>> GOOD AFTERNOON, IT IS MY ENORMOUS PLEASURE TODAY TO INTRODUCE DR. BARNEY GRAHAM TO THE WALS LECTURE SERIES HERE IN PART OF OUR SPECIAL INTEREST GROUP FOR COVID-19. FIRST LET ME JUST SAY IF YOU HAVE QUESTIONS DURING THE TALK YOU CAN USE THE QUESTION FORM ON THE VIDEOCAST PAGE TO SUBMIT THEM, IT'S AT THE BOTTOM. IT SAYS THE LIVE FEEDBACK FORM. PLEASE USE THAT FORM TO SUBMIT QUESTIONS TO THE HOST. DO NOT LET US KNOW THAT YOU LIKE ME ARE HAVING TROUBLE WITH GETTING THIS SYSTEM TO WORK FOR YOU. YOU CAN BE ASSURED THAT THE SYSTEM WORKS FOR EVERYBODY ACCEPT THOSE OF US WHO ARE TRYING TO USE IT SO DON'T GET DIFFICULT. TODAY'S SPEAKER, BARNEY, IS JUST AN EXTRAORDINARY PERSON. HE IS THE CHIEF OF THE VIRAL PATHOGENESIS LABORATORY IN TRANSLATIONAL SCIENCE CORPS AT& THE VRC, WHERE HE ALSO SERVES ALONG WITH JULIE AND RICK AS DEPUTY DIRECTORS OF THE VRC. THE VRC IS WHERE CRITICAL ACTIVITY ADDRESSING COVID-19 IS TAKING PLACE. THERE'S NOBODY WHO IS MORE CRITICAL TO THIS ACTIVITY THAN BARNEY. AS AN IMMUNOLOGIST, VIROLOGIST, A PHYSICIAN, AND A CLINICAL TRIALIST, HE'S REALLY BEEN IN THE FOREFRONT OF VIRAL PATHOGENESIS IMMUNOLOGY AND VIRAL PATHOPHYSIOLOGY. FOR DECADES. TODAY YOU WILL HEAR HIM TALK ABOUT HIS OUTSTANDING WORK IN SARS COVID 2. HE'S BEEN INVOLVED IN VACCINES FOR A WHILE NOW. AND BASHNY GOT HIS M.D. FROM THE UNIVERSITY OF KANSAS IN 1979 AND THEN SERVED THERE AS AN INTERN, RESIDENT AND CHIEF RESIDENT BEFORE DOING HIS INFECTIOUS DISEASE FELLOWSHIP AT VANDERBILT. ALONG THE WAY HE ALSO GOT A Ph.D. IN MICROBIOLOGY AND IMMUNOLOGY. THEN ROSE THROUGH THE RANKS AT VANDERBILT TO BE ASSISTANT PROFESSOR ASSOCIATE AND FULL PROFESSOR BEFORE WE WERE LUCKY ENOUGH TO RECRUIT HIM HERE TO THE VRC WHERE HE FOUNDED THE CURRENT PROGRAM. HERE HE'S WORKED ON A VARIETY OF CRITICAL ELEMENTS, RSV, EBOLA, HIV, AND THEN OF COURSE NOW SARS COVID 2. BARNEY HAS BEEN AN EXTRAORDINARY VISITOR AND TERRIFIC CONTRIBUTOR TO THE COMPLEX TIME IN WHICH WE LIVE, A VOICE OF REASON AND STABILITY AS WE TRY TO UNDERSTAND BOTH THE THREAT AND THE RESPONSE. SO I'M GOING TO STOP HERE AND TURN IT OVER AND SAY THANK YOU AGAIN BARNEY, FOR JOINING US TODAY. >> THANKS, STEVE. GOOD AFTERNOON, EVERYONE. I'M GOING TO TELL YOU A FEW STORIES ABOUT WAY WE HAVE BEEN THINKING ABOUT PANDEMIC PREPAREDNESS OVER THE LAST FEW YEARS AND USE THE NAME VIRUS COVID-19 EPIDEMIC PANDEMIC AS AN EXAMPLE OF WHAT WE HAVE BEEN TRYING TO COMMUNICATE OVER THIS -- THESE LAST FEW YEARS. I'M GOING TO START WITH INFLUENZA. WHEN PEOPLE THINK PANDEMICS THEY THINK ABOUT INFLUENZA. EVERYBOY THAT I KNOW THOUGHT THAT THE NEXT PANDEMIC CHALLENGE WOULD BE FROM INFLUENZA VIRUS. SO I'M -- I JUST WANT TO SPEND A FEW MINUTES ON INFLUENZA, MIX OF VIRUS WITH A SEGMENTED GENOME AND THOSE SEGMENTS REARRANGE OR REASSORT IN ANIMALS OR HUMANS WHERE THERE'S CO-INFECTIONS OR CO-INFLUENZA VIRUSES GET INTO THE SAME CELL YOU CAN END UP WITH AN ENTIRELY NEW GENE SEGMENT. AND WHEN THAT HAPPENS YOU CAN SOMETIMES GET A PANDEMIC STRAIN OF INFLUENZA. WE DO CELEBRATED -- DIDN'T CELEBRATE BUT WE JUST MEMORIALIZED THE PAN ARRAY OF THE 1918 INFLUENZA EPIDEMIC, IT LOOKS A ROT LIKE WHAT WE'RE DOING NOW WITH AUDITORIUMS FULL OF COTS BECAUSE THE HOSPITAL CAPACITY WAS EXCEEDED AND MASKS AND DISTANCING ENTERING INTO OUR EVERY DAY LIVES. THIS OUTBREAK IN 1918 WAS PARTICULARLY DIFFICULT BECAUSE NEARLY EVERYONE ON EARTH WAS EXPOSED WE HAD UP TO 100,000,000 EXCESS DEATHS DURING THOSE THREE YEARS OR SO AFTER THIS ENTERED. THIS WAS A SLIDE MADE BEFORE THIS OUTBREAK. BUT SOME OF THE ESTIMATES THIS TYPE OF THING HAPPEN AGAIN WERE UP TO 400,000,000 EXCESS DEATH, I THINK THERE WAS ONLY ABOUT 2,000,000,000 PEOPLE ON EARTH BACK IN THIS DAY. UP TO $5,000,000,000,000 COST FOR THE IMMEDIATE RESPONSE LET ALONE THE RECOVERY. HAD SUCH INNUANCE ON BOTH YOUNG AND VERY YOUNG THAT WE HAD A SIGNIFICANT DROP IN LIFE EXPECTANCY THAT YEAR, IF YOU JUST LOOK AT THE AVERAGE AGE OF DEATH IN 1918 IT DROPPED WAY DOWN. JUST TO MAKE THIS A LITTLE MORE PERSONAL, I'LL TELL YOU A STORY OF MY MATERNAL GRANDFATHER'S FIRST WIFE WHO DIED IN 1918, OTHERWISE I WOULDN'T BE GIVING THIS LECTURE OR BE HERE TO WORK ON INFLUENZA. I THINK THIS CURRENT OUTBREAK IS ALSO AFFECTING A LOT OF PEOPLE AT A PERSONAL LEVEL AND DURING THE 1918, IT WAS EVEN MORE SIGNIFICANT BECAUSE OF THIS W SHAPED MORTALITY CURVE WHICH A LOT OF YOUNG ADULTS GOT AN LRDS LIKE SYNDROME AND DIED FROM INFLUENZA. WITHOUT THE KIND OF SOPHISTICATED MEDICAL CARE WE HAVE NOW, THAT SAME KIND OF THING I THINK COULD POTENTIALLY BE HAPPENING NOW. JUST BE CLEAR SEVEN WAR IS NOT AS DANGEROUS AND SCARY AS THESE KIND OF PANDEMIC VIRAL THREATS. THIS IS A INDIAN AMERICAN VILLAGE AFTER THE OUTBREAK. WHAT YOU SEE IS THERE'S ONLY ONE OR TWO ADULTS LEFT. SO IN SOME POPULATIONS THERE'S PARTICULARLY SUSCEPTIBLE TO THIS KIND OF INFECTION. THIS IS WHAT POPULATES THIS CENTER OF THE MORTALITY CURVE. AND LIFE, EVERY DAY LIFE I GUESS LOOKED SOMEWHAT LIKE IT DOES NOW, EVEN