MY NAME IS STEVE HOLLAND, I'M SCIENTIFIC DIRECTOR OF NIAID. AND I WANT TO THANK YOU FOR JOINING US FOR OUR 9TH LECTURE IN THE NEW COVID-19 SPECIAL INTEREST GROUP SERIES. FIRST ITCH REPRODUCIBILITY I HAVE A COUPLE OF NIFTY ITEMS TO SHARE. WE ARE OFFERING CME FOR THIS LECTURE, THE CODE FOR THAT TODAY IS 24881. 24881. ALSO NEXT WEEK'S 3 O'CLOCK OUR SPEAKER WILL BE DR. NEVIN KROGAN UNIVERSITY OF CALIFORNIA SAN DIEGO, HE WILL PRESENT ON PROTEIN INTERACTION WITH SARS. IF YOU HAVE QUESTIONS ABOUT THIS TALK WE ARE HANDLING DIFFERENTLY THIS TIME. A LITTLE SECRET. A LECTURE YOU ARE ABOUT TO WATCH HAS BEEN PRE-RECORDED BECAUSE OUR SPEAKER IS IN MELBOURNE, AUSTRALIA, THAT'S A 14 HOUR TIME DIFFERENCE AND WE THOUGHT IT UNFAIR TO MAKE HER GIVE LIVE LECTURE AT SIX O'CLOCK IN THE MORNING. WE APPARENTLY DIDN'T THINK IT WOULD BE UNFAIR TO MAKE HER ANSWER QUESTIONS AT SEVEN O'CLOCK. SHE AGREED TO THIS SCHEME, BLESS HER HEART. SO THAT'S WE ARE GOING TO DO. AFTER THE VIDEO CAST AT FIVE CLOCK EASTERN TIME, 7 A.M. HER TIME WE WILL GO LIVE VIA WEBEX WITH CONTA IN HER HOUSE. IF YOU WANT TO PARTICIPATE IN Q&A, TURN OFF THE VIDEO CAST AND LAUNCH THE WEBEX. INFORMATION THIS WAS SENT IN NIH WIDE EMAIL MESSAGE ANNOUNCING THIS LECTURE. IF YOU DON'T HAVE THAT MESSAGE FIND THE LINK IN THE LECTURE DESCRIPTION ON THIS VERY PAGE YOU ARE WATCHING AT THE LECTURE AT VIDEOCAST.NIH.GOV. IT'S LIKE ONE OF THOSE URLs THAT GOES ON LONGER THAN -- TODAY'S LECTURER, DR. CONTA IS A VIROLOGIST AND PHYSICIAN. SHE IS THE DIRECTOR OF THE WHO COLLABORATING CENTER FOR RESEARCH AND HER REFERENCE AND RESEARCH ON INFLUENZA AT THE VICTORIAN INFECTIOUS DISEASES REFERENCE LABORATORY IN MELBOURNE, AUSTRALIA. SHE'S ALSO A PROFESSOR AND DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY AT THE UNIVERSITY OF MELBOURNE AND PROFESSOR AT THE PETER DOUGHERTY INSTITUTE FOR INFECTION AND IMMUNITY. YOU MIGHT REMEMBER HER AS I DO FROM HER DAYS AT THE NIH. SHE WAS A SENIOR INVESTIGATOR AND CHIEF OF THE EMERGING RESPIRATORY VIRUSES SECTION IN THE LABORATORY OF INFECTIOUS DISEASES OF THE NIAID. SPECK LACK LAR JOB AND WE HAVE CHAGRINED TO LOSE HER IN 2016 TO HER CURRENT POSITION IN AUSTRALIA. SHE RECEIVED HER -- FROM CHRISTIAN MEDICAL COLLEGE, UNIVERSITY OF -- IN I DIDIA, SHE COMPLETED HER FELLOWSHIP IN PEDIATRIC INFECTIOUS DISEASE AND MPH EPIDEMIOLOGY, UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER. HER RESEARCH FOCUSED ON NEWLY EMERGING VIRAL DISEASES OF GLOBAL IMPORTANCE INCLUDING PANDEMIC INFLUENZA, SARS, AND THE MIDDLE EAST RESPIRATORY SYNDROME OR MERS AND NOW OF COURSE LIKE ALL THE REST OF US SHE'S ENGAGED IN SARS COV 26789 HER RESEARCH IS VIROLOGY, PATHOGENSIS IMMUNE RESPONSE TOM INFECTION ABOUT VACCINATION AND DEVELOPMENT OF PRE-CLINICAL AND CLINICAL EVALUATION OF VACCINES. TODAY'S LECTURE FOCUS ON SARS 1 VACCINE DEVELOPMENT OR IMPORTANT LESSONS TO INFORM SARS 2 VACCINE DESIGN TESTING AND IMPLEMENTATION. NOW I WILL TURN IT OVER TO CONTA. THE TITLE IS COVID-19, THE AUSTRALIAN EXPERIENCE AND PER TECHTIVE THROUGH A SARS ONE LENS. THANK YOU. >> THANK YOU, STEVE FOR THE INTRODUCTION. AND THANK YOU FOR THE INVITATION TO SPEAK TO YOU TODAY. I WAS A PART OF THE NIH INTRAMURAL COMMUNITY FOR MANY YEARS FIRST AS POST DOC AND LATER AS SENIOR INVESTIGATOR. YEARS AGO MY DAY JOB IS INFLUENZA. AND I'M DIRECTOR OF THE WHO COLLABORATING CENTER FOR REFERENCE AND RESEARCH ON INFLUENZA IN AUSTRALIA. AND PROFESSOR IN THE DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY AT THE UNIVERSITY OF MELBOURNE. TOGETHER IN THE PETER DOUGHERTY INSTITUTE FOR INFECTION AND IMMUNITY. WHEN THE VIRUS EMERGED I WAS IN AN ODD POSITION, MY EXPERIENCE WAS WITH SARS WAS MORE THAN TEN YEARS OLD BUT IT WAS QUITE INFORMATIVE ABOUT THE NEW VIRUS. MY NETWORK WAS ALL IN THE UNITED STATES, NOT IN AUSTRALIA. WE HAVE BSL 3 FACILITIES AT THE DOUGHERTY INSTITUTE BUT IT'S WET LAB. AND MUCH -- DON'T HAVE ACCESS TO ANIMAL BSL 3 HERE. AND AS YOU WILL SEE MUCH OF THE WORK THAT I DID WHEN I WAS AT THE NIH ON SARS INVOLVED ANIMAL WORK. SO I HAVE HAD AN OPPORTUNITY BACK AND WILL SHARE SOME OF THE MY PERSPECTIVES THROUGH OUR EXPERIENCE WITH WHAT IS NOW I GUESS CALLED SARS 1. SO THE FIRST REPORTS OF THIS ATYPICAL PNEUMONIA CAME FROM WUHAN IN CHINA AND WHAT THE CHINESE AND MANY OTHER COUNTRIES REGION INCLUDING SINGAPORE AND HONG KONG, WHO HAD LIVED THROUGH THE SARS OUTBREAK IN 2002 AND THREE AND SUBSEQUENT AVIAN INFLUENZA AND INFECTIONS THEY DEVELOPED A SURVEILLANCE SYSTEM TO MONITOR ATYPICAL PNEUMONIA CASES. IN DECEMBER OF '19 THEY OBSERVED A CLUSTER OF SEVERE PNEUMONIA IN WUHAN IN WHICH AT LEAST THESE INITIAL REPORT THEY WERE SEVEN PEOPLE ADMITTED TO THE INTENSIVE CARE UNIT. AND ALL EXCEPT THE FIRST OF THESE CASES WAS IN -- HAD EXPOSURE TO A LIVE MARKET. WHERE THEY WERE EITHER MARKET PEDDLERS OR DELIVERY MEN FROM THE MARKET. AND THEY -- THIS IS A MAP OF WUHAN SHOWING WHERE WUHAN SITS AND THE -- IMAGE OF THE SEAFOOD MARKET, IT WAS CALLED A SEAFOOD MARKET BUT IT WAS ACTUALLY A MARKET THAT YOU COULD BUY VIRTUALLY ANY LIVE ANIMAL. WILD ANIMALS. AND IN DIFFERENT PARTS OF THE MARKET. SO IN THE INVESTIGATION OF THIS OUTBREAK, THEY NOTED THAT THEY WERE ABLE TO IDENTIFY THE -- THERE IS A VERY WELL KNOWN VIROLOGIST AT THE WUHAN INSTITUTE OF VIROLOGY AND HER LAB ACTUALLY PUT THIS VIRUS