IT IS A TREMENDOUS PLEASURE TO
ENTINTRODUCE YOSHI KAWAOKA
WITHOUT KNOWING HIM PERSONALLY
WHEN I DID TRAINING IN THE LAB
IN GERMANY AND HE WAS INFECTIOUS
GROUP.
GOT TO KNOW HIM AS COLLABORATOR
WHEN WE STARTED TO WORK ON 1918
FLU AND EXB EBOLA AND WE BECAME
FRIENDS OVER THAT COLLABORATION
UNTIL TODAY.
DR. YOSHI HAS A DVM FROM
UNIVERSITY IN JAPAN, I LEAVE THE
YEARS OUT.
WE ARE ALL VERY YOUNG STILL.
SO HIS RESEARCH CAREER IS A
TREMENDOUS JOURNEY.
AS I SAID HE DID A POST DOC IN
MEMPHIS AND WENT TO ASSISTANT
MEMBER ASSOCIATE MEMBER
ASSOCIATE PROFESSORSHIP POSITION
AND BECAME FULL PROFESSOR
UNIVERSITY OF MADISON WISCONSIN,
WISCONSIN MADISON WHERE HE IS
STILL TODAY AND BECAME A UNIQUE
SITUATION FOR ME AT LEAST AND I
ALWAYS ADMIRE THIS THROUGHOUT
FULL PROFESSOR UNIVERSITY OF
TOKYO.
ONLY TWO YEARS AFTER HE JOINED
MEDICINE.
HE KEPT THOSE TWO AFFILIATIONS
THROUGHOUT HIS CAREER GOING BACK
AND FORTH BETWEEN THOSE TWO
CONTINENTS AND NEVER GETTING
TIRED OF FLYING BACK AND FORTH
THOUGH HE TOLD ME TODAY HE IS A
LITTLE TIRED OF IT AND THAT OF
COURSE WAS HAMPERED QUITE A BET
BY SARS COV-2 EMERGENCE AND
COVID PANDEMIC.
JUST RESENTLY HE BECAME DIRECTOR
OF RESEARCH CENTER FOR GLOBAL
VIRAL INFECTIONS NATIONAL CENTER
FOR GLOBAL HEALTH AND MEDICINE
IN JAPAN AND THIS IS HIS LATEST
ENDEAVOR, HE HAD MANY MORE
AFFILIATIONS OVER THE YEARS AND
STILL MAY HAVE MORE THAT I DON'T
KNOW ABOUT.
IN TERMS OF SCIENTIFIC
PRODUCTIVITY, IT IS ABSOLUTELY
FASCINATING, PUBMED LISTS 700
PEER REVIEWED PUBLICATIONS PLUS
150 MORE CONTRIBUTIONS, MANY
PATENTS, UNCOUNTABLE NATIONAL
AND INTERNATIONAL INVITED
PRESENTATIONS.
AND MANY, MANY AWARDS TO MENTION
A FEW, THE ROBERT COUGH AWARDED
THE PRESTIGIOUS GERMAN AWARDS.
THE MEDAL OF HONOR, PURPLE
RIBBON FROM JAPAN AND AWARD FROM
JAPAN ACADEMY AWARD FROM THE
EMPEROR OF JAPAN.
BECAME MEMBER OF THE NATIONAL
ACADEMY SCIENCES IN THE U.S. IN
2013 AND IN 2015, THE COLLEGE
FINALLY PRIZE FOR MICROBIOLOGY.
AS I SAID THIS IS A FEW OF HIS
HONORS AND AWARDS.
HIS PROFESSIONAL INTEREST IS
INFLUENZA.
HE DEVELOPED REVERSE GENETICS TO
STUDY PATHOGENESIS DEVELOP
VACCINES AND MANY OTHER ASPECTS
OF HIS AREAS OF RESEARCH AND
STILL DOES THAT TODAY.
HE IS ALSO DONE TREMENDOUS WORK
ON EBOLA STARTING WITH REVERSE
GENETICS CREATING A VACCINE THAT
IS IN CLINICAL TRIALS, STUDYING
PATHOGENESIS, AND EVEN DOING
FIELD STUDIES WHICH HE STILL
CONTINUES TO DO IN WEST AFRICA.
SOMETHING I BELIEVE VERY NEW TO
HIM AT THE TIME IT STARTED.
OF COURSE AS MANY OF INVOLVED IN
SARS COV-2 AND WE WILL HEAR THAT
TODAY IN HIS PRESENTATION.
IT IS AN HONOR AND PLEASURE TO
BE HERE AND INTRODUCE YASHI.
DON'T WANT TO STEAL MORE TIME
FROM YOUR TALK.
WE ARE LOOKING FORWARD TO
FASCINATING JOURNEY THROUGH SARS
COV-2, GO AHEAD.
THANKS FOR COMING AND ACCEPTING
THE INVITATION TO SPEAK.
>>THANK YOU FOR THAT NICE
INTRODUCTION.
I WOULD LIKE TO ALSO THANK FOR
INVITING ME TO TALK TO YOU SOME
OF THE WORK.
TODAY AS HINES MENTIONED, I GET
TO TALK ABOUT SARS COV-2 WHAT WE
HAVE BEEN WORKING ON SO I'M
GOING TO COVER FOUR TOPICS.
FIRST ANIMAL MODELS.
AT THE BEGINNING OF THIS
PANDEMIC WE NEEDED TO ANIMAL
MODELS TO STUDY.
SARS COV-2 WE INFECTED DIFFERENT
ANIMAL SPECIES AND FOUND THE
PROTOTYPE SARS COV-2 DIDN'T
REPLICATE WELL IN MARMOSET AND
REGULAR MICE.
AS YOU KNOW SOME OF THE RECENT
SOME OF THE VARIANT VIRUSES CAN
INFECT REGULAR MICE BUT WE ALSO
FOUND THAT THE HOSTS ARE HIGHLY
SUSCEPTIBLE.
IN FACT, CATS WHO WENT WITH THE
COVID-19 PATIENT BECAME PCR
POSITIVE.
SO WE INOCULATED CATS WITH SARS
COV-2 THEN EXAMINED WHETHER THE
VIRUS REPLICATES IN CATS OR NOT
AND THEN CO-HOUSED UNINFECTED
CAT TO SEE WHETHER THE DEVICE
CAN BE TRANSMITTED FROM
INOCULATED CAT TO UNINFECTED
CAT.
WE FOUND THAT THE VIRUS
REPLICATES QUITE WELL IN THE
INOCULATED CAT AND THE VIRUS CAN
BE TRANSMITTED TO CO-HOUSED
UNINFECTED CAT WITH TWO TO FIVE
DAYS OF CO-HOUSING.
WE FOUND THE VIRUS REPLICATES
WELL IN MORE THAN 10,000
INFECTIOUS UNITS IN THE NASAL
SWABS AND WHAT IS INTERESTING IS
THAT NONE OF THESE ANIMALS
SHOWED NO SYMPTOMS.
SO WHAT THIS TELLS US IS THAT
THE VIRUS CAN BE TRANSMITTED
FROM HUMANS TO CAT AND TRANSMIT
AMONG CATS WITHOUT CAUSING ANY
SYMPTOMS.
SO WE DON'T KNOW WHETHER THE
VIRUS CAN BE TRANSMITTED FROM
CATS TO HUMANS.
NOW, WE LET SOME OF THESE CATS
FOR 28 DAYS THEN EUTHANIZED AND
EXAMINED LUNG PATHOLOGY.
SO THIS WORK WAS DONE BY
(INDISCERNIBLE) IN OUR
DEPARTMENT.