IN 1918. SO THE QUESTION IS, WHAT CAN WE DO BETTER THAN WHEN WE COULD DO THEN. I'M GOING TO FRAME THIS AROUND EMERGING VIRUS INFECTION IN GENERAL. STARTING WITH HIV BECAUSE IT CAME AND WAS DISCOVERED, IT SHOWED UP IN 1981, THE VIRUS WASN'T DISCOVERED UNTIL 1983 AND WE DIDN'T HAVE DIAGNOSTIC KITS UNTIL 1984. SO COMPARED TO WHAT'S BEEN DONE DURING THIS OUTBREAK WITH THESE KIND OF INTERVENTIONS AND DIAGNOSTICS BEING AVAILABLE WITHIN WEEKS OR MONTHS, IT'S QUITE DIFFERENT THAN IT WAS SEVERAL YEARS AGO. SO MOST EMERGING INFECTIONS ARE ZOONOTIC OR VECTOR BORN. WE HAVE HAD A NUMBER OF VIRUSES COME THROUGH OVER THE LAST FEW DECADES INCLUDING FLAMING VIRUSES, EBOLA, ZIKA, ACUTE MY LITIS AND THESE CORONA VIRUS, SARS, MERS AND SARS 2. THEY NOT ONLY COME THROUGH THE ZOONOTIC SOURCES, AND VECTORS BUT THEY ALSO ARE -- COME FROM US. THEY ARE SPREAD LARGELY THROUGH PERSON TO PERSON CONTACT AND AIR TRAVEL WHICH IS AS EVERYONE KNOWS EXPENSIVE. SO ANYTHING THAT HAPPENS ANYWHERE CAN BE EVERYWHERE WITHIN 24 HOURS BECAUSE OF THIS KIND OF EXTREME MOBILITY. THE VRC WAS FOUNDED BACK AROUND 2000, THE WORK ON HIV VACCINES. WE HAVEN'T MADE AN HIV VACCINE THAT'S EFFECTIVE YET. STILL A MAJOR PROGRAM AT THE VRC BUT THE TECHNOLOGY THAT IS LEVERAGED BY WORKING ON HIV HAS MADE ALL THESE OTHER THINGS POSSIBLE. SO THE INFLUENZA AND EBOLA PROGRAMS AND ALL THESE OTHER PROGRAMS, EMERGING INFECTIOUS DISEASE RESPONSES HAVE ALL BEEN USING TECHNOLOGY THAT WAS TRIGGERED BY WORKING ON HIV VACCINE. SO EVEN THOUGH WE DON'T HAVE AN HIV VACCINE, IT HAS CREATED A LOT OF OTHER POTENTIAL VACCINES RESOURCES. THE VRC IS NOT JUST BUILDING 40 BASIC RESEARCH BUILDING ON CAMPUS BUT THERE IS A PROCESS DEVELOPMENT GROUP OF 100 ENGINEERS IN GAITHERS BEARING, ANOTHER ZOO OR SO PEOPLE WORKING ON GMP MANUFACTURENING FREDERICK. WE HAVE A LARGE GROUP IN THE CLINIC DOING TRIALS AND BUILDING -- IN BUILDING 10. ANOTHER GROUP IN GAITHERS BEARING DOING LABORATORY PRACTICE ANALYSIS OF OUR CLINICAL SAMPLES. WE HAVE MADE OVER THE YEARS A NUMBER OF DIFFERENT VACCINE PLATFORMS. TODAY AT THE END WE WILL BE TALKING ABOUT mRNA BUT WE HAVE ALSO MADE NUCLEIC ACID VACCINES WITH DNA, WE HAVE USED GENE BASED VECTORS, PROTEIN BASED VIRUS LIKE PARTICLES AND A VARIETY OF PROTEINS INCLUDING SELF-ASSEMBLY NANOPARTICLES. ALSO MADE A NUMBER OF ANTIBODIES AND HAVE SENT THOSE TO MANY DIFFERENT PLACES IN THE WORLD. THIS IS MANAGED BY A RELATIVELY SMALL GROUP OF INVESTIGATORS LED BY JOHN MOSCOLA PICTURED HERE IN THE MIDDLE. ONE OF THE GOALS OF THE VRC IS TO TRY TO DEAL WITH THESE VACCINE CHALLENGES WHICH INCLUDE EMERGING VIRUSES BUT ALSO VACCINES RATHER UNMET NEEDS AND EFFORTS TO IMPROVE CURRENTLY LICENSED VACCINES. THE TRADITIONAL APPROACHES ARE WHAT'S CURRENTLY AVAILABLE IS OKAY BUT IT'S NOT REALLY DOING AS MUCH AS WE LIKE IT TO. WE CAN SEE THAT PASSIVE SURVEILLANCE AND CONTACT TRACING AND QUARANTINE ARE SOMEWHAT BEHIND THE CURVE. SO BETWEEN SINCE ABOUT 2009 THERE'S BEEN A NUMBER OF KEY TECHNOLOGIES THAT HAVE EMERGED THAT HAVE CHANGED OUR CAPACITY FOR MAKING NEW VACCINES OR CONCEDING OF NEW VACCINES. SO WHAT I WANT TO TALK ABOUT TODAY IS HOW DO THESE NEW TECHNOLOGIES HELP US ADDRESS WHAT APPEARS TO BE OR SEEMS TO BE AN ESCALATING FREQUENCY OF EMERGING INFECTIONS AND WHAT CAN WE DO ABOUT THAT. SO THE KEY ONE FOR ME AT LEAST IN THIS WILL COME UP SEVERAL TIMES IS STRUCTURE BASED VACCINE DESIGN. BEING ABLE NOW TO RAPIDLY DEFINE STRUCTURES OF PROTEINS IS ALLOWED US TO KNOW IN DETAIL ATOMIC LEVEL DETAIL OF THE SURFACE CONTOURS OF PROTEIN AND EXACTLY WHERE ANTIBODIES COMBINED AND NEUTRAIZE THE VIRUS. THE OTHER BIG TECHNOLOGY IS ABILITY FOR SINGLE CELL SORTING HIGH THROUGH PUT SEQUENCING AND BIOINFORMATICS THAT NOT ONLY GIVES YOU ABILITY TO RAPIDLY ISOLATE HUMAN ANTIBODIES BUT HELPS YOU DEFINE ANTIBODY LINEAGES THAT CAN BE ASSOCIATED WITH PROTECTION OR SOME OTHER OUTCOME OF INFECTS. AND GIVING NEW MOLECULAR TARGETS FOR A VACCINE PROGRAM. IT'S ALSO USED TO ANALYZE THE CLINICAL SAMPLES. THEN EVEN MORE RECENTLY, THERE'S BEEN A LOT OF ADVANCES IN PROTEIN ENGINEERING OF SELF-ASSEMBLY NANOPARTICLES WHICH GIVES YOU A DISPLAY FORMAT FOR SHOWING THE IMMUNE SYSTEM AND ORDERLY ARRAY OF ANTIGENS AND REALLY GOOD RESPONSES. SO THIS CATEGORY OF NEW TECHNOLOGIES CONTRIBUTEDS TO PRECISION. WE ALSO HAVE RAPID DNA SYNTHESIS. GET STARTED QUICKLY AND PLATFORM TECHNOLOGIES LIKE DNA AND RNA THAT WE'LL TALK ABOUT AND THE ABILITY TO MAKE RAPID CELL LINES OR RAPIDLY MODIFYING ANIMALS BE BETTER MODELS GIVE US A CHANCE FOR BETTER SPEED. SO WITH THOSE IMPROVED PRECISION AN BETTER SPEED, WHAT CAN WE DO ABOUT INCREASING NUMBER OF E EMERGENCYING INFECTION? WE THINK USING THESE NEW TECHNOLOGIES THAT WE CAN START DEVELOPING A MORE GENERALIZABLE APPROACH THAT CAN FACILITATE EVEN MORE WAY OF THINKING ABOUT THIS INFORMATION ENGINEERING WAY INSTEAD OF ITERATIVE EMPIRICAL WAY THAT HAS BEEN TRADITIONALLY. SO THIS CONCEPT OF SYNTHETIC VACCINOLOGY, ANY TIME ANYONE IN THE