MY NAME IS BARNEY GRAHAM AND I'M DEPUTY DIRECTOR OF THE VACCINE RESEARCH CENTER. LET ME INTRODUCE DR. CORBETT TODAY. RECEIVED HER UNDER GRADUATE DEGREE FROM THE UNIVERSITY OF MARYLAND BALTIMORE COUNTY AND THE PHD FROM THE UNIVERSITY OF NORTH CAROLINA. SHE'S A SENIOR RESEARCH FELLOW IN THE VILE RAL PATHOGEN CYST LAB AT THE VRC. THE LAST SIX YEARS HER PHOTOGRAPHIC WORK HE ISED ON C BIOLOGY, ESPECIALLY SPIKE STRUCTURE, ANTIBODIES, MECHANISMS OF NEUTRALIZATION AND VACCINE DEVELOPMENT. DURING THIS COVID CRISIS, SHE AND HER TEAM MADE THE FIRST SPIKE PROTEIN THAT WAS THE BASIS FOR DYING NOTHING SIS A DIAGNOSTIC VACCINE . SHE'S BEEN CENTRAL TO THE DEVELOPMENT. MODERNA THAT WERE THE FIRST INTERPHASE 1 AND PHASE 2 TRIALS IN THE U.S. SHE'S BEEN RECOGNIZED FOR HER WORK BY SEVERAL ORGANIZATIONS THIS YEAR INCLUDING THE AMERICAN SOCIETY OF MICROBIOLOGY WHO NAMED HER THE RECIPIENT OF THIS YEAR'S EARLY CAREER APPLIED AND BIOTECH RESEARCH AWARD. DR. BET. I AM A SENIOR RESEARCH FELLOW AND DR. GRAHAM'S LAB AND EVEN THOUGH HE GAVE ME LOTS OF CREDIT, IN THAT INTRODUCTION, OBVIOUSLY HE ALSO HAS FUELED A LOT OF THE WORK THAT I'M GOING TO TALK ABOUT TODAY. PARTICULARLY HE IS BEEN SOMEWHAT OF THE BRAINCHILD AROUND UNDERSTANDING PROTOTYPE PATHOGEN DEVELOPMENT AND VACCINE DEVELOPMENT IN THAT SPHERE. THE WORK I'M GOING TO TALK ABOUT TODAY IS PARTICULAR TO OUR COLLABORATIVE EFFORT WITH MODERNA, WHICH WE HAVE BEEN DEVELOPING A VACCINE FOR COVID-19 CALLED mRNA-1273 AND I REALLY WANTED TO SPEND SOME TIME TODAY DISCUSSING HOW THOSE EFFORTS WERE ABLE TO MOVE SO RAPIDLY BASED ON SOME OF THE RESEARCH THAT WE'VE DONE IN PRIOR YEARS AT THE VACCINE RESEARCH CENTER. SO CORONAVIRUSES ARE LARGE FAMILY OF MRNA VIRUSES, THERE ARE FOUR CORONAVIRUSES THAT ARE CONSIDERED ENDEMIC OR SEASONAL IN THAT THEY CIRCULATE EVERY YEAR AND THEY INFECT HUMANS AND CALLS GENERALLY MILD DISEASE. YOU SEE THAT TWO OF THOSE CORONAVIRUSES, OC-43 AND HK-1 SIT IN THIS BETA CORONAVIRUS SUBFAMILY THAT IS THE SAME SUBFAMILY FOR THE EPIDEMIC STRAINS OF CORONAVIRUS. SO YOU ALL MAY REMEMBER THAT CLOSE TO TWO DECADES AGO, WHEN SARS STARTED TO CIRCULATE AMONG HUMANS, EVENTUALLY CAUSING OVER 8,000 CASES WORLDWIDE, CIRCULATING TO 32 COUNTRIES, AND THEN LATER, AROUND THE TIME WHERE I BEGAN MY POST DOCK RESEARCH FELLOW IN DR. BARNEY GRAHAM'S LAB AT THE BRC THE MMRS EPIDEMIC BEGAN AND SINCE THAT TIME, UP INTO 2019, THERE WERE OVER 2,000 CASES OF MMRS WORLDWIDE AND 27 COUNTRIES THAT THE VIRUS HAD INFECTED. SO, WE KNEW THAT CORONAVIRUSES POSE AS THIS GLOBAL HEALTH THREAT, AND THIS SLIDE ACTUALLY REMAINS UNCHANGED AS ONE OF THE FIRST SLIDES THAT I EVER PRESENTED AND AT THE VACCINE RESEARCH CENTER. REALLY HIGHLIGHTING SOME OF THE WORK FROM DR. RALPH BARRICK'S LAB AT THE UNIVERSITY OF NORTH CAROLINA. WERE IN THESE TWO MANUSCRIPTS, HE REALLY SHOWS QUITE ELOQUENTLY, THAT THERE WAS THIS VIRUS CALLED WIV-1 THAT WAS IN THE SARS SUBFAMILY OF CORONAVIRUSES AND HE DEEMED IT POISED FOR HUMAN INFECTION. SO WE KNEW, FOR A WHILE, THAT CORONAVIRUSES WERE AN IMMINENT GLOBAL HEALTH THREAT AND SO WITH THAT HOW DO WE THINK ABOUT VACCINE ELEMENT. WHILE THESE TERMS ARE ELEMENTARY, THE WAY WE THINK ABOUT CORONAVIRUS VACCINE DEVELOPMENT IS FAIRLY SIMPLE. AND THAT BECAUSE CORONAVIRUS IS ALWAYS POISE FOR HUMAN EMERGENCE, WE NEED A VACCINE THAT IS FAST. SO SOMETHING THAT HAS THE TECHNOLOGY THAT IS ABLE TO BE PRODUCED IN VAST QUANTITIES VERY QUICKLY. ALSO, ROW LIABLE. SO TECHNOLOGY THAT HAS AT LEAST BEEN TESTED IN HUMANS. I HAVE UNIVERSAL HERE, BECAUSE I IMAGINE THAT WITH A THOUSAND PEOPLE WATCHING THIS VIDEO CAST, SOME OF US ARE INFLUENZA VERROLOGISTS AND UNDERSTAND THAT UNIVERSAL VACCINE FROM THE FLU PERSPECTIVE IS THE CLASSICAL WAY WE THINK ABOUT IT. BEGINNING OUR WORK FOR CORONAVIRUSES, WE IN MORE OF ANNA TAL SIZED FASHION THOUGHT ABOUT UNIVERSAL VACCINE AS NOT PRE-EMPTIVE AND SOMETHING THAT WOULD COVER ALL OF THE FUTURE OUTBREAKS BUT SOMETHING THAT COULD BE A PLUG AND PLAY STRATEGY, SHALL AN OUTBREAK OUTBREAK APPLY. THIS IS THE I TOLD YOU SO SLIDE IN OBVIOUS OBVIOUSLY IT GOES WITHOUT SAYING THAT THE 2019 EMERGENCE OF SARS-CoV-2 HAS BEEN DEVASTATED AND CAUSED OVER 35 MILLION CASES WORLDWIDE, AND THIS FAMILY OF VIRUSES SITS ALSO NEXT TO THE SARS-1 CORONAVIRUSES AND BECAUSE OF THIS EMERGENCE OF SARS-CoV-2 WE KNEW WE NEEDED A FAST, RELIABLE AND A TAL SIZED UNIVERSAL VACCINE SOLUTION. IT MEANS THAT YOU KICK A PROTO œTIP I CAN VIRUS WITHIN ONE OF THE 24 VIRAL FAMILIES THAT HAS THE POTENTIAL TOWN FACT HUMANS, CORONAVIRUS IS OBVIOUSLY BEING ONE OF THEM. YOU STUDY IN SOME DEPTH THE VACCINE DEVELOPMENT OF VACCINE FOR ONE OF THE VIRUSES IN THAT FAMILY. AND THEN YOU GENERATE ENOUGH KNOWLEDGE THAT THAT KNOWLEDGE CAN BE APPLIED WIDELY ACROSS VIRUSES WITHIN THAT FAMILY. IN THE PERFECT WORLD, ALTHOUGH IT DIDN'T HAPPEN FOR A PARTICULAR CORONAVIRUS AT LEAST BY MRNA VACCINE PLATFORM, YOU WOULD DEVELOP A COUNTER MEASURE SUCH AS A VACCINE THROUGH THE PHASE 1 CLINICAL TRIAL PHASE. SO, TOGETHER, THIS IS CALLED THE PRO PO TYPE PACKAGING APPROACH FOR PANDEMIC PREPAREDNESS AND REALLY THE WORK THAT WE'VE DONE AROUND SARS-CoV-2 VACCINE DEVELOPMENT IS A PROOF OF CONCEPT FOR THAT APPROACH. AND SO, I LIKE TO CALL IT THE PLUG-AND-PLAY APPROACH BUT YOU KNOW, IT'S BASICALLY THE IDEA THAT WE HAD SO MUCH