AND SHE FOUND THAT THE
PATHOLOGICAL CHANGES LASTED FOR
28 DAYS IN THE LUNGS.
SO THIS MAY ALSO HAPPEN IN
HUMANS.
SO NOW WE INFECTED HAMSTERS WITH
SARS COV-2 THEN EXAMINED THE
VIRUS DATA ON DAY 3 AND FOUND
THAT THE MORE THAN 10 TO THE 8TH
INFECTIOUS UNITS IN NASAL
TERMINATE IN THE LUNGS.
ON THE 6 VIRUS TITER DROPPED BY
TWO LOG UNITS.
AND WE DIDN'T FIND ANY VIRUS IN
KIDNEY, INTESTINE AND BLOOD.
WE ALSO EXAMINED LUNG LESIONS BY
USING MICROCD.
BEFORE INFECTION AND SEVEN DAYS
POST INFECTION AND 16 DAYS POST
INFECTION OF THE SAME ANIMAL.
AS YOU CAN SEE LUNG LESIONS ARE
MOST PROMINENT ON DAY 7 MOSTLY
BECAUSE OF BASIC STAIN.
SOME IN OUR DEPARTMENT EXAMINED
THIS CT SCAN AND FOUND THAT
HAMSTERS INFECTED WITH SARS
COV-2 SHARE CT IMAGING
CHARACTERISTICS WITH HUMANS
COVID-19 DISEASE.
TOGETHER WITH THIS HAMSTER HIGH
REPLICATION OF THIS VIRUS IN
RESPIRATORY ORGANS, HAMSTERS ARE
USED FOR MODEL FOR COVID-19
STUDIES.
SO WE USED THIS MODEL ANIMAL
MODEL TO EXAMINE POINT MUTATION
ON VIRUS TRANSMISSION.
BETTY CULLIVER FOUND THAT THE
MUTATION AT 614 OF THE S PROTEIN
FROM D TO G WAS RESPONSIBLE FOR
THIS DOMINANCE OF THE DEVICE
LATER ON.
SO IN COLLABORATION WITH THE --
WE EXAMINED THIS PARTICULAR
MUTATION OF VIRUS TRANSMISSION.
SO RALPH MADE ISOGENIC VIRUS
THAT ONLY DISPOSITION.
SO THE ONE VIRUS CONTAINS
MUTATION DISPOSITION IN THE S
PROTEIN AND THE OTHER VIRUS
CONTAINS G AT THIS POSITION.
SO WE INOCULATED THIS VIRUS INTO
HAMSTER, NEXT DAY WE CO-HOUSED
UNINFECTED ANIMAL IN THE SAME
CAGE BUT THESE TWO ANIMALS
DIVIDED BY MESH.
SO THAT THEY DON'T TOUCH EACH
OTHER.
SO THE ONLY WAY THE VIRUS
TRANSMITTED FROM THIS INOCULATED
HAHAMSTER TO CO-HOUSED UNINFECTD
ANIMAL IS RESPIRATORY DROPLETS
OR AEROSOL.
SO EXAMINE TRANSMISSION ON DAY 4
POST EXPOSURE AND WE DID THIS
WITH EIGHT PAIRS FOR EACH VIRUS
AND FOUND THAT IN BOTH VIRUSES
WE SAW TRANSMISSION IN ALL EIGHT
PAIRS OF ANIMALS.
ON DAY 2 POST EXPOSURE WE DIDN'T
SEE ANY TRANSMISSION WITH THE
VIRUS CONTAINING D AT
DISPOSITION, WE SAW TRANSMISSION
IN FIVE OUT OF EIGHT PAIRS WITH
THE DEVICE CONTAINING GLYCENE AT
THIS POSITION.
SO THIS DATA SHOW THAT S
MUTATION G PROMOWS BETTER
TRANSMISSION.
NOW I WILL TALK ABOUT OMICRON.
SO YOU KNOW DELTA WAVE WAS
REPLACED BY OMICRON BA 1 AND
THEN BA 2.
AND NOW IN UNITED STATES BA 2,
12.1 BECAME DOMINANT AND IN
SOUTH AFRICA, AFTER BA 1 WAVE BA
2 APPEARED AND THEN BA 4 AND BA
5 ARE NOW DOMINATING.
SOME OF THE EUROPEAN COUNTRIES
HAVE BA 4, BA 5 OR BOTH.
BUT TO THEM GOING TO TALK ABOUT
BA TODAY, THE GENUS BA 1.
AND THIS WORK WAS DONE IN THE --
AS A PART OF THIS SAVE -- MANY
PEOPLE ARE INVOLVED IN THIS
PROJECT, MANY FROM NIH VRC AND
ALSO MY PEOPLE IN MY GROUP IN
TOKYO AND MADISON.
SO WE FIRST TESTED IN MICE USING
FOUR DIFFERENT MOUSE STRAINS,
FOUR DIFFERENT BA 1 CLINICAL
ISOLATES.
AND TESTED DIFFERENT INOCULATING
DOSES.
SO THE DATA COLOR CODED ALL THE
OMICRON DATA BA 1 DATA IN
DIFFERENT COLORS, THE OTHER
VARIANTS PROTO VIRUSES ARE SHOWN
IN BLACK.
IN THE ACE TWO EXPRESSING
TRANSGENIC MICE BA 1 DIDN'T
CAUSE ANY BODY WEIGHT LOSS.
THAT WAS ALSO THE CASE IN 129
MOUSE STRAIN.
AND ALSO B 6 MOUSE.
WE ALSO EXAMINED VIRUS TITER BY
INFECTING THE ANIMALS WITH
ISOLATE.
IN H 2 TRANSGENIC MICE AND ALSO
BALB/C MICE, BA 1 ISOLATE DIDN'T
REPLICATE AS GOOD AS PROTOTYPE
OR BETA VARIANT IN BOTH NASAL
TERMINATE AND LUNGS.
WE THEN EXAMINED HAMSTERS BY
INFECTING HAMSTERS WITH
INFECTIOUS UNITS.
AS YOU CAN SEE THE ANIMALS
INFECTED WITH THE OMICRON BA 1
DIDN'T LOSE BODY WEIGHT UNLIKE
ANIMALS INFECTED WITH OTHER
VIRUS.
WE THEN EXAMINED THE VIRUS TITER
IN RESPIRATORY ORGANS AND YOU
CAN SEE WE DIDN'T SEE ANY
DIFFERENCE BETWEEN DELTA AND
OMICRON IN NASAL TERMINATE BUT
WE SAW SUBSTANTIAL REDUCTION IN
TITER IN OMICRON INFECTED
ANIMALS IN LUNGS.
WE THEN EXAMINED RESPIRATORY
FUNCTION BY USING WHOLE BODY THE
ANIMALS INFECTED WITH OMICRON
WAS SIMPLY INFECTED WITH ANIMALS
IN THESE PARAMETERS DIFFERENT
FROM ANIMALS INFECT WITH DELTA
VARIANT WHICH SHOWS THE
RESPIRATORY FAILURE.
WE ALSO EXAMINED THE LUNG LESION
BY USING MICROCT AND AS YOU CAN
SEE ANIMALS INFECTED WITH DELTA
VARIANT SHOWED MULTIBILL LUNG
CONDENSATIONS AND NO DUALS AND
WE DON'T SEE THOSE IN OMICRON
INFECTED ANIMALS.
WE DID SEE LUNG -- IN ANIMALS
INFECTED WITH OMICRON.
BUT CT SCORING CLEARLY SHOWED
THE DIFFERENCE IN TERMS OF LUNG
LESIONS BETWEEN DELTA AND
OMICRON INFECTED ANIMALS.