WORLD IS -- HAS A VIRUS THAT CAN BE SEQUENCED, AND TRANSFERRED TO PLACES THAT UNDERSTAND WHAT THE TARGET OF A VACCINE SHOULD BE, ET CETERA, USE THAT DNA TO SYNTHESIZE PROTEINS MADE WITH ANTIBODIES AND RAPIDLY GET A VACCINE PROGRAM STARTED EVEN WITHIN JUST A FEW WEEKS OF HAVING A NEW VIRUS ISOLATED AND SEQUENCED. THE PLATFORM TECHNOLOGIES HELP MORE ON THE OTHER END WHERE YOU ARE TRYING TO MAKE A PRODUCT MORE QUICKLY. THEY FACILITATE AND SPEED THAT PROCESS BECAUSE THEY USE THE SAME CHEMICALS, THE SAME PURIFICATION PROCESS, THE SAME ANALYSIS END POINTS THAT FOR EVERY PRODUCT THEY MAKE. BUT YOU CAN PUT A SARS SPIKE LIKE WE DID IN 2003 WHERE HEMOGLUTENIN OR PANDEMIC VIRUS IN 2009 OR ZIKA VIRUS GENES THAT MAKE A PARTICLE AND YOU CAN SEE OVER THE LAST 15, 20 YEARS THAT TIME FOR MANUFACTURING HAS DROPPED DOWN TO AROUND 100 DAY THE TIME YOU CAN FIND SEQUENCE, WE THINK SOME TECHNOLOGIES CAN GET DOWN TO EVEN 50 DAYS SO YOU CAN HAVE A GMP PRODUCT WITHIN A FEW WEEKS AFTER THE FIRST SIGN OF TROUBLE. THE THING THAT CHANGED THE WAY I HAVE THOUGHT ABOUT VACCINE DEVELOPMENT WAS OUR EXPERIENCE WITH RSV. RSV HAS BEEN A RECOGNIZED PROBLEM SINCE THE 1950s. VACCINE EFFORTS HAVE BEEN SOLVED BY VACCINE ENHANCED ILLNESS SYNDROMES BACK IN THE '60s AND THEN JUST A LACK OF EFFICACY SINCE THEN. SO IN 2013 IN COLLABORATION WITH PETER QWONG AND POST-DOC IN HIS LAB AT THE TIME WE WERE ABLE TO SOLVE THE STRUCTURE OF PRE-FUSION OR PRE-REARRANGED STRUCTURE OF THE FUSION GLYCO PROTEIN ON THE SURFACE VIRUS SURFACE OF RSV. WHAT HAD TYPICALLY BEEN HAPPENING THIS PROTEIN IS VERY META STABLE SO IT TRIGGERS EVEN SPONTANEOUSLY IN THIS POST VISION FORM, KILLS THIS PROTEIN, DESIGNED TO REARRANGE AND PULL MEMBRANES TOGETHER SO IT'S MASS REARRANGEMENT THAT OCCURS. YOU CAN SEE THAT THE DISCOVERY OF THIS NEUTRALIZATION SENSITIVE EPITOPE, THIS EPIDOES NOT EXIST ON REARRANGED MOLECULE. WHAT WE KNOW FROM OUR EXPERIENCE FOR THE LAST 30 YEARS IS USING THIS MOLECULE FOR VACCINATION INDUCEMENT OF PEOPLE ONLY INCREASE NEUTRALIZING ACTIVITY BY TWO OR THREEFOLD. IF YOU CAN FIND WAYS TO STABILIZE THIS MOLECULE, WITH THE TRIMERRIZATION DOMAIN AND INTERNAL MUTATIONS, YOU CAN NOW BOOST PEOPLE AND GET RESPONSES UP TOP 16 FOLD ABOVE BACKGROUND WHICH NOW MEANS YOU CAN DO MATERNAL IMMUNIZATION AND TRANSFER ANTIBODY THAT COULD LAST SEVERAL MONTHS. SO THIS IDEA OF STRUCTURE BASED DESIGN DEFINING THE NATIVE STRUCTURE STABILIZING THAT STRUCTURE, HAS BEEN APPLIED TO RSV SUCCESSFULLY. RSV F IS ONE OF SEVERAL OTHER CLASS 1 FUSION PROTEINS AMONG ENVELOPE VIRUSE THAT YOU ARE FAMILIAR WITH, EVEN INFLUENZA, HIV AND EBOLA BUT MOST SIMILAR TO THE PARAMIXEL VIRUS F PROTEINS SHOWN HERE, THEY ARE A LITTLE DIFFERENT SHAPE BUT THEY HAVE THE SAME DOMAIN STRUCTURE. BUT IT IS ALSO LIKE CLASS ONE FUSION PROTEIN SPIKE IN CORONA VIRUS. EVEN THOUGH IT'S MAIN STRUCTURE IS A LITTLE DIFFERENT, IT'S OVERALL ORGANIZATION AND FUNCTION IS THE SAME. SO CAN WE LEARN NOT ONLY WITHIN VIRUS FAMILIES BUT ACROSS VIRUS FAMILIES. WE HAVE USED THIS TECHNOLOGY NOW TO IMPROVE OR MAKE NEW VERSIONS OF MEASLES AND MUMPS, CANDIDATE VACCINES USING MAKING A PRE-F FOR MEASLES WHICH ARE BOTH PARAMIXEL VIRUS OR PREF FOR MUMPS. USING THE POST F MOLECULE REARRANGED IS LESS IMMUNOGENIC THAN THE PREF MOLECULE THAT CAN BE STABILIZED. WE HAVE DONE THE SAME THING FOR ZIKA VIRUS, YOU CAN SEE PRE AND POST AND FROM SPECIFIC ANTIBODY FROM BINDING HERE. YOU CAN EVEN DO OTHER THINGS LIKE ADD A HEMOGLUTENIN OR G PROTEIN HINDER OR THE HN PROTEIN MUMPS AND HAVE A SINGLE CHAIN OF PRE-F WITH THE OTHER IMPORTANT ANGIOGENIC TARGET ON THESE VIRUSES. AND NOW HAVE A WAY OF RAPIDLY DESIGNING LIVER UNDAUNTED GENERAL. -- ANTIGEN. SO THE CORONA VIRUSES ARE A LARGE FAMILY OF -- IS A LOT OF VETERINARY CORONA VIRUSES THAT ARE -- HAVE HIGH IMPACT. THERE'S HUNDREDS IF NOT THOUSANDS OF CORONA VIRUSES HIDING AND ANIMALS AND ESPECIALLY IN BATS. WE HAVE FOUR CORONA VIRUSES THAT ROUTINELY CIRCULATE IN THE HUMAN POPULATION. THOSE ARE ENDEMIC CORONA VIRUSES ALPHA CORONA VIRUSES BETA CORONA VIRUSES AND THEY CAUSE 40% OF THE COMMON COLD IN HUMANS. NOW OVER THE LAST 15 OR SO YEARS WE HAVE HAD 3 NEW BETA CORONA VIRUSES AND A COUPLE OF SUB CLADES THAT THREE NEW BETA CORONA VIRUSES EMERGE. THE FIRST WAS THE FIRST SARS WHICH I THINK HILLARY FOLK SPUE YOU LAST WEEK. IT CAME -- SPOKE TO YOU ABOUT LAST WEEK. IT CAME ON IN DECEMBER. AND WAS SCARY, EVEN LIKE THE CURRENT SARS AND SPREAD THROUGHOUT THE WORLD, THROUGH MOST OF THE WORLD BUT THEN ABOUT SIX MONTHS LATER IN JULY, THIS PEERED AND HAS -- DISAPPEARED AND HAS NOT COME BACK. THAT SARS HAD A 10% CASE FATALITY RATE AT LEAST AMONG DIAGNOSED CASES. I WANTED TO JUST POINT OUT HERE THIS TIME LINE I SHOWED YOU EARLIER THAT WE DID THIS 20 MONTHS VACCINE BUT NOTICE THIS VIRUS MERGE IN THE SYNDROME EMERGED IN MARCH. IT TOOK OVER A MONTHS TO -- THE VIRUS EMERGED IN NOVEMBER OF 2002, IT TOOK UNTIL MARCH TO DIAGNOSE IT AS A VIRUS AND ANOTHER MONTH TO GET IT