KNOWLEDGE BASED ON WORK FROM US AND OTHER LABS PREVIOUSLY, THAT WE WERE ABLE TO PULL THE TRIGGER ON VACCINE DEVELOPMENT AND START THE BALL ROLLING TOWARDS PHASE 1 CLINICAL TRIAL. SO, THIS SLIDE I ACTUALLY ADAPTED FROM DR. BARNEY GRAHAM BECAUSE IT REALLY SHOWS HOW WE CAN UTILIZE NEW TECHNOLOGIES TO CONTINUE USUALLY TRANSFORM VACCINOLOGY AND THE WAY WE GO ABOUT THIS IS KIND OF IN TWO BUCKETS THE FIRST BEING PRECISION. WHERE, WE REALLY UNDERSTAND RESPONSES AND UNDERSTAND STRUCTURE BAYS VACCINE DESIGN AND PROTEIN ENGINEERING BY WAY OF DISPLAYING ANTIGENS ON NANO PARTICLES AND ALSO WITH SPEED. UTILIZING DIFFERENT PLATFORMS FOR DELIVERY OF THESE VACCINE ANTIGEN THAT'S ARE MANUFACTURED QUICKLY LIKE RNA AND UNDERSTANDING HOW YOU CAN PLAY ON THAT ON THE ONSET OF THE PANDEMIC. SO, THE VACCINE TARGET IS THE CORONAVIRUS SPIKE PROTEIN SO THE CORONAVIRUS SPIKE PROTEIN SITS ON THE SURFACE OF A CORONAVIRUS AND IT IS THE PROTEIN THAT FACILITATES FINDING TO THE HOST CELL AND THE PARTICULAR CASE OF SARS-CoV-2, THE HO HUMAN CELL IS THE ACE 2 ON PROTEIN AND THE SPIKE PROTEIN BINDS THE RECEPTORS BINDING DOMAIN HOUSED IN THIS GLOB YOU LAR HEAD REGION AND UNDER THAT, IN THE STEAM, IF YOU ARE A FLU VERROLOGIST BUT WE CALL IT THE SU REGION WHERE THE FUSION MACHINERY O'ER ESSENTIALLY HOW I THINK TO THINK OF IT, THE DIRTY WORK OF THE PRE TEEN IS HOUSED. SO THE FUSION HELP TIED IS HOUSED HERE IN THIS STEM REGION OR SU REGION OF THE SPIKE PROTEIN. SO WE DID LOTS OF WORK OVER THE LAST DECADE IN GENERAL OF THE VACCINE RESEARCH CENTER BUT PARTICULARLY IN THE LAST SIX YEARS SINCE I'VE BEEN THERE, TO UNDERSTAND THE SPIKE PROTEINS AND HOW WE MIGHT BEST ILLICIT VACCINE RESPONSES USING THE SPIKE PROTEIN, ET CETERA. SO, WHEN THE SARS COVID-19 PANDEMIC BEGAN, WHICH WAS AT THE TIME THE VIRUS WAS CALLED THE 2019 CORONAVIRUS WHICH STARTED TO CIRCULATE WITH THE FIRST REPORT WITH THIS RESPIRATORY SYSTEM HAPPENING IN AN OUTBREAK IN CHINA AT THE END OF THE LAST YEAR. SO, IT TOOK A COUPLE OF WEEKS FOR THE SEQUENCES OF THIS 2019 CORONAVIRUS TO BE PUBLISHED ONLINE AND BECAUSE WE HAD SO MUCH EXTENSIVE WORK ON OTHER CORONAVIRUSES, IT WAS VERY EASY FOR US TO GO THROUGH ALL OF THESE STEPS THAT I WILL DISCUSS IN SOME DOUGH TAIL TO GET TO PHASE 1 CLINICAL TRIAL, 66 DAYS AFTER THAT VIRAL SEQUENCE WAS RELEASED AT THE VRC WHEN THE MMRS VIRUS CIRCULATED THEY EXPLORED VARIOUS APPROACHES TO MMRA CORONAVIRUS VACCINE DEVELOPMENT. ACTUALLY, EVEN WHEN THE SARS-CoV-2 STARTED TO CIRCULATE THEY EXPLORED VARIOUS APPROACHES BUT THEY DON'T DETAIL THAT WORK HERE, JUST BECAUSE I WANTED TO PLAY ON THE IDEA THAT FOR SO LONG, MMRS CORONAVIRUS AND THE SPIKE PROTEIN FROM MMRS CORONAVIRUS HAS SERVED AS OUR PROTOTYPE FOR THIS PATHOGEN APPROACH FOR VACCINE DEVELOPMENT. NEVERTHELESS, MANY OF THE VACCINE APPROACHES THAT WERE EXPLORED BY THE VRC WERE DNA APPROACHES WHERE YOU EITHER DELIVER THE S1 PORTION OF THE PROTEIN OR THE FULL SPIKE VERY A DNA. YOU WILL SEE ON THIS LAST PORTION OF THIS GRAPHIC, WHICH SHOWS THE NEUTRALIZING ANTIBODY RESPONSES WITH ALL OF THOSE VACCINE APPROACHES, IS THAT TWO THINGS STAND OUT. THE FIRST IS BE A WAY OF GIVING TWO DOSES OF A PROTEIN, YOU CAN TRUNCATE THE TRANCE MEMBRANE REGION OF THE SPIKE PROTEIN BUT UNFORTUNATELY, THAT PROTEIN REALLY WAS HINDERED FROM FUTURE VACCINE DEVELOPMENT AS A PROTEIN ANTIGEN FOR SEVERAL REASONS BECAUSE OF ITS INSTABLITY. AND SO, WE SOUGHT TO STABILIZE IT IN ITS PRE FUSION CONFIRMATION TO INCREASE ITS EXPRESSION AND ITS ABILITY AND TO TEST IT AS A VACCINE CANDIDATE. SO, AT THE TIME, AS WE THINK ABOUT PROTEINS, THE BEST PROTEIN FOR DELIVERY OF CORONAVIRUSES WAS THE S-1 REGION OF THE SITE PROTEIN WHICH YOU EXPRESS AS YOU CAN SEE HERE IN THE LIGHT BLUE BOX. THIS STABILIZATION OF THE PRE FUSION VIRUS PROTEINS IS NOT REALLY A NOVEL CONCEPT BUT SOMETHING THAT HAS BEEN TRIED AND TRUE WITH MANY OF THESE FUSION PROTEINS AND THE PROVE OF PROOF OF CONCEPT UNDERSTANDING THE IMPACTS OF THE PRE FUSION STABILIZATION OF THESE TYPES OF PROTEIN COMES FROM WORK WITH DR. GRAHAM AN D JASON MACLELLAN AND PETER FONG WHERE YOU CAN STABILIZE THE PRE FUSION VERSION OF RESPIRATORY VIRUS F PROTEINS AND YOU CAN SEE THAT THESE RED SURFACES ON THIS PRE FUSION MOL ACTUAL ARE EXPOSES. THEY ARE THE MOST NEUTRAL SENSITIVE EP TOTES ON THE MOL ACTUAL WHEN IT'S IN ITS POST FUSION NOT STABILIZED AND FLIPPING, THE RED SURFACES ARE INCLUDED IN THAT PROTEIN, WHICH HINDERS IT FROM ELICITING THE MOST ROBUST ANTIBODY RESPONSE THAT'S YOU WOULD NEED TO MAKE IT A VIABLE AND THE BEST VACCINE ANTIGEN. WE TOOK THAT KNOWLEDGE AND WANTED TO EXPLORE A STABILIZATION OF CORONAVIRUS SPIKES AND WHEN I GOT TO THE LABORATORY IN 2014, ACTUALLY I THINK I'M COMING UP ON MY SIX-YEAR ANNIVERSARY. NEVERTHELESS, WE'RE REALLY LOOKING TO STABILIZE CORONAVIRUS SPIKE STRUCTURES, MOSTLY INTERESTED IN THE MARS CORONAVIRUS SPIKE BECAUSE THAT WAS THE CURRENT VIRUS THAT WAS CIRCULATING EPIDEMICALLY ACROSS THE WORLD BUT WE WERE ABLE TO, IN COLLABORATION WITH ANDREW WARD'S LAB AND JASON MACLELLAN'S LAB IT WAS BEHAVED WHEN YOU EXPRESSED IT IN ITS SOL YOU ABLE FORM SO WE WERE ABLE TO SOLVE THE STRUCTURE OF THE FIRST HUMAN CORONAVIRUS SPIKE PROTEIN IN 2016. AT THE SAME TIME, DAVID SAW THE STRUCTURE FOR MHB WHICH IS ANOTHER CORONAVIRUS AND THEN THERE WAS REALLY THIS KIND OF