THIS CAN BE SEEN BY CT SCAN
MOVIE, YOU CAN SEE MORE SEVERE
LESIONS IN DELTA INFECTED
ANIMALS THAN IN THE OMICRON
INFECTED ANIMALS.
PATHOLOGICALLY WE SAW LESIONS IN
LUNGS OF ANIMALS INFECTED WITH
DELTA BUT NOT IN LUNGS OF
ANIMALS INFECTED WITH OMICRON
VIRUS.
HISTOPATHOLOGICALLY WE SAW EDEMA
IN THE HEMORRHAGE IN ANIMALS
INFECTED DELTA VIRUS BUT
INFLAMMATION OF LUNGS WITH
ANIMALS INFECTED WITH OMICRON IS
LIMITED.
HISTOLOGY SHOWS THIS DIFFERENCE
ON DAY 6 POST INFECTION.
NOW IN SITU HYBRIDIZATION ALSO
SHOW THAT THERE ARE MANY VIRAL
RNA POSITIVE CELLS IN LUNGS.
AND ALSO EPITHELIAL CELLS LINING
BRONCHUS OF ANIMALS INFECTED
WITH DELTA VIRUS.
BUT VERY FEW VIRUS RNA POSITIVE
CELLS IN ANIMALS INFECTED WITH
OMICRON VARIANT.
SO THIS DATA SHOW THE OMICRON BA
1 VARIANT ATTENUATED IN HAMSTERS
AND MICE.
OTHER SHOWED SIMILAR DATA.
NOW I WILL TALK ABOUT COMPARISON
BETWEEN BA 1 AND BA 2.
SO THE GROUP IN JAPAN REPORTED
STUDIES USING THE RECOMBINANT
SARS COV-2 CONTAINING S PROTEIN
FROM DIFFERENT VIRUS.
SO THEY GENERATED RECOMBINANT
VIRUSES POSSESSING Z GENE FROM
DIFFERENT VIRUSES,ER IN THE
BACKGROUND OF WUHAN LIKE SARS
COV-2.
THEY SHOW THE VIRUS CONTAINING
BA 1 S PROTEIN DIDN'T CAUSE BODY
WEIGHT LOSS, THIS IS IN HAMSTERS
BUT THE VIRUS CONTAINING BA 2 S
PROTEIN CAUSED BODY WEIGHT LOSS.
ALSO THE AMOUNT OF VIRAL RNA IN
LUNGS IS HIGHER WITH VIRUS
CONTAINING BA 2 S PROTEIN
COMPARED WITH VIRUS CONTAINING
BA 1 S PROTEIN.
THEY ALSO EXAMINE PATHOLOGY AND
FOUND THAT VIRUS CONTAINING BA 2
S PROTEIN CAUSE MORE SEVERE
PATHOLOGICAL CHANGES.
WE ALSO EXAMINE THE RESPIRATORY
FUNCTION BY USING WHO BODY
PLESTHOGRAPHY, THE VIRUS
CONTAINING BA 2 PROTEIN CAUSED
RESPIRATORY FAILURE.
SO BASED ON THIS DATA THEY
CONCLUDED THE VIRUS CONTAINING
THE BA 2 S PROTEIN IS MORE
PATHOGENIC THAN THE VIRUS
CONTAINING BA 1 S PROTEIN.
SO WE EXAMINED THE PATHOGENICITY
AND COMPARED BETWEEN BA 1 AND BA
2 USING THE CLINICAL ISOLATES.
AND THIS WORK WAS DONE IN
COLLABORATION WITH MANY PEOPLE.
THE ONE AT UTAH STATE UNIVERSITY
WHO PROVIDED US WITH TRANSGENIC
HAMSTERS EXPRESSING HUMAN H 2
PROTEIN.
AND THE GROUP AT THE NIH VRC AND
AUBREY GORDON, UNIVERSITY OF
MICHIGAN AND MIKE DIAMOND,
WASHINGTON UNIVERSITY.
SO WE COMPARED VIRUS REPLICATION
OF BA 1 AND BA 2 ICE RATES IN
BALBC AND THEY REPLICATE TO
SIMILAR EXTENT IN H NASAL
DETERMINANT AND ON DAY FIVE WE
SAW HIGHER REPLICATION WITH BA 1
COMPARED WITH BA 2.
ON DAY 2 THE TITLERS ARE SIMILAR
THOUGH STATISTICALLY SLIGHTLY
DIFFERENT.
IN SITU HYBRIDIZATION AND
HISTOPATHOLOGY SHOW KNOW
DIFFERENCE BETWEEN BA 1 AND BA 2
INFECTED ANIMALS.
WE THEN EXAMINE BODY WEIGHT
CHANGE UPON INFECTION OF
HAMSTERS WITH 10 TO THIRD OR 10
TO FIFTH INFECTIOUS UNITS AND WE
DID NOT SEE ANY DIFFERENCE
BETWEEN BA 1 AND BA 2.
THE RESPIRATORY FUNCTIONS AS
MEASURED BY WHOLE BODY
PLETHSMAGRAPHY, WE DID NOT SEE
ENDARCH BETWEEN BA 1 AND BA 2,
BOTH ANIMALS ARE SIMILAR TO
INFECTED.
VIRUS REPLICATION ON DAY 3 WITH
TWO DOSES 10 TO THIRD OR 10 TO
FIFTH IN NASAL TERM FANTASTIC
WITH SIMILAR TITER BA 1 AND 2
WITH THE 10 TO 3RD INTEGRATION
WE SAW BA 1 WAS HIGHER IN BA 2
IN LUNG TITER.
WITH 10 TO 5TH INTEGRATION WE
DIDN'T SEE ANY DIFFERENCE.
THE HISTOPATHOLOGICALLY AND IN
SITU HYBRIDIZATION SHOW NO
DIFFERENCE BETWEEN BA 1 AND 2 IN
HAMSTER.
TUSHNATE WE THEN INVOLVED BA 1
AND BA 2 MIX, WE INTENDED TO MIX
ONE TO ONE BUT WHEN WE ANALYZE
BY SEQUENCING WE FOUND RATIO WAS
3 TO 7.
WE THEN EXAMINED THE VIRUS RATIO
DAY 2 AND DAY 4 IN BOTH TIME
POINT BA 1 BECAME MORE PREVALENT
IN NASAL TURBINATE AND LUNG IN
MOST ANIMALS.
SO THIS DATA SHOW THAT FOR ALL
PARAMETERS TESTED, BA 1 AND BA 2
SHOW SIMILAR PATHOGENICITY.
THIS IS SIMILAR TO WHAT IS
HAPPENING IN CLINICAL SETTING
SHOWN IN THIS PRE-PRINT,
CLINICAL PROFILE OF ILLNESS
REMAINS SIMILAR BETWEEN BA 2 AND
BA 1.
BUT RECENT PRE-PRINT SHOWS
SOMETHING DIFFERENT.
IN THIS PREPRINT DESCRIBE BA 2
WAS ASSOCIATED WITH REPORTING
MORE SYMPTOMS WITH GREATER
DISRUPTION TO DAILY ACTIVITIES
THAN BA 1.
NOW, BA 1, BA 11 AND BA 2 DIFFER
IN THEIR S PROTEIN.
THIS PICTURE WAS I BORROWED IT
FROM DAVID HO'S PAPER PUBLISHED
IN NATURE.
THE INSTITUTION SHOWN IN BLACK,
SUBSTITUTION COMMON BETWEEN BA 1
AND BA 2.