SEQUENCED SO COMPARED TO WHAT'S HAPPENING NOW IS A VAST DIFFERENCE, BECAUSE OF THIS SEQUENCING TECHNOLOGY THAT WE ARE REFERRING TO. THE INITIAL VACCINE DELIVERED BY DNA USING THIS FREE INJECTION DEVICE HAD SOMEHOW GENICITY THIS VIRUS ASSAY RELATIVELY CENTERED SO THIS WAS NOT A VACCINE THAT REALLY COULD BE TAKEN FORWARD. AND WHEN THE VIRUS DISAPPEARED, PEOPLE STOPPED THINKING ABOUT IT. BUT THEN ABOUT TEN YEARS LATER ANOTHER CORONA VIRUS CAME LOCATED IN THE MIDDLE EAST. IT HAD A MUCH HIGHER CASE FATALITY RATE, ALMOST 40%, BUT DIDN'T SEEM TO GET TRANSPORTED OUT OF THE COUNTRY ANY GREAT EXTENT EXCEPT ONE BIG OUTBREAK IN SOUTH KOREA, A LITTLE OVER 180 PEOPLE. SO WITH TWO BETA CORONA VIRUSES COMING TEN YEARS APART KNOWING JUST SEEMED OBVIOUS THAT THIS WAS GOING TO HAPPEN AGAIN. PEOPLE STARTED MAKING VACCINES APPROACHES FOR THIS BOTH BY PROTEINS, GENE DELIVERY DEVICES OR EVEN LIVE ATTENUATED VIRUSES. WE EVEN MADE A VACCINE THAT WAS IN MONKEYS USING DNA ONLY, DNA BOOST WITH PROTEIN OR PROTEIN ALONE AND YOU CAN SEE NOW WE ARE GETTING IMMUNE RESPONSES UP ININTO THE RANGE OF OVER A THOUSAND. SO THIS IS A MUCH MORE IMMUNOGENIC APPROACH VACCINATION BUT AGAIN, IT EVEN SEEMEDDED TO HAVE SOME EFFICACY IN THE MONKEY MODELS BUT AGAIN, THE DISEASE DIDN'T SPREAD THAT FAR AND THERE WAS NOT LOT MOTIVATION TO MAKE VACCINE PRODUCTS FOR THIS. WE ALSO ISOLATED MONOCLONAL ANTIBODIES FROM MICE AND MONKEYS AND HUMANS AND FOUND SOME THAT HAD PRETTY HYPOTEN SAY AND EVEN GENERATED SOME THAT COULD POTENTIALLY BE USED IN ANOTHER OUTBREAK BUT AGAIN THEY HAVEN'T BEEN MANUFACTURED FOR YEARS BECAUSE THE SENSE WAS THAT MERS WAS NOT URGENT ENOUGH TO DO THAT. THE REAL BREAK THROUGH CAME LIKE FOR RSV WHEN WE WERE ABLE TO SOLVE THE STRUCTURE OF A SPIKE PROTEIN ON A HUMAN CORONA VIRUS. THE STORY BEHIND THIS IS ONE OF OUR LAB PEOPLE TRAVELED TO THE MIDDLE EAST, CAME BACK SICK WITH HIS PREGNANT WIFE. BOTH WERE SICK AND BOTH HAD PCR PRODUCTS THAT WERE CORONA VIRUS. WE THOUGHT HE WOUL HAVE THE MERS CORONA VIRUS BUT HE HAD ONE OF THE ENDEMIC VIRUS HPN 1. WE TRIED TO SELL THE STRUCTURE FOR A WHILE BUT UNSUCCESSFUL BUT WHEN WE STARTED WORKING ON IT BECAUSE IT WAS LOW CONTAINMENT AND WE CAN DO A LOT WITH THIS VIRUS WITHOUT BL 3 SPACE, TURNED OUT THIS SPIKE PROTEIN WAS MORE STABLE THAN SARS OR MERS SPEAKS SO IT ALLOWED US IN COLLABORATION WITH JASON AND ANDREW WARD AT SCRIPS TO GET THIS CRYOEM STRUCTURE SPIKE OF HP 1. WHEN WE GOT THAT STRUCTURE, WE EXAMINED IT AS WE DID FOR RSVF COUPLE OF MUTATIONS WERE FOUND, PROPROLIENS FOUND AT THE HELIX TO STABILIZE THE PROTEIN. THOSE TWO STABILIZING PROLIEN PATIENTSES IF YOU ALIGNED THE SEQUENCES FOR MERS AND SARS, COULD BE INSERTED THE SAME PLACE AND LARGELY STABILIZE BOTH MERS AND SARS. SO WE ARE STABILIZING THE PROTEIN IN THIS CONFIRMATION THAT PRESERVED SENSITIVE EPITOPES BUT MORE IMPORTANTLY IN OUR OPINION WAS THAT IT ALSO INCREASED STRESS LEVELS. SO THE MERS SPIKE WAS EXPRESSED TRANSFECTED CELLS UP TO 50 FOLD HIGHER THAN IT WAS FOR THE WILD TYPE VERSION OF THE PROTEIN WHICH MADE NOW POSSIBLE TO MAKE FULL LENGTH PROTEIN BEFORE WE WERE ONLY MAKING THE S 1 PORTION WHICH OBVIOUSLY DOESN'T HAVE THE RIGHT CONFIRMATION. SO THIS ALLOWED US TO MAKE FULL LENGTH STABILIZED SPIKE PROTEINS. AND ALLOWED US TO SOLVE THE STRUCTURES THEN OF THE MERS AND THE SARS AND MAP SOME OF THE ANTIBODIES WE HAD TO THE END TERMINAL DOMAIN OR THERE'S A COUPLE OF WAYS ANTIBODIES COMBINE RECEPTOR BINDING DOMAIN, THIS IS THE RECEPTOR BINDING DOMAIN, STICKING UP, THESE RBDs FLIP UP ONE AT A TIME UNTIL THEY COMBINE THEIR RECEPTOR FOR MERS WITH THE DPP 4 AND THIS ANTIBODY HERE IS BINDING THE EXACT RECEPTOR BINDING SITE. THIS ANTIBODY IS ON THE OTHER SIDE OF THE RBD, THERE IS ANOTHER HERE THAT IS NEUTRALIZING. THE MTD HAS ANTIBODIES THAT COME THIS WAY AND ANOTHER ONE THIS FROM THE SIDE THAT NEUTRALIZE BY BINDING THIS BOB ON THE EDGE OF THE VIRUS HERE. THERE IS EVEN AN ANTIBODY SIMILAR TO ONES DESCRIBED FOR INFLUENZA THAT CAN BIND STEM OF THE SPIKE PROTEIN AND NEUTRALIZE VIRUS. SO HAVING THIS STRUCTURE AND MAKING PROTEINS OFFICIALLY CHANGED EVERYTHING. ALSO ALLOWED TO ISOLATE OR SOLVE STRUCTURES OF OTHER ENDEMIC CORONA VIRUSES LIKE THE ALPHA CORONA VIRUS 9E AND VETERINARY AND EVEN SOME SARS LIKE POTENTIAL EMERGING CORONA VIRUSES FROM BATS SHOWN HERE DEFINED BY RALPH BARRETT. IT ALLOWED US TO MAKE ENOUGH PROTEIN TO MU RECOGNIZE SO INSTEAD OF JUST USING THE S 1 PROTEIN LIKE BEFORE OR THE WILD TYPE PROTEIN THAT WAS VERY DIFFICULT TO MANUFACTURE WE COULD USE A STABILIZING IN A FORM PREFUSION F AND PREFUSION SPIKE PROTEIN AND EVEN DOWN TO VERY SMALL DOSES OF PROTEIN YOU CAN GET STILL PRESERVE NEUTRALIZING TITERS EVEN ABOVE 10,000. YOU CAN SHOW THAT THAT STABILIZE SPIKE WHAT WE CALL THE S 2P, TWO PROLIENS HAD HIGHER LEVELS OF NEUTRALIZING ACTIVITY, BROAD RANGE OF STRAINS FOR MERS. WE CAN SHOW THAT THAT PROTEIN COULD PROTECT VPP 4 TRANSGENIC MICE THAT ARE OTHERWISE HAVE FATAL DISEASE