ONSLAUGHT OF LITERATURE DESCRIBING VARIOUS SPIKE STRUCTURES FOR DIFFERENT CORONAVIRUSES UNDERSTATING THAT UNDERSTANDING HOW THE SPICE AND FLIPPING FROM THEIR POST AND FUSION CONFIRMATION AND AROUND THE SAME TIME, OUR GROUP AND GEORGE GAL'S GROUP PUBLISHED THE STRUCTURE FOR MARS CORONAVIRUS AND SARS CORONAVIRUS SPIKE PROTEINS. WHAT IS INTERESTING ABOUT THE PAPER THAT WE PUBLISHED IS THAT WE CALLED IT THIS RATIONEDLY DESIGNED PRE FUSION MARS SPIKE ANTIGEN BECAUSE WE DID A THING ESSENTIALLY. WE REALLY LOOKED STRATEGICALLY AT THE SEQUENCES OF THE VARIOUS BETA CORONAVIRUS VIRUSES, PARTICULAR LOW THOSE THAT INFECT HUMANS SO HERE YOU WILL SEE THE SCHEMATIC FOR HK-1, MMRA AND SARS AND I DRAW YOUR ATTENTION TO THIS S-2 REGISTER ON WHERE AROUND THIS ONE REGION CLOSE TO THE FUSION PEPTIDE, THERE'S SOME GENETICS IN THE SIMILARITIES WITH THESE PROTEINS. WE SCANNED THIS REGION AROUND THIS AREA TO ASK THE QUESTIONS, WHERE CAN WE PUT STABILIZING MUTATIONS TRYING OVER HUNDREDS OF MUTATIONS BUT THEN AT THAT TIME, JASON MACLELLAN'S LAB AND VERY CLOSE COLLABORATION WITH US, WE CAME ACROSS THESE MUTATIONS THAT ARE IN THE APEX OF THE CENTRAL HELIX AND IT'S CALLED THE 2P MUTATIONS SO INSERTING TWO PROTEINS HERE IN THIS REGION, ALLOW FOR US TO EFFECTIVELY STABILIZE THE MMRS AND SARS SPIKE PROTEIN AND THEIR CONFUSION CONFIRMATION. THE FIRST INKLING WE'VE DONE WAS JUST BY THE ABILITY OF THE TWO PROTEIN VERSIONS OF THE PROTEINS TO BE EXPRESSED UP TO 50 FOLD GREATER THAN THE WILD TYPE VERSIONS AND ALSO LOOKING AT NEGATIVE SAINT EM WHERE IN THE WILD TYPE VERSION OF THESE PROTEINS, YOU SEE THE SPONTANEOUS FLIPPING INTO THIS POST FUSION CONFIRMATION AS OPPOSED TO THE MUTATIONS YOU SEE MUSHROOM SHAPE CONFUSION STRUCTURE. IT WAS ALMOST LUCKY BUT EXTREMELY GLORIFYING TO SEE THAT THOSE TWO ROTATIONS COULD STABLE AND HB1, MMRS AND SARS AND WE EVEN GOT INCREASED EXPRESSION WITH OTHER CORONAVIRUS AND THE CORONAVIRUSES AND AND AND THEN HERE WHAT WAS THEN AT THE TIME THE POTENTIALLY EMERGING CORONAVIRUS WIB-1 SPIKE PROTEIN THAT AGAIN, IS A VERY POST AKIN TO SARS-CoV-2. SO, WE WANTED TO, AS A PROOF OF PRINCIPLE AROUND THE 2P SPIKE PROTEINS, COMPARE WHAT WE KNEW WHICH WAS THE MMRS S-1 TO THE VERSION OF THE FULL LENGTH SPIKE TO THIS STABILIZED PRE FUSION S2P VERSION OF THE SPIKE SO IN A VERY SMALL STUDY, WE TESTED AND SHOWED WHEN YOU LOOK AT THE NEUTRALIZATION CAPACITY OF THESE DIFFERENT VACCINE ANTIGENS IN MICE THE TWO VERSIONS OF THESE SPIKE PROTEINS I WILL IS ITS MORE ROBUST NEUTRALIZATION AND A DOSE-BEARING WAY. IT WASN'T JUST THE HAMOLOGIST NEUTRALIZATION COVERING THE VIRUSES. SO, THAT WAS AT THE TIME, AT LEAST ENOUGH FOR US TO REALLY SAY OK, NOW WE HAVE THIS VACCINE ANTIGEN THAT I WILL IS ITS ROBUST ANTIBODY RESPONSES BUT OBVIOUSLY, IN CASE OF A PANDEMIC, YOU DON'T REALLY HAVE THE TIME TO TRIGGER MANUFACTURING OF GMP QUALITY PROTEIN AND SO WE WANTED TO REALLY TAKE ADVANTAGE OF A COLLABORATION THAT WE HAD WITH MODERNA WHERE THEY USED AN MRNA LIPID NANO PARTICLE TO DELIVER THERAPEUTICS BUT IN THIS CASE A VACCINE. THE INTERESTING THING ABOUT THIS TYPE OF TECHNOLOGY IS THAT IT IS FAST AND IT'S RELIABLE AND IT'S ITALICIZED UNIVERSAL, THE WAY WE'RE THINKING ABOUT A KIND OF PLUG-AND-PLAY STRATEGY. YOU CAN INSERT WHATEVER THERAPY PROTEIN YOU HAVE. IN THIS CASE, WE DO IT FOR CORONAVIRUS SPIKE PROTEINS AND THEN THEY TAKE THE MRNA SEQUENCE OF THE PROTEIN AND MANUFACTURE THE MNRA AND A LIPID NANO PARTICLE DELIVERED INTO THE MUSCLE CELLS OF A PERSON OR ANIMAL AND THEN THE MUSCLE CELLS ARE ABLE TO READ THE MESSAGE OF THAT MNRA AND SPIT OUT SPIKE PROTEINS. WE TESTED THIS AS A PROOF OF CONCEPT WITH MMRS S2P AND THIS FIGURE HIDES IN THE SUPPLEMENT OF OUR PAPER WHERE WE DETAIL SOME OF THE RESULTS FROM THE MOUSE STUDIES WITH THE MRNA1223 AND IT'S INTERESTING TO NOTE THAT WE DIDN'T JUST START AND WE HAD A VERY CLEAR VERSION OF SEVERAL THINGS ABOUT DELIVERING THESE SPIKE PROTEINS VIA MRNA THAT HELPED US TO MOVE SO QUICKLY. SO THE FIRST THING THING THAT WE TESTED USING MMRS AS OWE PROTOTYPE PATHOGEN WAS THE ABILITY TO ILLICIT KNEW RALLIZING ANTIBODY RESPONSES COMPARING EITHER A TRANCE MEMBRANE ANCHORED VERSION OF MMS-S2-3 AND YOU CAN SEE THESE ELICITED SMALL ROBUST NEUTRALIZATION IN MICE AND THE SECOND THING WE WANTED TO TEST AND CONFIRM IS THAT BY MRNA DOES THE WILD TYPE VERSION OF ILLICIT COMPARED TO THE S2P VERSION AND THE PERCENT SPIKE PROTEIN AND SO KNOWING THAT, WE WERE ABLE TO TAKE ADVANTAGE OF ANOTHER COLLABORATION THAT WE HAVE WITH RALPH'S LAB AT THE UNIVERSITY OF NORTH CAROLINA WHERE THEY ARE EXPERTS IN ANIMAL MODELS FOR CORONAVIRUS PATHOGENSIS SO THEY HAVE 288-330 MOUSE BUT IT'S A HUMAN DTP4 TRANCE AGAIN I CAN MOUSE MODEL WHICH YOU CAN ETHALLY INFECT THESE MICE WITH MERS CORONAVIRUS SO YOU CAN SEE WITH THE MRNA EXPRESSING THE MERS IN A DOSE STUDY THAT WE GET PROTECTION OF AGAINST THE LEGAL CHALLENGE WITH ONE MICRO GRAHAM AND .1 MICRO GRAM OF MRNA. THE INTERESTING THING TO NOTE AND ALTHOUGH IT'S A SIDE NOTE, IS EVEN AT THE SUB PROTECTED DOSE OF .01 MICRO GRAMS OF MRNA WE DID NOT SEE ANY DISEASE ENHANCEMENT SO IT'S SELF-PROTECTION BUT NOT VACCINE ENHANCEMENT AND THOSE DATA ARE ALSO CAPTURED WHEN YOU LOOK AT THE DISEASE IN THE LUNG AND SO FIRST LOOKING AT VIRAL REPLICATION IN THE LUNG, AGAIN, ONE MICRO GRAM AND .1 