IMMUNOASSAY CHANGES SHOWN IN
GREEN RESIDUE SPECIFIC FOR BA 1
AND BA 11.
AND BA 1.1 CONTAINS ONE
ADDITIONAL MUTATION OF 346 FROM
ARGININE TO LYSINE.
CHANGES SHOWN IN BLUE SPECIFIC
FOR BA 2.
MANY PAPERS DESCRIBE
NEUTRALIZATION OF OMICRON
VARIANTS BY USING THE SERA FROM
PATIENTS OR VACCINEES.
WE ALSO DID SIMILAR EXPERIMENTS,
THESE ARE THE SERA FROM VACCINE
CANDIDATES, VACCINEES AND
INFECTED AND THEN VACCINATED AND
ONE MONTH TO THREE MONTHS AND
SIX MONTHS AFTER VACCINATION.
AGAINST WUHAN DELTA AND THREE
DIFFERENT OMICRON VARIANTS.
THESE ARE THE SERA FROM PEOPLE
WHO RECEIVED THREE PFIZER
VACCINATIONS.
AND THESE SERA FROM THE mRNA
VACCINES AND THEN OMICRON
INFECTION.
IN ALL CASES, THE -- YOU SEE
HIGHER TITER AGAINST WUHAN NEXT
DELTA, AND THEN OMICRON.
WE ALSO DID SIMILAR
NEUTRALIZATION ASSAY USING
HAMSTERS HERE.
SO HAMSTERS WERE INFECTED WITH
ANCESTRAL VIRUS DELTA BA 1 BA
1.1 OR BA 1.
1 -- BA 2 AND TESTED
AGAINST SAME VIRUSES.
AND AS YOU SEE, BA 1 INFECTED
HAMSTERS HERE REACT WELL WITH BA
2 BUT LESS SO AGAINST OTHER
OMICRON VARIANTS AND BA 1 OR BA
1.1 INFECTED HAMSTERS REACT WITH
ALL THREE BA OMICRON VARIANTS,
LESS SO WUHAN AND DELTA.
REVERSE THE SAME WITH ANCESTRAL
OR DELTA INFECTED HAMSTERS HERE.
THESE RESULTS ARE QUITE SIMILAR
TO THOSE WE SEE WITH HUMANS
HERE.
SO HAMSTER SERA ARE QUITE USEFUL
TO ANTIGEN ANALYSIS.
IN FACT (INDISCERNIBLE) USED
THIS HAMSTER SCALE TO GENERAL
RATE ANTIGENIC OF SARS COV-2 S
PROTEIN.
THIS TECHNIQUE WAS ORIGINALLY
DEVELOPED BY DERRICK SMITH AND
(INDISCERNIBLE) AND USED THIS
METHOD TO PERFORM ANGIOGENIC
ANALYSIS.
THE ONE GREEK UNIT HERE
CORRESPONDS TO TWO FULL DILUTION
OF SERA.
AND THIS -- THIS IS THE 6
PROTEIN G ONE OF THE ANCESTRAL
VIRUS.
THESE ARE THE OTHER VARIANTS.
AND AS YOU CAN SEE, BA 1 AND BA
2 ARE LOCATED HERE WHICH IS FAR
AWAY FROM ANCESTRAL VIRUS.
THESE TRANSGENIC RESPONSE TO
ANGIOGENIC DIFFERENCES.
IN MANY GROUP DESCRIBED
NEUTRALIZATION AGAINST THESE
OMICRON VARIANTS, WE ALSO DID
EXPERIMENTS USING OMICRON AND
FOUND THAT ANTIBODIES REACT --
DID NOT NEUTRALIZE ANY OF THE
OMICRON VARIANTS BA 1 BA 1.1, BA
2.
ONE OF THE NOT NEUTRALIZED BA 1
AND BA 1.1 BUT DID NEUTRALIZE BA
2 THOUGH TO LESSER EXTENT
COMPARED WITH THE ORIGINAL WUHAN
VIRUS.
THE TRANSGENIC ANTIBODIES ONE
NEUTRALIZED BA 2 AS WELL AS
WUHAN VIRUS.
SO THIS COCKTAIL REACTED WITH BA
2 ONLY 15 FOLD LESS COMPARED
WITH THE WUHAN LIKE VIRUS.
S 309 WHICH IS A PRECURSOR OF
(INAUDIBLE) HAD REACTIVITY
AGAINST BA 1 AND BA 1.1 WITH
PROTEIN FOLD REDUCTION.
50 FOLD REDUCTION AGAINST THE BA
.2 VARIANT.
SO DIFFERS AMONG OMICRON
VARIANTS, WE THEN EXAMINED THE
EFFICACY OF THESE MONOCLONAL
ANTIBODIES AGAINST OMICRON
VARIANTS IN HAMSTERS.
SO WE FIRST INFECTED HAMSTERS
WITH 10 TO THE THIRD INFECTIOUS
UNITS AND THEN WITH THESE
VIRUSES AND THEN NEXT DAY WE
INOCULATED FIVE CHILDREN WITH
ANTIBODY IN (INAUDIBLE) AND CAM
MINUTED VIRUS TITER ON DAY 4.
AGAINST THE 614G VIRUS
(INAUDIBLE) PRECURSOR IS 309
REGENERON COCKTAIL AND ASTRA
ZENECA COCKTAIL REDUCE VIRUS
TITER IN LUNGS AND REGENERON
COCKTAIL AND ASTRA ZENECA
COCKTAIL AGAINST BA 1 ASTRA
ZENECA REDUCED TITER IN THE
LUNGS, NONE REDUCED TITTER IN
NASAL TURBINATE.
AGAINST BA 2 ALL THREE ANIMALS
-- ANTIBODIES REDUCED TITER
THOUGH THE WE DID NOT SEE
STATISTICAL DIFFERENCE WITH THIS
REGENERON ANTIBODY COCKTAIL IN
LUNG TITERS.
BUT NONE OF THESE ANTIBODIES
REDUCE TITER IN NASAL TURBINATE.
BECAUSE OF THIS ANGIOGENIC
DIFFERENCES, AS YOU ALL KNOW,
THE VACCINE EFFECTIVENESS OF
MRNA AGAINST OMICRON IS
REDUCED.
BUT THE QUESTION HERE IS THAT
OMICRON INFECTION IN HUMANS, DUE
TO IMMUNITY WANING OR ANGIOGENIC
CHANGES IN INFECTED VIRUS OR
BOTH.
WE ATTEMPTED TO ANSWER THIS
QUESTION UNDER CONTROLLED
CONDITIONS, USING OMICRON
VARIANT AND ISOLATE THAT ARE NO
LONGER CIRCULATING IN NATURE.
THAT IS WUHAN LIKE ISOLATE AND
NOT ISOLATE WITH ONLY 614G SPIKE
MUTATION IN HAMSTER MODEL.
SO WE INFECTED HAMSTERS WITH
614G VIRUS OR WUHAN LIKE VIRUS
AND 7 MONTHS OR 22 MONTHS AFTER
INFECTION WE CHALLENGE THOSE
ANIMALS WITH EITHER OMICRON OR
614G VIRUS.
ON DAY 4 POST INFECTION WE
EXAMINED THE VIRUS SITE.
IN AGE MATCHED NAIVE ANIMALS,
THESE 614G VIRUS REPLICATED WELL
AS EXPECTED.
BUT IN THE ANIMALS PREVIOUSLY
INFECTD WITH 614G SEVEN MONTHS
AGO WUHAN LIKE VIRUS 22 MONTHS
AGO, IN THESE ANIMALS 614G VIRUS
DIDN'T REPLICATE.