INTO VERA CELLS AND IN SEROLOGY CIRCLES OF COURSE YOU ARE FORTUNATE IF THE VIRUS GROWS AND INOCULATE. SO THIS VIRUS DID -- CELLS AND CORONA VIRUS LIKE PARTICLES SEEN ON THIN SECTION ELECTRON MICROSCOPY. THEY USED APPLICO INS USING CORONA VIRUS PRIMERS, SORRY, THEY AMPLIFIED THE GENOME USING CORONA VIRUS PRIMERS AND USED THAT TO IDENTIFY THAT THE ETIOLOGIC AGENT WAS A CORONA VIRUS. THEY COMPARED THE SEQUENCE DATA AND IDENTIFY A CLOSE RELATIVE WAS A BACK VIRUS AND THEY ALSO WENT ON TO IDENTIFY RECEPTOR AS ANGIOTENSIN CONVERTING ENZYME 2. SHOWN IN THIS PAPER THAT WAS PUBLISHED IN NATURE SHORTLY AFTER, THERE WAS SEROLOGIC EVIDENCE -- RECOVERED PATIENTS. SO THIS WAS THE EVIDENCE THAT THIS NEW CLUSTER OF ATYPICAL PNEUMONIA WAS CAUSED BY CORONA VIRUS. THE TRANSMISSION DYNAMICS REPORTED ONLINE IN NEW ENGLAND JOURNAL OF MEDICINE IN LATE JANUARY ARE OUTLINED ON THIS SLIDE AND THIS IS A PAPER FROM A GROUP IN HONG KONG AND IT SHOWS THAT THE PNEUMONIA CASES THAT WERE LINKED TO THE WUNAN SEAFOOD MARKET WERE IDENTIFIED AT THE END OF THE DECEMBER, EARLY JANUARY AS I SHOWED YOU BUT THERE WAS THEN AN EXPLOSION OF CASES IN THE REGION. THE CHINA CDC PUBLICLY SHARED THE GENE SEQUENCE AND SO PEOPLE WERE ABLE TO UPDATE THEIR PRIMERS IN ORDER TO IDENTIFY THIS VIRUS IF IT EMERGE OUTSIDE CHINA. AND AT THE END OF JANUARY THE FIRST CONFIRMED CASES OCCURRED OUTSIDE WUHAN. SO THIS IS ESSENTIALLY WHEN AUSTRALIA WENT INTO ACTION. THEY -- THE SUCCESS IN CONTROLLING THIS OUTBREAK IN AUSTRALIA TO A NUMBER OF DIFFERENT PROCESSES AND I'M GOING TO SPEND A FEW MINUTES TALKING ABOUT THOSE. SO THEY FORMED A NATIONAL CABINET COMPRISED OF MINISTERS, PREMIERS AND CHIEF MINISTERS SO AUSTRALIA IS A FEDERATION OF STATES AND HEALTH IS A RESPONSIBILITY OF EACH STATE. SO THERE'S A FEDERAL -- PRIME MINISTER BUT EACH STATE MAKES THEIR OWN HEALTH DECISIONS. NORMALLY IT'S A COUNCIL OF AUSTRALIAN GOVERNMENTS CALLED THE COAG THAT HAS THE AUTHORITY SO THE PRIME MINISTER WHO IS SCOTT MORRIS ON FORMED THE NATIONAL CABINET IN MID MARCH AND THAT'S BEEN MEETING REGULARLY MAKING ALL THE DECISIONS RELATED TO COVID-19 AND THEY FEEL THAT HAS BEEN SO SUCCESSFUL THAT THEY ARE PERMANENTLY -- THE COAG WITH THIS NATIONAL CABINET. THERE ARE TWO MAJOR COMMITTEES THAT INFORM THE NATIONAL CABINET, FIRST IS AUSTRALIAN HEALTH PROTECTION PRINCIPLE COMMITTEE, AHPPC. THIS IS A KEY DECISION MAKING COMMITTEE FOR HEALTH EMERGENCIES. ALL THE STATE AND TERRITORY CHIEF HEALTH OFFICERS DEFENSE, EMERGENCY MANAGEMENT, AND SOME INVITED EXPERT ADVISORS WERE PART OF THIS AHPPC AND IT'S CHAIRED BY CHIEF MEDICAL OFFICER OF AUSTRALIA WHO IS BRENDAN MURPHY. THIS COMMITTEE NORMALLY MEETS THREE OR FOUR TIMES A YEAR REPORTS DIRECTLY TO HEALTH MINISTERS BUT SINCE THE NATIONAL CABINET WAS FORMED HPCC HAS BECOME A DIRECT ADVISORY COMMITTEE TO THE CABINET AND MEATING DAILY -- MEETING DAILY SINCE THE 27 OF JANUARY SO SOON AS THE INFORMATION CAME OUT, OF THE VIRUS OUTSIDE THE PROVINCE THAT WUHAN IS IN, AHPPC HAS BEEN MEETING WITH THE DATA DAILY. THE OTHER IMPORTANT COMMITTEE IS COMMUNICABLE DISEASES NETWORK OF AUSTRALIA, CDNA. THIS IS THE TECHNICAL ADVISORY COMMITTEE THAT COMPRISES REPRESENTATIVES OF ALL THE STATE AND TERRITORY PUBLIC HEALTH UNITS AS WELL AS SOME INVITED EXPERTS. THIS COMMITTEE REVIEWS EPIDEMIOLOGIC EVIDENCE, WRITES THEORIES OF NATIONAL GUIDELINES DESCRIBING PUBLIC HEALTH MANAGEMENT AND ADVISES ON TECHNICAL ASPECTS OF INFECTIOUS DISEASE CONTROL. THE CHAIR IS A MEMBER OF AND REPORTS DIRECTLY -- AND THIS COMMITTEE ALSO MET DAILY FROM THE END OF JANUARY AND JUST RECENTLY WENT TO MEETINGS IN MAY. SO WITH THE KEY SCIENTIFIC ADVICE THAT WAS THROUGH THE AHPPC WAS BASED ON MODELING AND THE INFORMATION I'M SHARING WITH YOU IS COURTESY JODY MCVERNON, HEAD OF EPIDEMIOLOGY AND IS A MATHEMATICAL MODELER AT THE DOUGHERTY INSTITUTE, SHE AND COLLEAGUES WERE INVITED TO BE ADVISOR TO THE AHPCC. WHAT THEY DID LOOKED AT THE DATA COMING OUT OF DIFFERENT COUNTRIES, AND MODELED THE EFFECT OF THE OUTBREAKS IN NEIGHBORING COUNTRIES. SO THE SOURCE COUNTRY WAS CHINA AND THE -- THEY ARE CONCERNED ABOUT IS AUSTRALIA. WE KNEW AUSTRALIA IS AN ISLAND SO IF ANY INTRODUCTION INITIALLY CAME FROM CHINA IT CAME FROM INTERMEDIARY COUNTRIES. -- SO THEY MODELED MODELED FROM WHAT THE IMPORTATION RISK WOULD BE AND IMPLEMENTED THE MODELING MEASURES AND AS SHOWN ON THIS GRAPH WHERE ON -- SINCE THE BEGINNING OF THE OUTBREAK AND HERE IS BED DEMAND WHAT THE DEMAND WOULD BE IF THERE WAS UNCONTROLLED OUTBREAK, IN BLUE -- IN LIGHT BLUE IS THE -- OF APPROPRIATE QUARANTINE AND ISOLATION MEASURES AND IN THE DARK BLUE WAS THE QUARANTINE -- SO THIS WAS ESSENTIALLY USED TO INFORM THE DECISIONS THAT WERE MADE ABOUT MEASURES THAT TOOK EFFECT. SO AUSTRALIA IMPLEMENTED TRAVEL RESTRICTIONS ON ARRIVALS FROM MAINLAND CHINA AT THE VERY END OF JANUARY EARLY FEBRUARY. THIS IS WHAT THE EPIDEMIC IN AUSTRALIA LOOKED LIKE JUST AFTER THE PEAK. SO THE EPIDEMIC PEAKED IN LATE MARCH AND YOU CAN SEE HERE COLOR CODED IN PURPLE ARE ALL THE OVERSEAS ACQUIRED INFECTIONS. IN THIS TEAL BLUE ARE INFECTIONS LOCALLY ACQUIRED AND THERE WERE SOME OF COURSE WERE UNKNOWN ORIGIN. SO THE INITIAL LIMITS ON THE BORDER ON -- IN TERMS OF TRAVEL WERE CHINA BUT THEN THAT WAS AT IRAN, SOUTH KOREA AND ITALY AND GRADUALLY ADDED. AND STARTING HERE IN