PROTECT THE LUNG FROM VIRAL REPLICATION AND THEN ALSO DISEASE FOR IN THIS CASE IT'S LUNG HEMORRHAGE YOU SEE THE SAME. THIS SERVED AS A PROVE OF CONCEPT EXPERIMENT THAT WE CAN DELIVER CORONAVIRUS SPIKE PROTEINS BY THE MRNA PLATFORM AND IT ALSO SERVES AS A VALIDATION THAT WE KNOW WHAT TYPES OF DOSES TO TARGET TO REALLY LOOK AT BOTH PROTECTIVE LEVELS OF IMMUNITY AND ALSO SUB PROTECTIVE LEVELS OF IMMUNITY FOR THESE PARTICULAR CORONAVIRUS SPIKE PROTEINS DELIVERED BY MRNA. SO, WHEN THIS VIRUS CAME OUT AT THE END OF DECEMBER WE CAME UP WITH A PLAN TO AT LEAST, IF THE VIRUS WAS A CORONAVIRUS, AND IF IT WAS AKIN TO CORONAVIRUSES THAT WE'RE FAMILIAR WITH IN THE BETA CORONAVIRUS FAMILY, THAT WE WOULD PLUG THOSE THROW MUTATIONS INTO THE BACKBONE OF THE SPIKE PROTEIN AND DO SEVERAL THINGS. OBVIOUSLY, WE WOULD MOVE IN THE DIRECTION OF MAKING A VACCINE WITH MODERNA AND TESTING IT THROUGH PHASE 1 OF A CLINICAL TRIAL. AT THE TIME, WE WERE NOT AWARE THAT IT WOULD BE SUCH A DEVASTATING PANDEMIC AND REALLY WANTED THIS PROJECT TO SERVE AS A PROOF OF CONCEPT AROUND PANDEMIC PREPAREDNESS. ALSO, IN THE SECOND ARM OF WHAT WE DID, IS WE PUT THOSE TWO MUTATIONS INTO THE BACKBONE OF THE SPIKE PROTEIN AND PUBLISHED THE SPIKE PROTEIN IN COLLABORATION WITH JASON MACLELLAN AND THEY INCORPORATED INTO THE OTHER SPIKE STRUCTURES THAT ARE IN THE LITERATURE AS WELL. SO, I WILL DETAIL NOW THE ANIMAL EXPERIMENT THAT'S WE DID TO GET TO THE POINT OF WHICH WE WERE ABLE TO GO INTO PHASE ONE CLINICAL TRIAL IN 66 DAYS. BEGINNING, IN THE TIME WHEN WE STARTED TO LOOK AT RESPONSES IN ANIMALS, WE FIRST TESTED OUR VACCINE IN THE MOUSE MODEL. I WILL SHOW YOU JUST A LITTLE BIT ABOUT WHAT WE SAW WHEN WE TESTED M mRNA-1273 IN MICE. WE TESTED THE VACCINE GIVEN PRIME AT WEEK ZERO AND A BOOST AT WEEK THREE. AND THEN CHALLENGING THOSE ANIMALS AT WEEK EIGHT ASKING THE QUESTION, HOW WELL DOES MED PROTECMRNA-1273 PROTECT IN THE LUNG AND THE NASAL. IT'S CLEAR THAT EVEN THIS DOSE OF ONE MICRO GRAHAM OF MRNA-1273 PROTECTS THE MICE FROM THIS PARTICULAR CHALLENGE, WHICH IS A MOUSE ADAPTED STRAIN OF SARS-CoV-2 AND YOU SEE THE DOSE EFFECT OF mRNA-1273 WHICH IS CLEAR SO THEN ALSO ABOUT WHAT IS IMPORTANT IS THAT EVEN AT THE SUB PROTECTIVE DOSES, THERE'S NOT ANY ENHANCED VIRAL REPLICATIONS SO IT'S NOT ASSIGNED THERE'S ENHANCED ILLNESS. THE SAME IS TRUE FOR THE UPPER AREA WITH THE NASAL. THIS PARTICULAR GRAPH SHOWS THREE OUST FOUR OF THE ANIMALS HAVING NO VIRAL REPLICATION IN THEIR NOSE. HAPPENS WITH ONE DOSE? SO, WE PRIME THE ANIMALS AND THEN CHALLENGE THEM SEVEN WEEKS LATER AND THEN SHOW THAT WITH A 10 MICRO GRAHAM OR ONE MICRO GRAHAM DOSE OF mRNA-1273 WE WERE ALSO ABLE TO PROTECT IN THE LOWER AIRWAY. WE ACTUALLY DIDN'T TAKE NASAL IN THIS CASE BUT ALSO ABLE TO PROTECT THE LOWER AIRWAY USING mRNA-1273. THAT WAS A GOOD SIGN TOWARDS THE UTILITY OF THE VACCINE IN AN OUTBREAK SETTING LIKE WE HAVE, FOR EXAMPLE. WE NEXT TESTED THE NON HUMAN PRIME AT MODEL AND WE'RE UTILIZING THE MODEL HERE WHERE WE PRIMED AT WEEK ZERO AND BOOSTED AT WEEK FOUR, CHALLENGES FOUR WEEKS LATER AND ASSESSED FOR ANTIBODY AND T-CELL RESPONSE AND PROTECTION IN BOTH UPPER AND LOWER AIRWAY. I WANT TO POINT OUT THAT THE DOSES THAT WE CHOSE FOR THESE STUDIES, THIS PARTICULAR STUDY, WERE STRATEGIC IN 100 MICRO GRAHAM DOSE IS THE DOSE THROUGH THE HUMAN CLINICAL TRIALS AND IT'S NOW THE DOSE THAT IS IN THE PHASE 3 CLINICAL TRIAL AND THEN WE WANTED TO TEST A 10 FOLD LESS DOSE OF THE mRNA-1273 TO ASSESS WHETHER THERE MIGHT BE ANY CELL PROTECTION, ET CETERA. AND SO, THIS PARTICULAR SLIDE SHOWS THE ANTIBODY RESPONSES IN THE MODEL. WE SHOW THE RESPONSES EITHER BEFORE VACCINATION AND AFTER THE FIRST DOSE OF VACCINATION AND THE SECOND DOSE OF VACCINATION AND YOU CAN SEE AS YOU MIGHT EXPECT, THERE'S AN INCREASE IN BINDING IGT TIEDERS AFTER THE FIRST DOSE OF mRNA-1273 THAT REMAIN STEADY UP TO FOUR WEEKS AFTER THAT FIRST DOSE THAT IS THEN BOOSTED UPON A SECOND DOSE OF mRNA-1273 AND REMAINS FAIRLY STEADY THROUGH THE END OF THIS EXPERIMENT THAT WAS FOUR WEEKS AFTER THE SECOND DOSE OF THE VACCINE. FOR NEUTRALIZING ANTIBODIES, THE STORY IS A LITTLE BIT DIFFERENT. NUMBER ONE, THERE'S SOME VARIABILITY BETWEEN THE INDIVIDUAL ANIMALS, PARTICULARLY IN THE LOWER DOSE GROUP OF 10 MICRO GRAMS OF mRNA-1273. IT GOES TO SAY WITH A SINGLE DOSE OF mRNA-1273 YOU DO GET SOME MODEST LEVELS OF NEUTRALIZING RESPONSES PARTICULARLY IN THE 100 MICRO GRAHAM OR CLINICAL LIKE RELEVANT DOSE AND THEN AFTER A SECOND DOSE OF mRNA-1273, YOU GET A BOOST IN THAT RESPONSE THAT REMAINS STEADY OVER THE COURSE OF THE EXPERIMENT. SO HONING IN ON THE PRE CHALLENGE ANTIBODY RESPONSES, ESSENTIALLY FOUR WEEKS AFTER THE SECOND VACCINATION, WE SHOW THERE ARE SEVERAL BINDING ASSAYS THAT SHOW HOW WELL WE ARE ELICITING ANTIBODIES USING THIS PARTICULAR VACCINE IN THE NHP MODEL. WE START HERE WITH THE BINDING ANTIBODY RESPONSES TO THE SPIKE PROTEIN SO THIS IS AN ASSAY WHERE WE TAKE THE SERUM FROM THE 100 MICRO GRAHAM OR 10 MICRO GRAM ANIMALS COMPARE TAG TO A PANEL OF SERUM THAT WAS TAKEN FROM HUMANS THAT WITHIN HUMANS THAT HAVE RECOVERED FROM COVID-19 DIS TEAS DISEASE. FOR THE FUNCTIONAL ASSAYS THAT WE CHOSE, WE LOOKED AT OUR NEUTRALIZATION ASSAY WHICH WE USE AT THE VACCINE RESEARCH CENTER AND WE ALSO IN CLOSE COLLABORATION WITH ADRIAN