AND YOU CAN COMPLETELY PROTECT THEM WITH A RELATIVELY LOW DOSE OF PROTEIN. SO ABOUT THREE OR FOUR YEARS AGO WE DECIDED WE THOUGHT WE KNEW HOW TO MAKE A BETTER CORONA VIRUS ANTIGEN BUT IF ANYTHING EVER HAPPENED AGAIN WE WANTED TO BE ABLE TO DELIVER IT QUICKLY. SO WE COLLABORATED WITH (INAUDIBLE) mRNA VACCINE COMPANY WHO HAS A PLATFORM TECHNOLOGY AND CAN DELIVER GENES ENCODED BY mRNA WHICH TENDS TO BE MORE POTENT, WE FOUND IN ZIKA AND OTHER SYSTEMS, THEN THE DNA THAT WE USED BEFORE. AGAIN, THE THE STABILIZED VERSION OF mRNA EVEN DOWN TO THIS TEN NANOGRAMS DOSES WAS ABLE TO PRESERVE VERY GOOD LEVELS OF NEUTRALIZING ACTIVITY SHOWN HERE WITH THIS 60 NANOGRAM DOSE IN MICE. PROBLEM HERE IS THAT WE NEVER FINISHED TAKING THAT mRNA INTO HUMANS BECAUSE STILL THERE'S NOT A LOT OF INCENTIVE FOR WORKING ON SOMETHING THAT SEEMS TO BE REGIONAL DISEASE. WE WILL GET BACK TO THAT IN A MINUTE. BUT THE POINT WAS WE COULD TAKE SPIKE FROM SEVERAL CORONA VIRUS STRAINS AND STABILIZE WITH PROLIEN MUTATION, SHOW THE STABILIZED SPIKES WERE MORE IMMUNOGENIC AND PROTECTIVE THAN WILD TYPE FOR MONOMERIC SUBUNITS AND THOUGHT IT COULD BE A GENERAL SOLUTION FOR BETA CORONA VIRUS VACCINE ANTIGENS. CORONA VIRUS IS ENTERING THE HUMAN POPULATION FOR HUNDREDS OF YEARS, YOU HAVE SEEN HERE THAT TWO ALPHA CORONA VIRUSES ARE THOUGHT TO HAVE COME IN A FEW HUNDRED YEARS AGO, MANY ORIGINATE IN BATS OR RODENTS THEN COME THROUGH SOME ANIMAL INTERMEDIATE HOST WHERE IT CAN BE AMPLIFIED LIKE THE CAMEL FOR MERS. OR THE CAT FOR THE FIRST SARS INFECTION. THESE EVENTS OCCUR EVERY SO OFTEN AND THE OC 43 WAS THOUGHT TO BE THE PANDEMIC THAT OCCURRED IN 1880 THAT WAS NEVER REALLY DEFINED. AND THEN 1881 WAS DISCOVERED IN A LITTLE OVER AROUND 20 YEARS AGO. IF SOMETHING ELSE OCCURRED, THESE HAPPEN MORE OFTEN WE WANTED TO BE READY. THEN HEARD END OF DECEMBER 2019 ABOUT THE NEW SARS 2 CORONA VIRUS. WE WERE ON THE PHONE WITH OUR COLLABORATORS AT MADERN ON 6 JANUARY WHEN WE HEARD A RUMOR IT MIGHT BE A CORONA VIRUS. SO WHEN THE SEQUENCES WERE RELEASED ON FRIDAY NIGHT, THE 10TH, THE NEXT MORNING THE SEQUENCES WERE ANALYZED AND WE DEFINE MUTATIONS WE WANTED TO MAKE AND ORDERED THE SEQUENES AND WITHIN A WEEK WE WERE ABLE TO GET SEQUENCES, MADE PROTEINS, DOING ELISA ASSAYS BUT ALSO WITH JASON MCCLELLAN, GET A STRUCTURE OF THE PRE-FUSION SPIKE USING HIS NEW CRYOELECTRON MICROSCOPY SYSTEM AT UC AUSTIN. SO THE SPIKE STRUCTURE WAS SOLVED QUICKLY. AND THE PROTEIN WAS MADE QUICKLY. PROTEIN IS CRITICAL BECAUSE THIS IS THE ONLY WAY THE VIRUS CAN GET INTO CELLS. THIS RECEPTOR BINDING DOMAIN OF ONE OF THE PROTOMERS AND TRIMER FLIPS UP SO IT CAN INTERACT WITH ACE 2 MOLECULE THAT INITIATES THE UNFOLDING OF THIS TOP PART AND LEAVES BOTTOM PART AS FUSION MACHINERY, THIS IS THE FIRST STEP. THE WAY YOU BLOCK THAT STEP IS ANTIBODIES. WE KNOW IF WE MAKE ANTIBODIES THE END MATERIALNAL DOMAIN RECEPTOR -- TERMINAL DOMAIN RECEPTOR BINDING DOMAIN AND EVEN STEM WE CAN CREATE NEUTRALIZING ACTIVITY AND PROTECT AGAINST THIS INFECTION. BASED ON THIS PREVIOUS WORK OF STRUCTURE BASED DESIGN, ANTED BODY IDENTIFICATION AND -- ANTIBODY AND MAPPING OF FOOTPRINT AND NEUTRALIZATION ALLOWED US TO TAKE THIS RAPID START, WITHIN THREE DAYS FROM THE SEQUENCE RELEASE, MADERNA TOOK A RISK AND STARTED GMP MANUFACTURING OF THE mRNA PRODUCT BASED ON PRIOR WORK OF KNOWING HOW TO MAKE THESE STABILIZE MUTATIONS. BY THE END OF JANUARY WE WERE MAKING PROTEINS DOING ELISAS AND HAVING A STRUCTURE. THE STRUCTURE WAS IMPORTANT BECAUSE WE STILL DIDN'T HAVE ANY MONOCLONAL ANTIBODIES. USUALLY IN THE STRUCTURE BASED WORK WE HAVE ANTIBODIES TO GUIDE THE KNOWING YOU ARE MAKING THE RIGHT THING. BUT IN THIS CASE SINCE WE CAN SOLVE THE STRUCTURE AND ELECTRON MICROSCOPY WE WERE CONFIDENT WE HAD THE RIGHT PROTEIN AND IT WAS IMMUNOGENIC IN MICE YOU CAN MAKE NEUTRALIZING ACTIVITY THAT'S PUBLISHED AND THEN MADERNA WAS ABLE TO SEND EMP MATERIAL TO DMID INVESTIGATORS HOLDING THE IND AND DOING -- SETTING UP TRIAL SITES WITHIN THEIR EXTRAMURAL VPU NETWORK. SO WITHIN 40 DAYS MADERNA DELIVERED A GMP PRODUCT. THE LAST 24 DAYS WAS REALLY JUST TRYING TO GET THROUGH THE IRB PROCESS AND THE IND PROCESS. FIRST TIME I HAVE SEEN MANUFACTURING OUTPACE THE CLINICAL PROCESS, REGULATORY PROCESS. AND EVEN THAT COULD HAVE BEEN SHORTENED IF WE HAD TAKEN THE MERS mRNA VACCINE ALL THE WAY THROUGH INTO PHASE 1 TRIAL. SO THIS THREE WEEKS COULD HAVE BEEN SHORTENED EVEN FURTHER. COMPARED TO WHAT WAS DONE IN THE PAST THE FASTEST PREVIOUS TIME LINE, ZIKA WAS A HUNDRED DAYS, A HUNDRED DAYS FROM THE TIME WE SELECT SEQUENCING, IT TOOK A LITTLE OVER THREE MONTHS THAT WE WANTED TO USE SO THIS WAS 200 DAYS SO THIS IS ABOUT 140 DAYS SHORTER THAN ZIKA EFFORT. THERE IS A LOT OF OTHER THINGS GOING ON. I WANT TO TELL YOU STORY OF MRNA BECAUSE THAT HAS -- WE HAVE ALREADY STARTED THE CLINICAL TRIAL ON THE 16TH OF MARCH, WE IMMUNIZED INITIAL SENTINEL COHORT WITH SECOND DOSE AND WE ARE GOING TO BE HAVING ANTIBODY