WELCOME TO A VERY SPECIAL WEDNESDAY NOON LECTURE. THE ANNUAL OPPORTUNITY TO HEAR FROM A DISTINGUISHED SCIENTIST WORKING IN AREAS OF IMMUNOLOGY WHICH WERE THE INCREDIBLE CONTRIBUTIONS OF OUR LONG TERM NIH SCIENTIFIC LEADER BILL PAUL WHO WAS CHIEF OF THE NIAID LABORATORY OF IMMUNOLOGY. IT'S QUITE A WEEK WE'RE HAVING HERE WITH NOBELS BEING ANNOUNCED THIS WEEK. I CAN SAY FOR ONE MOMENT, HOW PLEASED WE WERE ALL MONDAY MORNING AT 5:30 A.M. TO LEARN ONE OF OUR OWN SCIENTISTS, HARVEY ALTER WAS AMONGST THOSE CHOSEN FOR THE NOBEL PRIDE IN MEDICINE AND PHYSIOLOGY FOR THE WORK HE DID ON HEPATITIS C WITH TWO OTHER COLLEAGUES. WE HAD A WONDERFUL DAY WITH HARVEY ON MONDAY PHYSICALLY DISTANCED APPROPRIATELY BUT HOLDING A PRESS CONFERENCE AND SOCIAL MEDIA ACTIVITIES AND REMINDING OURSELVES OF WHAT A WONDERFULLY GENTLE SELF-EFFACING GUY WHO JUST WANTED TO HELP PEOPLE AVOID A HORRIBLE ILLNESS. CONGRATS TO HARVEY AND AGAIN TODAY FINDING OUT AFTER SOME ANTICIPATION OVER THE LAST THREE OR FOUR YEARS THE NOBEL COMMITTEE DECIDED IT WAS TIME FOR CRISPR KAS TO BE RECOGNIZED THAT CHANGED EVERYTHING IN MOLECULAR BIOLOGY AND AWARDED TO TWO WOMEN MAKING IT MORE WONDERFUL BOTH HIGHLY DESERVING OF THE RECOGNITION. IT'S NICE TO HAVE SOME REALLY GOOD WONDERFUL THINGS HAPPENING IN THE MIDST OF WHAT IS ADMITTEDLY A TOUGH YEAR. WE'RE DOING IT VIRTUALLY AND MORE PEOPLE ARE ABLE TO LINK IN AND TAKE ADVANTAGE OF THE SCIENCE WE'RE ABOUT TO HEAR FROM OUR SPEAKER. BEFORE I GET TO INTRODUCE THE SPEAKER THOUGH I WANT TO SAY SOMETHING ABOUT BILL PAUL BECAUSE SOME OF THE NEWER ARRIVALS AT THE NIH MAY NOT KNOW ABOUT THIS LEGENDARY CHARACTER. HE WAS A SHINING ICON AND INTERNATIONAL GIANT IN CONTEMPORARY IMMUNOLOGY. HE HAD AN ENORMOUS IMPACT ON SCIENCE AS WELL AS BEING A TRAINER OF MANY DISTINGUISHED LEADERS WHO HAVE GONE ON TO BECOME QUITE LEGENDARY THEMSELVES IN THE FIELD AND MANY OF WHOM ARE THEMSELVES NOW INVOLVED IN TRYING TO UNRAVEL THE IMMUNOLOGICAL MYSTERIES OF THE COVID-19 PANDEMIC. I'M ALSO HAPPY TO SAY AMONGST THE FOLKS JOINING US REMOTELY, IS BILL'S WIDOW, MARILYN. IT'S GREAT YOU CAN JOIN THE GATHERING. I'M EVER JOYED LOOKING BACK AT YOUR MEMORIES OF BILL WHILE I WAS PREPARING TO DO THE INTRODUCTION AND FOUND EYE SET OF REMARKS -- A SET OF REMARKS YOU PUT IN THE FRONTIERS OF IMMUNOLOGY CONTRIBUTE TO BILL AN ENTIRE SPECIAL ISSUE AND YOU SAID AND I'M QUOTING EVERY DAY HE WENT TO WORK WAS A JOYFUL DAY. EVERY EVENING HE WORKED AT HOME WAS A JOYFUL EVENING. AT THE END OF THE DAY HE SAID HE'D QUIT ONLY WHEN HE REALIZED HE HAD TO READ SOMETHING THREE TIMES. HE TOOK THAT AS A SIGNAL HE WAS TIRED AND SHOULD STOP AND HAVE SOME ICE CREAM. WELL DESERVED ICE CREAM. I'M GOING REMEMBER THAT THE NEXT TIME I REALIZE I HAD TO READ SOMETHING THREE TIMES BECAUSE IT DOES HAPPEN. WHAT A WONDERFUL WAY TO REFLECT ON BILL AND FOR THOSE WHO KNEW HIM, HE RADIATED THAT JOY AND THE EXPERIENCE OF DOING SCIENCE AND LEARNING THINGS ABOUT THE IMMUNE SYSTEM. AND MARILYN IF YOU'RE ABLE TO UNMUTE AND SAY A WORD TO THE ASSEMBLED GROUP IT WOULD BE WONDERFUL TO HEAR YOUR VOICE FOR A MINUTE. ARE YOU THERE? >> THANK YOU FOR THE OPPORTUNITY? AND FOR CONDUCTING THE LECTURE THOUGH IT HAS TO BE VIRTUAL, I'M SURE BILL WOULD HAVE APPROVED OF THAT DECISION. NOW I HAVE A LITTLE SENTENCE I'D LIKE TO ADD. I HOPE IT'S NOT TOO EMBARRASSING BUT I HAVE WONDERFUL MEMORIES OF THE TIME WE WERE LIVING IN NEW YORK AND BILL AND I AND RUTH AND VICTOR WOULD SPEND SOCIAL TIME AND SCIENCE TIME TOGETHER. THOSE WERE WONDERFUL YEARS. THEN I HAVE ANOTHER MEMORY I'D LIKE TO SHARE OF MICHELLE AND MY SON MATTHEW PLAYING BASKETBALL AT A GORDON CONFERENCE AND THESE TWO TEEN AGE BOYS WERE HAVING A LOT OF FUN WHILE THEIR PARENTS WERE DOING SCIENCE AND THIS IS A LONG TIME AGO. WAY BEFORE iPHONES AND CAMERAS SO I DON'T HAVE A PHOTO TO SHARE. BUT I DO HAVE THAT LOVELY IMAGE ETCHED IN MY OWN MIND. THANK YOU FOR LETTING ME SHARE THAT AND THANK YOU AND CONGRATULATIONS ON MICHELLE HONORING BILL THIS AFTERNOON. >> THANK YOU FOR THAT WONDERFUL REFLECTION. I DIDN'T KNOW ABOUT THOSE CONNECTIONS. I'M GLAD YOU WERE ABLE TO SHARE THEM. I KNOW WE'RE 550 PEOPLE ARE WATCHING AND THE NUMBER IS STILL GROWING. BUT IT'S TIME FOR KNOW INTRODUCE THE ACTUAL PRESENTER. MICHEL NUSSENZWEIG OF ROCKEFELLER UNIVERSITY. MAYBE AFTER WHAT WE'VE BEEN THROUGH THIS YEAR WE CAN ALL USE A BIG BOWL OF ICE CREAM AND THIS IS OUR INTELLECTUAL VERSION OF THAT BECAUSE MICHEL WHO IS A GRADUATE STUDENT, WAS ABLE TO IDENTIFY THE DENDRITIC CELLS AND NOW RISING TO THE CHALLENGE OF COVID-19 WHICH IS WHAT HE'S GOING