SO IMMUNITY AGAINST ANGIOGENIC
SIMILAR VIRUS LASTS FOR AT LEAST
22 MONTHS.
AFTER INFECTION.
IN AGE MATCHED ANIMALS OMICRON
VIRUS REPLICATED WELL, THOUGH TO
LESSER EXTENT AS I DESCRIBED.
BUT IN ANIMALS PREVIOUSLY
INFECTED WITH 614G OR WUHAN LIKE
VIRUS, OMICRON DIDN'T REPLICATE
IN LUNGS, BUT DID REPLICATE IN
NASAL TURBINATE.
100 FOLD REDUCTION COMPARED WITH
NAIVE ANIMALS.
THIS DIFFERENCE IN REPLICATION
HERE IS DUE TO THE ANGIOGENIC
DIFFERENCE BETWEEN THE PROTOTYPE
VIRUS AND OMICRON.
SO PRODUCTIVITY IMMUNITY LASTS
FOR 22 MONTHS AFTER THE ANTIGEN
IS -- WHEN THE ANTIGEN IS
DETERMINED VIRUS IS SIMILAR TO
THAT OF THE INITIAL VIRUS LISTED
-- AT LEAST IN HAMSTERS.
WE THEN EXAMINED PROTECTION OF
WEAKER INFECTION AGAINST THE
VACCINATED ANIMALS.
AND SO WE VACCINATED HAMSTERS
WITH MODERNA mRNA ONCE OR
TWICE AND SEVEN MONTHS LATER WE
CHALLENGED THESE ANIMALS WITH
OMICRON OR PROTOTYPE VIRUS.
THEN EXAMINED THE DATA ON DAY 4.
AS YOU CAN SEE THE VIRUS TITER
IS REDUCED ABOUT SIX LOG UNITS
IN LUNGS, IN ANIMALS CHALLENGED
WITH THE PROTOTYPE VIRUS.
AFTER TWO DOSES OF VACCINATION.
TWO AND A HALF LOG UNIT
REDUCTION IN NASAL TURBINATE IN
ANIMALS VACCINATED TWICE.
SO THAT IS AGAINST PROTOTYPE
CHALLENGE.
BUT IN ANIMALS CHALLENGED WITH
OMICRON WE SAW ONLY TWO LOG
REDUCTION IN ANIMALS VACCINATED
TWICE.
IN LUNGS AND ONE AND A HALF LOG
UNIT REDUCTION IN ANIMALS
RECEIVING TWO DOSES VACCINATION.
SO THIS DIFFERENCE IS DUE TO THE
ANGIOGENIC DIFFERENCES.
SO THE PROTOTYPE VACCINE IS
PROTECTIVE AGAINST THE PROTOTYPE
VACCINE IS PROTECTIVE AGAINST
PROTOTYPE VIRUS EVEN SEVEN
MONTHS ASP VACCINATION.
BUT LESS PROTECTIVE AGAINST
ANTIGENICALLY DIFFERENT OMICRON
VARIANT.
WE TESTED LOW MOLECULAR WEIGHT
COMPOUNDS, REMDESIVIR,
POLYMERASE INHIBITOR,
NIRMATRELVIR PROTEASE INHIBITOR.
ALL THREE WORK GAINS BA 1, BA
1.1 BA 2 QUITE WELL IN VITRO.
WE THEN TESTED THE EFFICACY OF
THIS COMPOUNDS AND S 217622
PRODUCE BY -- COMPANY CLINICAL
TRIAL IN HAMSTER MODEL.
WE INFECTED HAMSTERS WITH BA 1
OR BA 2 WITH 10 TO THIRD
INFECTIOUS UNITS.
NEXT DAY WE STARTED TREATMENT,
TWICE A DAY ORALLY.
WITH THESE COMPOUNDS AND THEN ON
DAY 4 WE EXAMINED THE VIRUS
TITER.
NOW AGAINST BA 121-7622 WORKED
WELL REDUCED VIRUS TITER TO ZERO
IN LUNGS.
AND 217622 ALSO REDUCED VIRUS
TITER IN NASAL TURBINATE.
AGAINST BA 2 ALL THREE COMPOUNDS
REDUCED VIRUS TITERS
SUBSTANTIALLY ALMOST TO ZERO AND
TO UNDETECTABLE LEVEL AND
NIRMATRELVIR ALSO REDUCED VIRUS
TITER IN NASAL TURBINATE.
SO SMALL MOLECULE DRUGS
CURRENTLY APPROVED OR IN
CLINICAL TRIALS EFFECTIVELY
INHIBIT REPLICATION OMICRON BA 1
AND BA 2 IN LUNGS OF HAMSTERS.
NOW I'M GOING TO TALK ABOUT
IMAGING.
THE AIM OF THE STUDIES TO
UNDERSTAND COVID-19 PATHOGENESIS
BY USING IMAGING SYSTEMS AND
THIS WORK WAS DONE BY
(INDISCERNIBLE).
IN THAT GROUP WE ESTABLISHED
MULTIPLE DIFFERENT IMAGING
SYSTEMS FOR INFLUENZA RESEARCH.
TODAY I WILL TALK ABOUT TWO
PHOTON MICROSCOPY.
SO THIS IS HOW WE DO THIS
EXPERIMENT.
WE HIT MICE WITH LASER AND
PROJECT IMAGE ON MONITOR.
MISO IN HEATED STAGE AND TO LOOK
INSIDE THE LUNGS WE PLACED
WINDOW CONNECTED TO VACUUM PUMP,
WE HAVE ANESTHESIA MACHINE,
MECHANICAL VENTILATOR, TO
PREVENT CONTAMINATION OF THIS
DEVICE WE PUT HEPA FILTER AND WE
PLACED THE ENTIRE SYSTEM IN BSL
3 SO OPERATOR WITH PROTECTIVE
GEAR.
THIS IS HOW WE DO THIS
EXPERIMENT.
WE PERFORM TRACHEOTOMY AND
INSERTED CANNELLA.
MAKE INCISION, AND EXPOSE LUNG.
LUNG MOVES LIKE THIS.
SO WE NEED TO STOP THE MOVEMENT
TO DO THE EXPERIMENT.
SO WE PLACE THE THORACIC WINDOW
THROUGH THE VACUUM SO THAT
SURFACE OF THE LUNG BECAME
STABILIZED.
THEN PLACE OBJECTIVE LENS ON TOP
OF THIS LUNG AND THEN OBSERVE.
SO THIS IS HOW OUR SET UP IN BSL
3 AND THIS IS DR. (INAUDIBLE)
PERFORMING THIS EXPERIMENT.
SO WE USE WOE ESTABLISH THE
SYSTEM FOR INFLUENZA FIRST AND
THEN NOW USE THE SYSTEM FOR SARS
COV-2.
SO WE INFECTED H 2 EXPRESSING
TRANSGENIC MICE WITH SARS COV-2
EXPRESSING VENUS FLUORESCENT
PROTEIN.
WHICH IS GENERATED BY DR.
KAMITANI AT GUNMA UNIVERSITY.
WE INJECTED DEXTRAN TO LOOK AT
BLOOD FLOW ANTIBODY TO
NEUTROPHIL, ANTIBODY 2 PLATELET.
AND THIS IS LUNG OF ANIMALS
INFECT WITH SARS COV-2
EXPRESSING VENUS PROTEIN.
AND GRAY INDICATES BLACK FILL,
GREEN INDICATES VIRUS INDICATED
WITH CELLS, RED INDICATES
NEUTROPHIL, CIENNE INDICATES
PLATELETS.