DATA AT LEAST ON THE FIRST FEW SUBJECTS BY THE MIDDLE OF MAY. BUT MEANTIME THERE IS OTHER EFFORTS GOING ON. SO I WANTED TO SHOW YOU THIS, THERE IS 115 DIFFERENT CANDIDATE VACCINES BEING DEVELOPED AT DIFFERENT PARTS OF THE WORLD AS SHOWN HERE ON THIS CHART, SHOWING MANY OF THEM ARE IN NORTH AMERICA BUT THEY ARE REALLY COMING FROM ALL OVER THE WORLD, EUROPE AND CHINA AND OTHER PARTS OF ASIA. THEY ARE ALL SORTS OF TYPES OF VACCINE CONCEPTS. SO INACTIVATED, VECTOR BASED RECOMBINANT PROTEINS, PEPTIDE BASED VIRAL LIKE PARTICLES, ET CETERA. SO WHAT I THINK WE REALLY NEED IS ABOUT TEN GOOD VACCINE PROGRAMS AND 115 MAKES ACTUALLY MORE DIFFICULT TO SPLIT FROM AND FIGURE OUT HOW TO ADVANCE ANY GIVEN ONE BEST PRODUCT. I WANT TO SAY SOMETHING MORE ABOUT HOW WE SHOULD BE PREPARED. WE ARE LUCKY IN THIS CASE THAT WAS A CORONA VIRUS BECAUSE WE KNEW HOW TO MAKE AN ANTIGEN. BUT IF IT HAD BEEN AN ARENA VIRUS OR BUNYA VIRUS, IT WOULD HAVE BEEN TAKEN MONTHS OR YEARS TO FIGURE OUT WHICH SEQUENCES AN WHICH ANTIGENS WE WOULD LIKE TO USE. BUT THE QUESTION IS, IS IT REALLY GOOD TO HAVE 150 VACCINE CANDIDATES? IT GETS TO HOW YOU PREPARE AHEAD OF TIME. I'M GOING TO JUST SAY A FEW MORE WORDS THEN END WITH THIS. WE LIKE TO THINK OF A PROTOTYPE PATHOGEN APPROACH TO THIS& PROBLEM. OTHER GROUPS LIKE WHO AND SEPE COALITION FOR EPIDEMIC PREPAREDNESS AND INNOVATION USE THESE PRIORITY PATHOGEN APPROACHES AND MERS AND SARS TYPE CORONA VIRUSES ARE DEFINITELY ON THEIR LIST BUT THEY ALSO HAVE SOME BUNYA VIRUSES AND EVEN SOME ARENA VIRUSES ON THAT LIST THAT HAVE NOT BEEN SOLVED YET. AND THEN WE HAVE TALKED ABOUT THE PLATFORM AAPPROPRIATES, THIS ALLOWS YOU TO GO FAST -- APPROACHES BUT WHAT IS IT YOU HAVE TO WORK ON AHEAD OF TIME TO BE READY TO KNOW WHAT TO DO. SO THERE IS MORE THAN 100 VIRUS FAMILIES ON EARTH THAT HAVE BEEN RECOGNIZED BUT ONLY 25 FAMILIES HAVE BEEN SHOWN TO INFECT HUMANS. THERE IS VACCINE PRODUCTS ASSOCIATED WITH 13 FAMILIES BUT IN THE OTHER 12 FAMILIES THERE'S I THINK AT LEAST 17 PRIORITY VIRUSES THAT DON'T HAVE ANY VACCINES AVAILABLE. WITHIN THOSE FAMILIES THERE IS ABOUT A LITTLE OVER 100 OTHER VIRUSES THAT COULD POTENTIALLY BE THREATS FROM HUMAN TO HUMAN. AND WE ARE BECOMING MORE VIRULENT THAT YOU LIKE TO TAKE CARE OF SO THIS IS A LARGE -- A SOLVABLE PROBLEM WE THINK. WITH THE NEW TECHNOLOGIES THAT WE HAVE, BY DIVIDING THE WORK MAYBE BETWEEN MECHANISMS OF ENTRY LIKE CLASS ONE FUSION PROTEIN VIRUSES ARE LISTED HERE, CLASS 2 THE BETAS AND ALPHAS AND BUNYAS FIT INTO THIS CATEGORY. THE LAST THREE LIKE HERPES, NON-ENVELOPE VIRUSES COULD BE OVER HERE, DEDICATED GROUP OF INVESTIGATORS TRYING TO SOLVE STRUCTURES MAKE MONOCLONAL ANTIBODIES, DEVELOP BASIC CORE INFORMATION WE NEED ABOUT REPLICATION PROCESS, AND ANGIOGENIC DIVERSITY AND THING LIKE THAT THAT YOU NEED TO HAVE TO DESIGN VACCINES. IF THEY CAN BE PAIRED WITH CORE LABORATORY FUNCTIONS THAT DO THE PROTEIN PRODUCTION AND ALL OF THESE OTHER FEATURES INCLUDING PROCESS DEVELOPMENT AND MANUFACTURING AND GETTING THROUGH PHASE 1 CLINICAL TRIALS, WE THINK THAT USING THAT AT LEAST ONE PROTOTYPE FOR EVERY FAMILY OR GEE NEWS THAT IS DISTINCT THAT HAVING THAT INFORMATION AHEAD OF TIME WAS SOME PRODUCTS ON THE SHELF AND OTHERS AT LEAST THROUGH ANIMAL PHASE TESTING, WILL ALLOW US TO GET OFF TO MUCH BETTER STARTS ON EITHER PREPAREDNESS OR PANDEMIC RESPONSE. SO WE KNOW A LOT ABOUT TARGET ANTIGENS AND WE CAN QUICKLY DESIGN THINGS THAT MAKE SENSE FROM SEQUENCE THAT'S GIVEN TO US. WE CAN MAKE ANIMAL MODELS IF IT'S ALL REQUIRED IS RECEPTOR. THEY CAN BE MADE THROUGH TRANSGENIC TECHNIQUES AND THEN ANALYSIS AND UNDERSTANDING WHAT -- HOW TO DELIVER VACCINE IS ALSO UNKNOWN WITH THESE SINGLE CELL ANALYSIS, GIVES YOU -- AND GIVES YOU EPITOPE SPECIFIC PHENOTYPING YOU CAN DO PROTEIN ENGINEERING AND EITHER DISPLAY THINGS TRIMERS AND MONOMERS ON COMPLEX SELF-ASSEMBLY NANOPARTICLES, YOU CAN GIVE IT BY PATCHES, YOU CAN GIVE BY GENE BASED OR VECTOR BASED TYPE DELIVERY. IF WE COULD DO THIS IN A SYSTEMATIC COMPREHENSIVE WAY OVER ALL THESE 25 VIRUS FAMILIES WE WOULD BE MUCH DIFFERENT POSITION TO HAVE SOMETHING ON THE SHELF OR SOMETHING WE CAN RAPIDLY MAKE. SO IN SUMMARY, THESE TECHNOLOGIES ARE TRANSFORMING VACCINOLOGY COMBINING ATOMIC LEVEL ANTIGEN DESIGN WITH PLATFORM MANUFACTURING HAS A WAYS OF CREATING GENERALIZABLE SOLUTIONS FOR ANTIGEN DESIGN AND WE THINK THEY TOGETHER CREATE A POSSIBILITY AND FEASIBLE PROTOTYPE PATHOGEN APPROACH WITH PANDEMIC PREPAREDNESS RATHER THAN SELECTING A FEW OFF THE TOP THAT YOU WOULD BE WORRIED ABOUT YOU WOULD DO IT IN A MORE COMPREHENSIVE WAY. I WANT TO THANK SOME PEOPLE HERE. INVESTIGATORS AT THE THE VRC HAVE BEEN VERY INVOLVED IN ALL THESE STEPS AND PETER QONG AND I WORK TOGETHER TO SOLVE THAT INITIAL RSVF PROTEIN PROBLEM. THESE ARE THE PEOPLE IN MY LAB, I WANT TO PINTOES SPECIALLY (INDISCERNIBLE) WHO LED A SMALL GROUP OF CORONA VIRUS PEOPLE OVER THE LAST FIVE YEARS. INCLUDING (INDISCERNIBLE) AND JEFFREY