLE, WE ARE JUST COMING IN WITH THE FIRST GENERATION NOW TO FIND EFFICACY BUT FOR SURE, YEAH. >> ONE POINT LILY WAS DOING BAMLIMAMAB, THAT BECAME SETROPIMAB. DO YOU WANT TO TALK ABOUT MORE FACILE DELIVERY SELF-ADMINISTRATION IN THE FUTURE? >> SURE, RAJ. WE RECOGNIZE QUITE EARLY ONE LIMITATION IS THE TIME NEEDED FOR INFUSION. THOUGH WE REDUCED THAT DOWN SIGNIFICANTLY FROM ONE HOUR TO 21 MINUTES TO OUR ANTIBODY COMBINATION, THAT'S STILL NEED HOUR POST INFUSION CHAIR TIME SO WE CONTINUE TO BE QUITE INTERESTED IN ALTERNATIVE ADMINISTRATION AND CONTINUE TO HAVE SUB Q FORMULATION IN CLINICAL PLANS YES. >> JOHN. >> THANKS, RAJ, QUICK COMMENT ABOUT THE REGENCOV FORMULATION THAT IS AVAILABLE IF ONE ORDERS FROM AMERICAN SOURCE UNDER THE DISTRIBUTION PROGRAM, JUST THIS WEEK WE SHIPPED CO-FORMULATED PRODUCT WHICH IS TEN MILLILITER SINGLE VILE OF CO-MINGLED CO-FORMULATED PRODUCT EASIER IN SUBCUTANEOUS ADMINISTRATION. YOU HAVE TO WITHDRAW INTO FOUR SYRINGES AND IT IS EASIER FOR IV ADMINISTRATION. >> MICROPHONE COMMENT AND UNMUTE YOURSELF ON THE FEDERAL GOVERNMENT ROLE IN THE DISTRIBUTION. OBVIOUSLY (INAUDIBLE) INITIALLY BUT MY UNDERSTANDING IS IT WON'T BE DISTRIBUTED BY FEDERAL GOVERNMENT. WE HAVE ONE MORE -- TWO MORE BIG TOPICS TO GET TO. WHAT IS IS THE ROLE OF FEDERAL GOVERNMENT AND WHAT WHERE WILL IT BE GOING FORWARD? >> SO THE FEDERAL GOVERNMENT WAS RESPONSIBLE FOR WE PROCURED BOTH INITIALLY (INAUDIBLE) THEN OF COURSE WE ALSO PROCURED REGENCOV. WE HAVE NOT PROCURED SITROVIMAB. FOR THE PRODUCTS PROCURED BY FEDERAL GOVERNMENT THERE IS AN ETHICAL OBLIGATION FOR US TO ENSURE TO THE GREATEST DEGREE POSSIBLE THEY ARE AVAILABLE TO EVERYONE IN THE UNITED STATES. THEN SUBSEQUENTLY SHARED THEM GLOBALLY. BUT IT IS CRITICAL FOR US TO DO IT ETHICALLY AND I WILL SAY I DON'T WANT -- I WANT TO SAY THE PRINCIPLES THAT WE PROMULGATED UNDER CONDITIONS OF SCARCITY, THAT IS THE REAL CRUX OF THE ETHICAL ISSUE IS WHAT THE LEVEL OF AVAILABLE PRODUCT IS RELATIVE TO DEMAND. SO UNDER CONDITIONS OF SCARCITY WHICH THANKFULLY DON'T EXIST IN THE UNITED STATES AT THE MOMENT, I WILL APPEARANCE NETICALLY A SITE THAT WISHES TO ADMINISTER EITHER PRODUCTS, SIMPLY HAS TO CALL OR CAN EMAIL COVID-19 THERAPEUTIC AT HHS.GOV AND PRODUCTS ARE AVAILABLE FREE OF CHARGE. BUT THAT WAS NOT THE CASE WHEN EUA FIRST CAME OUT. THEY WERE IN SHORT SUPPLY INITIALLY BY DEFINITION AND SUBSEQUENTLY UNFORTUNATELY WE SAW THE BIG INCREASE IN CASES IN THE UNITED STATES AROUND TURN OF THE NEW YEAR. RECEIVE TWO PRINCIPLES WE INSIST UPON ARE GEOGRAPHIC EQUITY REFERRING TO THE FACT THAT NO