MID -- IN LATE MARCH, THERE WERE THE RESTRICTIONS -- SOCIAL RESTRICTIONS RECOMMENDED FOR THE COMMUNITY. THIS IS WHAT THE FURTHER OUTBREAK LOOKS LIKE ON THE RIGHT HAND SIDE. SO I SHOWED YOU WHAT WAS ON THE LEFT AND NOW GOING ON INTO JUNE, YOU CAN SEE THAT -- CASES IN AUSTRALIA CAME FROM OVERSEAS TRAVELERS, AND WE HAVE SOME SPREAD WITHIN AUSTRALIA AND BUT RELATIVELY SMALL COMPARED TO THE -- SO EPIDEMIC CONTROL WAS REALLY LARGELY BASED ON PUBLIC HEALTH MEASURES. BUT ONE TAKE AWAY FROM THIS IS OF COURSE THAT THE POPULATION REMAINS LARGELY SUSCEPTIBLE. SO THIS IS A SLIDE THAT SHOWS YOU WHAT THE FULL EPIDEMIC LOOKED LIKE, AS I SAID, WE -- THE PEAK WAS LATE MARCH. AND WE CONTINUE TO HAVE A VERY SMALL STRAGGLING NUMBER OF CASES SINCE. AS IN MANY CASES NOW THIS IS JUST LOOKING AT PEOPLE THAT WERE HOSPITALIZED AND THAT ARE ON VENTILATORS FOR COVID-19 ACROSS AUSTRALIA FROM EARLY APRIL TO JUNE. AND AS IN MANY OTHER COUNTRIES THE MOST OF THE PROPORTION OF THE HOSPITALIZATION -- HOSPITALIZED PATIENTS GO TO ICU OR REQUIRE VENTILATION. THAT HAS BEEN DROPPED OFF SIGNIFICANTLY. IF YOU LOOK AT TOTAL CONFIRMED CASES WHICH IS THE BLACK LINE AND THE REMAINING ACTIVE CASES WHICH IS IN THE ORANGE LINE HERE, TRACING FROM LATE MARCH TO NOW, YOU CAN SEE THAT WE REALLY HAVE VERY FEW ACTIVE CASES AND YET WHAT'S IMPORTANT TO POINT OUT IS THAT THIS IS HAPPENING WITH THESE NUMBERS ARE REALLY TRUE BECAUSE WE ARE TESTING A LOT. SO THE GREEN DOTS REPRESENT THE AVERAGE DAILY CASES IN THIS LINE, AND THE INDIVIDUAL PINK BARS ARE THE AVERAGE DAILY TESTS. SO IT'S IMPORTANT TO KNOW WHEN THE NUMBERS ARE GOING DOWN THAT YOU ARE STILL TESTING. IN THIS SLIDE, THIS IS SOMETHING THAT THE AUSTRALIAN GOVERNMENT DEPARTMENT OF HEALTH PUTS TOGETHER AND UPDATES FROM PERIODICALLY AND SO THE TOTAL NUMBER OF CASES AS OF YESTERDAY WERE 7,335 TOTAL CASES WITH 102 DEATHS AND 6,851 RECOVERED CASES. THIS IS A MAP OF AUSTRALIA SHOWING YOU THE NUMBER OF CASES AND THE DEATHS IN THE DIFFERENT STATES AND TERRITORIES. THERE'S A LOT OF INFORMATION PACKED INTO THIS SLIDE ABOUT THE NUMBER OF TESTS PERFORMED, AND THE DEMOGRAPHICS. SO IN CONCLUSION ON THE PUBLIC HEALTH SIDE AND IN TERMS OF OUTBREAK THERE'S EXCELLENT COMMUNICATION BETWEEN FEDERAL AND STATE GOVERNMENTS. HPPC AND CDNA THE TWO COMMITTEES I TOLD YOU ABOUT ADVISED THE CHIEF MEDICAL OFFICER AND THE CHIEF MEDICAL OFFICER WAS THE LINK TO THE NATIONAL CABINET. GOVERNMENT DECISIONS WERE INFORMED BY SCIENCE, LARGELY INFECTIOUS DISEASE MODELING. THAT HELPED TO -- BASED ON COVID-19 EPIDEMIOLOGY AND GLOBAL SPREAD. SO THEY DID A NUMBER OF SCENARIO MODELS THAT SUPPORT AD COMBINED PUBLIC HEALTH CLINICAL AND WHOLE OF SOCIETY RESPONSE TO MITIGATE THE DISEASE IMPACTER. AND I MUST SAY THAT THE AUSTRALIAN POPULATION ACTUALLY WAS VERY COMPLIANT WITH THE RELATIONS SO THE CURRENT ESTIMATES OF THE EFFECTIVE REPRODUCTIVE NUMBER INDICATE NUMBERS ARE CONSTRAINING THE EPIDEMIC. WE HAVE A FEW CASES IN H CERTAIN GROUPS. THE ONGOING EVALUATION OF CAREFULLY STAGED RELAXATION TO ENSURE WE DON'T EXCEED HEALTH SECTOR CAPACITY BUT I THINK WE HAVE HAD PRETTY QUIET TIME, THERE WAS A LOT OF CONCERN AS WE STARTED OPENING UP BUT THE EXIT STRATEGY IS GOING TO BE A JOURNEY. SO THAT IS A SNAP SHOT WHAT THE AUSTRALIAN EXPERIENCE WAS AND AS YOU ARE AWARE IT IS QUITE DIFFERENT FROM THE U.S. EXPERIENCE. IT IS CERTAINLY SOMETHING WE WERE PREPARING FOR, FOR A SURGE IN CASES, THAT DIDN'T ACTUALLY HAPPEN THEN WE WERE ALSO PREPARING FOR A SECOND WAVE WHICH COULD STILL HAPPEN. SO NOW SWITCHING TO A VIEW OF SARS CORONA VIRUS 2 FROM MY EXPERIENCE WITH SARS CORONA VIRUS 1, THIS IS A SCHEMATIC OF THE VIRUS, IT HAS AN RNA GENOME WITH A VERY LARGE 30-KILO BASE GENOME. AND IT'S A PLUS STRAND RNA VIRUS. IN TERMS OF THE PROTEINS IT'S SIMPLE, THERE ARE ONLY FOUR PROTEINS, THE SPIKE PROTEIN THAT IS PRESENT THAT IS PRESENT ON THE -- HAS SPIKES OR CORONAS ON THE SURFACE OF THE VIRION AND THAT IS ATTACHMENT PROTEIN AN TARGET OF THE PROTECTED IMMUNE RESPONSE. THERE'S ALSO AN ENVELOPE PROTEIN, MEMBRANE PROTEIN AND NUCLEAR PROTEIN THAT ENCAPSULATES THE RNA. THE GENOME ORGANIZATION OF SARS MERS AND SARS CORONA VIRUS 2 ARE SHOWN ON THIS SLIDE. IT'S OF CURSE A LOT OF ATEXT TO THE SPIKE -- ATTENTION TO SPIKE PROTEIN BECAUSE IT IS THE RECEPTOR BINDING PROTEIN. AND IT IS RESPONSIBLE FOR VIRUS ENTRY. SO GOING BACK THEN TO 2004 THE FIRST EXPERIMENTS AT MY -- THAT MILADI DID WHEN I WAS AT THE NIH WAS TO TRY TOE MY LAB DID WAS TO TRY TO ESTABLISH AN ANIMAL MODEL AND IT WAS SOMETHING WE OFFERED TO DO IN THE CDC IDENTIFIED SARS AS A CORONA VIRUS, AND SAID WE WOULD CERTAINLY TRY TO DEVELOP AN ANIMAL MODEL. SO WE ADMINISTERED THE -- INTRANASALLY TO NORMAL HEALTHY SIX TO EIGHT WEEK OLD C MICE AND TO WHAT WE USUALLY DO WITH ANY OTHER RESPIRATORY VIRUSES WE STUDY AND TO SACRIFICE MICE AT SERIAL TIME POINTS AND LOOK AT THE AMOUNT OF VIRUS AND THIS -- AXIS IS THE BASE 1050 PER GRAM OF TISSUE SO VIRUS TITER IN THE TISSUE AND LUNGS AND UPPER RESPIRATORY TRACT. WE TRIED THREE DOSES FROM TEN DIC 50 TO A THOUSAND OR 10,000. YOU CAN SEE THAT WE DEMONSTRATED HIGHER DOSES DID CERTAINLY INFECT THE MICE, AND VIRUS WAS CLEAR BY DAY SEVEN. SO THESE MICE SHOWED NO CLINICAL SIGNS OF ILLNESS AND THEY CLEARED THE VIRUS. WHAT WE DID DEMONSTRATE IN THIS WAS THE ANIMALS THAT HAD