McDERMOTT'S LAB AND BRITA IN THE VRC ARE UTILIZING A BINDING INHIBITION ASSAY THAT SAYS WHAT IS THE QUANTITY OF ANTIBODIES THAT YOU HAVE THAT ARE ABLE TO INHIBIT RECEPTIVE BINDING DOMAIN IN MSD PLATFORM AND THEN WE ALSO LOOKED AT LIVE VIRUS NEUTRALIZATION AND THE STORY REMAINS THE SAME. WITH mRNA-1273, IMMUNIZATION IN THESE NHPs WORE GETTING ROBUST NEUTRALIZING AND FUNCTIONAL ANTIBODY RESPONSES THAT ARE EITHER IN THE UPPER PART OF HUMAN CONVALESCENCE OR SURPASSING WHAT YOU SEE WITH HUMAN CONVALESCENCE ERA. SO THAT WAS REALLY GRATIFYING TO SEE AND SECONDLY, ONE OF THE THINGS THAT WE SHOWED IN THE WAY OF ANTIBODY RESPONSES IN THE NHPs AND THIS PLAYS OFF OF SOME WORK THAT OBVIOUSLY YOU DON'T HAVE TIME TO SHOW HERE, BUT ONE OF THE REASONS WHY WE CHOSE TO DELIVER THE FULL SPOKE PROTEIN AS OPPOSED TO THE RECEPTORS FINDING DOMAIN IS BECAUSE OF OUR INTERNAL JUST VERY ROBUST KNOWLEDGE AROUND UNDERSTANDING INTERMINAL DOMAINS SPECIFIC ANTIBODY RESPONSES. SO WITH THAT, WE WANTED TO MAKE SURSURE WE WERE ELICITING ANTIBODY ACROSS THE RECEPTIVE BINDING DOMAIN REGION AND THESE S-1 REGION WHICH WE ARE. IT DOES IN FACT SURPASS WHAT WE SEE WITH HUMAN CONVALESCENCE ERA. NOW, LET'S TALK A LITTLE BIT ABOUT T-CELL RESPONSES AND PARTICULARLY AS YOU THINK ABOUT THE LITERATURE BEHIND SOME OF THE PREVIOUS RESPIRATORY VIRUS VACCINES. THEY'RE INDICK AT THIS TIME OF INDICATIVE OF VACCINE SAFETY. YOU WANTED TO SHOW IN BOTH THE NHP MODEL AND MOUSE MODEL THAT WE ARE ELICITING A TH-1 BIAS RESPONSE AS OPPOSED TO A TH-2 RESPONSE WHICH IS A VACCINE INDUCED ENHANCEMENT. THIS WAS DONE BY KATHY FOLDS IS LEADING THAT WORK WHERE WE SHOWED WITH 100 MICRO GRAM DOSE WE GET 7/7 ANIMALS THAT HAVE MEMORY FOR T. CELL RESPONSES THAT ARE TH-1 AND FOUR OUT OF THE EIGHT ANIMALS AND YOU LITERALLY GET NO TH-2 LIKE RESPONSES. ALSO, VERY IMPORTANT TO NOTE, THAT WE GET TF-H RESPONSES IN THESE ANIMALS AS WELL WHICH CORRELATES WITH WHAT WE SEE WITH THE ROBUST ANTIBODY RESPONSES. SO TAKING INTO ACCOUNT VIRAL REPLICATION IN BOTH THE UPPER AIRWAY, USING NASAL SWABS AND A LOWER AIRWAY, AND SO WE LOOK AT VIRAL REPLICATION VIA SUB GENOMIC RNA AND SHOW THAT SIMILAR TO OTHER GROUPS THAT HAD PUBLISHED THEIR VACCINE CANDIDATES IN NHP BEFORE, THAT IN THE LOWER AIRWAY YOU GET VERY RAPID CLEARANCE OF THE VIRAL REPLICATION AND IN OUR PARTICULAR CASE IN THE 100 MICRO GRAM DOSE AND THE 10 MICRO GRAM DOSE. WHY LIKE TI DON'T LIKE TO SAY EASY BUT WE CAN ROBUSTLY PROTECT THE LOWER AIRWAY FROM VIRAL REPLICATION AND INTERESTINGLY ENOUGH, THE SAME REMAINS TRUE FOR THE UPPER AIRWAY WITH VIRAL REPLICATION IN THE NASAL SWAB. LOOKING AT THE 100 MICRO GRAM DOSE YOU YOU WOULD SEE BY DAY TWO, IT WAS CLEARED THE UPPER AIRWAY OF VIRAL REPLICATION AND COMPARISON TO FIVE OUT OF SIX AND IN THE PBS GROUP AND AND EMPLOY WE MIGHT BE ABLE TO IMPEDE VIRAL TRANSMISSION IN THE DYNAMICS OF THE VIRUS TRANSMIT FORECAST WE'RE ABLE TO DECREASE THE AMOUNT OF OUR REPLICATION IN THE UPPER AIRWAY. SO ME mRNA-1273 IS IN PHASE 3 CLINICAL TRIAL BUT PRIOR TO THAT, ACTUALLY IN A VERY ODD AND REVERSE ORDER, THE PHASE 1 CLINICAL TRIAL RESULTS WERE PRELIMINARILY PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE. SO SINCE THEN, THERE HAVE BEEN TWO PHASE 1 CLINICAL TRIALS OF ONE IN YOUNGER ADULT AND THE OTHER OLDER ADULTS THAT HAVE BEEN AND HUMANS. AND SO, WE IN YOUNGER ADULTS, WE TOOK THREE DOSE APPROACH, 25, 100 MICRO GRAMS AND 2 OTHER MICRO GRAMS OF mRNA-1273 AND IN OLDER ADULTS WE TESTED 25 AND 100 MICRO GRAMS OF mRNA-1273. GIVEN A PRIME AND BOOST FOUR WEEKS APART, AND THEN ASSESSING IMMUNE RESPONSES OVER THE COURSE OF THE YEAR AND THE DATA YOU WILL SEE WILL BE A COUPLE WEEKS AFTER THE SECOND DOSE OF MRNA-1273. SO THESE STUDIES WERE LED BY TWO DIFFERENT TEAMS. ONE LISA JACKSON'S TEAM IN SEATTLE AND ANOTHER TEAM DR. ANDERSON'S TEAM IN EMERY AND THE FIRST OF THESE RESPONSES THAT WE SHOW ARE IN YOUNGER ADULTS, WHERE LISA JACKSON'S GROUP WAS ABLE TO, IN 45 PARTICIPANTS, TEST THE ABILITY OF mRNA-1273 TO ILLICIT SPIKES SPECIFIC BINDING RESPONSES. YOU CAN SEE AFTER ONE DOSE OF mRNA-1273 IN HUMANS, YOU GET ROBUST SPIKES-SPECIFIC FINDING ANTIBODY RESPONSE THAT'S IS INCREASED UPON WITH A BOOST OF mRNA-1273. HONING IN ON THE 100 MICRO GRAM GROUP BECAUSE IT'S THE DOSE WITH THEELEOLDER ADULTS AND MOST RELEVANT IN THIS CASE YOU CAN SEE THAT WITH THE CONVALESCENT PANEL THAT IS TESTED AGAIN THAT WE'RE ELICITING ANTIBODY RESPONSES THAT ARE IN THE UPPER PORT I'LL OF THE RESPONSES THAT WE SEE IN HUMANS THAT HAVE RECOVERED FROM COVID INFECTION. SO, WITH THE NEUTRALIZING ANTIBODY RESPONSES THE STORY IS SLIGHTLY DIFFERENT THAN WHAT YOU SEE WITH NON HUMAN PRIME IT'S A THERE'S A BLIP OF A ANTIBODY RESPONSE AFTER ONE DOSE BUT YOU DO SEE ROBUST NEUTRALIZING ANTIBODY RESPONSES FOLLOWING TWO DOSES OF mRNA-1273. THAT IS ON PAR WITH SOME OF THE HIGH LEVELS OF NEW ACTIVITY THAT YOU SEE IN PEOPLE WHO HAVE RECOVERED FROM COVID-19 INFECTION. WHAT DOES THAT MEAN THOUGH FOR OLDER-AGED ADULTS? INTERESTINGLY ENOUGH, IN ANOTHER TYPE OF NEUTRALIZATION ASSAY YOU CAN SEE WITH THE PEOPLE THAT HAVE GOTTEN -- THAT ARE OVER 55 YEARS OF AGE, COMPARING US TO PEOPLE THAT ARE IN THE YOUNGER AGE GROUP AND YOU GET THE SAME BEVEL OF NEUTRALIZING AND THIS GOES TO SHOW IT WAS REALLY GOOD TO SEE AS WELL. SO IN CONCLUSION, THERE ARE