ONE IN THE COUNTRY SHOULD BE MORE OR LESS LIKELY OR LESS AVAILABLE TO THAT PERSON BASED SIMPLY UPON WHERE HE OR SHE LIVES. SECONDLY, THE STICKIER ISSUE IN CONDITIONS OF SCARCITY IS CALLED TEMPORAL EQUITY. WHAT THAT REFERS TO IS IF YOU LOOK SAY FIRST WEEK OF DECEMBER WHEN FIRST TRYING TO GET PRODUCTS OUT AGGRESSIVELY, WE KNEW OF COURSE THAT EVEN IF WE WERE TO USE EVERYTHING% WEEK OF DECEMBER THERE WERE STILL MANY, MANY, PAS WHO WERE SUBSEQUENTLY GOING TO GET IT. SOMEONE WITH WITH COVID-19 TODAY HAS NEITHER NOER OR LESS EQUITABLE -- NOR LESS EQUITABLE -- WHAT IS WORD, NO MORE LESS WORTH IN TERMS OF GETTING THIS PRODUCT ON BEHALF OF PAUL OF US. SO WE HAVE GOT A PLAN FLOWER AND WE HAVE A PLAN FOR LATER AND IT IS VERY, VERY COMPLICATED UNDER CONDITIONS OF SCARCITY. THERE ARE LOTS OF ISSUES BUT WE WANT TO GO ON. THANKS, RAJ. >> THANK YOU. WE'LL TURN OTHER CRITICAL ISSUE, DOING REAL TIME VARIANT SURVEILLANCE AND APPLY TO CARE OF INDIVIDUAL PATIENT. SO DR. FRED KORLEY, IF YOU CAN COMMENT YOUR THOUGHTS ON IS THERE TIME TO HAVE RAPID TEST TO DO A DIAGNOSTIC TEST AND KNOW WHAT VARIANT IS WHAT IS SERO LOGIC STATUS IS AND GIVE RIGHT ANTIBODY OR WHERE WE BE WITH THAT? KIND OF A PERSONALIZED APPROACH. >> I HOPE THAT THAT IS WHAT WE CAN BE IN NEAR FUTURE. BECAUSE AS WE HAVE HEARD FROM ALL THE LECTURERS THROUGHOUT THE DAY, IT IS IMPORTANT TO MAKE SURE WE ARE GIVING THE RIGHT ANTIBODY TREATMENT TO THE RIGHT PATIENT AT THE RIGHT TIME. WHO IS THE RIGHT PATIENT. PEOPLE WHO DO NOT HAVE THE OWN ANTIBODY LEVELS. WHAT ARE THE RIGHT ANTIBODY TEST, TESTS AND HOW QUICKLY CAN WE HAVE TURN AROUND. IF WE CAN HAVE GOLD STANDARD ANTRALLIZATION TEST, THERE ARE OTHER MARKERS STRONGLY CORRELATED WITH ANTIBODY LEVELS LIKE INFLAMMATORY TESTS FOR EXAMPLE, WHICH CAN BE A VERY GOOD SURROGATE WHETHER A PATIENT IS EARLY IN COURSE OF DISEASE OR NOT. AS WE LEARN MORE ABOUT IMPORTANCE OF VARIANTS BEING ABLE TO DO RAPID POINT OF CARE TEST TO UNDERSTAND VARIANT TO MAKE SURE YOU ARE GIVEN THE RIGHT MONOCLONAL ANTIBODY, NOT ALL ARE THE SAME. SO MAKING SURE WE TARGETING THE RIGHT PEOPLE IS WHAT WE NEED TO STRIVE FOR. >> LOUD AND CLEAR. IF WE CAN JOIN TESTING WITH TREATMENT AND IF WE COULD CON JOIN TESTING WITH PRECISION TESTING, WE WOULD BE IN A MUCH BETTER PLACE. SO THERE ARE NUMBER OF UNMET NEEDS. PEOPLE TALK HOWEVER WE COME AND THERE IS STILL WAYS TO GO TO GET THAT RIGHT ANTIBODY TO THE RIGHT PATIENT AT THE RIGHT TIME. >> IT IS GETTING TO BE A LITTLE STRETCH THOUGH, IF WE HAVE TO TEST FOR RESISTANCE BEFORE WE CAN GIVE THESE AGENT, WE DO NEED BETTER THERAPIES. EASY