SO TO THE 5 -- 10 TO 5 OR 10 TO 3 VIRUS INKNOCK ALMOST HAD NEUTRALIZING ANTIBODY RESPONSE SO WE CHALLENGED THESE MICE AGAIN WITH THE SAME DOSES OF VIRUS TO SEE IF THEY COULD BE REINFECTED AND PRIMARY INFECTION ACTUALLY GAVE VERY ROBUST PROTECTION FROM RECHALLENGE. THIS WAS COMPARED TO A NAIVE SET OF MICE THAT WERE INCLUDED THAT WERE OBVIOUSLY SERO NEGATIVE AND THEY SUPPORTED VIRUS REPLICATION IN THE DETERMINANTS. WE ALSO DID IN THE SAME STUDY WE LOOKEDDED TO SEE WHETHER WE CAN TRANSFER SERUM FROM THESE PREVIOUSLY INFECTED MICE AND SEE IF THAT WOULD PROTECT NAIVE MICE. SO WE TOOK SERUM FROM THE RECOVERED MICE THAT HAD A TITER OF 1 TO 1,000 AND WE MADE -- DILUTION OF THAT, ADMINISTERED THAT INTO NAIVE MICE AND HAD A GROUP THAT GOT A NON-IMMUNE SERUM, MOUSE SERUM AND THEN WE CHALLENGED ALL THESE MICE WITH SARS CORONA VIRUS AND DEMONSTRATED THAT IN FACT THE -- OF IMMUNE SERUM FROM RECOVERED MOUSE PROTECTED THE NAIVE MICE FROM CHALLENGE VIRUS REPLICATION IN THE LUNGS. IN AN EXPERIMENT -- TIME BY OUR COLLEAGUES IN THE LABORATORY OF INFECTIOUS DISEASES, THEY DID A VERY ELEGANT EXPERIMENT WHERE THEY USE BOVINE HUMAN INFLUENZA VIRUS AS VECTOR AND INSERTED THE SARS SPIKE AND E OR N PROTEIN OR COMBINATION OF S M AND E OR M AND E AND THEN THEY HAD AN EMPTY VECTOR BOVINE HUMAN INFLUENZA VIRUS AS CONTROL AND LIVE VIRUS AS CONTROL. SO THEY INFECTEDDED GOLDEN SYRIAN HAMSTERS WITH THESE VIRUSES AND DEMONSTRATED ONLY THOSE ANIMALS THAT GOT A VIRUS THAT INCLUDED THE SPIKE THE LIVE VIRUS OR THE VECTOR VIRUS THAT CONTAINED THE SPIKE PROTEIN, ELICITED ANTIBODIES IN THE HAMSTERS AND ONLY THOSE ANIMALS WERE PROTECTED SUBSEQUENT CHALLENGE. COMPARED TO THE EMPTY VECTOR. SO THE TWO CONCLUSIONS FROM THESE TWO EXPERIMENTS WERE THAT MICE RECOVERED FROM SARS CORONA VIRUS INFECTION WERE PROTECTED FROM REINFECTION, THIS IS MOW DEMONSTRATED WITH SARS 2 INFECTION OF RHESUS MACAQUES. NEUTRALIZING ANTIBODY CONFERRED PROTECTION. SARS CORONA VIRUS 2 AND PETER'S EXPERIMENT THE SPIKE PROTEIN WAS THE ONLY SPECIFIC TARGET OF NEUTRALIZATION AND IS A PROTECTIVE ANTIGEN. SO MY LAB WHEN AT THE NIH DEVELOPED A NUMBER OF DIFFERENT ANIMAL -- WE EXPLORED A NUMBER OF MOUSE MODELS HAMSTERS AN NUMBER OF SPECIES OF PRIMATES. AND I'LL GIVE YOU A FEW SNAP SHOTS AS WAS THE CASE WITH SARS CORONA VIRUS 2 -- OVER AGE 50 IN THAT CASE OLDER IN THIS CASE, IN THIS PANDEMIC BUT OLDER INDIVIDUALS HAD MORE SERIOUS DISEASE. AS I HAD SAID, THE YOUNG MICE CLEARED THE VIRUS WITHIN SEVEN DAYS WITH NO CLINICAL SIGNS, NO WEIGHT LOSS, RUFFLED FUR OR ANYTHING. SO WE ENDED UP ACTUALLY EVALUATING OLDER MICE AND WE CALL THEM AGED, ALTHOUGH PEOPLE IN THAT STUDY AGING TELL ME THAT A 12 MONTH OLD MOUSE IS NOT REALLY AN AGED MOUSE THAT NEEDS TO BE 18 TO 24 MONTHS. USE 12 MONTH OLD MICE AND IN THE LOWER SET OF BARS WHICH IS THE SOLID ARE THE OLDER MUSICAL -- IN INFECTED WITH SARS AND THE UPPER ARE THE ANIMALS THAT GOT THE MOCK IMMUNIZATION. WHAT WE SAW WAS A VERY -- AND THE VIRUS ACTUALLY REPLICATED TO HIGHER TITER, THERE WAS MUCH MORE EVIDENCE OF -- WITH ALVEOLAR DAMAGE. WE EXPLORED THIS FURTHER IN TERMS OF THE IMMUNE MECHANISMS GOING ON AND IN THIS SCHEMATIC WHERE AS YOU WILL SEE THE Y AXIS DOESN'T ACTUALLY HAVE A SCALE BAR BECAUSE WE TRIED TO COMBINE WHAT'S GOING ON WITH THE VIRUS TITER IN -- PNEUMONITIS THAT APPEARS LATER IN LIGHT BLUE AND EVENTS THAT OCCURRED IN TERMS OF CYTOKINE, CHEMOKINE RESPONSES, T-CELL RESPONSES AND SO ON ARE SUMMARIZED HERE. WE DID FIND IN THIS MODEL THAT DEPLETING THESE ANIMALS OF CD4 T-CELLS BUT NOT CD8 T-CELLS, HERE WE DEPLETED WITH ANTI-CD8 ANTIBODY OR ANTI-CD4 ANTIBODY OR BOTH, THAT IF YOU DEPLETED WITH ANTI-CD4 ANTIBODY YOU SEE A DELAYED VIRAL CLEARANCE AND THAT WAS SEEN AGAIN WITH THE IMMUNOHISTOCHEMISTRY AS WELL. THE OTHER ITEM WAS WE WANTED TO STILL USE YOUNG MICE AND SO WE MOUSE ADAPTED THE VIRUS BY SERIAL PASSAGE IN MICE. THIS IS TUN WITH A NUMBER OF DIFFERENT -- DONE WITH A NUMBER OF VIRUSES, WITH INFLUENZA, EBOLA AND MANY OTHER VIRUSES THAT IF YOU WANT TO READ OUT THAT INVOLVES SOME VIRULENTS THAT -- SO WHAT WE DID IN THE MOUSE -- YOUNG MICE WAS WE INOCULATED THEM WITH SARS, WAITED TWO TO THREE DAYS, HARVESTED THE LUNGS, MADE A TEN -- AND AGAIN INOCULATED THAT INTO THE NEXT SET OF MICE. WE REPEATED THIS IN GROUPS OF THREE MICE -- TIMES AND BY PASSAGE 15 WE HAD VIRUS THAT WAS LETHAL FOR MICE AT FOUR LOGS. THE VIRUS REPLICATED, THESE ARE THREE -- SERIAL DELUSIONS OF THE VIRUS GIVEN TO MICE AND THERE WAS A VERY ROBUST UP TO TEN TO THE 8, TEN TO THE 9 TCID VIRUS PER GRAM OF TISSUE WHEN WE ADMINISTERED THE MOUSE ADAPTIVE VIRUS. WE WERE INTERESTED IN UNDERSTANDING WHAT MADE THIS VIRUS LETHAL FOR MICE, TURNS OUT IN FACT IF YOU LOOK HERE ON THE IMMUNOHISTOCHEMISTRY, THESE TWO NORMAL SARS BINDING STRAIN VERSUS THE MOUSE ADAPTED VIRUS SHOWN HERE IN THE PINK STAINING CELLS ARE THE CELLS THAT ARE STAINED FOR SARS SPIKE ANTIGEN. YOU CAN SEE THAT THERE'S A LOT MORE VIRAL ANTIGEN IN THE MOUSE ADAPTED VIRUS INFECTED HAHN IN THE NORMAL VIRUS. AND THIS WAS TRUE AT DAY 3 AND 4. IT ISN'T FAIR TO LOOK AT INFLAMMATORY CHANGES -- STAIN BUT IN THE INTEREST OF TIME I HAVE INCLUDED THE HNE STAINS BUT THE MOUSE ADAPTED VIRUS DID NOT -- AT DAY THREE AND FOUR WAS NOT ASSOCIATED INTENSE INFLAMMATORY RESPONSE SO REALLY THE MICE DIE AT DAY