TO TALK TO US ABOUT TODAY, USING A COMBINATION OF BIOCHEMISTRY AND MOLECULAR GENETICS AS A FOG -- ROCKEFELLER PROFESSOR HAS PIONEERED IN ANTIBODY BASED THERAPIES FOR HIV AND HIS TREND IS TREND IS ATTENTION TO WHAT MAY BE DONE FOR SARS COV2 A TOPIC THAT COULDN'T BE MORE TIMELY. THIS MORNING THE LILLY COMPANY RELEASED INFORMATION THEY FEEL THEY HAVE ENOUGH PRELIMINARY DATA ABOUT A MONOCLONAL ANTIBODY DIRECTED AGAINST SARS COV2 THEY INTEND TO GO TO FDA AND ASK FOR EMERGENCY USE AUTHORIZATION. THIS IS STARTING TO WORK. I WANT TO HEAR FROM MICHEL ABOUT THE INS AND OUTS AND HOW WE BRING IT FORWARD TO THE GLOBAL PANDEMIC. WITHOUT FURTHER ADO LET ME ASK YOU VIRTUALLY TO WELCOME OUR SPEAKER FOR THE WILLIAM WALL LECTURE THE HUMAN ANTIBODY RESPONSES TO SARS COV2. >> THANK YOU, FRANCIS. THANK YOU, MARILYN. IT'S REALLY SUCH AN HONOR TO DO THIS. AS MARILYN MENTIONED MY PARENTS AND BILL AND MARILYN WERE CLOSE AT THE ALL TIME THEY WERE WORKING AT NYU AND A GOT TO MEET BILL AT THAT TIME AND EVENTUALLY WHEN I BECAME A SCIENTIST, BILL WAS INCREDIBLY SUPPORTIVE IN SO MANY WAYS AND I GOT INTERACT WITH HIM AT NIH AT THE HOWARD HUGHES AND A BUNCH OF MEETING WHERE BILL WOULD OCCASIONALLY TAKE KNOW DINNER WITH MARILYN SO IT'S A GREAT HONOR TO DO THIS FOR BILL. WHAT I'LL TALK ABOUT TODAY, FIRST, OF IMMUNOLOGY WHICH IS RELEVANT TO UNDERSTANDING HOW PEOPLE RESPOND TO THE CORONAVIRUS. SOMETHING ABOUT HOW WE CAME TO WORK ON THE CORONAVIRUS AND THE EXPERIMENTS. THIS SLIDE SHOWS YOU WHAT I'M GOING TO TALK ABOUT TODAY SO NOT SIMPLY THE WORK OF ONE LABORATORY BUT THE WORK OF DIFFERENT LABORATORIES AND SUPPORTED ENTIRELY OR IN VERY LARGE PART BY THE NIH. AND I SHOULD SAY THAT THAT SUPPORT COMES FROM THE VERY TOP AND MANY COLLEAGUES AT NIH AND I SHOUT-OUT TO MANY WHO HAVE BEEN INVOLVED IN DESIGNING AND HELPING EXECUTE SOME OF THE EXPERIMENTS THE ANIMAL EXPERIMENTS THAT I'M GOING TO TALK ABOUT AT THE END OF THE TALK. SO WITH THAT, LET'S GET STARTED. SO FIRST THING IS WHAT MY LAB HAS BEEN INTERESTED IN FOR A LONG TIME IS THIS PROBLEM THAT OFHERM HERMAN EISEN DISCOVERED IS THERE'S RHYTHMIC INCREASE IN THE AFFINITY OF ANTIBODIES AFTER INFECTION. WE LEARNED A LOT ABOUT HOW THIS HAPPENED. ILLUSTRATED IN PART ON THIS SLIDE. SO THE IMMUNE SYSTEM OF COMPOSED OF CELLS. EACH CELL HAS A UNIQUE RECEPTOR WITH A SPECIFICITY AND WHEN THE IMMUNE SYSTEM IS CHALLENGED BY A VIRUS OR SOME PATHOGEN, CELLS THAT HAVE THE CORRECT RECEPTORS ARE EXPANDED. WHAT HAPPENS IN THE B CELL COMPARTMENT IS THEY DON'T JUST UNDER GO CLONAL EXPANSION THEY ALSO DIVERSIFY THEIR ANTIBODY GENES DURING CLONAL EXPANSION. THIS IS REALLY A STRANGE THING AND THEY DO IT BY MUTATIONS SOMATIC MUTATION SO THE ENZYME AID DISCOVERED BY COLLEAGUES AND ANOTHER GROUP IN FRANCE AT THE SAME TIME GOES INTO THE GENOME AND MAKES SMALL MUTATIONS IN ANTIBODY GENES AND INSTEAD OF A MONOMORPHIC NONO CLONAL EXPANSION YOU GET LIMB POE FOE SIGHT DIFFER -- LYMPHOCYTES AND THERE'S A SELECTION FOR CELLS PRODUCING HIGH ANTIBODIES WHICH IS HOW YOU GET THE AFFINITY MATURATION DISCOVERY BY EISEN AND YOU GET A MISMATCH IN DNA AND THAT MISMATCH IS THEN PROFESSORED TO CREATE SOMATIC -- PROCESSED TO TO CREATE SOMATIC CONVERSIONS AND IT'S DANGEROUS BECAUSE IT CAN CAUSE CHROMOSOME TRANS LOCATION OR MUTATIONS THAT ARE CANCER PRODUCING AND IN FACT MOST THE LYMPHOMAS IN HUMANS COME AS A BYPRODUCT OF THIS MUTATION AND IN FACT THIS IS CRITICAL. AND HERE'S IN THESE EXAMPLES FROM HIV. THESE ARE FOUR DIFFERENT HIV ANTIBODIES. YOU CAN SEE THEIR SPR TRACES AND HAVE AN AFFINITY FOR THE ANTIGEN BUT IF YOU TAKE AWAY THE MUTATIONS THAT GOES AWAY. AND IMPORTANTLY THE ANTIBODIES ARE NEUTRALIZING AND IF YOU TAKE IT AWAY ALL THE NEUTRALIZING ANTIBODIES GOES AWAY THIS REACTION HAPPENS IN SPECIAL STRUCTURES THAT ARE IN EMPLOYED ORGANS CALLED GERMINAL CENTERS A DARK AND LIGHT ZONE. AND WHAT MY COLLEAGUES AND I HAVE DONE OVER THE LAST SEVERAL YEARS IS DEVELOP A MODEL TO TRY TO EXPLAIN HOW THE SELECTION PROCESS WORKS IN THE GERMINAL CENTERS. WHAT WE FOUND AND THIS IS THE WORK OF MANY LABS AND WE HAVE CONTRIBUTED SIGNIFICANTLY TO THIS IS THE DARK ZONE THAT FIRST COMPARTMENT SO WHERE THE LYMPHOCYTES ARE UNDERGOING THE CLONAL EXPANSION AND WHERE THEY'RE MUTATING. THIS STRUCTURE IS DYNAMIC AND CELLS MOVE FROM ONE ZONE TO ANOTHER AND AN ORCHESTRATED SET OF MOVEMENTS ONCE THEY FINISH MIGRATING THEY GO TO THE LIGHT ZONE AND THE LIGHT ZONE WHERE THE PINK STUFF WAS IN THE PREVIOUS SLIDE IS WHERE THE CELLS WITH NEW RECEPTORS THAT HAVE BEEN MUTATED TEST THEIR RECEPTORS ON THE INTI GEN. THEY TEST