TO GIVE. AS INITIAL RESPONSE TO PANDEMIC THESE CAN BE DEVELOPED QUICKLY, I WORRY IF WE HAVE TO DO WE SHOULD DO SURVEILLANCE ABSOLUTELY BUT IF WE HAVE TO INDIVIDUALLY TEST PEOPLE FOR VARIANTS BEFORE WE CAN GET ANTIBODY IT WILL GET HARD. WE HAVE TO MAKE CRITICAL LINKAGE BETWEEN TESTING TREATMENT IN THE SAME LOCATION AT THE SAME TIME. >> UNLESS THERE IS A TEST TO GIVE POSITIVE SARS COV-2 AND VARIANT AND MULTIPLE -- THE SAME DAY AND ASSAY, BUT I HEAR WHAT YOU ARE SAYING. BEFORE WE ASK FOR FUTURE OF ANTIBODY, YOU ARE GETTING TO THE FUTURE OF ANTIBODY QUESTION, THE KEY POPULATION THAT I THINK WITH ARE ALL MOST WORRIED IN THE UNITED STATES AT LEAST IS IMMUNOSUPPRESSED PATIENTS. ONE QUESTION TO THROW TO THE GROUP, DR. O'BRIEN TO COMMENT ON, PREVENTION AND TREATMENT OF IMMUNOCOMPROMISED PATIENT WHOSE MAY NOT HAVE RESPONDED TO THE VACCINE. DO WE NEED TO DO A TRIAL? OR ONCE AUTHORIZED CAN WE OR ONCE APPROVED CAN WE USE THEM OFF LABEL? NOT PERHAPS ENOUGH CASES OF THESE TO DO A CLINICAL TRIAL HOW ARE WE GOING TO USE ANTIBODIES TO PREVENT COVID AND ALSO TREAT FEW PEOPLE BUT IMPORTANT PEOPLE WHO DEVELOP COVID AFTER VACCINE AND IMMUNOCOMPROMISE. I WILL THROW TO THE GROUP STARTING WITH DR. O'BRIEN. >> THE REGEN COV COMBINATION IS EFFECTIVE AGAINST VARIANTS OF CONCERNS THAT ARE CIRCULATING TO DATE. WE HAVE BEEN ADVOCATES FOR USING COMBINATION THERAPY TO PROTECT AGAINST RESISTANCE. SO USING THAT COMBINATION IN A COMPASSIONATE USE PROGRAM HAS TAUGHT A FEW THINGS. I DON'T KNOW IF EVERYBODY IS AWARE BUT CURRENTLY UNDER THE EMERGENCY USE AUTHORIZATION, ACROSS AVAILABLE ANTIBODIES FOR OUTPATIENT TREATMENT THERE IS RESTRICTION TO HAVE HAD INFECTION FOR TEN DAYS. SO PROLONGED INFECTION VIRAL SHEDDING YOU ARE OUTSIDE OF THAT. SO WE HAD PATIENTS REFERRED TO US THROUGH OUR COMPASSIONATE USE PROGRAM WHO NEED TREATMENT AND IT IS OUTSIDE OF THE DEFINITION OF THE EUA. WE HAVE TREATED OVER 150 PATIENTS AND OVER HALF HAVE SEVERE IMMUNOCOMPROMISED TRANSPLANT ON IMMUNOSUPPRESSION, HEMATOLOGIC MALIGNANCIES ON B CELL DEPLETING AGENTS, PRIMARY IMMUNODEFICIENCIES. ON AVERAGE THEY HAD A DIAGNOSIS OF COVID-19 MORE THAN A MONTHS MANY TIMES MONTHS OF ILLNESS. SO WE HAVE BEEN LOOK AT THE DATA ON THESE PATIENTS, ANOTHER PAPER COMING OUT SOON AND ONCE THEY GET TREATED, IN THOSE WITH VIRAL LOAD DATA, THIS IS NOT THROUGH CLINICAL TRIAL THEIR VIRAL LOAD REDUCTIONS LOOK SIMILAR SIMILAR TO THOSE IN OUTPATIENT TREATMENT TRIAL. THEIR SYMPTOMS GET BETTER. SO FOR VAST MAJORITY THEIR SYMPTOMS GET BETTER. THIS IS NOT A CLINICAL TRIAL SO IT IS -- YOU HAVE TO WEIGHT THE