FOUR POST INFECTION FROM AN OVERWHELMING VIRAL INFECTION. SO TO SUMMARIZE THAT PART WE ADAPTED THIS VIRUS FOR INCREASE VIRULENCE -- HIGH TITER IN THE LUNGS BUT WAS NOT ASSOCIATED WITH SIGNIFICANT INFLAMMATION. ADAPTATION INVOLVES SIX MUTATION S IDENTIFIED BY US AND IN COLLABORATION WITH RALPH'S LAB -- NORTH CAROLINA HE MADE A RECOMBINANT VIRUS HE INSERTEDDED EACH -- AND TOGETHER AND A REVERSE GENETICS DERIVED MOUSE ADAPTED 15 VIRUS WAS GENERATED THAT RECAPITULATED THE LETHAL PHENOTYPE. SO THIS VIRUS COULDN'T BE REALLY USED TO STUDY THE PATHOGENSIS OF SARS BECAUSE THE MICE DIED OF VIRAL INFECTION RATHER THAN PNEUMONITIS. BUT IT IS CERTAINLY A VERY ROBUST CHALLENGE FOR EFFICACY OF VACCINES AND ANTI-VIRAL DRUGS. SO WE ALSO DEVELOPED A GOLDEN SYRIAN HAMSTER MODEL AND THIS BECAME OUR GO TO MODEL OUR FAVORITE MODEL BECAUSE HAMSTERS CAN BE INFECT WITH VERY MODEST DOSES, SO THIS IS THREE LOGS, TEN TO THE THREE TCID 50 OF VIRUS INTRODUCE INTRANASALLY AND IN A SIMILAR FASHION YOU CAN SEE VIRUS REPLICATING OUT TO THESE NASAL DETERMINANTS AND THE LUNGS. THE VIRUS REPLICATED IN THE LUNGS UNTIL DAY 7 POST INFECTION, ANIMALS MAKE A ROBUST NEUTRALIZING ANTIBODY RESPONSE. AND IN FACT THEY DEVELOPED QUITE A ROBUST PNEUMONITIS BY IMMUNOHISTOCHEMICAL STAINING IN THE LUNGS YOU CAN SEE IN THE NASAL DETERMINANTS YOU CAN SEE ANTIGEN PRESENTING ITSELF LINING THE RESPIRATORY TRACT. SO I WAS SHOWING THESE SLIDES AT A MEETING -- PATHOLOGISTS AND SOME OF THEM SAID TO ME THESE ANIMALS HAVE TO BE SICK WHETHER YOU KNOW IT OR NOT AND WE -- MEASURES OF CLINICAL DISEASE IN THESE ANIMALS. BUT WE ENDED UP WITH THE VERY CLEVER STRATEGY THAT WAS DEVELOPED BY ONE OF THE STUDENTS IN THE LAB AND THAT WAS TO PUT THEM ON AN ACTIVITY WHEEL AND SO WE COULD LET THESE HAMSTERS RUN IN A BIOSAFETY CABINET, LINE UP FOUR CAGES AND -- CONNECTED TO A COUNTER SO WE CAN -- WE RECORD THE NUMBER OF REVOLUTIONS THE HAMSTERS RAN ON THE ACTIVITY WHEEL. SO TYPICALLY A HAMSTER ONES 400 -- A NIGHT, WE WOULD INFECT THEM WITH SARS AND RUN LESS THAN 10 REVOLUTIONS A NIGHT AND THEN AS THEY RECOVERED AFTER ABOUT DAY 10 TO 14 THEY WOULD START RUNNING AGAIN. WE INITIALLY EVALUATED THE VIRUS IN THREE DIFFERENT SPECIES OF NON-HUMAN PRIMATES. SO WE LOOKED AT RHESUS CYNAMOLOGOUS MACAQUES AND AFRICAN GREEN MONKEYS. THE VIRUS TITERS IN THE UPPER RESPIRATORY TRACK AND LOWER RESPIRATORY TRACK, 10 TO THE 6 IT WAS ADMINISTERED INTRANASALLY, WE SAW NO SIGN OF DISEASE IN ANY ANIMALS BUT DID SEE AFRICAN GREEN MONKEYS SUPPORTED MORE ROBUST VIRAL REPLICATION THAN RHESUS OR CYNAMOLOGOUS. SO WHERE ARE THESE SIMILAR OBSERVATIONS WITH SARS CORONA VIRUS 2? THE HAMSTER MODEL SHOWS ROBUST INFECTION OF THE -- RESPIRATORY TRACK, TURNS OUT TO BE I THINK FROM WHAT I CAN READ, LITERATURE STUDIES OURSELVES THAT THE HAMSTER MODEL IS MORE ROBUST THAN THE THIRD MODEL IS. THAT IS CERTAINLY CONSISTENT WITH WHAT WE SAW WITH SARS. NON-HUMAN PRIMATE MODELS CAN BE INFECTED BUT THE FINDINGS VARY BETWEEN THE SPECIES. THERE'S CERTAINLY ATTEMPTS TO MOUSE ADAPT SARS CORONA VIRUS 2 AND I THINK THERE'S SOME HINTS FROM THE ANIMAL MODELS THAT ARE IN DEVELOPMENT OF AN AGE DEPENDENCE. THE REASON THAT WE DEVELOPED ALL THESE MODELS WAS OF COURSE TO EVALUATE HOW VACCINES AND ANTI-VIRAL DRUGS WORK AND WE FOCUSED WHEN I WAS IN LID ON EVALUATING SARS VACCINE APPROACHES, WE COLLABORATED WITH PEOPLE AT THE NIH AND IN ACADEMIA AND INDUSTRY AND EVALUATED ABOUT NINE VACCINES AND ABOUT FOUR ANTIBODY -- AND MANY OF -- MANY SIMILAR APPROACHES ARE BEING USED FOR SARS CORONA VIRUS 2 WITH THE NOTABLE ADDITION OF SOME OF THE NEWER TECHNOLOGIES INCLUDING MRNA AND NANOPARTICLES WITH -- ONE OF THE QUESTIONS THAT WE -- THAT HAS COME UP AND IS SORT OF -- IS AN IMPORTANT QUESTION FOR VACCINES IS THE LONGEVITY OF THE SERUM NEUTRALIZING ANTIBODY RESPONSE. SO I WENT BACK TO WHAT WE HAD DONE WITH SARS AND I WILL SHOW YOU TWO EXAMPLES OF WHEN WE TRIED TO LOOK -- TO SEE HOW LONG IMMUNITY FROM THE VACCINES OR INFECTION MIGHT LAST. THIS IS AN EXPERIMENT ON HAMSTERS WHERE WE INFECTED HAMSTERS WITH THE VIRUS, SARS COV 2 OR A PURIFIED SPIKE PROTEIN OR A MODIFIED VACCINIA -- IN THE SPIKE SO THE MVAS AND THE SPIKE VACCINES -- AND THEN WE INOCULATED AS A POSITIVE CONTROL WITH THE VIRUS ITSELF. AND WE KEPT THESE ANIMALS AROUND FOR EIGHT MONTHS AND YOU CAN SEE THAT THE INFECTION CERTAINLY INDUCED ANTIBODY THAT LASTED, AS DID THE PURIFIED SPIKE PROTEIN. THE ANTIBODY INDUCED BY THE MBA EXPRESSING S PROTEIN WAS A BIT -- CERTAINLY MORE MODEST AND DECLINED OVER TIME. WE CHALLENGED THESE ANIMALS INITIALLY ONE MONTH POST VACCINATION AND THIS JUST DEMONSTRATES THE INFECTION AND BOTH SPIKE PROTEIN AND MVA EXPRESSING THE SPIKE PROTEIN WERE VERY EFFECTIVE IN PROTECTING HAMSTERS FROM CHALLENGE WITH SARS. AND THE CONTROLS HERE WERE PBS OR MVA, AND EMPTY MVA SO THIS SHOWS YOU THAT THE VACCINES WERE PROTECTIVE ONE MONTH POST VACCINATION, THIS IS NOW LOOKING EIGHT MONTHS POST VACCINATION AND IN THE SOLID DARKER COLORS REPRESENT DAY TWO POST CHALLENGE WHICH IS WHEN YOU WOULD SEE PEAK VIRUS REPLICATION AND AT 14 DAYS POST CHALLENGE JUST TO SEE IF THERE WAS ANY EVIDENCE OF DELAY IN CLEARANCE. SO YOU CAN SEE THAT ANIMALS THAT WERE VACCINATED EIGHT MONTHS -- THE SPIKE PROTEIN OR THAT HAD BEEN INFECTED EIGHT MONTHS EARLIER WERE VERY WELL