SEVERAL CORONAVIRUS SPIKE THAT HAVE TO DATE BEEN STABILIZED IN THEIR PRE FUSION CONFIRMATION BY INCLUDING THE TWO PROTEIN MUTATIONS IN THE REGION OF THE PROTEIN. VACCINATION WITH THESE PRE FUSION VERSIONS OF THE SPIKE PROTEIN PARTICULARLY IN THE PROTEIN CONTEXT I WILL IS ITS MORE ROBUST NEUTRALIZING ANTIBODY RESPONSES THAT S-1 AND ALSO THE PROTEINS IN THEIR WILD TIME FORMATION AND DELIVERY OF BOTH THE MERS AND SARS-CoV-2 BY MRNA IS PROTECTIVE IN ANIMAL MODELS AND LASTLY, mRNA-1273 I WILL IS ITS ROBUST IMMUNE RESPONSES IN HUMANS. SO, I DO WANT TO JUST QUICKLY TAKE US BACK TO WHERE IT ALL STARTED WITH THE MERS IN MICE AS WE THINK ABOUT FUTURE DIRECTIONS AROUND CONTINUING TO BE AROUND PANDEMIC PREPAREDNESS FOR CORONAVIRUSES. SO WE ELICITED RESPONSES WITH THESE PROTEINS IN MICE AND ALSO DELIVERED BY MRNA AS YOU CAN SEE, IN THE HUMAN DATA FROM MRNA1273, THOSE RESPONSES ARE LARGELY MONO SPECIFIC TO THE PARTICULAR VIRUS. AND WE HAVE SOME HYPOTHESIS AROUND THAT BUT ESSENTIALLY AS WE THINK FORWARD, IN THE CORONAVIRUS VACCINATIONS IT WILL BE IMPORTANT TO NOT JUST START ON THE ONSET OF THE PANDEMIC WITH WHAT OUR UNIVERSAL STRATEGIES FOR VACCINES BUT TO THINK OUTSIDE OF THE BOX TO ILLICIT MORE CROSS REACTIVE AND CROSS PROTECTIVE IMMUNE RESPONSES. AND SO THE ON GOING EFFORTS IN THAT SPHERE ARE REALLY TOWARDS UNIVERSAL CORONAVIRUS VACCINE DEVELOPMENT AND IN THIS CASE, I DON'T HAVE THE UNIVERSAL A TAL SIZE BEAU THEY WANTED THOUGH THINK ABOUT THAT FROM A REAL CLASSICAL UNIVERSAL VACCINE APPROACHES. THE WAYS THAT WE THINK ABOUT DOING THAT ARE TO OPTIMIZE THE ANTIGEN DESIGNS WE HAVE TO HONE IN ON MORE POTENT AND CROSS REACTIVE EPITOPES AND NANO PARTICLES CAN BE USED TO HONE IN ON MORE CROSS REACTIVE AND IT GOES WITHOUT SAYING THAT UTILIZING GENE-BASED DELIVERY SUCH AS MRNA TO SHORTEN THE MANUFACTURE ABILITY TIMELINE IS IMPORTANT AS WE THINK ABOUT SPEED OF UNIVERSAL CORONAVIRUS VACCINES. SO, I AM EXTREMELY THANKFUL FOR THE TEAM THAT STARTED OUT WITH ME SO I KEPT THIS PICTURE AS THE ORIGINAL TEAM AT THE VRC THAT HAS WORKED ON CORONAVIRUSES FOR YEARS, ACTUALLY EVEN BEFORE I GOT TO THE VACCINE RESEARCH CENTER. LED BY DR. BARNEY GRAHAM AND JOHN'S LAB AND EVERYONE HAS BEEN SUCH A TREMENDOUS HELP AND SINCE THE ONSET OF THIS PANDEMIC, IT'S BEEN A LARGE BRC WIDE EFFORT TO GET mRNA-1273 THROUGH THE CLINICAL TRIAL PROJECTORY SO I THINK EVERYONE AT THE VACCINE RESEARCH CENTER, I THANK THEM FOR EVERYTHING THEY'VE DONE. THIS PROJECT HAS REALLY BEEN FUELED OVER THE LAST SIX YEARS BY CLOSE COLLABORATIONS, NOT JUST WITH MODERNA BUT ACADEMIC LABS ACROSS THE COUNTRY. JASON MACLELLAN, ANDREW WARD'S LABS FOR STRUCTURE STUDIES AND NEIL KING FOR NANO PARTICLE DESIGN, AND WE WORKED VERY CLOSELY WITH RALPH'S LAB FOR ASSESSING OUR VACCINE CANDIDATES IN THEIR MOUSE CHALLENGE MODELS. AND FOR THE WORK THAT WE SAW IN THE PRE CLINICAL MOUSE EXPERIMENT HAD A LARGE AMOUNT OF CONTRIBUTORS AND COLLABORATORS MODERNA WAS INFLUENTIAL TO GET THEM OFF THE GROUND QUICKLY AND ALTHOUGH I DIDN'T SHOW IT, WE REALLY WORKED VERY CLOSELY WITH RALPH'S LAB AT THE TIME AS THEY WERE OPTIMIZING THE MOUSE MODELS AND US ON TA MISSING THE VACCINE STRATEGY TESTING IT IN MOUSE STRAINS, ET CETERA. THE WORK IN THE NON HUMAN MODELS, BOB CEDAR FROM THE VRC CAME TOGETHER TO ASSIST WITH THESE STUDIES AND HAS BEEN SO HELPFUL IN MY UNDERSTANDING OF VACCINE INDUCED IMMUNE RESPONSES IN NHPs AND ALSO MAR ROW ROADER'S LAB HAS BEEN HELPFUL AS WELL AND THE PATHOLOGY IN THIS FLIGHT DECK WAS DONE BY NIAID'S OWN LAB AND WITHOUT FURTHER ADIEU, I WILL TAKE A FEW QUESTIONS. >> HELLO EVERYBODY, THANK YOU FOR WATCHING AND THANK YOU FOR A FANTASTIC TALK. THERE ARE A LOT OF QUESTIONS COMING IN. SO WE'RE GOING TO GO RIGHT TO THEM. THERE WAS ACTUALLY A FLURRY OF QUESTIONS ADDRESSING THE DURATION OF THE IMMUNE RESPONSE PARTICULARLY AS IN HUMAN REINFECTIONS ARE STARTING TO APPEAR. WOULD YOU LIKE TO START WITH THAT FIRST? >> RIGHT, SO I CAN TELL YOU ABOUT WHAT WE KNOW. I CAN TELL YOU ABOUT WHAT WE'RE DOING. IN THE FIRST PAPER WITH THE MOUSE STUDIES, WE AT LEAST TESTED THE ABILITY OF MRNA-1273 TO PROTECT OUT TO THROTHREE MONTHS POST VACCINATION. THE DATA IS SI SYNONYMOUS IN WHAT WE SEE WITH VACCINATION SO AT LEAST THREE MONTHS OUT. SOME OF THE GOOD THINGS THAT ALSO CAME OUT OF THOSE MOUSE STUDIES IN THIS WORK WAS DONE BY A TRACY RUCKFUL FORD AND ANTHONY DEPACEYO IN OUR LAB. WE LOOKED AT MEMORY T-CELL RESPONSE AND WE STILL HAVE THOSE REBUST C-4TH-1T-CELL RESPONSES AND THEIR M.P. R MEMORY RESPONSES ACTUALLY. WE HAVE A DURABILITY STUDY THAT'S ON GOING NOW AND NON HUMAN PRIME IT'S A AND I EXPECT THAT YOU SAW ALL OF THE BLEED SCHEDULE FROM THE PHASE 1 LYNN 1 CLINICAL TRIAL THAT SOME OF THE LATTER BLEEDS, AS WE ARE ABOUT SIX MONTHS INTO THE FIRST PHASE 1 CLINICAL TRIAL NOW WE'LL START TO COME OUT SOON. DURABILITY IS -- THERE ARE A COUPLE OF QUESTIONS THAT IN CORONAVIRUS PARTICULARLY COVID-19 VACCINOLOGY THAT OVERHANG FROM THE FIELD. ONE OF THEM IS DURABILITY AND THE OTHER ONE IS THE REALLY SPECIFIC ROLE THAT T-CELLS PLAY SO BOTH OF THESE WE'RE TRYING TO TEASE APART IN THE BEST WAY THAT WE CAN. UNFORTUNATELY, WE WON'T HAVE THE DATA FOR A COUPLE MONTHS SO IT WILL BE GOOD TO SEE. >> A LITTLE BIT ON THE TOPIC OF CURSORY ACTIVITY, HAVE YOU TESTED AT ALL CURSORY ACTIVITY WITH OTHER