WEATHHETHER OR NOT THEY CAN STILL POINT AND COMPETE FOR BINDING TO THE ANTIGEN. THE CELLS WITH THE MOST ANTIGEN CAN PRESENT THAT TO CELLS THAT LIVE IN THE LIGHT ZONE AND ONLY THE CELLS THAT HAVE THE BEST RECEPTORS ARE SELECTED BY THE T CELLS ON THE BASIS OF HOW MUCH ANTIGEN THEY PICKED UP AND GO BACK DOWN AND DIVIDE AGAIN AND MUTATE AGAIN AND GO BACK DOWN AND COME BACK UP AGAIN AND REPEAT THE CYCLE. YOU CAN IMAGINE HOW THAT WOULD RAPIDLY LEAD TO THE SELECTION OF CELLS WITH HIGH AFFINITY RECEPTORS. NOW, THERE ARE TWO PRODUCTS OF THIS REACTION AND THE TWO PRODUCTS OF THE REACTION ARE MEMORY B CELLS AND PLASMA CELLS. AND THEY'RE REALLY VERY DIFFERENT CELL TYPES. THE PLASMA CELL IS PRODUCING THE ANTIBODIES WE'RE FINDING IN OUR PLASMA BEING USED IN THE CORONAVIRUS INFECTION. AND THE MEMORY CELLS IS A RESERVOIR, SOMETHING TO COME BACK TO. PEOPLE STUDIED PLASMA CELLS QUITE A BIT AND IT'S CLEAR THEY'RE SELECT FROM THIS ENVIRONMENT FROM THE GERMINAL CENTER ENVIRONMENT BASED TON THE AFFINITY. HIGH AFFINITY B CELLS GET TRANSFORMED TO ANTIBODIES. LESS IS KNOWN ABOUT THE MEMORY CELL. AND IT'S BEEN STUDIED PRIMARILY BY CAPTURING IT USING ANTIGENS. SO THAT REQUIRES THAT CELL HAVE A CERTAIN AFFINITY IN ORDER TO BE SEEN. WHAT I'LL TALK ABOUT IN THE NEXT FEW SLIDES IS THE WORK OF A POST-D POST-DOCTORAL IN THE LAB WHO DECIDED TO FIND OUT MORE ABOUT MEMORY CELLS NOT BY THEIR ABILITY TO BIND ANTIGEN BUT BY LINEAGE TRACING AND SHE DID THIS BY LABELLING CELLS THAT ARE ENTERING THE GERMINAL CENTER SO ONCE THEY'RE LABELLED THEY STAY LABELLED AND THE PRODUCTS ARE LABELLED. AND SHE DID THIS WITH A TAMOXIFEN INDUCIBLE CREAM. AND WHAT IS THE MEMORY OF B CELLS IF WE TAKE ALL COMERS AND COMPARE THEM TO CELLS IN GERM INIAL CENTERS? THERE'S AN IMMUNIZATION AND WE LABEL THEM AROUND DAY FIVE TWO OR THREE DAYS MORE AND NOW LOOK IN THAT GERMINAL CENTER OR IN MEMORY CELLS 42 DAYS LATER FOR ANTIGEN BINDING. AND WHAT YOU CAN SEE HERE IS THAT IT'S EASY TO FIND CELLS THAT BIND TO THE ANTIGEN IN THE GERMIN SIGNAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TOA SIGNAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TOL SIGNAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TOIGNAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY GNAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TONAL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY AL CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY L CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TO CENTER. THAT'S EXPECTED BUT BUT IN THE MEMORY COMPARTMENT AS THE FEW CELLS WITH SUFFICIENT AFFINITY TO BE SEEN BY THE ANTIGEN AND THAT'S SHOWN IN MULTIPLE EXPERIMENTS ON THE RIGHT. NOW, THIS IS TRUE THROUGHOUT THE IMMUNE RESPONSE. SO YOU CAN SEE HERE IF WE LABEL FROM DAY 9 OR DAY 15 IF WE LABEL FROM DAY 21, IT'S ALWAYS THE SAME. THERE ARE CELLS IN THE GERMINAL CENTER WITH RARE AFFINITY BUT RARE IN THE MEMORY COMPARTMENT. ALL RIGHT, SO DOES THAT MEAN THAT MEMORY CELLS DON'T HAVE ANY AFFINITY FOR THE ANTIGEN? NO. THAT'S NOT THE CASE. WHAT WE DID TO TRY TO UNDERSTAND THIS WAS TO CLONE THE ANTIBODIES FROM CELLS LABELS CELLS AT THE SAME TIME AND TO BIND WITH AN ANTIGEN ON A CHIP. THIS IS WHAT THE FLOW CYTOMETRY LOOKS LIKE AND THERE'S CELLS WITH AFFINITY IN THE GERMINAL CENTER BUT HARD TO DETECT ONE IN THIS CASE OUT OF 41 THAT HAVE THE DEMONSTRABLE MONOVEIL ENT -- MONOVALENT AFFINITY BUT IT'S ON THE FOLLICULAR DENDRITIC CELLS AND THOSE ARE POLYMERS SO TRY WITH A POLY VALENT SITUATION. AND A FEW MORE OF THE ONES WE COULDN'T DETECT IN THE GERMINAL CENTER ALSO COME UP. WE CAN FURTHER INCREASE THE SO-CALLED LA VIDITY OF THE ASSAY BY MAKE TETTRIMER AND YOU SEE MORE OF THE MEMORY CELLS HAVE SOME AFFINITY. SO THE MEMORY CELLS ARE COMING IN THAT COMPARTMENT WITH ACTUALLY VERY LOW LEVELS OF AFFINITY. THERE ARE CELLS LIKE THIS ONE HERE WITH RELATIVELY HIGHER AFFINITY AND BY AND LARGE THE CELLS ARE VARIANTS THAT HAVE LOWER AFFINITY FOR THE ANTIGEN. FOR PLASMA CELLS THE SELECTION IS CLEAR IT'S BASED ON AFFINITY. FOR MEMORY CELLS, WHO YOU GET IS A WHOLE COLLECTION OF LYMPHOCYTES AND IT MAY BE A WAY FOR THE IMMUNE SYSTEM TO LOOK FORWARD TO VARIANTS OF THE PATHOGEN. SO THE PATHOGEN IS GOING TO EVOLVE AND THE IMMUNE SYSTEM IS CREA CREATING A WAY OF DEALING WITH THAT EVOLUTION. NOW I WANT TO TELL YOU A LITTLE BIT ABOUT HOW WE GOT TO CORONAVIRUS IN TWO OR THREE SLIDES. SO WHAT WE STARTED TO WORK ON WAS HIV BECAUSE IT WAS AND IS A MAJOR PUBLIC HEALTH PROBLEM. AND VERY LITTLE UNDERSTANDING OF WHY WE DON'T REALLY HAVE A GOOD VACCINE. IT WAS KNOWN AT THE