PROTECTED COMPARED TO ANIMALS THAT GOT THE MVA EXPRESSING SPIKE OR PBS CONTROL. WE DID A SIMILAR EXPERIMENT IN MICE AND THIS IS A COLLABORATION WITH GSK AND THESE ARE ANIMALS THAT GOT -- HARP CHALLENGED EARLY -- THAT WERE CHALLENGED EARLY FOUR WEEKS AFTER THOSE TWO OR LATE WHICH IS 18 WEEKS SO A LITTLE OVER SIX MONTHS SO ABOUT SIX MONTHS -- AND THE LUNGS WERE HARVESTED TWO DAYS POST CHALLENGE. SO THIS IS A SPIKE PROTEIN ACTIVATED VACCINE WHERE THE AMOUNT OF IMMUNOGEN WAS MEASURED IN TERMS OF AMOUNT OF SPIKE PROTEIN AS .5 OR TWO MICROGRAMS WITH AND WITHOUT AN ASO 1B ADJUVANT. THE POSITIVE CONTROL WAS SARS INFECTION AND NEGATIVE CONTROL WAS INFLUENZA -- ACTIVATED INFLUENZA. AND YOU CAN SEE THAT THE EARLY CHALLENGE WORKED -- VACCINES WERE VERY WELL PROTECTIVE AGAINST EARLY -- AND THE ADJUVANTED VACCINE WORKED QUITE WELL EVEN SIX MONTHS LATER. WE DID NOT SEE ANY EVIDENCE OF ENHANCED INFLAMMATION IN THE LUNGS AND THESE ARE DATA LOOKING AT 18 WEEKS POST CHALLENGE AND THESE -- THE LUNG HISTOLOGY IS DONE FIVE DAYS FOLLOWING CHALLENGE. SO ON TOP ARE THE -- ARE THE INACTIVATED INFLUENZA WITH THE -- WITH ADJUVANT, ON THE LEFT IS THE EACHNESS AND ON THE RIGHT IS IMMUNOHISTOCHEMISTRY SO YOU CAN SEE A LOT OF EVIDENCE OF INFLAMMATION AND ANTIGEN IN ANTIGEN HERE IS IN BROWN. THE SPIKE PROTEIN WITH AND WITHOUT ADJUVANT WERE PROTECTIVE -- PROTECTED WELL FROM INFLAMMATION AND ANTIGEN. SO THE CURRENT STRATEGIES FOR SARS CORONA VIRUS 2 AGAIN FOCUS LARGELY ON THE SPIKE PROTEIN, AND THE SPIKE PROTEIN IS DELIVERED BY A NUMBER OF DIFFERENT METHODS INCLUDING RNA, DNA, RECOMBINANT PROTEIN VECTORED OR INACTIVATED VACCINE. THIS IS JUST OFF VACCINE TRACKER, FROM THE NEW YORK TIMES, SHOWING THE NUMBER THAT THERE ARE MORE THAN 105 VACCINES IN DEVELOP T PRE-CLINICAL DEVELOPMENT AND IN FACT MOVING ALONG AT AN INCREDIBLY FAST PACE COMPARED TO WHAT IS -- NORMALLY HAPPENS IN IF VACCINE DEVELOPMENT. SO IN TERMS OF VACCINE DEVELOPMENT, GOOD NEWS IS THAT THE OPTIMAL -- FOR THE VACCINES WAS KNOWN AND THAT WAS SPIKE OR S PROTEIN. THERE'S CERTAINLY NEW VACCINE PLATFORMS AVAILABLE INCLUDING mRNA, PROTEIN VECTOR VACCINES THAT CAN BE ADAPTED VERY RAPIDLY. AND WHAT HAS BEEN NEW IS GLOBAL FUNDING CONSORTIUM WAS ALREADY PREPARING FOR VIRUS X. AND NOW WE KNOW WHAT VIRUS X IS. THERE'S BEEN A NEW WILLINGNESS TO EVALUATE VACCINES IN THE MIDST OF EPIDEMIC AS WE ALL LEARNED FROM EBOLA. THE CHALLENGES ARE THAT THERE ARE NO LICENSED CORONA VIRUS VACCINES FOR USE IN HUMANS, THERE'S NO CLINICAL EXPERIENCE WITH SAFETY IMMUNOGENICITY OR EFFICACY. AND SO WHAT HAD HAPPENED WITH SARS VACCINE DEVELOPMENT IS WE LOOKED AT MANY DIFFERENT VACCINES, THERE WERE VACCINES DEVELOPED USING A WHOLE RANGE OF TECHNOLOGIES BUT MOST ALL THE PHARMACEUTICAL INDUSTRY PARTNERS MAY GO, NO GO DECISIONS BASED ON WHETHER SARS REAPPEARED. WHEN IT DIDN'T REAPPEAR, THOSE PROGRAMS ENDED. CERTAINLY WITH EMERGENCE OF MERS THERE WAS INCREASE IN ACTIVITY AROUND DEVELOPMENT OF VACCINES. BUT AGAIN NONE OF THOSE MADE IT QUITE FAR INTO -- INTO LICENSURE FOR USE IN HUMANS. SO I THINK WE REALLY -- THERE'S CERTAINLY SOME SAFETY CONCERNS RAISED -- VACCINES BEING CONSIDERED NOW FOR SARS CORONA VIRUS 2. THE MILLION DOLLAR QUESTION IS WHETHER SARS CORONA VIRUS 2 WILL BECOME SEASONAL VIRUS. I THINK IT'S LIKELY IT WILL, WE CERTAINLY DON'T MOW THE HISTORY HOW OTHER HUMAN CORONA VIRUSES EMERGED AND WHETHER THEY EMERGED IN PANDEMICS BEFORE THEY BECAME ESTABLISHED AS SEASONAL RESPIRATORY VIRUSES. IF THEY -- IF SARS CORONA VIRUS 2 BECOMES A SEASONAL RESPIRATORY VIRUS, I DON'T THINK IT WILL BEHAVE THE WAY INFLUENZA DOES IN TERMS OF THE RATE OF ANGIOGENIC DRIFT AND NEED TO -- VACCINES -- LEVEL BECAUSE CORONA VIRUSES CERTAINLY DON'T SEEM TO DRIFT THE WAY INFLUENZA VIRUSES DO. BUT THE CAVEAT IS OF COURSE THAT WE HAVE NEVER PUT A HUMAN CORONA VIRUS UNDER THE SODIUM PRESSURE BOTH THE PANDEMIC AND VACCINE MIGHT. SO WHERE ARE THESE VIRUSES COMING FROM? AS MOST MANY OF YOU KNOW, THERE WERE CORONA VIRUSES IN ALMOST EVERY SPECIES HAS THEIR OWN CORONA VIRUS SO CORONA VIRUSES FALL INTO ALPHA, BETA, GAMMA AND DELTA VIRUSES, THAT THE GAMMA AND DELTA CORONA VIRUSES ARE PRESENT IN -- SPECIES, ALPHA AND BETA CORONA VIRUSES ARE PRESENT IN A VARIETY OF DIFFERENT SPECIES. THE ONES THAT I HAVE IDENTIFIED WITH RED ARROW ARE THOSE THAT HAVE BEEN ISOLATED FROM HUMANS THAT INCLUDE THE HUMAN CORONA VIRUSES ML 63 AND 229E, OC 43, OC 43 HERE AND HKU 1 HERE. MERS IS OFF BY ITSELF, HKU VIRUSES AND SARS IS DOWN HERE. THIS NEW VIRUS 2 THIS CLUSTER WAS IDENTIFIED HERE AND IT IS RELATED TO ORIGINAL SARS VIRUS BUT MORE CLOSELY RELATED TO VIRUSES FROM BATS. SO SARS AND MERS CORONA VIRUSES THAT EMERGE TO CAUSE SIGNIFICANT MORBIDITY AND MORTALITY IN HUMANS IN 2002 AND 2003 AND 2012 ONWARDS WITH MERS HAVE BOTH PASSED THROUGH IMMUNE HOSTS CATS AND SMALL CARNIVORESS IN THE KISS OF SARS AND CAMELS IN THE CASE OF MERS. SO THESE TWO VIRUS -- THESE VIRUSES SPILLED OVER INTO HUMANS WITH REPEATED INCURSIONS FROM THE INTERMEDIATE HOSTS INTO HUMANS AND THERE WAS THREAD SPREAD FROM PERSON TO PERSON BUT REQUIRED A VERY CLOSE CONTACT. THE GAME CHANGER IN THE CASE OF SARS CORONA VIRUS 2 IS THE FACT THAT IT SPREAD FROM PERSON TO PERSON SO EFFICIENTLY THROUGH THE RESPIRATORY TRACT. SO CERTAINLY AS I SAID, THE DOMESTIC ANIMALS, BATS, WE