HUTCHINSON HERE. I WANT TO THANK THEM, KAYLEN HAS BEEN INVOLVED IN HELPING TO DO THE PROGRAM MANAGEMENT FOR THIS GROUP OVER THESE LAST FEW MONTHS. THE OTHER PROGRAM HEADS LISTED HERE HAVE BEEN VERY INVOLVED AND HILLARY MARSTEN AND CRISTNA HAVE BEEN VERY INVOLVED IN DEVELOPING IDEAS AROUND THE PROTOTYPE PATHOGEN APPROACH. ALSO WANT TO THANK JASON MCCLELLAN WHO HAS BEEN A LONG TERM COLLABORATOR, WE WORKED WITH HIS GROUP AT DART MOUTH AND NOW UT AUSTIN. ANDREW WARD HELP WITH THE INITIAL SOLUTION OF HKE 1 CORONA VIRUS SPIKE AND ONGOING COLLABORATIONS WITH INVESTIGATORS AT VANDERBILT AND UNC THAT HAVE BEEN VERY HEALTHFUL AND OTHER PROJECTS WITH KNEEL KING WHO IS THE ONE DESIGNING THESE NANOCAGES. I WILL END HERE BY JUST THANKING ALL THE DIFFERENT GROUPS EITHER GOVERNMENT GROUPS, DIFFERENT DIVISIONS DIFFERENT AGENCIES, ACADEMIA AND PUBLIC HEALTH GROUPS THAT HELPED AND BEEN ACTIVELY INVOLVED IN GETTING THROUGH THIS INITIAL PHASE OF VACCINE DEVELOPMENT. SO THANK YOU VERY MUCH. >> THANK YOU VERY MUCH, BARNEY, FOR A WONDERFUL COMPREHENSIVE TALK. PRESENTATION OF THIS VERY ISSUE AND TOPIC IN THE COVID PANDEMIC. BEFORE I START WITH QUESTIONS WE HAVE FROM THE AUDIENCE, I WANT TO REMIND EVERYONE YOU CAN CLAIM CME CREDIT AND THE CODE FOR THAT IS 24873. ALSO JUST ANOTHER QUICK REMINDER THAT WE'RE GOING TO HAVE DR. FRANK TALK ABOUT HIGH DOSES NEXT WEEK AT THE SAME TIME SAME DAY. THE QUESTIONS THAT ARE COMING IN -- WE WOULD LIKE TO KNOW IF THERE ARE POWERPOINT STUDIES IN ANIMAL MODELS TO SORT WHICH VACCINES ARE MOST LIKELY TO BE SUCCESSFUL. WHETHER YOU CAN USE THESE TO SHORT CUT THE SORTING PROBLEMS AND IMMUNIZATION PROTOCOLS. >> WELL, YES WE ARE DOING A LOT OF ANIMAL MODEL WORK. WE ARE DOING IMMUNOGENICITY STUDIES THE MICE. SOME OF THOSE WILD TYPE MICE CAN NOW BE INFECTED WITH A SLIGHTLY MODIFIED SARS 2 CORONA VIRUS MODIFIED COUPLE OF AMINO ACIDS AND RECEPTOR BINDING DOMAIN AND NOW THAT VIRUS CAN INFECT WILD TYPE MICE SO THOSE MICE ARE BEING CHALLENGED AND WE ARE LOOKING FOR PROTECTION THERE. WE ARE ALSO DOING STUDIES IN HUMAN PHASE 2 RECEPTOR TRANSGENIC MICE, THOSE MICE WERE DEVELOPED BY RALPH BACK 15 YEARS FOR THE FIRST SARS. TURNED OUT THEY ALSO ARE EFFECTIVE FOR BINDING AND LETTING VIRAL ENTRY OCCUR FOR THIS SARS 2. IN PARALLEL WE ARE DOING STUDIES IN NON-HUMAN PRIMATES AND OTHER STUDIES ARE BEING STARTED IN OTHER TYPES OF ANIMAL MODELS. BUT IN ORDER TO MOVE THE VACCINE THROUGH THE STAGES WE HAVE TO DEMONSTRATE IMMUNOGENICITY AND POTENTIAL FOR EFFICACY OR DEMONSTRATION OF EFFICACY IN ANIMAL MODELS. AND WE HAVE TO SHOW THAT THE VACCINES ARE SAFE. SO HAVE TO SHOW THERE IS ABSENCE OF ANY SAFETY SIGNAL IN THE PATHOLOGY OR IN THE IMMUNE RESPONSE PATTERNS, BOTH IN ANIMALS AND IN HUMANS AS WE ENROLL MORE PEOPLE BUT A LOT OF THESE THINGS CAN BE DONE IN PARALLEL AND THEN THERE'S INCREMENTAL STEPS TAKEN AND ENROLLMENT PROCESS OF THE TRIALS THAT KEEP ADVANCING. >> THANK YOU VERY MUCH. THE OTHER QUESTION IS WHETHER THERE ARE ANY PRELIMINARY RESULTS WITH VACCINE SUGGESTING GOOD TITERS OF NEUTRALIZING ANTIBODIES. >> I CAN'T REALLY TALK ABOUT THAT BECAUSE IT'S PART OF THIS LICENSURE PATHWAY. THE HOPE WITH THIS PRODUCT IS THAT WE CAN RAPIDLY ADVANCE AND GET LICENSURE QUICKLY AND THAT VACCINE BELONGS TO MADERNA. THERE'S REASONS I CAN'T TALK ABOUT THOSE RESULTS BECAUSE IT IS UPRIGHT COMPANY ON THE STOCK -- A PRIVATE COMPANY ON THE STOCK MARKET. CAN'T TALK ABOUT THAT. >> THE OTHER QUESTION THAT RELATES TO ONE OF YOUR OTHER ONES WHETHER THERE IS ANY EVIDENCE OF ANY PROTECTING IMMUNE ALLELES SIMILAR TO WHAT WE SEE FOR HIV FOR EXAMPLE WITH HLAV 27 OR 58. PEOPLE WHO DEVELOP COVID DISEASE OR NOT. >> RIGHT. SO THERE IS A BIG QUESTION WHY SOME PEOPLE GET SICK AND SOME DON'T GET VERY SICK. THERE IS A LOT OF SPECULATION ABOUT THAT RIGHT NOW BUT I DON'T THINK WE REALLY KNOW FOR SURE WHY THAT IS HAPPENING. THE BEST GUESS MOST OF THESE RNA VIRUSES ARE VERY -- HAVE A LOT OF GENES AND PROTEINS TO INTERFERE WITH TYPE 1 AND TYPE 3 AND SOMETIMES TYPE 2 INTERFERON SIGNALING PROCESSES OR EFFECTER MECHANISMS. INNATE IMMUNE RESPONSE HOW YOU ARE INTERACTING WITH THE VIRUS FROM THE BEGINNING OFTEN DETERMINES HOW HIGH THE VIRUS CAN REPLICATE BEFORE YOUR OTHER IMMUNE VECTORS COME IN LIKE CD8 T-CELLS THAT YOU ARE REFERRING TO WITH THOSE HLA RESTRICTIONS. SO WE DON'T KNOW IF IT'S FACTORS IN THE INNATE IMMUNE RESPONSE OR COMING TO CD8 T-CELLS A DAY LATE OR HAVING THE WRONG SPECIFICITY TO CLEAR VIRUS RAPIDLY ENOUGH BEFORE IT GETS TO TOO HIGH LEVEL. ALL THESE THINGS STILL HAVE TO BE WORKED OUT. >> ANOTHER QUESTION IS REGARDING THE DURATION OF THE IMMUNE RESPONSE IF THERE IS ANY SENSE HOW LONG SUFFICIENT IMMUNE RESPONSE CAN LAST AFTER CORONA VIRUS INFECTION. WHICH I THINK PROBABLY IS SOMETHING A LOT OF PEOPLE ARE WONDERING, WHETHER THERE WILL BE A NEED FOR NEW VACCINE EVERY YEAR FOR EXAMPLE OR BASED ON THE DATA THAT YOU SHOW, MAYBE THIS IS A GOOD OPPORTUNITY TO LOOK TO MORE UNIVERSAL. >> RIGHT. SO WE