TIME THAT THERE WERE PEOPLE OCCASION INDIVIDUALS THAT WOULD BE ABLE TO CREATE SEROLOGIC ACTIVITY ANTIBODIES THAT WERE ABLE TO NEUTRALIZE THE VIRUS AND IF YOU WERE ABLE TO REPRODUCE THAT, THEN YOU CAN CREATE A VACCINE BUT THESE PEOPLE WERE UNUSUAL. THEIR IMMUNE RESPONSE IS UNUSUAL BECAUSE IT DEVELOPED AFTER TWO FOR THREE YEARS NOT LIKE THE SLIDE AT THE BEGINNING WHERE YOU GET HIGH AFFINITY RIGHT AWAY. THIS SAY PROCESS THAT TOOK YEARS -- IS A PROCESS THAT TOOK YEARS TO HAPPEN AND WERE INTERESTED TO FINDING OUT WHAT ARE THESE PEOPLE, WHAT ARE THEY DOING AND HOW DID THEY DO IT? WE STARTED THE EXPERIMENTS WITH A LOT OF HELP FROM THE CAN -- VRC TO RECRUIT INDIVIDUALS AND DEVELOPED THE SAME TECHNOLOGY THAT'S BEEN USED BY JUST ABOUT EVERYBODY CLOTH ANTIBODIES FROM HUMANS -- CLONING ANTIBODIES FROM HUMAN FROM THAT TIME ON. THAT IS TO SELECT THESE PEOPLE, TAKE OUT THEIR LYMPHOCYTES FROM THEIR BLOOD AND INCUBATE THE LYMPHOCYTES WITH THE PROTEIN TARGET YOUR INTERESTED IN. IN THE CASE OF THE HIV IT'S THE HIV SPIKE. IN THE CASE OF THE ZIKA VIRUS, IT'S THE ZIKA VIRUS SPIKE. IN THE CASE OF MALARIA, IT'S MALARIA ANTIGENS AND SO ON. AND USING THE TECHNOLOGY CAN SORT OUT AND SEE THE CELL THAT BINDS AND HAS A GOOD RECEPTOR THAT BINDS THE ANTIGEN SORT THOSE AS SINGLE CELLS AND REPRODUCE THE ANTIBODIES BY MOLECULAR BIOLOGY TECHNIQUES. IN HIV THIS LEDDED TO -- LED TO THE FINDING OF POTENT ANTIBODIES B OUR GROUP AND OTHERS THAT ADOPT THE TECHNIQUE AND THE VRC IMPROVED ON THE TECHNIQUES AND THE ANTIBODIES HAVE NOW BEEN ADVANCED INTO THE CLINIC FOR THERAPIES AND PREVENTION. IN FACT WE'LL SOON HEAR ABOUT A VERY LARGE TRIAL SPONSORED BY NIH USING AN ANTIBODY DISCOVERED BY VRC FOR HIV PREVENTION. ESSENTIALLY WE HAVE BEEN LOOKING AT EXPERIMENTS LOOKING AT HUMAN ANTIBODY RESPONSES AND WE WERE PREPARED TO DO THE SAME WHEN THE CORONAVIRUS CAME UP. AND BEING IN NEW YORK WE WERE HIT EARLY AND HARD BY THIS ENDEMIC AND WE WERE ABLE TO RAPIDLY RECRUIT INDIVIDUALS THAT HAD RECOVERED FROM THE DISEASE TO ROCKEFELLER UNIVERSITY HOSPITAL WHERE WE SCREENED 2,000 PEOPLE AND THEN EVENTUALLY RECRUITED 150 VOLUNTEERS TO COME TO THE UNIVERSITY TO GIVE BLOOD THAT WE COULD THEN EXAMINE IN A VARIETY OF WAYS BOTH THE SERUM AND CELLS AND THAT'S THE WORK I'M GOING TELL YOU ABOUT NOW. SO FOR THE CORONAVIRUS WE KNEW A LOT ABOUT IT AND IT WAS CLEAR THE SPIKE FROM THIS VIRUS INTERACTS WITH HUMAN CELLS THROUGH THIS RECEPTOR ACE 2 AND IT'S THIS RECEPTOR BETWEEN THE RECEPTOR BINDING DOMAIN WE WERE MOST INTERESTED IN BECAUSE IF ANTIBODIES COULD BLOCK THIS THEY COULD BLOCK THE INFECTION AND IF WE COULD LEARN ABOUT THE ANTIBODIES WE COULD LEARN SOMETHING ABOUT HOW HUMANS DEAL WITH THE VIRUS. SO WHAT WE DID INITIALLY WAS TO TAKE THOSE 150 SERA AND LOOK FOR THE ABILITY TO BIND TO THAT REGION OF THE SPIKE. THE SO-CALLED RECEPTOR BINDING DOMAIN, RBD. YOU SEE THE DATA HER AND THE AREAS UNDER THE CURVES AND WHAT YOU CAN SEE HERE IS THAT THESE CONTROLS ARE PEOPLE BEFORE CORONA ESSENTIALLY AND THIS IS THE GROUP OF 148 AND THERE IS REACTIVITY BUT IT IS NOT A HUGE AMOUNT OF REACTIVITY. SO PEOPLE THAT HAVE RECOVERED HAVE MADE ANTIBODIES BUT NOT TREMENDOUS NUMBERS TO THIS RBD. THE BINDING OF THE ANTIBODIES IS INTERESTING BUT MORE INTERESTING IS NEUTRALIZATION AND THIS WAS WORK DONE IN A LAB YOU HEARD A LITTLE BIT ABOUT LAST WEEK. THEY PRODUCED A PSEUDOVIRUS BY USING AN HIV BACKION -- BACKBONE AND INSERTING THE SPIKE SO THE PSEUDOVIRUS HAS THE CORONA SPIKE ON IT AND HAS A GOOD ASSAY. SO WHAT WE DID TOGETHER WAS TO TEST THE SERA FIRST FOR NEUTRALIZING ACTIVITY AND THE PSEUDOVIRUS ASSAY IS QUITE A GOOD ASSAY AND CORRELATES VERY WELL WITH THE NEUTRALIZING ACTIVITY AGAINST THE ACTUAL SARS VIRUS. THAT WORK WAS DONE IN CHARLIE RICE'S LAB AND YOU SEE MONOCLONAL ANTIBODIES AND STRONG ASSAYS. THIS SHOWS THE TOP 60 OF THE 148 AND WHAT IS REMARKABLE HERE IS THAT HALF THE PEOPLE HAVE TITERS BELOW AND THE RED HAVE BELOW THIS WITH ONE WILL THIRD 1-50. SO NOT A LOT OF NEUTRALIZING ACTIVITY IN THESE INDIVIDUALS. THE NEUTRALIZATION IN THIS CASE IS HAS BIVALENT BINDING AND WHEN YOU MAKE A YOU MAKE A FAB IT TAKES MORE OF THAT TO NEUTRALIZE THE VIRUS THAN A BIVALENT ANTIBODIES AND IT'S BEEN CONFIRMED IN LABS AS WELL AS OTHER DATA I JUST SHOWED YOU. IF YOU'RE ONLY HOLDING ON WITH ONE HAND AND LET GO IT MAY FALL AWAY. THEY'RE LOW LEVELS OF NEUTRALIZING ANTIBODIES AND PRESENT IN NEARLY ALL INFECTED INDIVIDUALS. AND CROSS LINKING IS AN IMPORTANT MECHANISM HERE IN NEUTRALIZATION. WHAT ABOUT THE CLINIC AND THE pWITH SOME OF THESE THINGS.LATE FIRST OF ALL