ALL HAVE OUR OWN CORONA VIRUSES AND CORONA VIRUSES CHANGE, ALTER THEIR GENOMES BY RECOMBINATION WHERE THEY CAN PICK UP WHOLE SECTIONS OF THE RNA GENOME FROM OTHER CORONA VIRUS SPECIES FROM DIFFERENT HOSTS. THIS HAPPEN CERTAINLY HAPPENS IN NATURE, SO BATS HAVE CORONA VIRUSES THAT HAVE PORTIONS OF THEIR GENOME THAT ARE RELATED TO OTHER CORONA VIRUSES, BUT WHAT HAPPENS WHEN WE -- CLOSE PROXIMITY AND WE LOSE -- WHEN THE ANIMALS LOSE THEIR -- INTO CLOSE PROXIMITY WITH HUMANS PARTICULARLY WILD ANIMALS -- CLOSE TOGETHER THERE'S MUCH MORE AN EXCHANGE. SO THIS IS SORT OF -- THIS IS MY ASSESSMENT IN WHAT'S BEEN GOING ON -- COMING. SO PANDEMIC -- ACTIVITIES HAVE LARGELY BEEN FOCUSED ON INFLUENZA. EVEN THOUGH THE ZOONOTIC RISK OF CORONA VIRUSES AND OTHER VIRUS FAMILIES LIKE -- VIRUSES WAS KNOWN. SO I DO THINK WE NEED TO PAY MORE ATTENTION TO THE ZOONOTIC SOURCES OF VIRUSES. WE HAVE HAD CORONA VIRUS VACCINES OR ANTI-VIRAL DRUGS AND THERE WAS A LOTS OF OPPORTUNITIES BOTH WITH SARS AND SUBSEQUENTLY WITH MERS TO DEVELOP PAN CORONA VIRUS DRUGS AND SOME MORE EXPERIENCE WITH CORONA VACCINES. WHAT WAS DIFFERENT THIS TIME IS EFFICIENT TRANSMISSION BY THE RESPIRATORY ROUTE THAT MAKES IT MORE REMINISCENT OF PANDEMIC INFLUENZA. WHAT'S WORKED WELL IS CAPABILITY TO IDENTIFY THE VIRUS AND TEST FOR IT. THE INFLUENZA PANDEMIC PREPAREDNESS PLANS WITH ADAPTED QUICKLY AND GOVERNMENT DECISIONS CERTAINLY THIS IS TRUE IN AUSTRALIA WHERE -- KEEP IN MIND FOR THE FUTURE THERE ARE OTHER CORONA VIRUSES INFLUENZA VIRUS AND MIX OF VIRUSES WITH PANDEMIC POTENTIAL THAT EXIST IN ANIMAL HOSTS AND WORLD OF ONE HEALTH WHERE HUMAN ANIMAL PUBLIC HEALTH AND THE ENVIRONMENT ARE CLOSELY INTERTWINED AND WE NEED TO ACKNOWLEDGE THIS AND -- WORK ON THIS TOGETHER. SO THIS IS MY LAST SLIDE. I'M GOING TO ACKNOWLEDGE THE PEOPLE THAT DID THE WORK THAT I'VE -- TO YOU AT THE NIH. I THINK THAT THERE WERE THREE BIG REASONS FOR -- WE HAVE VERY SUCCESSFUL VERY PRODUCTIVE PROGRAM ON SARS AND I THINK THAT THAT WAS BECAUSE OF THREE THINGS. ONE WAS I HAD AN ABSOLUTELY FABULOUS TEAM THAT WORKED INCREDIBLY -- AND WORKED ON SO MANY DIFFERENT ANIMAL MODELS, IT WAS NEVER BIGGER THAN A TEAM OF FOUR OR FIVE PEOPLE BUT WE WORKED VERY WELL TOGETHER. THE SECOND WAS -- RESEARCH PROGRAM AND THAT GAVE US THE ABILITY TO RESPOND VERY QUICKLY. WE HAD A BSL 3 LAB AND WE QUICKLY FOUND A WAY TO WORK WITH ANIMALS, WE HAD A LOT OF SUPPORT FROM -- LABORATORY CHIEF AT TIME. THE COMPARATIVE MEDICINE BRANCH, THE BIOSAFETY, JUST A HUGE AMOUNT OF SUPPORT IN THE INTRAMURAL PROGRAM. AND THE THIRD REALLY CRITICAL PART WAS THE CORONA VIRUS COMMUNITY. THE NIH IN THEIR WISDOM HAD -- SUPPORTED A SMALL DEDICATED GROUP OF CORONA VIROLOGISTS OVER THE YEARS AND -- INCREDIBLY OPEN TO WORKING WITH -- DOESN'T REALLY HAVE THAT DOESN'T ALWAYS HAPPEN IN SCIENCE, SOMETIMES PEOPLE CLOSE RANKS, BUT I HAVE HAD GREAT COLLABORATION PARTICULARLY WITH RALPH, MARK DENNISON, THE NUMBER OF DIFFERENT PEOPLE IN THE CORONA VIRUS COMMUNITY AND REMAIN LIFE LONG COLLABORATORS AND FRIENDS. WE HAD A LOT OF SUPPORT FROM THE INFECTIOUS DISEASE PATHOLOGY ACTIVITY, AND AS I SAID WE WORKED ON VACCINES AND ANTIBODIES DEVELOPED BY MANY DIFFERENT PEOPLE. SO I WILL CLOSE ACKNOWLEDGING THAT SUPPORT I HAVE NOW COMES FROM THE AUSTRALIAN GOVERNMENT DEPARTMENT OF HEALTH. MAJOR COLLABORATING CENTER SO I DON'T WORK FOR THE WHO BUT THE HOST COUNTRY ACTUALLY SUPPORTS, THE WHO COLLABORATING CENTERS. SO WITH THAT I WILL STOP AND SEE IF I CAN STOP SHARING MY SLIDES. >> THANK YOU, KANTA, FOR THAT GREAT LECTURE, THANKS, EVERYONE FOR JOINING US TODAY. IN CASE YOU MISSED IT EARLIER, THE SECRET CME CODE FOR TODAY IS 24881. THAT IS 24881. THEN PLEASE JOIN US AT FIVE O'CLOCK TODAY IMMEDIATELY FOLLOWING THIS LECTURE FOR A LIVE QUESTION-AND-ANSWER SESSION WITH DR. SUBBARAO VIA WEBEX. YOU SHOULD HAVE THE LINK TO REGISTER IN TWO PLACES, YOU CAN LOOK AT THE WEBEX LINK RIGHT DOWN AT THE BOTTOM OF THIS VIDEO CAST OR IT WILL THEN IN THE EMAIL ABOUT THE LECTURE THAT WAS DISTRIBUTED ON MONDAY, TO ALL NIH STAFF. YOU MAY ALSO SUBMIT A QUESTION USING THE LIVE FEEDBACK -- ANY TIME, THIS IS AT THE -- AT THE VERY -- IN THE WEBEX LINK IS LOCATED THERE. THANK YOU AGAIN FOR JOINING TODAY. DO WE HAVE TIME FOR ONE QUESTION? YES. WE DO. SO I'M GOING TO START WITH A QUESTION. FIRST THERE'S A QUESTION ABOUT WHAT MIGHT IT TAKE FOR THIS -- WHAT THINGS DO YOU THINK WILL BE INVOLVED IF THIS BECOMES A YEARLY SEASONAL VIRAL INFECTION? WHAT FACTORS MAY INFLUENCE THAT AND WHAT -- HOW DO YOU SEE IT? DO YOU SEE IT BECOMING LESS PATHOGENIC IN THAT CASE OR DO YOU THINK IT WILL STAY WITH THIS PATHOGENICITY BUT CONTINUE TO HAVE YEARLY SEASONAL OUTCOMES, OUTBREAKS? >> THAT'S A REALLY GOOD QUESTION. CERTAINLY CORONA VIRUSES, HUMAN CORONA VIRUSES AND HAY THEY -- THEY CAUSE ANNUAL ILLNESS NOT SEASONAL ALWAYS, CORONA VIRUSES IN CIRCULATION WILL SEE 43229E K HKU 1 AND NL 63, ACCOUNT FOR QUITE A PROPORTION OF COMMON COLD INFECTIONS THOUGH THEY CAN ALSO CAUSE MORE SEVERE DISEASE. SO IT -- WILL HAPPEN IF THIS VIRUS BECOMES A SEASONAL VIRUS. WE KNOW SARS INDUCED ANTIBODIES THAT LASTED FOR MANY YEARS. AND SO IT'S POSSIBLE THAT PEOPLE THAT -- FROM COVID-19 WILL HAVE ANTIBODIES THAT WILL PROTECT THEM FROM REINFECTION. WHAT WE DON'T KNOW IS WHETHER THAT PROTECTION WILL LAST A