EVIDENCE THAT WAY. THAT IS ENCOURAGING TO US. WE DON'T HAVE MANY TRULY IMMUNOCOMPROMISED PARTICIPANTS IN OUR CLINICAL TRIALS, THAT IS HARDER QUESTION BUT THE ANTIBODIES NEUTRALIZE THE VIRUS, THE VIRAL TITERS COME DOWN BUT THERE IS EVIDENCE TO SUPPORT THIS IS GOOD STRATEGY FOR TREATMENT. SIMILARLY FOR PREVENTION, WE ADVOCATE FOR VACCINES OF COURSE BUT THOSE WHO DO NOT HAVE GOOD RESPONSE, ON CHEMOTHERAPIES, B CELL DEFICIENCY, THESE PATIENTS MAY BENEFIT FROM PREVENTION WITH ANTIBODIES SO WE ARE IN DISCUSSION WITH THE FDA, NOT ONLY FOR ACUTE PREVENTION POST EXPOSURE PROPHYLAXIS SIMILAR TO HOUSEHOLD STUDY WE DID, BUT ALSO FOR CHRONIC PREVENTION, WE HAVE DONE A MULTIPLE DOSE STUDY FOR SAFETY, AND WE HAD PATIENTS RESPONSIBILITY. LASTLY COMPASSIONATE USE PROGRAM WE HAVE OPENED UP TO PREVENTION. FOR IMMUNOCOMPROMISED PATIENTS. WE KNOW THIS IS UNMET NEED AS DISCUSSIONS ARE ONGOING. >> WE ARE BEING ASKED TO WRAP UP BECAUSE OF THE TIME CONSTRAINTS. THIS WAS A RICH SESSION. A LOT REAL WORLD THAT COMES TO THE FLOOR SO THANK YOU FOR THAT. ANY LAST COMMENTS FUTURE. WHERE DO YOU THINK LILY IS GOING WITH ANTIBODIES. THIS IS AN ISSUE WE CAN'T LOSE SITE OF, THE PANDEMIC IS RAGING SO WE NEED ORAL THERAPIES TO BE HONEST BUT WE NEED -- YOU WANT TO GET THE LAST WORD WHERE LILY IS GOING FUTURE, THAT WILL BE THE LAST QUESTION. >> WE HAVE A PARTNERSHIP WITH GSK TO LOOK AT COMBINATION OF ANTIBODIES INCLUDING OUR OWN SECOND GENERATION ANTIBODY WHICH WE BELIEVE IS BROADLY NEUTRALIZING AND WE ARE PLANNING FOR FUTURE IN OUS WHERE SOME OF THOSE PROBLEMS WITH THESE VARIANTS OF CONCERN MAY GO ON FOR YEARS. SO CONTINUE TO WORK SECOND GENERATION ANTIBODIES AND EASE OF ADMINISTRATION. CONTINUE TO FOCUS. >> I WANT TO THANK THE PANELISTS FOR A ROBUST DISCUSSION, WE KEPT IT MOVING AT A PRETTY QUICK PACE SO THANK YOU FOR THAT. I'M GOING TO TURN THINGS BACK TO CAESAR. SAY A SINCERE THANK YOU TO ALL OF YOU. >> THANK YOU, EVERYONE. FROM SESSION THREE FOR THE REPRESENTATION AND THIS ANIMATED PANEL DISCUSSION. I WOULD LIKE TO NOW INVITE BACK DR. MCDERMOTT AND DR. SCHMALJOHN TO JOIN DR. GANDHI TO PROVIDE A BRIEF CLOSING REMARKS FROM THE RESPECTIVE SESSIONS. DR. COLLINS SENDS HIS REGRETS HE IS UNABLE TO JOIN THE CLOSING SESSION DUE TO UNEXPECTED COMMITMENT. >> ALL RIGHT. I WILL KICK OFF AND I WILL SPEAK REALLY SLOWLY SO RAJ HAS SOME TIME TO GET HIS NOTES TOGETHER. SO IN OUR SESSION WE HAVE AN EXCELLENT PRESENTATION ABOUT THE COVID COLLABORATION WHICH IS ACCORDING TO GROUP PERFORMING ESSENTIALLY ORTHOGONAL ASSAYS IN HEAD TO HEAD COMPARISON, OF MANY, MANY DIFFERENT