AND IF YOU WANT TO GIVE IT NEUTRALIZING AND THEY GENERALLY HAVE BETTER TITERS AND MEN ARE BETTER TITERS THAN WOMEN. THE NEUTRALIZING ACTIVITY BECAUSE THESE ARE ALL PROBABLY CO-DEPENDENT VARIABLES. NEUTRALIZING ACTIVITY CORRELATES WITH THE SYMPTOMS AND SYMPTOM SEVERITY AND AGE. THE LONGER YOU'RE INFECTED THE MORE ANTIGEN YOU HAVE AND THE BETTER IT IS FOR YOUR IMMUNE SYSTEM IN TERMS OF BEING EXPOSED TO ANTIGEN AND BEING ABLE TO PRODUCE ANTIBODIES. MEN THAT ARE SICKER THAN WOMEN FIT IN TO THAT OR HOSPITALIZED INDIVIDUALS AS WELL. AND THERE'S MONOCLONAL ANTIBODIES BEING PRODUCED AND WE DID THAT THE WAY I MENTIONED EARLIER WHICH IS TO TAKE CELLS AND STAIN THEM WITH THE ANTIGEN THE SARS COV2 SPIKE RBD AND USE THAT TO SORT CELLS AND USE MOLECULAR BIOLOGY AND THIS WAS THE BAIT, THE RBD. WE KNOW THIS THE INTERACTION. WE DON'T SEE CELLS THAT BIND TO THE RBD AND CONTROL AND THEY MUST BE THERE BUT THEY ARE RARE. IN ALL THE INDIVIDUALS WE CAN FIND THESE CELLS. SO DIFFERENT PEOPLE MAKE SIMILAR ANTIBODIES AND YOU CAN SEE THAT OUTLINED HERE IN THE PLOT. AND SOME MUCH THESE ANTIBODIES WERE VERY POTENT THAT'S SHOWN HERE AGAINST THE AUTHENTIC SARS COV2 IN CHARLIE RICE'S LAB WHO'S BEEN A CLOSE COLLABORATOR IN THE PROJECT AND YOU CAN SEE THE ANTIBODIES ARE NANO GRAM POTENCY AGAINST THE VIRUS. AND AGAIN THIS IS A MUCOSAL INFECTION. ANTIBODIES HAVE A COMBINATION TO PRODUCE THINGS LIKE IGA AND IGA EXISTS AS A MONOMER IN BLOOD AND AS A POLYMER AND AT THE SAME TIME THEY WERE PRODUCING IGGs THEY WERE PRODUCING RELATED IGAs TO SOMEWHAT EXPECTED AND WE DID THEM FOR THREE INDIVIDUALS AND IN EVERY CASE WE CAN SEE RELATED CLONES PRESENT AS IGGs AND IGAs. AND WHY THE MUCOSAL DELIVERY VACCINES ARE WORKING IN THE ANIMAL MODELS AND NOT JUST PRESENT AS A DIMER BUT MULTIMER TO CROSS LINK THE VIRUS. POTENT ANTIBODIES IN MANY INDIVIDUALS IN ALL INDIVIDUALS ESSENTIALLY. THE B CELLS PRODUCING THE B CELLS ARE RARE IN CIRCULATION AND HAVE LOW LEVELS OF SOMATIC MUTATION AND NEARLY IDENTICAL ANTIBODIES IN DIFFERENT PEOPLE AND SOME OVER REPRESENTATION OF PARTICULARLY THE GENES AND WE'LL GO OVER THAT WHEN WE GO OVER MECHANISMS. AND HIGHER POTENCY FOR THE IGA DIMERS AND SO NOW LET'S TALK A LITTLE BIT ABOUT THE MECHANISMS. THE ACE THE RECEPTOR BINDS TO THE RBD WHEN THE RBD IS THE CONFIGURATION. IT'S A TRIMER AND THEY CAN FLOP UP OR DOWN BUT ONLY WHEN THEY'RE UP THEY'RE ACCESSIBLE TO THE VAs. THE ANTIBODIES WE CLONE, MANY OF WHICH WERE POTENT, HAVE BEEN STUDIED STRUCTURALLY TO TRY TO EXPLAIN HOW THEY NEUTRALIZE AND A LAB WE'VE BEEN WORKING WITH CLOSELY HAS DEFINED FOUR DIFFERENT GROUPS OF ANTIBODIES. THE FIRST ONE SHOWN HERE BINDS TO THE SAME SURFACE AS THE RBD AND IT ONLY BINDS TO THE RBD WHEN IT'S IN THE UP CONFIGURATION. SO THIS CLASS ONLY BINDS UP RBDs VERY SIMILAR TO ACE 2. AND THE V GENES THAT ARE IN THIS GROUP ARE OVER REPRESENTED IN PART BECAUSE THE STRUCTURES THAT INTERACT WITH THIS SURFACE THE CDRH1 AND CDRH2 ARE ENCODED IN THE GENOME AND NOT PART OF CDRH3 FORMED DURING THE RECOMBINATION. UNLIKE THE ANTIBODIES A GREAT DEAL OF THE BINDING ENERGY IS COMING FROM THE GENOME ENCODED PART OF THE ANTIBODY. IT MAY EXPLAIN WHY THEY'RE OVERREPRESENTED IN THE GROUP. THERE'S A SECOND GROUP THAT CAN BIND THE RBD IN BOTH UP AND DOWN CONFIGURATIONS. AND THERE ARE SOME VERY INTERESTING EXAMPLES IN THIS GROUP FOR MECHANISMS OF NEUTRALIZATION AND THIS GROUP DOES SOMETHING ELSE. IT BINDS YES TO THE SURFACE THAT INTERACTS WITH THE ROBINSON. THAT'S SHOWN HERE. -- RBD, THAT'S SHOWN HERE. BUT IN THE TRIMER THERE'S A NEXT DOOR RBD AND IT HAS A FOOTPRINT NOT ONLY IN ONE RBD BUT IN BOTH. IN THIS ONE IT'S NOT ON THE INTERACTION SURFACE. AND IT'S REACHING INTO A POCKET OF THE NEXT DOOR OF RBD AND WHEN THIS HAPPENS THIS THING LOCKS DOWN THE RBD SO IT IS IN A DOWN CONFIGURATION AND IT'S BLOCKED FROM BINDING ACE 2 IN TWO DIFFERENT WAYS. IT'S BLOCKED BECAUSE IT'S UNAVAILABLE FOR ACE 2. IT'S LOCKED DOWN AND ALSO THE ACE 2 BINDING SURFACE IS OCCUPIED. SO THESE LOCK DOWN ANTIBODIES ARE IN FACT VERY VERY POTENT. AND SO FOR THERE'S ONLY TWO EXAMPLES OF THIS KIND OF ANTIBODY. ONE IS SHOWN HERE C144. THE OTHER WAS RECENTLY REPORTED. A THIRD CATEGORY DOES NOT BLOCK THE ACE BINDING DIRECTLY BUT INTERFERES WITH IT IN SOME OTHER WAY AND BINDS TO A COMPLEMENTARY SURFACE. THIS TYPE OF ANTIBODY AN EXAMPLE IS S3O9 AND THE ANTIBODY WE CLONED C135. SO I COMBINED BOTH UP AND DOWN RBDs BUT DOES NOT BLOCK ACE 2 BINDING DIRECTLY. IT'S ANOTHER WAY. SO FOUR CLASSES. ONE CLASS REPRESENTED BY UP ONLY AND ONE UP AND DONE INCLUDING A BLOCKING THE ACE