SARS-CoV-2 VIRUSES? >> SO, YOU MEAN FOR THIS PARTICULAR VACCINE? WE DIDN'T REALLY DELVE INTO CROSS REACTIVITY WITH THIS PARTICULAR VACCINE BECAUSE WE KNOW SO MUCH ABOUT JUST LACK OF CROSS REACTIVITY HAVING STUDIED FULL LENGTH SPIKE PROTEINS, DELIVER BY MRNA IN THE CONTEXT OF MERS FOR SO LONG. SO NEW YORK CITY WE HAVEN'TSO, NO, THERE'S PROBABLY NONE. AT ALL. >> THE OTHER QUESTION HAS TO DO WITH BOOSTING. IS THERE ANY PLAN TO SEE BOOSTING WITH PROTEIN WOULD HELP DURATIONAL RESPONSES? >> OK, WE HAVE REAL VACCINOLOGISTS ON HERE. I LIKE IT. NOT WITH mRNA-1273. THERE ARE OTHER STUDIES THAT WE'RE PLANNING IN THE NON PRIME AT MODEL FOR OTHER PLATFORMS. SO THIS IS JUST ONE PLATFORM TO REALLY KIND OF JUST SHOW YOU THE STUDY FROM BEGINNING TO END. THERE ARE OBVIOUS HUNDREDS OF DIFFERENCE OF PLATFORMS OR HUNDREDS OF DIFFERENCE OF VACCINE CANDIDATES IN SEVERAL DIFFERENT PLATFORMS. PROTEIN BASED APPROACHES AND SO FIGURING OUT THE BEST COMBINATION OF THOSE DIFFERENT PLATFORMS TO ILLICIT DURABILITY IS ACTUALLY A QUESTION AND I'M ASSUMING THAT THAT PERSON HAS AN UNDERSTANDING THAT YOU CAN BOOST RESPONSES FOR GONE-BASED DELIVERY WITH PROTEIN AND GET MORE DURABLE RESPONSES AND THAT'S BEEN SHOWN IN CONTEXT OF OTHER VACCINES PREVIOUSLY. WE'RE NOT GOING TO DO IT FOR MRNA BUT WE WILL TEST SOME COMBINATION OF PLATFORMS WITH PROTEIN BOOSTING. >> GREAT. THE OTHER QUESTION HAS TO DO WITH INTER NASAL ADMINISTRATION. WHETHER THE mRNA-1273 IS SUITABLE OR FEASIBLE FOR INTER NASAL ADMINISTRATION AND HOW IT COULD EFFECT AGAIN HE IS TEE AND EFFICACY OR PROTECTIVE AVAILABILITY. >> WELL, ONE MIGHT EXPECT THAT YOU KNOW, FOR A VACCINE WHERE YOU REALLY NEED CLASSICAL MUTUAL IMMUNITY. LIKE THE IMMUNITY THAT THEY TALK ABOUT. THAT MUCOSAL IMMUNOLOGISTS TALK ABOUT AND YOU NEED TO CHANGE THE ROUTE OF DELIVERY FOR SOME OF THESE VACCINES. THAT'S THE REASON WHY SOME CANDIDATES HAVE ACTUALLY PUBLISHED INTER NASAL DELIVERY. WE DO NOT HAVE PLANS TO DO THAT. PARTIALLY BECAUSE I THINK THAT THE NHP DATA ACROSS THE FIELD, NOT JUST FOR mRNA-1273, SUGGESTS YOU DON'T NEED THAT CLASSICAL KIND OF IMMUNITY TO ILLICIT PROTECTION. AND I THINK THAT THE STUDIES THAT PEOPLE ARE DOING WILL DEFINITELY BE INFORMATIVE FOR FUTURE PANDEMICS AND SHALL THERE BE ANY. BUT IN THIS PARTICULAR CASE, I DON'T THINK IT'S NECESSARY. SO WE'RE NOT TESTING THAT. >> REGARDING THE DURATION OF RESPONSE HOW DO YOU THINK THE mRNA-1273 APPROACH IS TO DNA AS FAR AS DURATION. >> HOW I DO THINK VERSUS SAYING WE HAVEN'T TESTED IT YET? [LAUGHTER] SO, YOU KNOW, I DON'T KNOW. I ACTUALLY DON'T, I KNOW THAT WE HAVE THIS IDEA AROUND DURABILITY BECAUSE OF WHAT IS COME OUT IN REGARDS TO NATURAL INFECTION. UNDERSTANDING THAT IN THESE KIND OF TWO-PRONGED WAY, FOR VACCINES, IT'S THAT WE ARE DELIVERING AN OPTIMAL ANTIGEN VIA A PLATFORM THAT I WILL IS ELICIT MEMOR Y T-CREM RESPONSES AND ANTIBODY RESPONSES EVEN IF THEY WAIN, ANTIBODY RESPONSES THEY WON'T GO TO THE LEVEL OF SUB PROTECTION, AT LEAST FOR QUITE A WHILE. I DON'T KNOW, AND I CAN'T SAY I HAVEN'T SEEN ANY TRUE DURABILITY STUDY WHETHER IT'S FROM PHASE 1 OR IN THE NON PRIMATE MODELS FROM ANY OF THE OTHER CANDIDATES TO SAY AND I DON'T EVEN BELIEVE THAT IN THE CONTEXT OF CORONAVIRUS DNA DELIVERY, IF I'M MISSPEAKING I'M SORRY, BUT I DON'T BELIEVE THAT FOR THE PHASE 1 TRIALS THAT CAME OUT FOR MERS HAD ANY DURABILITY DATA. >> WHAT KNOWLEDGE DID YOU HAVE THAT LED YOU TO GIVE AND STUDY PRIMARILY OF TWO DOSE VACCINE AS OPPOSED TO A SINGLE DOSE? WHAT LED YOU TO STUDY AT TWO DOSES WHICH PERHAPS AT A NATIONAL ROLL OUT PROGRAM COULD POTENTIALLY CREATE SOME -- >> YEAH, THAT IS ONE OF THE DISADVANTAGES, IF YOU CAN EVEN CALL TAY DISADVANTAGE, OF HAVING TO MOVE QUICKLY IS THAT YOU REALLY HAVE TO DO THINGS WITH USING THE BEST OF THE KNOWLEDGE AS YOU HAVE BEFORE. SO, THE BEST OF THE KNOWLEDGE THAT WE HAD BEFORE, USING THIS PARTICULAR PLATFORM, GIVING THESE STP ANTIGENS WERE BASED ON THE TWO-DOSE APPROACH. WE HADN'T TESTED MERS IN A ONE-DOSE CHALLENGE EVEN IF A MASS MODEL PREVIOUSLY. WE KNEW THAT WE GOT, YOU KNOW, THIS THREE OR FOUR FOLD INCREASE IN ANTIBODY RESPONSES WITH THE BOOST SO WHY NOT? SO THAT'S THE WAY THAT THE PHASE 1 CLINICAL TRIAL WAS SET UP, ET CETERA. IT'S GOOD TO SEE THESE PROTECTION IN THE MOUSE MODEL IN THIS PARTICULAR CASE AFTER ONE DOSE, BUT HOW THAT MIGHT PLAY OUT IN HUMANS, ONE CAN ONLY SAY AND PARTICULARLY AS PEOPLE ARE SEEMINGLY CONCERNED ABOUT DURABILITY, HOW THAT MIGHT PLAY OUT FOR THE DURABILITY OF THE RESPONSES AS WELL. SO, WE JUST USE WHAT WE HAD IN OUR KNOWLEDGE BASE TO DESIGN THE EXPERIMENTS THE BEST THAT WE COULD. >> THE OTHER QUESTION IS HOW LONG DOES THE EXPRESSION OF THIS SPIKE PROTEIN CONTINUE WITH THE mRNA-1273 VACCINE? >> SO, IT'S TRANSIENT. WHEN WE SEE IN FIGURE 3 OR SOMETHING IN THE NATURE PAPER, THE EXPRESSION IN CELL CULTURE. ON THE CELL SURFACE GOES DOWN AFTER 72 HOURS AND SO IT IS VERY TRANSPARENT. >> WOULD YOU LIKE TO COMMENT ON HOW THERE WERE DIFFERENCE THIS IS VACCINE RESPONSES IN THE DIFFERENT HOUSE STRAINS? >> YEAH. SO, HOLISTICALLY SPEAKING, NO. SO THE THREE MOUSE STRAINS THAT WE LOOKED AT WERE C-56, BLACK 6s, AND THEN C3B6s AND REALLY THE POINT OF THAT WAS TO SEE, YOU KNOW, BASICALLY SO WE WOULD HAVE THE ABILITY TO CHALLENGE ANY ONE OF THOSE, WHICH ONE RALPH BARRICK DECIDED WAS BEST