TYPE 1 AND TYPE 2 PNEUMOCYTES
ARE INFECTED IN THE TRANSGENIC
ANIMALS.
NOW WE OBSERVE -- WE FOUND THAT
ENHANCED -- WE FOUND ENHANCED
VASCULAR PERMEABILITY IN ANIMALS
INFECTED WITH SARS COV-2, YOU
SEE CLOUDNESS OF ALVEOLI IN THE
VIRUS INFECTED ANIMALS.
THIS ACTUALLY CAN BE QUANTIFIED
BY EXAMINING THE AMOUNT OF
DEXTRAN LEADING TO ALVEOLI.
YOU SEE INCREASE VASCULAR
PERMEABILITY AS THE INFECTION
PROGRESSED.
WE ALSO EXAMINED NUMBER OF
NEUTROPHILS INCREASE OVER TIME.
NEUTROPHILS SHOWN IN RED IN
NAIVE ANIMALS MOVE FAST BUT
NEUTROPHILS IN THE VIRUS
INFECTED ANIMALS, THE NUMBER IS
INCREASE AS SHOWN HERE.
ALSO THEY DON'T MOVE.
THO MOVEMENT CAN BE TRACED.
THEN QUANTIFIED.
AS YOU CAN SEE, NEUTROPHILS IN
NAIVE ANIMALS MOVE QUICKLY, AS
SHOWN IN THIS DIAGRAM.
BUT NEUTROPHIL IN VIRUS INFECTED
ANIMALS ON DAY 6, THEY DON'T
MOVE.
WE ALSO FOUND THAT MICROTHROMBUS
LIKE STRUCTURE COMPOSED OF
PLATELET SHOWN IN SIGH YEN AND
NEUTROPHILS SHOWN IN RED.
AND NEUTROPHILS THAT REMAIN IN
THE BLOOD VESSEL MAY CAUSE
THROMBUS FORMATION SEEN IN
COVID-19 PNEUMONIA.
WE ALSO FOUND FORMATION
MICROTHROMBI IN CAPILLARIES OF
VIRUS INFECTED LUNGS.
SO WE EXTRACTED PLATELET SIGNALS
FROM ORIGINAL IMAGE, IDENTIFIED
PLATELETS BASED OR FLUORESCENT
INTENSITY AND SIZE AND MADE
HISTOGRAM.
AS YOU CAN SEE SINGLE PLATELET
PROPORTION OF SINGLE PLATELET
REDUCED AFTER INFECTION AND
AGGRAVATED PLATELETS THROMBUS
INCREASE AFTER INFECTION OVER
TIME.
NOW, LUNG IS ONE O OF THE PLACES
WHERE PLATELETS ARE GENERATED
FROM MEGA KARYOCYTES.
IN UNINFECTED LUNGS, MEGA
KARYOCYTES ARE TORN APART BY FOR
PLATELET GENERATION BY STEADY
BLOOD FLOW.
OR CARRIED AWAY BY THE BLOOD
FLOW.
SO YOU CAN SEE THE GENERATION OF
PLATELETS FROM MEGAKARYOCYTES IN
LUNGS.
SO THIS IS IN NAIVE ANIMAL.
IN VIRUS INFECTED LUNGS, BLOOD
FLOW IS CONGESTED AND
MEGAKARYOCYTES ARE MORE EASILY
TRAPPED IN BLOOD VESSELS WHICH
MAY BE A CAUSE OF EMBOLISM.
SO WE NEXT EXAMINE BLOOD FLOW BY
INFECTING H 2 EXPRESSING
TRANSGENIC MICE WITH SARS COV-2
AND SIX DAYS POST INFECTION WE
INTRODUCED FLUORESCENT LABELED
ERYTHROCYTES.
THEN PERFORM 2 PHOTON
MICROSCOPY.
WE THEN TOOK SHOT EVERY 1.2
SECONDS AND THEN OVERLAID.
FUL SO THIS IS THE NAIVE ANIMAL,
THIS IS SARS COV-2 INFECTED
ANIMALS AND YOU SEE THE
ACCUMULATION OF ERYTHROCYTES
PASS THROUGH THESE CAPILLARIES.
SO WHEN ERYTHROCYTES PASS
THROUGH YOU SEE RED.
IF THEY DON'T GO THROUGH YOU
DON'T SEE ANY RED.
BLUE INDICATES BLOOD FLOW.
SO IN NAIVE ANIMALS AS YOU
EXPECT, ERYTHROCYTES PASS
THROUGH CAPILLARIES, BUT IN SARS
COV-2 INFECTED ANIMALS THERE ARE
AREA YOU DON'T SEE ANY
ERYTHROCYTES GOING THROUGH.
SO IN LUNGS INFECTED WITH SARS
COV-2 CAPILLARIES AVAILABLE FOR
OXYGEN EXCHANGE ARE LIMITED.
SO 2 PHOTON LASER MICROSCOPY
REVEAL FUNCTIONAL FAILURE OF
LUNG ARE DUE TO THROMBI
FORMATION IN MICE INFECT WITH
SARS COV-2.
SO LAST FEW MINUTES I'M GOING TO
TALK ABOUT STABILITY OF SARS
COV-2 IN AEROSOL.
TWO GROUPS PREVIOUSLY DESCRIBED
THE STABILITY OF SARS COV-2 IN
AEROSOL USING ROTATING DRUMS
SIMILAR TO (INAUDIBLE).
DESCRIBE THAT HALF LIFE OF SARS
COV-2 IN AEROSOL IS
APPROXIMATELY 1.1 HOUR.
ANOTHER GROUP REPORTED THAT
INFECTIVITY OF SARS COV-2
REMAINS FOR UP TO 16 HOURS IN
AEROSOL.
SO THEY COULDN'T DETERMINE HALF
LIFE.
SO WE WANTED TO TIME THE
STABILITY OF SARS COV-2 IN
AEROSOL IN SETTING DIFFERENT
FROM THAT USE IN THE PREVIOUS
STUDIES.
SO WE SET UP A SYSTEM IN BSL 3
FACILITY.
HERE WE HAVE NEBULIZER CHAMBER
AND HUMIDIFIER TO CONTROL THE
HUMIDITY OF THIS CHAMBER AND
THEN AIR SAMPLER.
NEBULIZER REDUCES DROPLETS IN
AEROSOL CONTAINING SARS COV-2 AT
THE SPEED OF 2-METER PER SECOND.
THE OTHER PARTICLE SIZE RELEASED
AT TIME OF -- RELEASE OF THIS
DEVICE AT THE TIME OF THE
RERELEASE IS 5.5 MICROLITER.
THE CHAMBER WAS THEN PRODUCED BY
THE (INDISCERNIBLE) UNIVERSITY
BY USING NEBULIZER WE SPRAYED
AEROSOL CONTAINING SARS COV-2
FOR FIVE MINUTES, FOR FIRST ONE
MINUTE THERE WERE TOO MANY
PARTICLES TO COUNT BUT THEN WE
WERE ABLE TO COUNT NUMBER OF
AEROSOLS.
NUMBER OF TOTAL PARTICLES
RELATIVELY HIGH FOR FIRST 24
HOURS.
THERE WAS A DIFFERENCE IN NUMBER
OF DIFFERENT SIZE PARTICLES OVER
TIME.
THE PARTICLES WITH DIAMETER FIVE
MICROMETER REDUCED IN FIRST FEW
HOURS.
AND PARTICLES WITH DIAMETER OF 2
MICROMETER INCREASE AND THEN
DECREASED.
PARTICLE WITH DIAMETER OF 1
MICROMETER GRADUALLY INCREASED
AND THEN REDUCED.