INTERACTION DIRECTLY AND A THIRD CLASS WHICH DOES IT BY A MECHANISM WE STILL DON'T UNDERSTAND COMPLETELY BUT CAN BIND BOTH UP AND DOWN RBDs. SO THESE SHOULD BE COMPLIMENTARY WHEN YOU COMBINE SOMETHING LIKE THIS FOR EXAMPLE WITH SOMETHING LIKE THAT. THAT'S WHAT WE'VE DONE AND I'LL SHOW YOU NEXT AND HUMAN RBD ANTIBODIES. GROUP 1 BINDING IT THE OPEN CONFIGURATION OVERREPRESENTED VH353 IN PART BECAUSE THE BINDING IS MEDIATED IN A VERY SIGNIFICANT MANNER BY CDRH1 AND 2 AND GROUP 1 AND 2 TO OPEN AND CLOSE AND SOME ENHANCE THE PARENT AFFINITY BY USING TWO HANDS ARTIFICIALLY ESSENTIALLY. ONE HAND ON ONE RBD AND ANOTHER HAND ON THE OTHER AND ONE OUTSIDE. IF THEY'RE COMPLIMENTARY MAY PREVENT THE EMERGENCE OF AN ANTIBODY ESCAPE AND MAY BECOME A PROBLEM IN THE CORONAVIRUS. THERE'S IT'S AN EXPERT DONE IN PAUL NASH'S LAB CRATING AN RBD VIRUS THAT'S A COMPETENT VIRUS WITH THE SARS SPIKE IF YOU DO IT IN THE PRESENCE OF THE 135 ANTIBODY AND IN THE CONTROL SITUATION ALL THE ANTIBODIES THAT WE'RE TESTING ALL THREE OF THEM THE VIRUS IS SENSITIVE. NOW IF YOU PASS IT WITH 135 IT BECOMES VERY RESISTANT BUT NOT TO THE OTHER ANTIBODIES AND THE COMPLIMENTARY ANTIBODIES. AND IF YOU DO IT WITH THE TWO ANTIBODIES YOU DO NOT SEE THE RESISTANCE SO YOU CAN TRY PRETTY HARD TO PASSAGE THE VIRUS IN THE PRESENCE OF THE COMBINATION OF ANTIBODIES BUT YOU JUST DO NOT SEE EMERGENCE OF RESISTANCE. THIS IS TRUE NOT JUST IN THIS SYSTEM BUT TRUE FOR AUTHENTIC SARS VIRUS WHICH HAS A MUCH MORE DIFFICULT TIME MAKING MUTATIONS. SO RSV THIS ONE USED HAS AN EASY TIME MAKING MUTATIONS. SARS DOES NOT AND SARS MUTATIONS DO ARISE AND THEY DO ARISE IN THE PRESENCE OF RESISTANCE ARISES IN THE PRESENCE OF ANTIBODY IN VITRO. SO HUMAN ANTIBODIES CAN SELECT FOR RESISTANT VARIANCE AND THEY BIND DIRECTLY TO THE ANTIBODY TARGET SITES AND WE KNOW THIS FROM THE STRUCTURES AND COMBINATIONS CAN PRESENT THE EMERGENCE OF THIS RESISTANCE. SO NOW WHAT ABOUT WHAT HAPPENS TO THE ANTIBODIES IN TERMS OF PREVENTION OF INFECTION OR THERAPY. THIS EXPERIMENT WAS DONE IN DICK BOWENS LAB AT COLORADO STATE AND THIS WAS IN FACT THE EXPERIMENT I MENTIONED EARLIER THAT WAS VERY MUCH PARTICIPATION IN HELPING TO DESIGN THIS AND EVENTUALLY LOOK AT THE DATA HERE. THEY SHOULD BE THE GOLD STANDARD FOR THIS DISEASE WHEN THEY GET SICK AND THE INFECTION THEY GET IS A RAPIDLY PROGRESSING INFECTION BY DAY 3 IS THE PEAK OF THE INFECTION IN THE LUNGS. BY DAY 5 IT'S GONE IN TERMS OF THE VIRUS AND TWO KINDS OF EXPERIMENTS. AND THE WINDOW IS THREE AND WE'RE GIVING IT AT 12 HOURS? WHO DO YOU GET WE KNOW THEY'RE IN THE ANIMALS AND YOU CAN SEE IT'S REALLY IN THREE OUT OF FOUR OF THESE ANIMALS AND THE ANTIBODIES WERE DELIVERED IP. THIS PERSON OR THIS HAMSTER FAILED BUT PERHAPS THE ANTIBODIES WERE INJECTED IN THE GUT AND NOT THE PERINEAL CAVITY AND THESE PROTECT AND THIS ONE ISN'T. LOOKS LIKE VERY GOOD PREVENTION AT VERY LOW DOSES OF ANTIBODIES. MORE IMPRESSIVE FOR ME IS THERAPY. HERE I GAVE SLIGHTLY HIGHER DOSES BECAUSE THEY WERE WORRIED BECAUSE HOW IS IT GOING TO WORK IN THE SHORT PERIOD OF TIME. IT KNOCKS IT ALL DOWN BY FOUR OR FIVE ORDERS OF MAGNITUDE. SO VERY IMPRESSIVE RESULTS UP THIS MODEL. WHAT ABOUT MACAQUES? THEY WERE DEEPLY INVOLVED IN PLANNING THOSE EXPERIMENTS AND GETTING EXECUTED. AND HERE YOU GIVE THEM ONE DAY BEFORE AND YOU GIVE THEM TO ME ME -- THE MONKEYS INTRAOCULARLY AND INTRANASALLY AND YOU SEE THE KILOGRAMS AND VERY GOOD PROTECTION AND YOU SEE THE KILOGRAM DOSE IN A COUPLE OF THE ANIMALS AND IMPRESSIVE IN THE MACAQUE MODEL FOR THERAPIES. AND COLLEAGUES AT DAVIS WE LOOKED AT THE LUNG TISSUE AND THE EXPERIMENT WAS DONE BY GIVING THE ANIMALS ANTIBODY ONE DAY AFTER INFECTION. THE PEAK IS VERY EARLY ON IN THE MODEL. BETWEEN DAYS THREE AND FOUR, SOMETHING LIKE THAT. AND WHAT WAS DONE HERE IS TO LOOK AT LUNG SECTIONS BY TWO PATHOLOGISTS WHO DID THIS BLINDED AND THEN THEY GRADED THE LUNGS BASED ON WHAT THEY SAW. ALVEOLI LOOKED NORMAL AND VARIOUS DEGREES OF THICKENING THAT INDICATE PNEUMONITIS AND TOSE DELIVERED EARLY WERE HAVING A SIGNIFICANT EFFECT ON THE LUNG. WE RECRUITED 148 INDIVIDUALS AND STUDIED THEIR IMMUNE RESPONSES IS A THIS VIRUS. IN DOING SO WE WERE ABLE TO TO FIND INTERESTING THINGS ABOUT HOW HUMANS RESPOND TO THIS VIRUS INCLUDING THE FACT THAT THERE ARE CLONELY EXPANDED GROUP OF LYMPHOCYTES PRODUCING HIGH-AFFINITY ANTIBODIES AND HUMANS DO THE SAME THING IN HOW THEY NEUTRALIZE THE VIRUS. WE'VE BEEN ABLE TO USE THE ANTIBODIES TO DEFINE DIFFERENT CLASSES OF NEUTRALIZERS AND COMPLIMENTARY SITES ON THE VIRUS THAT ARE TARGETED BY THESE