MONOCLONAL ANTIBODIES DERIVED FROM ACADEMIA AND COMMERCIAL SOURCES, GOOD TO TO SEE THOSE WERE NOT JUST U.S. BUT GLOBAL. ALL THIS WAS DONE IN A VERY CLEVER BLINDED FASHION IN ORDER TO KEEP THE ANONYMITY OF EACH OF THE ANTIBODIES. THE CONSORTIUM PERFORMS COMPETITION ANALYSES THAT REVEALED GROUPS OF REACTIVITIES OR COMMUNITIES WHICH ARE CONFIRMED BY NEGATIVE STAIN EM HEADACHE CHOOSE COCKTAILS OF ANTIBODIES BASED ON FUNCTIONAL SPATIAL CHARACTERISTICS SO THEN WE GOT AROUND TO HAVING A DISCUSSION AND WE DIDN'T GET AROUND TO NEUTRALIZATION ASSAY SO MUCH SO SOME OF THE PARTICIPANTS WERE DID NOT FIGURE GREATLY IN DISCUSSION. MOTIVATED BY ERICA REECE TALK WE DISCUSSED FOUR COCKTAILS. AS CHRIS BONDS HAS ACTUALLY WRITTEN THE PAPER ON CLASSIFICATION AS WELL AS IAN WILSON, HE KICKED OFF AND HE EXPANDED UPON THIS SELECTION OF ANTIBODIES WHICH DEMONSTRATE GROUPS SUCH AS ONES THAT CROSS LINK. THESE REFER TO BY ERICA AS THE RBD 5 ANTIBODIES, THAT DON'T ACTUALLY DEMONSTRATE ACE 2 COMPETITION BUT AFFORD GOD PROTECTION. SO -- GOOD PROTECTION. THIS BRINGS OUT THE WHOLE CONCEPT OF NEUTRALIZATION VERSUS FC MEDIATED IMMUNITY. AND DR. MIKE DIAMOND GAVE US A VERY NICE PRAISING OF HIS WORDS, HE'S BEEN DOING IN MICE AND HAMSTERS, LOOKING AT ANTIBODIES AND THEIR CHARACTERISTICS. HE ALSO SAID FC FUNCTIONS IF YOU WILL REMEMBER OUR TEXT BOOKS ALSO INCLUDE COMPLIMENT MEDIATED IMMUNITY. WE WENT ON AND DISCUSSED WITH DR. WALKER AND DR. BISPECIFIC ANTIBODIES AND MUTATIONS TO ENGENDER A LONGER HALF LIFE AND DR. -- BY SPECIFIC ANTIBODIES SHE'S BEEN DEVELOPING MAY OR MAY NOT HAVE SYNERGISTIC EFFECTS. THERE ARE OTHER THINGS BUT I WILL MOVE ON. THANK YOU VERY MUCH FOR THE PANEL, THANK YOU, VERY MUCH FOR THE ORGANIZERS TODAY. WELL DONE CESAR AND HIS TEAM, GREAT MEETING. THANK YOU. >> THANK YOU SO MUCH, DR. SCHMALJOHN, SESSION 2. >> I WON'T BE AS NICE THE TALK. I WILL TALK FAST. I THINK THAT WHAT WE LEARNED IN OUR SESSION FOCUSED ON ANIMAL MODELS AND PREDICTIVE ASSAYS IS WE KNOW A LOT MORE THAN WE DID TEN MONTHS AGO LAST TIME THIS WAS HELD. WE STILL DON'T KNOW EVERYTHING, HAVE A LONG WAY TO GO. SOME OF THE IMPORTANT TAKE HOME MESSAGES WE HEARD FROM OUR MAIN SPEAKER RALPH BACRIC, HE SAID A LOT OF THINGS I PICKED OUT A COUPLE. ONE THING HE MENTIONED IS THAT BY TARGETING CONSERVED REGIONS OF CAR B CORONA VIRUSES WE CAN PROVIDE CROSS PROTECTIVE CROSS CROSS REACTIVE AND SOMETIMES CROSS PROTECTIVE IMMUNITY TO RELATED CORONA VIRUSES WHICH IS GOING TO BE IMPORTANT NOT ONLY FOR THE VARIANTS EMERGING NOW BUT FOR FUTURE PANDEMIC PREPAREDNESS. HE ALSO SHOWED REALLY