HAVE ACTUALLY BEEN WORKING HARD LAST FEW YEARS LOOKING FOR CROSS REACTIVE ANTIBODIES BETWEEN DIFFERENT CORONA VIRUS STRAINS AND MAKING THINGS WE THINK COULD BE CONSENSUS OR UNIVERSAL CORONA VIRUS TYPE PAN CORONA VIRUS TYPE VACCINE ACROSS CORONA VIRUS OR EVEN WITHIN CLADES OF BETA CORONA VIRUS. THAT WILL REQUIRE MORE WORK AND TIME. RIGHT NOW JUST THE IMMUNITY TO THIS ONE CORONA VIRUS, WE DON'T REALLY KNOW WHERE ARE MUCH ABOUT LONG TERM IMMUNITY FROM INFECTION LET ALONE YET FROM VACCINATION. ONE OF THE GOOD THINGS ABOUT BEING ABLE TO MAKE THIS PROTEIN, IT ALSO SERVES AS A SUBSTRATE FOR DIAGNOSTIC ASSAYS AND IMMUNE RESPONSE ASSAYS SO YOU CAN START TRACKING ANTIBODY RESPONSES LIKE THIS. A LOT OF PEOPLE ARE A LITTLE SLOW AND DON'T MAKE REALLY GOOD POTENT IMMUNE RESPONSES EARLY ON AT LEAST IN A MAGNITUDE THAT CAN CREATE NEUTRALIZING ACTIVITY IN SERUM. SO WE ARE STILL LEARNING ABOUT THAT. WE ARE -- A LOT OF PEOPLE ARE MAKING MONOCLONAL ANTIBODIES AT DIFFERENT POINTS AFTER INFECTION AND THAT WILL ALSO INSTRUCT US ON ANTIBODY LINEAGES THAT WE CAN TARGET AND WHAT IT WILL TAKE TO MAKE NEUTRALIZING ACTIVITY AND WE'LL JUST HAVE TO SEE HOW LONG AND DURABLE THE IMMUNITY IS. IT MAY BE SOMETHING WE WOULD END UP HAVING TO BOOST LATER. I DON'T THINK THIS VIRUS IS GOING TO MUTATE TO THE EXTENT INFLUENZA DOES WHERE YOU HAVE TO MAKE A NEW TYPE OF VACCINE EVERY YEAR. BUT WE'LL HAVE TO SEE. >> THAT WOULD BE GOOD NEWS. ANOTHER QUESTION HAS TO DO WITH ANTIBODY DEPENITENT ENHANCEMENT, WHETHER YOU CAN COMMENT ON THE RACE OF -- (INAUDIBLE) CAUSED BY VACCINE AND WHAT ARE THE WAYS CAN BE AVOIDED. >> THERE IS A LOT OF DISCUSSION AND CONCERN AROUND DIFFERENT TYPES OF WAYS A VACCINE CAN POTENTIALLY ENHANCE DISEASE. ADE IS ONE TYPE OF PHENOMENON THAT CAN OCCUR USUALLY IN VIRUSES WITH MACROPHAGE TROPISM LIKE DENGHE OR FELINE INFECTIOUS PER TO NIGHTIS VIRUS, THIS VIRUS IN CATS CAUSED A VASCULAR SYNDROME AND IS MACROPHAGE TROPIC AND WHAT WE WERE SHOWN AS CORONA VIRUS TO HAVE ANTIBODY DEPENDENT ENHANCEMENT OR REPLICATION IN MACROPHAGES. SO THERE ARE SOME TYPES OF VIRUSES THAT HAVE MACROPHAGE APPROPRIATE TROPISM THAT VARIANTS CAN BE ENHANCED BY BINDING ANTIBODY THAT DOES NOT NEUTRALIZE. SO THAT IS A THING WE ARE LOOKING AT. WE THINK THAT FOR THIS RESPIRATORY VIRUS THAT IS TROPIC FOR EPITHELIAL CELLS AN AIRWAYS OR THE LUNG, THAT DON'T HAVE FC RECEPTORS THAT THIS IS NOT -- WE DON'T THINK IT'S A MAJOR CONCERN BUT WE ARE DEFINITELY GOING TO BE LOOKING AT IT IN VITRO AND IN ANIMAL MODELS. ANOTHER CONCERN IS SOMETHING CALLED VACCINE ASSOCIATED ENHANCE RESPIRATORY DISEASE WHICH HAS A DIFFERENT SET OF PHENOMENON. THIS WAS EXEMPLIFIED MOSTLY BY THE RSV AND MEASLES VACCINES IN THE 1960s THAT WERE WHOLE INACTIVATED VACCINES WHERE ESPECIALLY IN RSV CHILDREN IN YOUNGEST AGE COHORT WHEN THEY GOT INFECTED THE NEXT WINTER SEASON, DEVELOPED A HIGH RATE OF HOSPITALIZATION UP TO 80% OF PEOPLE INFECTED HAD TO BE HOSPITALIZED. AND IT CAUSED AN ABERRANT PATHOLOGY. THAT WAS ALSO ASSOCIATED WITH ANTIBODIES THAT HAD POOR NEUTRALIZING ACTIVITY BUT HAD GOOD BINDING ACTIVITY. SO ONE OF THE OUTCOMES THERE SHOWN WAS INNATE IMMUNE COMPLEXES THAT DEPOSITED IN THE SMALL AIRWAYS AN FIXED COMPLIMENT ACTIVATED COMPLIMENT AND THAT WAS THOUGHT TO HAVE BEEN PART OF THE SYNDROME. THE OTHER PART WAS A THT VIRUS CD4 T-CELL RESPONSE THAT INCREASED MUCOUS PRODUCTION AND AIRWAY SENSITIVITY THAT ADD TO AIRWAY OBSTRUCTION THAT IS THE BASIS FOR A LOT OF THESE DISEASES. SO THE WAY TO MITIGATE THAT IS TO HAVE AN ANTIGEN THAT'S WELL DESPINED, THAT -- DESIGNEDDED THAT WILL INDUCE ANTIBODY, HIGH LEVELS OF NEUTRALIZING POTENCY AND NOT ANTIBODIES THAT DON'T NEUTRALIZE AND TO DELIVER WITH A GENE BASED VECTOR, A TH 1 BIAS EVENT OR CD8 T-CELLS AND TH 1 CD4s OR IF YOU ARE USING A PROTEIN TO USE A TH 1 BIAS ADJUVANT. SO I THINK WHAT WE HAVE LEARNED ABOUT RSV OVER THE YEARS AND WHAT THE FDA LEARNED, DECIDED ABOUT RSV OVER THE LAST SEVEN OR EIGHT YEARS ALSO HELPED PREPARE THE REGULATORY FRAME WORK FOR THIS. SO I THINK THERE IS A WAY TO GET THROUGH THIS IN INCREMENTAL STEPS LITTLE BY LITTLE MORE AND MORE DATA ABOUT PROTECTION. OR PATHOLOGY AND KEEP ENROLLING SUBJECTS. >> WELL, THANK YOU VERY MUCH, BARNEY, FOR A GREAT PRESENTATION ON VACCINE AND HOW LONG DO YOU THINK WILL BE BEFORE WE HAVE A LARGE -- >> WE ARE PUSHING VERY HARD TO TRY TO GENERATE THIS DATA ON NEUTRALIZING ACTIVITY AND EFFICACY OR DISEASE ENHANCEMENT, IF YOU HAVE A LIMITING DOSE OF VACCINE THAT IS PROTECTIVE. THE QUESTION IS DO YOU HAVE PARTIAL PROTECTION OR ENHANCED PATHOLOGY? AND WE CAN GENERATE THOSE ANSWERS IN JUST A FEW MONTHS I THINK IN MICE AND MONKEY MODELS. AS WE GET MORE HUMAN IMMUNE WE CAN ALSO CHECK FOR NEUTRALIZING ACTIVITY AND ABSENCE OF TH 2 RESPONSES SO THESE THINGS H ALLOW US TO ESCALATE AND RAMP UP TRIALS HOPEFULLY WITHIN A FEW MONTHS. >> THANK YOU VERY MUCH, ROUND OF APPLAUSE AND HOPE TO SEE Y'ALL AGAIN NEXT WEEK. THANKS AGAIN, BARNEY. >> THANK YOU.