PARTICLES WITH DIAMETER OF .3 OR
.5 MICROMETER GRADUALLY
INCREASE.
SO WHAT THIS INDICATES IS THAT
WATER IN AEROSOLS HAVE UPGRADES
AND SIZE OF AEROSOLS CHANGED
OVER TIME BUT THE TOTAL NUMBER
OF AEROSOLS REMAINS LARGELY THE
SAME.
AIR SAMPLER, THE OPENING OF THE
AIR SAMPLER WE HAVE GELATIN
FILTER WHICH COLLECTS VIRUS
PARTICLE DURING CERTAIN OF AIR.
THIS FILTER DISSOLVES IN CULTURE
MEDIA EASILY TO SO THAT WE CAN
DETERMINE AMOUNT OF INFECTIOUS
VIRUS IN THE VIRAL RNA COPY
NUMBER.
SO HERE WE HAVE NEBULIZER TO
SPRAY AEROSOL CONTAINING SARS
COV-2 INTO CHAMBER AND THEN AT
DIFFERENT TIME POINTS, WE GET
THE RECOVER VIRUS BY USING AIR
SAMPLER.
THE RESULTS ARE SHOWN IN THIS
SLIDE.
BLUE INDICATES INFECTIOUS VIRUS
TITER.
GOLD INDICATES VIRUS RNA COPY
NUMBER.
THE FIRST LUNG WE SEE REDUCTION
IN TITER MOST LIKELY LARGE
PARTICLE SETTLING.
BUT AFTER ONE HOUR WE SEE TITER
REMAIN RELATIVELY STABLE.
WE CAN DETERMINE PERCENTAGE OF
INFECTIOUS VIRUS DIVIDING VIRUS
TITER BY VIRUS RNA COPY NUMBER.
WE FOUND THAT THE PERCENTAGE OF
INFECTIOUS SARS COV-2 IN AEROSOL
REMAINED CONSTANT FOR THREE
HOURS.
SARS COV-2 IN AEROSOL SETTING IS
STAIN SO GOOD INDOOR VENTILATION
IS IMPORTANT.
IN SUMMARY SARS COV-2
NATURALIZED SHOWED SIMILAR
PATHOGENICITY TO BA 1 NATURAL
ISOLATES IN MICE AND HAMSTERS
AND CURRENTLY IMPROVED
POLYMERASE AND PROTEASE
INHIBITORS ARE IMPROVED IN
OMICRON VARIANTS AND 2 PHOTON
LASER MICROSCOPY CAN BE USED TO
ANALYZE SARS COV-2 PATHOGENESIS
IN MICE AND BECAUSE SARS COVE 26
IN AEROSOLS IS STABLE, FREQUENT
VENTILATION IS IMPORTANT.
THANK YOU VERY MUCH FOR YOUR
ATTENTION.
WONDERFUL TALK AS USUAL.
I'M (INAUDIBLE) AND YOU CAN
SUBMIT YOUR QUESTIONS TO SEND
LIVE FEEDBACK BUTTON IN THE
MIDDLE OF YOUR SCREEN.
WE HAVE A LOT OF QUESTIONS SO I
WILL START WITH A FEW OF THEM.
WHAT DO YOU THINK ANY ANIMAL
MODEL THAT RECAPITULATES THE
CARDIAC NEUROLOGICAL SYMPTOMS WE
SEE IN HUMANS?
>> RIGHT.
NONE ANIMAL MODELS -- WILL
CAPTURE EVERYTHING.
THE HAMSTERS ARE HIGHLY
SUSCEPTIBLE SO IT IS A GOOD
ANIMAL MODEL VIROLOGICAL
STUDIES.
AND PROBABLY GOOD ANIMAL MODELS
FOR PATHOGENESIS IN RESPIRATORY
ORGANS.
BUT WHETHER THIS IS GOOD ANIMAL
MODEL FOR KNOWN RESPIRATORY
ORGANS REQUIRE MORE STUDIES.
WE SEE SOME ANTIGEN CELLS IN THE
HEART SO THERE MAYBE SOME
REPLICATION IN HEART BUT WHETHER
THAT CAUSE DISEASE IN -- SIMILAR
DISEASE IN HAMSTER OR NOT I'M
NOT SURE.
>> SINCE YOU HAVE ANIMALS THAT
YOU HAVE KEPT FOR MANY MONTHS
POST INFECTION, DO YOU SEE ANY
OF THOSE ANIMALS THAT MIMIC LONG
TERM SEQUELAE OR
(INDISCERNIBLE)?
>> YES, THAT IS THE QUESTION TO
ADDRESS.
WE HAVEN'T DONE ANY EXPERIMENTS.
I THINK THIS ANIMAL MODEL IS ONE
OF THE GOOD ONE BECAUSE IT WAS A
SMALL ANIMAL SO WE CAN KEPT
ANIMALS LONG TIME EASIER THAN
MONKEYS SO I THINK WE AND OTHERS
WILL BE DOING THAT.
>> ONE QUESTION ASKED ORIGINAL
SARS COV-2 STRAIN ARE PROTOTYPE
STRAIN EVOKES HYPERIMMUNE
HYPERCOAGULOPATHY IN PATIENTS,
US RIGHT?
BUT IN YOUR ANIMAL MODELS THAT
SHOWED LESS SEVERITY DO YOU
THINK THE OMICRON VARIANT CAUSE
A LESS HYPERIMMUNETY?
>> IN HAMSTER MODELS OMICRON IS
(INAUDIBLE) AND MAYBE SO IN
HUMANS.
BUT ATTENUATION IN HAMSTERS WITH
OMICRON MAYBE MORE PROMINENT
COMPARED WITH IN HUMANS.
SO BECAUSE OF THAT I AM NOT SURE
WHETHER I CAN ADDRESS THE
QUESTION.
ANTIGEN MULTIPLE STUDIES ON
DRUGS AND VACCINES AND
THERAPEUTIC ANTIBODIES, IN
HAMSTERS DO YOU SEE SARS COV-2
DRIFTING OR ESCAPING TREATMENT
OVER TIME AS OBSERVED IN
(INDISCERNIBLE)?
>> CLEARLY MONOCLONAL ANTIBODIES
BECAUSE OF MUTATION IN S
PROTEINS AND VARIANTS, SOME OF
THE VARIANTS ESCAPE FROM THIS
TREATMENT.
BUT AT LEAST WITH THIS NORMAL
MOLECULAR WEIGHT COMPOUNDS, THEY
ARE EFFICACIOUS AGAINST THE
VIRUSES WE TESTED INCLUDING ALL
THE VARIANTS WE TESTED.
SO THAT IS THAT.
>> AND IN THE STUDIES THAT YOU
MENTION IN THE (INAUDIBLE)
STUDIES HAVE YOU TRIED THAT WITH
OMICRON VARIANTS?
ARE THERE DIFFERENCES?
>> WE HAVEN'T DONE THAT.
WE WANT TO DO THAT EXPERIMENT.
>> I THINK ONE OF THE QUESTIONS
THAT IS WE ARE NOW SEEING BREAK
THROUGH INFECTIONS FOLLOWING
VACCINATION.
SO CAN ANY OF THESE ANIMAL
MODELS INFORM US THE DEVELOPMENT
OF MORE EFFECTIVE OR MORE
AVAILABLE RESPONSES FOR
VACCINES?
>> I THINK AS I DESCRIBED, IT IS
ALWAYS IMPORTANT TO SEE
DIFFERENT ANIMAL MODELS OR
DIFFERENT ANIMAL SPECIES CAN
RECOGNIZE PROTEIN, IN THIS CASE
S PROTEIN, THE SAME WAY AS
HUMANS.