INTERESTING STUDIES FROM COLLABORATIVE CROSS MICE IN WHICH THEY WERE ABLE TO SHOW THAT VIRULENCE IN THIS MODEL IS A MULTI-GENE TRAIT. THAT IS JUST NOW BEING CORRELATED BACK TO HUMANS WHICH SHOULD BE REALLY INTERESTING AS THIS CORRELATION GOES FORWARD. DR. DE WIT TALKED ABOUT ANIMAL MODELS AND PREDICTIONS AND SAID NEUTRALIZING ANTIBODIES ARE STILL PROBABLY THE MOST IMPORTANT PREDICTOR FROM ANIMAL MODELS OF PROTECTIVE IMMUNITY BUT OF COURSE T-CELLS ARE RECOGNIZED AS BEING IMPORTANT AS WELL. DR. VIRGIN AS WELL AS SOME OF THE OTHER PANELISTS INDICATED THE FC RECEPTOR ANTIBODY IS VERY IMPORTANT. AND THAT STUDIES ARE UNDERWAY TO ENGINEER FC FOR BETTER FUNCTION. ANTIBODY EFFICACY IS A DOCUMENT BY NATION OF -- COMBINATION OF NEUTRALIZING AND EFFECTOR FUNCTIONS. DR. VIRGIN AND DE WIT BOTH SAID IT IS IMPORTANT TO CONTINUE DEVELOPING ANIMAL MODELS THAT REFLECT VULNERABILITIES WE SEE IN HUMANS IN PARTICULAR CO-MORBIDITIES, AND MODELS FOR SEQUELAE TO IMPROVE LONG COVID AND NEUROLOGICAL COMPLICATIONS SO SIMPLY DON'T EXIST NOW. KEVIN SAUNDERS TOLD US ABOUT PREDICTIVE ASSAYS FOR PROTECTION. THEY HAVE SEEN IN VRC THEY STILL BELIEVE LIKE IN ANIMAL MODELS THAT NEUTRAL NEUTRALIZING RESPONSES ARE AN IMPORTANT PREDICT TORR FOR ASSAYS AND THEY FOUND PSEUDOVIRUS AND LIVE VIRUS AS IS GENERALLY CORRELATED, HOWEVER IT IS NOT AN ABSOLUTE CORRELATION. IF YOU ARE GOING TO TRY TO DO ASSAY TO ASSAY CORRELATION YOU NEED TO CONTINUE USING SOME OF THE WELL CHARACTERIZED STANDARD PANELS THAT HAVE BEEN RECENTLY DEVELOPED AND DISTRIBUTED. WE HAD A TALK IN A DONE OF SLIDES FROM TOM ABOUT BIODISTRIBUTION OF ANTIBODY WHERE THEY GO IN TISSUE AND CORRELATED THIS WITH SITES OF INFECTION. THIS MIGHT SHED LIGHT ON WAYS THAT WE WOULD BE ABLE TO DO TARGETED ANTIBODY THERAPY TO WHERE IT IS NEEDED IN SITES OF INFECTION. THEN FROM A REGULATORY PERSPECTIVE DR. ELLIS TOLD US WHAT SORT OF INFORMATION THE AGENCY IS GOING TO BE LOOKING FOR IN ORDER TO APPROVE ANTIBODY THERAPEUTICS GOING FORWARD. AND THEN BACK TO DR. BARIC'S TALK FOR MODELING, WE NEED TO CONTINUE MODELING, WITH ENNEAD IN PARTICULAR HE MENTIONED A MODEL THAT WILL EXTEND THE THERAPEUTIC WINDOW SO WE CAN GET A GOOD LOOK AT ANTIBODIES AS THERAPIES NOT JUST AS PROPHYLACTICS. THAT IS WHAT I HAVE GOT. THANK YOU. >> THANK YOU SO MUCH. THE LAST SESSION KICKED OFF BY TALKING ABOUT CHALLENGES RELATED TO SETTING UP INFRASTRUCTURE FOR CLINICAL TRIALS ANTIBODIES WITH OUTPATIENT. SHE STRESSED A COUPLE OF THINGS LIKE WHERE YOU DO AT THE SITES, THE ISSUES AROUND STAFFING, HAVING PROPER VENTILATION, NUMBER OF ISSUES