ANTIBODIES. AND ALL THESE THINGS CAN HAVE A ROLE IN THIS PANDEMIC. BOTH FOR PROTECTION IN PEOPLE THAT FOR EXAMPLE DON'T RESPOND TO VACCINES. PEOPLE LIKE ME THAT ARE OLD ENOUGH THAT HAVE A PROBLEM WITH VACCINE RESPONSES AND IN THERAPY FOR PEOPLE WHO HAVE NOT RECEIVED A VACCINE OR HAVE AND STILL GET INFECTED. ANTIBODIES ARE BEING DEVELOPED BY A SERIES OF DIFFERENT COMPANIES WITH A LOT OF HELP FROM OPERATION WARP SPEED AND THE NIH. AND THIS IS JUST A LIST AND THE TWO FURTHEST ALONG ARE REGENERON AND LILLY. THEY MAY NOT HAVE THE BEST ANTIBODIES BUT OTHERS WILL COME ALONG AND I'M VERY OPTIMISTIC THE AGENTS WILL BE AVAILABLE IN THE NEAR FUTURE WITH HELP FOR PREVENTION AND THERAPY. WITH THAT I WANT TO SAY AGAIN THAT WHAT I'VE TALKED ABOUT IS AN EFFORT BY MANY LABS. WE DID THE ANTIBODY CLOTH -- CLONING PART AND WORKED WITH CHARLIE AND PAUL ON THE NEUTRALIZATION ASSAYS AND PAMELA BORKEMAN AND HER LAB AND A POST-DOC IN HER LAB DID ALL THE STRUCTURED WORK WITH A LOT OF HELP FROM OTHERS THERE BUT LED THAT EFFORT. AND THE CLINICAL COLLEAGUES WERE ESSENTIAL IN GETTING US STARTED BECAUSE THE HARDEST PART IT SEEMS TO ME ONE OF THE HARDEST PARTS OF THIS WHOLE THING IS THE CLINICAL ASPECT, GETTING PEOPLE HERE AND GETTING CLINICAL PROTOCOLS AND CONVINCING PEOPLE IT'S A GOOD THING TO DO. AND FINALLY AT DAVIS AND TULANE FOR THE MONKEY STUDIES AND THE MOEN LAB IN COLORADO FOR ALL THE WORK ON THE HAMSTERS AND I HAVEN'T HAD TIME TO TALK ABOUT MICE BUT WE'VE DONE THE SAME THING IN MICE WITH RALPH BARRISH'S LAB. WITH THAT I'M HAPPY TO TAKE QUESTIONS, IF THERE ARE ANY? >> WE'RE ALL APPLAUDING. MICHEL, THANK YOU FOR A WONDERFUL BRILLIANT PRESENTATION WORKING THROUGH SOME OF THE DETAILS OF THE IMMUNE SYSTEM AND IT'S ABILITY TO GENERATION THIS KIND OF VERY SPECIFIC BIOMOLECULES I TOLD THEM HAVE YOU A BIOTECHNOLOGY FACTORY IN YOUR BODY AND KEEPS A RECORD OF WHAT IT'S DONE IN THE PAST AND CAN PULL THEM OUT OF THE FILE IF IT NEEDS TO AND HOW VACCINES ARE SUPPOSED TO PROTECT. IF YOU PERMIT ME I'LL ASK THE FIRST QUESTION BUT IF PEOPLE HAVE OTHER QUESTIONS THEY WANT TO POSE, TO REMIND YOU ON THE VIDEO CAST WEBSITE IF YOU SEE THE WORD SEND LIVE FEEDBACK AT THE BOTTOM OF THE WEB PAGE YOU CAN SEND IN A QUESTION AND I'LL TRY TO PUT FORWARD TO MICHEL. MICHEL, AT THE END YOU WERE TALKING ABOUT THE POTENTIAL HERE OF THESE NEUTRALIZING MONOCLONAL ANTIBODIES IN THE PRIMATE MODEL TO BE PRETTY DARNED EFFECTIVE IN TERMS OF PREVENTION AND TREATMENT. WE KNOW THAT IN THE HUMAN TRIALS THAT WE'VE HEARD A BIT ABOUT THOUGH NONE OF THIS IS REALLY PUBLISHED IT'S PRESS RELEASES IT'S AS IF INDIVIDUALS TREATED EARLY AFTER THEY DEVELOPED SYMPTOMS DO IN FACT HAVE A LOWER LIKELIHOOD, THIS SAY -- IS A LILLY VACCINE AND THE HOSPITALIZATION NUMBERS ARE INTERESTING. EVERYBODY'S WONDERING WHAT'S THE WINDOW OF OPPORTUNITY FOR THERAPEUTICS? IT KIND OF MAKES SENSE THIS WOULD WORK BEST IF YOU START EARLY BUT HOW LONG WILL THAT WINDOW EXTEND IF YOU HAVE SOMEBODY WHO'S ALREADY IN THE HOSPITAL OR WORSE YET SOMEBODY IN THE ICU REALLY SICK? ARE MONOCLONAL ANTIBODIES GOING TO WORK IN THAT STAGE OR IS THAT LATE FOR THIS TO WORK? >> I THINK THOSE PEOPLE GET THE LEAST BENEFIT FROM THIS. THEIR DISEASE IS REALLY NOT DRIVEN BY VIRAL REPLICATION. THEIR DISEASE IS DRIVEN BY THE DAMAGE THE VIRUS HAS ALREADY DONE. SO THEY ARE GOING TO GET THE LEAST BENEFIT. THAT'S NOT TO SAY THERE'LL BE SOME BENEFIT BUT THE LEAST. THE PEOPLE THAT WILL BENEFIT MOST FROM THIS ARE FOR FOR EXAMPLE THE CONTACTS. IF SOMEONE IN YOUR IMMEDIATE VICINITY IS INFECT AND KNOWN TO BE INFECTED ALL THE CONTACTS WOULD BENEFIT AND PEOPLE DIAGNOSED EARLY WHO DO NOT HAVE SYMPTOMS OR HAVE MILD SYMPTOMS WOULD ALSO POTENTIALLY BENEFIT AND THE FURTHER DOWN YOU GO AND THE MORE DAMAGE THE VIRUS DOES, AND THE LESS VIRUS THERE IS IN THE SYSTEM THE LESS LIKELY ANY INTERVENTION LIKE THIS WILL BE A BENEFIT. >> ALSO, IT'S WHETHER YOUR OWN IMMUNE SYSTEM HAS HAD A CHANCE TO MOUNT ITS OWN DEFENSES AND REGENERON SAID THE PEOPLE WHO BENEFITWARD ZERO NEGATIVE AT THE TIME THEY GOT THE ANTIBODY. THOSE ALREADY ZERO POSITIVE DIDN'T SEEM TO GET A LOT OF BENEFIT. >> AND THOSE WILL BE PEOPLE LATER ON BECAUSE THE ADAPTIVE SYSTEM TAKES AT LEAST A WEEK OR TWO TO GET TO ANTIBODIES SO IF YOU HAVE ANTIBODIES YOU'VE BEEN INFECTED FOR A WHILE AND THIS IS CONSISTENT WITH THE EARLY THERAPY IDEA. >> LET ME START WAY BASIC QUESTION AND IS IT TRUE THAT HIGH AFFINITY MEMORY B CELLS ARE DELETED. >> WHAT I SHOWED AND WANT TO CONVEY IS THERE ARE HIGH AFFINITY B CELLS IN THE MEMORY COMPARTMENT. IT'S OBVIOUS THERE ARE