AND AS I SHOWED, HAMSTERS SERA
GIVE SIMILAR REACTIVITY AGAINST
DIFFERENT VARIANTS AS WE SEE IN
HUMANS.
SO IN -- BECAUSE OF THAT I THINK
HAMSTER MAYBE A GOOD ANIMAL
MODEL FOR STUDYING VACCINE
EFFICACY AGAINST DIFFERENT
VARIANTS.
>> IN YOUR ANIMAL MODEL IF I
READ THAT BA 1 VERSUS BA 2 YOU
SAW BA 1 WAS OVERCOMING BA 2 IN
THE MIXTURE EXPERIMENT, RIGHT?
>> YES.
>> BUT NOW IN HUMANS AT LEAST WE
ARE SEEING THAT BA 2 OR BA 2, OR
BA 1.1 -- WHAT IS GOING ON AND
HOW CAN WE UNDERSTAND THAT?
>> I THINK THAT IS DUE TO
IMMUNITY HUMAN.
HERE WE USE NAIVE ANIMALS SO THE
NEXT OBVIOUS EXPLAIN IS TO BE
DONE IN ANIMALS PREVIOUSLY
VACCINATED OR INFECTED.
>> AND DO YOU SEE TRANSMISSION
IN THE TWO BARE I CAN'T WANT, BA
2 VERSUS BA 21.1?
>> THAT IS A REALLY IMPORTANT
QUESTION AND NOT ONLY OUR GROUP
BUT ALSO SEVERAL OTHER GROUP
TESTED HAMSTER FOR AIRBORNE
TRANSMISSION.
AND WE DON'T SEE AIRBORNE
TRANSMISSION IN OMICRON VARIANT
IN HAMSTERS.
SO AT THE MOMENT THERE IS NO
GOOD AIRBORNE TRANSMISSION
ANIMAL MODEL SYSTEM.
WE DO SEE DIRECT TRANSMISSION.
BETWEEN HAMSTERS WITH OMICRONS
WE TESTED MULTIPLE OMICRON
VARIANTS CO-HOUSING HAMSTERS AND
THEY DO TRANSMIT QUITE WELL BUT
WE DON'T SEE THE BA 1
TRANSMISSION ANY MORE.
>> FOR EXAMPLE YOU MENTIONED THE
OMICRON CAN NOW INFECT SOME OF
THE WILD TYPE MICE, RIGHT?
SO THAT MEAN SOME CHANGE IN
USAGE OF RECEPTOR OR OTHER
PATHOGENICITY.
SO DOES THESE NEW VARIANTS WE
ARE NOW ENCOUNTERING, ARE THOSE
CHANGING IN HAMSTERS SAY TO BODY
TISSUES OR NEUROLOGICAL TISSUES?
>> YEAH THAT, IS POSSIBLE.
THE MUTATION IN S PROTEIN ALLOWS
SOME OF THE VARIANTS RECOGNIZE
HUMAN -- MOUSE BETTER SO THAT IS
WHY WE SEE REPLICATION OF
VARIANTS IN REGULAR MICE.
FOR THE SAME REASON YOU
DESCRIBED, IT IS POSSIBLE THAT
VARIANTS MAY RECOGNIZE HOST
MOLECULES DIFFERENT.
>> IN YOUR ANIMAL HAMSTERS
STUDIES, HOW LONG IS VIRUS
PERSIST IN THOSE HAMSTERS IN
DIFFERENT TISSUES?
>> USUALLY BY DAY 6, 7 VIRUS IS
GONE.
BUT WE DID ONLY INFECTIOUS VIRUS
TESTING SO IF WE DO EXTENSIVE
SEARCH BY PCR AFTER ONE MONTHS
WE MAY SEE SOMETHING THERE SO WE
SHOULD ACTUALLY DO THAT.
>> OKAY.
COMING FROM IAN.
IS THERE DIFFERENCIAL
SENSITIVITY IN OMICRON VARIANTS
VERSUS PROTOTYPE VARIANTS
VIRUSES IN YOUR SAMPLING MODELS
THAT YOU USED?
>> WE HAVEN'T DONE THAT
EXPERIMENT.
AS I MENTION I THINK WE SHOULD
DO THAT.
IT'S VERY IMPORTANT.
>> AND ANOTHER ONE IS DO YOU
KNOW DIFFERENCES IN OMICRON
COMPARED TO THE OTHER -- DO YOU
THINK UP ENDING THE SEQUENCE IN
VACCINE SPIKE SEQUENCE OF BA 1,
2, 3 OR 4 SHOULD BE PURSUED?
>> YES WE SHOULD, YES.
>> WHAT WOULD YOU RECOMMEND,
BECAUSE AS YOU SHOWED US WHEN
YOU HAVE INFECTION WITH BA 1 OR
2 USING DIFFERENTIAL IMMUNE
RESPONSE TO PREVIOUS STRAIN,
WHAT DO YOU THINK IS GOING ON
MORE LIKE ANGIOGENIC PHENOMENA
OR IMMUNE RESPONSE THAT YOU DO
NOT HAVE SAY MUCH MORE BROADER
PROTECTION AGAINST DIFFERENT
STRAINS?
>> WE HAVEN'T SEEN ORIGINAL
ANGIOGENIC PORTION YET.
IT REFERS TO HUMANS ANIMALS
DON'T RESPOND TO THE MOST RECENT
ONE, BUT CLEARLY MAINTAIN IMMUNE
RESPONSES TO OTHER VIRUS.
FUL SO AT LEAST WE ARE NOT
SEEING THIS SAME PORTION, WE SEE
MORE LIKE MORE BROAD CROSS
REACTIVITY.
SO AS LONG AS THAT LASTS, THAT'S
GOOD.
BUT WE WILL SEE WHETHER --
BECAUSE WE ARE ONLY TWO YEARS OR
THREE YEARS IN PANDEMIC BEEN
EXPOSED TO VARIANTS.
SO I THINK TIME TELLS.
>> OUT OF THE THREE OMICRON
VARIANTS DIAGNOSED BA 1 BA 2 BA
4 BA 5 WHAT WOULD BE YOUR CHOICE
OF SPIKE VACCINE?
OFF THOSE THREE STRAINS?
>> THAT IS A VERY DIFFICULT
QUESTION BECAUSE WHETHER WE NEXT
WITH DESCENDENT OMICRON OR NOT.
SO THAT BECOMES RESISTANT IF THE
NEXT CIRCULATING VIRUS WILL BE
SEDESCENDENT OF OMICRON, THE
(INAUDIBLE) VACCINE CANDIDATE IN
THE SO CALLED BACK VERSED IMMUNE
RESPONSES, ANYTHING BETWEEN THE
ORIGINAL VIRUS AND OMICRON,
ANYTHING BETWEEN IN THAT MAP
WILL BE COVERED BY USING OMICRON
VARIANTS AS A VACCINE SO IN
BETWEEN EVERYTHING WOULD BE
COVERED SO OMICRON VACCINE MAY
BE VIABLE CHOICE BECAUSE YOU
RECOVER THERE.
>> WELL, THANK YOU SO MUCH,
YOSHI.
WONDERFUL TALK, WE HAD LOT OF
QUESTIONS, TIME IS SHORT SO I
THINK WE WILL THANK YOU, AND WE
LOOK FORWARD TO HEARING FROM YOU
AGAIN.
THANK YOU SO MUCH.
>> THANK YOU VERY MUCH.
APPRECIATE IT.