FOR HIS MOUSE ADAPTED STRAIN AT THE TIME. WHAT WE SAW IS THAT YOU DID GET THIS HIERARCHAL ANTIBODY RESPONSES SO, BLACK 6 MICE HAD LESS NEUTRALIZING ANTIBODIES THAN THE C3B6s. WE ONLY LOOKED AT AT LEAST, AT THAT TIME, I CAN'T SPEAK ON UNPUBLISHED DATA, WE LOOKED AT T-CELL RESPONSES IN THE C3B6s. SO WE WEREN'T ABLE TOLL COMPARE AT THE TIME BUT WE DIDN'T REALLY SEE ANY STARK DIFFERENCES BETWEEN THE DIFFERENT MODELS. AND WE SINCE HAVE ACTUALLY USED NOT IN A CONTEXT OF mRNA-1273 BUT FOR PROTEIN BASED VACCINES WE'VE ACTUALLY CHALLENGED SOME ANIMALS THAT -- SOME BLACK 6s WITH THE C PROTECTION AND SO. >> DO YOU KNOW WHAT OTHER EPI DOSE ARE TARGETED FOR INTO NEUTRALIZING ANTIBODIES. >> YES. [LAUGHTER] I MEAN, SO THE -- THERE'S A SLEW OF ANTIBODIES FOR SARS-CoV-2 THAT HAVE COME OUT IN THE LITERATURE, TONS. PEOPLE HAVE FOUND NEUTRALIZING ANTIBODIES THAT TARGET THE NTD REGION OF THE S-1 MAIN NEUTRALIZING ANTIBODY RESPONSES. THE MOST ROBUST NEUTRALIZING ANTIBODIES TO DATE THAT HAVE BEEN ISOLATED ARE ANTIBODIES THAT ARE THE RECEPTORS BINDING DOMAIN THAT INHIBIT ACE 2 BINDING AND HAVE THE ABILITY TO BIND THE UP OR DOWN VERSION OF THE RECEPTORS BINDING DOMAIN PROTEIN. SO, YEAH. THEY TARGET OTHER REGIONS BUT THE MOST ROBUST ONCE ARE IN THE RBD. >> GREAT. >> HOW IMPORTANT IS THE NANO PARTICLES IN OTHER WORDS, WHAT CELL TYPES ARE EXPRESSING THE mRNA-1273 AND HOW IMPORTANT IS THAT TO THE TYPE OF ADAPTIVE RESPONSES AT LEAST IN THE EFFICACY OBSERVED? >> SO I DON'T KNOW HOW IMPORTANT IT IS FOR THE TYPE OF -- FOR THE EFFICACY THAT IS OBSERVED. THE mRNA-1273 IS BEING EXPRESSED BY THE MUSCLE CELLS. AND THE NANO PARTICLE DELIVERY SYSTEM IS ACTUALLY NOT NECESSARILY USED FOR THE TARGETING OF THE VACCINE BUT MORE SO FOR JUST EFFICIENT DELIVERY OF THE mRNA-1273. THE OTHER QUESTION IS HOW TO DO WITH THE CONTROLS WHETHER YOU USED OR CONSIDERED USING SCRAMBLED MRNA OR MISMATCHED. >> THIS PERSON IS PROBABLY A REVIEWER. SO, WE HAVE USED SO MUCH OF THE SCRAMBLED SO HERE WE CHOSE TO USE PBS. MODERNA HAS USED THAT CONTROL WIDELY TOO. ASSUMING THAT THE QUESTION COMES FROM THE IDEA THAT YOU GET OFF TARGET AND INNATE RESPONSES THAT MIGHT HAVE THE ABILITY TO HAVE SOME ALL TARGET IMMUNOGENICITY BUT IT'S NOT TRUE. CAN YOU SEE IT IN OUR STUDY IN A OFF-SHOT WAY, WHEN YOU SEE THE DOSE EFFECT OF THE VACCINE. SO, WHEN YOU GET DOWN INTO THOSE DOSES OF .01 MICRO GRAMS WERE IN THE MOUSE, FOR EXAMPLE, WHERE YOU DON'T HAVE ANY NEUTRALIZING ANTIBODY RESPONSES, YOU WOULD EXPECT THAT A PARTICLE WOULD HAVE SIMILAR BASELINE RESPONSES TOO. THE OTHER QUESTION HAS TO DO WHETHER YOU COULD ELABORATE ON THIS SAFETY AND THE DELIVERY OF THE MRNA? >> SO, THE PHASE 1 CLINICAL TRIAL ASSESSES SAFETY OF THE MRNA AND I GUESS WE'RE IN THE SIX OR SEVEN MONTHS OUT FROM THE BEGINNING OF THAT PHASE 1 LYNN CAL TRIAL. THERE WERE SOME REACT TO (INAUDIBLE) WITH THE 250 MICRO GRAHAM DOSE OF THE MRNA. I NOTED THAT ALSO PFIZER IS USING AN MRNA PLATFORM AND THEY SAW SIMILAR TYPES OF ISSUES WITH THEIR HIGHER DOSES AND ALSO, MORE WITH THEIR RBD CON INFRASTRUCTURE SO THE 100 MICROGRAM DOSE MOVING FORWARD AND THAT'S IN THE PHASE 3 CLINICAL TRIAL HAS BEEN DEEMED SAFE BASED ON THE PHASE 1 DATA AND SAFETY AS WE THINK ABOUT IT FROM THE PRE CLINICAL STANDPOINT IN ASSESSING THE SAFETY SIGNALS AROUND VACCINE INDUCED ENHANCEMENT, WE HAVEN'T SEEN ANY REAL ISSUE WITH ANY VACCINE INDUCED ENHANCEMENT IN ANY OF THE ANIMAL MODELS. AND FINALLY, YOU KNOW, THERE'S A LOT OF SPECULATION AND SOME CONCERN OBVIOUSLY WHICH MAY TURN INTO A REALITY ABOUT POTENTIALLY BECOMING ENDEMIC, AN ENDEMIC VIRUS, HOW DO YOU SEE THAT FEEDING INTO THE PICTURE OF THE DEVELOPMENT OF A UNIVERSAL VACCINE OR EASILY ADAPTABLE VACCINE, HOPEFULLY IN THE FUTURE? >> YEAH, I MEAN THAT WHEN YOU HAVE 40 MILLION PEOPLE AROUND THE GLOBIN FACTETHE GLOBE INFECTED, ALSO, GIVEN THE FACT THAT THIS PANDEMIC HAS SEASONS NOW, I AGREE THIS VIRUS HAS THE POTENTIAL T TO BE ENDEMIC. HOW IT FITS INTO THE UNIVERSAL VACCINE IS INTERESTING BECAUSE WHEN WE THINK ABOUT ENDEMIC OR SEASONAL CORONAVIRUSES FOR HUMANS, WE THINK ABOUT MILD DISEASE. OBVIOUSLY, A SIGNIFICANT PORTION OF THE PEOPLE WHO GET SARS-CoV-2 DO HAVE MILD DISEASE BUT THERE ARE OTHER SERIOUS EFFECTS OF BEING INFECTED WITH THIS VIRUS SO IT'S A LITTLE BIT DIFFERENT. AND HOW PARTICULARLY AS GEARS CONTINUE TO GO AND HOW PEOPLE WILL BE CONSTANTLY EXPOSED, MAYBE EVEN CONSTANTLY EFFECTED IF THEY'RE NOT VACCINATED WITH A VACCINE, I THINK WE'LL HAVE SOME EFFECT ON UNIVERSAL CORONAVIRUS VACCINE DEVELOPMENT. IN THE SIMILAR WAY THAT YOU KNOW, CONSTANT EXPOSURE TO INFLUENZA STRAINS HAS AN EFFECT ON UNIVERSAL INFLUENZA VACCINE DEVELOPMENT. WE'LL HAVE TO UNDERSTAND HOW TO GO AROUND THAT IN ORDER TO ILLICIT PRE-EMPTIVE ANTIBODY RESPONSES TO WHAT ARE UNKNOWN STRAINS OF CORONAVIRUS. >> SO, ELABORATING A LITTLE BIT ON THE SAFETY, HOW PRONE IS THE MRNA TO POST TRANSLATIONAL MODIFICATION? >> NOT REALLY AT ALL. >> ALL RIGHT. I THINK WE HAVE GONE THROUGH MOST OF THE QUESTIONS AND IT'S ALREADY AFTER THE HOUR. THANK YOU SO MUCH. THIS WAS ABSOLUTELY WONDERFUL. AND THANK YOU EVERYBODY FOR WATCHING AND IF THERE ARE ANY FURTHER QUESTIONS, I THINK WE CAN GO DIRECTLY TO THE SPEAKER. THANK YOU VERY MUCH AND WE HOPE TO SEE YOU AGAIN IN A COUPLE OF WEEKS, IT WAS A FANTASTIC TALK. THANK YOU, AGAIN.