THAT RELATED TO THAT. ONE THING THAT I TOOK FROM THAT PART OF THE DISCUSSION WAS THE IMPORTANCE OF LINKING TESTING AND TREATMENT THAT IS IF YOU TEST IN BUN PLACE AND TREAT IN ANOTHER, THEN YOU INTRODUCE A GAP THAT CAN LEAD TO FALL OFF IN TERMS OF CLINICAL TRIALS ENROLLMENT AND THEN DELAY GETTING IMPORTANT ANSWERS. MARK WILLIAMS FROM LILY COMMENTED ON LOCATIONS, THINGS LIKE HOME INFUSION AND THEN PUTTING THE LOCATION OF YOUR CLINICAL TRIAL IN THE COMMUNITIES THAT ARE HARDEST HIT. IF YOU HAVE TRIALS IN A PLACE DISTANCED FROM THE HARDEST HIT COMMUNITIES IS INEQUITABLE BUT NOT GOOD FOR CLINICAL TRIALS. THERE IS DISCUSSION AROUND IMPLEMENTATION AND IMPORTANCE OF MESSAGING. MESSAGES FOR PATIENTS, SO THEY UNDERSTAND THE BENEFITS OF THESE ANTIBODIES BUT MOST IMPORTANTLY ALSO MESSAGING CLINICIANS SINCE PATIENTS TRUST THEIR CLINICIANS BOTH NEED TO BE PART OF EQUATION WHEN IT COMES TO IMPLEMENTING ANTIBODIES. DR. ADA AD MORE -- OHIO ADIMORA AROUND ISSUES OF MESSAGING AND INFORMATION. MAKE SURE THEY HAVE A REFERRAL MECHANISM TO GET INTO AUTHORIZED ANTIBODIES LOCATION SO IF THEY DON'T HAVE A PRIMARY CARE PHYSICIAN THAT CREATES A BARRIER TO EQUITABLE DISTRIBUTION OF ANTIBODIES AND THEY DON'T HAVE ACCESS TO CARE THAT TOO INTRODUCES AN EQUITY ISSUE. SO THOSE ARE SOME OF THE THINGS WE NEED TO THINK ABOUT AS WE MAKE SURE THESE ARE EQUITABLY DISTRIBUTED. DR. MEAGAN O'BRIEN REJOAN RON TALKED ADMINISTRATION OF ANTIBODIES AND HOW SUBCUTANEOUS DELIVERY HAS NOW BEEN INCLUDED AS ALTERNATIVE TO IV BUT NOT FAVORED ALTERNATIVE BUT YET BECAUSE DATA IS NOT QUITE AS ROBUST AS INTRAVENOUS ADMINISTRATION, IS WILL A WAY TO SELF ADMINISTRATION, THAT IS WHERE I THINK ANTIBODIES WOULD BE MOST EASILY IMPLEMENTED, HAVE SMALLER VOLUMES SELF-ADMINISTERED NOT THERE YET BUT REGENERON AND LILY MENTIONED THEY ARE WORKING ON IT. JOHN REDD TALKED ROLE OF THE FEDERAL GOVERNMENT IN ANTIBODY DISTRIBUTION AND REALLY THE GOAL WILL IS TO MAKE SURE THAT THERE IS EQUITABLE DISTRIBUTION ACROSS THE COUNTRY. THAT PEOPLE DON'T GET DENIED ANTIBODIES AROUND SCARCITY. JUST BECAUSE OF WHERE THEY LIVE AND WHEN THE ANTIBODIES -- WHEN THE NEED ARISES. THEN THE LAST COUPLE OF THEMES CAN WE DEVELOP A RAPID TEST THAT GUIDE TREATMENT, DR. DOORLY TALKED ABOUT THE RIGHT -- KORLEY TALKED ABOUT THE RIGHT ANTIBODY AT THE RIGHT PATIENT AT THE RIGHT TIME AND INTEGRATE VARIANT SPECIFIC ASSAY INTO STANDARDS SARS COV-2 ASSAY. NEAR THE END WE TALKED REALLY VULNERABLE POPULATIONS LIKE IMMUNOCOMPROMISED PATIENTS, DR. O'BRIEN MENTIONED COMPASSIONATE USE OF ANTIBODIES WITH TREATMENT, LOOKING FORWARD