LIFETIME. IT MAY NOT. BECAUSE MANY RESPIRATORY VIRUSES INCLUDING RSV AND CORONA VIRUSES, THE IMMUNITY IS NOT LIFE LONG, YOU DO GET REINFECTED. SO I THINK IN SOME SENSES WE JUST HAVE TO WAIT AND SEE WHAT HAPPENS WHEN -- IN THE SUBSEQUENT SEASONS. I THINK IF THE VIRUS PERSISTS WITH THE LEVEL OF VIRULENCE THAT IT DOES, THEN PEOPLE THAT WERE PROTECTED THIS GO AROUND MAY BE SUSCEPTIBLE -- MAY BE TARGETS FOR SEVERE DISEASE IN THE FUTURE AND THAT'S CERTAINLY A CONCERN IN COUNTRIES LIKE AUSTRALIA AND NEW ZEALAND THAT REALLY DIDN'T SUFFER QUITE AS MUCH WITH THIS FIRST WAVE OF THE PANDEMIC. SO AGAIN, WE HAVE TO STAY TUNED AND SEE WHAT HAPPENS. >> SO SECOND QUESTION -- EXCUSE ME. THAT'S MY DOG IN THE BACKGROUND. ONE OF THE SIDE EFFECTS OF HAVING A WEBEX LECTURE. BUT BASED ON THE AUSTRALIA EXPERIENCE, WHEN OR WHAT ARE YOUR CONCERNS ABOUT A SECOND WAVE? WHAT DO YOU THINK IS GOING TO CONTRIBUTE TO THAT? DO YOU THINK IT WILL BE FROM THE OUTSIDE? FROM TRAVEL? AND HOW DO YOU FEEL -- DO YOU FEEL YOU ARE BETTER PREPARED FOR THE SECOND WAVE? >> RIGHT. SO AUSTRALIA HAS -- IS AN ISLAND AND CERTAINLY EVEN IN FIRST WAVE WE HAVE SEEN ALMOST ALL THE DISEASE HAS BEEN INTRODUCED OVERSEAS. AUSTRALIANS ARE BIG TRAVELERS SO WHEN THEY TRAVEL AGAIN WE WILL SEE THE INTRODUCTION OF VIRUS FROM OVERSEAS, IT'S A SMALL POPULATION AND CERTAINLY THE PLAN IS TO DO VERY CAREFUL TRACING, CONTACT TRACING AND THAT IS CERTAINLY THE PLAN GOING FORWARD. WHAT THEY ARE DOING RIGHT NOW IS PEOPLE THAT RETURN CERTAINLY AUSTRALIANS, CITIZENS AND PERMANENT RESIDENTS WHO WANT TO RETURN CAN RETURN AND WHEN THEY RETURN THEY ARE ALL TAKEN TO HOTELS. THEY ARE QUARANTINED AT HOTELS FOR TWO WEEKS. THEY HAVE A SWAB DONE DAY THREE AND DAY 11 AT THIS POINT AND THEY ARE ONLY ALLOWED TO GO HOME AFTER 14 DAYS. SO HOW LONG THAT PLAN WILL STAY IN EFFECT IN TERMS OF HOTEL QUARANTINE IS NOT CLEAR BUT I SUSPECT THAT EVEN ONCE WE ARE ALLOWED TO TRAVEL AGAIN, WE WILL PROBABLY HAVE A SELF-QUARANTINE PROCESS. >> QUITE IMPRESSIVE, DEFINITELY. IN TERMS OF THE ANIMAL MODELS, IN TERMS OF DATA YOU HAVE SEEN WITH SARS COV 2 WHAT IS -- WHAT ARE YOUR THOUGHTS ABOUT THE DIFFERENCES BETWEEN SARS COV 1 AND SARS COV 2 IN TERMS OF ANIMAL MODELS AND THOUGHTS ON WHAT MAYBE SOME OF THE MOST PROMISING ANIMAL MODELS FOR SARS COV 2? >> SO I -- I MEAN -- SOMETHING I FEEL A BIT HANDICAPPED BECAUSE I'M NOT ACTUALLY DOING THE EXPERIMENTS MYSELF SO IT'S JUST BEING ON FOR ME LATE NIGHT CALLS WITH THE WHO OR THE NIH. BUT CERTAINLY A LOT OF THE EXPERIENCE THAT WE HAD WITH SARS 1 I THINK ARE SEEN WITH SARS 2 AS WELL. AND I THINK MANY OF THE SAME PRINCIPLES ARE AT PLAY. SO CERTAINLY THE -- I THINK MOUSE ADAPTED VIRUS WILL BE VERY USEFUL. UNLIKE SARS 1, SARS 2 DOESN'T INFECT A NORMAL MOUSE BECAUSE THE MOUSE ACE 2 DOESN'T BIND SARS QUITE AS WELL AS IT DID SARS 1 SPIKE. SO THERE'S CERTAINLY THE USE OF HUMAN ACE 2 EXPRESSING MICE THAT HAS BEEN NECESSARY FOR SARS 2 THAT WAS NOT NECESSARY FOR SARS 1. BUT AGAIN, THERE ARE REPORTS OF MOUSE -- THAT ALLOWS YOU TO OVERCOME THAT. IN EVEN A NORMAL MOUSE EXPRESSING A MOUSE -- IS SO THAT'S PROBABLY ONE OF THE MOST NOTABLE DIFFERENCES. AND I THINK THERE HAVE BEEN SOME DIFFERENCES IN THE EXPERIENCE WITH NON-HUMAN PRIMATES SPECIES. I WILL SAY EVEN WITH SARS 1 WE LEARNED AND CERTAINLY WITH HIV -- WE DIDN'T -- WITHIN GIVEN SPECIES OF NON-HUMAN PRIMATES THERE ARE DIFFERENCES SO EVEN RHESUS -- INDIAN RHESUS BEHAVE DIFFERENTLY THAN CHINESE RHESUS AND WE SAW DIFFERENCES AT OUR EXPERIENCE AT THE NIH WITH CYNAMOLOGOUS MACAQUES COMPARED TO EXPERIENCE IN NETHERLANDS BUT THERE ARE MORE SIMILARITIES THAN NOT AND PROBABLY THE MOST NOTABLE DIFFERENCE IS THE ABILITY OF THE MOUSE ACE 2 TO BIND WELL TO THE SARS COV 2 SPIKE. >> THEN FINALLY, I THINK MOST OF THE QUESTIONS WILL TAKE LATER, I JUST GOT SOME COMING IN BUT YOUR FEELINGS ABOUT ADJUVAT VERSUS NON-ADJUVANT FOR THESE TYPES OF VACCINES. >> CERTAINLY IN THE ANIMAL MODELS AND WITHIN VACCINES AND SPIKE PROTEIN VACCINES WE TESTED WITH SARS 1, ADJUVANTS HELPED. SO ADJUVANTS CERTAINLY DID IMPROVE THE IMMUNE RESPONSES. THAT'S A GROSS GENERALIZATION BUT THAT WAS CERTAINLY TRUE IN ALL THE VACCINES WE TESTED WITH AND WITHOUT ADJUVANTS, CERTAINLY ENHANCE THE IMMUNOGENICITY. HAVING SAID THAT, THERE WERE CONCERNS ABOUT THE -- OF SOME INFLAMMATORY CHANGES THAT WERE SEEN IN MOUSE MODELS AND IN NON-HUMAN PRIMATES THAT WE DID NOT SEE IN OUR HANDS BUT WERE -- BY OTHERS. THOSE IMPORTANT TO NOTE WERE OBSERVATIONS MADE IN THE ABSENCE OF PERSISTENT VIRUS REPLICATION. SO THE ANIMALS WERE PROTECTED FROM CHALLENGE VIRUS REPLICATION BUT THERE WERE SOME INFLAMMATORY CHANGES IDENTIFIED IN THE LUNGS AND AT LEAST SOME OF THE REPORTS SUGGEST THAT THOSE WERE ASSOCIATED WITH ADJUVANTED VACCINES OR VACCINES THAT CONTAINED THE NUCLEAR PROTEIN OF SARS. SO THESE ARE THINGS THAT NEED TO BE LOOKED AT WITH SARS 2 VACCINES. >> THANK YOU, THESE ARE ALL REALLY IMPORTANT POINTS. SO I KNOW THAT MANY OF YOU MAY HAVE MORE QUESTIONS AND SO AGAIN, PLEASE JOIN US FOR THE WEBEX CHAT WITH DR. SUBB ARAO, STARTING AT 5 P.M. THE LINK IS RIGHT BELOW THIS, YOU CAN CLICK ON IT OR IT WILL BE IN THE EMAIL THAT WAS SENT AROUND ON MONDAY AND THE REMINDER EMAILS. THANK YOU AGAIN FOR A GREAT LECTURE AND WE LOOK FORWARD TO CONTINUING THIS DISCUSSION AT FIVE O'CLOCK.