BECAUSE WE'VE CLONED THEM FROM THAT COMPARTMENT. AND THE COMPARTMENT IS DEVOTED TO VARIANCE AND CREATING AN ADDITIONAL LEVEL OF IMMUNOLOGIC DIVERSITY. AND LOOKING FORWARD TO A MUTANT PATHOGEN. >> GOT IT. YOU TALKED ABOUT THE POSSIBILITY MUTATION CREATES THE POSSIBILITY OF ESCAPE SO A QUESTION COULD VIRAL ESCAPE LEAD TO THE REAPPEARANCE OF THE DISEASE THAT OCCURS AT ABOUT DAY 10? >> THAT'S A GOOD QUESTION AND I DON'T KNOW THE ANSWER AND I DON'T FOE THAT'S BEEN STUDIED. IT WOULD BE AN INTERESTING SORT OF STUDY TO DO TO FOLLOW THE VIRUS IN PEOPLE THAT ARE SICK FOR A LONG TIME AND THAT ARE VEREMIC FOR A LONG TIME TO SEE IF IT'S INVOLVING THOSE INDIVIDUALS. >> IF YOU SELECTED FOR VIRUS STRAIN THAT NO LONGER WOULD RESPOND TO THE MONOCLONAL YOU'D STILL HAVE THAT PERSON'S OWN IMMUNE SYSTEM KIND OF READY TO TAKE ON THE CHALLENGE. BUT WE WANT TO SEE WHAT HAPPENS. >> YES, IT WILL BE VERY INTERESTING TO LOOK AT AND THE LILLY TRIAL IN PARTICULAR BECAUSE IT'S GOING WITH A SINGLE ANTIBODY TO SEE IF THEY ARE SELECTING FOR VARIANCE IN THE PEOPLE THAT ARE BEING TREATED. AND I'VE SEEN A LITTLE BIT OF THE DATA WHICH JUST GOT PUT FOR YARD IN THE LAST FEW DAYS AND IT DOES LOOK WITH THE MONOTHERAPY THERE'S THE POSSIBILITY OF A STRAIN EMERGING WHICH IS ALREADY THERE. IT'S NOT THAT IT HAPPENED AS A MUTATION IN THE COURSE OF THE INFECTION BUT THE VIRUS ALREADY HAS HETEROGENEITY IN THE GENOME SEQUENCE. THAT'S NOT TERRIBLY COMMON MAYBE LESS THAN 1% STRAIN GETS SELECTED FOR BUT IN THEIR EXPERIENCE WITH THE MONOCLONAL MONOTHERAPY THE IMMUNE SYSTEM KICKED IT OUT ANYWAY BUT WE'D LIKE TO BE SURE. >> YOU'LL GIVE SOME POPULATIONS THAT WILL REQUIRE THIS FORM OF THERAPY WILL BE FOR EXAMPLE CANCER PATIENTS WHERE THEIR IMMUNE SYSTEMS ARE WIPED OUT. THAT WILL NOT BE A POSSIBILITY FOR THOSE PEOPLE. IN GENERAL IN HIV PEOPLE LEARN THIS LESSON EARLY ON THAT MONOTHERAPIES JUST WEREN'T SUFFICIENT FOR THIS KIND OF VIRAL PATHOGEN AND HERE IT WILL BE SAFER TO HAVE COMBINATIONS LIKE THE REGENERON COMBINATION AND THE COMBINATION WITH YOU WERE STUDYING. >> THE QUESTIONS ARE PILING UP AND WE'RE ABOUT AT THE END OF THE HOUR MAYBE I'LL ASK YOU ONE MORE SOMEWHAT RANDOMLY CHOSEN AND TRIGGERED A BIT BY THE PUBLIC INFORMATION ABOUT THE TREATMENT OF THE PRESIDENT. WOULD YOU EXPECT TREATMENT WITH STEROIDS TO EFFECT THE QUALITY OF AN ANTIBODY RESPONSE PROVIDING STEROIDS. I THINK WE'RE TALKING ABOUT A SITUATION WHERE MONOCLONALS WOULD BE DELIVERED AS A THERAPEUTIC THAT HAPPENED BUT WHAT DO STEROIDS DO IN GENERAL TO THE ANTIBODY RESPONSE TO SOMEBODY WHO'S GOT INFECTED WITH COVID? SHOULD WE BE PASSING THEM AROUND WILLY-NILLY? >> I DON'T KNOW ENOUGH DETAILS ABOUT WHAT HAPPENED IN THIS PARTICULAR CASE BUT THE RECOMMENDATION IS THE STEROID SHOULD BE GIVEN TO PEOPLE SERIOUSLY ILL AND NOT EARLY ON BECAUSE IN FACT IT COULD INTERFERE WITH IMMUNITY. IT'S HARD TO GUESS WHAT PHYSICIANS WERE THINKING. >> WE WON'T GO THERE SINCE WE'RE NOT IN THE ROOM WHERE IT HAPPENED. FINALLY, DOES ANY OF WHAT YOU LEARNED SO FAR ANSWER HOW LONG IMMUNITY MAY BE SUSTAINED BECAUSE WE ARE THINKING OF THAT IN TERMS OF INFECTION AND WILL IT KEEP VEXING US BECAUSE IMMUNITY IS NOT LASTING AS LONG AS WE WISH IT WOULD? >> I THINK WE SHOULD TAKE OUR LESSONS FROM THE OTHER CORONAVIRUSES. IT'S LIKELY WE WILL HAVE IMMUNITY IN THE SENSE THAT WE WILL MEMORY CELLS THAT ARE PRESENT AND ABLE TO RESPOND RAPIDLY. WHAT THAT MEANS IS OUR SERUM LEVELS OF LEVEL MAY BE TOO LOW TO PROTECT US IN SOME CASES. EVEN IF THE SERUM LEVELS ARE LOW AND GET INFECT WITH THE CORONAVIRUS IT MAY BE YOUR IMMUNE SYSTEM WILL KICK IN ENOUGH IT WILL NOT BE A SERIOUS INFECTION. SO IF YOU'VE BEEN THROUGH IT ONCE, THE CHANCES ARE YOU'LL DOUGH FINE THE SECOND -- DO FINE THE SECOND TIME AS WELL. THAT'S PRETTY MUCH WHAT HAPPENS WITH THE OTHER CORONAVIRUSES. >> RIGHT. AND WE HAD THE CASE OF A GENTLEMAN FROM HONG KONG WHO GOT INFECTED A SECOND TIME CLEARLY WAY SECOND VIRUS AND GENOMIC VERY DIFFERENT AND HAD NO SYSTEMS -- SYMPTOMS AT ALL. MICHEL, AS THE BEEN A WONDERFUL LECTURE AND WONDERFUL WAY TO HONOR BILL PAUL AND THE PRESENTATION YOU GAVE AND THE DISCUSSION HAD WAS JUST WHAT I WAS HOPING FOR BRINGING TOGETHER IMMUNOLOGY AND THE CURRENT COVID CRISIS IN TRYING TO FIGURE OUT HOW TO BRING THE SCIENTIFIC TOOLS TO THE FOREFRONT TO GET US THROUGH THIS AND WE ARE GOING TO GET THROUGH THIS THOUGH WE'RE NOT QUITE THERE YET. >> IT'S A GREAT HONOR AND I'M DELIGHTED TO BE ABLE TO DO THIS. >> PLEASE JOIN ME, EVERYBODY IN THANKING OUR BILL PAUL LECTURER FOR 2020. HAVE A WONDERFUL REST OF THE DAY, EVERYBODY.