TO SEEING THE DATA ON ABOUT 150 PEOPLE WHO ARE IMMUNOCOMPROMISED AND WHOM COMPASSIONATE USE ANTIBODIES WERE GIVEN AND ALSO PREVENTION. THAT IS WHAT WE ARE LOOKING TO AS YOU HAVE A PATIENT WHO IS IMMUNOCOMPROMISED MAY NOT HAVE RESPONDED TO THE VACCINE. WITH PASSIVE IMMUNIZATION HAVE A ROLE IN PREVENTING COVID. THE FUTURE OF ANTIBODY DEVELOPMENT GLOBAL EQUITY IS THE MAJOR THEME THERE, THIS PANDEMIC RAGES AROUND THE WORLD STILL, THEN HAVING BROAD SPECTRUM ANTIBODIES THAT DEAL WITH SOME OF THESE VARIANTS OF CONCERN NOW AND ONES WE MIGHT HAVE IN THE FUTURE. THAT IS THE REAL WORLD SESSION. I WILL CONCLUDE. >> THANK YOU VERY MUCH. THANK YOU FOR THE THREE OF YOU FOR BEING AMAZING, MODERATORS, TO SHARING THE TAKE HOME MESSAGES FROM EACH OF TODAY'S SESSIONS. THERE HAVE BEEN SIGNIFICANT PROGRESS IN THE SCIENTIFIC FIELD, THE LAST NIH ANTIBODY SUMMIT HELD TEN MONTHS AGO. WE CAN NOW BETTER UNDERSTAND THE STRUCTURE ACTIVITY RELATIONSHIP OF THE ANTIBODIES, THE EPITOPES THEY TARGET, HOW TO COMBINE THEM, HOW TO INTEGRATE BETTER, IN VITRO ASSAY WITH THE ANIMAL STUDIES SO INFORM CLINICAL TRIAL DESIGN, AND HOW RAPIDLY TEST IN EFFECTIVE CLINICAL TRIALS AND THEIR VERY CHALLENGING CIRCUMSTANCES. WE CONTINUE MONITORING STUDYING AND LEARNING THE IMPACT OF EMERGING VARIANTS OF CONCERN ON THE ACTIVITY OF THE ANTIBODY TO MAXIMIZE SUCCESS OF PREVENTION AND THERAPEUTIC STRATEGIES. WE HEAR ALSO TODAY KEY SCIENTIFIC KNOWLEDGE GAPS AND CHALLENGES THAT PREVENT THE BROAD USE AND IMPLEMENTATION OF ANTIBODY INTERVENTION AND MANY OPPORTUNITIES WE HAVE TO FURTHER CATALYZE IMPROVE AND ADVANCE ANTIBODY CLINICAL DEVELOPMENT. IN THE COMING WEEKS THE NIH WILL TAKE INTO CONSIDERATION THE DISCUSSIONS AND KEY SCIENTIFIC QUESTIONS IDENTIFIED AT THIS MEETING AS WE PLAN THE NEXT STEPS IN ADVANCING THE DEVELOPMENT, FOR CLINICAL TESTING AND CLINICAL EVALUATION OF ANTI-SARS COV-2 ANTIBODIES FOR THE TREATMENT AND PREVENTION OF COVID-19. FINALLY ON BEHALF OF THE ORGANIZING COMMITTEE, WE WOULD LIKE TO THANK THE PRESENTER MODERATOR, DISCUSSION PAPER AUTHORS AND PANEL MEMBER WHOSE PARTICIPATED IN THE SUMMIT. WE ALSO WOULD LIKE TO THANK THE SUBJECT MATTER EXPERTS TEAM WHO HELP US SHAPE THE AGENDA. JAMES FOR THE AB SPORT AND TODAY WEBCAST WILL BE ARCHIVED ON THE NIH WEBSITE AND MEETING REPORT WILL BE FROM THIS SUMMIT WILL BE POSTED IN THE NEXT FEW WEEKS. WE ALSO WOULD LIKE TO THANK ALL ATTENDEES THAT PARTICIPATED TODAY THAT I HERE WENT UP TO 800 AT SOME POINT. AND THAT WRAP UP THE MEETING THIS SUMMIT TODAY. SO STAY SAFE AND HAVE A GREAT REST OF YOUR DAY. GOODBYE, EVERYONE.